[go: up one dir, main page]

WO2015042580A1 - Compositions et méthodes de traitement d'une douleur neuropathique - Google Patents

Compositions et méthodes de traitement d'une douleur neuropathique Download PDF

Info

Publication number
WO2015042580A1
WO2015042580A1 PCT/US2014/056985 US2014056985W WO2015042580A1 WO 2015042580 A1 WO2015042580 A1 WO 2015042580A1 US 2014056985 W US2014056985 W US 2014056985W WO 2015042580 A1 WO2015042580 A1 WO 2015042580A1
Authority
WO
WIPO (PCT)
Prior art keywords
polypeptide
seq
week
administered
amino acids
Prior art date
Application number
PCT/US2014/056985
Other languages
English (en)
Inventor
Eve M. VERSAGE
Original Assignee
Biogen Idec Ma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biogen Idec Ma Inc. filed Critical Biogen Idec Ma Inc.
Publication of WO2015042580A1 publication Critical patent/WO2015042580A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1883—Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to protein chemistry, molecular biology, and vascular biology.
  • Neublastin also known as artemin and enovin, is a 24 kDa homodimeric, secreted protein that promotes the outgrowth and survival of neurons of the peripheral and central nervous system (Baudet et al, 2000, Development, 127:4335; Masure et al., 1999, Eur. J. Biochem., 266:892; Rosenblad et al, 2000, Mol. Cell Neurosci., 15(2): 199).
  • Neublastin mRNA is expressed predominantly in embryonic kidney and lung, and in adults, is expressed highest in pituitary gland, trachea, and placenta (Baudet et al, 2000, Development,
  • Neublastin is a member of the glial cell line-derived neurotrophic factor (GDNF) ligand family.
  • GDNF ligands activate both Ras and phosphatidylinositol-3 -kinase signal transduction pathways by engaging the membrane-bound c-RET receptor tyrosine kinase.
  • This c-RET-mediated signaling requires an additional co-receptor, a glycosylphosphatidyl inositol (GPI)-anchored GDNF family receptor alpha (GFRa) protein, which confers ligand specificity to c-RET.
  • GPI glycosylphosphatidyl inositol
  • GFRa GDNF family receptor alpha
  • Neublastin shows highest affinity for GFRa3 in vitro, however in studies using human fibroblasts, neublastin can stimulate c-RET-dependent signaling through either GFRa3 or GFRal (Baudet et al, 2000, Development, 127:4335; Masure et al, 1999, Eur. J. Biochem. 266:892; Rosenblad et al, 2000, Mol. Cell Neurosci., 15(2): 199).
  • Neublastin and the other GDNF family members are members of the transforming growth factor beta (TGF beta) superfamily and thus, are characterized by the presence of seven conserved cysteine residues with similar spacing which form the structure of a cysteine knot (Saarma, 1999, Microsc. Res. Tech., 45:292). Each monomer contains two disulfide bonds that form a closed loop structure encircling the third disulfide to form a tight knot structure. The seventh cysteine contained within each monomer forms an intermolecular disulfide bond, covalently linking the monomers to form the final dimer product (Rattenholl et al 2000, J. Mol. Biol, 305:523). Summary
  • the present invention is based, at least in part, on the discovery that administration of neublastin within a dosage range of 100-1,600 ⁇ g/kg body weight elicits a reduction in pain in human subjects with painful lumbar radiculopathy.
  • the invention features a method of treating neuropathic pain in a human subject in need thereof by administering to the human subject a polypeptide comprising an amino acid sequence that is at least 80% identical to amino acids 15-113 of SEQ ID NO: l, wherein the polypeptide, when dimerized, binds to a complex containing GFRalpha3 and RET, and wherein the polypeptide is administered at a dosage of 100-1,600 ⁇ g/kg body weight of the human subject.
  • polypeptide comprising an amino acid sequence that is at least 80% identical to amino acids 15-113 of SEQ ID NO: l, wherein the polypeptide, when dimerized, binds to a complex containing GFRalpha3 and RET for treating neuropathic pain in a human subject when administered at a dosage of 100-1,600 ⁇ g/kg body weight of the human subject.
  • the amino acid sequence contained in the polypeptide can optionally be at least 90% identical (e.g., at least 95% or 98% identical) to amino acids 15-113 of SEQ ID O: l .
  • the polypeptide contains or consists of amino acids 10-1 13 of SEQ ID NO: l, amino acids 15-1 13 of SEQ ID NO: l, amino acids 15-113 of SEQ ID NO:2, amino acids 15-113 of SEQ ID O:3, amino acids 15-1 13 of SEQ ID O:4, amino acids 15-113 of SEQ ID NO:5, amino acids 15-113 of SEQ ID NO:8, or amino acids 15-1 13 of SEQ ID NO:9.
  • polypeptide can contain or consist of the amino acid sequence of SEQ ID NO: 1, the amino acid sequence of SEQ ID NO:2, the amino acid sequence of SEQ ID NO:3, the amino acid sequence of SEQ ID NO:4, the amino acid sequence of SEQ ID NO:5, the amino acid sequence of SEQ ID NO:8, or the amino acid sequence of SEQ ID NO:9.
  • the polypeptide is administered at a dosage of 200-1,200 ⁇ g/kg body weight of the human subject.
  • the polypeptide is administered at a dosage of 200-800 ⁇ g/kg body weight of the human subject.
  • the polypeptide is administered at a dosage of 400-800 ⁇ g/kg body weight of the human subject.
  • the polypeptide is administered at a dosage of 300-500 ⁇ g/kg body weight of the human subject. In some embodiments, the polypeptide is administered at a dosage of 150, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 1, 100, 1,200, 1,300, 1,400, 1,500, or 1,600 ⁇ g/kg body weight of the human subject.
  • the polypeptide can be administered to the human subject, for example, via systemic administration (e.g., subcutaneous or intravenous administration).
  • systemic administration e.g., subcutaneous or intravenous administration.
  • the method comprises multiple administrations of the polypeptide.
  • the multiple administrations can include at least three administrations of the polypeptide within one week (e.g., every other day).
  • administration can optionally be 44-52 hours (e.g., about 48 hours) after the first
  • the administration and the third administration can optionally be 44-52 hours (e.g., about 48 hours) after the second administration.
  • the multiple administrations can include at least three administrations of the polypeptide within a period of three weeks.
  • the second administration can optionally be 6-8 days (e.g., 7 days) after the first administration and the third administration can optionally be 6-8 days (e.g., 7 days) after the second administration.
  • the multiple administrations can include at least two administrations of the polypeptide within one week. The same dosage of the polypeptide can optionally be provided to the human subject at each of the multiple administrations described above.
  • the polypeptide may subsequently be administered at the same or at a different dose and/or dosing frequency as a means to maintain a therapeutic effect.
  • the dose level of the polypeptide is increased (as compared to the initial dosing) but the dosing frequency is decreased (as compared to the initial dosing).
  • the polypeptide is subsequently administered at an interval of once per month (e.g., by intravenous administration), optionally for a period of at least 2, 3, 4, 5, or 6 months.
  • the polypeptide is subsequently administered at an interval of once per week (e.g., by subcutaneous administration), optionally for a period of at least 2, 3, 4, 5, or 6 months.
  • the polypeptide is subsequently administered at an interval of once every two weeks (e.g., by subcutaneous administration), optionally for a period of at least 2, 3, 4, 5, or 6 months.
  • the polypeptide is subsequently administered three times per week (e.g., by subcutaneous administration), optionally for a period of at least 2, 3, 4, 5, or 6 months.
  • the polypeptide is subsequently administered three times per week every other week (e.g., by subcutaneous administration), optionally for a period of at least 2, 3, 4, 5, or 6 months.
  • the neuropathic pain is associated with painful lumbar radiculopathy, painful diabetic neuropathy, post-herpetic neuralgia, post-traumatic neuralgia, post-surgical neuralgia, or a complex regional pain syndrome, or is induced by a therapeutic drug.
  • the neuropathic pain is associated with leprosy, Lyme disease, infection by a virus, or a cancer.
  • Fig. 1 is an alignment of wild type human (SEQ ID NO: 10), mouse (SEQ ID NO: 1 1), and rat (SEQ ID NO: 12) pre pro neublastin polypeptides.
  • the left and right vertical lines indicate, respectively, the start of the mature 1 13 amino and 104 amino acid forms.
  • the RRXR heparin binding motif is boxed.
  • Figs. 2A-2B are graphs depicting Likert general sciatica pain assessment scores by week for subjects in Part I of the study (Fig. 2 A) and Part II of the study (Fig. 2B).
  • Figs. 3A-3B are graphs depicting Likert back pain assessment scores by week for subjects in Part I of the study (Fig. 3A) and Part II of the study (Fig. 3B).
  • Figs. 4A-4B are graphs depicting Likert leg pain assessment scores by week for subjects in Part I of the study (Fig. 4A) and Part II of the study (Fig. 4B).
  • Figs. 5A-5D are graphs depicting Likert general sciatica pain assessment scores by time point for subjects in Part I of the study from day 0 to day 17 (Fig. 5A), Part I of the study from day 0 to day 71 (Fig. 5B), Part II of the study from day 0 to day 7 (Fig. 5C), and Part II of the study from day 0 to day 61 (Fig. 5D).
  • Figs. 6A-6D are graphs depicting Likert back pain assessment scores by time point for subjects in Part I of the study from day 0 to day 17 (Fig. 6A), Part I of the study from day 0 to day 71 (Fig. 6B), Part II of the study from day 0 to day 7 (Fig. 6C), and Part II of the study from day 0 to day 61 (Fig. 6D).
  • Figs. 7A-7D are graphs depicting Likert leg pain assessment scores by time point for subjects in Part I of the study from day 0 to day 17 (Fig. 7A), Part I of the study from day 0 to day 71 (Fig. 7B), Part II of the study from day 0 to day 7 (Fig. 7C), and Part II of the study from day 0 to day 61 (Fig. 7D).
  • Figs. 8A-8B are graphs depicting Short-Form McGill Pain Questionnaire sciatica pain assessment scores by week for subjects in Part I of the study (Fig. 8A) and Part II of the study (Fig. 8B).
  • the present invention provides compositions and methods for treating neuropathic pain in a human subject. As disclosed in the accompanying examples, administration of neublastin was found to elicit pain reduction in human subjects with painful lumbar radiculopathy. Neublastin Polypeptides
  • a mature form of wild-type human neublastin is 113 amino acids in length and has the
  • Polypeptides having the amino acid sequence of SEQ ID NO: 1 or biologically active variants of thereof can be used in the methods described herein.
  • a variant neublastin polypeptide can contain one or more additions, substitutions, and/or deletions, as detailed in the following sections. Wild-type neublastin polypeptides and biologically active variants thereof are collectively referred to herein as "neublastin polypeptides.”
  • a variant neublastin polypeptide can vary in length from the corresponding wild-type polypeptide.
  • the mature human neublastin polypeptide of SEQ ID NO: 1 consists of the carboxy terminal 1 13 amino acids of pre pro neublastin (SEQ ID NO: 10), not all of the 113 amino acids are required to achieve useful neublastin biological activity. Amino terminal truncation is permissible.
  • a variant neublastin polypeptide can contain, for example, the carboxy terminal 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 11 1, 112, or 113 amino acids of SEQ ID NO: 1 (i.e., its length can be 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 1 10, 1 1 1, 112, or 113 amino acids).
  • a variant neublastin polypeptide can also vary in sequence from the corresponding wild-type polypeptide.
  • certain amino acid substitutions can be introduced into the neublastin sequence without appreciable loss of a neublastin biological activity.
  • a variant neublastin polypeptide (i) contains one or more amino acid substitutions, and (ii) is at least 70%, 80%, 85%, 90%, 95%, 98% or 99% identical to SEQ ID NO: 1 (or 70%, 80%, 85%, 90%, 95%, 98% or 99% identical to amino acids 15-113 of SEQ ID NO: 1).
  • a variant neublastin polypeptide differing in sequence from SEQ ID NO: l may include one or more amino acid substitutions (conservative or non-conservative), one or more deletions, and/or one or more insertions.
  • Fig. 1 is an alignment of the wild type human, mouse, and rat pre pro neublastin polypeptides.
  • the vertical lines in Fig. l indicate the start of the mature 1 13 amino acid form (left vertical line) and 104 amino acid form (right vertical line) of neublastin.
  • the RRXR heparin binding motif is boxed.
  • This alignment of bioactive forms of neublastin indicates specific exemplary residues (i.e., those that are not conserved among the human, mouse, and rat forms) that can be substituted without eliminating bioactivity.
  • Percent identity between amino acid sequences can be determined using the BLAST 2.0 program. Sequence comparison can be performed using an ungapped alignment and using the default parameters (Blossom 62 matrix, gap existence cost of 1 1, per residue gap cost of 1, and a lambda ratio of 0.85). The mathematical algorithm used in BLAST programs is described in Altschul et al, 1997, Nucleic Acids Research 25:3389-3402.
  • a conservative substitution is the substitution of one amino acid for another with similar characteristics.
  • Conservative substitutions include substitutions within the following groups: valine, alanine and glycine; leucine, valine, and isoleucine; aspartic acid and glutamic acid; asparagine and glutamine; serine, cysteine, and threonine; lysine and arginine; and phenylalanine and tyrosine.
  • the non-polar hydrophobic amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine.
  • the polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine and glutamine.
  • the positively charged (basic) amino acids include arginine, lysine and histidine.
  • the negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Any substitution of one member of the above-mentioned polar, basic or acidic groups by another member of the same group can be deemed a conservative substitution.
  • Non-conservative substitutions include those in which (i) a residue having an electropositive side chain (e.g., Arg, His or Lys) is substituted for, or by, an electronegative residue (e.g., Glu or Asp), (ii) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by, a hydrophobic residue (e.g., Ala, Leu, He, Phe or Val), (iii) a cysteine or proline is substituted for, or by, any other residue, or (iv) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, He, Phe or Trp) is substituted for, or by, one having a smaller side chain (e.g., Ala, Ser) or no side chain (e.g., Gly).
  • an electropositive side chain e.g., Arg, His or Lys
  • an electronegative residue e.g., Glu or Asp
  • a biologically active variant neublastin polypeptide when dimerized, binds to a ternary complex containing GFRa3 and RET. Any method for detecting binding to this complex can be used to evaluate the biological activity a variant neublastin polypeptide. Exemplary assays for detecting the ternary complex-binding ability of a variant neublastin polypeptide are described in WO00/01815 (the content of which is incorporated herein by reference).
  • a variant neublastin polypeptide can also be assessed to evaluate its ability to trigger the neublastin signaling cascade.
  • the Kinase Receptor Activation (KIRA) assay can be used to assess the ability of a variant neublastin polypeptide to induce RET autophosphorylation (See also, Sadick et al, 1996, Anal. Biochem., 235(2):207).
  • Substitutions at one or more of the following amino acid residues are expected to result in a variant neublastin polypeptide having reduced or absent heparin binding ability as compared to wild type neublastin: Arg 48, Arg 49, Arg 51, Ser 46, Ser 73, Gly 72, Arg 39, Gin 21, Ser 20, Arg 68, Arg 33, His 32, Val 94, Arg 7, Arg 9, or Arg 14.
  • Reference to a neublastin amino acid reside by position number refers to the numbering of residues relative to SEQ ID NO: l .
  • a neublastin amino acid residue designated for substitution can be substituted with a non-conservative amino acid residue (e.g., glutamic acid) or a conservative or amino acid residue.
  • exemplary amino acids that can be substituted at a residue identified herein include glutamic acid, aspartic acid, and alanine.
  • variant neublastin polypeptides that exhibit reduced or absent heparin binding are disclosed in Table 1 and in WO 2006/023781 (the content of which is incorporated herein by reference). Amino acid residues of the variant neublastin
  • polypeptides that are mutated as compared to the corresponding wild type position are bolded and underlined in Table 1.
  • neublastin polypeptide e.g., 113, 99, or 104 amino acids in length
  • a polypeptide can optionally contain heterologous amino acid sequences in addition to a neublastin polypeptide.
  • heterologous refers to a sequence that originates from a source foreign to the particular host cell, or, if from the same host cell, is modified from its original form.
  • exemplary heterologous sequences include a heterologous signal sequence (e.g., native rat albumin signal sequence, a modified rat signal sequence, or a human growth hormone signal sequence) or a sequence used for purification of a neublastin polypeptide (e.g., a histidine tag).
  • Neublastin polypeptides can be isolated using methods known in the art. Naturally occurring or recombinantly produced neublastin polypeptides can be isolated from cells or tissue sources using standard protein purification techniques. Alternatively, mutated neublastin polypeptides can be synthesized chemically using standard peptide synthesis techniques. The synthesis of short amino acid sequences is well established in the peptide art. See, e.g., Stewart, et ah, Solid Phase Peptide Synthesis (2d ed., 1984).
  • neublastin polypeptides are produced by recombinant DNA techniques.
  • a nucleic acid molecule encoding a neublastin polypeptide can be inserted into a vector, e.g., an expression vector, and the nucleic acid can be introduced into a cell.
  • Suitable cells include, e.g., mammalian cells (such as human cells or CHO cells), fungal cells, yeast cells, insect cells, and bacterial cells (e.g., E. coli).
  • the cell is preferably cultured under conditions allowing for expression of a neublastin polypeptide.
  • the neublastin polypeptide can be recovered from a cell suspension if desired.
  • recovered means that the mutated polypeptide is removed from those components of a cell or culture medium in which it is present prior to the recovery process.
  • the recovery process may include one or more refolding or purification steps. Buffers and methods for inducing folding of a denatured neublastin polypeptide are described in, e.g., WO 2006/023782.
  • Variant neublastin polypeptides can be constructed using any of several methods known in the art.
  • One such method is site-directed mutagenesis, in which a specific nucleotide (or, if desired a small number of specific nucleotides) is changed in order to change a single amino acid (or, if desired, a small number of predetermined amino acid residues) in the encoded variant neublastin polypeptide.
  • site-directed mutagenesis kits are commercially available.
  • One such kit is the "Transformer Site Directed Mutagenesis Kit” sold by Clontech Laboratories (Palo Alto, CA).
  • a neublastin polypeptide can be incorporated into a pharmaceutical composition containing a therapeutically effective amount of the polypeptide and one or more adjuvants, excipients, carriers, and/or diluents.
  • Acceptable diluents, carriers and excipients typically do not adversely affect a recipient's homeostasis (e.g., electrolyte balance).
  • Acceptable carriers include biocompatible, inert or bioabsorbable salts, buffering agents, oligo- or
  • polysaccharides polymers, viscosity-improving agents, preservatives and the like.
  • One exemplary carrier is physiologic saline (0.15 M NaCl, pH 7.0 to 7.4).
  • Another exemplary carrier is 50 mM sodium phosphate, 100 mM sodium chloride. Further details on techniques for formulation and administration of pharmaceutical compositions can be found in, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES (Maack Publishing Co., Easton, Pa.).
  • compositions containing a neublastin polypeptide can be systemic or local.
  • Pharmaceutical compositions can be formulated such that they are suitable for parenteral and/or non-parenteral administration.
  • Specific administration modalities include subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intrathecal, oral, rectal, buccal, topical, nasal, ophthalmic, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration.
  • Administration may be by periodic injections of a bolus of the pharmaceutical composition or may be made more continuous by intravenous or intraperitoneal
  • a reservoir which is external (e.g., an IV bag) or internal (e.g., a bioerodable implant, a bioartificial organ, or a colony of implanted neublastin production cells).
  • a pharmaceutical composition may be achieved using suitable delivery means such as: a pump (see, e.g., Annals of Pharmacotherapy, 27:912 (1993); Cancer, 41 : 1270 (1993); Cancer Research, 44: 1698 (1984), incorporated herein by reference); microencapsulation (see, e.g., U.S. Pat. Nos. 4,352,883; 4,353,888; and
  • parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump delivery, encapsulated cell delivery, liposomal delivery, needle-delivered injection, needle-less injection, nebulizer, aeorosolizer, electroporation, and transdermal patch.
  • Formulations suitable for parenteral administration conveniently contain a sterile aqueous preparation of the neublastin polypeptide, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Formulations may be presented in unit-dose or multi-dose form.
  • An exemplary formulation contains a neublastin polypeptide described herein and the following buffer components: sodium succinate (e.g., 10 mM); NaCl (e.g., 75 mM); and L- arginine (e.g., 100 mM).
  • a neublastin polypeptide can be used for treating or preventing neuropathic pain.
  • a neublastin polypeptide (or a pharmaceutical composition comprising same) can be used in the treatment of a number of peripheral neuropathies associated with neuropathic pain, including: (a) trauma-induced neuropathies, such as those caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders related to neurodegeneration, (b) chemotherapy-induced neuropathies, (c) toxin-induced neuropathies (including but not limited to neuropathies induced by alcoholism, vitamin B6 intoxication, hexacarbon intoxication, amiodarone, chloramphenicol, disulfiram, isoniazide, gold, lithium,
  • drug-induced neuropathies including therapeutic drug-induced neuropathic pain (such as caused by anti-cancer agents, particularly anti-cancer agents selected from the group consisting of taxol, taxotere, cisplatin, nocodazole, vincristine, vindesine and vinblastine; and such as caused by anti-viral agents, particularly anti-viral agents selected from the group consisting of ddl, DDC, d4T, foscarnet, dapsone, metronidazole, and isoniazid), (e) vitamin-deficiency-induced neuropathies (including but not limited to vitamin B 12 deficiency, vitamin B6 deficiency, and vitamin E deficiency), (f) idiopathic neuropathies, (g) diabetic neuropathies, (h) pathogen-induced nerve damage, (i) inflammation-induced nerve damage, (j) neurodegeneration, (k) hereditary
  • herpes zoster which may lead to post-herpetic neuralgia), a human immunodeficiency virus (HIV), and a papilloma virus), (n) auto-immune neuropathies (including but not limited to Guillain-Barre syndrome, chronic inflammatory de-myelinating polyneuropathy, monoclonal gammopathy of undetermined significance and
  • polyneuropathy polyneuropathy
  • trigeminal neuralgia and entrapment syndromes including but not limited to Carpel tunnel
  • other neuropathic pain syndromes including post-traumatic neuralgia, phantom limb pain, multiple sclerosis pain, complex regional pain syndromes (including but not limited to reflex sympathetic dystrophy and causalgia), neoplasia- associated pain, vasculitic/angiopathic neuropathy, and painful lumbar radiculopathy
  • sciatica (commonly referred to as sciatica).
  • neuropathic pain conditions that can be treated or prevented by administration of a neublastin polypeptide are reviewed in the following sections.
  • Radicular pain is defined as spinal nerve root dysfunction causing dermatomal pain and paresthesias, myotomal weakness, and/or impaired deep tendon reflexes.
  • Lumbar radiculopathy refers to a pathologic process involving the lumbar nerve roots causing radicular symptoms into a lower extremity.
  • the nerve root pathology arises primarily from direct neural compression irrespective of whether the etiology is an acute herniated or displaced disc, bony spurs, foraminal stenosis, central stenosis, or hypermobility of a vertebral segment.
  • Painful lumbar radiculopathy is diagnosed mainly by history and clinical examination, where the patient describes pain radiating along a dermatomal distribution in the leg. The patient may also describe associated sensory or motor symptoms.
  • the neurological examination will find ipsilateral straight leg raising induced pain in case of fifth lumbar root (L5) or first sacral root (SI) compression, and usually detects neurological deficits localizing to a single root distribution.
  • the most useful test for confirming the presence of a radiculopathy is needle electromyogram (EMG); however, the needle EMG examination can identify only the root or roots that are physiologically involved, not the precise anatomic site of pathology in the lumbar spinal canal.
  • the most accurate imaging study to assess neural structures within the lumbar spine is magnetic resonance imaging (MRI) scanning.
  • MRI magnetic resonance imaging
  • a neublastin polypeptide can be administered to reduce the severity of neuropathic pain that has already appeared.
  • Prophylactic treatment would commence after determination of the initial diagnosis of diabetes or diabetes-associated symptoms and before the onset of neuropathic pain.
  • Prophylactic treatment may also commence upon determining that a subject is at risk for developing diabetes or diabetes- associated symptoms.
  • a neublastin polypeptide is administered to prevent the appearance of neuropathic pain or reduce the severity of the pain if it occurs.
  • a neublastin polypeptide is administered to treat or prevent appearance of neuropathic pain including but not limited to neuropathic pain associated with leprosy or Lyme disease or neuropathic pain associated with infection by a virus, particularly a virus selected from the group consisting of a herpes virus (and more particularly by a herpes zoster virus, which may lead to post-herpetic neuralgia), a human immunodeficiency virus (HIV), and a papilloma virus).
  • Prophylactic treatment is indicated after determination of infection and before onset of neuropathic pain.
  • Symptoms of acute viral infection often include the appearance of a rash. Other symptoms include, for example, the development of persistent pain in the affected area of the body, which is a common complication of a herpes zoster infection (shingles). Post-herpetic neuralgia can last for a month or more, and may appear several months after any rash-like symptoms have disappeared. Dosage and Frequency of Administration
  • a neublastin polypeptide (or a pharmaceutical composition comprising same) can be administered to a human subject experiencing neuropathic pain (e.g., painful lumbar radiculopathy) at a dosage of 100-1,600 ⁇ g/kg body weight of the human subject, per dose. Administration can be, for example, by intravenous or subcutaneous administration.
  • neuropathic pain e.g., painful lumbar radiculopathy
  • Exemplary dosage ranges include: 200-1,200 ⁇ g/kg body weight of the human subject, per dose; 200-800 ⁇ g/kg body weight of the human subject, per dose; 400-800 ⁇ g/kg body weight of the human subject, per dose; and 300-500 ⁇ g/kg body weight of the human subject, per dose.
  • a neublastin polypeptide can be administered at a dosage of 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1,000, 1,050, 1, 100, 1, 150, 1,200, 1,250, 1,300, 1,350, 1,400, 1,450, 1,500, 1,550, or 1,600 ⁇ g/kg body weight of the human subject.
  • the above neublastin polypeptide doses can be administered to the human subject in a single administration or repeatedly over the course of multiple administrations of the polypeptide.
  • Examples of dosing regimens comprising multiple administrations include, e.g., two administrations of the polypeptide within one week, three administrations of the polypeptide within one week, and three administrations of the polypeptide within a period of three weeks.
  • the same or different dosages of the neublastin polypeptide can be
  • the polypeptide may subsequently be administered to the human subject to maintain a therapeutic effect by administration at the same or at a different dose, at the same or at a different dosing frequency, and by the same or different route of administration.
  • subsequent dosing regimens include subsequent administration at an interval of once per month, subsequent administration at an interval of once per week, subsequent administration at an interval of once every two weeks, subsequent administration three times per week, and subsequent administration three times per week every other week.
  • the subsequent administrations can continue for any period of time, such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer.
  • the efficacy of neublastin in treating neuropathic pain can be evaluated by questioning human subjects on the status of their neuropathic pain symptoms pre- and post- treatment.
  • Part II assessed administration of BGOOOIO or placebo three times weekly for one week (Cohorts E to G). In Part II, subjects were dosed every 48 hours.
  • BGOOOIO is a soluble recombinant protein produced by Chinese hamster ovary
  • hNBN human neublastin
  • each BGOOOIO monomer contains one asparagine- linked glycosylation site, therefore, as expressed in CHO cells, the BG00010 dimer has a potential for two, one, or no glycosylations.
  • the species with two glycosylations per dimer is the predominant form produced with a lesser amount of monoglycosylated product and little nonglycosylated material.
  • BG00010 was supplied as a liquid drug product in vials containing 1.6 mg/mL of BG00010 formulated with 10 mM sodium succinate, 75 mM sodium chloride, and 100 mM L-arginine hydrochloride, at pH 5.5.
  • BG00010 was stored at 2 to 8°C (36 to 46°F), in a monitored, locked refrigerator, and was protected from light, protected from freezing, and was not to be shaken. Saline provided by the study site was used as placebo.
  • Vigorous exercise i.e., aerobic exercise for greater than 30 minutes
  • Alcohol use was prohibited from 24 hours prior to administration of study treatment until one week after administration of study treatment (Day 7), and for 24 hours prior to other visits.
  • the placebo-treated subjects in Part II of the study showed a change from baseline in the mean general sciatica pain score during Weeks 1 and 2 of -0.51 and -0.84 points. These were the greatest decreases from baseline seen in Part II of the study for placebo-treated subjects.
  • the BGOOOlO-treated subjects in Part II of the study showed a decrease in general sciatica pain that was observed at Week 1 and was maintained as a greater change from baseline than placebo-treated subjects for the duration of the study.
  • the greatest level of mean pain reduction was observed at Week 2 in the subjects that received 400 ⁇ g/kg, with a change from baseline in the mean pain score of -4.24 points.
  • FIGs. 8A-8B A graphical presentation of mean VAS scores over time at each dose level is presented in Figs. 8A-8B (Fig. 8A is subjects in Part I; Fig. 8B is subjects in Part II).
  • the 800 ⁇ g/kg BG00010 dose group showed the greatest mean decrease from baseline in the VAS score, with the greatest mean decrease seen at Day 43 (change of -34 points). The greatest mean decrease from baseline for placebo-treated subjects was seen at Day 71 (change of -20.67 points). For the other dose groups in Part I of the study, no notable benefit in pain reduction versus placebo-treated subjects was seen.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des méthodes de traitement d'une douleur neuropathique chez un patient humain par administration d'un polypeptide de neuroblastine à une dose de 100 à 1600 μg/kg de poids corporel du patient humain.
PCT/US2014/056985 2013-09-23 2014-09-23 Compositions et méthodes de traitement d'une douleur neuropathique WO2015042580A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361881200P 2013-09-23 2013-09-23
US61/881,200 2013-09-23

Publications (1)

Publication Number Publication Date
WO2015042580A1 true WO2015042580A1 (fr) 2015-03-26

Family

ID=51726865

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/056985 WO2015042580A1 (fr) 2013-09-23 2014-09-23 Compositions et méthodes de traitement d'une douleur neuropathique

Country Status (1)

Country Link
WO (1) WO2015042580A1 (fr)

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4352883A (en) 1979-03-28 1982-10-05 Damon Corporation Encapsulation of biological material
US4353888A (en) 1980-12-23 1982-10-12 Sefton Michael V Encapsulation of live animal cells
US4407957A (en) 1981-03-13 1983-10-04 Damon Corporation Reversible microencapsulation of a core material
US4883666A (en) 1987-04-29 1989-11-28 Massachusetts Institute Of Technology Controlled drug delivery system for treatment of neural disorders
US4968733A (en) 1988-09-01 1990-11-06 Akzo N.V. Process for producing microporous powders and membranes
US4976859A (en) 1988-09-01 1990-12-11 Akzo N.V. Integral asymmetric polyether-sulfone membrane, process for its production, and use for ultrafiltration and microfiltration
US5084350A (en) 1990-02-16 1992-01-28 The Royal Institution For The Advance Of Learning (Mcgill University) Method for encapsulating biologically active material including cells
US5158881A (en) 1987-11-17 1992-10-27 Brown University Research Foundation Method and system for encapsulating cells in a tubular extrudate in separate cell compartments
WO1992019195A1 (fr) 1991-04-25 1992-11-12 Brown University Research Foundation Vehicule implantable immuno-isolateur et biocompatible servant a apporter des produits therapeutiques selectionnes
US5284761A (en) 1987-11-17 1994-02-08 Brown University Research Foundation Method of encapsulating cells in a tubular extrudate
WO1995005452A2 (fr) 1993-08-12 1995-02-23 Cytotherapeutics, Inc. Compositions et procedes ameliores pour l'administration de molecuiles a activite biologique a l'aide de cellules modifiees genetiquement comprises dans des capsules biocompatibles immuno-isolatrices
WO2002051433A2 (fr) * 2000-12-22 2002-07-04 Genentech, Inc. Nouvelle utilisation de l'artemine, membre de la famille de ligands du facteur de croissance gdnf
WO2002078730A2 (fr) * 2001-03-28 2002-10-10 Biogen, Inc. Traitement utilisant des polypeptides de neublastine
WO2006023782A2 (fr) 2004-08-19 2006-03-02 Biogen Ideca Ma Inc. Repliement des proteines de la famille du facteur de croissance transformant beta
WO2006023781A2 (fr) 2004-08-19 2006-03-02 Biogen Idec Ma Inc. Variants de neublastine

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4352883A (en) 1979-03-28 1982-10-05 Damon Corporation Encapsulation of biological material
US4353888A (en) 1980-12-23 1982-10-12 Sefton Michael V Encapsulation of live animal cells
US4407957A (en) 1981-03-13 1983-10-04 Damon Corporation Reversible microencapsulation of a core material
US4883666A (en) 1987-04-29 1989-11-28 Massachusetts Institute Of Technology Controlled drug delivery system for treatment of neural disorders
US5284761A (en) 1987-11-17 1994-02-08 Brown University Research Foundation Method of encapsulating cells in a tubular extrudate
US5158881A (en) 1987-11-17 1992-10-27 Brown University Research Foundation Method and system for encapsulating cells in a tubular extrudate in separate cell compartments
US4968733A (en) 1988-09-01 1990-11-06 Akzo N.V. Process for producing microporous powders and membranes
US4976859A (en) 1988-09-01 1990-12-11 Akzo N.V. Integral asymmetric polyether-sulfone membrane, process for its production, and use for ultrafiltration and microfiltration
US5084350A (en) 1990-02-16 1992-01-28 The Royal Institution For The Advance Of Learning (Mcgill University) Method for encapsulating biologically active material including cells
WO1992019195A1 (fr) 1991-04-25 1992-11-12 Brown University Research Foundation Vehicule implantable immuno-isolateur et biocompatible servant a apporter des produits therapeutiques selectionnes
US5798113A (en) 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800828A (en) 1991-04-25 1998-09-01 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
WO1995005452A2 (fr) 1993-08-12 1995-02-23 Cytotherapeutics, Inc. Compositions et procedes ameliores pour l'administration de molecuiles a activite biologique a l'aide de cellules modifiees genetiquement comprises dans des capsules biocompatibles immuno-isolatrices
WO2002051433A2 (fr) * 2000-12-22 2002-07-04 Genentech, Inc. Nouvelle utilisation de l'artemine, membre de la famille de ligands du facteur de croissance gdnf
WO2002078730A2 (fr) * 2001-03-28 2002-10-10 Biogen, Inc. Traitement utilisant des polypeptides de neublastine
WO2006023782A2 (fr) 2004-08-19 2006-03-02 Biogen Ideca Ma Inc. Repliement des proteines de la famille du facteur de croissance transformant beta
WO2006023781A2 (fr) 2004-08-19 2006-03-02 Biogen Idec Ma Inc. Variants de neublastine

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Annals of Pharmacotherapy", vol. 27, 1993, pages: 912
"REMINGTON'S PHARMACEUTICAL SCIENCES", MAACK PUBLISHING CO.
ALTSCHUL ET AL., NUCLEIC ACIDS RESEARCH, vol. 25, 1997, pages 3389 - 3402
BAUDET ET AL., DEVELOPMENT, vol. 127, 2000, pages 4335
CANCER RESEARCH, vol. 44, 1984, pages 1698
CANCER, vol. 41, 1993, pages 1270
MASURE ET AL., EUR. J. BIOCHEM., vol. 266, 1999, pages 892
RATTENHOLL ET AL., J. MOL. BIOL., vol. 305, 2000, pages 523
ROSENBLAD ET AL., MOL. CELL NEUROSCI., vol. 15, no. 2, 2000, pages 199
SAARMA, MICROSC. RES. TECH., vol. 45, 1999, pages 292
SADICK ET AL., ANAL. BIOCHEM., vol. 235, no. 2, 1996, pages 207
STEWART ET AL.: "Solid Phase Peptide Synthesis", 1984
WANG RUIZHONG ET AL: "Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury.", NATURE NEUROSCIENCE APR 2008, vol. 11, no. 4, April 2008 (2008-04-01), pages 488 - 496, XP002733519, ISSN: 1097-6256 *

Similar Documents

Publication Publication Date Title
EP1993590B1 (fr) Compositions et procedes d'administration de proteines de la famille des ligands gdnf
ES2349043T3 (es) Variantes de neublastina.
US20220313770A1 (en) Immunotherapy for angiogenic disease
US20130096065A1 (en) Neublastin variants
US8642732B2 (en) Polymer-conjugated glycosylated neublastin
JP2009161515A (ja) ニューロパシーの疼痛を処置するためのニューブラスチンポリペプチドの使用
KR20120130752A (ko) 혈관신생-관련된 안질환의 치료를 위한 조성물 및 방법
AU2019275508A1 (en) Compositions and methods for treatment during non-acute periods following cns neurological injury
US20040077543A1 (en) Treatment using neublastin polypeptides
AU2023336200A1 (en) Methods of treating chronic inflammatory demyelinating polyneuropathy using anti-fcrn antibodies
WO2015042580A1 (fr) Compositions et méthodes de traitement d'une douleur neuropathique

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14784393

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14784393

Country of ref document: EP

Kind code of ref document: A1