Elamipretide Effects in Adults with Primary Mitochondrial Myopathy: Phase 2 Double-Blind, Randomized, Placebo-Controlled Crossover Trial (MMPOWER-2) Authors: Karaa A 1 , Haas R 2 , Goldstein A 3 , Vockley G 3 , Cohen BH 4 1 Massachusetts General Hospital, Boston, MA., 2 UC San Diego School of Medicine, San Diego, CA, 3 Children’s Hospital of Pittsburgh, Pittsburgh, PA, 4 Akron Children’s Hospital, Akron, OH CONCLUSIONS • ELAM-treated patients showed a 19.8-meter improvement in the 6MWT vs. placebo at the end of a 4-week treatment period • ELAM participants had improved – PMMSA Total Fatigue – PMMSA Total Fatigue During Activities – PMMSA “most bothersome” symptom score – Neuro-QoL Fatigue-Short Form, and • ELAM participants who walked <450 meters at baseline experienced a greater improvement in 6MWT (vs placebo) than participants who walked ≥450 meters at baseline • There were no serious AEs – The most frequently reported AE was local injection site reactions – ELAM treatment was well tolerated by most participants • Results of this trial are encouraging and support the initiation of a phase 3 trial Procedures and Outcomes • Primary objective: To evaluate the effect of 4 weeks of a once daily dose of SC ELAM on the distance walked during the 6MWT 7 – Baseline and end of each treatment period values recorded (in meters) • Additional efficacy endpoints: – Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) subscale scores 7 (completed daily; assessed the severity of 10 most common PMM symptoms Q Tiredness and muscle weakness at rest and during activities – PMMSA Total Fatigue During Activities score Q Tiredness and muscle weakness during activities – Neuro-QoL Fatigue Item Bank 8 • Secondary objectives – Evaluate the safety and tolerability of ELAM Efficacy Findings Functional Assessments • ELAM resulted in an improvement of 19.8 meters (6MWT - end of treatment period) compared with placebo (95% confidence interval [CI], -2.8, 42.5; p = 0.0833) Figure 5. • ELAM patients reported less fatigue during activities as assessed by the PMMSA Total Fatigue During Activities score throughout the treatment period (Figure 7) – ELAM treatment culminated in a 0.8-point reduction in symptom severity at the end of treatment vs. placebo (95% CI, -1.2, -0.3; p = 0.0018) • Both scores, trended to return to baseline upon discontinuation of ELAM – For individual items relating to myopathic symptoms of the individual PMMSA symptoms assessment, ELAM patients (vs placebo) had improvements in: Q Tiredness at rest (p = 0.0008) Q Tiredness during activities (p = 0.0046) Q Muscle weakness at rest (p = 0.0007) Q Muscle weakness during activities (p = 0.0019) Q Muscle pain (p = 0.0079) Q Severity of “most bothersome symptoms” (p = 0.0111) Neuro-QoL Fatigue-Short Form • ELAM therapy resulted in improved Neuro-QoL Fatigue-Short Form scores – ELAM treatment yielded a 4-point reduction in the T-score vs. placebo (95% CI, -7.0, -1.0; p = 0.0115) Safety Evaluation • Injection site reactions were the most commonly reported AEs with ELAM (80%) (Table 2) • Most commonly characterized by erythema (57%), pruritus (47%), pain (20%), urticaria (20%), and irritation (10%) • Seventy percent of patients reported mild injection site reactions such as moderate bruising, discomfort, erythema, induration, irritation, and/or pain • During the trial, there were no serious AEs or deaths reported INTRODUCTION Trial Design and Participants METHODS RESULTS REFERENCES 1. Mancuso M, Hirano M. NORD Physician Guide to Mitochondrial Myopathies (MM). Nat Org Rare Disord. 2016:1-8. 2. Mancuso M, McFarland R, Klopstock T, Hirano M. International workshop: outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Neuromuscul Disord. 2017:1-12. doi:10.1016/j.nmd.2017.08.006. 3. Pfeffer G, Horvath R, Klopstock T, et al. New treatments for mitochondrial disease—no time to drop our standards. Nat Rev Neurol. 2013;9(8):474-481. doi:10.1038/nrneurol.2013.129.New. 4. Tarnopolsky M. Exercise testing as a diagnostic entity in mitochondrial myopathies. Mitochondrion. 2004;4:529-542. doi:10.1016/j.mito.2004.07.011. 5. DiMauro S, Mancuso M, Naini A. Mitochondrial encephalomyopathies: Therapeutic approach. Ann N Y Acad Sci. 2004;1011:232-245. doi:10.1196/annals.1293.023. 6. Karaa A, Haas R, Goldstein A, Vockley J, Cohen B. Randomized dose-escalationtrialofelamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;0:1-10. Published Ahead of Print on March 2, 2018 as doi: 10.1212/WNL.0000000000005255 7. Crapo RO, Casaburi R, Coates AL, et al. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-117. doi:10.1164/rccm.166/1/111. 8. Cella D, Lai JS, Nowinski CJ, et al. Neuro-QOL-Brief measures of health-related quality of life for clinical research in neurology. Neurology. 2012;78:1860-1867. Acknowledgements: Patients and families for their participation. MitoAction and the United Mitochondrial Disease Foundation for helping with recruitment. We also thank Harvard Catalyst (http://catalyst.harvard.edu/ about/citingsupport.html). Medical writing assistance was provided by Cathy R. Winter, PhD, and James A. Shiffer, RPh, Write On Time Medical Communications, LLC. Anthony Aiudi, PharmD (Stealth BT) edited the manuscript and tables for non-intellectual content. Jeffrey S. Finman, PhD Jupiter Point Pharma Consulting, LLC for statistical consultation. Study funding: Trial funded by Stealth BioTherapeutics, Newton, MA Figure 2. MMPOWER Primary Endpoint: Change in Distance Walked at Day 5 20.4 13.5 36.5 64.5 (P=0.053) 0 10 20 30 40 50 60 70 80 90 Placebo Low Mid High Mean Change Baseline to Day 5 (meters) (0.01 mg/kg/hour) (0.1 mg/kg/hour) (0.25 mg/kg/hour) Meters Dose Response Assessed for eligibility (n=36) Excluded (n=6) ♦ Not meeting trial criteria (n=3) ♦ Declined to participate (n=2) ♦ Other reasons (n=1) When receiving ELAM: Analysed (n=30) ♦ Excluded from analysis (n=0) Lost to follow-up (n=0) Discontinued intervention (n=0) Allocated to ELAM (TP1), then to PBO (TP2) (n=14) ♦ Received ELAM (n=14) ♦ Received PBO (n=14) Lost to follow-up (n=0) Discontinued intervention (n=1) ♦ (n= ♦ ♦ Allocated to PBO (TP1), then to ELAM (TP2) 16) Received PBO (n=16) Received ELAM (n=16) When receiving PBO: Analysed (n=30) ♦ Excluded from analysis (n=0) Randomized (n=30) event Discontinued ELAM (TP2) due to adverse Allocation Follow-Up Enrollment* ITT Analysis Abbreviations: ELAM: elamipretide; PBO: placebo; TP1: Treatment Period 1; TP2: Treatment Period 2; ITT: Intent-to-Treat population * MMPOWER-2 was a multicenter, randomized, double-blind, placebo-controlled, crossover trial conducted in 4 US sites Figure 4. MMPOWER-2 Consort Flow Diagram Event, n (%) Elamipretide N = 30 Placebo N=30 Injection site reactions Erythema 17 (56.7) 1 (3.3) Pruritus 14 (46.7) 0 (0) Pain 6 (20.0) 1 (3.3) Urticaria 6 (20.0) 0 (0) Irritation 3 (10.0) 1 (3.3) Bruising 2 (6.7) 2 (6.7) Dizziness 3 (10.0) 1 (3.3) Abdominal pain 2 (6.7) 1 (3.3) Dysarthria 2 (6.7) 0 (0) Urinary tract infection 2 (6.7) 0 (0) Viral upper respiratory tract infection 2 (6.7) 0 (0) Diarrhea 1 (3.3) 2 (6.7) Fall 1 (3.3) 3 (10.0) Muscle spasms 1 (3.3) 2 (6.7) Back pain 0 (0) 2 (6.7) Headache 0 (0) 2 (6.7) Table 2. Treatment-emergent Adverse Events (AEs) (≥2 Participants) Figure 3. MMPOWER-2 Study Design Treatment period 1 Treatment period 2 Follow-up Washout Crossover Week 4 n=14 Elamipretide 40 mg SC QD Randomization (1:1) Enrollment N = 30 Elamipretide 40 mg SC QD Placebo SC QD Placebo SC QD n=16 Week 8 Week 14 Week 12 FIGURE 6. PMMSA Total Fatigue* 4 6 8 10 12 Pre-dose Week 1 *Total of 4 questions, each scored 1 = not at all, to 4 = severe (score range 4-16) Week 2 Week 3 End of treatment period Two weeks post-treatment P = 0.0023 P = 0.0062 P = 0.0283 P = 0.0006 P = 0.2247 Elamipretide Placebo FIGURE 7. PMMSA Fatigue During Activities* Pre-dose Week 1 Week 2 Week 3 End of treatment period Two weeks post-treatment Elamipretide Placebo *Total of 2 questions, each scored 1 = not at all, to 4 = severe (score range 2-8) 3 4 5 7 P = 0.0085 P = 0.0557 P = 0.0028 P = 0.0018 P = 0.1013 2 6 Elamipretide Placebo Pre-dose Week 1 Week 2 Week 3 End of treatment period Two weeks post-treatment • Primary mitochondrial myopathies (PMMs) are genetic disorders that impair normal mitochondrial function, primarily affecting skeletal muscle, 1,2 resulting in: – decreased tolerance to physical exercise because of skeletal muscle respiratory chain dysfunction – debilitating muscle weakness, muscle atrophy, limited exercise capacity, and symptoms of fatigue. • The progression of PMM disease significantly compromises daily activity performance in the majority of cases 3–5 • Currently, there are no US FDA–approved therapies for PMM • An initial trial (MMPOWER) in genetically confirmed PMM patients evaluated 3 different daily IV doses of ELAM (0.01, 0.1, and 0.25 mg/kg/hour, for 2 hours) for 5 days. High dose ELAM treatment produced improvements in 6MWT 6 • MMPOWER-2 evaluated chronic daily dosing of subcutaneous (SC) ELAM Patient-Reported Outcomes • ELAM participants reported less total fatigue as assessed by PMMSA Total Fatigue score throughout the treatment period (Figure 6) – At the end of the treatment period, there was a 1.7-point reduction in symptom severity in ELAM participants compared with placebo (95% CI, -2.6, -0.8; p = 0.0006) Figure 5. MMPOWER-2 Primary Endpoint: Change in Distance Walked Based on Measures of 6MWT 0 385 380 375 370 390 395 Average Distance Walked in 6 MWT (meters) 400 End of Treatment Period 19.8 M (95% Cl, -2.8, 42.5; P = 0.08) Baseline Distance Walked Difference Elamipredtide vs Placebo (M) <450 M ≥450 M 24.3* 8.6 † Subgroup Analysis Based on Baseline Distance Walked 6 Minute Walk Test Elamipretide Placebo Pre-specified subgroup analysis: *: n=22 (95% CI, -6.2, 54.7; p = 0.11) † : n=8 (95% CI, -28.0, 45.2; p = 0.57) Treatment sequence A:B (ELAM:PBO) n = 14 Treatment sequence B:A (PBO:ELAM) n = 16 All Participants N = 30 Age, mean (range), years 41.5 (17-63) 48.6 (25-65) 45.3 (17-65) Gender, n (%) Female Male 10 (71) 4 (29) 15 (94) 1 (6) 25 (83) 5 (17) Race/ethnicity n (%) White Multiple (white/Asian/ other) Non-Hispanic or Latino Hispanic or Latino 13 (93) 1 (7) 14 (100) 0 16 (100) 0 15 (94) 1 (6) 29 (97) 1 (3) 29 (97) 1 (3) Weight, mean (SD), kg 60.5 (±10.0) 69.2 (±16.3) 65.1 (±14.2) BMI, mean (range), kg/m 2 22.8 (15.8-33.2) 25.3 (19.0-36.0) 24.1 (15.8-36.0) Baseline 6MWT, mean (SD), meters 381.2 (±30.4) 396.5 (±36.3) 389.4 (±23.6) Baseline 6MWT, n (%), meters <450 ≥450 13 (93) 1 (7) 9 (56) 7 (44) 22 (73) 8 (27) Table 1. MMPOWER-2 Patient Baseline Characteristicss Abbreviations: 6MWT = 6-minute walk test; BMI = body mass index; SD = standard deviation. Demographic and Other Baseline Characteristics • Of the 36 eligible, genetically-confirmed participants from MMPOWER, 30 were randomized in MMPOWER-2 (Table 1) Intermembrane space Cardiolipin Protons accumulate, gradient drives ATP production Oxygen in intermembrane space forms reactive oxygen species ELAM ELAM ELAM ELAM ELAM ELAM Lack of protons, reduced gradient, reduced ATP Electrons Electrons supply energy to pump protons Water ATP O 2 O 2 O 2 ATP ATP ATP ATP O 2 e O 2 Inner Membrane Healthy • Adequate ATP Production • Low ROS emission • Electron carriers close to each other • High membrane curvature • Physiological cardiolipin content • Diminished ATP Production • High ROS emission • Electron carriers spread apart • Low membrane curvature • Pathophysiological cardiolipin content • Restoration of ATP Production • Decreased ROS emission • Electron carriers back together • Higher membrane curvature • Normalized cardiolipin content Disease Elamipretide Figure 1. Restoration of Mitochondrial Bioenergetics SPIMM 202 MDA Poster_v4.indd 1 3/8/18 1:18 PM