A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy

Phase 2

Terminated

Conditions: Primary Mitochondrial Myopathy

Interventions: Drug: Bocidelpar
Drug: Placebo

Registration Number: NCT04641962

Lead Sponsor: Astellas Pharma Inc

Brief Summary: The purpose of this study was to evaluate the dose response of Bocidelpar on functional improvement relative to placebo, safety, and tolerability in participants with Primary Mitochondrial Myopathy.

Detailed Description: Efficacy (i.e., functional improvement) was assessed by a functional motor test, 6-minute walk test (6MWT). The study consisted of the following portions: screening (4 weeks); double-blind treatment period with 2 doses of Bocidelpar vs matching placebo (24 weeks) and follow up (4 weeks).

Participants were randomly placed into 1 of 3 arms (Bocidelpar 30 mgs, Bocidelpar 75 mgs or placebo).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 34

Inclusion Criteria

Participant agrees and is able to adhere to the study requirements for the length of the study, including performing 6MWT.
Diagnosed with primary mitochondrial myopathy (PMM), consisting of the following:
- Molecular genetic abnormality (i.e., nuclear or mitochondrial) known to be associated with mitochondrial dysfunction (such as, but not limited to, mitochondrial DNA (mtDNA) single deletions in chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS); mtDNA m.3243 A > G pathogenic nuclear or mitochondrial genome variants demonstrated to cause primary mitochondrial disease), and
- Participant reported symptoms (i.e., muscle weakness, fatigue and exercise intolerance) or physical examination findings of myopathy that are the predominant symptoms of the participant's mitochondrial disorder.
Participant has been on stable dose regimen of coenzyme Q10 (CoQ10), carnitine, creatine, or other mitochondrial disease- focused vitamins or supplemental therapies for the treatment of symptoms of the mitochondrial disease for at least 3 months prior to randomization and intends to stay on a stable dose for duration of study period.
Participant has been on stable exercise regimen within 4 weeks prior to randomization and intends to stay on a stable regimen for duration of study period (for participants who participate in a regular exercise regimen).
Female participant is not pregnant and at least one of the following conditions apply:
- Not a woman of childbearing potential (WOCBP).
- WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 30 days after final study treatment administration.
Female participant must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final study treatment administration.
Female participant must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final study treatment administration.
Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 30 days after final study treatment administration.
Male participant must not donate sperm during the treatment period and for 30 days after final study treatment administration.
Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final study treatment administration.
Participant agrees not to participate in another interventional study while participating in the present study.

Exclusion Criteria

Participant has additional signs and/or symptoms due to non-myopathic process (e.g., cerebellar dysfunctions, movement disorder, peripheral neuropathy, stroke or other) or a gait problem not attributed to the myopathy that would interfere with the participant's performance during 6MWT or 5 times sit to stand (5XSTS).
Participant has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening.
Participant has any condition, which makes the participant unsuitable for study participation.
Participant has cardiac troponin I (cTnI) > upper limit of normal (ULN) at screening.
Participant has estimated glomerular filtration rate (eGFR) calculated by the chronic kidney disease epidemiology collaboration equation < 60 milliliter per minute per 1.73-meter square at screening or a history of chronic kidney disease stage 3 or greater.
Participant has at screening*: total bilirubin (TBL) > ULN or transaminase(s) (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) > ULN in the absence of elevations in CK. Participants who have a slightly elevated TBL and/or ALT and/or AST and are suitable candidates for the study may be enrolled after discussion of the case with the medical monitor and completion of further evaluation as warranted.
Participant has psychiatric conditions such as schizophrenia, bipolar disorder or major depressive disorder that has not been under control within 3 months prior to screening.
Participant has a history of suicide attempt, suicidal behavior or has any suicidal ideation within 1 year prior to screening that meets criteria at a level of 4 or 5 by using the Columbia- Suicide Severity Rating Scale (C-SSRS) or who is at significant risk to commit suicide.
Participant has severe behavioral or cognitive problems that preclude participation in the study.
Participant has undergone an in-patient hospitalization that precludes participation in the study, within the 30 days prior to the randomization.
Participant has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments.
Participant has clinically significant and unstable respiratory disease and/or cardiac disease (medical history or current clinical findings), or prior interventional cardiac procedure (e.g. cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to randomization. Participants with pacemakers are allowed in the study per investigator's discretion and after discussion with the medical monitor, and as long as it is used for prevention and there is no underlying cardiac dysfunction.
Participant has a corrected mean QT interval using Fridericia's correction (QTcF) > 450 msec for male participants and > 480 msec for female participants at screening or randomization. If QTcF exceeds these limits, one additional triplicate ECG can be repeated on the same day in order to determine the participant's eligibility.
ECG evidence of acute ischemia, atrial fibrillation or active conduction system abnormalities. The following conduction system abnormalities may be permitted per the investigator's discretion, only after discussing the case with the medical monitor:
- First degree atrioventricular (AV)- block
- Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
- Right bundle branch block
- Left fascicular block
- Bi-fascicular block
Participant requires any ventilatory support, inclusive of any respiratory device to support breathing such as home ventilators and any form of non-invasive positive pressure ventilation (including continuous positive airway pressure [CPAP], bilevel positive airway pressure [BiPAP], and average volume-assured pressure support [AVAPS]). Participants who require oxygen therapy (even by low flow nasal cannula [LFNC]) are not candidates for this study.
Participant has severe vision impairment that may interfere with their ability to complete all study requirements.
Participant has an intractable seizure disorder that may interfere with their ability to complete all study requirements.
Active malignancy or any other cancer from which the participant has been disease-free for < 5 years, except for curative treated localized non-melanoma skin cancer (e.g., basal cell or squamous cell carcinoma).
Participant has a solid organ transplant and/or is currently receiving treatment with therapy for immunosuppression.
Participant has severe scoliosis or kyphoscoliosis that significantly impair respiratory capacity and pulmonary function tests or limit positioning due to pain who would be likely to require orthopedic surgical intervention within a year after study randomization.
Participant has a positive test for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection at screening.
Participant has previously received Bocidelpar.
Participant has a history of active substance abuse within 1 year prior to randomization.
Participant has used any peroxisome proliferator-activated receptor (PPAR) ligands such as fibrates and thiazolidinediones within 4 weeks prior to randomization.
Participant has initiated the use of CoQ10, carnitine, creatine or other mitochondrial disease-focused supplements for the treatment of symptoms of the mitochondrial disease within 3 months prior to study randomization.
Participant has a known or suspected hypersensitivity to Bocidelpar or any components of the formulation used.
Participant has symptomatic coronavirus disease 2019 (COVID-19) infection within 3 months prior to study randomization that required treatment (Monoclonal antibodies, ventilator support, hospitalization) and/or led to long-term sequelae or lingering symptoms.
Participant has body mass index (BMI) below 17 kg/ m^2 or above 35 kg/ m^2 at screening.
Participant has signs or symptoms of bulbar weakness, such as dysphagia, dysphonia, hoarseness or drooling/sialorrhea, due to either neuropathy or myopathy.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DBT Bocidelpar 30 mgs	Bocidelpar	Participants received Bocidelpar 30 milligrams (mgs) orally once daily during the double blind treatment period. The Participants were followed up for another 4 weeks after the completion of treatment period.
DBT Bocidelpar 75mgs	Bocidelpar	Participants received Bocidelpar 75 mg orally once daily during the DB treatment period.. The Participants were followed up for another 4 weeks after the completion of treatment period.
DBT: Placebo to OLE Period: Bocidelpar 30 mg	Bocidelpar	Participants received Bocidelpar matching placebo orally once daily during the DB treatment period and received 30 mg ASP0367 in the OLE period.
DBT: Placebo to OLE Period: Bocidelpar 30 mg	Placebo	Participants received Bocidelpar matching placebo orally once daily during the DB treatment period and received 30 mg ASP0367 in the OLE period.
DBT Bocidelpar 30 mg or 75mg to Open label Extension Period: Bocidelpar 30 mg	Bocidelpar	Participants received Bocidelpar 30 mg or 75 mg orally once daily during the DB treatment period and received 30 mg Bocidelpar in the OLE period.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment Emergent Adverse Events	From first dose up to week 52	An Adverse event (AE) was any untoward medical occurrence in a participant administered a study drug, and which dint have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE was defined as an AE observed after starting administration of the study drug through 28 days after the last dose.
Number of Participants With Suicidal Ideation and/ or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)	From the first dose up to week 52	The C-SSRS was a questionnaire used for suicide risk assessment. Affirmative or negative responses were provided to items 1 to 5 for suicidal ideation (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) and items 6 to 10 for suicide behavior (6. Preparatory acts or behavior, 7. Aborted attempt, 8. Interrupted attempt, 9. Actual attempt, 10. Completed suicide). The overall data was reported.
Change From Baseline in Distanced Walked During a 6 Minute Walk Test (6MWT).	Baseline, week 24	6MWT assessed functional capacity and endurance by measuring the distance walked in 6 minutes. This test helped to assess exercise tolerance, physical fitness, disease progression, and treatment effectiveness in individuals with myopathy. The total distance walked by a participant, as well as distance per minute was calculated by rounding to the nearest meter.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Change From Baseline in Patient Global Impression of Severity (PGIS) at Week 24	Baseline, week 24	PGIS score was a patient-reported measure that reflected the individual's overall perception of the severity of their condition on a Likert scale. PGIS score were calculated as -1= mild change from baseline, -2=moderate change from baseline,-3=severe change from baseline,0= none, 1= mild, 2= moderate and 3= severe. The questionnaire asked the participant to best describe the severity of the participant's most bothersome pre-defined symptom over the past week.
Change From Baseline in Quality of Life in Neurological Disorders (Neuro-QoL) Short Form Fatigue Score	Baseline, week 24	The Neuro-QoL Short Form Fatigue score was an 8-item self- assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities. Participants had five response options for each item: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always. The questionnaire was scored by adding the response to each of the item and then transformed into T-scores based on the scoring manual with a score range of minimum=29.5, maximum=74.1. T-score distributions rescaled raw scores into standardized scores with a mean of 50 and a SD of 10. Higher scores indicated a greater level of fatigue.
Change From Baseline in Time to Perform the 5 Times Sit to Stand (5XSTS) Test	Baseline, week 24	The 5XSTS test was a functional assessment that measured the time taken to stand up from a seated position five times in a row, as quickly as possible. The duration from the time instructor indicated "Go" until the time participant's body touched the chair following the fifth repetition was recorded and reported.
Change From Baseline in Neuro-QoL Short Form Lower Extremity Function (Mobility) Scores	Baseline, week 24	The Neuro-QoL Short Form Lower Extremity Function (Mobility) score was an 8-item self- assessment questionnaire evaluating the functioning of one's lower extremities. Participants responded to questions on a 1-5 scale. Participants had five response options for each item: 1=Unable to do,2=With much difficulty,3=With some difficulty,4=With a little difficulty, 5=Without any difficult. The questionnaire was scored by adding the response to each of the item and then transformed into T-scores based on the scoring manual with a score range of minimum=16.5, maximum=58.6. T-score distributions rescaled raw scores into standardized scores with a mean of 50 and a SD of 10. Higher scores indicated better function.
Number of Participants With Patient's Global Impression of Change (PGIC) Score at Week 24	Week 24	The PGIC scale evaluated the participant's symptom and assessed if there had been any improvement or decline in clinical status. The participant rated their perceived change on a 7-point scale, with 1 indicating very much improved, 2 = Much Improved, 3=Minimally Improved, 4= No Change, 5=Minimally Worse, 6=Much Worse and 7 indicating 'very much worse".
Change From Baseline in Modified Fatigue Impact Scale (MFIS)	Baseline, week 24	MFIS was a self-reported questionnaire designed to evaluate the impact of fatigue on physical, cognitive and psychosocial functioning. The MFIS consisted of 21 items scored 0-4 (0=Never, 1=Rarely, 2=Sometimes, 3=Often, and 4=Almost always). The total MFIS score ranged from 0 to 84, with three subscales: Physical range 0-36, Cognitive range 0-40, and Psychosocial range 0-8. Higher scores indicated higher level of fatigue.

Trial Locations

Locations (11): University of California, San Diego
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La Jolla, California, United States
Stanford University Medical Center
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Stanford, California, United States
Children's Hospital Colorado
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Aurora, Colorado, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Columbia University Irving Medical Center
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New York, New York, United States
Akron Children's Hospital
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Akron, Ohio, United States
Cleveland Clinic
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Cleveland, Ohio, United States
Children's Hospital of Philadelphia
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Philadelphia, Pennsylvania, United States
Baylor College of Medicine
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Houston, Texas, United States
University of Texas Health Science Center at Hosuton
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Houston, Texas, United States
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University of California, San Diego
🇺🇸La Jolla, California, United States