RU2820132C2 - Method for improving lower urinary tract symptoms - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: presented group of inventions relates to urology. Disclosed are methods for reducing mean obstructive voiding symptoms (MOVS) in mammals having obstructive lower urinary tract symptoms (LUTS), selected from a group consisting of strain, weak jet, interrupted jet and incomplete emptying, and benign prostatic hyperplasia (BPH). Methods include identifying mammals having BPH and the above symptoms and administering a composition containing a peptide Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu (fexapotide triflutate).

EFFECT: presented group of inventions provides improvement of MOVS due to introduction of a composition containing fexapotide triflutate.

12 cl, 7 tbl, 4 ex

Description

[0001] This application contains a Sequence Listing provided electronically in ASCII format and is therefore incorporated herein by reference in its entirety.

[0002] This application claims priority to US Patent Application No. 16/410685, filed May 13, 2019, the contents of which are incorporated herein by reference in their entirety.

1. Field covered by the embodiments

[0003] Embodiments include methods for improving lower urinary tract symptoms (LUTS), and more specifically, improving obstructive bowel symptoms in patients with LUTS using compositions containing small peptide compounds and a pharmaceutically acceptable carrier.

2. Description of the state of the art

[0004] The European Association of Urology (EAU) and American Urological Association (AUA) guidelines define LUTS as filling symptoms (daytime frequency, urgency, and nocturia), voiding symptoms (obstructive symptoms) (straining, weak stream). , interrupted stream and incomplete emptying), or post-micturition symptoms (post-urinary leakage) that affect the lower urinary tract (LUT). Oelke M, et al ., European Association of Urology, Eur. Urol . July 2013; 64(1):118-40.

[0005] Benign prostatic hyperplasia (BPH) is a histological diagnosis that refers to a non-malignant proliferation of smooth muscle and epithelial cells of the prostate gland. Lee C, et al ., "Intrinsic and extrinsic factors controlling benign prostatic growth," Prostate, 1997;31:131-138; Auffenberg GB, et al ., "Established medical therapy for benign prostatic hyperplasia," Urol Clin North Am ,. 2009;36:443-459. The exact etiology is unknown. Progression of BPH can lead to benign prostatic enlargement (BPE), which is determined by the size of the prostate gland (abnormal). Approximately 50% of men with histological BPH develop DPV. BOP may eventually cause bladder outlet obstruction (BOO), which is also called benign prostatic obstruction (BPO) when associated with BPO. OVOM and DPZ are determined by urodynamic parameters. Some patients may have ARVD but not have significant LUTS, while other patients may have LUTS and experience significant deterioration in QoL, but without the presence of ARVD. Park, H. J., et al ., "Urinary Tract Symptoms (LUTS) Secondary to Benign Prostatic Hyperplasia (BPH), World J. Men's Health , No. 31(3), 193-207 (2013).

[0006] Lower urinary tract symptoms (LUTS) in men are mainly classified into 2 main types of symptoms: 1) “irritation” symptoms, also called “fullness” symptoms; and 2) “obstructive,” also called “voiding” symptoms. Symptoms of irritation/fullness include urinary urgency, higher frequency of urination, and nocturia (the need to urinate more frequently after falling asleep at night). Obstructive voiding symptoms include a weak urine stream, having to push or strain to evacuate urine, a feeling of incomplete emptying after urination, and stopping and starting to urinate several times during a bowel movement.

[0007] B Guidelines have been developed in the United States and Europe to assist clinicians in the management of LUTS, BPH, and LUTS/BPH. Oelke M, et al., European Association of Urology, Eur. Urol. July 2013; 64(1):118-40. The guideline discusses treatment options from watchful waiting (WW) for men who have symptoms but are not bothersome enough to require medication or surgery, to medication, to surgery. Guidelines for drug treatment include the use of alpha blockers (alpha adrenergic receptor antagonists), 5-alpha reductase inhibitors (5ARIs), antimuscarinics (anticholinergics), PDE5 inhibitors (tadalafil), combination therapies, and vasopressin analogues. Combination therapies such as an alpha blocker with a 5ARI or an antimuscarinic agent are also recommended.

[0008] Surgical treatment of the prostate, such as transurethral resection of the prostate, is indicated for men with absolute indications or drug-resistant LUTS. Indications for surgery include severe conditions such as urinary retention, gross hematuria, urinary tract infection, and bladder stones. Proposed minimally invasive treatments include transurethral microwave therapy and transurethral acupuncture. An alternative to catheterization for men who cannot undergo surgery includes prostatic stents. Despite the various treatment options available, there remains an unmet medical need for effective and safe treatments for these bothersome symptoms, some of which may be caused by prostate enlargement, which can lead to more serious problems such as chronic urinary tract infections, incontinence, acute or chronic urinary retention and kidney failure.

[0009] Certain agents known to have the ability to destroy and thus either promote removal or inhibit further growth of harmful or unwanted cells and tissues are described in US Pat. No. 6,924,266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446 and 8716247; and US Patent Application Publications No. 2017/0360885; 2017/0020957; 2016/0361380 and 2016/0215031, the contents of each of which are incorporated by reference in their entirety. One such drug is known as fexapotide triflutate.

[0010] There is a need for a treatment that can improve the symptoms of patients with LUTS without the risks and side effects of traditional drug therapies or surgery. There is also a need for treatments that can improve obstructive bowel symptoms in patients with LUTS without the risks and side effects of conventional drug therapy or surgery.

[0011] Throughout this specification, including the prior art description above, any and all publicly available documents described herein, including any and all published US patent applications, are specifically incorporated by reference in their entirety. The foregoing description of the prior art is not intended in any way to imply that any of the documents described herein, including pending US patent applications, are prior art for the present invention. Moreover, it is not intended that any disadvantages associated with the described products, methods and/or devices be stated herein without limiting the embodiments. Indeed, aspects of the embodiments may include certain features of the described products, methods and/or devices without their described disadvantages.

ESSENCE OF IMPLEMENTATION OPTIONS

[0012] There remains a need in the art for new less toxic and less frequent (eg, avoiding the need to take medications every day or once a week) treatments to improve the quality of life of patients with LUTS. There also remains a need in the art for treatments that improve obstructive bowel symptoms in patients with LUTS. Embodiments satisfy these needs.

[0013] The present invention is based in part on the discovery that certain peptides, including the specific peptide described by the amino acid sequence Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys -Arg-Cys-Leu (fexapotide triflutate or "FT") is capable of causing significant improvement in lower urinary tract symptoms (LUTS), and more specifically, improvement in obstructive bowel symptoms in patients with LUTS.

[0014] The present invention is also based in part on the discovery that the use of FT, either alone or in combination with an additional active agent capable of treating and/or eliminating unwanted cellular proliferation in mammals, provides undesirable improvement in patients having obstructive bowel symptoms associated with LUTS.

[0015] The compositions can be administered intramuscularly, orally, intravenously, intraperitoneally, intracerebrally (intraparenchymal route), intracerebroventricular route, intratumoral route, intralesional route, intradermal route, intrathecal route, intranasal route, intraocular route, intraarterial route, topically, transdermal route, via aerosol, infusion, bolus injection, implantable device, sustained release system, etc. Alternatively, the FT peptide may be expressed in vivo by introducing a gene that expresses the peptide, by introducing a vaccine that induces such production, or by introducing cells, bacteria or viruses that express the peptide in vivo due to genetic modification or otherwise.

[0016] In another embodiment, administration of a composition containing FT, either alone or in combination with at least one additional active substance capable of treating and/or eliminating unwanted cellular proliferation in mammals, improves mean scores of obstructive voiding symptoms (MOVS), measured in accordance with the International Prostate Symptom Scoring System (IPSS), by more than 30% compared to the administration of a control composition that does not contain FT.

[0017] In another embodiment, administration of a composition containing FT, either alone or in combination with at least one additional active substance capable of treating and/or eliminating unwanted cell proliferation in mammals in mammals, improves the average scores of irritating filling symptoms ( MISS), measured according to the International Prostate Symptom Scoring System (IPSS), by more than 20% compared to the administration of a control composition that does not contain FT.

[0018] Both the foregoing general description and the following detailed description are illustrative and explanatory, and are intended to provide further explanation of the claimed embodiments. Other objects, advantages and features will be readily apparent to those skilled in the art from the following detailed description of embodiments.

DETAILED DESCRIPTION OF PREFERRED IMPLEMENTATION OPTIONS

[0019] Before describing the embodiments, it is understood that the present invention is not limited to the specific methodology, protocols, cell lines, vectors and reagents described, as these may vary. It should also be understood that the terminology used in the present description is provided only for the purpose of describing specific embodiments and is not intended to limit the scope of the present embodiments, which are limited only by the accompanying claims.

[0020] Terms and expressions used in this description are defined as follows unless otherwise indicated. Throughout this description, the singular form includes the plural of entities referred to unless the context clearly indicates otherwise. Thus, for example, reference to “host cell” includes reference to a plurality of such host cells, and reference to “antibody” refers to one or more antibodies and equivalents thereof known to those skilled in the art, etc.

[0021] Amino acids and amino acid residues described in the present description can be given in accordance with the one-letter or three-letter code shown in the table below.

Table 1

Amino acid Single letter designation Three letter designation Alanin A Ala Arginine R Arg Asparagine N Asn Aspartic acid D Asp Cysteine C Cys Glutamine Q Gln Glutamic acid E Glu Glycine G Gly Histidine H His Isoleucine I Ile Leucine L Leu Lysine K Lys Methionine M Met Phenylalanine F Phe Proline P Pro Serin S Ser Threonine T Thr Tryptophan W Trp Tyrosine Y Tyr Valin V Val

[0022] Fexapotide triflutate ("FT"), as used herein, is a 17-mer peptide having the amino acid sequence: Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu -Ile-Lys-Arg-Cys-Leu (SEQ ID NO. 1). FT is described in US Pat. No. 6,924,266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446 and 8716247, and US Patent Application Publication No. 2017/0360885; 2017/0020957; 2016/0361380 and 2016/0215031. The disclosures of these patents and published applications are incorporated herein by reference in their entirety.

FT corresponds to:

SEQ ID NO.1 : IDQQVLSRIKLEIKRCL or Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu.

[0023] The term “fragment” refers to a protein or polypeptide that consists of a contiguous subsequence of the amino acid sequence of the protein or peptide and includes naturally occurring fragments such as splice variants and fragments generated by natural protease activity in vivo . Such a fragment may be truncated at the N-terminus, C-terminus and/or internally (eg, through natural splicing). Such fragments can be prepared with or without the N-terminal methionine. The term "fragment" includes fragments, both identical and different, of the same protein or peptide with a common or non-common amino acid sequence, joined together either directly or through a linker. One skilled in the art will be able to select an appropriate fragment for use in the embodiments without undue experimentation using the guidance and techniques described herein.

[0024] The term “variant” refers to a protein or polypeptide that has one or more amino acid substitutions, deletions and/or insertions from the amino acid sequence of the protein or peptide and includes naturally occurring allelic variants or alternative splicing variants of the protein or peptide. The term "variant" includes the replacement of one or more amino acids in a peptide sequence with similar or homologous amino acid(s) or dissimilar amino acid(s). There are many scales on which amino acids can be ranked as similar or homologous (Gunnar von Heijne, Sequence Analysis in Molecular Biology, p. 123-39 (Academic Press, New York, N.Y. 1987). Preferred options include substitutions with alanine in one or several amino acid positions. Other preferred substitutions include conservative substitutions that have little or no effect on the overall net charge, polarity or hydrophobicity of the protein. Conservative substitutions are listed in Table 2 below.

table 2

Conservative amino acid substitutions

Basic: arginine
lysine
histidine Acidic: glutamic acid
aspartic acid Uncharged polar: glutamine
asparagine
serine
threonine
tyrosine Non-polar: phenylalanine
tryptophan
cysteine
glycine
alanine
valine
proline
methionine
leucine
isoleucine

Table 3 shows another scheme of amino acid substitutions:

Table 3

Initial balance Substitutions Ala gly;ser Arg lys Asn gln;his Asp glu Cys ser Gln asn Glu asp Gly ala;pro His asn;gln Ile eu;val Leu ile;val Lys arg;gln;glu Met leu;tyr;ile Phe met;leu;tyr Ser thr Thr ser Trp tyr Tyr trp;phe Val ile;leu

[0025] Other options may consist of less conservative amino acid substitutions, such as selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone at the site of the substitution, such as, for example, sheet or helix conformation, (b) charge, or the hydrophobicity of the molecule at the target site, or (c) the volume of the side chain. In general, substitutions that are expected to have a greater effect on function are substitutions in which (a) the glycine and/or proline is replaced by another amino acid or is deleted or inserted; (b) a hydrophilic moiety, eg seryl or threonyl, replaces (or is replaced by) a hydrophobic moiety, eg leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (c) a cysteine residue replaces (or is replaced by) any other residue; (d) a residue having an electropositive side chain, for example lysyl, arginyl or histidyl, replaces (or is replaced by) a residue having an electronegative charge, for example glutamyl or aspartyl; or (e) a residue having a bulky side chain, such as phenylalanine, replaces (or is replaced by) a residue that does not have such a side chain, such as glycine. Other variants include variants designed to provide new glycosylation and/or phosphorylation site(s), or variants designed to remove existing glycosylation and/or phosphorylation site(s). Variants include at least one amino acid substitution at a glycosylation site, a proteolytic cleavage site, and/or a cysteine residue. Variants also include proteins and peptides with additional amino acid residues before or after the amino acid sequence of the protein or peptide on the linker peptides. For example, a cysteine residue can be added to both the N-terminus and the C-terminus of FT to allow cyclization of the peptide through disulfide bond formation. The term "variant" also includes polypeptides that have the amino acid sequence FT with at least one and up to 25 or more additional amino acids flanking either the 3' end or the 5' end of the peptide.

[0026] The term "derivative" refers to a chemically modified protein or polypeptide that is chemically modified either through natural processes such as processing and other post-translational modifications, but also by chemical modification methods, such as the addition of one or more molecules of polyethylene glycol, sugars, phosphates and/or other such molecules, where the molecule or molecules are not naturally associated with wild type or FT proteins. Derivatives include salts. Such chemical modifications are well described in major reference books and more detailed monographs, as well as in voluminous scientific literature, and are well known to those skilled in the art. It will be appreciated that the same type of modification may be present to the same or varying degrees in multiple regions of a given protein or polypeptide. Also, a given protein or polypeptide may contain many types of modifications. Modifications can occur anywhere in the protein or peptide, including the peptide backbone, amino acid side chains, and the N or C termini. Modifications include, for example, acetylation, acylation, ADP-ribosylation, amidation, flavin covalent addition, heme moiety covalent addition, nucleotide or nucleotide derivative covalent addition, lipid or lipid derivative covalent addition, phosphotidylinositol covalent addition, cross-linking, cyclization, disulfide bond formation , demethylation, covalent cross-linking, cysteine formation, pyroglutamate formation, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, glycosylation, lipid addition , sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, selenoylation, sulfation, transfer RNA-mediated addition of amino acids to proteins, such as arginylation and ubiquitinylation. See, for example, Proteins--Structure And Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993) and Wold, F., "Posttranslational Protein Modifications: Perspectives and Prospects," pgs. 1-12 in Posttranslational Covalent Modification Of Proteins, B. C. Johnson, Ed., Academic Press, New York (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990) and Rattan et al., “Protein Synthesis: Posttranslational Modifications and Aging,” Ann. N.Y. Acad. Sci. 663:48-62 (1992). The term "derivatives" includes chemical modifications that cause the protein or polypeptide to become branched or cyclic, with or without branching. Cyclic, branched and branched ring proteins or polypeptides can be the result of post-translational natural processes, and can also be produced entirely by synthetic methods.

[0027] The term “homolog” refers to a protein that is at least 60 percent identical to FT in its amino acid sequence when determined by standard methods typically used to compare the similarity in amino acid positions of two polypeptides. The degree of similarity or identity between two proteins can be readily calculated by known methods, including, but not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo H. and Lipman, D., SIAM, J. Applied Math., 48:1073 (1988). Preferred methods for determining identity are designed to provide the best possible match between the sequences being tested. Methods for determining identity and similarity are encoded in publicly available computer programs.

[0028] Preferred computer programs useful for determining the identity and similarity between two sequences include, but are not limited to, the GCG software package (Devereux, J., et al., Nucleic Acids Research, 12(1): 387 (1984) ), BLASTP, BLASTN, and FASTA, Atschul, S. F. et al., J. Molec. Biol., 215: 403-410 (1990). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol., 215: 403-410 (1990). As an example, using a computer algorithm such as GAP (Genetic Computer Group, University of Wisconsin, Madison, Wis.), two proteins or polypeptides to be determined for percent sequence identity are aligned to maximize matches their corresponding amino acids (the “match coverage” determined by the algorithm).

[0029] The algorithm uses a deletion penalty (which is calculated as the product of 3 and the average diagonal; "average diagonal" is the average of the diagonal of the comparison matrix used; "diagonal" is the score or number that is assigned to each absolute amino acid match by a particular matrix comparison), and the deletion penalty (which is typically {quotient (1/10)} times the deletion penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62. The algorithm can also use a standard comparison matrix (see Dayhoff et al. in: Atlas of Protein Sequence and Structure, vol. 5, supp. 3 for the PAM250 comparison matrix; see Henikoff et al., Proc. Natl. Acad. Sci USA, 89:10915-10919 for comparison matrices BLOSUM 62). The algorithm then calculates percent identity. Homologues typically have one or more amino acid substitutions, deletions and/or insertions relative to the protein or peptide, as appropriate.

[0030] The term "fusion protein" refers to a protein where one or more peptides are recombinantly fused or chemically conjugated (including covalently and non-covalently) to a protein such as, but not limited to, an antibody or antibody fragment such as Fab -fragment or short-chain Fv. The term "fusion protein" also refers to multimers (ie, dimers, trimers, tetramers and higher order multimers) of peptides. Such multimers include homomeric multimers containing one peptide, heteromeric multimers containing more than one peptide, and heteromeric multimers containing at least one peptide and at least one other protein. Such multimers may result from hydrophobic, hydrophilic, ionic and/or covalent associations, bonds or compounds, may be formed by cross-linking using linker molecules, or may be linked indirectly, for example, through the formation of liposomes.

[0031] The term "peptide mimetic" or "mimetic" refers to biologically active compounds that mimic the biological activity of a peptide or protein, but are no longer peptide in chemical nature, i.e. they no longer contain any peptide bonds (ie amide bonds between amino acids). As used herein, the term "peptide mimetic" is used in a broader sense to include molecules that are no longer fully peptide in nature, such as pseudopeptides, semipeptides and peptidoids. Examples of peptide mimetics in this broader sense (where part of the peptide is replaced by a structure lacking peptide bonds) are described below. Whether completely or partially non-peptide, peptide mimetics in accordance with embodiments provide a spatial arrangement of reactive chemical moieties that is highly similar to the three-dimensional arrangement of active groups in the peptide on which the peptide mimetic is based. As a result of this similar active site geometry, the peptide mimetic has effects on biological systems that are similar to the biological activity of the peptide.

[0032] Peptide mimetics according to embodiments are preferably substantially similar, with respect to both three-dimensional shape and biological activity, to the peptides described herein. Examples of methods for structural modification of a peptide to produce a peptide mimetic known in the art include inversion of backbone chiral centers resulting in D-amino acid residue structures that may, particularly at the N-terminus, result in increased resistance to proteolytic degradation without adverse effects. influence on activity. An example is given in the article "Tritriated D-ala.sup.1-Peptide T Binding", Smith C. S. et al., Drug Development Res., 15, pp. 371-379 (1988). The second way is to modify the cyclic structure to improve stability, such as interchain imides and N-C lactams (Ede et al. in Smith and Rivier (Eds.) "Peptides: Chemistry and Biology", Escom, Leiden (1991), pp.268-270 ). An example of this is conformationally restricted thymopentin-like compounds, such as those described in US Pat. No. 4,457,489 (1985) to Goldstein, G. et al., the contents of which are incorporated herein by reference in their entirety. The third method is to replace the peptide bonds in the peptide with pseudopeptide bonds, which provide resistance to proteolysis.

[0033] A number of pseudopeptide bonds have been described that generally do not affect the structure or biological activity of the peptide. One example of this approach is the substitution of pseudopeptide retroinverso bonds ("Biologically active retroinverso analogues of thymopentin", Sisto A. et al in Rivier, J. E. and Marshall, G. R. (eds) "Peptides, Chemistry, Structure and Biology", Escom, Leiden (1990), pp.722-773) and Dalpozzo, et al. (1993), Int. J. Peptide Protein Res., 41:561-566, incorporated herein by reference). According to this modification, the amino acid sequences of the peptides may be identical to the peptide sequences described above, except that one or more peptide bonds are replaced by a pseudopeptide retroinverse bond. Preferably, the majority of the N-terminal peptide bonds are substituted, since the substitution provides resistance to proteolysis by exopeptidases acting at the N-terminus. Additional modifications can also be made by replacing the chemical groups of amino acids with other chemical groups of similar structure. Another suitable pseudopeptide linkage known to enhance resistance to enzymatic degradation with little or no loss of biological activity is the reduced isosteric pseudopeptide linkage (Couder, et al. (1993), Int. J. Peptide Protein Res., 41 :181-184, incorporated herein by reference in its entirety).

[0034] Thus, the amino acid sequences of these peptides may be otherwise identical to the FT sequence except that one or more peptide bonds are replaced by an isosteric pseudopeptide bond. Preferably, the majority of the N-terminal peptide bonds are replaced, since such replacement provides resistance to proteolysis by exopeptidases acting at the N-terminus. The synthesis of peptides with one or more reduced isosteric pseudopeptide bonds is known in the art (Couder, et al. (1993), cited above). Other examples include the addition of ketomethylene or methyl sulfide bonds to replace peptide bonds.

[0035] Peptoid derivatives of peptides are another class of peptide mimetics that retain important structural determinants for biological activity but nonetheless lack peptide bonds, thereby conferring resistance to proteolysis (Simon, et al., 1992, Proc. Natl Acad. Sci. USA, 89:9367-9371, incorporated herein by reference in its entirety). Peptoids are oligomers of N-substituted glycine residues. A number of N-alkyl groups have been described, each corresponding to a side chain of a naturally occurring amino acid (Simon, et al. (1992), cited above). Some or all of the amino acids of the peptides may be replaced with an N-substituted glycine corresponding to the amino acid replaced.

[0036] The term "peptide mimetic" or "mimetic" also includes reverse D-peptides and enantiomers, as defined below.

[0037] The term “reverse D-peptide” refers to a biologically active protein or peptide consisting of D-amino acids arranged in the reverse order of the L-amino acid sequence of the peptide. Thus, the C-terminal residue of an L-amino acid peptide becomes the N-terminal residue of a D-amino acid peptide, and so on. For example, the peptide ETESH becomes H _d S _d E _d T _d E _d , where E _d , H _d , S _d and T _d are D-amino acids corresponding to L-amino acids E, H, S and T, respectively.

[0038] The term "enantiomer" refers to a biologically active protein or peptide where one or more L-amino acid residues in the amino acid sequence of the peptide are replaced by the corresponding D-amino acid residue(s).

[0039] "Composition" as used herein refers broadly to any composition containing FT and optionally an additional active agent. The composition may include a dry composition, an aqueous solution, or a sterile composition. Compositions containing FT can be used as hybridization probes. The probes may be stored in lyophilized form and may be associated with a stabilizer such as a carbohydrate. In hybridization, the probe can be used in an aqueous solution containing salts such as NaCl, detergents such as sodium dodecyl sulfate (SDS), and other components such as Denhardt's solution, milk powder, salmon sperm DNA, etc.

[0040] In one embodiment in which an additional active agent is used in conjunction with FT, the term "active agent" is used to refer to any substance capable of eliminating unwanted cellular proliferation and/or tissue growth. Suitable active agents may include, but are not limited to: (i) anti-cancer active agents (such as alkylating agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA/DNA antimetabolites and antimitotic agents); (ii) active substances for the treatment of benign growths, such as anti-acne and anti-wart agents; (iii) antiandrogenic compounds (cyproterone acetate (1α, 2β-methylene-6-chloro-17α-acetoxy-6-dehydroprogesterone) tamoxifen, aromatase inhibitors); (iv) alpha1-adrenergic receptor blockers (tamsulosin, terazosin, doxazosin, prazosin, bunazosin, indoramin, alfulzosin, silodosin); (v) 5α-reductase inhibitors (finasteride, dutasteride); (vi) phosphodiesterase type 5 (PDE5) inhibitors (tadalafil) and combinations thereof.

[0041] Also, the present invention is based in part on the discovery that the use of FT, either alone or in combination with an additional active substance capable of treating and/or eliminating unwanted cellular proliferation in mammals, provides unexpected improvement in patients suffering from obstructive bowel symptoms, associated with LUTS. Without being bound by any particular theory or practice, the inventor surprisingly discovered that administration of FT to a mammal provided unexpectedly excellent improvement in patients having LUTS. The inventor unexpectedly discovered during clinical trials for the treatment of BPH that administration of FT, alone or in combination with another active substance, significantly improved symptoms in patients with LUTS, including both irritative symptoms and obstructive bowel symptoms.

[0042] Patients treated with the compositions described herein demonstrated a significant improvement in mean obstructive voiding symptoms (MOVS) scores as measured by the International Prostate Symptom Scoring System (IPSS) of more than 30% compared to control administration compositions that do not contain FT. Embodiments may result in an improvement in mean obstructive voiding symptom scores (MOVS) as measured by the IPSS ranging from about 30% to about 150%, or from about 35% to about 125%, or from about 45% to about 105%. Patients treated with the compositions described herein demonstrated a significant improvement in mean irritant filling symptom scores (MISS) measured according to the International Prostate Symptom Scoring System (IPSS) of more than 20% compared to administration of a control composition. which does not contain FT. Embodiments may result in an improvement in mean irritant filling symptom scores (MISS) measured according to the IPSS ranging from about 20% to about 50%, or from about 25% to about 40%, or from about 30% to about 35%.

[0043] The inventor found that administration of conventional oral BPH medications to patients with LUTS demonstrated significant reductions in mean obstructive voiding symptom scores (MOVS) measured according to the IPSS and mean irritable filling symptom scores (MISS) measured according to with IPSS, compared with patients treated with placebo alone. The inventors found that the reduction in MOVS was approximately 50% and the reduction in MISS was approximately 40%. Thus, conventional therapies for the treatment of BPH would not be expected to improve the symptoms of patients having LUTS, which makes the significant improvement found within the scope of the present invention, which includes the administration of FT, even more surprising.

[0044] Embodiments include a method of treating a mammal having LUTS, comprising administering one or more times FT to the mammal, either alone or in combination with administering an additional active agent. The method includes, but is not limited to, administering a composition containing FT intramuscularly, orally, intravenously, intraperitoneally, intracerebrally (intraparenchymal route), intracerebroventricular route, intralesional route, intraocular route, intraarterial route, intrathecal route, intratumor route, intranasal route, topically, transdermally, subcutaneously, intradermally, transrectally, transperitoneally, either alone or as a conjugate with a carrier.

[0045] The use of the invention may be beneficial to any mammal, including humans, mice, rabbits, dogs, sheep and other livestock, any mammal that is being treated or can be treated by a veterinarian, zookeeper, or sanctuary worker. Preferred mammals are humans, sheep and dogs. Throughout this description, mammals and patients are used interchangeably.

[0046] One skilled in the art will appreciate that other smaller FT fragments may be selected so that the peptides have the same or similar biological activity. Other fragments can be selected by one skilled in the art so that the peptides have the same or similar biological activity. Peptides according to embodiments encompass these other fragments. Typically, peptides according to these embodiments have at least 4 amino acids, preferably at least 5 amino acids, and more preferably at least 6 amino acids.

[0047] Embodiments also include methods of treating mammals (or patients) having LUTS, comprising administering a composition containing FT that includes two or more FT sequences linked to each other, along with an additional active agent. Since FT has the desired biological activity, therefore, two or more FT sequences will also have the desired biological activity.

[0048] The FTs and fragments, variants, derivatives, homologues, fusion proteins and mimetics thereof covered by this embodiment can be produced using methods known to those skilled in the art, such as recombinant DNA technology, synthesis and isolation of natural peptides, proteins , variants, their derivatives and homologues. FT and fragments, variants, derivatives, homologues, fusion proteins and mimetics thereof can be prepared from other peptides, proteins and fragments, variants, derivatives and homologues thereof using methods known to those skilled in the art. Such methods include, but are not limited to, the use of proteases to cleave the peptide or protein into FT. To obtain the FT peptide described herein, you can use any method described, for example, in US patent No. 6924266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446 and 8716247, and US Patent Application Publication No. 2017/0360885; 2017/0020957; 2016/0361380 and 2016/0215031.

[0049] Embodiments of the present invention provide methods for treating mammals with LUTS that improve obstructive and/or irritative symptoms associated with LUTS, as defined by the IPSS. Such a method involves administering to a mammal in need thereof a therapeutically effective amount of FT, either alone or in combination with an additional active agent. The mammals in need of this may be mammals having LUTS, regardless of whether the mammals also have benign prostatic hyperplasia (BPH), or the mammals in need of this are mammals having both BPH and LUTS. Mammals in need may also be any mammal that would benefit from improvement in symptoms associated with LUTS.

[0050] The additional active agent, if used, may be one or more active agents selected from (i) anti-cancer active agents (such as alkylating agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA/DNA antimetabolites, and antimitotic agents ); (ii) active substances for the treatment of benign growths, such as anti-acne and anti-wart active substances (salicylic acid); (iii) antiandrogenic compounds (cyproterone acetate (1α,2β-methylene-6-chloro-17α-acetoxy-6-dehydroprogesterone)), tamoxifen, aromatase inhibitors); (iv) alpha1-adrenergic receptor blockers (tamsulosin, terazosin, doxazosin, prazosin, bunazosin, indoramin, alfulzosin, silodosin); (v) 5α-reductase inhibitors (finasteride, dutasteride); (vi) phosphodiesterase type 5 (PDE5) inhibitors (tadalafil) and combinations thereof. Preferably, the additional active agent is selected from the group consisting of tamsulosin, finasteride, terazosin, doxazosin, prazosin, tadalafil, alfuzosin, silodosin, dutasteride, combinations of dutasteride and tamsulosin, and mixtures and combinations thereof.

[0051] The therapeutic compositions described herein may contain a therapeutically effective amount of FT in admixture with a pharmaceutically acceptable carrier. In some alternative embodiments, the additional active agent may be administered in the same composition with the FT, and in other embodiments, the composition containing the FT is administered by injection while the additional active agent is formulated as an oral agent (gel, capsule, tablet, liquid, etc.). The carrier material may be water for injection, preferably supplemented with other materials commonly used in solutions for administration to mammals. Typically, FT is administered in the form of a composition containing purified FT peptide together with one or more physiologically acceptable carriers, excipients or diluents. Exemplary suitable vehicles are neutral buffered saline or saline mixed with serum albumin. Preferably, the product is formulated as a lyophilisate using suitable excipients (eg sucrose). If desired, other standard carriers, diluents and excipients may be included. The compositions of these embodiments may also contain buffers known to one of ordinary skill in the art at an appropriate pH range, including Tris buffer at a pH of about 7.0-8.5, or an acetate buffer at a pH of about 4.0-5.5 which may further include sorbitol or a suitable substitute thereof.

[0052] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders and granules. In such solid dosage forms, the additional active agent and/or FT may be mixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or dry diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (c) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (d) humectants such as glycerin; (e) disintegrants such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain complex silicates and sodium carbonate; (f) dissolution retardants such as paraffin; (g) absorption accelerators such as quaternary ammonium compounds; (h) wetting agents such as acetyl alcohol and glycerol monostearate; (i) adsorbents such as kaolin and bentonite; and (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills, dosage forms may also contain buffering agents.

[0053] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water and other solvents, solubilizing agents and emulsifiers. Exemplary emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil. oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbitan fatty acid esters, or mixtures of these substances, etc.

[0054] In addition to such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and fragrances.

[0055] The actual dosages of active ingredients in the compositions of these embodiments may be varied to achieve amounts of FT and additional active agent that are effective to achieve the desired therapeutic response for the particular composition and route of administration. Thus, the dosage chosen depends on the desired therapeutic effect, route of administration, desired duration of treatment, and other factors.

[0056] In the case of mammals, including humans, effective amounts can be administered based on body surface area. Dosage relationships for animals of various sizes and species, and humans (based on mg/m ² body surface area) are described by EJ Freireich et al., Cancer Chemother. Rep., 50 (4):219 (1966). Body surface area can be approximately determined from the height and body weight of an individual (see, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY pp. 537-538 (1970)).

[0057] The total daily dose of FT peptide and additional active agent administered to the host may be in single or divided doses. Unit dosage compositions may contain such quantities of such subsets as may be used to formulate a daily dose. However, it will be understood that the specific dosage level for any particular patient depends on various factors, including body weight, general health, sex, diet, time and route of administration, potency of the drug administered, rate of absorption and excretion, combination with other drugs, and the severity of the specific disease being treated. Preferably, the composition is administered only once as an injection or infusion, or in another preferred embodiment, the composition is administered twice. In this embodiment, the time period between administrations of the composition may vary from 2 months to 10 years, or from 8 months to 4 years, or may be more than one year (eg, 1 to 2 years).

[0058] The method of administering a composition containing FT, in accordance with embodiments, includes, but is not limited to, administering the composition intramuscularly, orally, intravenously, intraperitoneally, intracerebrally (intraparenchymal route), intracerebroventricular route, intratumoral route, at the site of injury, intradermal route, intrathecal route, intranasal route, intraocular route, intra-arterial route, topical, transdermal route, aerosol route, infusion route, bolus injection, implantable device, sustained release system, etc. You can use any method of administration described, for example, in US patents No. 6924266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446; and 8716247, and US Patent Application Publications No. 2017/0360885; 2017/0020957; 2016/0361380 and 2016/0215031.

[0059] In certain embodiments, the invention relates to a method of improving symptoms in a mammal having LUTS, optionally including mammals also having BPH, which includes identifying a mammal having BPH, which optionally also has LUTS, and administering to the mammal at least once a therapeutically effective amount of FT (SEQ ID NO. 1 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu)). In certain embodiments, the isolated FT peptide may be administered in combination with at least one active agent selected from the group consisting of (1) a 5α-reductase inhibitor and/or antiestrogen, (2) a 5α-reductase inhibitor and/or an aromatase inhibitor, (3) 5α-reductase inhibitor and/or 17β-HSD inhibitor, (4) 5α-reductase inhibitor, antiestrogen and aromatase inhibitor, (5) 5α-reductase inhibitor, antiestrogen and 17β-HSD inhibitor, (6) 5α-reductase inhibitor , aromatase inhibitor, anti-estrogen and 17β-HSD inhibitor, (7) 5α-reductase inhibitor, antiandrogen and anti-estrogen, (8), 5α-reductase inhibitor, antiandrogen and aromatase inhibitor, (9) 5α-reductase inhibitor, antiandrogen and 17β- inhibitor HSD, (10) 5α-reductase inhibitor, antiandrogen, antiestrogen and aromatase inhibitor, (11) 5α-reductase inhibitor, antiandrogen, aromatase inhibitor and 17β-HSD inhibitor, (12) 5α-reductase inhibitor, antiandrogen, aromatase inhibitor, antiestrogen and 17β-HSD inhibitor, (13) 17β-HSD inhibitor and antiestrogen, (14) 17β-HSD inhibitor and aromatase inhibitor, (15) 17β-HSD inhibitor, aromatase inhibitor and antiestrogen, (16) 17β-HSD inhibitor, antiandrogen and antiestrogen , (17) 17β-HSD inhibitor, antiandrogen and aromatase inhibitor, (18) 17β-HSD inhibitor, antiandrogen, antiestrogen and aromatase inhibitor, (19) antiestrogen and aromatase inhibitor and (20) antiestrogen, aromatase inhibitor and antiandrogen, (21) LHRH agonist or antagonist, 5α-reductase inhibitor and antiestrogen, (22) LHRH agonist or antagonist, 5α-reductase inhibitor and aromatase inhibitor, (23) LHRH agonist or antagonist, 5α-reductase inhibitor and 17β-HSD inhibitor, (24) agonist or LHRH antagonist, 5α-reductase inhibitor, anti-estrogen and aromatase inhibitor, (25) LHRH agonist or antagonist, 5α-reductase inhibitor, anti-estrogen and 17β-HSD inhibitor, (26) LHRH agonist or antagonist, 5α-reductase inhibitor, aromatase inhibitor, antiestrogen and 17β-HSD inhibitor, (27) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen and antiestrogen, (28), LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen and aromatase inhibitor, (29) LHRH agonist or antagonist , 5α-reductase inhibitor, antiandrogen and 17β-HSD inhibitor, (30) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen, anti-estrogen and aromatase inhibitor, (31) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen, aromatase inhibitor and 17β-HSD inhibitor, (32) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen, aromatase inhibitor, anti-estrogen and 17β-HSD inhibitor, (33) LHRH agonist or antagonist, 17β-HSD inhibitor and anti-estrogen, (34) agonist or LHRH antagonist, 17β-HSD inhibitor and aromatase inhibitor, (35) LHRH agonist or antagonist, 17β-HSD inhibitor, aromatase inhibitor and antiestrogen, (36) LHRH agonist or antagonist, 17β-HSD inhibitor, antiandrogen and antiestrogen, (37) LHRH agonist or antagonist, 17β-HSD inhibitor, antiandrogen and aromatase inhibitor, (38) LHRH agonist or antagonist, 17β-HSD inhibitor, antiandrogen, anti-estrogen and aromatase inhibitor, (39) LHRH agonist or antagonist, anti-estrogen and aromatase inhibitor and (40 ) LHRH agonist or antagonist, antiestrogen, aromatase inhibitor, and antiandrogen.

[0060] The following examples are provided to illustrate the illustrated embodiments. However, it should be understood that the embodiments are not limited to the specific conditions or details described in these examples. Throughout the description, any and all references to public domain documents, including US patents, are specifically incorporated by reference. In particular, embodiments expressly incorporate by reference the examples contained in US Pat. No. 6,924,266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446 and 8716247, and US Patent Application Publication No. 2017/0360885; 2017/0020957; 2016/0361380 and 2016/0215031, each of which demonstrate that certain peptides described therein are effective in promoting cell death in vivo in normal rodent muscle tissue, subcutaneous connective tissue, dermis and other tissues.

Example one

[0061] In patients with BPH, who did not necessarily also have LUTS, the urologist administered an intraprostatic injection of either a) FT (SEQ ID NO. 1 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys- Leu-Glu-Ile-Lys-Arg-Cys-Leu), 2.5 mg) in phosphate-buffered saline, pH 7.2 (“PBS”), or b) PBS alone in double-blind conditions in the room under ultrasound guidance . Patients were followed for 1 to 6 years with regular physical examination, laboratory tests, and symptom assessment. Symptom assessment was performed according to the International Prostate Symptom Scoring System (IPSS), which is a quantitative scale used to determine improvement or worsening of prostate symptoms. The IPSS quantifies the following: 1) incomplete emptying of the bladder after urination; 2) frequent urination; 3) stopping and starting during urination; 4) imperative urge to urinate; 5) weakness of the urine stream; 6) the need to push or strain during urination; 7) the need to urinate after falling asleep at night (nocturia).

[0062] IPSS positions 1, 3, 5, and 6 include an obstructive emptying symptoms scale, and IPSS positions 2, 4, and 7 include an annoying filling symptoms scale. Differences between baseline scores for irritating filling symptoms and follow-up scores; and baseline scores for obstructive voiding symptoms from follow-up scores were calculated in FT-treated individuals and placebo-treated controls. Surprisingly, the degree of improvement in scores for obstructive emptying symptoms in subjects who received a single prior FT injection was significantly better than the changes observed for annoying filling symptoms. The results are summarized in Table One.

Table 1

Treatment Number of patients MISS (SD) MOVS (SD) SEQ ID NO: 1 - FT 287 1.89 (3.10) 3.44 (4.90)* Control 217 1.41 (3.36) 2.35 (4.71)

*p=0.012 t-test versus placebo control.

[0063] As shown in Table 1, patients treated with the compositions described herein demonstrated an improvement in mean obstructive voiding symptoms (MOVS) measured according to the International Prostate Symptom Scoring System (IPSS) by more than 46% compared to administration of a control composition that does not contain FT. Table 1 also shows that patients treated with the compositions described herein demonstrated an improvement in mean irritant filling symptom scores (MISS) measured according to the IPSS by more than 34% compared to administration of a control composition that did not contains FT. Administration of FT thus provides greater improvement in MOVS and MISS in patients suffering from BPH. Because patients with BPH may or may not also have LUTS, the improvement would likely be even greater in patients with both BPH and LUTS.

Example two

[0064] In the second group of analysis, patients with BPH who did not necessarily also have LUTS were given an intraprostatic injection of PBS vehicle alone, pH 7.2, by a urologist in a double-blind, in-office setting under ultrasound guidance. Patients were followed for 1 to 3 years with regular physical examination, laboratory tests, and symptom assessment. Patients who received only PBS vehicle injections and were then additionally treated with conventional oral drug therapy used to treat BPH, including alpha blockers such as tamsulosin, terazosin, doxazosin or 5-alpha reductase inhibitors such as finasteride, dutasteride , or phosphodiesterase type 5 inhibitors (PDE5 inhibitors), such as tadalafil, were evaluated before and after administration of placebo and after administration of additional conventional oral medications for BPH. The IPSS quantifies the following: 1) incomplete emptying of the bladder after urination; 2) frequent urination; 3) stopping and starting during urination; 4) imperative urge to urinate; 5) weakness of the urine stream; 6) the need to push or strain during urination; 7) the need to urinate after falling asleep at night (nocturia). IPSS points 1, 3, 5 and 6 include a scale for obstructive emptying symptoms and points 2, 4 and 7 of the IPSS include a scale for irritable filling symptoms. Differences between baseline scores for distressing filling symptoms and follow-up scores; and baseline scores for obstructive voiding symptoms from follow-up scores were calculated for patients receiving blinded placebo and for patients receiving blinded placebo followed by conventional oral BPH medications. The degree of improvement in outcomes for obstructive emptying symptoms and irritable filling symptoms in individuals who received subsequent oral treatment for BPH after a prior placebo injection was not significantly better, and in fact, was worse, than the changes in individuals after an initial placebo injection. The results are summarized in Table Two.

table 2

Treatment Number of patients MISS (SD) MOVS (SD) Placebo + conventional drug treatment 42 0.83 (2.66) 1.14 (4.04) Control 217 1.41 (3.36) 2.35 (4.71)

[0065] The results in Table 2 show that patients with BPH who were administered a conventional oral drug for the treatment of BPH showed no improvement in either MOVS or MISS compared to patients who were administered only placebo control. Indeed, LUTS symptoms appeared to worsen to some extent in patients given a common oral drug to treat BPH. Thus, agents known to be effective in the treatment of BPH would not be expected to provide symptomatic improvement in patients who also have LUTS, let alone provide the significant improvement shown herein in patients who treated FT.

Example three

[0066] In the third study group, patients with BPH, who also did not necessarily have LUTS, were given an intraprostatic injection of PBS vehicle alone, pH 7.2, by a urologist in a double-blind, in-office setting under ultrasound guidance. Patients were followed for 1 to 3 years with regular physical examination, laboratory tests, and symptom assessment. 131 patients injected with PBS vehicle alone were cross-injected 1-3 years later with FT (SEQ ID NO. 1 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu- Glu-Ile-Lys-Arg-Cys-Leu), 2.5 mg) in phosphate-buffered saline, pH 7.2 ("PBS"). Differences from baseline scores for obstructive voiding symptoms were calculated from follow-up scores in patients who received placebo in a blinded manner (group one); patients who received blind placebo followed by oral administration of conventional BPH medications (group two) and patients who received blind placebo followed by FT treatment (group three). The degree of improvement in outcomes for obstructive voiding symptoms in individuals who received a subsequent FT injection after a previous placebo injection was significantly better than the change in individuals after an initial placebo injection and significantly better than the improvement in patients who received a blinded placebo injection followed by oral administration of conventional drugs against BPH. The results are summarized in Table Three.

Table 3

Treatment Number of patients MOVS (SD) Control 217 2.35 (4.71) Placebo + conventional drug therapy 42 1.14 (4.04) SEQ ID NO: 1 - FT 131 4.80 (4.74)* **

*p<0.0001, t-test comparing placebo alone;

**p<0.0001, t-test compared with placebo followed by oral administration of conventional medications for BPH

[0067] As shown in Table 3, patients treated with the compositions described herein exhibited an improvement in mean obstructive voiding symptoms (MOVS) scores as measured by the International Prostate Symptom Scoring System (IPSS) by more than 104% compared to administration of a control composition that does not contain FT, and more than 320% compared to administration of a placebo control followed by oral administration of a conventional anti-BPH drug. Because FT has previously been described to be effective in the treatment of BPH, and because established therapies for BPH (e.g., conventional oral drug therapy - see Example 2 above) have been found to be ineffective in treating both irritative and obstructive symptoms symptoms, FT administration was not expected to improve obstructive voiding symptoms in patients with LUTS, let alone provide a 300% improvement over other known BPH therapies.

Example four

[0068] In the fourth study group, patients with BPH, who also did not necessarily have LUTS, were given an intraprostatic injection of either PBS vehicle, pH 7.2, or FT alone by a urologist in a double-blind, in-office setting under ultrasound guidance. Patients were followed for 1 to 3 years with regular physical examination, laboratory tests, and symptom assessment. 217 patients received a double dose of placebo alone in a blinded manner (group one). 287 patients received dual administration of FT alone in a blinded manner (group two). After 1 to 3 years, 131 patients who received PBS vehicle injections alone were cross-injected with FT (group three). The final group of 189 patients received FT in a blinded manner, followed by a second FT injection 1–3 years later (group four). The difference between baseline and follow-up scores for obstructive voiding symptoms was calculated for patients who received placebo in a blinded manner (n=217) and compared with groups 2–4 that received FT (n=607). The degree of improvement in obstructive voiding symptoms in all subjects receiving FT injection was significantly better than the changes found in subjects receiving placebo injection alone. The results are summarized in Table Four.

Table 4

Treatment Number of patients MOVS (SD) SEQ ID NO: 1 - FT 607 4.82 (4.94)* Control 217 2.35 (4.71)

*p<0.0001, t-test versus placebo control.

[0069] As shown in Table 4, patients treated with the compositions described herein demonstrated an improvement in mean obstructive voiding symptoms (MOVS) scores as measured by the International Prostate Symptom Scoring System (IPSS) by more than 105% compared to administration of a control composition that does not contain FT.

[0070] The results of the above examples illustrate the unexpectedly superior effect of the FT peptide in improving symptoms in patients with LUTS. Those skilled in the art will appreciate that various modifications and changes can be made to the methods and compositions of the present embodiments without departing from the spirit and scope of the embodiments.

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LIST OF SEQUENCES

<110>NYMOX CORPORATION

AVERBACK, Paul

<120>WAY TO IMPROVE SYMPTOMS ON THE LOWER SIDE

URINARY TRACT

<130>063307-0504596

<140>16/410,650

<141>2019-05-13

<160>1

<170>PatentIn version 3.5

<210>1

<211>17

<212>PROTEIN

<213>Artificial sequence

<220>

<223>Synthetic peptide

<400>1

Ile Asp Gln Gln Val Leu Ser Arg Ile Lys Leu Glu Ile Lys Arg Cys

1 5 10 15

Leu

<---

Claims (17)

1. A method of reducing mean obstructive voiding symptoms (MOVS) in a mammal having lower urinary tract obstructive voiding symptoms (LUTS) and benign prostatic hyperplasia (BPH) by more than 30% compared to MOVS in mammals administered a control composition , which does not contain SEQ ID NO: 1, where the method includes: (a) identifying mammals having benign prostatic hyperplasia (BPH) that also have obstructive lower urinary tract voiding symptoms, where the obstructive symptoms are selected from the group consisting of straining, weak stream, interrupted stream, and incomplete voiding; And (b) administering by intraprostate injection to the mammal identified in step (a) a composition comprising SEQ ID NO: 1 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu -Ile-Lys-Arg-Cys-Leu). 2. The method according to claim 1, where the composition further contains a carrier. 3. The method of claim 1, wherein, when the composition is administered to mammals, mean obstructive voiding symptoms (MOVS) scores are measured according to the International Prostate Symptom Scoring System (IPSS) and said MOVS are reduced by an amount ranging from 30 to 150% , compared to MOVS measured in accordance with the IPSS in mammals administered a control composition that does not contain SEQ ID NO: 1. 4. The method of claim 3, wherein the mean obstructive voiding symptom scores (MOVS) measured according to the IPSS are reduced by an amount ranging from 35 to 125%. 5. The method of claim 3, wherein the mean obstructive voiding symptom scores (MOVS) measured according to the IPSS are reduced by an amount ranging from 45 to 105%. 6. The method of claim 1, wherein, when the composition is administered to mammals, mean obstructive voiding symptoms (MOVS) measured according to the IPSS are reduced by more than 300% compared to MOVS measured according to the IPSS in mammals in which administered an oral drug treatment known to be useful in the treatment of benign prostatic hyperplasia (BPH). 7. The method according to claim 1, where the composition is administered more than once. 8. A method for reducing mean obstructive voiding symptoms (MOVS) in mammals having obstructive voiding symptoms of the lower urinary tract (LUTS) and benign prostatic hyperplasia (BPH), wherein the obstructive voiding symptoms are selected from the group consisting of straining, weak stream, intermittent jet and incomplete emptying, where the method includes: (a) identifying mammals having benign prostatic hyperplasia (BPH) that also have obstructive lower urinary tract voiding symptoms (LUTS), selected from the group consisting of straining, weak stream, interrupted stream, and incomplete voiding; And (b) administering to the mammals identified in (a) above a composition containing a therapeutically effective amount of the peptide consisting of SEQ ID NO: 1 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys -Leu-Glu-Ile-Lys-Arg-Cys-Leu), wherein the method reduces mean obstructive voiding symptom scores (MOVS) measured according to the International Prostate Symptom Scoring System (IPSS) by more than 30% compared to MOVS measured according to the IPSS in mammals administered the control composition, which does not contain SEQ ID No. 1. 9. The method of claim 8, wherein the composition comprises a therapeutically effective amount of the peptide consisting of SEQ ID No. 1 and a carrier. 10. The method of claim 8, wherein the composition is administered more than once. 11. The method of claim 8, wherein the method reduces mean obstructive voiding symptom scores (MOVS) as measured by the IPSS by an amount in the range of 30 to 150%, or in the range of 35 to 125%, or in the range of 45 up to 105%. 12. The method of claim 8, wherein the method reduces mean obstructive voiding symptom scores (MOVS) as measured by the IPSS by more than 300% compared to MOVS in patients treated with an oral drug treatment known to is useful for the treatment of benign prostatic hyperplasia (BPH).