Elamipretide Effects in Adults with Primary Mitochondrial Myopathy: Phase 2 Double-Blind, Randomized, Placebo-Controlled Crossover Trial (MMPOWER-2)

Authors: Karaa A1, Haas R2, Goldstein A3, Vockley G3, Cohen BH4

1Massachusetts General Hospital, Boston, MA., 2UC San Diego School of Medicine, San Diego, CA, 3Children’s Hospital of Pittsburgh, Pittsburgh, PA, 4Akron 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 6MWT7

– Baseline and end of each treatment period values recorded (in meters)• Additional efficacy endpoints:

– Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) subscale scores7 (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 Bank8

• Secondary objectives – Evaluate the safety and tolerability of ELAM

Efficacy FindingsFunctional 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)

Met

ers 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)

eventDiscontinued 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 = 30Placebo

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-upWashout

Crossover

Week 4

n=14 Elamipretide40 mg SC QD

Ran

dom

izat

ion

(1:1

)

Enr

ollm

ent

N =

30

Elamipretide40 mg SC QD

PlaceboSC QD

PlaceboSC QD

n=16

Week 8 Week 14Week 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 weekspost-treatment

P = 0.0023

P = 0.0062P = 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 weekspost-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 = 0.0557P = 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 weekspost-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 cases3–5

• 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 6MWT6

• 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

Ave

rage

Dis

tanc

e W

alke

din

6 M

WT

(met

ers)

400

End of Treatment Period

19.8 M (95% Cl, -2.8, 42.5; P = 0.08) Baseline

DistanceWalked

DifferenceElamipredtidevs Placebo (M)

<450 M

≥450 M

24.3*

8.6†

Subgroup Analysis Based onBaseline Distance Walked

6 Minute Walk Test

ElamipretidePlacebo

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 (%)WhiteMultiple (white/Asian/other)Non-Hispanic or LatinoHispanic or Latino

13 (93)1 (7)14 (100)0

16 (100)015 (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/m2 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

Protonsaccumulate,

gradientdrives ATPproduction

Oxygen inintermembrane

space formsreactive oxygen

species

ELAM

ELAM

ELAM

ELAM

ELAM

ELAM

Lack of protons,reduced gradient,

reduced ATP

Electrons

Electronssupply energy

to pumpprotons

WaterATP

O2

O2

O2

ATP

ATP

ATP

ATP

O2

eO2

InnerMembrane

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