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WO2024092154A1 - Methods and compositions for the treatment of neurodegenerative disease - Google Patents

Methods and compositions for the treatment of neurodegenerative disease Download PDF

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Publication number
WO2024092154A1
WO2024092154A1 PCT/US2023/077952 US2023077952W WO2024092154A1 WO 2024092154 A1 WO2024092154 A1 WO 2024092154A1 US 2023077952 W US2023077952 W US 2023077952W WO 2024092154 A1 WO2024092154 A1 WO 2024092154A1
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WIPO (PCT)
Prior art keywords
amino
guanidinopentanamide
oxopropan
oxadiazol
dimethylphenyl
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Application number
PCT/US2023/077952
Other languages
French (fr)
Inventor
Hatim A. ZARIWALA
James Wakefield
Martin Redmon
Anthony ABBRUSCATO
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Stealth Biotherapeutics Inc.
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Publication date
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Priority to AU2023367200A priority Critical patent/AU2023367200A1/en
Publication of WO2024092154A1 publication Critical patent/WO2024092154A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present technology relates generally to methods for achieving optimal levels of bevemipretide (also known as “(R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide” or “SBT-272”), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, in brain tissue of subjects suspected of having, suffering from, or at risk for a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar De
  • Neurodegenerative disease and disorders affect a subject’s activities such as balance, movement, talking, breathing and/or heart function. Neurodegenerative disease and disorders are generally incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells. In many cases, the neurodegenerative disease is often directly or indirectly attributable to the death of the subject. Typically, there are drugs available to address symptoms but all too often there are no treatments that curtail the progression or severity of the disease or disorder itself. Additionally, there are challenges associated with developing a therapeutic that can cross the blood-brain barrier and achieve optimal concentrations in brain tissue.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD with dementia dementia with Lewy bodies, Multiple System Atrophy
  • Huntington’s disease HTT proteinopathy
  • FTLD Frontotemporal Lobar Degeneration
  • tauopathy and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • the present disclosure provides a method of treating a neurodegenerative disease or condition in a subject in need thereof, comprising dosing the subject with an effective amount of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide.
  • the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD with dementia dementia with Lewy bodies
  • Multiple System Atrophy Huntington’s disease
  • HTT proteinopathy Frontotemporal Lobar Degeneration (FTLD)
  • tauopathy a tauopathy
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered subcutaneously.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in a single daily dose.
  • the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight.
  • the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in multiple daily doses.
  • the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
  • the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
  • the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
  • dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM.
  • dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
  • dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
  • dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
  • CSF cerebral spinal fluid
  • dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
  • dosing achieves a plasma:CSF peptide ratio of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
  • dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
  • dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
  • the present disclosure provides a method of treating mitochondrial dysfunction in a subject in need thereof, comprising dosing the subject with an effective amount of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide.
  • the mitochondrial dysfunction is associated with a neurodegenerative disease or condition selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
  • a neurodegenerative disease or condition selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered subcutaneously.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in a single daily dose.
  • the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. [0028] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in multiple daily doses.
  • the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
  • the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
  • the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
  • dosing achieves a brain concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 100 nM.
  • dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
  • dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
  • dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
  • CSF cerebral spinal fluid
  • dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
  • dosing achieves a plasma:CSF peptide ratio of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
  • dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
  • dosing achieves a brain:CSF ratio of“(R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
  • the present disclosure provides a method of dosing (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide in a subject in need thereof, comprising administering SBT-272 to the subject subcutaneously.
  • the subject suffers from a neurodegenerative disease or condition, or the subject suffers from mitochondrial dysfunction.
  • the mitochondrial dysfunction is associated with a neurodegenerative disease or condition.
  • the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD with dementia dementia with Lewy bodies
  • Multiple System Atrophy Huntington’s disease
  • HTT proteinopathy Frontotemporal Lobar Degeneration (FTLD)
  • tauopathy a tauopathy
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in a single daily dose.
  • the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight.
  • the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
  • (R)-2-amino-N-((S)- l-(((S)-5-amino-l -(3 -benzyl- 1,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in multiple daily doses.
  • the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
  • the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
  • the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
  • dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM.
  • dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
  • dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
  • dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
  • CSF cerebral spinal fluid
  • dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
  • dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
  • dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
  • dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
  • the present disclosure provides the use of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide in the preparation of a medicament for treating a neurodegenerative disease or condition in a subject in need thereof, wherein the medicament is formulated for dosing a subject by subcutaneous delivery.
  • the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD with dementia dementia with Lewy bodies
  • Multiple System Atrophy Huntington’s disease
  • HTT proteinopathy Frontotemporal Lobar Degeneration (FTLD)
  • tauopathy a tauopathy
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in a single daily dose.
  • the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. [0064] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in multiple daily doses.
  • the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
  • the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
  • the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
  • dosing achieves a brain concentration of the (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 100 nM.
  • dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
  • dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
  • dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
  • CSF cerebral spinal fluid
  • dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
  • dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
  • dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
  • dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
  • the present disclosure provides the use of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide in the preparation of a medicament for treating mitochondrial dysfunction in a subject in need thereof, wherein the medicament is formulated for dosing a subject by subcutaneous delivery.
  • the mitochondrial dysfunction is associated with a neurodegenerative disease or condition.
  • the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD with dementia dementia with Lewy bodies
  • Multiple System Atrophy Huntington’s disease
  • HTT proteinopathy Frontotemporal Lobar Degeneration (FTLD)
  • tauopathy a tauopathy
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in a single daily dose.
  • the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. [0082] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
  • the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in multiple daily doses.
  • the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
  • the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
  • the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
  • dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM.
  • dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
  • dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
  • dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
  • CSF cerebral spinal fluid
  • dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
  • dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
  • dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
  • dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
  • the subject of methods disclosed herein is human.
  • the subject of uses disclosed herein is human.
  • the subject with a tauopathy has been diagnosed as having Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia.
  • the subject has been diagnosed as having a primary age-related tauopathy.
  • the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy.
  • the ALS is familial.
  • the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or TARDBP gene.
  • FIG. 1A is an illustration depicting the association between SBT-272 and cardiolipin on the inner mitochondrial membrane (IMM).
  • FIG. IB is a series of electron micrographs of mitochondria in hTDP-43 neurons treated with vehicle and treated with 100 nM SBT-272 showing engagement of SBT-272 with cardiolipin.
  • FIG. 2A is a chart showing the in vivo pharmacokinetic (PK) and pharmacodynamic (PD) response to SBT-272 brain exposure in rats.
  • Rat brain SBT-272 concentrations up to 36 hours after a single dose of SBT-272 (5 mg/kg; subcutaneous (SC); n 8 rats per time-point).
  • FIGs. 2B-2D SBT-272 (5 mg/kg SC, 4 and 24 hours before injury) prevented the loss of mitochondrial respiratory control ratio (RCR) in rat brain following cerebral ischemiareperfusion injury induced via stereotactic delivery of 240 pM ET-1 (artificial cerebrospinal fluid in shame) in the piriform region.
  • FIG. 2B is a schematic showing the experimental design. Dotted lines indicate left and right subsection of hemibrain used for RCR and PK analysis (FIG. 2B).
  • ET1 endothelin-1, vasoconstrictive peptide (*P ⁇ 0.05, Kruskal-Wallis followed by Dunn’s test).
  • FIGs. 3A-3B are charts summarizing data demonstrating optimal in vitro effects between 10-100 nM SBT (FIG. 3A) and optimal in vivo effects between 10-100 nM SBT (FIG. 3B)
  • FIG. 4A is a chart showing rat PK profiles of SBT-272 in plasma, CSF, and brain.
  • FIG. 4B is a diagram showing the rotation of injection sites.
  • FIG. 4C is a chart showing nonhuman primate PK profiles of SBT-272 in plasma, CSF, and brain.
  • FIG. 5A is a chart showing the steady state PK from rodent and nonhuman primate. Rat 10 mg/kg, 5 daily doses, and nonhuman primates 5 mg/kg, 10 daily doses.
  • FIG. 5B is a chart showing the trough (SBT-272) at steady state after repeated dosing in various tissues.
  • FIGs. 6A-6B are charts illustrating the study design for the first in-human trial with SBT-272 subcutaneous injection.
  • FIG. 7 is a chart showing interim SBT-272 interim PK data in healthy subjects, 40 mg once daily.
  • C1-C6 alkyl is intended to encompass, Cl, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C5, C3-C4, C4-C6, C4- C5, and C5-C6 alkyl.
  • Certain compounds of the present application can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms can exist, for example, because it is difficult or impossible to remove all the solvent from the compound post synthesis. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present application. Certain compounds of the present application may exist in multiple crystalline or amorphous forms. Certain compounds of the present application may exist in various tautomeric forms. Certain compounds of the present application may exist in various salt forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the present disclosure.
  • amino acid includes both a naturally occurring amino acid and a non-natural amino acid.
  • amino acid includes both isolated amino acid molecules (i.e., molecules that include both, an aminoattached hydrogen and a carbonyl carbon-attached hydroxyl) and residues of amino acids (z.e., molecules in which either one or both an amino-attached hydrogen or a carbonyl carbon-attached hydroxyl are removed).
  • the amino group can be alpha-amino group, betaamino group, etc.
  • amino acid alanine can refer either to an isolated alanine H-Ala-OH or to any one of the alanine residues H-Ala-, -Ala-OH, or -Ala-.
  • amino acids found in the compounds described herein can be either in D or L configuration.
  • An amino acid that is in D configuration may be written such that “D” precedes the amino acid abbreviation.
  • D-Arg represents arginine in the D configuration.
  • amino acid includes salts thereof, including pharmaceutically acceptable salts. Any amino acid can be protected or unprotected.
  • Protecting groups can be attached to an amino group (for example alpha-amino group), the backbone carboxyl group, or any functionality of the side chain.
  • an amino group for example alpha-amino group
  • the backbone carboxyl group or any functionality of the side chain.
  • phenylalanine protected by a benzyloxycarbonyl group (Z) on the alpha-amino group would be represented as Z-Phe-OH.
  • OH for these amino acids, or for peptides (e.g., Lys-Val-Leu-OH) indicates that the C- terminus is the free acid.
  • NH2 in, for example, Phe-D-Arg-Phe-Lys-NH2 indicates that the C-terminus of the protected peptide fragment is amidated.
  • certain R and R’ separately, or in combination as a ring structure, can include functional groups that require protection during the liquid phase or solid phase synthesis.
  • amino acid has isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated as D form, for example, D-Arg.
  • D form for example, D-Arg.
  • many amino acid residues are commercially available in both D- and L-form.
  • D-Arg is a commercially available D-amino acid.
  • a capital letter “D” used in conjunction with an abbreviation for an amino acid residue refers to the D-form of the amino acid residue.
  • DMT refers to 2,6-di(methyl)tyrosine e.g., 2,6-dimethyl-L-tyrosine; CAS 123715-02-6).
  • hydrate refers to a compound which is associated with water.
  • the number of the water molecules contained in a hydrate of a compound may be (or may not be) in a definite ratio to the number of the compound molecules in the hydrate.
  • the term "pharmaceutically acceptable salt” refers to a salt of a therapeutically active compound that can be prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, pro
  • Salts derived from pharmaceutically acceptable inorganic acids include salts of boric, carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic and sulfuric acids.
  • Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids (e.g., acetic, butyric, formic, propionic and trifluoroacetic acids), amino acids (e.g., aspartic and glutamic acids), aromatic carboxylic acids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenyl acetic acids), aromatic hydroxyl acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic, l-hydroxynaphthalene-2-carboxylic and 3 -hydroxynaphthal ene-2-carboxylic acids), ascorbic, dicarboxylic acids (e.g., fumaric, maleic, oxalic and succin
  • the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methyl sulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.
  • the salt is a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt, a maleate salt, a trifluoroacetate salt, a hydrochloride salt, or a tosylate salt.
  • salts of amino acids such as arginate and the like
  • salts of organic acids such as glucuronic or galactunoric acids and the like
  • Certain specific compounds of the present application may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts or exist in zwitterionic form.
  • These salts may be prepared by methods known to those skilled in the art.
  • Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present technology.
  • peptidomimetic refers to a compound of Formula (II): or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, as more fully described and/or claimed in WIPO published application: WO2019/118878 (See below for a definition of variables AA1, AA2, Rl, R2a, R2b, R3 and X).
  • the peptidomimetic is (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide (Compound I, as illustrated below as Formula I), or a pharmaceutically acceptable salt (e.g. Compound (la), illustrated below as a tris-HCl salt as Formula (la)), stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • Compound I as illustrated below as Formula I
  • a pharmaceutically acceptable salt e.g. Compound (la), illustrated below as a tris-HCl salt as Formula (la)
  • small molecule refers to any organic compound that affects a biologic process with a molecular weight less than 900 daltons. It is to be understood that for purposes of this definition, the molecular mass is calculated without reference to any associated (i.e. non-covalently bonded) molecules such as salts, water or other solvent molecules.
  • a “small molecule peptidomimetic” is a peptidomimetic with a free-base molecular weight less than 900 daltons.
  • a small molecule peptidomimetic is (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide (CAS# 2356106-71-1; free-base molecular weight of 607.76) or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • solvate refers to forms of the compound that are associated with a solvent, possibly by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane(s), DMSO, THF, diethyl ether, and the like.
  • tautomer refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7t electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • SBT-272 or “bevemipretide” refers to the peptidomimetic of formula:
  • SBT-272 or “bevemipretide” are also referred to in scientific literature as CAS# 2356106-71-1 (in its free base form). Bevemipretide can be administered as the pharmaceutically acceptable salt, such as a tris-HCl salt (CAS# 2589640-11-7) having the formula:
  • administering or the “administration” of an agent (i.e. therapeutic agent) or compound/drug product (including a composition) to a subject includes any route of introducing or delivering to a subject a compound/drug product to perform its intended function. Administration may be carried out by any suitable route, such as oral administration. Administration can be carried out subcutaneously. Administration can be carried out intravenously. Administration can be carried out intraocularly. Administration can be carried out systemically.
  • administration may be carried out topically, intranasally, intraperitoneally, intradermally, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
  • Administration includes self-administration, the administration by another or administration by use of a device (e.g., an infusion pump).
  • ameliorate or “ameliorating” a disease, disorder or condition refers to results that, in a statistical sample or specific subject, make the occurrence of the disease, disorder or condition (or a sign, symptom or condition thereof) better or more tolerable in a sample or subject administered a therapeutic agent relative to a control sample or subject.
  • carrier or “pharmaceutically acceptable carrier” refer to a diluent, adjuvant, excipient, or vehicle with which a compound/drug product/composition (including a medicament) is administered or formulated for administration.
  • pharmaceutically acceptable carriers include liquids, such as water, saline, oils and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, silica particles (nanoparticles or microparticles) urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used.
  • suitable pharmaceutical carriers are described in Remington ’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.
  • the phrase “delaying the onset of’ refers to, in a statistical sample, postponing, hindering the occurrence of a disease, disorder or condition, or causing one or more signs, symptoms or conditions of a disease, disorder or condition to occur more slowly than normal, in a sample or subject administered a therapeutic agent relative to a control sample or subject.
  • the term “effective amount” refers to a quantity of a compound/composition/drug product sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g, an amount that treats, prevents, inhibits, ameliorates, or delays the onset of the disease, disorder or condition, or the physiological signs, symptoms or conditions of the disease or disorder.
  • the amount of a compound/composition/drug product administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. In some embodiments, it will also depend on the degree, severity and type of disease.
  • compositions/drug products can also be administered in combination with one or more additional therapeutic compounds/agents (a so called “co-administration” where, for example, the additional therapeutic agent could be administered simultaneously, sequentially or by separate administration).
  • inhibit or inhibiting refers to the reduction in a sign, symptom or condition (e.g. risk factor) associated with a disease, disorder or condition associated with a Huntington’s disease and/or a HTT proteinopathy by an objectively measurable amount or degree compared to a control. In one embodiment, inhibit or inhibiting refers to the reduction by at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction by at least 5 percent compared to control (or control subject).
  • a sign, symptom or condition e.g. risk factor
  • inhibit or inhibiting refers to the reduction by at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction by at least 5 percent compared to control (or control subject).
  • inhibit or inhibiting refers to a reduction by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent compared to a control (or control subject).
  • prevention or “preventing” of a disease, disorder, or condition refers to results that, in a statistical sample, exhibit a reduction in the occurrence of the disease, disorder, or condition in a sample or subject administered a therapeutic agent relative to a control sample or subject, or exhibit a delay in the onset of one or more symptoms of the disease, disorder, or condition relative to the control sample or subject. Such prevention is sometimes referred to as a prophylactic treatment.
  • the term “separate” therapeutic use refers to an administration of at least two active ingredients (e.g. therapeutic agents) at the same time or at substantially the same time by different routes.
  • the term “sequential” therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this definition.
  • the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
  • a “subject” refers to a living animal.
  • a subject is a mammal.
  • a subject is a non-human mammal, including, without limitation, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, minipig, horse, cow, or non-human primate.
  • the subject is a human.
  • a “synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of the agents. For example, lower doses of one or more agents may be used in treating Huntington’s disease and/or a HTT proteinopathy.
  • the terms “treating” or “treatment” refer to therapeutic treatment, wherein the object is to reduce, alleviate or slow down (lessen) a pre-existing disease or disorder, or its related signs, symptoms or conditions.
  • a subject is successfully “treated” for a disease if, after receiving an effective amount of the compound/composition/drug product or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, the subject shows observable and/or measurable reduction in or absence of one or more signs, symptoms or conditions associated with the disease, disorder or condition.
  • the present disclosure provides a peptidomimetic compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof:
  • R 2b is H or Me
  • R 3 and R 4 are independently selected from H and (Ci-Ce)alkyl
  • R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 5 and R 6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
  • R 7 is selected from H, (Ci-Ce)alkyl, cycloalkyl, and aryl;
  • R 8 and R 9 are independently selected from H, (Ci-Ce)alkyl, cycloalkyl, and aryl; or R 8 and R 9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl; n is 1, 2, or 3;
  • AAi is , some embodiments, , some embodiments,
  • AA2 is , R 1 , some embodiments, In some embodiments, In some embodiments, R 9
  • R 2a is . , . In some embodiments, In some embodiments,
  • R 2b is H. In some embodiments, R 2b is methyl.
  • R 3 is H. In some embodiments, R 3 is (Ci-Ce)alkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. [0151] In some embodiments, R 4 is H. In some embodiments, R 4 is (Ci-Ce)alkyl.
  • R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl.
  • R 3 and R 4 are the same. In some embodiments, R 3 and R 4 are different.
  • R 5 is H. In some embodiments, R 5 is methyl.
  • R 6 is H. In some embodiments, R 6 is methyl.
  • R 5 and R 6 are the same. In some embodiments, R 5 and R 6 are different. In some embodiments, both R 5 and R 6 are H.
  • R 5 and R 6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl.
  • the heterocyclyl is a 4-6 membered ring.
  • the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.
  • R 7 is H. In some embodiments, R 7 is (Ci-Ce)alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is cycloalkyl. In some embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 7 is aryl. In some embodiments, R 7 is phenyl.
  • R 8 is H. In some embodiments, R 8 is (Ci-Ce)alkyl. In some embodiments, R 8 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is cycloalkyl. In some embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 8 is aryl. In some embodiments, R 8 is phenyl.
  • R 9 is H. In some embodiments, R 9 is (Ci-Ce)alkyl. In some embodiments, R 9 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is cycloalkyl. In some embodiments, R 9 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 9 is aryl. In some embodiments, R 9 is phenyl.
  • R 8 and R 9 are the same. In some embodiments, R 8 and R 9 are different. In some embodiments, both R 8 and R 9 are H. In some embodiments, R 8 and R 9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.
  • X is
  • X is In some embodiments, X is
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • the peptidomimetic is a small molecule peptidomimetic.
  • the peptidomimetic is a peptidomimetic of Formula I or Formula la.
  • the peptidomimetics disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms can exist, for example, because it is difficult or impossible to remove all the solvent from the peptidomimetic post synthesis. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present application. Certain peptidomimetics of the present application may exist in multiple crystalline or amorphous forms.
  • Certain peptidomimetics of the present application may exist in various tautomeric forms. Certain peptidomimetics of the present application may exist in various salt forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the present application.
  • the chiral centers of the peptidomimetic disclosed herein may be in either the R- or S- configuration as discussed in more detail below. IV. Chiral/Stereochemistry Considerations
  • Peptidomimetics described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high- pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high- pressure liquid chromatography
  • a pure enantiomeric peptidomimetic is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S" form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • amino acids which are more commonly described in terms of “D” and “L” enantiomer, it is to be understood that for a “D”-amino acid the configuration is “R” and for an “L”-amino acid, the configuration is “S”.
  • 'substantially free' refers to: (i) an aliquot of an "R" form compound that contains less than 2% "S” form; or (ii) an aliquot of an "S" form compound that contains less than 2% "R” form.
  • the term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 90% by weight, more than 91 % by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition or medicament comprising enantiomerically pure "R” form compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure "R” form compound.
  • the enantiomerically pure "R” form compound in such compositions can, for example, comprise, at least about 95% by weight "R” form compound and at most about 5% by weight "S” form compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure "S” form compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure "S” form compound.
  • the enantiomerically pure "S" form compound in such compositions can, for example, comprise, at least about 95% by weight "S” form compound and at most about 5% by weight "R” form compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • the peptidomimetic compounds described herein may be prepared, in whole or in part using well known peptide synthesis methods, such as conventional liquid-phase (also known as solution-phase) peptide synthesis or solid-phase peptide synthesis, or by peptide synthesis by means of an automated peptide synthesizer (Kelley et al., Genetics Engineering Principles and Methods, Setlow, J. K. eds., Plenum Press NY. (1990) Vol. 12, pp.l to 19; Stewart et al., Solid-Phase Peptide Synthesis (1989) W. H.; Houghten, Proc. Natl. Acad. Sci. USA (1985) 82: p.5132).
  • peptide synthesis methods such as conventional liquid-phase (also known as solution-phase) peptide synthesis or solid-phase peptide synthesis, or by peptide synthesis by means of an automated peptide synthesizer (Kelley et al., Genetics Engineering Principles and
  • the peptidomimetic thus produced can be collected or purified by a routine method, for example, chromatography, such as gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reverse phase column chromatography, and HPLC, ammonium sulfate fractionation, ultrafiltration, and immunoadsorption.
  • chromatography such as gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reverse phase column chromatography, and HPLC, ammonium sulfate fractionation, ultrafiltration, and immunoadsorption.
  • peptides are typically synthesized from the carbonyl group side (C -terminus) to amino group side (N-terminus) of the amino acid chain.
  • an amino-protected amino acid is covalently bound to a solid support material through the carboxyl group of the amino acid, typically via an ester or amido bond and optionally via a linking group.
  • the amino group may be deprotected and reacted with (z.e., “coupled” with) the carbonyl group of a second amino-protected amino acid using a coupling reagent, yielding a dipeptide bound to a solid support.
  • the resin is optionally treated with a capping reagent to thereby cap (render inactive towards subsequent coupling steps) any unreacted amine groups.
  • steps z.e., deprotection, coupling and optionally capping
  • the peptide may be cleaved from the solid support.
  • the peptidomimetics (or peptide portions thereof) can also be prepared in solution.
  • the protecting groups used on the amino groups of the amino acid residues (of peptides and/or peptidomimetics) include 9- fluorenylmethyloxycarbonyl group (Fmoc) and t-butyloxycarbonyl (Boc).
  • Fmoc 9- fluorenylmethyloxycarbonyl group
  • Boc t-butyloxycarbonyl
  • the amino protecting group may be formyl, acrylyl (Acr), benzoyl (Bz), acetyl (Ac), trifluoroacetyl, substituted or unsubstituted groups of aralkyloxycarbonyl type, such as the benzyloxycarbonyl (Z), p-chlorobenzyloxycarbonyl, p- bromobenzyloxy carbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2(p- biphenylyl)isopropyloxycarbonyl, 2-(3,5- dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphonoethyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group (Fmoc), substituted or unsubstituted groups of alpha-buty
  • the solid support material used in the solid-phase peptide synthesis method is a gel-type support such as polystyrene, polyacrylamide, or polyethylene glycol.
  • materials such as controlled-pore glass, cellulose fibers, or polystyrene may be functionalized at their surface to provide a solid support for peptide synthesis.
  • Coupling reagents that may be used in the solid-phase (or solution-phase) peptide synthesis described herein are typically carbodiimide reagents.
  • carbodiimide reagents include, but are not limited to, N,N’ -di cyclohexylcarbodiimide (DCC), l-(3- dimethylaminopropyl)-3 -ethylcarbodiimide (EDC) and its HC1 salt (EDC HC1), N- cy cl ohexyl-N’ -isopropylcarbodiimide (CIC), N,N’ -diisopropylcarbodiimide (DIC), N-tert- butyl-N’ -methylcarbodiimide (BMC), N-tert-butyl-N’-ethylcarbodiimide (BEC), bis[[4-(2,2- dimethyl-l,3-dioxo
  • the amino acids can be activated toward coupling to a peptide or peptidomimetic by forming N-carboxyanhydrides as described in Fuller et al., Urethane-Protected a-Amino Acid N-Carboxyanhydrides and Peptide Synthesis, Biopolymers (Peptide Science), Vol. 40, 183-205 (1996) and WO2018/034901.
  • the small molecule peptidomimetics disclosed herein can be used, alone or in combination, with other therapeutically active ingredients to address the needs of subjects suffering from a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
  • the subject with a tauopathy has been diagnosed as having Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia.
  • the subject has been diagnosed as having a primary age-related tauopathy.
  • the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy.
  • the ALS is familial.
  • the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or TARDBP gene.
  • the small molecule peptidomimetic In order to be administered to a subject in need thereof, the small molecule peptidomimetic will generally need to be formulated for the suitable route of administration.
  • the formulated product can be considered a composition or medicament comprising the small molecule peptidomimetic and optionally one or more additional active therapeutic agents.
  • a pharmaceutical composition of the present application may further comprise at least one additional therapeutic agent other than a small molecule peptidomimetic (e.g., an additional therapeutic agent for use in a combination therapy).
  • the at least one additional therapeutic agent can be an agent useful in the treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD dementia
  • dementia with Lewy bodies dementia with Lewy bodies
  • Multiple System Atrophy Huntington’s disease
  • HTT proteinopathy Frontotemporal Lobar Degeneration (FTLD)
  • tauopathy and other disease where T
  • compositions of the present application can be prepared, for example, by combining one or more compounds of the present application (e.g., a small molecule peptidomimetic) with a pharmaceutically acceptable carrier and, optionally, one or more additional therapeutical agents.
  • compounds of the present application e.g., a small molecule peptidomimetic
  • compositions of the present application may contain an effective amount of a therapeutic compound/agent (or compounds/agents) as described herein and may optionally be disbursed (e.g., dissolved, suspended or otherwise) in a pharmaceutically acceptable carrier.
  • a therapeutic compound/agent or compounds/agents
  • the components of the pharmaceutical composition(s) may also be capable of being commingled with the compounds of the present application, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical efficiency.
  • an “effective amount” refers to any amount of the active compound (or compounds; alone or as formulated) that is sufficient to achieve a desired biological effect.
  • an effective prophylactic (z.e., preventative) or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular condition or disease of a particular subject.
  • the effective amount for any particular indication can vary depending on such factors as the disease, disorder or condition being treated, the particular compound or compounds being administered, the size of the subject, or the severity of the disease, disorder or condition.
  • the effective amount may be determined during pre-clinical trials and/or clinical trials by methods familiar to physicians and clinicians.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular compound and/or other therapeutic agent(s) without necessitating undue experimentation.
  • a maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.
  • a dose may be administered by oneself, by another or by way of a device (e.g., a pump).
  • the therapeutically effective amount can, for example, be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration.
  • the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
  • Compounds (alone or as formulated in a pharmaceutical composition/medicament) for use in therapy or prevention can be tested in suitable animal model systems.
  • suitable animal model systems include, but are not limited to, rats, mice, chicken, cows, monkeys, rabbits, pigs, minipigs and the like, prior to testing in human subjects.
  • any of the animal model system known in the art can be used prior to administration to human subjects.
  • dosing can be tested directly in humans.
  • Dosage, toxicity and therapeutic efficacy of any therapeutic compounds/agents, compositions (e.g., formulations or medicaments), other therapeutic agents, or mixtures thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit high therapeutic indices are advantageous. While compounds that exhibit toxic side effects may be used, in such cases it may be prudent to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • an effective amount of a therapeutic compound/agent disclosed herein sufficient for achieving a therapeutic or prophylactic effect can range from about 0.000001 mg per kilogram body weight per day to about 10,000 mg per kilogram body weight per day.
  • the dosage ranges are from about 0.0001 mg per kilogram body weight per day to about 100 mg per kilogram body weight per day.
  • dosages can be 1 mg/kg body weight or 100 mg/kg body weight every day, every two days or every three days or within the range of 1-100 mg/kg every week, every two weeks or every three weeks.
  • a single dosage of a therapeutic compound/agent disclosed herein ranges from 0.001-10,000 micrograms per kg body weight.
  • a therapeutic compound/agent disclosed herein dissolved or suspended in a carrier range from 0.2 to 2000 micrograms per delivered milliliter. In some embodiments, the dose regimen meets pharmacokinetic target concentrations in target tissues to achieve a desired therapeutic outcome.
  • An exemplary treatment regime can entail administration once per day, twice per day, thrice per day, once a week, or once a month.
  • a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, or until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regimen.
  • an effective amount of a therapeutic compound/agent disclosed herein may be administered in a single daily dose.
  • the single daily dose comprises about 0.1 mg/kg to about 10 mg/kg of body weight, about 0.1 mg/kg of body weight to about 0.9 mg/kg of body weight, about 0.1 mg/kg of body weight to about 0.3 mg/kg of body weight, about 0.3 mg/kg of body weight to about 0.6 mg/kg of body weight, about 0.6 mg/kg of body weight to about 1.0 mg/kg of body weight, about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight.
  • a single daily dose comprises about 1 mg to about 60 mg. In some embodiments, a single daily dose comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or about 18 mg to about 48 mg. In some embodiments, the single daily dose comprises ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. In some embodiments, the SBT-272 is administered in multiple daily doses. In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
  • the multiple daily doses comprise, 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. In some embodiments, the multiple daily doses comprise ascending doses of 20 mg once daily for 7 days, 40 mg once daily for 7 days, and 60 mg once daily for 7 days.
  • dosing SBT-272 achieves a brain concentration of the peptide of between about 10 nM and about 100 nM. In some embodiments, dosing achieves a brain cortex SBT-272 concentration of about 650 nM to about 690 nM. In some embodiments, dosing achieves a brain ISF SBT-272 concentration of about 20 nM to about 30 nM.
  • dosing achieves a cerebral spinal fluid (CSF) SBT-272 concentration of about 2 nM to about 12 nM. In some embodiments, dosing achieves a plasma SBT-272 concentration of about 10 nM to about 14 nM. In some embodiments, dosing achieves a SBT-272 plasma:CSF ratio of between about 1.0 and about 6.5. In some embodiments, dosing achieves a SBT-272 braimplasma ratio of between about 50 and about 180. In some embodiments, dosing achieves a SBT-272 brain:CSF ratio of between about 180 and about 330.
  • CSF cerebral spinal fluid
  • a therapeutically effective amount of a therapeutic compound/agent disclosed herein may be defined as a concentration of compound existing at the target tissue of 10' 12 to 10' 4 molar, e.g., approximately 10' 7 molar.
  • This concentration may be delivered by systemic doses of 0.001 to 100 mg/kg or equivalent dose by body surface area.
  • the schedule of doses would be optimized to maintain the therapeutic concentration at the target tissue, such as by single daily or weekly administration, but also including continuous administration (e.g., oral, systemic, topical, subcutaneous, intra-nasal, parenteral infusion or transdermal application).
  • intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 0.01 pg/kg/day to 80 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 0.01 pg/kg/day to 100 pg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 0.1 pg/kg/day to 10 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 10 pg/kg/day to 2 mg/kg/day.
  • intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 500 pg/kg/day to 5 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 1 mg/kg/day to 100 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 1 mg/kg/day to 50 mg/kg/day.
  • daily oral doses of a compound (alone or as formulated) will be, for human subjects, from about 0.01 micrograms/kg per day to 250 milligrams/kg per day. In some embodiments, daily oral doses of a compound (alone or as formulated) will be, for human subjects, from about 1 milligrams/kg per day to 100 milligrams/kg per day or from about 10 milligrams/kg per day to 75 milligrams/kg per day or It is expected that oral doses of a compound (alone or as formulated) in the range of 0.1 to 50 milligrams/kg, in one or more administrations per day, will yield therapeutic results.
  • Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.
  • an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface.
  • Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan.
  • Routes of administration include but are not limited to oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmical, intrathecal, intracerebroventricular, iontophoretical, transmucosal, intravitreal, or intramuscular administration.
  • Administration includes self-administration, the administration by another and administration by a device (e.g., a pump).
  • a therapeutic compound/agent disclosed herein can be delivered to the subject in a formulation or medicament (z.e., a pharmaceutical composition).
  • a formulation or medicament z.e., a pharmaceutical composition
  • Formulations and medicaments can be prepared by, for example, dissolving or suspending a therapeutic compound/agent disclosed herein in water, a pharmaceutically acceptable carrier, salt, (e.g., NaCl or sodium phosphate), buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutically acceptable ingredients.
  • the pharmaceutical compositions can include a carrier (e.g., a pharmaceutically acceptable carrier), which can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • a carrier e.g., a pharmaceutically acceptable carrier
  • polyol e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like
  • suitable mixtures thereof for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation.
  • isotonic agents for example, sugars (e.g., trehalose), polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous or intraocular application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such
  • pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • the dosing formulation can be provided alone or in a kit containing all necessary equipment (e.g., vials of drug, vials of diluent, syringes and needles) for a treatment course (e.g., 1, 2, 3, 4, 5, 6, 7 days or more of treatment).
  • the therapeutic compounds/agents or pharmaceutical compositions when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion (for example by IV injection or via a pump to meter the administration over a defined time).
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • a compound can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex.
  • Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.
  • compositions suitable for injection can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • a composition for administration by injection will generally be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and may be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • Sterile injectable solutions e.g., a formulation or medicament
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • typical methods of preparation include vacuum drying and freeze drying, which can yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or corn starch; a lubricant such as magnesium stearate or sterates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or corn starch
  • a lubricant such as magnesium stearate or sterates
  • a glidant such as colloidal silicon dioxide
  • compositions for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carb
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above that may be chemically modified so that oral delivery of the derivative is efficacious.
  • the chemical modification contemplated is the attachment of at least one moiety to the therapeutic agent(s), ingredient(s), and/or excipient(s), where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982).
  • Other polymers that could be used are poly-1, 3-dioxolane and poly-1, 3, 6-tioxocane.
  • PEG polyethylene glycol
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the present application (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.
  • the therapeutic compound/agent or pharmaceutical composition can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1-2 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic compound/agent or pharmaceutical composition could be prepared by compression.
  • Colorants and flavoring agents may all be included.
  • the compound or pharmaceutical composition of the present application (or derivative) may be formulated and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • diluents could include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress® and Avicel®.
  • Disintegrants may be included in the formulation of the therapeutic compound/agent or composition into a solid dosage form.
  • Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, karaya gum or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
  • MC methyl cellulose
  • EC ethyl cellulose
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • An anti -frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process.
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (PEG) of various molecular weights, CarbowaxTM 4000 and 6000.
  • Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added.
  • the glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • surfactant might be added as a wetting agent.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride.
  • Non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the present application or derivative either alone or as a mixture in different ratios.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Solutions, gels, ointments, creams or suspensions may be administered topically.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • compounds or compositions for use according to the present application may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the formulation, medicament and/or other therapeutic compound/agent can be delivered in the form of an aerosol spray from a pressurized container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic compound/agent and a suitable powder base such as lactose or starch.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Nasal delivery of a therapeutic compound/agent or pharmaceutical composition of the present application is also contemplated.
  • Nasal delivery allows the passage of a therapeutic compound/agent or pharmaceutical composition to the blood stream directly after administering the therapeutic compound/agent or pharmaceutical composition to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present application solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the therapeutic compound/agent or pharmaceutical composition.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the therapeutic compound/agent or pharmaceutical composition.
  • pulmonary delivery of the compounds disclosed herein is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., IntJ Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl.
  • Contemplated for use in the practice of this technology are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • UltraventTM nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo.
  • Acorn II® nebulizer manufactured by Marquest Medical Products, Englewood, Colo.
  • the Ventolin® metered dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina
  • the Spinhaler® powder inhaler manufactured by Fisons Corp., Bedford, Mass.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy.
  • the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes, or other types of carriers is contemplated.
  • Chemically modified compound of the present application may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer can, for example, comprise a compound/therapeutic agent of the present application (or derivative) dissolved in water at a concentration of about 0.01 to 50 mg of biologically active compound per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the present application caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device may generally comprise a finely divided powder containing the compound of the present application (or derivative) suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including tri chi orofluorom ethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1, 1,2- tetrafluoroethane, or combinations thereof.
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device may comprise a finely divided dry powder containing compound of the present application (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • the compound(s)/therapeutic agent(s) of the present application (or derivative) can advantageously be prepared in particulate or nanoparticulate form with an average particle size of less than 10 micrometers (pm), most preferably 0.5 to 5 pm, for most effective delivery to the deep lung.
  • any suitable mode of delivering the therapeutic compounds/agents or pharmaceutical compositions to the eye or regions near the eye can be used.
  • ophthalmic formulations generally, see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N.Y. (1993) and also Havener, W.
  • compositions suitable for administration in or near the eye include, but are not limited to, ocular inserts, minitablets, and topical formulations such as eye drops, ointments, and in situ gels.
  • a contact lens is coated with a pharmaceutical composition comprising a therapeutic compound/agent disclosed herein.
  • a single dose can comprise from between 0.1 ng to 5000 pg, 1 ng to 500 pg, or 10 ng to 100 pg of the therapeutic compounds/agents or pharmaceutical compositions administered to the eye.
  • Eye drops can comprise a sterile liquid formulation that can be administered directly to the eye.
  • eye drops comprise at least one therapeutic compound/agent disclosed herein and may further comprise one or more preservatives.
  • the optimum pH for eye drops equals that of tear fluid and is about 7.4.
  • the therapeutic compound/agent can be present in the drop solution from about 0.1% to about 5% (w/v or v/v depending on the physical nature (i.e. solid or liquid) of the active ingredient).
  • the therapeutic compound/agent can be present in the drop solution from about 1% to about 3% (w/v or v/v, as appropriate).
  • In situ gels are viscous liquids, showing the ability to undergo sol-to-gel transitions when influenced by external factors, such as appropriate pH, temperature, and the presence of electrolytes. This property causes slowing of drug drainage from the eyeball surface and increase of the active ingredient bioavailability.
  • Polymers commonly used in in situ gel formulations include, but are not limited to, gellan gum, poloxamer, silicone containing formulations, silica-based formulations and cellulose acetate phthalate.
  • the therapeutic compound/agent is formulated into an in-situ gel (as the pharmaceutical composition/medicament).
  • therapeutic compound/agent or pharmaceutical composition may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Ointments are semisolid dosage forms for external use such as topical use for the eye or skin.
  • ointments comprise a solid or semisolid hydrocarbon base of melting or softening point close to human core temperature.
  • an ointment applied to the eye decomposes into small drops, which stay for a longer time period in conjunctival sac, thus increasing bioavailability.
  • Ocular inserts are solid or semisolid dosage forms without disadvantages of traditional ophthalmic drug forms. They are less susceptible to defense mechanisms like outflow through nasolacrimal duct, show the ability to stay in conjunctival sac for a longer period, and are more stable than conventional dosage forms. They also offer advantages such as accurate dosing of one or more therapeutic compounds/agents, slow release of one or more therapeutic compounds/agents with constant speed and limiting of one or more therapeutic compounds ’/agents’ systemic absorption.
  • an ocular insert comprises one or more therapeutic compounds/agents as disclosed herein and one or more polymeric materials.
  • the polymeric materials can include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the aforementioned polymers.
  • An ocular insert can comprise silica.
  • An ocular insert can comprise liposomes, nanoparticles or microparticles of degradable or biodegradable polymer (as described in more detail below).
  • Minitablets are biodegradable, solid drug forms, that transit into gels after application to the conjunctival sac, thereby extending the period of contact between active ingredient (i.e. the therapeutic compounds/agents disclosed herein) and the eyeball surface, which in turn increases a therapeutic compounds’/agents’ bioavailability.
  • active ingredient i.e. the therapeutic compounds/agents disclosed herein
  • the advantages of minitablets include easy application to conjunctival sac, resistance to defense mechanisms like tearing or outflow through nasolacrimal duct, longer contact with the cornea caused by presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation in the place of application due to the swelling of the outer carrier layers.
  • Minitablets can comprise one or more of the therapeutic compounds/agents disclosed herein and one or more polymers.
  • polymers suitable for use in in a minitablet formulation include cellulose derivatives, like hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), Carbopol® or carbomer, chitosan, and starch (e.g., drum-dried waxy maize starch).
  • minitablets further comprise one or more excipients.
  • excipients include mannitol and magnesium stearate.
  • the ophthalmic or intraocular formulations and medicaments may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenyl ethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like.
  • auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenyl ethanol
  • buffering ingredients such as sodium chloride,
  • the viscosity of the ocular formulation comprising one or more therapeutic compounds/agents is increased to improve contact with the cornea and bioavailability in the eye.
  • Viscosity can be increased by the addition of hydrophilic polymers of high molecular weight which do not diffuse through biological membranes and which form three-dimensional networks in the water.
  • Nonlimiting examples of such polymers include polyvinyl alcohol, poloxamers, hyaluronic acid, carbomers, and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.
  • a therapeutic compound/agent disclosed herein may also be formulated as a depot preparation.
  • Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the therapeutic agent(s) is/are administered as a depot formulation wherein the active therapeutic agent(s) is/are encapsulated by, or disposed within, silica-based microparticles.
  • the ocular formulation can be injected into the eye, for example as a sol-gel (e.g., a silica sol-gel).
  • the ocular formulation is a depot formulation such as a controlled release formulation (see below).
  • Such controlled release formulation may comprise particles, such as microparticles or nanoparticles.
  • compositions also may comprise suitable solid or gel-phase carriers or excipients.
  • suitable solid or gel-phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, silica/silicone and polymers such as polyethylene glycols.
  • Suitable liquid or solid pharmaceutical preparation forms can, for example, be aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions can be suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527-33 (1990).
  • the therapeutic agent(s), including specifically but not limited to a therapeutic compound/agent disclosed herein, may be provided in particles.
  • Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the therapeutic compound/agent or the other therapeutic agent(s) as described herein.
  • the particles may contain the therapeutic compound(s)/agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
  • the therapeutic compound(s)/agent(s) also may be dispersed throughout the particles.
  • the therapeutic compound(s)/agent(s) also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic compound(s)/agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or nonbiodegradable material or combinations thereof.
  • the particles may be microcapsules which contain the therapeutic compound(s)/agent(s) in a solution or in a semi-solid state.
  • the particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic compound(s)/agent(s).
  • Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein.
  • polyhyaluronic acids casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, polyethylene glycols (PEGs), polyvinylalcohols (PVAs), poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly-lactic acid (PLA), poly(lactic -co- glycolic) acid (PLGA), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly(£-caprolactone) or mixtures of two or more of the foregoing.
  • PEGs polyethylene glycols
  • PVAs polyvinylalco
  • Therapeutic compounds/agents or other therapeutic agent(s) or mixtures thereof can be formulated in a carrier system.
  • the carrier can be a colloidal system.
  • the carrier or colloidal system can be a liposome, a phospholipid bilayer vehicle.
  • therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof can be encapsulated in a liposome while maintaining integrity of the therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof.
  • One skilled in the art would appreciate that there are a variety of methods to prepare liposomes. (See Lichtenberg, et al., Methods Biochem.
  • an active agent can also be loaded into a particle prepared from pharmaceutically acceptable ingredients including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes.
  • Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.
  • the carrier can also be a polymer, e.g., a biodegradable, biocompatible polymer matrix.
  • the therapeutic compound or other therapeutic agent or mixtures thereof can be embedded in the polymer matrix, while maintaining integrity of the composition.
  • the polymer can be a microparticle or nanoparticle that encapsulates the therapeutic agent or agents.
  • the polymer may be natural, such as polypeptides, proteins or polysaccharides, or synthetic, such as poly a-hydroxy acids. Examples include carriers made of, e.g., collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharide, fibrin, gelatin, and combinations thereof.
  • the polymer is poly-lactic acid (PLA), poly lactic/glycolic acid (PLGA) or a mixture thereof.
  • the polymeric matrices can be prepared and isolated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can lead to prolonged duration of therapeutic effect. (See Reddy, Ann. Pharmacother 34(7-8):915-923 (2000)). A polymer formulation for human growth hormone (hGH) has been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).
  • polymer microsphere sustained release formulations are described in PCT publication WO 99/15154 (Tracy, et al.), U.S. Pat. Nos. 5,674,534 and 5,716,644 (both to Zale, et ah)' , PCT publication WO 96/40073 (Zale, et ah)' , and PCT publication WO 00/38651 (Shah, et al.).
  • U.S. Pat. Nos. 5,674,534 and 5,716,644 and PCT publication WO 96/40073 describe a polymeric matrix containing particles of erythropoietin that are stabilized against aggregation with a salt.
  • the nanoparticles or microparticles can be silica-based or silane-based (See for example: W02002/080977 entitled: “Biodegradable carrier and method for preparation thereof’).
  • the therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof are prepared with carriers that will protect the therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Such formulations can be prepared using known techniques.
  • the materials can also be obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • the therapeutic compound(s)/agent(s) may be contained in controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations.
  • sustained release also referred to as “extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom to thereby make it available to the subject. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”
  • a long-term sustained release implant or depot formulation may be particularly suitable for treatment of chronic conditions.
  • implant and “depot formulation” is intended to include a single composition (such as a mesh) or composition comprising multiple components (e.g. a fibrous mesh constructed from several individual pieces of mesh material) or a plurality of individual compositions where the plurality remains localized and provide the long-term sustained release occurring from the aggregate of the plurality of compositions.
  • Long-term release means that the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 2 days.
  • the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 7 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 14 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient for at least 90 days.
  • the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least one year. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 15-30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 30-60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 60-90 days.
  • the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 90-120 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 120-180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for up to one year. In some embodiments, the long-term sustained release implants or depot formulation are well-known to those of ordinary skill in the art and include some of the release systems described above. In some embodiments, such implants or depot formulation can be administered surgically. In some embodiments, such implants or depot formulation can be administered topically or by injection.
  • the small molecule peptidomimetics disclosed herein can be used, alone or in combination, with other therapeutically active ingredients to address the needs of subjects suffering from a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology
  • the small molecule peptidomimetic In order to be administered to a subject in need thereof, the small molecule peptidomimetic will generally need to be formulated for the suitable route of administration.
  • the formulated product can be considered a composition or medicament comprising the small molecule peptidomimetic and optionally one or more additional active therapeutic agents.
  • the small molecule peptidomimetic (alone or in combination with another active ingredient) is to be administered to the subject by injection, it will typically be formulated into an injectable liquid or liquid suspension.
  • the diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier can be water, saline or a buffered aqueous solution.
  • the selected active ingredient(s) can be formulated into a pill, tablet, capsule or other vehicle for such administration as discussed above in the section entitled: “Pharmaceutical Compositions, Routes of Administration, and Dosing” or as otherwise known to those of ordinary skill in the art.
  • the small molecule peptidomimetic (alone or in combination with another active therapeutic agents) can be formulated for ocular administration, buccal administration, topical administration, nasal administration or any other of the modes of administration previously discussed herein or that are known to those of ordinary skill in the art.
  • any of the formulations (which can also be referred to as a medicament or composition when formulated for administration to a subject having a certain affliction or medical condition that requires medical attention) described in the section above entitled: “Pharmaceutical Compositions, Routes of Administration, and Dosing” can be applied to produce a composition (i.e. a formulation or medicament) suitable for administration to a subject in need thereof.
  • this application is directed to compositions, formulations and medicaments suitable for administration to a subject suffering from, or believed to be suffering from a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • the present disclosure provides a formulation or medicament comprising a peptidomimetic, such as (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and/or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar De
  • a neurodegenerative disease such as, but
  • the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the peptidomimetic is (R)- 2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • the formulation or medicament is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the formulation or medicament is administered daily for the remainder of the life of the subject.
  • the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology comprising stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
  • a neurodegenerative disease such as, but not limited to amyotroph
  • the subject is a mammal. In some embodiments, the mammalian subject is a human.
  • the formulation or medicament is administered orally. In some embodiments, the formulation or medicament is administered subcutaneously. In some embodiments, the formulation or medicament is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
  • the formulation or medicament embodies a combination therapy.
  • the use of the formulation or medicament further comprises separately, sequentially, or simultaneously administering an additional treatment to the subject.
  • the additional treatment comprises administration of a therapeutic agent.
  • the additional therapeutic agent can be one used to treat the disease itself or otherwise be used to address symptoms or conditions associated with the disease (in this case a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology).
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology).
  • a neurodegenerative disease such
  • the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escitalopram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine).
  • Xenazine® tetrabenazine
  • Austedo® deutetrabenazine
  • Risperdal® risperidone
  • Haldol® haloperidol
  • Thorazine® chlorpromaz
  • the therapeutic agent is elamipretide (also known as SS-31 or bendavia).
  • the combination of formulation or medicament and the additional treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- syn
  • the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt).
  • pharmaceutically acceptable salt comprises a monoacetate salt, a bis-acetate salt, a tri-acetate salt, a monotrifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.
  • the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
  • the present disclosure provides a method for treating, preventing, inhibiting, ameliorating or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptidomimetic, such as (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l
  • the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the peptidomimetic is (R)- 2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • the peptidomimetic is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, once diagnosed, the peptidomimetic is administered daily for the remainder of the life of the subject.
  • the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology comprising, but not limited to, stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
  • a neurodegenerative disease such as, but not
  • the subject is a mammal. In some embodiments, the mammalian subject is a human.
  • the peptidomimetic is administered orally. In some embodiments, the peptidomimetic is administered subcutaneously. In some embodiments, the peptidomimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
  • the method involves a combination therapy.
  • the method further comprises separately, sequentially, or simultaneously administering an additional treatment to the subject.
  • the additional treatment comprises administration of a therapeutic agent.
  • the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escital opram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine).
  • the therapeutic agent is elamipretide (also known as SS-31 or bendavia).
  • the combination of peptidomimetic and an additional therapeutic treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein
  • the pharmaceutically acceptable salt of the peptidomimetic comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt).
  • pharmaceutically acceptable salt comprises a monoacetate salt, a bisacetate salt, a tri-acetate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri- trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.
  • the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
  • the present disclosure provides a use of a composition in the preparation of a medicament for treating, preventing, inhibiting, ameliorating or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of a peptidomimetic, such as (R)-2- amino-N-((S)- 1 -((( S)-5 -amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,
  • the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the peptidomimetic is (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl- l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • the medicament is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the medicament is administered daily for the remainder of the life of the subject.
  • the use of the medicament for the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology comprising, but not limited to, stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and
  • a neurodegenerative disease
  • the subject is a mammal. In some embodiments, the mammalian subject is a human.
  • the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for subcutaneous administration. In some embodiments, the medicament is formulated for administration, topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
  • the medicament is separately, sequentially, or simultaneously used with an additional treatment.
  • the additional treatment comprises use of a therapeutic agent.
  • the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escitalopram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine).
  • the therapeutic agent is elamipretide (also known as SS-31 or bendavia).
  • the combination of medicament and an additional treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-s
  • the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt).
  • pharmaceutically acceptable salt comprises a monoacetate salt, a bis-acetate salt, a tri-acetate salt, a mono- trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.
  • the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
  • the present disclosure provides a peptidomimetic, such as (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and/or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy
  • a neurodegenerative disease
  • the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the peptidomimetic is (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
  • the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • the peptidomimetic is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for
  • the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology comprising, but not limited to, stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
  • a neurodegenerative disease such as, but not
  • the subject is a mammal. In some embodiments, the mammalian subject is a human.
  • the peptidomimetic is formulated for administration orally. In some embodiments, the peptidomimetic is formulated for administration subcutaneously. In some embodiments, the peptidomimetic is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
  • the peptidomimetic is separately, sequentially, or simultaneously used with an additional treatment.
  • the additional treatment comprises use of a therapeutic agent.
  • the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escitalopram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine).
  • the therapeutic agent is elamipretide (also known as SS-31 or bendavia).
  • the combination of medicament and an additional treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
  • a neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-s
  • the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt).
  • pharmaceutically acceptable salt comprises a monoacetate salt, a bis-acetate salt, a tri-acetate salt, a mono- trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.
  • the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
  • SBT-272 a small molecule that penetrates the central nervous system (CNS) and can be used to treat mitochondrial dysfunction in neurodegenerative diseases, targets cardiolipin (CL), restoring mitochondrial structure and cellular energetics (FIGs. 1A and IB).
  • CL is the inner mitochondrial membrane (IMM) phospholipid responsible for the structural integrity of the IMM folds, or cristae, which harbor the protein complexes of the electron transport chain that are essential for oxidative phosphorylation and adenosine triphosphate (ATP) generation (OXPHOS).
  • IMM inner mitochondrial membrane
  • ATP adenosine triphosphate
  • Paradies G et al., Cells 8:728 (2019).
  • Homogenates (96 pL) were transferred to 1/5 mL microcentrifuge tubes with surface that minimized binding (REF 04-212-3500, Nerbe Plus, Germany). Homogenates were frozen and kept at -80°C until sample extraction for LC/MS/MS analysis. Two samples (twice 96 pL) collected, one kept if repeat required.
  • Brain sample preparation Extraction of spiked brain homogenate standards: to 100 pL of spiked rat brain homogenate standard sample add 10 pL of IS spiking solution; add 400 pL of deproteinization solution, 1% formic acid in MeOH; vortex mix the samples for 100 seconds at 2800 rpm; centrifugate samples at 12000 rpm for 30 min at 5°C; transfer supernatants to LC vials and use for analysis.
  • Extraction of brain homogenate study samples to 96 pL of rat brain homogenate study sample, add 4 pL of DMSO and 10 pL of IS spiking solution; add 400 pL of deproteinization solution, 1% formic acid in MeOH; vortex mix the samples for 10 seconds at 2800 rpm; incubate samples on orbital shaker for 10 min at 2000 rpm; vortex mix the samples for 10 seconds at 2800 rpm; centrifugate samples at 12000 rpm for 30 minutes in 5 °C; transfer supernatants to LC vials and use for analysis.
  • SBT-272 is brain penetrant and exhibited optimized biodistribution across the blood-brain-barrier, as evaluated in rats after a single dose of 5 mg/kg delivered subcutaneously (SC).
  • SBT-272 Improves Mitochondrial Integrity and Motility in Upper Motor Neurons with TDP-43 Pathology, Poster presented at Keystone poster session, 2022; Guatam, et al., The mitochondrial targeted peptidomimetic SBT-272 protects corticospinal motor neurons with mutant TDP43 pathology, Poster presented at NEALS poster session, 2021; Gautam, et al., SBT-272 improved mitochondria structure and function and preserved upper motor neurons with TDP-43 pathology, Platform poster presentation, presented at NEALS poster session, 2022; Bido, et al., The mitochondrial targeted drug SBT-272 attenuates dompaminergicneuron loss, alpha-synuclein burden and neuroinflammation in a mouse model of Parkinson ’s Disease, Poster presented at Muscle Disorder Society (MDS) poster session, 2021); (c) protect MAPT-P301L(+) iPSC derived tauopathy neurons from rotenone induced cell death (
  • Examples 3 and 4 demonstrate the assessment of plasma, cerebrospinal fluid (CS), and brain homogenate PK results from pre-clinical studies (rodent and nonhuman primate) and emerging Phase 1 clinical plasma PK data in the context of both single doses and steady state achieved through chronic dosing of SBT-272.
  • Example 3 Pre-Clinical Rodent and Nonhuman Primate Studies
  • in vitro (FIG. 3 A) and in vivo (FIG. 3B) correlations indicate a 10 to 100 nM brain concentration as a potential target for pharmacodynamic effect.
  • SBT-272 has been shown to demonstrate in vitro and in vivo activity in transgenic hTDP-43 models. See Guatam M., Platform presentation. NEALS, 2022. In addition, it has been demonstrated that, in more than one model, SBT-272 has reported activity on neuroprotection, survival benefits, lowering of protein aggregates, and improved mitochondrial function. See Keefe, et al. (2019); Gautam, et al. (2022); Guatam, et al. (2021).
  • Gautam, et al., SBT-272 improved mitochondria structure and function and preserved upper motor neurons with TDP-43 pathology, Platform poster presentation, presented at NEALS poster session (2022); Bido, et al. (2021); Silva, et al. (2022); and Zariwala, et al., Effects of the mitochondria-targeting small molecule SBT-272 in the R6/2 transgenic mice of Huntington ’s Disease, Poster presented at Keystone Symposia poster Session, 2022.
  • Test compounds were SBT-272.
  • the molecular weight of SBT-272 is 607.75 g/mol in the salt-free form, and 717.13 g/mol in the salt form.
  • the batch specific 24 months stability data showed potency as free base value of 0.797, therefore, an adjusted correction factor of 1.25 was used.
  • the probes were perfused with a slow flow of aCSF with or without 0.2% BSA at a flow rate of 0.12 pL/min, and a carrier flow of ultrapurified H2O at a flow rate of 0.8 pL/min. After 2 hours of prestabilization, five consecutive microdialysis samples were collected in 30-minute intervals. Samples from the beaker content were collected at the start and end of the microdialysis experiment. All samples were collected into 300 pL polystyrene microvials (Microbiotech/se AB, Sweden; 4001029) and stored at -80 °C until analysis.
  • carprofen (5 mg/kg, s.c.) was administered for peri- and post-operative analgesia.
  • Coordinates for the tip of the probe were for PFC: AP +3.4 mm (to bregma), lateral +0.8 mm (to midline), ventral -5.0 mm (to dura) and for STR: AP +0.9 mm (to bregma), lateral -3.0 mm (to midline), ventral -6.0 mm (to dura).
  • the incisor bar was set at - 3.3 mm. Coordinates were based on “The rat brain in stereotaxic coordinates” by Paxinos and Watson (2009).
  • the probes were attached to the skull with stainless steel screws and dental cement.
  • Probes were perfused with a slow flow of artificial CSF (aCSF: containing 147 mM NaCl, 3.0 mM KC1, 1.2 mM CaCh and 1.2 mM MgCh) with 0.2% BSA (w/v) at a flow rate of 0.12 pL/min and a carrier flow of ultrapurified H2O at a flow rate of 0.8 pL/min.
  • aCSF artificial CSF
  • BSA w/v
  • Samples were collected into polystyrene microvials (Microbiotech/se AB, Sweden; 4001029) using an automated fraction collector (UV 8301501, TSE, Univentor, Malta).
  • the microdialysis sampling schedules are shown in Table 5 and Table 6.
  • Blood samples 50 pL were collected in lithium heparin tubes via the jugular vein catheter according to the sampling schedule shown in Table 7.
  • Plasma was collected into polystyrene microvials.
  • CSF samples were collected into polystyrene microvials via the cistema magna cannula according to the sampling schedule shown in Error! Reference source not found..
  • the animals were euthanized and a terminal blood sample was collected. Terminal brain tissue was snap frozen. All samples were stored at -80 °C.
  • SBT-272 Concentrations of SBT-272 were determined by HPLC with tandem mass spectrometry (MS/MS) detection. Microdialysis and CSF samples were mixed with phosphoric acid, acetonitrile and internal standard (Glafenine) containing solution. Brain tissue was homogenized using phosphoric acid and homogenates were mixed with methanol and acetonitrile and IS containing solution. Plasma samples were precipitated using methanol, acetonitrile, phosphoric acid and IS containing solution and subsequently centrifuged. The resultant supernatant was used as for HPLC-MS analysis.
  • MS/MS tandem mass spectrometry
  • the MS analyses were performed using an API 6500 MS/MS system consisting of an API 6500 MS/MS detector and a Turbo Ion Spray interface (both from Applied Biosystems, The Netherlands).
  • the acquisitions were performed in positive ionization mode, with optimized settings for the analytes.
  • the instrument was operated in multiple-reaction-monitoring (MRM) mode. MRM transitions for the analytes are shown in Table 8. Suitable in-run calibration curves were fitted using weighted (1/x) regression, and the sample concentrations were determined using these calibration curves. Accuracy was verified by quality control samples after each sample series. Data were calibrated and quantified using the Analyst data system (Applied Biosystems).
  • FIG. 5A shows the mean levels of SBT-272 in brain homogenate, brain ISF, CSF, and plasma samples from adult male SD rats following 5 daily s.c. administrations of 10 mg/kg SBT-272. Compartment ratios of SBT-272 (plasma:CSF 1.03; braimplasama 178; and brain:CSF 182) are also shown in FIG. 5A.
  • Test system Details regarding the test system are provided below:
  • Husbandry Each animal was housed in its own stainless steel cage. Housing set-up was as described in the Guide for the Care and Use of Laboratory Animals (National Research Council). Animals were separated during designated procedures/activities. The animal room environment was maintained at a temperature of 18°C to 24°C, humidity of 30% to 70%, and a light cycle of 12 hours light and 12 hours dark (except during designated procedures). The diet consisted of Envigo Teklad Certified Hi -Fiber Primate Diet #7195C, twice daily, except during designated procedures, in amounts appropriate for the size and age of the animals. Animals were provided with municipal tap water, treated by reverse osmosis and ultraviolet irradiation and was made freely available to each animal via an automatic watering system (except during designated procedures).
  • Veterinary care Veterinary care was available throughout the course of the study and animals were examined by veterinary staff as warranted.
  • Study design The study design is described in Table 9. a Based on the most recent body weight measurement.
  • Antibiotic Penicillin G Procaine - Subcutaneously or intramuscularly, starting at least
  • Analgesic Buprenorphine - Intramuscularly, at least 30 minutes prior surgery
  • Anesthesia Sedation using ketamine/acepromazine mixture, intramuscularly, followed by intubation and maintained under isoflurane/oxygen gas
  • Perifix Polyamide Epidural catheter 20G closed tip implanted approximately at the L5 level of lumbar vertebrae using hemilaminectomy approach and fluoroscopy imaging. Once the dura matter is incised and the catheter is inserted, the tip of the catheter is advanced up to approximately the LI level of lumbar vertebra. Cerebrospinal fluid (approximately 0.25 ml) is collected via dripping method from the catheter and may be used as the pre-dose samples (Week -1). Around 0.5ml of Omnipaque or an equivalent contrast agent is injected using a syringe attached to the catheter to confirm its placement via fluoroscopy or x-ray. Confirmation of catheter patency is assessed via CSF flow.
  • a small incision is made on the skin of lumbar area to expose the muscle in order to anchor the catheter using non-absorbable knots glued on the catheter.
  • Catheter is tunneled and exteriorized at the level of interscapular area and placed in jacket pocket. Surgical site is rinsed with warm sterile saline prior to closure.
  • Postoperative Fruits and/or vegetables buffet and crushed cookies mixed with banana are provided to the animals for at least 5 days postsurgery.
  • a catheter patency check (flush with 0.3 mL artificial CSF) is performed at least twice daily, except on days of CSF collection. On days of CSF collection, a single patency check may be done following the last CSF collections.
  • Topical wound cleaner e.g., Skintegrity or equivalent
  • exteriorization site three times weekly (or as needed) until considered healed.
  • Topical antibiotic (Polysporin Original) once daily for 7 days following surgery (including day of surgery) or as required.
  • Enrofloxacin (Baytril) - intramuscularly once daily for at least 2 days following surgery.
  • Buprenorphine slow release - Subcutaneously, at the end of surgery.
  • Catheter type Perifix Epidural Catheter (Product No. EC20CST, B. Braun Medical Inc.) Set-up: Jacket (exterior part of the catheter placed in a clean bag in a small pocket of the jacket)
  • the first day of dosing is designated as Day 1. Dose formulations are allowed to warm up at ambient temperature for at least 30 minutes prior to dosing, as appropriate. The animals are temporarily restrained for dose administration and are not be sedated. The volume for each dose is administered over 1 (preferred) or 2 (as necessary) separate injections within the designated area. Injection sites are rotated daily (see FIG. 4B). If a designated subcutaneous test site is not available for a given animal on any day, then the next available test site in the rotation should be used for dosing. The injection area is marked as frequently as required to allow appropriate visualization of administration sites. Hair may be clipped or shaved if required to improve visualization of the injection sites. On the last injection occasion for each quadrant, the last site of injection is circled, and the circled site is collected at necropsy.
  • CSF Sample Processing CSF samples re processed and stored within 1 hour of collection. Following each CSF collection, the sample is visually inspected, and the appearance is recorded. Samples are maintained on wet ice prior to and after centrifugation. Samples are centrifuged for 5 minutes in a refrigerated centrifuge (set to maintain 4°C) at 2000 g RCF within 1 hour of collection. The resultant supernatant is collected within 30 minutes (as quickly as possible) of centrifugation and will be visually inspected; the appearance of the supernatant and any traces of blood in the pellet re recorded. Precipitate (if any) is discarded.
  • CSF samples are separated into 2 approximately 100 pL equal aliquots into uniquely labelled low protein binding polypropylene tubes each containing 10 pL of 5% (v/v) phosphoric acid aqueous solution. Any remaining CSF will be transferred into a 3 rd low protein binding polypropylene tube containing a volume of 5% (v/v) phosphoric acid solution adjusted to result in a 1 : 10 ratio of acid solution: CSF. All samples are placed on dry ice and transferred to a freezer set to maintain -70°C. [0320] Plasma Sample Collection:
  • Plasma Sample Processing The samples are centrifuged within 20 minutes of collection and the resultant plasma is separated, and two 200 pL aliquots transferred to duplicate uniquely labeled clear polypropylene tubes, each containing 20 pL of 5% (v/v) phosphoric acid aqueous solution. Any remaining plasma is transferred into a 3 rd polypropylene tube containing a volume of 5% (v/v) phosphoric acid solution adjusted to result in a 1 : 10 ratio of acid solution: plasma. All samples are stored frozen immediately over dry ice pending storage in a freezer set to maintain -70°C.
  • Terminal Procedures The animals were sedated with an intramuscular injection of a combination of ketamine hydrochloride and acepromazine, and then euthanized by an intravenous overdose of sodium pentobarbital, followed by exsanguination. All animals scheduled for euthanasia were food deprived overnight. Animals underwent blood and SF sample collection (terminal) for bioanalysis evaluation. The following tissues were collected starting approximately 24 hours after the last dose on Day 10:
  • FIG. 5A shows the mean levels of SBT-272 in brain (cortex), CSF, and plasma samples from cynomolgus monkieys following 10 daily s.c. administrations of 5 mg/kg SBT-272.
  • the compartment ratios of SBT-272 (plasma:CSF 6.40; braimplasma 51; and brain:CSF 328) are also shown in FIG. 5A.
  • FIG. 5B shows the concentrations of SBT- 272 in various tissues at termination of the study.
  • FIGs. 4A, 4C, 5A, and 5B demonstrate that brain drug concentration in nonhuman primate met predictions based on rodent studies and provides confidence in clinical development (FIGs. 5A-5B). The ratio of drug across the three compartments reflects good translation from rodent to nonhuman primate.
  • Biodistribution of SBT-272 in cortical and spinal cord region support clinical development for neurodegenerative diseases, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson’s disease
  • PD dementia
  • dementia with Lewy bodies dementia with Lewy bodies
  • Multiple System Atrophy Huntington’s disease
  • HTT proteinopathy Frontotemporal Lobar Degeneration (FTLD)
  • tauopathy and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
  • the safety and tolerability of single and multiple ascending doses of SBT-272 administered via subcutaneous injection were evaluated in healthy volunteers.
  • the primary objective of this study is to evaluate the safety and tolerability of single and multiple ascending doses of SBT-272 administered via subcutaneous injection in healthy volunteers.
  • the secondary objects of this study are to: (a) evaluate the plasma PK of SBT-272 in healthy volunteers following subcutaneous administration of single and multiple ascending doses; and (b) to determine an appropriate dose range for subsequence clinical evaluation.
  • the emerging SBT-272 clinical PK profile is consistent with non-clinical allometric scaling predictions.
  • SBT-272 has a consistent safety profile based on an interim data analysis.
  • SBT-272 has demonstrated in vitro and in vivo correlations in models of neurodegeneration to help establish target minimum and maximal brain concentration to achieve pharmacodynamic effect.
  • Preclinical data suggest that brain exposure necessary to drive pharmacodynamic effect might translate to humans given excellent correlation between species in steady state brain concentration at trough.
  • Clinical PK is consistent with expectations based on rat and nonhuman primate profiles. Plasma exposures observed in the Phase 1 study, at doses deemed generally safe, may result in therapeutic concentrations in the brain based on the observed relationship between plasma, CSF, and brain PK and signals efficacy in preclinical studies.
  • a range includes each individual member.
  • a group having 1-3 cells refers to groups having 1, 2, or 3 cells.
  • a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

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Abstract

The present disclosure provides methods for achieving optimal levels of bevemipretide (also known as "(R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide" or "SBT-272"), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, in brain tissue of subjects suspected of having, suffering from, or at risk for a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington's disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and α-synuclein are associated with the disease pathology.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/419,523, filed October 26, 2022, and U.S. Provisional Patent Application No. 63/419,599, filed October 26, 2022, the contents of which are incorporated herein by reference in their entireties.
TECHNICAL FIELD
[0002] The present technology relates generally to methods for achieving optimal levels of bevemipretide (also known as “(R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide” or “SBT-272”), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, in brain tissue of subjects suspected of having, suffering from, or at risk for a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
INTRODUCTION
[0003] The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the compositions and methods disclosed herein.
[0004] Neurodegenerative disease and disorders affect a subject’s activities such as balance, movement, talking, breathing and/or heart function. Neurodegenerative disease and disorders are generally incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells. In many cases, the neurodegenerative disease is often directly or indirectly attributable to the death of the subject. Typically, there are drugs available to address symptoms but all too often there are no treatments that curtail the progression or severity of the disease or disorder itself. Additionally, there are challenges associated with developing a therapeutic that can cross the blood-brain barrier and achieve optimal concentrations in brain tissue. Accordingly, there is a need to develop regimens suitable to achieve optimal brain tissue concentrations of a therapeutic in methods for treating neurodegenerative conditions such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
SUMMARY
[0005] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease or condition in a subject in need thereof, comprising dosing the subject with an effective amount of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide.
[0006] In some embodiments, the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
[0007] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered subcutaneously.
[0008] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in a single daily dose.
[0009] In some embodiments, the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight.
[0010] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. [0011] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in multiple daily doses.
[0012] In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
[0013] In some embodiments, the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
[0014] In some embodiments, the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
[0015] In some embodiments, dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM.
[0016] In some embodiments, dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
[0017] In some embodiments, dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
[0018] In some embodiments, dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
[0019] In some embodiments, dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM. [0020] In some embodiments, dosing achieves a plasma:CSF peptide ratio of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
[0021] In some embodiments, dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
[0022] In some embodiments, dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
[0023] In some aspects, the present disclosure provides a method of treating mitochondrial dysfunction in a subject in need thereof, comprising dosing the subject with an effective amount of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide.
[0024] In some embodiments, the mitochondrial dysfunction is associated with a neurodegenerative disease or condition selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
[0025] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered subcutaneously.
[0026] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in a single daily dose.
[0027] In some embodiments, the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. [0028] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
[0029] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in multiple daily doses.
[0030] In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
[0031] In some embodiments, the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
[0032] In some embodiments, the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
[0033] In some embodiments, dosing achieves a brain concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 100 nM.
[0034] In some embodiments, dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
[0035] In some embodiments, dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
[0036] In some embodiments, dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. [0037] In some embodiments, dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
[0038] In some embodiments, dosing achieves a plasma:CSF peptide ratio of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
[0039] In some embodiments, dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
[0040] In some embodiments, dosing achieves a brain:CSF ratio of“(R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
[0041] In some aspects, the present disclosure provides a method of dosing (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide in a subject in need thereof, comprising administering SBT-272 to the subject subcutaneously.
[0042] In some embodiments, the subject suffers from a neurodegenerative disease or condition, or the subject suffers from mitochondrial dysfunction.
[0043] In some embodiments, the mitochondrial dysfunction is associated with a neurodegenerative disease or condition.
[0044] In some embodiments, the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
[0045] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in a single daily dose. [0046] In some embodiments, the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight.
[0047] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
[0048] In some embodiments, (R)-2-amino-N-((S)- l-(((S)-5-amino-l -(3 -benzyl- 1,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is administered in multiple daily doses.
[0049] In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
[0050] In some embodiments, the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
[0051] In some embodiments, the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
[0052] In some embodiments, dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM.
[0053] In some embodiments, dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
[0054] In some embodiments, dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
[0055] In some embodiments, dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM.
[0056] In some embodiments, dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
[0057] In some embodiments, dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
[0058] In some embodiments, dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
[0059] In some embodiments, dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
[0060] In some aspects, the present disclosure provides the use of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide in the preparation of a medicament for treating a neurodegenerative disease or condition in a subject in need thereof, wherein the medicament is formulated for dosing a subject by subcutaneous delivery.
[0061] In some embodiments, the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
[0062] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in a single daily dose.
[0063] In some embodiments, the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. [0064] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
[0065] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in multiple daily doses.
[0066] In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
[0067] In some embodiments, the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
[0068] In some embodiments, the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
[0069] In some embodiments, dosing achieves a brain concentration of the (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 100 nM.
[0070] In some embodiments, dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
[0071] In some embodiments, dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
[0072] In some embodiments, dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. [0073] In some embodiments, dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
[0074] In some embodiments, dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
[0075] In some embodiments, dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
[0076] In some embodiments, dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
[0077] In some aspects, the present disclosure provides the use of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide in the preparation of a medicament for treating mitochondrial dysfunction in a subject in need thereof, wherein the medicament is formulated for dosing a subject by subcutaneous delivery.
[0078] In some embodiments, the mitochondrial dysfunction is associated with a neurodegenerative disease or condition.
[0079] In some embodiments, the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
[0080] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in a single daily dose.
[0081] In some embodiments, the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. [0082] In some embodiments, the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
[0083] In some embodiments, the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide is formulated to be administered in multiple daily doses.
[0084] In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight.
[0085] In some embodiments, the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses.
[0086] In some embodiments, the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days.
[0087] In some embodiments, dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM.
[0088] In some embodiments, dosing achieves a brain cortex concentration of (R)-2-amino- N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 650 nM to about 690 nM.
[0089] In some embodiments, dosing achieves a brain ISF concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 20 nM to about 30 nM.
[0090] In some embodiments, dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. [0091] In some embodiments, dosing achieves a plasma concentration of (R)-2-amino-N- ((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 10 nM to about 14 nM.
[0092] In some embodiments, dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 1.0 to about 6.5.
[0093] In some embodiments, dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 50 to about 180.
[0094] In some embodiments, dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide of about 180 to about 330.
[0095] In some embodiments, the subject of methods disclosed herein is human.
[0096] In some embodiments, the subject of uses disclosed herein is human.
[0097] In some embodiments of the methods and uses described herein, the subject with a tauopathy has been diagnosed as having Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia. In some embodiments, the subject has been diagnosed as having a primary age-related tauopathy. In some embodiments, the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy. In some embodiments, where the subject has been diagnosed as having ALS, the ALS is familial. In some embodiments, the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or TARDBP gene.
BRIEF DESCRIPTION OF THE DRAWINGS
[0098] FIG. 1A is an illustration depicting the association between SBT-272 and cardiolipin on the inner mitochondrial membrane (IMM). [0099] FIG. IB is a series of electron micrographs of mitochondria in hTDP-43 neurons treated with vehicle and treated with 100 nM SBT-272 showing engagement of SBT-272 with cardiolipin.
[0100] FIG. 2A is a chart showing the in vivo pharmacokinetic (PK) and pharmacodynamic (PD) response to SBT-272 brain exposure in rats. Rat brain SBT-272 concentrations up to 36 hours after a single dose of SBT-272 (5 mg/kg; subcutaneous (SC); n = 8 rats per time-point).
[0101] FIGs. 2B-2D: SBT-272 (5 mg/kg SC, 4 and 24 hours before injury) prevented the loss of mitochondrial respiratory control ratio (RCR) in rat brain following cerebral ischemiareperfusion injury induced via stereotactic delivery of 240 pM ET-1 (artificial cerebrospinal fluid in shame) in the piriform region. FIG. 2B is a schematic showing the experimental design. Dotted lines indicate left and right subsection of hemibrain used for RCR and PK analysis (FIG. 2B). FIG. 2C: individual respiratory control ratios (RCR) per animal (n = 8 per group) from the stroke-induced subsection of the right hemisphere. FIG. 2D: SBT-272 level in the brain homogenates from the same hemisphere after ET-1 injection. ET1 = endothelin-1, vasoconstrictive peptide (*P < 0.05, Kruskal-Wallis followed by Dunn’s test).
[0102] FIGs. 3A-3B are charts summarizing data demonstrating optimal in vitro effects between 10-100 nM SBT (FIG. 3A) and optimal in vivo effects between 10-100 nM SBT (FIG. 3B)
[0103] FIG. 4A is a chart showing rat PK profiles of SBT-272 in plasma, CSF, and brain.
[0104] FIG. 4B is a diagram showing the rotation of injection sites.
[0105] FIG. 4C is a chart showing nonhuman primate PK profiles of SBT-272 in plasma, CSF, and brain.
[0106] FIG. 5A is a chart showing the steady state PK from rodent and nonhuman primate. Rat 10 mg/kg, 5 daily doses, and nonhuman primates 5 mg/kg, 10 daily doses.
[0107] FIG. 5B is a chart showing the trough (SBT-272) at steady state after repeated dosing in various tissues.
[0108] FIGs. 6A-6B are charts illustrating the study design for the first in-human trial with SBT-272 subcutaneous injection. [0109] FIG. 7 is a chart showing interim SBT-272 interim PK data in healthy subjects, 40 mg once daily.
DETAILED DESCRIPTION
[0110] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present technology are described below in various levels of detail in order to provide a substantial understanding of the present technology. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this present technology belongs.
[OHl] In practicing the present technology, many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology and recombinant DNA are used. These techniques are well-known and are explained in, e.g., Current Protocols in Molecular Biology, Vols. I-III, Ausubel, Ed. (1997); Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989); DNA Cloning: A Practical Approach, Vols. I and II, Glover, Ed. (1985); Oligonucleotide Synthesis, Gait, Ed. (1984); Nucleic Acid Hybridization, Hames & Higgins, Eds. (1985); Transcription and Translation, Hames & Higgins, Eds. (1984); Animal Cell Culture, Freshney, Ed. (1986); Immobilized Cells and Enzymes (IRE Press, 1986); Perbal, A Practical Guide to Molecular Cloning,' the series, Meth. Enzymol., (Academic Press, Inc., 1984); Gene Transfer Vectors for Mammalian Cells, Miller & Calos, Eds. (Cold Spring Harbor Laboratory, N Y, 1987); an Meth. Enzymol., Vols. 154 and 155, Wu & Grossman, and Wu, Eds., respectively.
I. Chemical Definitions
[0112] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh Ed., inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
[0113] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are intended to comply with the standard rules of chemical valency known in the chemical arts. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example "C1-C6 alkyl" is intended to encompass, Cl, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C5, C3-C4, C4-C6, C4- C5, and C5-C6 alkyl.
[0114] Certain compounds of the present application can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms can exist, for example, because it is difficult or impossible to remove all the solvent from the compound post synthesis. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present application. Certain compounds of the present application may exist in multiple crystalline or amorphous forms. Certain compounds of the present application may exist in various tautomeric forms. Certain compounds of the present application may exist in various salt forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the present disclosure.
[0115] As used herein, the term “amino acid” includes both a naturally occurring amino acid and a non-natural amino acid. The term “amino acid,” unless otherwise indicated, includes both isolated amino acid molecules (i.e., molecules that include both, an aminoattached hydrogen and a carbonyl carbon-attached hydroxyl) and residues of amino acids (z.e., molecules in which either one or both an amino-attached hydrogen or a carbonyl carbon-attached hydroxyl are removed). The amino group can be alpha-amino group, betaamino group, etc. For example, the term “amino acid alanine” can refer either to an isolated alanine H-Ala-OH or to any one of the alanine residues H-Ala-, -Ala-OH, or -Ala-. Unless otherwise indicated, all amino acids found in the compounds described herein can be either in D or L configuration. An amino acid that is in D configuration may be written such that “D” precedes the amino acid abbreviation. For example, “D-Arg” represents arginine in the D configuration. The term “amino acid” includes salts thereof, including pharmaceutically acceptable salts. Any amino acid can be protected or unprotected. Protecting groups can be attached to an amino group (for example alpha-amino group), the backbone carboxyl group, or any functionality of the side chain. As an example, phenylalanine protected by a benzyloxycarbonyl group (Z) on the alpha-amino group would be represented as Z-Phe-OH.
[0116] With the exception of the N-terminal amino acid, all abbreviations of amino acids (for example, Phe) in this disclosure stand for the structure of — NH — C(R)(R') — CO — , wherein R and R' each is, independently, hydrogen or the side chain of an amino acid (e.g., R= benzyl and R — H for Phe). Accordingly, phenylalanine is H-Phe-OH. The designation “OH” for these amino acids, or for peptides (e.g., Lys-Val-Leu-OH) indicates that the C- terminus is the free acid. The designation “NH2” in, for example, Phe-D-Arg-Phe-Lys-NH2 indicates that the C-terminus of the protected peptide fragment is amidated. Further, certain R and R’, separately, or in combination as a ring structure, can include functional groups that require protection during the liquid phase or solid phase synthesis.
[0117] Where the amino acid has isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated as D form, for example, D-Arg. Notably, many amino acid residues are commercially available in both D- and L-form. For example, D-Arg is a commercially available D-amino acid.
[0118] A capital letter “D” used in conjunction with an abbreviation for an amino acid residue refers to the D-form of the amino acid residue.
[0119] The term “DMT” refers to 2,6-di(methyl)tyrosine e.g., 2,6-dimethyl-L-tyrosine; CAS 123715-02-6).
[0120] As used herein, the term "hydrate" refers to a compound which is associated with water. The number of the water molecules contained in a hydrate of a compound may be (or may not be) in a definite ratio to the number of the compound molecules in the hydrate.
[0121] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a therapeutically active compound that can be prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine (NEt3), trimethylamine, tripropylamine, tromethamine and the like, such as where the salt includes the protonated form of the organic base (e.g., [HNEt3]+). Salts derived from pharmaceutically acceptable inorganic acids include salts of boric, carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids (e.g., acetic, butyric, formic, propionic and trifluoroacetic acids), amino acids (e.g., aspartic and glutamic acids), aromatic carboxylic acids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenyl acetic acids), aromatic hydroxyl acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic, l-hydroxynaphthalene-2-carboxylic and 3 -hydroxynaphthal ene-2-carboxylic acids), ascorbic, dicarboxylic acids (e.g., fumaric, maleic, oxalic and succinic acids), glucuronic, mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids (e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic, isethionic, methanesulfonic, naphthalenesulfonic, naphthalene-l,5-disulfonic, naphthalene-2,6-disulfonic, p-toluenesulfonic acids (PTSA)), xinafoic acid, and the like. In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methyl sulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. In some embodiments, the salt is a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt, a maleate salt, a trifluoroacetate salt, a hydrochloride salt, or a tosylate salt. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts or exist in zwitterionic form. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present technology.
[0122] As used herein, the term "peptidomimetic" refers to a compound of Formula (II):
Figure imgf000020_0001
or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, as more fully described and/or claimed in WIPO published application: WO2019/118878 (See below for a definition of variables AA1, AA2, Rl, R2a, R2b, R3 and X). In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide (Compound I, as illustrated below as Formula I), or a pharmaceutically acceptable salt (e.g. Compound (la), illustrated below as a tris-HCl salt as Formula (la)), stereoisomer, tautomer, hydrate, and/or solvate thereof.
[0123] As used herein, the term "small molecule" refers to any organic compound that affects a biologic process with a molecular weight less than 900 daltons. It is to be understood that for purposes of this definition, the molecular mass is calculated without reference to any associated (i.e. non-covalently bonded) molecules such as salts, water or other solvent molecules. As used herein, a “small molecule peptidomimetic” is a peptidomimetic with a free-base molecular weight less than 900 daltons. An example of such a small molecule peptidomimetic is (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide (CAS# 2356106-71-1; free-base molecular weight of 607.76) or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
[0124] As used herein, the term "solvate" refers to forms of the compound that are associated with a solvent, possibly by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane(s), DMSO, THF, diethyl ether, and the like.
[0125] As used herein, the term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7t electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0126] As used herein, “SBT-272,” or “bevemipretide” refers to the peptidomimetic of formula:
Figure imgf000021_0001
(7?)-2-amino-A-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)- 1 -oxopropan-2-yl)-5-guanidinopentanamide
[0127] “ SBT-272” or “bevemipretide” are also referred to in scientific literature as CAS# 2356106-71-1 (in its free base form). Bevemipretide can be administered as the pharmaceutically acceptable salt, such as a tris-HCl salt (CAS# 2589640-11-7) having the formula:
Figure imgf000022_0001
Whenever the term, “SBT-272,” “bevemipretide,” or “(R)-2-amino-N-((S)-l-(((S)-5-amino- l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide” is used herein, its use is intended to also encompass pharmaceutically acceptable salts thereof, unless the context of its use is clearly contradictory to such an interpretation.
II. Other Definitions
[0128] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the technology are described below in various levels of detail in order to provide a substantial understanding of the present application. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs.
[0129] As used in this specification and the appended embodiments, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like.
[0130] As used herein, “administering” or the “administration” of an agent (i.e. therapeutic agent) or compound/drug product (including a composition) to a subject includes any route of introducing or delivering to a subject a compound/drug product to perform its intended function. Administration may be carried out by any suitable route, such as oral administration. Administration can be carried out subcutaneously. Administration can be carried out intravenously. Administration can be carried out intraocularly. Administration can be carried out systemically. Alternatively, administration may be carried out topically, intranasally, intraperitoneally, intradermally, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly. Administration includes self-administration, the administration by another or administration by use of a device (e.g., an infusion pump).
[0131] As used herein, to “ameliorate” or “ameliorating” a disease, disorder or condition refers to results that, in a statistical sample or specific subject, make the occurrence of the disease, disorder or condition (or a sign, symptom or condition thereof) better or more tolerable in a sample or subject administered a therapeutic agent relative to a control sample or subject.
[0132] As used herein the terms “carrier” or “pharmaceutically acceptable carrier” refer to a diluent, adjuvant, excipient, or vehicle with which a compound/drug product/composition (including a medicament) is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, oils and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, silica particles (nanoparticles or microparticles) urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington ’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.
[0133] As used herein, the phrase “delaying the onset of’ refers to, in a statistical sample, postponing, hindering the occurrence of a disease, disorder or condition, or causing one or more signs, symptoms or conditions of a disease, disorder or condition to occur more slowly than normal, in a sample or subject administered a therapeutic agent relative to a control sample or subject.
[0134] As used herein, the term “effective amount” refers to a quantity of a compound/composition/drug product sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g, an amount that treats, prevents, inhibits, ameliorates, or delays the onset of the disease, disorder or condition, or the physiological signs, symptoms or conditions of the disease or disorder. In the context of therapeutic or prophylactic applications, in some embodiments, the amount of a compound/composition/drug product administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. In some embodiments, it will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compounds/compositions/drug products can also be administered in combination with one or more additional therapeutic compounds/agents (a so called “co-administration” where, for example, the additional therapeutic agent could be administered simultaneously, sequentially or by separate administration).
[0135] As used herein, “inhibit” or “inhibiting” refers to the reduction in a sign, symptom or condition (e.g. risk factor) associated with a disease, disorder or condition associated with a Huntington’s disease and/or a HTT proteinopathy by an objectively measurable amount or degree compared to a control. In one embodiment, inhibit or inhibiting refers to the reduction by at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction by at least 5 percent compared to control (or control subject). In various individual embodiments, inhibit or inhibiting refers to a reduction by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent compared to a control (or control subject).
[0136] As used herein, “prevention” or “preventing” of a disease, disorder, or condition refers to results that, in a statistical sample, exhibit a reduction in the occurrence of the disease, disorder, or condition in a sample or subject administered a therapeutic agent relative to a control sample or subject, or exhibit a delay in the onset of one or more symptoms of the disease, disorder, or condition relative to the control sample or subject. Such prevention is sometimes referred to as a prophylactic treatment.
[0137] As used herein, the term “separate” therapeutic use refers to an administration of at least two active ingredients (e.g. therapeutic agents) at the same time or at substantially the same time by different routes.
[0138] As used herein, the term “sequential” therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this definition. [0139] As used herein, the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
[0140] As used herein, a “subject” refers to a living animal. In various embodiments, a subject is a mammal. In various embodiments, a subject is a non-human mammal, including, without limitation, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, minipig, horse, cow, or non-human primate. In certain embodiments, the subject is a human.
[0141] It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described herein are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
[0142] As used herein, a “synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of the agents. For example, lower doses of one or more agents may be used in treating Huntington’s disease and/or a HTT proteinopathy.
[0143] As used herein, the terms “treating” or “treatment” refer to therapeutic treatment, wherein the object is to reduce, alleviate or slow down (lessen) a pre-existing disease or disorder, or its related signs, symptoms or conditions. By way of example, but not by way of limitation, a subject is successfully “treated” for a disease if, after receiving an effective amount of the compound/composition/drug product or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, the subject shows observable and/or measurable reduction in or absence of one or more signs, symptoms or conditions associated with the disease, disorder or condition. It is also to be appreciated that the various modes of treatment of medical conditions as described are intended to mean “substantial,” which includes total alleviation of conditions, signs or symptoms of the disease or disorder, as well as “partial,” where some biologically or medically relevant result is achieved. III. Peptidomimetics
[0144] In some embodiments, the present disclosure provides a peptidomimetic compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof:
Figure imgf000026_0001
Figure imgf000027_0001
R2b is H or Me;
R3 and R4 are independently selected from H and (Ci-Ce)alkyl;
R5 and R6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R5 and R6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl; R7 is selected from H, (Ci-Ce)alkyl, cycloalkyl, and aryl;
R8 and R9 are independently selected from H, (Ci-Ce)alkyl, cycloalkyl, and aryl; or R8 and R9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl; n is 1, 2, or 3;
Figure imgf000028_0001
* denotes the point of attachment of X to R1.
[0145] In some embodiments,
Figure imgf000028_0002
some embodiments, AAi is
Figure imgf000028_0003
, some embodiments,
Figure imgf000029_0001
, some embodiments,
Figure imgf000029_0002
[0146] In some embodiments,
Figure imgf000029_0003
some embodiments, AA2 is
Figure imgf000029_0006
, R1
Figure imgf000029_0004
Figure imgf000029_0005
, some embodiments,
Figure imgf000030_0001
In some embodiments,
Figure imgf000030_0002
Figure imgf000030_0003
In some embodiments,
Figure imgf000030_0004
R9
[0148] In some embodiments, R2a is
Figure imgf000030_0005
. , . In some embodiments,
Figure imgf000030_0007
In some embodiments,
Figure imgf000030_0006
Figure imgf000030_0008
[0149] In some embodiments, R2b is H. In some embodiments, R2b is methyl.
[0150] In some embodiments, R3 is H. In some embodiments, R3 is (Ci-Ce)alkyl. In some embodiments, R3 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. [0151] In some embodiments, R4 is H. In some embodiments, R4 is (Ci-Ce)alkyl. In some embodiments, R4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl.
[0152] In some embodiments, R3 and R4 are the same. In some embodiments, R3 and R4 are different.
[0153] In some embodiments, R5 is H. In some embodiments, R5 is methyl.
[0154] In some embodiments, R6 is H. In some embodiments, R6 is methyl.
[0155] In some embodiments, R5 and R6 are the same. In some embodiments, R5 and R6 are different. In some embodiments, both R5 and R6 are H.
[0156] In some embodiments, R5 and R6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.
[0157] In some embodiments, R7 is H. In some embodiments, R7 is (Ci-Ce)alkyl. In some embodiments, R7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R7 is methyl. In some embodiments, R7 is cycloalkyl. In some embodiments, R7 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R7 is aryl. In some embodiments, R7 is phenyl.
[0158] In some embodiments, R8 is H. In some embodiments, R8 is (Ci-Ce)alkyl. In some embodiments, R8 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R8 is methyl. In some embodiments, R8 is cycloalkyl. In some embodiments, R8 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R8 is aryl. In some embodiments, R8 is phenyl.
[0159] In some embodiments, R9 is H. In some embodiments, R9 is (Ci-Ce)alkyl. In some embodiments, R9 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R9 is methyl. In some embodiments, R9 is cycloalkyl. In some embodiments, R9 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R9 is aryl. In some embodiments, R9 is phenyl. [0160] In some embodiments, R8 and R9 are the same. In some embodiments, R8 and R9 are different. In some embodiments, both R8 and R9 are H. In some embodiments, R8 and R9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.
[0161] In some embodiments,
Figure imgf000032_0002
In some embodiments, X is
Figure imgf000032_0001
In some embodiments, X is
Figure imgf000032_0003
In some embodiments, X is
Figure imgf000032_0004
[0162] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
[0163] In some embodiments, the peptidomimetic is a small molecule peptidomimetic. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or Formula la. The peptidomimetics disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms can exist, for example, because it is difficult or impossible to remove all the solvent from the peptidomimetic post synthesis. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present application. Certain peptidomimetics of the present application may exist in multiple crystalline or amorphous forms. Certain peptidomimetics of the present application may exist in various tautomeric forms. Certain peptidomimetics of the present application may exist in various salt forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the present application. The chiral centers of the peptidomimetic disclosed herein may be in either the R- or S- configuration as discussed in more detail below. IV. Chiral/Stereochemistry Considerations
[0164] Peptidomimetics described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high- pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The peptidomimetics additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[0165] As used herein, a pure enantiomeric peptidomimetic is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. With respect to amino acids (which are more commonly described in terms of “D” and “L” enantiomer, it is to be understood that for a “D”-amino acid the configuration is “R” and for an “L”-amino acid, the configuration is “S”. In some embodiments, 'substantially free', refers to: (i) an aliquot of an "R" form compound that contains less than 2% "S" form; or (ii) an aliquot of an "S" form compound that contains less than 2% "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 90% by weight, more than 91 % by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
[0166] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition or medicament comprising enantiomerically pure "R" form compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure "R" form compound. In certain embodiments, the enantiomerically pure "R" form compound in such compositions can, for example, comprise, at least about 95% by weight "R" form compound and at most about 5% by weight "S" form compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure "S" form compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure "S" form compound. In certain embodiments, the enantiomerically pure "S" form compound in such compositions can, for example, comprise, at least about 95% by weight "S" form compound and at most about 5% by weight "R" form compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
V. Synthesis of Peptidomimetics
[0167] The peptidomimetic compounds described herein may be prepared, in whole or in part using well known peptide synthesis methods, such as conventional liquid-phase (also known as solution-phase) peptide synthesis or solid-phase peptide synthesis, or by peptide synthesis by means of an automated peptide synthesizer (Kelley et al., Genetics Engineering Principles and Methods, Setlow, J. K. eds., Plenum Press NY. (1990) Vol. 12, pp.l to 19; Stewart et al., Solid-Phase Peptide Synthesis (1989) W. H.; Houghten, Proc. Natl. Acad. Sci. USA (1985) 82: p.5132). The peptidomimetic thus produced can be collected or purified by a routine method, for example, chromatography, such as gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reverse phase column chromatography, and HPLC, ammonium sulfate fractionation, ultrafiltration, and immunoadsorption.
[0168] In a solid-phase peptide synthesis, peptides are typically synthesized from the carbonyl group side (C -terminus) to amino group side (N-terminus) of the amino acid chain. In certain embodiments, an amino-protected amino acid is covalently bound to a solid support material through the carboxyl group of the amino acid, typically via an ester or amido bond and optionally via a linking group. The amino group may be deprotected and reacted with (z.e., “coupled” with) the carbonyl group of a second amino-protected amino acid using a coupling reagent, yielding a dipeptide bound to a solid support. After coupling, the resin is optionally treated with a capping reagent to thereby cap (render inactive towards subsequent coupling steps) any unreacted amine groups. These steps (z.e., deprotection, coupling and optionally capping) may be repeated to form the desired peptide chain. Once the desired peptide chain is complete, the peptide may be cleaved from the solid support. The peptidomimetics (or peptide portions thereof) can also be prepared in solution.
[0169] In certain embodiments, the protecting groups used on the amino groups of the amino acid residues (of peptides and/or peptidomimetics) include 9- fluorenylmethyloxycarbonyl group (Fmoc) and t-butyloxycarbonyl (Boc). The Fmoc group is removed from the amino terminus with base while the Boc group is removed with acid. In alternative embodiments, the amino protecting group may be formyl, acrylyl (Acr), benzoyl (Bz), acetyl (Ac), trifluoroacetyl, substituted or unsubstituted groups of aralkyloxycarbonyl type, such as the benzyloxycarbonyl (Z), p-chlorobenzyloxycarbonyl, p- bromobenzyloxy carbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2(p- biphenylyl)isopropyloxycarbonyl, 2-(3,5- dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphonoethyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group (Fmoc), substituted or unsubstituted groups of alkyloxycarbonyl type, such as the tertbutyloxycarbonyl (BOC), tert-amyloxycarbonyl, diisopropylmethyloxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, 2 methylsulphonylethyloxycarbonyl or 2,2,2-trichloroethyloxycarbonyl group, groups of cycloalkyloxycarbonyl type, such as the cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, adamantyloxycarbonyl or isobornyloxycarbonyl group, and groups containing a hetero atom, such as the benzenesulphonyl, p-toluenesulphonyl, mesitylenesulphonyl, methoxytrimethylphenylsulphonyl, 2-nitrobenzenesulfonyl, 2-nitrobenzenesulfenyl, 4- nitrobenzenesulfonyl or 4-nitrobenzenesulfenyl group.
[0170] Many amino acids bear reactive functional groups in the side chain. In certain embodiments, such functional groups are protected in order to prevent the functional groups from reacting with the incoming amino acid. The protecting groups used with these functional groups must be stable to the conditions of peptide and/or peptidomimetic synthesis, but may be removed before, after, or concomitantly with cleavage of the peptide from the solid support (if support bound) or upon final deprotection in the case of solutionphase synthesis. Further reference is also made to: Isidro-Llobet, A., Alvarez, M., Albericio, F., “Amino Acid-Protecting Groups”; Chem. Rev., 109: 2455-2504 (2009) as a comprehensive review of protecting groups commonly used in peptide synthesis (which protection groups can also be used in peptidomimetic synthesis where the peptidomimetic comprises functional groups found in peptides).
[0171] In certain embodiments, the solid support material used in the solid-phase peptide synthesis method is a gel-type support such as polystyrene, polyacrylamide, or polyethylene glycol. Alternatively, materials such as controlled-pore glass, cellulose fibers, or polystyrene may be functionalized at their surface to provide a solid support for peptide synthesis.
[0172] Coupling reagents that may be used in the solid-phase (or solution-phase) peptide synthesis described herein are typically carbodiimide reagents. Examples of carbodiimide reagents include, but are not limited to, N,N’ -di cyclohexylcarbodiimide (DCC), l-(3- dimethylaminopropyl)-3 -ethylcarbodiimide (EDC) and its HC1 salt (EDC HC1), N- cy cl ohexyl-N’ -isopropylcarbodiimide (CIC), N,N’ -diisopropylcarbodiimide (DIC), N-tert- butyl-N’ -methylcarbodiimide (BMC), N-tert-butyl-N’-ethylcarbodiimide (BEC), bis[[4-(2,2- dimethyl-l,3-dioxolyl)]-methyl]carbodiimide (BDDC), and N,N-dicyclopentylcarbodiimide. DCC is a preferred coupling reagent. Other coupling agents include HATU and HBTU, generally used in combination with an organic base such as DIEA and a hindered pyridine- type base such as lutidine or collidine.
[0173] In some embodiments, the amino acids can be activated toward coupling to a peptide or peptidomimetic by forming N-carboxyanhydrides as described in Fuller et al., Urethane-Protected a-Amino Acid N-Carboxyanhydrides and Peptide Synthesis, Biopolymers (Peptide Science), Vol. 40, 183-205 (1996) and WO2018/034901.
[0174] Methods for preparation of representative small molecule peptidomimetics such as Compound I and Compound (la) can be found WO2019/118878, incorporated herein by reference. More specifically, the synthesis of the Compound (la) is specifically described in WO2019/118878 with respect to the synthesis of Compound 7a as described therein. Many other similar peptidomimetics were prepared as described therein - therefore demonstrating the feasibility and versatility of such methodologies to produce many different small molecule peptidomimetics.
VI. Pharmaceutical Compositions, Routes of Administration, and Dosing
[0175] The small molecule peptidomimetics disclosed herein can be used, alone or in combination, with other therapeutically active ingredients to address the needs of subjects suffering from a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology. In some embodiments, the subject with a tauopathy has been diagnosed as having Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia. In some embodiments, the subject has been diagnosed as having a primary age-related tauopathy. In some embodiments, the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy. In some embodiments, where the subject has been diagnosed as having ALS, the ALS is familial. In some embodiments, the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or TARDBP gene.
[0176] In order to be administered to a subject in need thereof, the small molecule peptidomimetic will generally need to be formulated for the suitable route of administration. The formulated product can be considered a composition or medicament comprising the small molecule peptidomimetic and optionally one or more additional active therapeutic agents.
[0177] In certain embodiments, a pharmaceutical composition of the present application may further comprise at least one additional therapeutic agent other than a small molecule peptidomimetic (e.g., an additional therapeutic agent for use in a combination therapy). The at least one additional therapeutic agent can be an agent useful in the treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology. Thus, in some embodiments, pharmaceutical compositions of the present application can be prepared, for example, by combining one or more compounds of the present application (e.g., a small molecule peptidomimetic) with a pharmaceutically acceptable carrier and, optionally, one or more additional therapeutical agents.
[0178] Pharmaceutical compositions of the present application may contain an effective amount of a therapeutic compound/agent (or compounds/agents) as described herein and may optionally be disbursed (e.g., dissolved, suspended or otherwise) in a pharmaceutically acceptable carrier. The components of the pharmaceutical composition(s) may also be capable of being commingled with the compounds of the present application, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical efficiency.
[0179] As stated above, an “effective amount” refers to any amount of the active compound (or compounds; alone or as formulated) that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic (z.e., preventative) or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular condition or disease of a particular subject. The effective amount for any particular indication can vary depending on such factors as the disease, disorder or condition being treated, the particular compound or compounds being administered, the size of the subject, or the severity of the disease, disorder or condition. The effective amount may be determined during pre-clinical trials and/or clinical trials by methods familiar to physicians and clinicians. One of ordinary skill in the art can empirically determine the effective amount of a particular compound and/or other therapeutic agent(s) without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. A dose may be administered by oneself, by another or by way of a device (e.g., a pump).
[0180] For any compound described herein the therapeutically effective amount can, for example, be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
[0181] Compounds (alone or as formulated in a pharmaceutical composition/medicament) for use in therapy or prevention can be tested in suitable animal model systems. Suitable animal model systems include, but are not limited to, rats, mice, chicken, cows, monkeys, rabbits, pigs, minipigs and the like, prior to testing in human subjects. In vivo testing, any of the animal model system known in the art can be used prior to administration to human subjects. In some embodiments, dosing can be tested directly in humans.
[0182] Dosage, toxicity and therapeutic efficacy of any therapeutic compounds/agents, compositions (e.g., formulations or medicaments), other therapeutic agents, or mixtures thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are advantageous. While compounds that exhibit toxic side effects may be used, in such cases it may be prudent to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
[0183] In some embodiments, an effective amount of a therapeutic compound/agent disclosed herein sufficient for achieving a therapeutic or prophylactic effect, can range from about 0.000001 mg per kilogram body weight per day to about 10,000 mg per kilogram body weight per day. Suitably, the dosage ranges are from about 0.0001 mg per kilogram body weight per day to about 100 mg per kilogram body weight per day. For example dosages can be 1 mg/kg body weight or 100 mg/kg body weight every day, every two days or every three days or within the range of 1-100 mg/kg every week, every two weeks or every three weeks. In some embodiments, a single dosage of a therapeutic compound/agent disclosed herein ranges from 0.001-10,000 micrograms per kg body weight. In some embodiments, a therapeutic compound/agent disclosed herein dissolved or suspended in a carrier range from 0.2 to 2000 micrograms per delivered milliliter. In some embodiments, the dose regimen meets pharmacokinetic target concentrations in target tissues to achieve a desired therapeutic outcome.
[0184] An exemplary treatment regime can entail administration once per day, twice per day, thrice per day, once a week, or once a month. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, or until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regimen.
[0185] In some embodiments, an effective amount of a therapeutic compound/agent disclosed herein (e.g., SBT-272) may be administered in a single daily dose. In some embodiments, the single daily dose comprises about 0.1 mg/kg to about 10 mg/kg of body weight, about 0.1 mg/kg of body weight to about 0.9 mg/kg of body weight, about 0.1 mg/kg of body weight to about 0.3 mg/kg of body weight, about 0.3 mg/kg of body weight to about 0.6 mg/kg of body weight, about 0.6 mg/kg of body weight to about 1.0 mg/kg of body weight, about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight. In some embodiments, a single daily dose comprises about 1 mg to about 60 mg. In some embodiments, a single daily dose comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or about 18 mg to about 48 mg. In some embodiments, the single daily dose comprises ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. In some embodiments, the SBT-272 is administered in multiple daily doses. In some embodiments, the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight. In some embodiments, the multiple daily doses comprise, 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. In some embodiments, the multiple daily doses comprise ascending doses of 20 mg once daily for 7 days, 40 mg once daily for 7 days, and 60 mg once daily for 7 days. In some embodiments, dosing SBT-272 achieves a brain concentration of the peptide of between about 10 nM and about 100 nM. In some embodiments, dosing achieves a brain cortex SBT-272 concentration of about 650 nM to about 690 nM. In some embodiments, dosing achieves a brain ISF SBT-272 concentration of about 20 nM to about 30 nM. In some embodiments, dosing achieves a cerebral spinal fluid (CSF) SBT-272 concentration of about 2 nM to about 12 nM. In some embodiments, dosing achieves a plasma SBT-272 concentration of about 10 nM to about 14 nM. In some embodiments, dosing achieves a SBT-272 plasma:CSF ratio of between about 1.0 and about 6.5. In some embodiments, dosing achieves a SBT-272 braimplasma ratio of between about 50 and about 180. In some embodiments, dosing achieves a SBT-272 brain:CSF ratio of between about 180 and about 330.
[0186] In some embodiments, a therapeutically effective amount of a therapeutic compound/agent disclosed herein may be defined as a concentration of compound existing at the target tissue of 10'12 to 10'4 molar, e.g., approximately 10'7 molar. This concentration may be delivered by systemic doses of 0.001 to 100 mg/kg or equivalent dose by body surface area. The schedule of doses would be optimized to maintain the therapeutic concentration at the target tissue, such as by single daily or weekly administration, but also including continuous administration (e.g., oral, systemic, topical, subcutaneous, intra-nasal, parenteral infusion or transdermal application).
[0187] In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 0.01 pg/kg/day to 80 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 0.01 pg/kg/day to 100 pg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 0.1 pg/kg/day to 10 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 10 pg/kg/day to 2 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 500 pg/kg/day to 5 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 1 mg/kg/day to 100 mg/kg/day. In some embodiments, intravenous or subcutaneous administration of a compound (alone or as formulated) may typically be from 1 mg/kg/day to 50 mg/kg/day.
[0188] Generally, daily oral doses of a compound (alone or as formulated) will be, for human subjects, from about 0.01 micrograms/kg per day to 250 milligrams/kg per day. In some embodiments, daily oral doses of a compound (alone or as formulated) will be, for human subjects, from about 1 milligrams/kg per day to 100 milligrams/kg per day or from about 10 milligrams/kg per day to 75 milligrams/kg per day or It is expected that oral doses of a compound (alone or as formulated) in the range of 0.1 to 50 milligrams/kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.
[0189] For use in therapy, an effective amount of the compound (alone or as formulated) can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmical, intrathecal, intracerebroventricular, iontophoretical, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, the administration by another and administration by a device (e.g., a pump).
[0190] A therapeutic compound/agent disclosed herein can be delivered to the subject in a formulation or medicament (z.e., a pharmaceutical composition). Formulations and medicaments can be prepared by, for example, dissolving or suspending a therapeutic compound/agent disclosed herein in water, a pharmaceutically acceptable carrier, salt, (e.g., NaCl or sodium phosphate), buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutically acceptable ingredients.
[0191] The pharmaceutical compositions (e.g., a formulation or medicament) can include a carrier (e.g., a pharmaceutically acceptable carrier), which can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation. In many cases, it will be advantageous to include isotonic agents, for example, sugars (e.g., trehalose), polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
[0192] Solutions or suspensions (e.g., a formulation or medicament) used for parenteral, intradermal, subcutaneous or intraocular application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. For convenience of the patient or treating physician, the dosing formulation can be provided alone or in a kit containing all necessary equipment (e.g., vials of drug, vials of diluent, syringes and needles) for a treatment course (e.g., 1, 2, 3, 4, 5, 6, 7 days or more of treatment).
[0193] The therapeutic compounds/agents or pharmaceutical compositions, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion (for example by IV injection or via a pump to meter the administration over a defined time). Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0194] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
[0195] For intravenous and other parenteral routes of administration, a compound can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.
[0196] Pharmaceutical compositions (e.g., a formulation or medicament) suitable for injection can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). A composition for administration by injection will generally be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and may be preserved against the contaminating action of microorganisms such as bacteria and fungi.
[0197] Sterile injectable solutions (e.g., a formulation or medicament) can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation include vacuum drying and freeze drying, which can yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
[0198] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or corn starch; a lubricant such as magnesium stearate or sterates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[0199] Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
[0200] Also specifically contemplated are oral dosage forms of the above that may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the therapeutic agent(s), ingredient(s), and/or excipient(s), where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the therapeutic agent(s), ingredient(s), and/or excipient(s) and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-1, 3-dioxolane and poly-1, 3, 6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol (PEG) moieties of various molecular weights are suitable.
[0201] For the formulation of the therapeutic agent(s), ingredient(s), and/or excipient(s), the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the present application (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
[0202] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.
[0203] The therapeutic compound/agent or pharmaceutical composition can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1-2 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic compound/agent or pharmaceutical composition could be prepared by compression.
[0204] Colorants and flavoring agents may all be included. For example, the compound or pharmaceutical composition of the present application (or derivative) may be formulated and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
[0205] One may dilute or increase the volume of the therapeutic compound/agent or pharmaceutical composition with an inert material. These diluents could include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress® and Avicel®.
[0206] Disintegrants may be included in the formulation of the therapeutic compound/agent or composition into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, karaya gum or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
[0207] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
[0208] An anti -frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (PEG) of various molecular weights, Carbowax™ 4000 and 6000.
[0209] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
[0210] To aid dissolution of the therapeutic compound/agent or composition (e.g. medicament) into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the present application or derivative either alone or as a mixture in different ratios.
[0211] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
[0212] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[0213] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Solutions, gels, ointments, creams or suspensions may be administered topically. The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[0214] For administration by inhalation, compounds or compositions (e.g. medicament) for use according to the present application may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, the formulation, medicament and/or other therapeutic compound/agent can be delivered in the form of an aerosol spray from a pressurized container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Pat. No. 6,468,798. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic compound/agent and a suitable powder base such as lactose or starch. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0215] Nasal delivery of a therapeutic compound/agent or pharmaceutical composition of the present application is also contemplated. Nasal delivery allows the passage of a therapeutic compound/agent or pharmaceutical composition to the blood stream directly after administering the therapeutic compound/agent or pharmaceutical composition to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.
[0216] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In some embodiments, the metered dose is delivered by drawing the pharmaceutical composition of the present application solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the therapeutic compound/agent or pharmaceutical composition. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.
[0217] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the therapeutic compound/agent or pharmaceutical composition.
[0218] Also contemplated herein is pulmonary delivery of the compounds disclosed herein. The compound or pharmaceutical composition is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., IntJ Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5): 143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206- 212 (1989) (al -antitrypsin); Smith et al., 1989, J Clin Invest 84: 1145-1146 (a- 1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.
[0219] Contemplated for use in the practice of this technology are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
[0220] Some specific examples of commercially available devices suitable for the practice of this technology are the Ultravent™ nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II® nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin® metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler® powder inhaler, manufactured by Fisons Corp., Bedford, Mass.
[0221] All such devices require the use of formulations suitable for the dispensing of the compound(s)/therapeutic agent(s). Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the present application may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
[0222] Formulations suitable for use with a nebulizer, either jet or ultrasonic, can, for example, comprise a compound/therapeutic agent of the present application (or derivative) dissolved in water at a concentration of about 0.01 to 50 mg of biologically active compound per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the present application caused by atomization of the solution in forming the aerosol.
[0223] Formulations for use with a metered-dose inhaler device may generally comprise a finely divided powder containing the compound of the present application (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including tri chi orofluorom ethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1, 1,2- tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
[0224] Formulations for dispensing from a powder inhaler device may comprise a finely divided dry powder containing compound of the present application (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound(s)/therapeutic agent(s) of the present application (or derivative) can advantageously be prepared in particulate or nanoparticulate form with an average particle size of less than 10 micrometers (pm), most preferably 0.5 to 5 pm, for most effective delivery to the deep lung.
[0225] For ophthalmic or intraocular indications, any suitable mode of delivering the therapeutic compounds/agents or pharmaceutical compositions to the eye or regions near the eye can be used. For ophthalmic formulations generally, see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N.Y. (1993) and also Havener, W.
H., Ocular Pharmacology, C.V. Mosby Co., St. Louis (1983). Nonlimiting examples of pharmaceutical compositions suitable for administration in or near the eye include, but are not limited to, ocular inserts, minitablets, and topical formulations such as eye drops, ointments, and in situ gels. In one embodiment, a contact lens is coated with a pharmaceutical composition comprising a therapeutic compound/agent disclosed herein. In some embodiments, a single dose can comprise from between 0.1 ng to 5000 pg, 1 ng to 500 pg, or 10 ng to 100 pg of the therapeutic compounds/agents or pharmaceutical compositions administered to the eye.
[0226] Eye drops can comprise a sterile liquid formulation that can be administered directly to the eye. In some embodiments, eye drops comprise at least one therapeutic compound/agent disclosed herein and may further comprise one or more preservatives. In some embodiments, the optimum pH for eye drops equals that of tear fluid and is about 7.4. For eye drops, the therapeutic compound/agent can be present in the drop solution from about 0.1% to about 5% (w/v or v/v depending on the physical nature (i.e. solid or liquid) of the active ingredient). In some embodiments, the therapeutic compound/agent can be present in the drop solution from about 1% to about 3% (w/v or v/v, as appropriate).
[0227] In situ gels are viscous liquids, showing the ability to undergo sol-to-gel transitions when influenced by external factors, such as appropriate pH, temperature, and the presence of electrolytes. This property causes slowing of drug drainage from the eyeball surface and increase of the active ingredient bioavailability. Polymers commonly used in in situ gel formulations include, but are not limited to, gellan gum, poloxamer, silicone containing formulations, silica-based formulations and cellulose acetate phthalate. In some embodiments, the therapeutic compound/agent is formulated into an in-situ gel (as the pharmaceutical composition/medicament).
[0228] For topical ophthalmic administration, therapeutic compound/agent or pharmaceutical composition may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Ointments are semisolid dosage forms for external use such as topical use for the eye or skin. In some embodiments, ointments comprise a solid or semisolid hydrocarbon base of melting or softening point close to human core temperature. In some embodiments, an ointment applied to the eye decomposes into small drops, which stay for a longer time period in conjunctival sac, thus increasing bioavailability.
[0229] Ocular inserts are solid or semisolid dosage forms without disadvantages of traditional ophthalmic drug forms. They are less susceptible to defense mechanisms like outflow through nasolacrimal duct, show the ability to stay in conjunctival sac for a longer period, and are more stable than conventional dosage forms. They also offer advantages such as accurate dosing of one or more therapeutic compounds/agents, slow release of one or more therapeutic compounds/agents with constant speed and limiting of one or more therapeutic compounds ’/agents’ systemic absorption. In some embodiments, an ocular insert comprises one or more therapeutic compounds/agents as disclosed herein and one or more polymeric materials. The polymeric materials can include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the aforementioned polymers. An ocular insert can comprise silica. An ocular insert can comprise liposomes, nanoparticles or microparticles of degradable or biodegradable polymer (as described in more detail below).
[0230] Minitablets are biodegradable, solid drug forms, that transit into gels after application to the conjunctival sac, thereby extending the period of contact between active ingredient (i.e. the therapeutic compounds/agents disclosed herein) and the eyeball surface, which in turn increases a therapeutic compounds’/agents’ bioavailability. The advantages of minitablets include easy application to conjunctival sac, resistance to defense mechanisms like tearing or outflow through nasolacrimal duct, longer contact with the cornea caused by presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation in the place of application due to the swelling of the outer carrier layers. Minitablets can comprise one or more of the therapeutic compounds/agents disclosed herein and one or more polymers. Nonlimiting examples of polymers suitable for use in in a minitablet formulation include cellulose derivatives, like hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), Carbopol® or carbomer, chitosan, and starch (e.g., drum-dried waxy maize starch). In some embodiments, minitablets further comprise one or more excipients. Nonlimiting examples of excipients include mannitol and magnesium stearate.
[0231] The ophthalmic or intraocular formulations and medicaments may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenyl ethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like.
[0232] In some embodiments, the viscosity of the ocular formulation comprising one or more therapeutic compounds/agents is increased to improve contact with the cornea and bioavailability in the eye. Viscosity can be increased by the addition of hydrophilic polymers of high molecular weight which do not diffuse through biological membranes and which form three-dimensional networks in the water. Nonlimiting examples of such polymers include polyvinyl alcohol, poloxamers, hyaluronic acid, carbomers, and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.
[0233] In addition to the formulations described above, a therapeutic compound/agent disclosed herein may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0234] In some embodiments, the therapeutic agent(s) is/are administered as a depot formulation wherein the active therapeutic agent(s) is/are encapsulated by, or disposed within, silica-based microparticles. In some embodiments, the ocular formulation can be injected into the eye, for example as a sol-gel (e.g., a silica sol-gel). In some embodiments, the ocular formulation is a depot formulation such as a controlled release formulation (see below). Such controlled release formulation may comprise particles, such as microparticles or nanoparticles.
[0235] The pharmaceutical compositions also may comprise suitable solid or gel-phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, silica/silicone and polymers such as polyethylene glycols.
[0236] Suitable liquid or solid pharmaceutical preparation forms can, for example, be aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions can be suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527-33 (1990).
[0237] The therapeutic agent(s), including specifically but not limited to a therapeutic compound/agent disclosed herein, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the therapeutic compound/agent or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic compound(s)/agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic compound(s)/agent(s) also may be dispersed throughout the particles. The therapeutic compound(s)/agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic compound(s)/agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the therapeutic compound(s)/agent(s) in a solution or in a semi-solid state. The particles may be of virtually any shape.
[0238] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic compound(s)/agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, polyethylene glycols (PEGs), polyvinylalcohols (PVAs), poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly-lactic acid (PLA), poly(lactic -co- glycolic) acid (PLGA), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly(£-caprolactone) or mixtures of two or more of the foregoing.
[0239] Therapeutic compounds/agents or other therapeutic agent(s) or mixtures thereof can be formulated in a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome, a phospholipid bilayer vehicle. In one embodiment, therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof can be encapsulated in a liposome while maintaining integrity of the therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof. One skilled in the art would appreciate that there are a variety of methods to prepare liposomes. (See Lichtenberg, et al., Methods Biochem. Anal., 33:337-462 (1988); Anselem, et al., Liposome Technology, CRC Press (1993)). Liposomal formulations can delay clearance and increase cellular uptake (See Reddy, Ann. Pharmacother ., 34(7-8):915-923 (2000)). For example, an active agent can also be loaded into a particle prepared from pharmaceutically acceptable ingredients including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.
[0240] The carrier can also be a polymer, e.g., a biodegradable, biocompatible polymer matrix. In one embodiment, the therapeutic compound or other therapeutic agent or mixtures thereof can be embedded in the polymer matrix, while maintaining integrity of the composition. The polymer can be a microparticle or nanoparticle that encapsulates the therapeutic agent or agents. The polymer may be natural, such as polypeptides, proteins or polysaccharides, or synthetic, such as poly a-hydroxy acids. Examples include carriers made of, e.g., collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharide, fibrin, gelatin, and combinations thereof. In some embodiments, the polymer is poly-lactic acid (PLA), poly lactic/glycolic acid (PLGA) or a mixture thereof. The polymeric matrices can be prepared and isolated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can lead to prolonged duration of therapeutic effect. (See Reddy, Ann. Pharmacother 34(7-8):915-923 (2000)). A polymer formulation for human growth hormone (hGH) has been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).
[0241] Examples of polymer microsphere sustained release formulations are described in PCT publication WO 99/15154 (Tracy, et al.), U.S. Pat. Nos. 5,674,534 and 5,716,644 (both to Zale, et ah)' , PCT publication WO 96/40073 (Zale, et ah)' , and PCT publication WO 00/38651 (Shah, et al.). U.S. Pat. Nos. 5,674,534 and 5,716,644 and PCT publication WO 96/40073 describe a polymeric matrix containing particles of erythropoietin that are stabilized against aggregation with a salt.
[0242] In some embodiments, the nanoparticles or microparticles can be silica-based or silane-based (See for example: W02002/080977 entitled: “Biodegradable carrier and method for preparation thereof’).
[0243] In some embodiments, the therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof are prepared with carriers that will protect the therapeutic compound(s)/agent(s) or other therapeutic agent(s) or mixtures thereof against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using known techniques. The materials can also be obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to specific cells with monoclonal antibodies to cell-specific antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
[0244] The therapeutic compound(s)/agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom to thereby make it available to the subject. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”
[0245] Use of a long-term sustained release implant or depot formulation may be particularly suitable for treatment of chronic conditions. The term “implant” and “depot formulation” is intended to include a single composition (such as a mesh) or composition comprising multiple components (e.g. a fibrous mesh constructed from several individual pieces of mesh material) or a plurality of individual compositions where the plurality remains localized and provide the long-term sustained release occurring from the aggregate of the plurality of compositions. “Long-term” release, as used herein, means that the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 2 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 7 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 14 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient for at least 90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least one year. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 15-30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 30-60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 60-90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 90-120 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 120-180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for up to one year. In some embodiments, the long-term sustained release implants or depot formulation are well-known to those of ordinary skill in the art and include some of the release systems described above. In some embodiments, such implants or depot formulation can be administered surgically. In some embodiments, such implants or depot formulation can be administered topically or by injection.
VII. Formulations and Medicaments:
[0246] The small molecule peptidomimetics disclosed herein (for example compounds of Formulas I and la) can be used, alone or in combination, with other therapeutically active ingredients to address the needs of subjects suffering from a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology. In order to be administered to a subject in need thereof, the small molecule peptidomimetic will generally need to be formulated for the suitable route of administration. The formulated product can be considered a composition or medicament comprising the small molecule peptidomimetic and optionally one or more additional active therapeutic agents. For example, if the small molecule peptidomimetic (alone or in combination with another active ingredient) is to be administered to the subject by injection, it will typically be formulated into an injectable liquid or liquid suspension. For example, this could be accomplished by dissolving or suspending the small molecule peptidomimetic in a suitable diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier as described previously herein (See the section above entitled: Pharmaceutical Compositions, Routes of Administration, and Dosing), optionally with one or more optionally one or more additional active therapeutic agents. In some embodiments, the diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier can be water, saline or a buffered aqueous solution.
[0247] Similarly, if the small molecule peptidomimetic (alone or in combination with another active therapeutic agents) is to be administered to the subject in oral form, the selected active ingredient(s) can be formulated into a pill, tablet, capsule or other vehicle for such administration as discussed above in the section entitled: “Pharmaceutical Compositions, Routes of Administration, and Dosing” or as otherwise known to those of ordinary skill in the art.
[0248] Similarly, the small molecule peptidomimetic (alone or in combination with another active therapeutic agents) can be formulated for ocular administration, buccal administration, topical administration, nasal administration or any other of the modes of administration previously discussed herein or that are known to those of ordinary skill in the art.
[0249] In brief, any of the formulations (which can also be referred to as a medicament or composition when formulated for administration to a subject having a certain affliction or medical condition that requires medical attention) described in the section above entitled: “Pharmaceutical Compositions, Routes of Administration, and Dosing” can be applied to produce a composition (i.e. a formulation or medicament) suitable for administration to a subject in need thereof. Thus, in some embodiments, this application is directed to compositions, formulations and medicaments suitable for administration to a subject suffering from, or believed to be suffering from a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0250] Thus, in some embodiments, the present disclosure present disclosure provides a formulation or medicament comprising a peptidomimetic, such as (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and/or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology in a subject in need thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is (R)- 2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
[0251] In some embodiments, the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0252] In some embodiments, the formulation or medicament is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the formulation or medicament is administered daily for the remainder of the life of the subject. [0253] In some embodiments, the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology comprising stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
[0254] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.
[0255] In some embodiments, the formulation or medicament is administered orally. In some embodiments, the formulation or medicament is administered subcutaneously. In some embodiments, the formulation or medicament is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
[0256] In some embodiments, the formulation or medicament embodies a combination therapy. Thus, in some embodiments, the use of the formulation or medicament further comprises separately, sequentially, or simultaneously administering an additional treatment to the subject. In some embodiments, the additional treatment comprises administration of a therapeutic agent. The additional therapeutic agent can be one used to treat the disease itself or otherwise be used to address symptoms or conditions associated with the disease (in this case a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology). In some embodiments, the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escitalopram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine). In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of formulation or medicament and the additional treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
[0257] In some embodiments, the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt). In some embodiments, pharmaceutically acceptable salt comprises a monoacetate salt, a bis-acetate salt, a tri-acetate salt, a monotrifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt. In some embodiments, the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
VIII. Therapeutic Methods And Related Uses
[0258] In one aspect, the present disclosure provides a method for treating, preventing, inhibiting, ameliorating or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptidomimetic, such as (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is (R)- 2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
[0259] In some embodiments, the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0260] In some embodiments, the peptidomimetic is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, once diagnosed, the peptidomimetic is administered daily for the remainder of the life of the subject.
[0261] In some embodiments, the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology comprising, but not limited to, stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
[0262] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human. [0263] In some embodiments, the peptidomimetic is administered orally. In some embodiments, the peptidomimetic is administered subcutaneously. In some embodiments, the peptidomimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
[0264] In some embodiments, the method involves a combination therapy. In practice of a combination therapy, the method further comprises separately, sequentially, or simultaneously administering an additional treatment to the subject. In some embodiments, the additional treatment comprises administration of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escital opram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine). In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of peptidomimetic and an additional therapeutic treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0265] In some embodiments, the pharmaceutically acceptable salt of the peptidomimetic comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt). In some embodiments, pharmaceutically acceptable salt comprises a monoacetate salt, a bisacetate salt, a tri-acetate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri- trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt. In some embodiments, the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt. [0266] In one aspect, the present disclosure provides a use of a composition in the preparation of a medicament for treating, preventing, inhibiting, ameliorating or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of a peptidomimetic, such as (R)-2- amino-N-((S)- 1 -((( S)-5 -amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl- l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
[0267] In some embodiments, the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0268] In some embodiments, the medicament is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the medicament is administered daily for the remainder of the life of the subject.
[0269] In some embodiments, the use of the medicament for the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology comprising, but not limited to, stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
[0270] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.
[0271] In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for subcutaneous administration. In some embodiments, the medicament is formulated for administration, topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
[0272] In some embodiments, the medicament is separately, sequentially, or simultaneously used with an additional treatment. In some embodiments, the additional treatment comprises use of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escitalopram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine). In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of medicament and an additional treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology. [0273] In some embodiments, the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt). In some embodiments, pharmaceutically acceptable salt comprises a monoacetate salt, a bis-acetate salt, a tri-acetate salt, a mono- trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt. In some embodiments, the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
[0274] In still another aspect, the present disclosure provides a peptidomimetic, such as (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and/or delaying the onset of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology in a subject in need thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I or la, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
[0275] In some embodiments, the subject has been diagnosed as having a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology. [0276] In some embodiments, the peptidomimetic is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the peptidomimetic is administered daily for the remainder of the life of the subject.
[0277] In some embodiments, the treating, preventing, inhibiting, or ameliorating comprises the treatment, prevention, inhibition, or amelioration of one or more signs or symptoms of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology comprising, but not limited to, stumbling, clumsiness, loss of coordination, loss of control of movements, difficulty swallowing, difficulty speaking, loss of ambulation, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty focusing, lapses in short term memory, loss of initiative, diminishing organizational skills, disorientation, loss of cognitive skills and weight loss.
[0278] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.
[0279] In some embodiments, the peptidomimetic is formulated for administration orally. In some embodiments, the peptidomimetic is formulated for administration subcutaneously. In some embodiments, the peptidomimetic is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
[0280] In some embodiments, the peptidomimetic is separately, sequentially, or simultaneously used with an additional treatment. In some embodiments, the additional treatment comprises use of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: Xenazine® (tetrabenazine), Austedo® (deutetrabenazine), Risperdal® (risperidone), Haldol® (haloperidol), Thorazine® (chlorpromazine), benzodiazepines, such as Klonopin® (clonazepam) and Valium® (diazepam), Lexapro® (escitalopram), Prozac® (fluoxetine), Zoloft® (sertraline), Seroquel® (quetiapine), Carbatrol® (carbamazepine), Depacon® (valproate sodium), and Lamictal® (lamotrigine). In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of medicament and an additional treatment has a synergistic effect in the prevention or treatment of a neurodegenerative disease, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0281] In some embodiments, the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt or a maleate salt (in each case a mono-, bis- or tri- (tris-) acid salt). In some embodiments, pharmaceutically acceptable salt comprises a monoacetate salt, a bis-acetate salt, a tri-acetate salt, a mono- trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt. In some embodiments, the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.
EXAMPLES
[0282] The present technology is further illustrated by the following examples, which should not be construed as limiting in any way.
Example 1 - SBT-272 Targets Cardiolipin, Restores Mitochondrial Structure and Cellular Energetics
[0283] SBT-272, a small molecule that penetrates the central nervous system (CNS) and can be used to treat mitochondrial dysfunction in neurodegenerative diseases, targets cardiolipin (CL), restoring mitochondrial structure and cellular energetics (FIGs. 1A and IB). CL is the inner mitochondrial membrane (IMM) phospholipid responsible for the structural integrity of the IMM folds, or cristae, which harbor the protein complexes of the electron transport chain that are essential for oxidative phosphorylation and adenosine triphosphate (ATP) generation (OXPHOS). Paradies G, et al., Cells 8:728 (2019).
Example 2 - SBT-272 in vivo pharmacokinetic (PK) and pharmacodynamic (PD) response in rats
[0284] Evaluation of SBT-272 exposure in brain tissues after subcutaneous dosing. Brain tissues were collected, at various time points (see FIG. 2A) following a single 5 mg/kg subcutaneous (SC) administration of SBT-272 (n = 8 rats per time point).
[0285] Briefly, issues samples were weighed in 2 mL microcentrifuge tubes (micro tube 2 mL, low protein binding, with screw cap, REF 72.694.600 (Sarstedt, Germany), weight of tissues was recorded in the study file. The centrifuge tubes were kept on ice throughout the procedure. Four times tissue weight purified deionized water with 0.1% formic acid (v/w) was added. Two metal beads were placed in each microcentrifuge tube (Metal Bead Lysing Matrix Bulk, MP, USA). Brain tissues were homogenized using Bead Ruptor (Omni International, USA) for 60 seconds using a speed of 4 ms per cycle. Homogenates (96 pL) were transferred to 1/5 mL microcentrifuge tubes with surface that minimized binding (REF 04-212-3500, Nerbe Plus, Germany). Homogenates were frozen and kept at -80°C until sample extraction for LC/MS/MS analysis. Two samples (twice 96 pL) collected, one kept if repeat required.
[0286] Brain sample preparation. Extraction of spiked brain homogenate standards: to 100 pL of spiked rat brain homogenate standard sample add 10 pL of IS spiking solution; add 400 pL of deproteinization solution, 1% formic acid in MeOH; vortex mix the samples for 100 seconds at 2800 rpm; centrifugate samples at 12000 rpm for 30 min at 5°C; transfer supernatants to LC vials and use for analysis. Extraction of brain homogenate study samples: to 96 pL of rat brain homogenate study sample, add 4 pL of DMSO and 10 pL of IS spiking solution; add 400 pL of deproteinization solution, 1% formic acid in MeOH; vortex mix the samples for 10 seconds at 2800 rpm; incubate samples on orbital shaker for 10 min at 2000 rpm; vortex mix the samples for 10 seconds at 2800 rpm; centrifugate samples at 12000 rpm for 30 minutes in 5 °C; transfer supernatants to LC vials and use for analysis.
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000072_0001
[0287] As shown in FIG. 2A, SBT-272 is brain penetrant and exhibited optimized biodistribution across the blood-brain-barrier, as evaluated in rats after a single dose of 5 mg/kg delivered subcutaneously (SC).
[0288] Improved respiratory control ratio after cerebral ischemia/r eperfusion. To assess its pharmacodynamic effect on mitochondrial function in the brain, SBT-272 was tested in a rat model of acute ischemia. The mitochondrial effects of SBT-272 were determined using the respiratory control ratio (RCR), the ratio of coupled respiration (supporting oxidative phosphorylation) to respiratory rate in the absence of ADP (“leak” respiration). The high mitochondrial RCR in sham -treated animals (9.0 ± 0.1) confirmed that the mitochondrial were healthy, as the majority of respiration accounted for replenishing cellular ATP levels (FIG. 2C). Consistent with mitochondrial injury, RCR declined significantly in this rat stroke model compared to controls (FIG. 2C). SBT-272 pretreatment 4 and 24 hours before endothelin toxin- 1 (ET-l)-induced stroke injury protected against the stroke-induced reduction in mitochondrial RCR (FIG. 2C). The brain concentration 24 hours after final treatment was assessed in the same hemibrain used for RCR measurements of individual animals and was found to be dose proportional (FIG. 2D). These results demonstrate that once daily SC dosing is sufficient for rodent studies.
[0289] Accordingly, collectively, these results demonstrate that the methods of the present technology for dosing SBT-272 achieve optimized distribution in brain tissue and are useful in methods for treating subjects diagnosed with neurodegenerative disease such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a-synuclein are associated with the disease pathology.
[0290] Previous reports have confirmed the activity of SBT-272 to: (a) prolong survival in male transgenic high copy number Sodl-G93A ALS mice (Keefe, et al., The cardiolipintargeting compound SBT-272 attenuates neurodegeneration, delays the onset of neurological signs and extends lifespan in male SOD1 G93A transgenic mice, Poster presented at NEALS Poster Session, 2019); (b) protect hTDP-43A315T+ motor neurons and AAV-A53T-human alpha synuclein+ dopaminergic neurons from neurodegeneration (Gautam, et al. SBT-272 Improves Mitochondrial Integrity and Motility in Upper Motor Neurons with TDP-43 Pathology, Poster presented at Keystone poster session, 2022; Guatam, et al., The mitochondrial targeted peptidomimetic SBT-272 protects corticospinal motor neurons with mutant TDP43 pathology, Poster presented at NEALS poster session, 2021; Gautam, et al., SBT-272 improved mitochondria structure and function and preserved upper motor neurons with TDP-43 pathology, Platform poster presentation, presented at NEALS poster session, 2022; Bido, et al., The mitochondrial targeted drug SBT-272 attenuates dompaminergicneuron loss, alpha-synuclein burden and neuroinflammation in a mouse model of Parkinson ’s Disease, Poster presented at Muscle Disorder Society (MDS) poster session, 2021); (c) protect MAPT-P301L(+) iPSC derived tauopathy neurons from rotenone induced cell death (Silva, et al., The Neuroprotective Effect of SBT-272 on Tauopathy Neuronal Models Expressing Tau-P301L, Poster presented at Gordon Research Conference (GRC) poster session, 2022); and (d) improve behavioral outcome in R6/2 model of Huntington’s Disease (Zariwala, et al., Effects of the mitochondria-targeting small molecule SBT-272 in the R6/2 transgenic mice of Huntington ’s Disease, Poster presented at Keystone Symposia poster Session, 2022).
Introduction to Examples 3 and 4
[0291] Examples 3 and 4 demonstrate the assessment of plasma, cerebrospinal fluid (CS), and brain homogenate PK results from pre-clinical studies (rodent and nonhuman primate) and emerging Phase 1 clinical plasma PK data in the context of both single doses and steady state achieved through chronic dosing of SBT-272. Example 3 - Pre-Clinical Rodent and Nonhuman Primate Studies
In vitro - In vivo correlations
[0292] As shown in FIGs. 3A and 3B, in vitro (FIG. 3 A) and in vivo (FIG. 3B) correlations indicate a 10 to 100 nM brain concentration as a potential target for pharmacodynamic effect. SBT-272 has been shown to demonstrate in vitro and in vivo activity in transgenic hTDP-43 models. See Guatam M., Platform presentation. NEALS, 2022. In addition, it has been demonstrated that, in more than one model, SBT-272 has reported activity on neuroprotection, survival benefits, lowering of protein aggregates, and improved mitochondrial function. See Keefe, et al. (2019); Gautam, et al. (2022); Guatam, et al. (2021). Gautam, et al., SBT-272 improved mitochondria structure and function and preserved upper motor neurons with TDP-43 pathology, Platform poster presentation, presented at NEALS poster session (2022); Bido, et al. (2021); Silva, et al. (2022); and Zariwala, et al., Effects of the mitochondria-targeting small molecule SBT-272 in the R6/2 transgenic mice of Huntington ’s Disease, Poster presented at Keystone Symposia poster Session, 2022.
Rat and Nonhuman Primate PK Profdes at Equivalent Dose Levels After Single or Repeated Dosing
[0293] As shown in FIGs. 4A and 4C, the time-concentration profile of SBT-272 in plasma, CSF, and brain is very similar in rat and nonhuman primate.
PK Profile of SBT-272 in Rat
[0294] Pharmacokinetic profde of SBT-272 in rat plasma, CSF, and brain (for FIG. 4A). Briefly, as described elsewhere herein, male Sprague-Dawley (SD) rats were subcutaneously administered a single, 10 mg/kg dose of SBT-272. Plasma, CSF, and brain (microdialysis) samples were obtained at the time points indicated on FIG. 4A and analyzed for SBT-272 concentration by HPLC with tandem mass spectrometry (HPLC-MS/MS).
[0295] Pharmacokinetic profde of SBT-272 in rat plasma, CSF, and brain (for FIG. 5 A). The objective of this study was to evaluate the pharmacokinetics of SBT-272 in microdialysate from the prefrontal cortex (PFC) and striatum (STR), and in plasma and CSF of freely-moving adult male Sprague-Dawley rats. The experiments and the analysis were performed at Charles River Laboratories Den Bosch B.V., location Groningen (Groningen, the Netherlands).
[0296] Test items. Test compound was SBT-272. The molecular weight of SBT-272 is 607.75 g/mol in the salt-free form, and 717.13 g/mol in the salt form. The batch specific 24 months stability data showed potency as free base value of 0.797, therefore, an adjusted correction factor of 1.25 was used.
[0297] In vitro experiments. In vitro experiments were performed to determine the recovery of SBT-272 using MetaQuant microdialysis probes with a 4 mm exposed ethylene vinyl alcohol (EC20) membrane (CRL, the Netherlands). To this end, probes were placed in beakers containing 10 nM SBT-272 in aCSF (147 mM NaCl, 3.0 mM KC1, 1.2 mM CaCh, 1.2 mM MgCh in ultrapurified H2O) with or without 0.2% BSA (w/v). The beaker contents were continuously stirred and kept at a constant temperature of 37 °C. The probes were perfused with a slow flow of aCSF with or without 0.2% BSA at a flow rate of 0.12 pL/min, and a carrier flow of ultrapurified H2O at a flow rate of 0.8 pL/min. After 2 hours of prestabilization, five consecutive microdialysis samples were collected in 30-minute intervals. Samples from the beaker content were collected at the start and end of the microdialysis experiment. All samples were collected into 300 pL polystyrene microvials (Microbiotech/se AB, Sweden; 4001029) and stored at -80 °C until analysis.
[0298] In vivo experiments: Animals. A total of six male Sprague-Dawley rats (309-329 g; CRL Sulzfeld, Germany) were used for the experiments. The experiments were conducted in strict accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council 2011) and were in accordance with European Union directive 2010/63 and the Dutch law. The experiments were carried out under license number
A VD23600202011187, issued by the national committee for licensing of animal experiments (Centrale Commissie Dierproeven) and were approved by the Animal Care and Use Committee (Instantie voor Dierenwelzijn) of Charles River Discovery Groningen.
[0299] Following arrival, animals were housed in groups of 5 in polycarbonate cages (56 X 33 X 20 cm) with wire mesh top in a temperature (22 ± 2 °C) and humidity (55 ± 15%) controlled environment on a 12 hour light cycle (07.00 - 19.00h). After surgery, animals were housed individually (cages 30 X 30 X 40 cm). Standard diet (A04 mod. R/M-M, Ssniff, Germany) and domestic quality mains water were available ad libitum. [0300] In vivo experiments: Surgery. Animals were anesthetized using isoflurane (2% and 800 mL/min O2). Before surgery, carprofen (5 mg/kg, s.c.) was administered for peri- and post-operative analgesia. A mixture of bupivacaine and epinephrine was applied to the incision site and periosteum of the skull for local analgesia.
[0301] In vivo experiments: Microdialysis probe implantation. Each animal was placed in a stereotaxic frame (Kopf instruments, USA). Guides for MetaQuant microdialysis probes with EC20 membranes (CRL, the Netherlands) were positioned aiming at the medial prefrontal cortex (PFC, 4 mm exposed membrane) and striatum (STR, 3 mm exposed membrane). Coordinates for the tip of the probe were for PFC: AP +3.4 mm (to bregma), lateral +0.8 mm (to midline), ventral -5.0 mm (to dura) and for STR: AP +0.9 mm (to bregma), lateral -3.0 mm (to midline), ventral -6.0 mm (to dura). The incisor bar was set at - 3.3 mm. Coordinates were based on “The rat brain in stereotaxic coordinates” by Paxinos and Watson (2009). The probes were attached to the skull with stainless steel screws and dental cement.
[0302] In vivo experiments: Cisterna magna and jugular vein cannulation. In the same surgical procedure, a stainless steel cannula (CRL Groningen, the Netherlands) was positioned in the cisterna magna to allow for CSF sampling and an indwelling cannula (35 - 42 mm, CRL Groningen, the Netherlands) was positioned in the jugular vein and exteriorized through an incision on top of the skull to allow for blood sampling. The end of each cannula was fixed in position with dental cement and attached to the skull with stainless steel screws.
[0303] In vivo experiments: Dose formulations. SBT-272 was formulated in sterile saline for QD day 1-5 dosing s.c. of 10 mg/kg in a volume of 5 mL/kg.
Figure imgf000076_0001
[0304] In vivo experiments: Experimental design. Microdialysis experiments were initiated at day 1 and day 6. MetaQuant microdialysis probes were inserted into the guides one day before microdialysis initiation. On the experimental day, probes were connected with flexible PEEK tubing (Western Analytical Products Inc. USA; PK005-020) to a microperfusion pump (Harvard Apparatus, USA). Probes were perfused with a slow flow of artificial CSF (aCSF: containing 147 mM NaCl, 3.0 mM KC1, 1.2 mM CaCh and 1.2 mM MgCh) with 0.2% BSA (w/v) at a flow rate of 0.12 pL/min and a carrier flow of ultrapurified H2O at a flow rate of 0.8 pL/min. After two hours of prestabilization, microdialysis samples were collected in 30- minute intervals. Experimental samples were collected at day 1, from 20-24 hours post-first dose and at day 6, 24-32 hours post-last dose. Samples were collected into polystyrene microvials (Microbiotech/se AB, Sweden; 4001029) using an automated fraction collector (UV 8301501, TSE, Univentor, Malta). The microdialysis sampling schedules are shown in Table 5 and Table 6. Blood samples (50 pL) were collected in lithium heparin tubes via the jugular vein catheter according to the sampling schedule shown in Table 7. Plasma was collected into polystyrene microvials. CSF samples were collected into polystyrene microvials via the cistema magna cannula according to the sampling schedule shown in Error! Reference source not found.. At the end of the experiment the animals were euthanized and a terminal blood sample was collected. Terminal brain tissue was snap frozen. All samples were stored at -80 °C.
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
[0305] Quantification of SBT-272. Concentrations of SBT-272 were determined by HPLC with tandem mass spectrometry (MS/MS) detection. Microdialysis and CSF samples were mixed with phosphoric acid, acetonitrile and internal standard (Glafenine) containing solution. Brain tissue was homogenized using phosphoric acid and homogenates were mixed with methanol and acetonitrile and IS containing solution. Plasma samples were precipitated using methanol, acetonitrile, phosphoric acid and IS containing solution and subsequently centrifuged. The resultant supernatant was used as for HPLC-MS analysis. For this purpose, an aliquot of each analytical sample was injected onto the HPLC column by an automated sample injector (Shimadzu, Japan). Chromatographic separation was performed using a Kinetex XB-C18 column (50 x 2.1 mm, 2.6 pm; Phenomenex, USA) held at a temperature of 35 °C. The mobile phases consisted of A: 0.2% trifluoracetic acid in ultrapurified H2O and B: 0.2% trifluoracetic acid in methanol. Elution of the compounds proceeded using a linear gradient of phases A and B at a total flow rate of 0.4 mL/min. The MS analyses were performed using an API 6500 MS/MS system consisting of an API 6500 MS/MS detector and a Turbo Ion Spray interface (both from Applied Biosystems, The Netherlands). The acquisitions were performed in positive ionization mode, with optimized settings for the analytes. The instrument was operated in multiple-reaction-monitoring (MRM) mode. MRM transitions for the analytes are shown in Table 8. Suitable in-run calibration curves were fitted using weighted (1/x) regression, and the sample concentrations were determined using these calibration curves. Accuracy was verified by quality control samples after each sample series. Data were calibrated and quantified using the Analyst data system (Applied Biosystems).
Figure imgf000080_0001
[0306] Data evaluation. Data were processed using Microsoft Excel and plotted in Prism 9 for Windows, version 9.3.1 (GraphPad Software, Inc., 1992-2020). The reported concentrations are corrected for dilutions, but not for probe recoveries.
[0307] Results: Using a perfusion fluid of 0.2% BSA in aCSF, relative recovery of SBT- 272 for MetaQuant microdialysis probes with a 4 mm exposed EC20 membrane was 73.1 ± 4.80% (mean ± SEM).
[0308] FIG. 5A shows the mean levels of SBT-272 in brain homogenate, brain ISF, CSF, and plasma samples from adult male SD rats following 5 daily s.c. administrations of 10 mg/kg SBT-272. Compartment ratios of SBT-272 (plasma:CSF 1.03; braimplasama 178; and brain:CSF 182) are also shown in FIG. 5A.
PK Profile of SBT-272 in Nonhuman Primate
[0309] Pharmacokinetic profile of SBT-272 in nonhuman primate plasma, CSF, and brain. The objective of this study was to determine the pharmacokinetic profile of SBT-272 in CSF and plasma when delivered by subcutaneous (SC) injection for 10 days to cynomolgus monkeys. SBT-272 solution was administered daily by SC injection for 10 days. The following parameters and endpoints were evaluated in this study: mortality, clinical observations, body weights, pharmacokinetic samples (CSF and plasma), and selected tissue collection. There was no mortality during the study. There were no differences in body weights noted throughout the course of the study that were considered to be related to the administration of SBT-272. Administration of SBT-272 by SC injection was well tolerated in cynomolgus monkeys at 5mg/kg/day. Additional details regarding the experimental protocol are provided below.
[0310] Test system. Details regarding the test system are provided below:
Species: Nonhuman primate
Strain/Breed: Cynomolgus monkey
Animal Condition: Non-naive
Animal Procurement Method: In-house colony
Animal Supplier: Charles River Laboratories
Animal Supplier Location: 531 Boul des Prairies, Laval, QC H7V 1B7 Canada
Animal Origin: Asia
Number of Males: 3
Age at the Initiation of Dosing: 18 to 60 months
Weight at the Initiation of Dosing: 1.4 to 5.0 kg
[0311] Animal screening. Prior to transfer from the colony, all animals were subjected to a health assessment to ensure that animals are healthy and suitable for use on the study.
[0312] Husbandry. Each animal was housed in its own stainless steel cage. Housing set-up was as described in the Guide for the Care and Use of Laboratory Animals (National Research Council). Animals were separated during designated procedures/activities. The animal room environment was maintained at a temperature of 18°C to 24°C, humidity of 30% to 70%, and a light cycle of 12 hours light and 12 hours dark (except during designated procedures). The diet consisted of Envigo Teklad Certified Hi -Fiber Primate Diet #7195C, twice daily, except during designated procedures, in amounts appropriate for the size and age of the animals. Animals were provided with municipal tap water, treated by reverse osmosis and ultraviolet irradiation and was made freely available to each animal via an automatic watering system (except during designated procedures).
[0313] Veterinary care. Veterinary care was available throughout the course of the study and animals were examined by veterinary staff as warranted. [0314] Study design. The study design is described in Table 9.
Figure imgf000082_0001
a Based on the most recent body weight measurement.
[0315] Surgical procedures.
Preoperative preparation:
Antibiotic: Penicillin G Procaine - Subcutaneously or intramuscularly, starting at least
30 minutes prior surgery
Analgesic: Buprenorphine - Intramuscularly, at least 30 minutes prior surgery
Meloxicam - Subcutaneously, prior to surgery; orally or subcutaneously, daily starting the morning after the surgery for 5 days Bupivacaine - Towards the end of surgery
Anesthesia: Sedation using ketamine/acepromazine mixture, intramuscularly, followed by intubation and maintained under isoflurane/oxygen gas
Surgical site: Intrathecal. Skin incision at the level of L5
Perifix Polyamide Epidural catheter 20G closed tip implanted approximately at the L5 level of lumbar vertebrae using hemilaminectomy approach and fluoroscopy imaging. Once the dura matter is incised and the catheter is inserted, the tip of the catheter is advanced up to approximately the LI level of lumbar vertebra. Cerebrospinal fluid (approximately 0.25 ml) is collected via dripping method from the catheter and may be used as the pre-dose samples (Week -1). Around 0.5ml of Omnipaque or an equivalent contrast agent is injected using a syringe attached to the catheter to confirm its placement via fluoroscopy or x-ray. Confirmation of catheter patency is assessed via CSF flow. A small incision is made on the skin of lumbar area to expose the muscle in order to anchor the catheter using non-absorbable knots glued on the catheter. Catheter is tunneled and exteriorized at the level of interscapular area and placed in jacket pocket. Surgical site is rinsed with warm sterile saline prior to closure. Postoperative: Fruits and/or vegetables buffet and crushed cookies mixed with banana are provided to the animals for at least 5 days postsurgery.
A catheter patency check (flush with 0.3 mL artificial CSF) is performed at least twice daily, except on days of CSF collection. On days of CSF collection, a single patency check may be done following the last CSF collections.
Topical wound cleaner (e.g., Skintegrity or equivalent) at exteriorization site three times weekly (or as needed) until considered healed.
Jacket is changed as needed.
Topical antibiotic (Polysporin Original) once daily for 7 days following surgery (including day of surgery) or as required.
Penicillin G Procaine - SC or intramuscularly in the PM following surgery for 2 days.
Enrofloxacin (Baytril) - intramuscularly once daily for at least 2 days following surgery.
Buprenorphine slow release - Subcutaneously, at the end of surgery.
Catheter type: Perifix Epidural Catheter (Product No. EC20CST, B. Braun Medical Inc.) Set-up: Jacket (exterior part of the catheter placed in a clean bag in a small pocket of the jacket)
[0316] Administration ofSBT-272.
Route of Administration: Subcutaneous injection into the scapular and mid-dorsal areas Treatment Frequency: Daily
Treatment Duration: 10 days
Method: The first day of dosing is designated as Day 1. Dose formulations are allowed to warm up at ambient temperature for at least 30 minutes prior to dosing, as appropriate. The animals are temporarily restrained for dose administration and are not be sedated. The volume for each dose is administered over 1 (preferred) or 2 (as necessary) separate injections within the designated area. Injection sites are rotated daily (see FIG. 4B). If a designated subcutaneous test site is not available for a given animal on any day, then the next available test site in the rotation should be used for dosing. The injection area is marked as frequently as required to allow appropriate visualization of administration sites. Hair may be clipped or shaved if required to improve visualization of the injection sites. On the last injection occasion for each quadrant, the last site of injection is circled, and the circled site is collected at necropsy.
[0317] In-life procedures, observations, and measurements.
Figure imgf000084_0001
[0318] CSF Sample Collection:
Figure imgf000084_0002
Figure imgf000085_0001
[0319] CSF Sample Processing. CSF samples re processed and stored within 1 hour of collection. Following each CSF collection, the sample is visually inspected, and the appearance is recorded. Samples are maintained on wet ice prior to and after centrifugation. Samples are centrifuged for 5 minutes in a refrigerated centrifuge (set to maintain 4°C) at 2000 g RCF within 1 hour of collection. The resultant supernatant is collected within 30 minutes (as quickly as possible) of centrifugation and will be visually inspected; the appearance of the supernatant and any traces of blood in the pellet re recorded. Precipitate (if any) is discarded. CSF samples are separated into 2 approximately 100 pL equal aliquots into uniquely labelled low protein binding polypropylene tubes each containing 10 pL of 5% (v/v) phosphoric acid aqueous solution. Any remaining CSF will be transferred into a 3rd low protein binding polypropylene tube containing a volume of 5% (v/v) phosphoric acid solution adjusted to result in a 1 : 10 ratio of acid solution: CSF. All samples are placed on dry ice and transferred to a freezer set to maintain -70°C. [0320] Plasma Sample Collection:
Figure imgf000086_0001
[0321] Plasma Sample Processing. The samples are centrifuged within 20 minutes of collection and the resultant plasma is separated, and two 200 pL aliquots transferred to duplicate uniquely labeled clear polypropylene tubes, each containing 20 pL of 5% (v/v) phosphoric acid aqueous solution. Any remaining plasma is transferred into a 3rd polypropylene tube containing a volume of 5% (v/v) phosphoric acid solution adjusted to result in a 1 : 10 ratio of acid solution: plasma. All samples are stored frozen immediately over dry ice pending storage in a freezer set to maintain -70°C.
[0322] Terminal Procedures. The animals were sedated with an intramuscular injection of a combination of ketamine hydrochloride and acepromazine, and then euthanized by an intravenous overdose of sodium pentobarbital, followed by exsanguination. All animals scheduled for euthanasia were food deprived overnight. Animals underwent blood and SF sample collection (terminal) for bioanalysis evaluation. The following tissues were collected starting approximately 24 hours after the last dose on Day 10:
Tissues Collected fresh then frozen Embedded in paraffin
Brain Xa Xb
Eye (retina) Xa Xb c
Spinal cord Xd X
(thoracic and lumbar) Last injection site® X X
Heart X X
Kidney (left) X
Liver (Right lateral lobe) X
Skeletal muscle X X
(unilateral)
X = performed a left side for biodistribution; snap frozen in liquid nitrogen, placed in dry ice, and stored at -70°C b right side for histopathology; preserved in 10% neutral buffered formalin (except the eye which was preserved in Davison’s solution), embedded in paraffin, and sent for histopathology. c whole eye d approximately 1-2 cm e Last injection site (for dose #10) divided into 2 halves, 1 frozen and 1 for paraffin block
[0323] The following subsections of the left side of the brain were collected fresh, sectioned, and then frozen separately: frontal cortex, temporal cortex, motor cortex, hippocampus, substantia nigra/midbrain, caudate nucleus, putamen, pons, medulla oblongata, globus pallidus, amygdala, thalamus, deep cerebellar nuclei.
[0324] Bioanalytical Summary. The concentration of SBT-272 in monkey K2EDTA plasma, CSF, and tissue samples was determined by HPLC-MS/MS analysis. Plasma samples were quantified against a monkey plasma standard curve and CSF samples were quantified against an artificial CSF standard curve. Brain and spinal cord samples were quantified against a monkey brain homogenate standard curve. All other tissues were quantified against a rat liver homogenate standard curve.
[0325] Bioanalytical Analysis - Materials and Methods - SBT-272 in Plasma:
1. Assay Range
2.00-1000 ng/mL Extraction Method
1. Aliquot 50 pL of sample, standards, or QCs into 96 well plate.
2. Aliquot 25 pL of internal standard (25 ng/mL water + 0.1% formic acid), briefly centrifuge at 4000 rpm, and vortex 5 minutes.
3. Precipitate proteins with 250 pL of 1 : 1 acetonitrile:methanol. Vortex briefly and centrifuge for 5 minutes at 4000 rpm.
4. Transfer 100 pL of the supernatant to clean 96 well plate.
5. Add 100 pL water + 0.1% formic acid, briefly centrifuge at 4000rpm and vortex 5 minutes. Equipment
Mass Spectrometer: SCIEX API-6500
HPLC Pumps: Schimadzu LC30 AD
HPLC Autosampler: Shimadzu SIL30 ACMP HPLC Conditions
Mobile Phase A: Water + 1% formic acid
Mobile Phase B: Acetronitrile + formic acid
Rinse Solvent: 1 : 1 methanol: water
Column: PS Cl 8
Flow Rate: 0.6 mL/min
Injection Volume: 7 pL
Time Module Events Parameter
3.00 Pumps Pump B Cone. 30
3.50 Pumps Pump B Cone. 95
4.00 Pumps Pump B Cone. 95
4.50 Pumps Pump B Cone. 20
5.00 Pumps Pump B Cone. 20
5.50 Pumps Pump B Cone. 95
5.90 Pumps Pump B Cone. 95
6.00 Pumps Pump B Cone. 5
6.60 System Controller STOP
1.5 Switching Valve To MS B
2.5 Switching Valve To Waste A MS Conditions
CAD gas 12 DP 80
CUR gas 20 EP 10
GAS 1 70 CE 50
GAS 2 70 CXP 20
ESI Voltage, V 4500 SBT-272 Transition, 608.3 ^ 303.3 m/z
ESI Temperature, °C 600 SBT-0480 Transition, 616.3 - 303.2 m/z
Dwell Time, ms 100 [0326] Bioanalytical Analysis - Materials and Methods - SBT-272 in CSF:
1. Assay Range
0.0500-50.0 ng/mL
2. Extraction Method
1. Aliquot 25 pL sample + 25 pL of artificial CSF with 5% phosphoric acid.
2. Aliquot 50 pL of internal standard (25 ng/mL water + 0.1% formic acid), briefly centrifuge, and vortex 5 minutes.
3. Centrifuge 5 minutes and vortex 5 minutes.
3. Equipment
Mass Spectrometer: SCIEX API-6500
HPLC Pumps: Schimadzu LC30 AD
HPLC Autosampler: Shimadzu SIL30 ACMP
4. HPLC Conditions
Mobile Phase A: Water + 1% formic acid
Mobile Phase B: Acetronitrile + formic acid
Rinse Solvent: 1 : 1 methanol: water
Column: PS Cl 8
Flow Rate: 0.6 mL/min
Injection Volume: 20 pL
Time Module Events Parameter
3.00 Pumps Pump B Cone. 40
3.50 Pumps Pump B Cone. 95
4.00 Pumps Pump B Cone. 95
4.10 Pumps Pump B Cone. 5
4.70 System Controller STOP
0.5 Switching Valve To MS B
2.0 Switching Valve To Waste A
5. MS Conditions
CAD gas 12 DP 80
CUR gas 20 EP 10
GAS 1 70 CE 50
GAS 2 70 CXP 20
ESI Voltage, V 4500 SBT-272 Transition, m/z 608.3
Figure imgf000089_0001
303.3
ESI Temperature, °C 600 SBT-0480 Transition, 616.3 - 303.2 m/z
Dwell Time, ms 100 [0327] Bioanalytical Analysis - Materials and Methods - SBT-272 in Tissue Homogenate:
1. Assay Range 2.00-1000 ng/g
2. Extraction Method
1. For every mg of tissue add 5 pL 1 : 1 acetonitrile:methanol and homogenize.
2. Aliquot 50 pL of sample, standards, or QCs into 96 well plate.
3. Aliquot 25 pL of internal standard (25 ng/mL water + 0.1% formic acid), briefly centrifuge, and vortex 5 minutes.
4. Add 100 pL water + 0.1% formic acid, briefly centrifuge and vortex 5 minutes.
3. Equipment
Mass Spectrometer: SCIEX API-6500
HPLC Pumps: Schimadzu LC30 AD
HPLC Autosampler: Shimadzu SIL30 ACMP
4. HPLC Conditions
Mobile Phase A: Water + 1% formic acid
Mobile Phase B: Acetronitrile + formic acid
Rinse Solvent: 1 : 1 methanol: water
Column: PS Cl 8
Flow Rate: 0.6 mL/min
Injection Volume: 7 pL
Time Module Events Parameter
3.00 Pumps Pump B Cone. 30
3.50 Pumps Pump B Cone. 95
4.00 Pumps Pump B Cone. 95
4.50 Pumps Pump B Cone. 20
5.00 Pumps Pump B Cone. 20
5.50 Pumps Pump B Cone. 95
5.90 Pumps Pump B Cone. 95
6.00 Pumps Pump B Cone. 5
6.60 System Controller STOP
1.0 Switching Valve To MS B
2.5 Switching Valve To Waste A
5. MS Conditions
CAD gas 12 DP 80
CUR gas 20 EP 10
GAS 1 70 CE 50
GAS 2 70 CXP 20
ESI Voltage, V 4500 SBT-272 Transition, m/z 608.3
Figure imgf000090_0001
303.3
ESI Temperature, °C 600 SBT-0480 Transition, 616.3 - 303.2 m/z
Dwell Time, ms 100 [0328] Results. FIG. 5A shows the mean levels of SBT-272 in brain (cortex), CSF, and plasma samples from cynomolgus monkieys following 10 daily s.c. administrations of 5 mg/kg SBT-272. The compartment ratios of SBT-272 (plasma:CSF 6.40; braimplasma 51; and brain:CSF 328) are also shown in FIG. 5A. FIG. 5B shows the concentrations of SBT- 272 in various tissues at termination of the study.
[0329] Summary. Collectively, the data shown in FIGs. 4A, 4C, 5A, and 5B demonstrate that brain drug concentration in nonhuman primate met predictions based on rodent studies and provides confidence in clinical development (FIGs. 5A-5B). The ratio of drug across the three compartments reflects good translation from rodent to nonhuman primate. Biodistribution of SBT-272 in cortical and spinal cord region support clinical development for neurodegenerative diseases, such as, but not limited to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), a tauopathy, and other disease where TDP-43, Tau protein, and a- synuclein are associated with the disease pathology.
Example 4 - Phase 1 Clinical Study
[0330] As shown in FIGs. 6A and 6B, the safety and tolerability of single and multiple ascending doses of SBT-272 administered via subcutaneous injection were evaluated in healthy volunteers. The primary objective of this study is to evaluate the safety and tolerability of single and multiple ascending doses of SBT-272 administered via subcutaneous injection in healthy volunteers. The secondary objects of this study are to: (a) evaluate the plasma PK of SBT-272 in healthy volunteers following subcutaneous administration of single and multiple ascending doses; and (b) to determine an appropriate dose range for subsequence clinical evaluation.
[0331] As shown in FIG. 7, the emerging SBT-272 clinical PK profile is consistent with non-clinical allometric scaling predictions. SBT-272 has a consistent safety profile based on an interim data analysis.
[0332] It is expected that the results of this study will demonstrate that the methods of the present technology are effective for achieving an optimal dose of SBT-272 in the subject and for treating neurodegenerative diseases or conditions in the subject. Summary
[0333] SBT-272 has demonstrated in vitro and in vivo correlations in models of neurodegeneration to help establish target minimum and maximal brain concentration to achieve pharmacodynamic effect. Preclinical data suggest that brain exposure necessary to drive pharmacodynamic effect might translate to humans given excellent correlation between species in steady state brain concentration at trough. Clinical PK is consistent with expectations based on rat and nonhuman primate profiles. Plasma exposures observed in the Phase 1 study, at doses deemed generally safe, may result in therapeutic concentrations in the brain based on the observed relationship between plasma, CSF, and brain PK and signals efficacy in preclinical studies.
EQUIVALENTS
[0334] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present technology is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
[0335] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.
[0336] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.
[0337] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.
[0338] Other embodiments are set forth within the following claims.

Claims

CLAIMS What is claimed is:
1. A method of treating a neurodegenerative disease or condition in a subject in need thereof, comprising dosing the subject with an effective amount of (R)-2-amino-N- ((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4- hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide.
2. The method of claim 1, wherein the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy.
3. The method of claim 1 or 2, wherein the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3- benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide is administered subcutaneously.
4. The method of any one of claims 1-3, wherein the (R)-2-amino-N-((S)-l-(((S)-5- amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide is administered in a single daily dose.
5. The method of claim 4, wherein the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight.
6. The method of claim 4, wherein the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days.
7. The method of any one of claims 1-3, wherein the (R)-2-amino-N-((S)-l-(((S)-5- amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide is administered in multiple daily doses. The method of claim 7, wherein the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight. The method of claim 7, wherein the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. The method of claim 7, wherein the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days. The method of any one of claims 1-10, wherein dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM. The method of any one of claims 1-11, wherein dosing achieves a brain cortex concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 650 nM to about 690 nM. The method of any one of claims 1-12, wherein dosing achieves a brain ISF concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 20 nM to about 30 nM. The method of any one of claims 1-13, wherein dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl- l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. The method of any one of claims 1-14, wherein dosing achieves a plasma concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 14 nM. The method of any one of claims 1-15, wherein dosing achieves a plasma:CSF peptide ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 1.0 to about 6.5. The method of any one of claims 1-16, wherein dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 50 to about 180. The method of any one of claims 1-17, wherein dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 180 to about 330. A method of treating mitochondrial dysfunction in a subject in need thereof, comprising dosing the subject with an effective amount of (R)-2-amino-N-((S)-l- (((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide. The method of claim 19, wherein the mitochondrial dysfunction is associated with a neurodegenerative disease or condition selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy. The method of claim 19 or 20, wherein the (R)-2-amino-N-((S)-l-(((S)-5-amino-l- (3-benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)- l-oxopropan-2-yl)-5-guanidinopentanamide is administered subcutaneously. The method of any one of claims 19-21, wherein the (R)-2-amino-N-((S)-l-(((S)-5- amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide is administered in a single daily dose. The method of claim 22, wherein the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. The method of claim 22, wherein the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. The method of any one of claims 19-21, wherein the (R)-2-amino-N-((S)-l-(((S)-5- amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide is administered in multiple daily doses. The method of claim 25, wherein the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight. The method of claim 25, wherein the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. The method of claim 25, wherein the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days. The method of any one of claims 19-28, wherein dosing achieves a brain concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 100 nM. The method of any one of claims 19-29, wherein dosing achieves a brain cortex concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 650 nM to about 690 nM. The method of any one of claims 19-30, wherein dosing achieves a brain ISF concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 20 nM to about 30 nM. The method of any one of claims 19-31, wherein dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl- l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. The method of any one of claims 19-32, wherein dosing achieves a plasma concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 14 nM. The method of any one of claims 19-33, wherein dosing achieves a plasma:CSF peptide ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 1.0 to about 6.5. The method of any one of claims 19-34, wherein dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 50 to about 180. The method of any one of claims 19-35, wherein dosing achieves a brain:CSF ratio of “(R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 180 to about 330. A method of dosing (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2- yl)-5-guanidinopentanamide in a subject in need thereof, comprising administering SBT-272 to the subject subcutaneously. The method of claim 37, wherein the subject suffers from a neurodegenerative disease or condition, or wherein the subject suffers from mitochondrial dysfunction. The method of claim 38, wherein the mitochondrial dysfunction is associated with a neurodegenerative disease or condition. The method of claim 38 or 39, wherein the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy. The method of any one of claims 37-40, wherein the (R)-2-amino-N-((S)-l-(((S)-5- amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide is administered in a single daily dose. The method of claim 41, wherein the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. The method of claim 41, wherein the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. The method of any one of claims 37-40, wherein (R)-2-amino-N-((S)-l-(((S)-5- amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5-yl)pentyl)amino)-3 -(4-hydroxy-2,6- dimethylphenyl)-l-oxopropan-2-yl)-5-guanidinopentanamide is administered in multiple daily doses. The method of claim 44, wherein the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight. The method of claim 44, wherein the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. The method of claim 44, wherein the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days. The method of any one of claims 37-47, wherein dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM. The method of any one of claims 37-48, wherein dosing achieves a brain cortex concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 650 nM to about 690 nM. The method of any one of claims 37-49, wherein dosing achieves a brain ISF concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 20 nM to about 30 nM. The method of any one of claims 37-50, wherein dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl- l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. The method of any one of claims 37-51, wherein dosing achieves a plasma concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 14 nM. The method of any one of claims 37-52, wherein dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 1.0 to about 6.5. The method of any one of claims 37-53, wherein dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 50 to about 180. The method of any one of claims 37-54, wherein dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 180 to about 330. Use of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide in the preparation of a medicament for treating a neurodegenerative disease or condition in a subject in need thereof, wherein the medicament is formulated for dosing a subject by subcutaneous delivery. The use of claim 56, wherein the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy. The use of claim 56 or 57, wherein the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3- benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide is formulated to be administered in a single daily dose. The use of claim 58, wherein the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. The use of claim 58, wherein the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. The use of claim 56 or 57, wherein the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3- benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide is formulated to be administered in multiple daily doses. The use of claim 61, wherein the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight. The use of claim 61, wherein the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. The use of claim 61, wherein the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days. The use of any one of claims 56-64, wherein dosing achieves a brain concentration of the (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 100 nM. The use of any one of claims 56-65, wherein dosing achieves a brain cortex concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 650 nM to about 690 nM. The use of any one of claims 56-66, wherein dosing achieves a brain ISF concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 20 nM to about 30 nM. The use of any one of claims 56-67, wherein dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2- yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. The use of any one of claims 56-68, wherein dosing achieves a plasma concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 14 nM. The use of any one of claims 56-69, wherein dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 1.0 to about 6.5. The use of any one of claims 56-70, wherein dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 50 to about 180. The use of any one of claims 56-71, wherein dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 180 to about 330. Use of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide in the preparation of a medicament for treating mitochondrial dysfunction in a subject in need thereof, wherein the medicament is formulated for dosing a subject by subcutaneous delivery. The use of claim 73, wherein the mitochondrial dysfunction is associated with a neurodegenerative disease or condition. The use of claim 74, wherein the neurodegenerative disease or condition is selected from a group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), PD with dementia, dementia with Lewy bodies, Multiple System Atrophy, Huntington’s disease, HTT proteinopathy, Frontotemporal Lobar Degeneration (FTLD), and a tauopathy. The use of claim 74 or 75, wherein the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3- benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide is formulated to be administered in a single daily dose. The use of claim 76, wherein the single daily dose comprises about 0.1 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, or about 0.6 to about 1.0 mg/kg of body weight. The use of claim 76, wherein the single daily dose comprises about 1 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 50 mg, or ascending doses of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg on successive days. The use of claim 74 or 75, wherein the (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3- benzyl-l,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l- oxopropan-2-yl)-5-guanidinopentanamide is formulated to be administered in multiple daily doses. The use of claim 79, wherein the multiple daily doses comprise about 5 mg/kg of body weight or about 10 mg/kg of body weight. The use of claim 79, wherein the multiple daily doses comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 daily doses. The use of claim 79, wherein the multiple daily doses comprise ascending doses of about 20 mg once daily for 7 days, about 40 mg once daily for 7 days, and about 60 mg once daily for 7 days. The use of any one of claims 73-82, wherein dosing achieves a brain concentration of the peptide of about 10 nM to about 100 nM. The use of any one of claims 73-83, wherein dosing achieves a brain cortex concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 650 nM to about 690 nM. The use of any one of claims 73-84, wherein dosing achieves a brain ISF concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 20 nM to about 30 nM. The use of any one of claims 73-85, wherein dosing achieves a cerebral spinal fluid (CSF) concentration of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2- yl)-5-guanidinopentanamide of about 2 nM to about 12 nM. The use of any one of claims 73-86, wherein dosing achieves a plasma concentration of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol- 5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 10 nM to about 14 nM. The use of any one of claims 73-87, wherein dosing achieves a plasma:CSF ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 1.0 to about 6.5. The use of any one of claims 73-88, wherein dosing achieves a braimplasma ratio of (R)-2-amino-N-((S)- 1 -(((S)-5-amino- 1 -(3 -benzyl- 1 ,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 50 to about 180. The use of any one of claims 73-89, wherein dosing achieves a brain:CSF ratio of (R)-2-amino-N-((S)-l-(((S)-5-amino-l-(3-benzyl-l,2,4-oxadiazol-5- yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-l-oxopropan-2-yl)-5- guanidinopentanamide of about 180 to about 330. The method of any one of claims 1-55, wherein the subject is human. The use of any one of claims 56-90, wherein the subject is human.
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