Safety, Tolerability, and Efficacy of MTP-131 for the Treatment of Mitochondrial Myopathy

Study Overview
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Brief Summary
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Phase 1/2, multi-center, randomized, double-blind, multiple ascending dose, placebo-controlled study that enrolled 36 subjects with mitochondrial myopathy associated with genetically confirmed mitochondrial disease to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of MTP-131 in this patient population.

Detailed Description
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This multi-center, randomized, double-blind, placebo-controlled study enrolled 36 subjects into 3 cohorts of 12 subjects each to evaluate treatment with 3 ascending doses of intravenous elamipretide (0.01, 0.10, and 0.25 mg/kg/hr infused for 2 hours). After each cohort, a Safety Monitoring Board (SMB) determined if dose escalation to the next higher dose of elamipretide was warranted. Each cohort went through 3 distinct periods: Screening, Treatment, and Follow-up. The Screening Period started with informed consent and may have lasted up to 40 days. During this period, screening procedures to determine subject eligibility for the study occurred, including confirmation of disease, which incorporated a committee review of the investigator-submitted diagnosis and genetic results. The Treatment Period began on Day 1 (Visit 2) and lasted for 5 days (until Day 5 [Visit 6]). Within each cohort, 9 subjects were randomized to active drug and 3 subjects were randomized to placebo on Day 1 and subjects received treatment once a day for 5 consecutive days. Safety, tolerability, and efficacy measures were performed at pre-specified times. The Follow-up Period began at the time of discharge on Day 5. Subjects returned to the study center for the Follow-up Visit on Day 7 (+1 day).

Official Title
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Phase 1/2 Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending-Dose Clinical Study for the Safety, Tolerability, and Efficacy of IV MTP-131 for Mitochondrial Myopathy in Genetically Confirmed Mitochondrial Disease

Conditions
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Mitochondrial Myopathy

Intervention / Treatment
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* Drug: elamipretide (low dose)
* Drug: elamipretide (intermediate dose)
* Drug: elamipretide (high dose)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of mitochondrial disease believed to impair the mitochondrial respiratory chain. Eligibility requires prior genetic confirmation of mitochondrial disease. Diagnosis of mitochondrial myopathy judged by the Investigators to be due to existing mitochondrial disease. Must be able to complete a Screening Visit 6MWT. Body mass index (BMI) score >15.0 and <35.0 kg/m2 at Screening Visit. Women of childbearing potential must agree to use birth control as specified in the protocol from the date they sign the ICF until two months after the last dose of study drug. Exclusion Criteria: 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. Had any exclusionary Newcastle Mitochondrial Disease Adult Scale (NMDAS) scores at Screening Visit. Hospitalized (admitted as in-patient) within 1 month prior to the Baseline Visit. A history of type 1 diabetes mellitus (T1DM). Uncontrolled Type 1 (T1DM) or Type 2 diabetes mellitus (T2DM), in the opinion of the investigator. A creatinine clearance <45 mL/min as calculated by the Cockcroft Gault equation. Requires pacemaker, defibrillator, or has undergone cardiac surgery within 2 years of Screening Visit. QTc elongation defined as a QTc >450 msec in male subjects and >480 msec in female subjects. Uncontrolled hypertension (>160 mmHg systolic or >100 mmHg diastolic) at Screening Visit. History of rhabdomyolysis defined as an acute rise in the serum creatine phosphokinase (CPK) value that, in the opinion of the investigator, caused clinically significant symptoms. Serum sodium more than 5 meq/L below the reference lower limit of normal at Screening Visit. Participated in another interventional clinical trial within 3 months of the screening visit or is currently enrolled in a non-interventional clinical trial judged by the Investigator to be incompatible with the current trial. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose<br>elamipretide 0.01 mg/kg/hr infused for 2 hours for 5 days | Drug: elamipretide (low dose)<br>* elamipretide (0.01 mg/kg/hr) administered as single day intravenous infusion over 2 hours for 5 days<br>* Other names: MTP-131;|
| Experimental: Intermediate dose<br>elamipretide 0.10 mg/kg/hr infused for 2 hours for 5 days | Drug: elamipretide (intermediate dose)<br>* elamipretide (0.10 mg/kg/hr) administered as single day intravenous infusion over 2 hours for 5 days<br>* Other names: MTP-131;|
| Experimental: High dose<br>elamipretide 0.25 mg/kg/hr infused for 2 hours for 5 days | Drug: elamipretide (high dose)<br>* elamipretide (0.25 mg/kg/hr) administered as single day intravenous infusion over 2 hours for 5 days<br>* Other names: MTP-131;|
| Placebo Comparator: Placebo<br>In each cohort, subjects received either IV elamipretide given once daily for 2 hours for 5 days or matching placebo. | Drug: Placebo<br>* placebo (at each dose cohort) administered as single day intravenous infusion over 2 hours for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT) | Change in distance walked as measured by meters on the 6-minute walk test from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Assessed at Baseline, Day 5 (end-of-treatment visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Maximum Oxygen Uptake (ml/kg/Min) | Change in maximum oxygen uptake as measured by mL/kg/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Ventilatory Efficiency (VE/VCO2 Slope) | Change in ventilatory efficiency as measured by the VE/VCO2 slope from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio) | Change in aerobic efficiency as measured by ΔO2 consumption/Δ work ratio from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio) | Change in oxygen utilization as measured by ΔVO2/ΔlogVE ratio from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds) | Change in oxygen uptake kinetics (mean response time) as measured by seconds from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Pre-exercise Lactate Levels (mg/dL) | Change in pre-exercise lactate levels as measured by mg/dL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Post-exercise Lactate Levels (mg/dL) | Change in post-exercise lactate levels as measured by mg/dL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Respiratory Exchange Ratio (VCO2/VO2) | Change in peak respiratory exchange ratio as measured by VCO2/VO2 from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Respiratory Rate (Breaths/Min) | Change in peak respiratory rate as measured by breaths/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Ventilation (L/Min) | Change in peak ventilation as measured by L/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Heart Rate (Beats/Min) | Change in peak heart rate as measured by beats per minute from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin) | Change in peak oxygen saturation as measured by percentage of O2-saturated hemoglobin from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Systolic Blood Pressure (mmHg) | Change in peak systolic blood pressure as measured by mmHg from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Diastolic Blood Pressure (mmHg) | Change in peak diastolic blood pressure as measured by mmHg from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Peak Borg Dyspnea | Change in peak Borg dyspnea as measured by 0-10 with 0 meaning no breathlessness and 10 meaning maximal breathlessness from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in VO2 Anaerobic Threshold (mL) | Change in VO2 anaerobic threshold as measured by mL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Watts | Change in watts from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Temperature (°C) | Change in temperature as measured by units of Celsius from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in ECG-PR Interval (Msec) | Change in PR interval as measured by ECG in milliseconds from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in ECG-QRS Complex (Msec) | Change in QRS complex as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in ECG-QT Interval (Msec) | Change in QT interval as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in ECG-QTc Interval (Msec) | Change in QTc interval as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening. | Number of participants with suicide ideation, suicidal behavior, or non-suicidal self-injurious behavior post-screening as measured on Days 1-5, and Day 7 on the Columbia Suicide Severity Rating Scale (CSSRS). A yes/no binary response is utilized in the following ten categories: 1 - Wish to be Dead; 2 - Non-specific Active Suicidal Thoughts; 3 - Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan; 5 - Active Suicidal Ideation with Specific Plan and Intent; 6 - Preparatory Acts or Behavior; 7 - Aborted Attempt; 8 - Interrupted Attempt; Category 9 - Actual Attempt (non-fatal); 10 - Completed Suicide. A yes/no binary response is also utilized in assessing self-injurious behavior without suicidal intent. A lower score means a better outcome whereas a higher score means a worse outcome. | Days 1-5 and Day 7. | 
| Change in Creatine Phosphokinase (IU/L) | Change in Creatine Phosphokinase as measured by IU/L from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Alanine Aminotransferase (ALT) (U/L) | Change in Alanine aminotransferase (ALT) as measured by (U/L) from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Aspartate Aminotransferase (AST) (U/L) | Change in aspartate aminotransferase (AST) as measured by U/L from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 
| Change in Eosinophils (10^9 Cells/L) | Change in eosinophils as measured by (10^9 cells/L) from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). | Baseline, Day 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mitochondrial Myopathy, Primary Mitochondrial Disease, Bendavia™, elamipretide