Fexapotide triflutate for the treatment of lower urinary tract symptoms

Abstract

A method for treating both obstructive and irritative lower urinary tract symptoms (LUTS) is disclosed, comprising identifying a patient with benign prostatic hyperplasia (BPH) and LUTS and administering a composition containing FT to the identified patient. This method is particularly effective in improving maximum urinary flow rate (Qmax) and nocturia.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 16 / 410,658, filed May 13, 2019, the entire contents of which are incorporated herein by reference.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in ASCII format, the contents of which are incorporated herein by reference in their entirety.

[0003] An embodiment includes a method of treating lower urinary tract symptoms (LUTS) by administering a composition comprising fexapotide triflutate ("FT"). The method is particularly effective in improving maximum urinary flow rate (Qmax) and nocturia. [Background technology]

[0004] Many medical treatments and procedures essentially involve the removal or destruction of harmful or unwanted tissue. Examples of such treatments include surgical removal of cancerous or precancerous growths, destruction of metastatic tumors by chemotherapy, and reduction of glandular (e.g., prostate) hyperplasia. Other examples include removal of unwanted facial hair, removal of warts, and removal of unwanted fatty tissue.

[0005] Benign prostatic hyperplasia (BPH) is common in older men and has symptoms that impact quality of life, including interference with activity and well-being. BPH can be a progressive disease with associated risks of urinary retention, infection, bladder stones, and kidney failure. While many men with mild to moderate symptoms do well without treatment, others may develop troublesome symptoms and complications that lead to medical therapy or surgery.

[0006] Benign prostatic hyperplasia (BPH) is a histological diagnosis of non-malignant proliferation of smooth muscle and epithelial cells of the prostate. Lee C et al., Intrinsic and extrinsic factors controlling benign prostatic growth, Prostate, 1997;31:131-138; Auffenberg GB et al., Established medical therapies for benign prostatic hyperplasia, Urol Clin North Am, 2009;36:443-459. The exact etiology is unknown. Progression of BPH may result in benign prostatic hyperplasia (BPE), diagnosed (pathologically) by the size of the prostate. Approximately 50% of men with histological BPH develop BPE. BPE may eventually lead to bladder outlet obstruction (BOO), also referred to as benign prostatic obstruction (BPO) when associated with BPE. BOO and BPO are diagnosed by urodynamic measurements. Some patients may have BPE without significant LUTS, while others may have LUTS and a significantly reduced QoL without BPE or BPH. See Park, HJ, et al., Urinary Tract Symptoms (LUTS) Associated with Benign Prostatic Hyperplasia (BPH), World J. Men's Health, No. 31(3), 193-207 (2013).

[0007] Lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia are generally classified into two types: 1) "irritative" symptoms, also known as "storage" symptoms, and 2) "obstructive" symptoms, also known as "voiding" symptoms. Irritative and voiding symptoms include urgency, frequency, and nocturia (the need to urinate frequently after going to bed at night). Obstructive and voiding symptoms include a weak urinary stream, the need to strain or exertion to expel urine, a feeling of residual urine, and frequent stops and starts during urination. Nocturia in particular is the most troublesome symptom, as it not only reduces the quality of sleep, but also causes chronic fatigue and inconvenience to spouses.

[0008] Guidelines have been established in the United States and Europe to assist physicians in the treatment of LUTS, BPH, and LUTS / BPH. See Oelke M, et al., European Association of Urology, Eur. Urol. 2013 July;64(1):118-40. The guidelines describe various treatment options ranging from watchful waiting (WW) for men who are symptomatic but do not require medication or surgical intervention, to medical treatment, and surgical intervention. Medical treatment guidelines include the use of alpha-blockers (alpha-adrenergic antagonists), 5-alpha-reductase inhibitors (5ARIs), antimuscarinics (anticholinergics), PDE5 inhibitors (tadalafil), combination therapy, and vasopressin mimetics. Combination therapy of alpha-blockers with 5ARIs and antimuscarinics is also recommended.

[0009] Prostate surgery, such as transurethral resection of the prostate, is indicated for men with absolute or drug-refractory BPH, LUTS, or acute urinary retention (AUR). Indications for surgery include severe symptoms such as urinary retention, gross hematuria, urinary tract infections, and bladder stones. Minimally invasive treatments include transurethral microwave therapy and transurethral needle therapy. Prostatic stents may be used as an alternative to catheter therapy for men who are unable to undergo surgery. Despite the existence of various treatment options, there remains an unmet medical need for effective and safe agents to treat the bothersome symptoms that can result from BPH. These symptoms can lead to more serious problems such as chronic urinary tract infections, incontinence, acute and chronic urinary retention, and renal failure.

[0010] Agents known to have the ability to destroy harmful or unwanted cells and tissues, thus facilitating their removal or inhibiting their further growth, are disclosed in U.S. Patent Application No. 14 / 808,713, filed July 24, 2015 ("Method of Reducing the Need for Surgery for Patients with Benign Prostatic Hyperplasia"), U.S. Patent Application No. 14 / 606,683, filed January 27, 2015 ("Method of Treating Diseases Requiring the Destruction or Removal of Cells"), U.S. Patent Application No. 14 / 738,551, filed June 12, 2015 ("Combination Compositions for Treating Diseases Requiring the Removal or Destruction of Unwanted Cellular Growths"), U.S. Patent Application Publication No. 2007 / 0237780 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237781 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237782 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237783 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237784 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237785 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237786 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237787 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237788 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237789 (now abandoned), U.S. Patent Application Publication No. 2007 / 0237789 (now abandoned), U.S. Patent No. 2003 / 0054990 (now U.S. Pat. No. 7,172,893), U.S. Patent Application Publication No. 2003 / 0096350 (now U.S. Pat. No. 6,924,266), U.S. Patent Application Publication No. 2003 / 0096756 (now U.S. Pat. No. 7,192,929), U.S. Patent Application Publication No. 2003 / 0109437 (now U.S. Pat. No. 7,241,738), U.S. Patent Application Publication No. 2003 / 0166569 (now U.S. Pat. No. 7,317,077), U.S. Patent Application Publication No. 2005 / 0032704 (now U.S. Pat. No. 7,408,021), and U.S. Patent Application Publication No. 2015 / 0148303 (now U.S. Pat. No. 9,243,035), the disclosures of which are incorporated herein by reference in their entireties.

[0011] One of the drugs disclosed in these publications is fexapotide triflutate (FT). FT has been shown to reduce prostate cells. In controlled clinical trials of BPH and some of its symptoms, FT produced greater overall improvement over placebo treatment over the long term.

[0012] There is a need for treatments that can improve or eliminate irritative and / or obstructive LUTS without the risks and side effects of traditional medications or surgery.There is a need for treatments that can improve irritative / storage symptoms and obstructive / voiding symptoms in patients with lower urinary tract symptoms without the risks and side effects of traditional medications or surgical intervention.

[0013] Throughout this description, including the foregoing description of the related art, all publicly available documents (including all U.S. patents and published patent applications) cited herein are specifically incorporated herein by reference in their entirety. The foregoing description of the related art is not an admission in any way that any of the above documents, including pending U.S. patent applications, are prior art to the present disclosure. Furthermore, any statements herein of disadvantages associated with the described products, methods, and / or apparatus are not intended to limit the embodiments in any way. Indeed, aspects of the embodiments may include certain features of the described products, methods, and / or apparatus without suffering from the described disadvantages. Summary of the Invention

[0014] There remains a need in the art for novel, less toxic, and less frequent (e.g., avoiding the need to take medications daily or weekly) treatments that can improve the QoL of patients with lower urinary tract symptoms. There is also a need for treatments that improve the irritative and obstructive symptoms of patients with lower urinary tract symptoms. Embodiments of the present invention meet these needs.

[0015] The present disclosure is based on the discovery that certain peptides, including the amino acid sequence Ile-Asp-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu (fexapotide triflutate or "FT"), can significantly improve lower urinary tract symptoms (LUTS) and also irritative and / or obstructive symptoms in LUTS patients.

[0016] The compositions can be administered intramuscularly, orally, intravenously, intraperitoneally, intraventricularly (intraparenchymal), intracerebroventricularly, intratumorally, intralesionally, intradermally, intrathecally, intranasally, intraocularly, intraarterially, topically, rectally, transperitoneally, transdermally, by aerosol, infusion, bolus injection, implantation device, sustained release system, etc. Alternatively, the FT peptide can be expressed in vivo, by administering a gene expressing the FT peptide, administering a vaccine that induces such production, or introducing cells, bacteria, or viruses that express the peptide in vivo by genetic modification, etc.

[0017] Another embodiment includes a method of improving the condition of nocturia, comprising identifying a patient with the condition (optionally including a patient with BPH) and administering a composition comprising FT to the identified patient, thereby reducing the proportion of patients with a change in nocturia frequency from baseline compared to a control group.

[0018] In yet another embodiment, the method includes identifying a patient with obstructive LUTS (optionally including a patient with BPH) and administering to the identified patient a composition comprising FT, whereby the method improves maximum urinary flow rate (Qmax), which reduces the proportion of patients who fail to achieve Qmax at least 12 months after a single administration compared to a control group.

[0019] Another embodiment includes a method of inhibiting urinary flow deterioration / obstruction as measured by an inability to provide a urine volume of 125 ml or more (regardless of prior oral water intake) comprising identifying a patient with obstructive LUTS (optionally including a patient with BPH as well) and administering to the identified patient a composition comprising FT. The method reduces the proportion of patients with worsening Qmax at least 12 months after a single administration compared to a control group.

[0020] Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the claimed embodiments. Other objects, advantages and features will become readily apparent to those skilled in the art from the following detailed description of each embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Before the embodiments are described, it is to be understood that the invention is not limited to the particular methodology, protocols, cell lines, vectors, and reagents described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of each embodiment of the present invention, which is limited only by the appended claims.

[0022] The terms and phrases used herein are defined as set forth below unless otherwise indicated. Throughout this specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "host cell" includes a plurality of host cells, and a reference to an "antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art.

[0023] The amino acids and amino acid residues described herein may be referred to according to the commonly accepted one-letter or three-letter codes set forth in the table below. [Table 1]

[0024] Fexapotide triflutate ("FT"), as used herein, refers to a 17-mer peptide having the following amino acid sequence: Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu (SEQ ID NO: 1). NO.1) FT is disclosed in U.S. Patent Nos. 6,924,266, 7,241,738, 7,317,077, 7,408,021, 7,745,572, 8,067,378, 8,293,703, 8,569,446, and 8,716,247, and U.S. Patent Application Publication Nos. 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 is expressed as follows: SEQ ID NO.1: IDQQVLSRIKLEIKRCL or Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu.

[0025] The term "fragment" refers to a protein or polypeptide consisting of a contiguous subsequence of the amino acid sequence of a protein or peptide, including naturally occurring fragments such as splice variants and fragments resulting from naturally occurring in vivo protease activity. Such fragments may be truncated at the amino terminus, carboxy terminus, and / or internally (such as by natural splicing). Such fragments may be prepared with or without an amino-terminal methionine. The term "fragment" includes identical or different fragments from the same protein or peptide, having common or non-common contiguous amino acid sequences linked directly or via a linker. Using the guidelines and procedures outlined herein, one skilled in the art will be able to select suitable fragments for use in the embodiments without undue experimentation.

[0026] The term "variant" refers to a protein or polypeptide in which one or more amino acid substitutions, deletions, and / or insertions are present when compared to the amino acid sequence of a protein or peptide described herein, and includes naturally occurring allelic variants or alternative splice variants of the proteins or peptides thus described. The term "variant" includes the substitution 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 criteria for which amino acids can be identified as similar or homologous (Gunnar von Heijne, Sequence Analysis in Molecular Biology, pp. 123-39 (Academic Press, New York, NY, 1987). Preferred variants include alanine substitutions at one or more 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 shown in Table 2 below. [Table 2] Table 3 shows another scheme for amino acid substitutions. [Table 3]

[0027] Other variants can consist of less conservative amino acid substitutions, such as selecting residues that have a more significant effect on (a) the structure of the polypeptide backbone in the region of the substitution, e.g., as a sheet or helix conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) maintaining the bulk of the side chain. In general, substitutions expected to have a more significant effect on function are those in which (a) glycine and / or proline are substituted for another amino acid or deleted or inserted; (b) hydrophilic residues, such as seryl or threonyl, are substituted for (or by) hydrophobic residues, such as leucyl, isoleucyl, phenylalanyl, valyl, or alanyl; (c) cysteine ​​residues are substituted for (or by) any other residue; (d) residues with electropositive side chains, such as lysyl, arginyl, or histidyl, are substituted for (or by) negatively charged residues, such as glutamyl or aspartyl; or (e) residues with large side chains, such as phenylalanine, are substituted for (or by) one that does not have such a side chain, such as glycine. Other mutants include those designed to either generate new glycosylation and / or phosphorylation sites or to delete existing glycosylation and / or phosphorylation sites. Variants include glycosylation sites, proteolytic cleavage sites, and / or at least one amino acid substitution at a cysteine ​​residue. Variants also include proteins and peptides that include additional amino acid residues before or after the protein or peptide amino acid sequence on the linker peptide. For example, cysteine ​​residues can be added to both the amino and carboxy termini of the FT peptide to allow for cyclization of the peptide by disulfide bond formation. The term "variant" also includes polypeptides having the amino acid sequence of FT with at least one and up to 25 or more additional amino acids adjacent to either the 3' or 5' end of the peptide.

[0028] The term "derivative" refers to a chemically modified protein or polypeptide that has been chemically modified not only by natural processes such as processing and other post-translational modifications, but also by chemical modification techniques, such as the addition of one or more polyethylene glycol molecules, sugars, phosphates, and / or other such molecules when such molecules are not naturally attached to the wild-type protein or FT. Derivatives include salts. Such chemical modifications are well described in basic textbooks and in more detailed monographs, as well as in a large body of research literature, and are well known to those skilled in the art. It will be recognized that the same type of modification may be present in the same or different degrees at several sites of a given protein or polypeptide. Also, a given protein or polypeptide may contain many types of modifications. Modifications can occur at any site of the protein or polypeptide, including the peptide backbone, the amino acid side chains, and the amino or carboxy termini. Modifications include, for example, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, glycosylation, lipid attachment, 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 ubiquitination.See, e.g., Proteins--Structure And Molecular Properties, 2nd ed., TECreighton, WH Freeman and Company, New York (1993); Wold, F., "Posttranslational Protein Modifications: Perspectives and Prospects," in Posttranslational Covalent Modification Of Proteins, pp. 1-12, BC 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. NY Acad. Sci. 663:48-62 (1992). The term "derivative" includes chemical modifications that result in a protein or polypeptide that is branched or branched and cyclic, or unbranched and cyclic. Cyclic, branched and branched circular proteins or polypeptides can result from posttranslation natural processes and can also be made by entirely synthetic methods.

[0029] The term "homolog" refers to a protein that is at least 60% identical to the amino acid sequence of FT, as determined by commonly used standard methods for comparing the similarity at the amino acid positions of two polypeptides. The degree of similarity or identity between two proteins may be determined by a number of methods, including but not limited to, Computational Molecular Biology, Lesk, A. M., Oxford Unversity Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., M Stockton Press, New York, 1991; and Carillo H. and Lipman, D., SIAM, J. Applied Math., 48:1073 (1988). Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs.

[0030] Preferred computer program methods useful in determining identity and similarity between two sequences include, but are not limited to, the GCG program 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)). For example, using a computer algorithm such as GAP (University of Wisconsin Genetics and Computer Group, Madison, Wisconsin), the two proteins or polypeptides for which the percent sequence identity is to be determined are aligned so that their respective amino acids are optimally matched (the "matched span" as determined by the algorithm).

[0031] A gap opening penalty (calculated as 3 times the average diagonal; "average diagonal" is the average of the diagonals of the comparison matrix used; "diagonal" is the score or number assigned to each perfect amino acid match by a particular comparison matrix) and a gap extension penalty (usually 1 / 10 of the gap opening penalty), as well as a comparison matrix such as PAM250 or BLOSUM62, are used in conjunction with the algorithm. Standard comparison matrices (for the PAM250 comparison matrix, see Dayhoff et al.: Atlas of Protein Sequence and Structure, vol.5, supp.3; for the BLOSUM62 comparison matrix, see Henikoff et al., Proc. Natl. Acad. Sci USA, 89:10915-10919) can also be used with the algorithm. The algorithm then calculates the percent identity. Homologs will typically have one or more amino acid substitutions, deletions, and / or insertions when compared to the corresponding protein or peptide, as the case may be.

[0032] The term "fusion protein" refers to a protein in which one or more peptides are recombinantly fused or chemically conjugated (including covalent and non-covalent) to a protein, such as (but not limited to) an antibody or an antibody fragment, such as a Fab fragment or a single chain Fv. The term "fusion protein" also refers to multimers (i.e., dimers, trimers, tetramers and higher multimers) of peptides. Such multimers include homomeric multimers comprising one peptide; heteromeric multimers comprising two or more peptides; and heteromeric multimers comprising at least one peptide and at least one other protein. Such multimers may be the result of hydrophobic, hydrophilic, ionic and / or covalent associations, bonds or links, may be formed by cross-linking using linker molecules, or may be linked indirectly, for example, by liposome formation.

[0033] The term "peptidomimetic" or "mimetic" refers to a biologically active compound that mimics the biological activity of a peptide or protein, but is no longer peptidic in chemical nature, i.e. no longer contains any peptide bonds (i.e. amide bonds between amino acids). In this specification, the term peptidomimetic is used in a broader sense, and includes molecules that are no longer completely peptidic in nature, such as pseudopeptides, semi-peptides and peptoids. Examples of peptidomimetics in this broader sense (where parts of a peptide are replaced with structures that lack peptide bonds) are described below. Whether completely non-peptidic or partially non-peptidic, peptidomimetics according to each embodiment provide a spatial arrangement of reactive chemical moieties that closely mimics the three-dimensional arrangement of the active groups of the peptide on which the peptidomimetic is based. As a result of this similarity in the geometry of the active site, peptidomimetics have an effect on biological systems that resembles the biological activity of peptides.

[0034] The peptidomimetics of the present invention are preferably substantially similar to the peptides described herein in both three-dimensional shape and biological activity. Examples of methods known in the art for structurally modifying peptides to generate peptidomimetics include inversion of the main chain chiral center to induce D-amino acid residue structures, which induce enhanced stability against proteolytic degradation, especially at the N-terminus, without adversely affecting activity. An example of this is described in the article "Tritriated D-ala1-Peptide T Binding", Smith CS et al., Drug Development Res., 15, 371-379 (1988). The second method is the modification of cyclic structures for stability, such as N to C interchain imides and lactams (Ede et al., in Smith and Rivier (eds.) "Peptides: Chemistry and Biology", Escom, Leiden (1991), pp. 268-270). An example of this is given in conformationally restricted thymopentin-like compounds such as those disclosed in U.S. Patent No. 4,457,489 (1985), Goldstein, G. et al., the disclosure of which is incorporated herein by reference in its entirety. A third method is to replace peptide bonds in the peptide with pseudopeptide bonds that confer resistance to proteolysis.

[0035] Some pseudopeptide bonds have been described, which generally do not affect peptide structure and biological activity. One example of this approach is to replace it with a retro-inverso pseudopeptide bond ("Biologically active retroinverso analogues of thymopentin", Sisto A. et al., in Rivier, JE and Marshall, GR (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 sequence of the peptide may be identical to that of the above peptide, except that one or more peptide bonds are replaced with a retro-inverso pseudopeptide bond. Preferably, the most N-terminal peptide bond is substituted, since such substitution will confer resistance to proteolysis by exopeptidases acting on the N-terminus. Further modifications can also be made by replacing the amino acid chemical groups with other chemical groups of similar structure. Another suitable pseudopeptide bond known to increase stability against enzymatic cleavage with little or no loss of biological activity is the reduced isostere pseudopeptide bond (Couder et al. (1993), Int. J. Peptide Protein Res., 41:181-184, incorporated herein by reference in its entirety).

[0036] Thus, the amino acid sequences of these peptides may be identical to that of FT, except that one or more peptide bonds are replaced by isostere pseudopeptide bonds. Preferably, the most N-terminal peptide bond is replaced, since such a replacement would confer resistance to proteolysis by exopeptidases acting on the N-terminus. The synthesis of peptides with one or more reduced isostere pseudopeptide bonds is known in the art (Couder et al. (1993), cited above). Other examples include the replacement of a peptide bond by the introduction of a ketomethylene or methylsulfide bond.

[0037] Peptoid derivatives of the peptides described herein represent another type of peptidomimetic that retains structural determinants important for biological activity but has peptide bonds removed, thereby rendering it resistant to proteolysis (Simon et al., 1992, Proc. Natl. Acad. Sci. USA, 89:9367-9371, incorporated herein in its entirety). Peptoids are oligomers of N-substituted glycines. Several N-alkyl groups have been described, each corresponding to the side chain of a natural amino acid (Simon et al. (1992), cited above). It is possible to replace some or all of the amino acids of a peptide with N-substituted glycines corresponding to the amino acid being replaced.

[0038] The term "peptidomimetic" or "mimetic" also includes reverse-D peptides and enantiomers, as defined below.

[0039] The term "reverse D peptide" refers to a biologically active protein or peptide consisting of D-amino acids arranged in reverse order as compared to the L-amino acid sequence of the peptide. Thus, the carboxy terminal residue of the L-amino acid peptide becomes the amino terminal residue of the D-amino acid peptide, etc. For example, the peptide ETESH would be HdSdEdTdEd, where Ed, Hd, Sd, and Td are the D-amino acids corresponding to the L-amino acids E, H, S, and T, respectively.

[0040] The term "enantiomer" refers to a biologically active protein or peptide in which one or more L-amino acid residues in the amino acid sequence of the peptide are replaced by the corresponding D-amino acid residue.

[0041] The term "composition" as used herein broadly refers to any composition containing FT and, optionally, additional active agents. The composition may include a dry formulation, an aqueous solution, or a sterile composition. The composition containing FT may be used as a hybridization probe. The probes may be stored in lyophilized form and may be associated with a stabilizer, such as a carbohydrate. For hybridization, the probe may be placed in an aqueous solution containing salts, such as NaCl; detergents, such as sodium dodecyl sulfate (SDS); and other components, such as Denhardt's solution, skim milk, salmon sperm DNA, etc.

[0042] In embodiments in which an additional active agent is used with FT, the term "active agent" is used to denote any agent that provides a therapeutic effect to a patient in need thereof, more preferably any agent that can remove unwanted cellular and / or tissue growths. 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 agents for treating benign growths, for example, anti-acne and anti-wart active agents, (iii) anti-androgenic compounds (cyproterone acetate (1α,2β-methylene-6-chloro-17α-acetoxy-6-dehydroprogesterone), tamoxifen, aromatase inhibitors), (iv) alpha 1-adrenergic receptor blockers (tamsulosin, terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin, silodosin), (v) 5α-reductase inhibitors (finasteride, dutasteride), (vi) phosphodiesterase type 5 (PDE5) inhibitors (tadalafil) and combinations thereof.

[0043] Throughout this specification, the terms "obstructive symptoms" and "voiding symptoms" and the terms "irritability symptoms" and "storage symptoms" are used interchangeably to refer to symptoms in patients with lower urinary tract symptoms (LUTS). The European Association of Urology (EAU) and the American Urological Association (AUA) guidelines define LUTS as irritative (voiding) symptoms (daytime frequency, urgency, nocturia), obstructive (voiding) symptoms (pressure, weak urinary flow, intermittent urinary flow, residual urine), and post-voiding symptoms (leakage after voiding) that affect the lower urinary tract (LUTS). See Park, HJ et al., "Urinary Tract Symptoms (LUTS) Associated with Benign Prostatic Hyperplasia (BPH)." World J. Men's Health, No. 31(3), 193-207 (2013).

[0044] Improvement of obstructive and irritative symptoms can be measured according to techniques known in the art. For example, it is known to use a uroflowmeter to determine the change in urine weight and obtain a continuous plot of flow rate over time. The plot is smoothed by an internal electronic filter to allow accurate (±5%) measurement of Qmax. See Schafer W et al., "Examples of Urodynamic Testing: Uroflowmetry, Filling Cystometry, and Pressure-Flow Studies," Neurourol Urodynamics, Vol. 21, pp. 261-74 (2002). There are various methods for measuring nocturia, but most involve the patient completing a questionnaire before and after treatment to establish a baseline, and determining the difference from the baseline after treatment (improvement, no improvement, worsening, etc.). Examples include the International Prostate Symptom Score (IPSS) nocturia question score evaluation, nocturnal voiding frequency evaluation (Boyarsky symptom score), Madsen-Iversen symptom score, ICSmale questionnaire, etc. See, e.g., Chartier-Kastler et al., "Measurement of Nocturia in Patients with LUTS / BPH and Its Impact on Sleep Quality and QoL," Eur. Urol. Supp., Vol. 5, pp. 3-11 (2006). The preferred method for measuring nocturia is the mean change from baseline in the nocturia question (question 7) of the IPSS. Question 7 asks patients how many times they had to get up to urinate between going to bed and getting up in the past month, with scores ranging from "none" (score 0) to "more than 5 times" (score 5).

[0045] Identification of LUTS patients with irritative and / or obstructive symptoms is typically performed by a licensed, experienced medical professional and is a separate diagnosis from benign prostatic hyperplasia (BPH). That is, although there is some overlap, patients with BPH do not always have LUTS, and patients with LUTS do not always have BPH. There are a number of techniques known in the art that are available to identify patients with irritative or obstructive LUTS. For example, Chapple et al., "Male Lower Urinary Tract Symptoms (LUTS)," An International Consultation on Male LUTS, Fukuoka, Japan, September 30-October 4, 2012, Societe Internatinoal d'Urologie, (2013) discloses established techniques for identifying patients suffering from obstructive symptoms ("Patient Assessment," Committee 2, Section 2.3, pp. 61-80 (103-122)) and for identifying patients suffering from nocturia ("Assessment," Committee 3, Section 3.6, pp. 155-162 (197-204)). Using the above guidelines and those described in the above publications, a person skilled in the art would be able to identify patients with obstructive LUTS and patients with nocturia.

[0046] The inventors have unexpectedly discovered, without intending to be limited to any particular theory or procedure, that administration of FT to a mammal results in an unexpectedly superior effect on improving irritative and obstructive symptoms in patients with LUTS. The inventors have discovered that such administration of FT results in an unexpectedly superior effect on improving symptoms in patients with LUTS, including both irritative and obstructive symptoms, compared to patients administered a control drug or placebo. Patients with LUTS may also have BPH, and in one embodiment, patients with LUTS do not have BPH. It is clear that the population of patients who have LUTS and BPH is a subset of the overall patient population suffering from BPH. Thus, a method of treating or improving BPH does not necessarily improve irritative and / or obstructive symptoms in patients with LUTS.

[0047] The inventors have found that approximately 3 months after a single dose of FT 2.5 mg, there is a moderate improvement in the reduction in the proportion of patients unable to achieve a urine volume of 125 ml or more compared to patients receiving a control drug (e.g., 3.9% for FT vs. 4.3% for control, i.e., a reduction of approximately 10%). There is also a moderate improvement in the reduction in the proportion of patients who exhibited a worsening of maximum flow compared to patients receiving a control drug (35.2% for FT vs. 37% for control, i.e., a reduction of approximately 5.1%). The inventors have unexpectedly found that approximately 12 months after a single dose of FT 2.5 mg, there is a marked improvement in the reduction in the proportion of patients unable to achieve a urine volume of 125 ml or more compared to patients receiving a control drug (e.g., 4.5% for FT vs. 5.9% for control, i.e., a reduction of approximately 31%). There is also a moderate improvement in the reduction in the proportion of patients who exhibited a worsening of maximum flow compared to patients receiving a control drug (35% for FT vs. 42% for control, i.e., a reduction of approximately 20%). These results show that FT, despite being administered once, provides long-term effects superior to short-term effects. Moreover, this effect was highly desirable and unexpected compared to conventional oral medications. The effects of conventional oral medications are not uniform; alpha blockers are almost immediate but only effective if taken continuously (long-term success rate is very low, i.e. long-term effects are low), while 5ARIs must be taken continuously for a long period of time to be effective and have many side effects.

[0048] Similarly, patients who received a single dose of FT 2.5 mg showed a modest improvement in mean nocturnal frequency score from baseline after 3 months, but these improvements were not significantly better than the control group (only resulting in an improvement of about 8%). However, the inventors unexpectedly found that patients who received a single dose of FT 2.5 mg were significantly less likely to show an increase in nocturnal frequency change from baseline after at least 12 months compared to the control group. This result also makes it clear that FT can have long-term effects even with a single dose.

[0049] In one embodiment, the inventors have discovered that the methods of administering FT described herein are effective in reducing the proportion of patients with BPH and LUTS who continue to have poor urinary flow / obstruction 12 months after administration of FT, as measured by the proportion of patients with a urine output less than 125 ml regardless of prior water intake ("Qmax not reached"). The inventors have discovered a reduction of at least 15%, about 15% to about 75%, about 20% to about 50%, about 25% to about 45%, about 30% to about 37%, or any value within these ranges, compared to a placebo control. Surprisingly, the inventors have discovered that the improvement in mean flow rate from baseline measured at 12 months after administration is similar in (1) patients administered FT and (2) patients administered a control drug.

[0050] In another embodiment, the inventors have discovered that the methods of administering FT described herein can significantly reduce the proportion of patients who exhibited a worsening of maximum flow rate ("Qmax worsening") 12 months after administration. The inventors have discovered that administration of a composition comprising FT reduces the proportion of patients whose Qmax worsened after 12 months by about 15% or more, about 15% to about 50%, about 15% to about 40%, about 18% to about 40%, about 19% to about 25%, or any value within these ranges, compared to a control group. Surprisingly, the inventors have also discovered that the improvement in mean flow rate from baseline measured 3 to 12 months after administration is comparable between (1) patients administered FT and (2) patients administered a control drug.

[0051] In another embodiment, the inventors have discovered that the methods of administering FT described herein significantly reduce the proportion of patients whose nocturia frequency change from baseline after 12 months is greater than 0 ZCV ("worsening nocturia") compared to a control group. The inventors have discovered that administration of a composition comprising FT reduces the proportion of patients whose nocturia worsens after 12 months by about 20% or more, about 20% to about 75%, about 25% to about 50%, about 30% to about 40%, about 32% to about 38%, or any value within these ranges, compared to a control group. Surprisingly, the inventors have also discovered that the average improvement in nocturia frequency per night is comparable between (1) patients administered FT and (2) patients administered a control drug.

[0052] The embodiments include a method of treating a mammal suffering from either irritative or obstructive symptoms (or both) of LUTS by administering a composition comprising FT. The composition may comprise FT as the only active agent, or FT may be administered in combination with another active agent. This method includes, but is not limited to, administering a composition comprising FT intramuscularly, orally, intravenously, intraperitoneally, intracerebrally (intraparenchyma), intraventricularly, intralesionally, intraocularly, intraarterially, intrathecally, intratumorally, intranasally, topically, transdermally, subcutaneously, intradermally, rectally, or transperitoneally, alone or in combination with a carrier.

[0053] Any mammal can benefit from the use of the present invention. Mammals include humans, mice, rabbits, dogs, sheep and other domestic animals, as well as any mammal that is or can be treated by veterinarians, zookeepers, and wildlife conservation workers. Preferred mammals include humans, sheep and dogs. The words "mammal" and "patient" are used interchangeably herein.

[0054] It will be clear to those skilled in the art that other smaller fragments of FT may be selected such that these peptides have the same or similar biological activity. Those skilled in the art may also select other fragments of FT such that these peptides have the same or similar biological activity. Thus, the term "FT" used in the embodiments encompasses these other fragments. Generally, the peptides of each embodiment have at least 4 amino acids, preferably at least 5 amino acids, and more preferably at least 6 amino acids.

[0055] Also, embodiments of the present invention include methods of treatment that include administering a composition comprising FT, which is comprised of two or more linked FT sequences, together with an additional active agent. To the extent that FT has the desired biological activity, the two or more FT sequences will also have the desired biological activity.

[0056] FT and its fragments, variants, derivatives, homologs, fusion proteins and mimetics encompassed by embodiments of the present invention can be produced using methods known to those of skill in the art. For example, methods such as recombinant DNA technology, protein synthesis, and isolation of natural peptides, proteins, variants, derivatives and homologs can be used. FT and its fragments, variants, derivatives, homologs, fusion proteins and mimetics can be produced from other peptides, proteins and their fragments, variants, derivatives and homologs using methods known to those of skill in the art. Such methods include, but are not limited to, the use of proteases to cleave peptides or proteins to FT. For example, any of the methods disclosed in U.S. Patent Nos. 6,924,266, 7,241,738, 7,317,077, 7,408,021, 7,745,572, 8,067,378, 8,293,703, 8,569,446, and 8,716,247, and U.S. Patent Application Publication Nos. 2017 / 0360885, 2017 / 0020957, 2016 / 0361380, and 2016 / 0215031, the disclosures of which are incorporated herein by reference in their entirety, may be used to prepare the FT peptides described herein.

[0057] When an additional active agent is used, the additional active agent can be one or more active agents selected from the following: (i) anticancer active agents (such as alkylating agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA / DNA antimetabolites, and mitotic inhibitors), (ii) active agents for treating benign growths, for example anti-acne and anti-wart active agents (salicylic acid), (iii) antiandrogenic compounds (cyproterone acetate (1α,2β-methylene-6-chloro-17α-acetoxy-6-dehydroprogesterone), tamoxifen, aromatase inhibitors), (iv) α1-adrenergic receptor blockers (tamsulosin, terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin, 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, a combination of dutasteride and tamsulosin, and mixtures and combinations thereof.

[0058] The therapeutic compositions described herein may include a quantity of FT mixed with a pharma- ceutically acceptable carrier. In some alternative embodiments, the additional active agent may be administered in the same composition as FT, and in other embodiments, the composition containing FT is administered as an injection, while the additional active agent is formulated in the form of an oral pharmaceutical (gel, capsule, tablet, liquid, etc.). The carrier material may be water for injection, preferably water supplemented with other materials typically included in solutions for administration to mammals. Typically, FT is administered in the form of a composition containing purified FT peptide (or chemically synthesized FT peptide) in combination with one or more physiologically acceptable carriers, excipients, or diluents. Neutral buffered saline or saline mixed with serum albumin are examples of suitable carriers. Preferably, the product is formulated as a lyophilizate using suitable excipients (e.g., sucrose). Other standard carriers, diluents, and excipients may be included if desired. The compositions of the embodiments may also include a buffer having a suitable pH range known to those skilled in the art, such as a Tris buffer having a pH of about 7.0 to 8.5, or an acetate buffer having a pH of about 4.0 to 5.5, which may further include sorbitol or a suitable substitute thereof.

[0059] 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 the 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 extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution setting retarders, 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. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0060] Liquid dosage forms for oral administration include pharma- ceutical acceptable emulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Examples of 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, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances.

[0061] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0062] The actual dosage level of the active ingredient in the composition of the present invention may vary to obtain an effective amount of FT and additional active agent to obtain the desired therapeutic response for a particular composition. Thus, the selected dosage level will depend on the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. In certain embodiments, the composition is contained in an appropriate amount of carrier (e.g., 10 ml of phosphate buffered saline having a pH of about 7.2) at about 0.5 to about 25 mg, about 1.0 to about 10 mg, about 2.0 to about 5.0 mg, 2.5 mg, or any amount therebetween.

[0063] For mammals, including humans, effective amounts can be administered based on body surface area. The interrelationship of doses (mg / mL) for animals of various sizes and species, and for humans, is given below. 2 Rep., 50(4):219 (1966). Body surface area can be approximately determined from the height and weight of an individual (see, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, pp. 537-538 (1970)).

[0064] It will be understood that the specific dosage level for any particular patient will vary depending on a variety of factors, such as body weight, general health, sex, diet, time and route of administration, potency of the administered drug, absorption and excretion rates, combination with other drugs, and the severity of the particular disease being treated. It is desirable to administer the composition at least twice, with at least the second administration occurring at least one year after the first administration. In this embodiment, the interval between administrations of the composition may vary, ranging from 1 year to 15 years, 1 year to 4 years, or 1 year to 2 years.

[0065] Methods of administering a composition comprising FT according to embodiments of the present invention include, but are not limited to, administering the composition intramuscularly, orally, intravenously, intraperitoneally, intraventricularly (intrasoft tissue), intraventricularly, intratumorally, intralesionally, intradermally, intrathecally, intranasally, intraocularly, intraarterially, topically, rectally, transperitoneally, transdermally, by aerosol, infusion, bolus injection, implantable device, sustained release system, etc. For example, any of the administration methods disclosed in U.S. Patent Nos. 6,924,266, 7,241,738, 7,317,077, 7,408,021, 7,745,572, 8,067,378, 8,293,703, 8,569,446, and 8,716,247, and U.S. Patent Application Publication Nos. 2017 / 0360885, 2017 / 0020957, 2016 / 0361380, and 2016 / 0215031, may be used.

[0066] In one embodiment, at least one active agent administered in combination with the FT peptide is selected from the group consisting of (1) 5α-reductase inhibitors and / or antiestrogens, (2) 5α-reductase inhibitors and / or aromatase inhibitors, (3) 5α-reductase inhibitors and / or 17β-HSD inhibitors, (4) 5α-reductase inhibitors, antiestrogens, and aromatase inhibitors, (5) 5α-reductase inhibitors, antiestrogens, and 17β-HSD inhibitors, (6) 5α-reductase inhibitors, inhibitors, aromatase inhibitors, antiestrogens, and 17β-HSD inhibitors, (7) 5α-reductase inhibitors, antiandrogens, and antiestrogens, (8) 5α-reductase inhibitors, antiandrogens, and aromatase inhibitors, (9) 5α-reductase inhibitors, antiandrogens, and 17β-HSD inhibitors, (10) 5α-reductase inhibitors, antiandrogens, antiestrogens, and aromatase inhibitors, (11) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (12) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (13) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (14) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (15) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (16) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (17) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (18) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (19) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (20) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (21) 5α-reductase inhibitors, antiandrog ductase inhibitors, antiandrogens, aromatase inhibitors, antiestrogens, and 17β-HSD inhibitors, (13) 17β-HSD inhibitors and antiestrogens, (14) 17β-HSD inhibitors and aromatase inhibitors, (15) 17β-HSD inhibitors, aromatase inhibitors and antiestrogens, (16) 17β-HSD inhibitors, antiandrogens, and antiestrogens, (17) 17β-HSD inhibitors, antiandrogens, and aromatase inhibitors, (18) 17β-HSD inhibitors, antiandrogens, antiestrogens, and aromatase inhibitors. (19) antiestrogens and aromatase inhibitors, (20) antiestrogens, aromatase inhibitors and antiandrogens, (21) LHRH agonists or antagonists, 5α-reductase inhibitors and antiestrogens, (22) LHRH agonists or antagonists, 5α-reductase inhibitors and aromatase inhibitors, (23) LHRH agonists or antagonists, 5α-reductase inhibitors and 17β-HSD inhibitors, (24) LHRH agonists or antagonists and 5α-reductase inhibitors,antiestrogens and aromatase inhibitors, (25) LHRH agonists or antagonists, 5α-reductase inhibitors, antiestrogens and 17β-HSD inhibitors, (26) LHRH agonists or antagonists, 5α-reductase inhibitors, aromatase inhibitors, antiestrogens and 17β-HSD inhibitors, (27) LHRH agonists or antagonists, 5α-reductase inhibitors, antiandrogens and antiestrogens, (28) LHRH agonists or antagonists, 5α-reductase inhibitors (29) LHRH agonists or antagonists, 5α-reductase inhibitors, antiandrogens, and 17β-HSD inhibitors, (30) LHRH agonists or antagonists, 5α-reductase inhibitors, antiandrogens, antiestrogens, and aromatase inhibitors, (31) LHRH agonists or antagonists, 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, and 17β-HSD inhibitors, (32) LHRH agonists or antagonists (33) LHRH agonists or antagonists, 17β-HSD inhibitors, and antiestrogens, (34) LHRH agonists or antagonists, 17β-HSD inhibitors, and aromatase inhibitors, (35) LHRH agonists or antagonists, 17β-HSD inhibitors, aromatase inhibitors, and antiestrogens, (36) LHRH agonists or antagonists, 17β-HSD inhibitors, antiandrogens and antiestrogens, (37) LHRH agonists or antagonists, 17β-HSD inhibitors, antiandrogens and aromatase inhibitors, (38) LHRH agonists or antagonists, 17β-HSD inhibitors, antiandrogens, antiestrogens and aromatase inhibitors, (39) LHRH agonists or antagonists, antiestrogens and aromatase inhibitors, and (40) LHRH agonists or antagonists, antiestrogens, aromatase inhibitors and antiandrogens.

[0067] Based on tissue culture genetic array data, FT is a novel molecule that stimulates the caspase pathway (activation of caspase 7, 8, 10, caspase recruitment domain 6, 11, 14, and DIABLO), tumor necrosis factor pathway (activation of TNF1, TNFSF6, TNFSF8, TNFSF9, CD70 ligand, TNFRSF19L, TNFRSF25, TRAF2, TRAF3, TRAF4, and TRAF6 receptor), and BCL pathway (activation of BIK, HRK, BCL2L10, and BCL3) in prostate epithelial cells in vitro. FT selectively induces loss of plasma membrane integrity, mitochondrial metabolic arrest, RNA depletion, DNA lysis and aggregation, cell fragmentation, and cell loss. The process of apoptosis is characterized by progressive ultrastructural changes, typical of membrane disruption and swelling, progressively deeper nuclear infiltration, and finally membrane blebbing, followed by cell death and fragmentation into apoptotic bodies. Histologically, typical apoptotic changes are evident throughout the injection site for several weeks following treatment, with immunohistochemical positivity for apoptotic markers.

[0068] FT has been extensively tested in patients with BPH and low-grade (T1c) prostate cancer. The compound and a placebo control have been administered rectally in over 1700 procedures in nine human clinical trials. In these large, long-term clinical trials in patients with BPH, FT was administered at a concentration of 0.25 mg / ml (2.5 mg of FT would reach approximately 15-20% of the prostate by volume). See, e.g., Shore et al., "The potential for NX-1207 in benign prostatic hyperplasia: an update for clinicians," Ther Adv. Chronic Dis., 2(6), pp. 377-383 (2011). Thus, compositions containing FT preferably contain 2.5 mg of FT.

[0069] The following examples are provided to illustrate the various embodiments of the present invention. However, it should be understood that the various embodiments are not limited to the specific conditions or details described in these examples. Throughout this specification, any or all references to publicly available documents, including U.S. patents, are specifically incorporated herein by reference. In particular, embodiments of the present invention expressly incorporate by reference the examples contained in U.S. Patent Nos. 6,924,266, 7,241,738, 7,317,077, 7,408,021, 7,745,572, 8,067,378, 8,293,703, 8,569,446 and 8,716,247, as well as U.S. Patent Application Publication Nos. 2017 / 0360885, 2017 / 0020957, 2016 / 0361380 and 2016 / 0215031, each of which discloses that certain peptides set forth therein are effective agents for inducing cell death in vivo in normal rodent muscle tissue, subcutaneous connective tissue, dermis and other tissues. EXAMPLES

[0070] Clinical trials were conducted on a large number of patients with BPH, some of whom had LUTS. All protocols were performed in accordance with regulations and by physicians.

[0071] [Example 1] Under double-blind conditions and ultrasound guidance by a urologist in a clinical setting, patients suffering from BPH and possibly LUTS received intraprostatic injections of either a) 2.5 mg FT in phosphate buffered saline ("PBS") at pH 7.2 or b) PBS alone. Patients were followed for 12 months to several years with regular physical examinations, laboratory tests, and symptom evaluations. Maximal urinary flow rate (Qmax) was measured at baseline and after 12 months using standard flowmeter measurements in subjects who were able to void sufficient amounts of urine (≥125 mL) to provide a valid test. Subjects who were unable to void ≥125 mL even after drinking as much water as they wanted were classified as "Qmax failures." The number of subjects who failed Qmax was compared between the different groups. The mean flow rate improvement was similar in FT-treated patients and the control group, but surprisingly, subjects who received vehicle injections as a control showed 31% more failures compared to the FT 2.5 mg treatment. The results of Example 1 are shown in Table 4 below. [Table 4]

[0072] The results in Table 4 reveal that administration of a composition containing FT reduced the proportion of patients who did not achieve Qmax compared to the control group (an improvement of about 31%). It was a completely unexpected result that administration of FT to patients could reduce the proportion of patients who did not achieve Qmax by 31% compared to the control group.

[0073] [Example 2] Under double-blind conditions and ultrasound guidance by a urologist in a clinical setting, patients suffering from BPH and possibly LUTS were given intraprostatic injections of either a) 2.5 mg FT in phosphate buffered saline ("PBS") at pH 7.2, or b) PBS alone. Patients were followed for 12 months to several years with regular physical examinations, laboratory tests, and symptom evaluations. Maximum urinary flow rates (Qmax) were measured after 3 and 12 months by reading a flowmeter using standard techniques. Although the improvement in mean flow rates was similar in the FT and control groups, it was surprisingly found that a significantly smaller proportion of patients receiving 2.5 mg FT showed worsening flow rates after 12 months compared to the vehicle-only control group. The results of Example 2 are shown in Table 5 below. [Table 5]

[0074] The results in Table 5 reveal that administration of a composition containing FT significantly reduced the proportion of patients whose Qmax worsened after 12 months compared to the control group (about 20% improvement). It was completely unexpected that administration of FT to patients could reduce the proportion of patients whose Qmax worsened by 20% compared to the control group.

[0075] [Example 3] Under double-blind conditions under ultrasound guidance by a urologist in a clinical environment, patients suffering from BPH and possibly LUTS were given intraprostatic injections of either 10 mL of phosphate buffered saline ("PBS") at pH 7.2 containing 2.5 mg of FT or 10 mL of PBS alone. Patients were followed for 12 months with regular physical examinations, laboratory tests, and symptom evaluations. The average frequency of nocturia in the previous month was recorded by a questionnaire completed by the patient. The average improvement in nocturia per night was similar between subjects treated with FT and the control group, but surprisingly, the proportion of patients treated with FT who showed worsening was significantly lower than the control group. The results of Example 3 are shown in Table 6 below. [Table 6]

[0076] The results in Table 6 reveal that administration of a composition containing FT significantly reduced the proportion of patients whose change in nocturia frequency from baseline to 12 months was greater than 0 compared to the control group (an improvement of approximately 36%). It was completely unexpected that administration of FT to patients could reduce the proportion of patients whose change in nocturia frequency from baseline to 12 months was greater than 0 by approximately 36% compared to the control group.

[0077] The results of the above examples provide surprising data for patients with BPH (whether or not they also have LUTS). Patients with BPH but without LUTS would not necessarily experience the improvement results provided in the examples. As a result, it is expected that such patients, starting from a baseline with few irritative and / or obstructive LUTS, would not necessarily show improvement in irritative and / or obstructive LUTS, skewing the results in an unfavorable direction. Thus, it is believed that identifying BPH patients who also have LUTS and administering a composition containing FT to such patients would result in even greater improvement in symptoms than those shown in Examples 1 to 3 above, respectively, in (a) reducing the proportion of patients who do not achieve Qmax after 12 months, (b) reducing the proportion of patients who show a worsening Qmax after 12 months, and (c) reducing the proportion of patients who show a change in nocturia frequency from baseline after 12 months that exceeds 0.

Claims

1. A composition for use in reducing the proportion of mammals identified as having obstructive voiding symptoms of lower urinary tract symptoms (LUTS) selected from the group consisting of pressure, weak stream, intermittent stream and residual urine, who are unable to void 125 mL or more of urine, said composition comprising a pharmaceutical agent consisting of SEQ ID NO. 1 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu) and neutral buffered saline, and capable of being administered to mammals identified as having benign prostatic hyperplasia (BPH) and having obstructive voiding symptoms of LUTS, said composition reduces the proportion of patients who are unable to void 125 mL or more of urine after 12 months or more following administration of said composition. A composition that reduces by 20% to 50% the proportion of patients who are unable to void 125 mL or more of urine after 12 months or more of administration of a control composition not containing 1.

2. The composition of claim 1, wherein the amount of SEQ ID NO. 1 contained in the composition is 2.5 mg / L.

3. 2. The composition of claim 1, wherein the composition is administrable by a method selected from the group consisting of oral administration, subcutaneous administration, intradermal administration, intranasal administration, intravenous administration, intramuscular administration, intrathecal administration, intranasal administration, intratumoral administration, topical administration, rectal administration, transperitoneal administration, and transdermal administration.

4. The composition of claim 1, wherein the composition reduces the percentage of patients who exhibit a worsening of maximum flow rate ("Qmax worsening") 12 months after administration by about 15% to about 45% as compared to the percentage of patients who exhibit a worsening of maximum flow rate ("Qmax worsening") 12 months after administration of a control composition not containing SEQ ID NO.

1.

5. The composition described in claim 4, wherein the composition can be administered more than once.

Images