Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study

Study Overview
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Brief Summary
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This randomized, double-blind, placebo-controlled, crossover study screened 32 subjects with primary mitochondrial myopathy (PMM) to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of subcutaneous elamipretide in this patient population.

Detailed Description
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This randomized, double-blind, placebo-controlled, crossover study screened 32 subjects with primary mitochondrial myopathy (PMM) who had completed participation in the SPIMM-201 study where they had received 5 days of intravenous (IV) elamipretide (0.01, 0.10, or 0.25 mg/kg/hour infused for 2 hours) or placebo (randomized 3:1). The primary objective was to evaluate the effect of single daily subcutaneous (SC) doses of elamipretide administered for 4 weeks on the 6-minute walking distance (6MWD). Subjects were randomized (1:1) to one of two sequence groups: 4-weeks of treatment with 40 mg elamipretide administered once daily SC in Treatment Period 1 followed by 4-weeks of treatment with placebo administered once daily SC in Treatment Period 2 (separated by a 4-week washout period), or vice versa. Each sequence group went through 5 distinct periods: Screening, Treatment Period 1, Washout, Treatment Period 2, and Follow-Up. Safety, tolerability, pharmacokinetics (PK), and efficacy of subcutaneous elamipretide in this patient population were analyzed.

Official Title
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A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Study to Evaluate Safety, Tolerability, and Efficacy of Subcutaneous Injections of MTP-131 in Subjects With Mitochondrial Myopathy Previously Treated in the SPIMM-201 Study

Conditions
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Primary Mitochondrial Disease

Intervention / Treatment
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* Drug: Elamipretide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject completed participation in the SPIMM-201 study without a significant protocol deviation that would suggest the subject may not be able to complete all study requirements in the opinion of the Sponsor Subject must reside in North America for the duration of the study Subject has not received study drug in the SPIMM-201 study within 3 weeks prior to Screening Women of childbearing potential must agree to use 1 of the methods of birth control specified in the protocol from the date they sign the informed consent form (ICF) until two months after the last dose of study drug Subject has been on stable (unchanged and constant) medications (including over-the counter treatments, vitamins, or supplements) for at least 1 month prior to the Baseline Visit Exclusion Criteria: Subject has any prior or current medical condition that, in the judgment of the Investigator, would prevent the subject from safely participating in and/or completing all study requirements (i.e. unstable angina or recent myocardial infarction) Subject has received any investigational compound and/or has participated in another interventional clinical study within 30 days prior to the Baseline Visit or is concurrently enrolled in any non-interventional research of any type judged to be scientifically or medically incompatible with the study as deemed by the Investigator in consultation with the Sponsor Subject experienced an adverse reaction to study drug in the SPIMM-201 study that contraindicates further treatment with elamipretide in the opinion of the Investigator and/or Sponsor Female subjects who are pregnant, planning to become pregnant, or lactating Subject has undergone an in-patient hospitalization within the 1 month prior to the Screening Visit or is likely to need in-patient hospitalization or a surgical procedure during the course of the study Subject has a creatinine clearance ≤30 mL/min as calculated by the Cockcroft Gault equation Subject has a corrected QT interval (QTc) elongation defined as a QTc >450 msec in male subjects and >480msec in female subjects. Note: At the initial electrocardiogram (ECG), if QTc exceeds these parameters, the ECG may be repeated 2 more times, and the average of the 3 QTc values used to determine the subjects eligibility Subject has uncontrolled hypertension in the judgment of the Investigator (e.g. elevated above >160 mmHg systolic or >100 mmHg diastolic despite appropriate treatment on two consecutive readings) Subject has a history of clinically significant hypersensitivity or allergy to any of the excipients contained in the study drug Subject has a history of active alcoholism or drug addiction during the year before the Screening Visit

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elamipretide, Then Placebo<br>Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. | Drug: Elamipretide<br>* 4 weeks of treatment with 40 mg elamipretide administered once daily subcutaneously<br>* Other names: MTP-131;Drug: Placebo<br>* 4 weeks of treatment with placebo administered once daily subcutaneously<br>|
| Placebo Comparator: Placebo, Then Elamipretide<br>Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks. | Drug: Elamipretide<br>* 4 weeks of treatment with 40 mg elamipretide administered once daily subcutaneously<br>* Other names: MTP-131;Drug: Placebo<br>* 4 weeks of treatment with placebo administered once daily subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distance Walked on the 6-minute Walk Test (6MWT) by Visit | Distance in meters walked on the 6-minute walk test (6MWT) at end of treatment, where end of treatment means end of week 4 for Period 1 and end of week 12 for Period 2. | End of Week 4 and End of Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wrist Accelerometer Counts by Day | Wrist Accelerometer Counts by the last 7 days prior to the date of the end of treatment visit; End of treatment being end of Week 4 for Treatment Period 1 and end of Week 12 for Treatment Period 2. Subjects wore an activity monitor, or wrist accelerometer, on their wrist daily (from the Screening Visit to the End-of-Study/Early Discontinuation Visit). As a measure of physical activity and mobility, subjects wore an activity monitor, or wrist accelerometer, which measured mean vector magnitude of accelerations per daywith higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data were used for the analysis of as the vector magnitude of the wrist data. | Last 7 days prior to the date of end of treatment visit | 
| Average Hip Accelerator Counts by Day | Average Hip Accelerator Counts by last 7 days predose, and prior to end of treatment; End of treatment being Week 4 for Treatment Period 1 and Week 12 for Treatment Period 2. As a measure of physical activity and mobility, subjects wore an activity monitor, or hip accelerometer, on their hip (or belt line) daily during waking hours (minimum of at least 7 consecutive days immediately prior to study drug administration in each Treatment Period [Predose; at Visit 2 for Treatment Period 1 and at Visit 4 for Treatment Period 2]), and at the end of each Treatment Period [at Visit 3 for Treatment Period 1 and Visit 5 for Treatment Period 2]), which measured average acceleration per day, with higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data was used for the analysis of mean vertical axis (Y) cou | Last 7 days prior to the date of end of treatment visit | 
| Neuro-QoL Fatigue Short Form Score: Total T-Scores (Question 1-8) | Participants respond to the following statements of the Quality of Life in Neurological Disorders Fatigue Assessment (Neuro-QOL Fatigue Item Bank at end of treatment: I felt exhausted;I felt that I had no energy; I felt fatigued; I was too tired to do my household chores;I was too tired to leave the house;I was frustrated by being too tired to do the things I wanted to do; I felt tired; I had to limit my social activity because I was tired.Individual response options range from a score of 1 to 5, where 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always for end of treatment, where end of treatment period is end of week 4 for period 1, and end of week 12 for period 2. Raw scores are calculated as simple summed scores to an Item Response Theory Metric referred to as the T-score metric. Higher T-score means more fatigue, which means a worse outcome, with possible scores ranging from 29.5 to 74.1. Mean population T-score and standard deviation was reported. | End of Week 4 and End of Week 12 | 
| Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue Score by Week | Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue score at end of treatment (sum of Q1 to Q4; tiredness/muscle weakness) is scored as follows: 1=Not at all, 2=Mild, 3=Moderate, and 4=Severe. Total score range is 4-16; lower score means less fatigue and better outcome, higher score means more fatigue and worse outcome. Participants rate the following: Tiredness at rest, Tiredness during activities, Muscle weakness at rest, Muscle weakness during activities, at the end of each treatment period, where end of treatment period is the weekly average of the last 7 days of week 4 for period 1 and the last 7 days of week 12 for period 2. | Last 7 days of Week 4 and Last 7 days of Week 12 | 
| Triple Timed Up and Go (3TUG) Test by Visit | Participant performed 3TUG test after the 6MWT, and after at least 15 minutes rest prior to study drug administration in each Treatment Period (End of Week 4 for Period 1 and End of Week 12 for Period 2.) Participant was directed to stand up from chair, walk at normal pace to the line on the floor 3 meters away,turn, walk back to the chair at normal pace, sit down again; activity was timed, in seconds. Activity is repeated 3 times consecutively without rest and an average time is calculated. | End of Week 4 and End of Week 12 | 
| Patient Global Assessment [PGA] Score by Visit, Continuous | Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome. | End of Week 4 and End of Week 12 | 
| Patient Global Assessment by Visit, Categorical | Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome. Excellent means excellent health, means better outcome; poor means poor health, means worse outcome. | End of Week 4 and End of Week 12 | 
| Physician Global Assessment (PhGA) By Visit, Continuous | Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome. | End of Week 4 and End of Week 12 | 
| Physician Global Assessment (PhGA) By Visit, Categorical | Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome. Excellent means excellent health, means better outcome; poor means poor health, means worse outcome. | End of Week 4 and End of Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Mitochondrial Disease, Mitochondrial Myopathy, Elamipretide, MTP-131, Bendavia™