SMA FOUNDATION Skeletal Muscle: PRESENTATION TEMPLATE a Critical Target in Treating SMA THERAPEUTIC STRATEGIES TO AMPLIFY SMN UPREGULATION CONFIDENTIAL 1
PATHOPHYSIOLOGICAL DEFECTS IN SMA Proprioceptive neuron Motor neuron loss Loss of synapses Motor neuron Delays in axonal development NMJ Muscle Synaptic dysfunction spindle Reduced myofiber size Skeletal muscle Impaired development Mitochondrial defects CONFIDENTIAL 2
MUSCLE PATHOLOGY IN SMA CONFIDENTIAL 3
TYPE I SMA MUSCLE: MANY SMALL MYOFIBERS FEATURES OF DELAYED MATURATION Type I SMA Round and small myofibers believed to be developmentally immature Takei et al., Medscape CONFIDENTIAL 4
SMA MUSCLES EXPRESS IMMATURE MUSCLE MARKERS Myogenic Myoblast Desmin Caveolin 3 Myogenin factor 5 determination 1 Immature Differentiated Myogenic regulatory factors muscle marker myocyte marker CONFIDENTIAL 5 Ripolone et al., 2015
TYPE II SMA MUSCLE: FEATURES OF NEUROGENIC ATROPHY MANY NORMAL-LOOKING MYOFIBERS Type II SMA large myofibers small myofibers normal myofibers Neuromuscular Disease Center, WUSTL CONFIDENTIAL 6
TYPE III SMA MUSCLE: FEATURES OF NEUROGENIC ATROPHY MANY NORMAL-LOOKING MYOFIBERS Type III SMA normal myofibers small myofibers Neuromuscular Disease Center, WUSTL CONFIDENTIAL 7
MODERATLY AFFECTED SMA MUSCLES EXHIBIT FIBER TYPE GROUPING Type II SMA patient Type 2 (fast) Type 1 (slow) • Hypertrophic myofibers appear to be mostly type 1 • Small and normal myofibers are type 1 and 2 CONFIDENTIAL 8 Neuromuscular Disease Center, WUSTL
NO UNDERLYING STRUCTURAL DAMAGE IN SMA MUSCLE – OPPORTUNITY TO RESCUE REMAINING FIBERS Duchenne Muscular Healthy SMA Dystrophy (DMD) SMA: small fiber clusters DMD: fiber size variation, interspersed with some increase connective tissue fibrosis, necrotic fibers hypertrophic fibers CONFIDENTIAL 9 Neuromuscular Disease Center, WUSTL
ONGOING MUSCLE DENERVATION IN SMA IS SLOW, AFTER AN INITIAL DENERVATION EARLY IN DEVELOPMENT MUNE trendlines 300 Normal 250 MUNE Values (NP area) 200 150 *1 - 3% of axons undergoing active degeneration Type 3 100 Type 2 50 Type 1 0 0 5 10 Years of Age CONFIDENTIAL 10 Adapted from Swoboda et al., 2005 *Charlotte Sumner (Johns Hopkins)
SMA MUSCLE IS AN EXCELLENT TARGET FOR MUSCLE- ENHANCING THERAPEUTICS • SMA muscles have a large number of normal fibers remaining • Unlike in DMD, no muscle structural damage in SMA muscle • Relatively slow muscle denervation CONFIDENTIAL 11
POTENTIAL MECHANISMS TO ENHANCE MUSCLE FUNCTION IN SMA CONFIDENTIAL 12
SELECT MECHANISMS TO ENHANCE MUSCLE FUNCTION Selective androgen receptor modulators Myostatin inhibitors (SARMS) stimulate muscle growth stimulate muscle growth Androgen Myostatin Mitochondria-targeting drugs improve energy production Androgen ActIIB Receptor Receptor Muscle atrophy Increased muscle size Fast troponin activators (FSTAs) CONFIDENTIAL 13 increase muscle’s sensitivity to calcium
MUSCLE-ENHANCING DRUGS IN CLINICAL DEVELOPMENT Clinical Trials Early Drug Lead Development Optimization Preclinical Phase 1 Phase 2 Phase 3 Trevogrumab, REGN1033 (Regeneron) (anti-myostatin antibody) sarcopenia ANTI-MYOSTATIN Bimagrumab, BYM338 (Novartis) (anti-ActIIB antibody) sarcopenia/ hip fracture/diabetes Domagrozumab, PF-06252616 (Pfizer) (anti-myostatin antibody) (anti-myostatin antibody) LGMD2I/DMD BMS-089 (BMS/Roche) (anti-myostatin adnectin) DMD ACE-083 (Acceleron) (Protein therapeutic) FSHMD SRK-015 (Scholar Rock) (anti-latent-myostatin antibody) SMA Enobosarm, GTx-024 (GTx) (SARM, oral) AR-related cancers, urinary incontinence SARM VK5211 (Viking Therapeutics) (SARM, oral) hip fracture GSK2881078 (GlaxoSmithKline) (SARM, oral) cachexia Tirasemtiv (Cytokinetics) (activator of troponin complex) ALS FSTA CK-2127107 (Cytokinetics/Astellas) (activator of troponin complex) SMA/COPD MITO Epicatechin (Cardero Therapeutics) (exercise mimetic) DMD/Friedreich's ataxia Olesoxime (Roche) (neuroprotective therapeutic) SMA CONFIDENTIAL 14 Based on publicly disclosed timelines, June 2017
MYOSTATIN INHIBITION IN SMA MOUSE MODELS CONFIDENTIAL 15
ANTI-MYOSTATIN DRUGS WORK IN VARIOUS SMA MODELS INTERMEDIATE MODEL SEVERE Δ 7 MILD C/C PHARMACOLOGICAL PRINCIPAL Ko, Myologica, Sumner, Lorson Sweeney INVESTIGATOR SMA Foundation AAV-dnMyostatin, MYOSTATIN AAV-Follistatin, Recombinant follistatin, AAV-ActRIIB-Fc, INHIBITION Therapeutics from 4 major ActRIIB-Fc (Acceleron) ACE-2494 APPROACH pharma/biotech companies (Acceleron) MUSCLE WEIGHT / – MUSCLE FUNCTION Sumner et al., 2009, Feng et al., 2016, REFERENCE Liu et al., 2016 Rose et al., 2009 Unpublished Results CONFIDENTIAL 16
C/C MOUSE MODEL REPRESENTS A MILD FORM OF SMA Smn Allele C Neo hSMN2 exons 7 and 8 42 kb fragment human SMN2 Reduced body and muscle weight, normal median survival CONFIDENTIAL 17 Osborne et al., 2012
MYOSTATIN INHIBITION LEADS TO AN INCREASE IN BODY WEIGHT AND MUSCLE MASS Two approaches were used to inhibit myostatin: soluble ActRIIB or protease-resistant myostatin propeptide Liu et al., 2016 #p<0.05 vs WT CONFIDENTIAL 18 *p<.05 vs C/C
MYOSTATIN INHIBITION IMPROVES MUSCLE FUNCTION AND DOES NOT OVEREXERT MOTOR UNITS IN TIBIALIS ANTERIOR MUSCLE in situ muscle function test Increase in maximal force No change in motor unit number WT C/C C/C- C/C- WT C/C C/C- C/C- sActRIIB dnMstn sActRIIB dnMstn Liu et al., 2016 #p<0.05 vs WT CONFIDENTIAL 19 *p<.05 vs C/C
ANTI-MYOSTATIN DRUGS WORK IN VARIOUS SMA MODELS INTERMEDIATE MODEL SEVERE Δ 7 MILD C/C PHARMACOLOGICAL PRINCIPAL Ko, Myologica, Sumner, Lorson Sweeney INVESTIGATOR SMA Foundation AAV-dnMyostatin, MYOSTATIN AAV-Follistatin, Recombinant follistatin, AAV-ActRIIB-Fc, INHIBITION Therapeutics from 4 major ActRIIB-Fc (Acceleron) ACE-2494 APPROACH pharma/biotech companies (Acceleron) MUSCLE WEIGHT / – MUSCLE FUNCTION Sumner et al., 2009, Feng et al., 2016, REFERENCE Liu et al., 2016 Rose et al., 2009 Unpublished Results CONFIDENTIAL 20
PHARMACOLOGICALLY INDUCED INTERMEDIATE MODEL ENABLES TESTING AFTER DISEASE ONSET • The pharmacological model is obtained by dosing severe delta7 mice with a low dose of an SMN-upregulating compound (SMN-C3 or SMN-C1) from birth • The model displays a range of disease phenotypes reminiscent of milder forms of SMA Wild-type Wild-type Δ 7 high dose Δ 7 high dose Δ 7 low dose Δ 7 low dose Δ 7 vehicle Naryshkin et al., 2014 CONFIDENTIAL 21 Feng et al., 2016
STUDY DESIGN TO TEST MYOSTATIN INHIBITORS IN SMA MICE AFTER DISEASE ONSET PND2: SMN-C1 PND21 PND48 Vehicle Δ 7 mice + Low SMN-C1 (0.1 mg/kg) Myostatin inhibitor MONOTHERAPY STUDY Δ 7 mice + Low SMN-C1 (0.1 mg/kg) Vehicle WT mice + DMSO Functional test/sacrifice Low dose SMN-C1/ Vehicle (DMSO) Myostatin inhibitor/ Vehicle CONFIDENTIAL 22
IS THERE A BENEFIT OF COMBINING MYOSTATIN INHIBITORS AND SMN UPREGULATING THERAPY? SMN-UPREGULATING MUSCLE-ENHANCING THERAPY THERAPY SMA mouse model CONFIDENTIAL 23
STUDY DESIGN TO TEST COMBINATION THERAPY IN SMA MICE AFTER DISEASE ONSET CONFIDENTIAL 24
CONCLUSIONS • SMA muscle is an excellent target for muscle-enhancing therapeutics • Many muscle-enhancing drugs are already in clinical development for other indications – potential rapid development for SMA • Strong preclinical evidence of efficacy of muscle-enhancing drugs in SMA mice • Myostatin inhibition alone and in combination with SMN upregulation increases muscle mass and improves muscle function in SMA mice • SMN-upregulation by itself may not be sufficient for some patients – combination therapies may provide significant benefit to these patients • Next major phase in clinical development strategy – combo trials with SMN upregulators and muscle-enhancing drugs CONFIDENTIAL 25
REMAINING QUESTIONS • Will these promising preclinical results translate into meaningful benefits for SMA patients? • How will efficacy be assessed in patients? • Which patient populations are expected to see the most impact? • What are the concerns for muscle-enhancing drugs in SMA patients? • Effect on SMA motor units? • Effect on fatigue? • Effect on contractures? CONFIDENTIAL 26
SMA FOUNDATION CONFIDENTIAL 28
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