A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy

Study Overview
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Brief Summary
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The purpose of the phase 2 portion of this study is to select a biologically-active ASP0367 dose level by pharmacokinetic (PK) and pharmacodynamic (PD) evaluation. The phase 2 portion of this study will also assess the safety and tolerability of ASP0367. The purpose of the phase 3 portion of this study is to assess the effect of ASP0367 on functional improvement relative to placebo and will also assess the safety and tolerability of ASP0367 relative to placebo. The phase 3 portion of this study will also assess the effect of ASP0367 on functional improvement and fatigue relative to placebo and will assess the effect of ASP0367 in overall participant functioning relative to placebo.

Detailed Description
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Efficacy (i.e., functional improvement) will be assessed by a functional motor test, 6-minute walk test (6MWT). The study consists of the following portions: screening (4 weeks); phase 2 dose selection portion with 2 doses of ASP0367 versus matching placebo (2 weeks); phase 3 portion with selected, single dose treatment versus placebo (up to 52 weeks); open-label extension (OLE) (24 weeks); and follow-up (4 weeks). During the phase 2 portion of the study, participants will be randomly placed into 1 of 3 arms (low dose ASP0367, high dose ASP0367 or placebo). The relevant dose level will be selected based on the pharmacokinetics/pharmacodynamics and overall safety. Participants will maintain their original Phase 2 dose level and no new participants will be enrolled in the study until phase 3 dose selection is made. After the phase 3 dose is selected, all participants except the placebo group will switch to the selected dose level of ASP0367 for the remainder of the phase 3 portion of the study (up to a total 52 weeks including the phase 2 portion). Participants who were originally assigned to placebo will remain on placebo for up to 52 weeks. The remaining enrollment of participants will be randomized to either ASP0367 or matching placebo at a ratio of 1:1. All participants who have completed the phase 3 portion of the study and are eligible for the OLE will be offered the opportunity to take ASP0367 for an additional 24 weeks.

Official Title
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A Randomized, Double-blind, Placebo-controlled Adaptive Phase 2/3 Study With Open-label Extension to Assess the Efficacy, Safety and Tolerability of ASP0367 in Participants With Primary Mitochondrial Myopathy

Conditions
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Primary Mitochondrial Myopathy

Intervention / Treatment
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* Drug: Bocidelpar
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant agrees and is able to adhere to the study requirements for the length of the study, including performing 6MWT, as well as the use of digital applications and video recordings. Diagnosed with primary mitochondrial myopathy (PMM), consisting of the following: Molecular genetic abnormality (i.e., nuclear or mitochondrial) known to be associated with causing mitochondrial dysfunction (such as, but not limited to, mitochondrial DNA (mtDNA) single, variable deletions in chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS); mtDNA m.3243 A > G common mutation in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); 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 3 months prior to randomization and intends to stay on a stable dose for duration of study period (for participants who take any above-mentioned medications or supplements). 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. Open-label Extension Continuation Criteria: • Participant must meet all of the following OLE criteria at the week 52 study visit in the treatment period to be eligible for OLE: Participant must continue to be able and willing to adhere to the study requirements. Participant who is eligible to continue in OLE. 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/may in addition to the myopathy affect 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 and is assessed as clinically significant. 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. 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 creatine kinase (CK). Participants who have a slightly elevated TBL and/or ALT and/or AST and are suitable candidates for the study, can be enrolled in the study as long as the investigator can rule out any underlying liver dysfunction by running additional tests and after discussing the case with the medical monitor. 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 with the exception of any of the following: 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 ventilator support. 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 requirem ents. 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 for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection at screening. Participant has previously received ASP0367. 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 within 3 months prior to study randomization. Participant has a known or suspected hypersensitivity to ASP0367 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 BMI below 18.5 kilogram per meter square (kg/m^2) or above 35 kg/m^2 at screening Participant has bulbar weakness due to either neuropathy or myopathy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 54 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2: Low dose ASP0367<br>Participants will receive ASP0367 once daily in the morning for 2 weeks. | Drug: Bocidelpar<br>* Oral<br>* Other names: ASP0367;|
| Experimental: Phase 2: High dose ASP0367<br>Participants will receive ASP0367 once daily in the morning for 2 weeks. | Drug: Bocidelpar<br>* Oral<br>* Other names: ASP0367;|
| Placebo Comparator: Phase 2: Placebo<br>Participants will receive placebo once daily in the morning for 2 weeks. | Drug: Placebo<br>* Oral<br>|
| Experimental: Phase 3: ASP0367<br>Participants will receive ASP0367 once daily in the morning for up to 52 weeks. | Drug: Bocidelpar<br>* Oral<br>* Other names: ASP0367;|
| Placebo Comparator: Phase 3: Placebo<br>Participants will receive placebo once daily in the morning for up to 52 weeks. | Drug: Placebo<br>* Oral<br>|
| Experimental: Open Label Extension: ASP0367<br>Participants will receive ASP0367 once daily in the morning for 24 weeks. | Drug: Bocidelpar<br>* Oral<br>* Other names: ASP0367;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 portion: Pharmacokinetics (PK) of ASP0367 in plasma: AUCtau | AUCtau: AUC from the time of dosing to the start of the next dosing interval at multiple dose conditions. AUCtau will be recorded from the PK plasma samples collected. | Day 14 | 
| Phase 2 portion: PK of ASP0367 in plasma: Cmax | Cmax: maximum concentration. Cmax will be recorded from the PK plasma samples collected. | Day 14 | 
| Phase 2 portion: Percent change from baseline peroxisome proliferator-activated receptor (PPAR) delta target gene expression levels in blood | Whole blood cell samples will be collected to measure percent change in target gene expressions | Baseline and Day 14 | 
| Phase 2 and Phase 3 portions: Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs) | Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 28 days after last dose of IP or moving to the OLE, whichever comes first. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. This includes events related to the comparator and events related to the study procedures. | Through Week 52 | 
| Phase 2 and Phase 3 portions: Number of participants with body weight change abnormalities and/or AEs | Number of participants with potentially clinically significant body weight changes. | Through Week 52 | 
| Phase 2 and Phase 3 portions: Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/or AEs | Number of participants with potentially clinically significant 12-lead ECG values. | Through Week 52 | 
| Phase 2 and Phase 3 portions: Number of participants with laboratory value abnormalities and/or AEs | Number of participants with potentially clinically significant laboratory values. | Through Week 52 | 
| Phase 2 and Phase 3 portions: Number of participants with vital sign abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Through Week 52 | 
| Phase 2 and Phase 3 portions: Number of participants with suicidal ideation and/ or behavior as assessed Columbia-Suicide Severity Rating Scale (C-SSRS) | The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response provided to the 5 items for suicidal ideation (1. Wish to be dead, 2. Nonspecific 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/or to the 6 items for suicidal behavior (1. Actual attempt, 2. Interrupted attempt, 3. Aborted attempt, 4. Preparatory acts or behavior, 5. Suicidal Behavior 6. Completed suicide). | Through Week 52 | 
| Phase 3 portion: Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs) | Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 28 days after last dose of IP or moving to the OLE, whichever comes first. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. This includes events related to the comparator and events related to the study procedures. | Through Week 80 | 
| Phase 3 portion: Number of participants with body weight change abnormalities and/or AEs | Number of participants with potentially clinically significant body weight changes. | Through Week 80 | 
| Phase 3 portion: Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/or AEs | Number of participants with potentially clinically significant 12-lead ECG values. | Through Week 80 | 
| Phase 3 portion: Number of participants with laboratory value abnormalities and/ or AEs | Number of participants with potentially clinically significant laboratory values. | Through Week 80 | 
| Phase 3 portion: Number of participants with vital sign abnormalities and/ or AEs | Number of participants with potentially clinically significant vital sign values. | Through Week 80 | 
| Phase 3 portion: Number of participants with suicidal ideation and/ or behavior as assessed Columbia-Suicide Severity Rating Scale (C-SSRS) | The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response provided to the 5 items for suicidal ideation (1. Wish to be dead, 2. Nonspecific 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/or to the 6 items for suicidal behavior (1. Actual attempt, 2. Interrupted attempt, 3. Aborted attempt, 4. Preparatory acts or behavior, 5. Suicidal Behavior 6. Completed suicide). | Through Week 80 | 
| Phase 3 portion: Change from baseline in distance walked in 6 minutes assessed in meters | The 6-minute walk test (6MWT) is a measurement of endurance that assesses walking distance over 6 minutes. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3 portion: Change from baseline in quality of life in neurological disorders (Neuro-QoL) Short Form Fatigue score | The Neuro-QoL Short Form Fatigue score is an 8-item self- assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities. Participants have five response options for each item: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always. The questionnaire is scored by adding the response to each of the items. Higher scores indicate a greater level of fatigue. | Baseline and Week 52 | 
| Phase 3 portion: Change from baseline in time spent on the 5 Times Sit to Stand (5XSTS) test | Change from baseline in time spent on the 5XSTS test. The test requires participants to sit with arms folded across chest and back against the chair and stand up and sit down 5 times in a row, as quickly as he/she can. | Baseline and Week 52 | 
| Phase 3 portion: Change from baseline in Modified Fatigue Impact Scale (MFIS) | MFIS is a modified form of the Fatigue Impact Scale questionnaire specific to measuring how fatigue impacts the lives of those affected by fatigue-like symptoms. The 21 items in the scale measure three domains of fatigue including physical, cognitive and psychosocial functioning. Participants have five response options for each item: 0=Never, 1=Rarely, 2=Sometimes, 3=Often, and 4=Almost always. The scale is scored by adding the response to each of the items. Higher scores indicate a greater level of fatigue. | Baseline and Week 52 | 
| Phase 3 portion: Change from baseline in Neuro-QoL Short Form Lower Extremity Function (Mobility) score | The Neuro-QoL Short Form Lower Extremity Function (Mobility) score is an 8-item self-assessment questionnaire evaluating one's ability to carry out various activities involving the trunk region and increasing degrees of bodily movement, ambulation, balance or endurance. Participants have 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 difficulty. The questionnaire is scored by adding the response to each of the items. Higher scores indicate a greater level of lower extremity function (Mobility). | Baseline and Week 52 | 
| Phase 3 portion: Score on Patient Global Impression of Change (PGIC) | The Patient Global Impression of Change evaluates participant's most bothersome symptom and assesses if there has been an improvement or decline in clinical status. Ratings range from (1) very much improved to (7) very much worse. | Week 52 | 
| Phase 3 portion: Change from baseline in Patient Global Impression of Severity (PGIS | The Patient Global Impression of Severity questionnaire assesses patient's impression of disease severity. The questionnaire asks the participant to best describe the severity of the participant's most bothersome pre-defined symptom over the past week scored from (1) None to (4) Severe. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP0367, fatigue, exercise intolerance, muscle weakness, Primary Mitochondrial Myopathy