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Methods and Compositions for Treating Muscle Disease and Disorders

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Methods and Compositions for Treating Muscle Disease and Disorders (19) *EP003256151B1* (11) EP 3 256 151 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/22 (2006.01) A61P 9/10 (2006.01) (2006.01) 05.08.2020 Bulletin 2020/32 A61P 9/12 (21) Application number: 16749691.8 (86) International application number: PCT/US2016/017102 (22) Date of filing: 09.02.2016 (87) International publication number: WO 2016/130518 (18.08.2016 Gazette 2016/33) (54) METHODS AND COMPOSITIONS FOR TREATING MUSCLE DISEASE AND DISORDERS VERFAHREN UND ZUSAMMENSETZUNGEN ZUR BEHANDLUNG VON MUSKELERKRANKUNGEN UND -STÖRUNGEN MÉTHODES ET COMPOSITIONS POUR TRAITER DES MALADIES ET DES TROUBLES MUSCULAIRES (84) Designated Contracting States: US-A1- 2011 178 017 US-A1- 2011 219 462 AL AT BE BG CH CY CZ DE DK EE ES FI FR GB US-A1- 2013 116 184 US-A1- 2013 230 581 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO US-A1- 2013 315 878 US-A1- 2014 039 053 PL PT RO RS SE SI SK SM TR • Anonymous: "PhaseBio Announces Promising (30) Priority: 09.02.2015 US 201562113943 P Pre-clinical Results for PB1046 in Models of 10.04.2015 US 201562145770 P Duchenne Muscular Dystrophy", Phase Bio , 22 21.04.2015 US 201562150679 P April 2015 (2015-04-22), XP002781492, Retrieved from the Internet: (43) Date of publication of application: URL:https://phasebio.com/phasebio-announce 20.12.2017 Bulletin 2017/51 s-promising-pre-clinical-results-for-pb104 6-in-models-of-duchenne-muscular-dystrophy / (73) Proprietor: Phasebio Pharmaceuticals, Inc. [retrieved on 2018-05-29] Malvern, Pennsylvania 19355 (US) • JONATHAN P MOW: "PhaseBio Pharmaceuticals Inc. Creating New and Better (72) Inventors: Biopharmaceuticals", JEFFERIES 2013 GLOBAL • GEORGOPOULOS, Lynne HEALTHCARE CONFERENCE , 1 June 2013 Malvern, Pennsylvania 19355 (US) (2013-06-01), pages 1-28, XP008185906, • ARNOLD, Susan Retrieved from the Internet: Malvern, Pennsylvania 19355 (US) URL:HTTP://PHASEBIO.COM/WP-CONTENT/UP • BALLANCE, David James LOADS Malvern, Pennsylvania 19355 (US) /2013/12/PHASEBIO-NONCON-JEFFERIES-PRE SENT ATION-2013.PDF (74) Representative: Cooley (UK) LLP Dashwood 69 Old Broad Street London EC2M 1QS (GB) (56) References cited: WO-A1-2007/065226 WO-A1-2012/170524 WO-A1-2013/177428 WO-A1-2014/081849 WO-A1-2015/172046 WO-A2-2016/081884 US-A1- 2011 053 854 US-A1- 2011 110 916 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 256 151 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 3 256 151 B1 • Free A. Et Al: "A Phase 1, Multi-center, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Safety/Tolerability, Pharmacokinetic and Hemodynamic Response Following Single Ascending Subcutaneous Doses of PB1046 (Vasomera(TM)) in Subjects with Essential Hypertension (Trial Registry No. NCT01523067)", Phase Bio Phasebio Pharmaceuticals, 1 November 2014 (2014-11-01), XP055360492, Retrieved from the Internet: URL:http://phasebio.com/wp-content/uploads /PB_pb1046-Controlled-Study-presentation.p df [retrieved on 2017-03-30] 2 EP 3 256 151 B1 Description BACKGROUND 5 [0001] Duchenne and Becker muscular dystrophies (DMD and BMD) represent the most frequent neuromuscular diseases in human, occurring in one of 3,500 to one in 6,000 live male births depending on the population studied (Bushby et al. (2010)). DMD and BMD are allelic disorders resulting from mutations in the dystrophin gene. In DMD, functioning dystrophin is completely absent from muscle, while in BMD there is some dystrophin present, although not in sufficient amounts for normal muscle function. In addition to skeletal muscle weakness, dystrophin deficiency in the 10 myocardium results in a progressive cardiomyopathy. [0002] Currently there are no approved therapies specific to the treatment of DMD/BMD. High dose corticosteroids are often used to treat muscle weakness and to maintain ambulation as long as possible, but these are associated with unacceptable side effects and/or suboptimal responses. It is also uncertain whether these therapeutics help or hinder cardiac function. Additional therapeutic approaches are needed to treat both the skeletal and cardiac abnormalities of 15 muscular dystrophies. SUMMARY OF THE INVENTION [0003] The present disclosure provides long-lasting Vasoactive Intestinal Peptide (VIP) therapeutics to treat, delay, 20 prevent, or ameliorate muscle myopathy. Myopathic muscles sustain damage during repeated contractions but, because they lack the ability to properly repair themselves, the muscles develop defects such as fibrotic lesions. These defects can inhibit muscle function, often by impairing the muscle’s ability to contract. Preventing, delaying, or ameliorating these defects from forming can treat muscle myopathy in patients. The VIP therapeutics disclosed herein can also improve cardiac function in patients with muscle myopathies. 25 In a first aspect of the invention, there is provided a pharmaceutical composition as defined in claim 1. [0004] The present disclosure provides a method for treating muscle myopathy comprising administering to a patient in need thereof a pharmaceutical composition comprising a Vasoactive Intestinal Peptide (VIP) and one or more elastin- like peptides (ELP). [0005] The present disclosure provides a method for protecting against muscle contraction-induced injury in a patient 30 in need thereof comprising administering a pharmaceutical composition comprising a Vasoactive Intestinal Peptide (VIP) and one or more elastin-like peptides (ELP). [0006] The present disclosure provides a method for slowing the progression of cardiomyopathy comprising admin- istering to a patient in need thereof a pharmaceutical composition comprising a Vasoactive Intestinal Peptide (VIP) and one or more elastin-like peptides (ELP). 35 [0007] The present disclosure provides a method for treating cardiomyopathy comprising administering to a patient in need thereof a pharmaceutical composition comprising a Vasoactive Intestinal Peptide (VIP) and one or more elastin- like peptides (ELP). [0008] In the embodiments of the invention, the pharmaceutical composition comprises the amino acid sequence of SEQ ID NO: 15. 40 BRIEF DESCRIPTION OF THE FIGURES [0009] 45 Figure 1A-B shows cardiac function monitored via echocardiography: n = 10 - 11, *P< 0.05 vs controls. Panel A shows the fractional area shortening in MDX (dystrophin deficient mice). Panel B shows the E/A ratio in MDX mice. PB1046 treatment preserves fractional area shortening after 32 weeks of treatment. PB1046 administration before cardiomyopathy developed preserved the QRS duration in mdx and double knockout mice, and slowed the deteri- oration of cardiac function (fractional area shortening and E/A ratios) in mdx mice. 50 Figure 2A-E shows the in vivo assessment of left ventricular function in MDX mice in a terminal procedure. n = 4 - 5 (MDX) and n = 2 (DKO), *P< 0.05 vs controls. Both mdx and double knockout treated animals showed preserved dP/dtmax (contraction) and faster Tau (relaxation). 55 Figure 3A-B shows the results from evaluation of skeletal muscle physiology in isolated extensor digitorum longus muscles from MDX mice. n = 4 - 16. Treatment with PB1046 maintained eccentric contraction compared with untreated mice, indicating that the muscles in the treatment group were more resistant to contraction-induced dam- age. 3 EP 3 256 151 B1 Figure 4A-C shows collagen content (Panels A-B) in MDX mice measured with Sirius Red staining. Macrophage identification (Panel C) was determined via immunohistochemistry n = 4 - 7, *P< 0.05 vs controls. The degree of fibrosis as determined by collagen deposition was reduced in both skeletal muscle (gastrocnemius) and cardiac muscle. 5 DETAILED DESCRIPTION [0010] Muscle myopathies, which may affect skeletal or cardiac muscle, are disorders in which muscle fibers no longer function correctly, resulting in muscle weakness which can lead to muscle wasting, paralysis, and even death. Cardiac 10 dysfunction is a frequent manifestation of various muscular myopathies, and is a common cause of death for individuals with these conditions. [0011] Often, in inherited myopathies such as muscular dystrophies, patients exhibit a mutation in the dystrophin gene. The dystrophin gene plays both a structural and regulatory role in muscle contraction. Dystrophin is part of a larger membrane-spanning complex, the dystrophin glycoprotein complex (DGC) (Lapidos et al. (2004)), the absence of which 15 directly impacts contractility. In many muscular myopathy patients (e.g. Duchenne or Becker Muscular Dystrophies, or dystrophin-associated cardiomyopathy), the dystrophin protein may be completely absent or only partially functioning. Absence of dystrophin increases intracellular calcium and results in an overproduction of nitric oxide, which triggers protein degradation, fibrosis, necrosis, the activation of macrophages, and ultimately results in skeletal and cardiomy- opathy (Townsend et al. (2011); Judge et al. (2011)). 20 [0012] In cardiomyocytes, these pathologic consequences are mediated in part by an increase in calcium permeability and increased myocyte calcium concentrations, which in turn initiates a cascade of events including expression of inflammatory cytokines within
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