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CAP-1002 for Advanced DMD: a New Treatment Option

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CAP-1002 for Advanced DMD: a New Treatment Option CAP-1002 for Advanced DMD: A New Treatment Option October 24, 2019 NASDAQ: CAPR Forward-Looking Statements Statements in this press release regarding the efficacy, safety, and intended utilization of Capricor's product candidates; the initiation, conduct, size, timing and results of discovery efforts and clinical trials; the pace of enrollment of clinical trials; plans regarding regulatory filings, future research and clinical trials; regulatory developments involving products, including the ability to obtain regulatory approvals or otherwise bring products to market; plans regarding current and future collaborative activities and the ownership of commercial rights; scope, duration, validity and enforceability of intellectual property rights; future royalty streams, revenue projections; expectations with respect to the expected use of proceeds from the recently completed offerings and the anticipated effects of the offerings, and any other statements about Capricor's management team's future expectations, beliefs, goals, plans or prospects constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements that are not statements of historical fact (including statements containing the words "believes," "plans," "could," "anticipates," "expects," "estimates," "should," "target," "will," "would" and similar expressions) should also be considered to be forward- looking statements. There are a number of important factors that could cause actual results or events to differ materially from those indicated by such forward-looking statements. More information about these and other risks that may impact Capricor's business is set forth in Capricor's Annual Report on Form 10-K for the year ended December 31, 2018 as filed with the Securities and Exchange Commission on March 29, 2019, and as amended by its Amendment No. 1 to Annual Report on Form 10-K/A filed with the Securities and Exchange Commission on April 1, 2019, in its Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2019, as filed with the Securities and Exchange Commission on August 8, 2019, and in its Registration Statement on Form S-3 as filed with the Securities and Exchange Commission on October 24, 2018, and as amended by its Amendment No. 1 to Form S-3 filed with the Securities and Exchange Commission on July 17, 2019, together with prospectus supplements thereto. All forward-looking statements in this press release are based on information available to Capricor as of the date hereof, and Capricor assumes no obligation to update these forward-looking statements. CAP-1002 is an Investigational New Drug and is not approved for any indications. CAP-2003 has not yet been approved for clinical investigation. 2 Call Participants ‒ Craig McDonald, M.D., is professor and chair of the Department of Physical Medicine and Rehabilitation and Director of the Neuromuscular Disease Clinics at the University of California, Davis. Dr. McDonald is an internationally recognized expert in the clinical management and rehabilitation of neuromuscular diseases including DMD. He is the national PI of the Capricor HOPE-2 Trial. ‒ Linda Marbán, Ph.D. – Chief Executive Officer, Capricor Therapeutics, Inc. ‒ AJ Bergmann, Chief Financial Officer, Capricor Therapeutics, Inc. 3 Dystrophin Deficient Muscular Dystrophy: Diagnosis, Natural History and Current Therapies Craig McDonald, MD Professor and Chair of PM&R Professor of Pediatrics Study Chair CINRG Duchenne Natural History Study University of California Davis Health Sacramento, CA 4 Disclosures ‣ Consulting work on Duchenne muscular dystrophy clinical trials for – Capricor Therapeutics, Inc. – Catabasis Pharmaceuticals, Inc. – PTC Therapeutics – Sarepta – Prosensa – GSK – Pfizer – Eli Lilly – Bristol Myers Squib – Italfarmaco – Mitobridge – Cardero Therapeutics 5 Duchenne Muscular Dystrophy . The most common muscular dystrophy of childhood . 1 in 3500-5500 boys . BMD is about 1 in 18000-35000 . X-linked recessive inheritance (Xp21.2) . males affected & females carriers . However, 1/3 cases are de novo mutation . Caused by mutation of dystrophin gene . Dystrophin gene is the largest gene in genome: 2.4 mb . 14 kb mRNA coding sequence . 3685 amino acid 427kDa protein 6 Duchenne Muscular Dystrophy Is a Devastating Progressive Disease with Significant Unmet Need ‣ Rare recessive x-linked disorder caused by mutation in the DMD gene ‣ Leads to dystrophin deficiency in muscle tissue and subsequently chronic activation of NF-kB ‣ Progressive disease that leads to devastating deteriorating muscle strength and early death ‣ Only supportive treatments are available – Physical therapy – Orthopedic Surgery for contractures and scoliosis – Assisted ventilation – Heart failure management (e.g., afterload reduction) – Off-label / labeled use of corticosteroids – Eteplirsen in the US for exon-51 mutations – Ataluren in the EU for nonsense mutations 7 Disease Progression Is Characterized by Muscle Damage and Replacement of Muscle Fibers with Fat Infiltration and Sclerosis, Resulting in Loss of Function Lack of dystrophin cause shearing of the sarcolemma and activation of NF-kB, increasing cellular damage and muscle fiber Fat infiltration, sclerotic loss changes and loss of muscle fibers Progressive loss of muscle fibers and replacement of functional muscle units by fat infiltration and sclerosis Loss of function; walking capacity preserved in spite of significant loss of Normal muscle tissue muscle strength due to Muscle tissue 19 year old ‣ Reserve capacity in muscle function DMD patient Post-Mortem ‣ Biomechanical compensations 8 Pathophysiology of DMD Gene abnormality at Xp21 loci ↓ Absence of dystrophin ↓ Muscle membrane injury ↓ Cascade of events leading to muscle fiber injury and degradation ↓ Cycles of degeneration ←→ regeneration ↓ Cell death (replacement by fat & connective tissue) 9 DMD pathomechanism Structural defect Membrane instability Apoptosis / Necrosis Inflammation Fibrosis Fiber Death Adapted from Engvall & Wewer (2003) FASEB 17:1579 10 Dystrophin Gene & Protein From: physrev.physiology.org • 8 different promoters • Differential tissue expression of dystrophin isoforms • 79 exons (0.6% of gene) and most of the gene composed of non-coding introns • Dystrophin protein organization: • N-terminal actin binding domain • 24 spectrin like repeats in the rod domain • Cysteine rich and c-terminal • Dystrophin is an important component of DAG complex at muscle membrane • Muscle membrane stability 11 • Cell signalling pathway Duchenne dystrophy = Absence of dystrophin Complete loss of function Becker dystrophy = Present, but abnormal Partial loss of function Large in-frame deletions Can be clinically very mild, asymptomatic BMD 12 (hyperCKemia) Types of mutations in Dystrophinopathies . Deletions account for majority of mutations ~65-72% of DMD ~85 % of BMD most in “hotspot” region of exon 45-53 . Point mutations and splicing region mutations ~25-30% most result in nonsense/frameshift (stop); rare missense . Duplications ~5-10% in minor “hotspot” region of exon 2-20 . Premature stop codon mutation ~13-15% 13 Reading Frame Rule Out-of-frame mutations result in disruption of ORF → premature stop codon → truncated dystrophin/non-functional protein → Absence of dystrophin → DMD In-frame mutations that preserve the ORF → replacements of amino acids in dystrophin → partially functional protein → BMD Majority of DMD and BMD follow this rule 14 Deletions that disrupt the codon reading frame produce severe Duchenne dystrophy DP427 muscle, neurons 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 DP260 retina 27 28 29 30 31 32 33 34 35 36 37 38 DP140 neurons, kidney 39 40 41 42 43 44 45 46 47 48 49 50 DP116 Schwann cells 51 52 53 54 55 56 57 58 59 60 61 DP71 - 45 universal 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 15 Deletions that do not disrupt the codon reading frame produce mild Becker dystrophy DP427 muscle, neurons 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 DP260 retina 27 28 29 30 31 32 33 34 35 36 37 38 DP140 neurons, kidney 39 40 41 42 43 44 45 46 47 48 49 50 DP116 Schwann cells 51 52 53 54 55 56 57 58 59 60 61 DP71 - 45 universal 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 16 DMD ↔ outlier DMD ↔ BMD Absent/nonfunctional dystrophin protein severe phenotype: DMD Smaller/partially functional/reduced amount of dystrophin mild phenotype: BMD . Mutations can result in phenotype within the spectrum . Genotype (mutation characterization)/phenotype correlation is not perfect nor easy . Clinical picture is better at predicting prognosis and disease progression; and immunochemical analysis of dystrophin rarely necessary 17 DMD vs. BMD • Immunostaining using Antibodies to different dystrophin epitopes • Antibody to C-terminus: • Absent staining: DMD • Present staining: BMD Antibody to Rod domain may be positive in DMD • Western Blot Analysis (using C-terminal): • < 2-3% quantity → Duchenne phenotype • 5 – 20% quantity → “Outlier” phenotype • 20 –80% quantity → Becker phenotype • or 90 – 100% & 18 abnormal structure/size from Novocastra DMD vs. BMD Duchenne Becker Clinical Onset 2 – 6 years 4 – 12 (or later) Age to wheelchair 7-13 years (no steroids) > 16 years (-) steroids 10 years (often in 3rd (+) steroids 13.5 years decade) Restrictive Lung Progresses to severe Mild severity RLD Disease RLD (2nd decade) Cardiomyopathy Severe Severe (mid to late 2nd (in 3rd to 4th decade) decade) Scoliosis Severe in 80-90% Rare Life
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