A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy

A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Assess the Efficacy, Safety and Tolerability of ASP0367 in Participants With Primary Mitochondrial Myopathy

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.

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).

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.