S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)

INCLUSION CRITERIA

Patients must meet all the following conditions to be eligible for enrollment into the study:

• Body mass index (BMI) ≥ 18.0 and ≤ 36.0 kg/m2 at screening.
• Confirmed genetic diagnosis of RYR1-RM and supporting clinical phenotype.
• Ambulatory. Able to walk ten meters (with or without assistance e.g. with a cane).
• Prior muscle biopsy with demonstrated leaky RyR1 channel.
• Must have a CYP2C8 extensive or intermediate metabolizer genotype.
• Daily use of medicines and dietary supplements need to be approved by the PI and Sponsor, or a drug/supplement-dependent wash-out prior to inclusion.
• For male subjects: is sterile or agrees to use an appropriate method of contraception, including a condom with spermicide, from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug administration. No restrictions are required for a vasectomized male subject provided the subject is at least 1-year post-bilateral vasectomy procedure prior to study drug administration on first day of the first dose. A male subject whose vasectomy procedure was performed less than 1 year prior to study drug administration on the first day of dosing must follow the same restrictions as a non-vasectomized male. Appropriate documentation of surgical procedure should be provided.
• For male subjects: agrees to not donate sperm from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug.
• For female subjects of childbearing potential: uses one of the following highly effective birth control methods:
• Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch.
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Depot/implantable hormone (e.g., Depo-provera®, Implanon).
• Bilateral tubal occlusion/ligation.
• Sexual abstinence:
• Refraining from heterosexual intercourse during the entire period of risk associated with the study requirements.
• If the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used.
• For female subjects of non childbearing potential; defined by at least 1 of the following criteria:
• Postmenopausal defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) serum level > 40mIU/mL. Appropriated documentation of FSH levels is required.
• Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure.
• Has a congenital condition resulting in no uterus.
• Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and study procedures (muscle biopsies and PK sampling).
• Able to provide written informed consent and understands the study procedures in the informed consent form (ICF).

EXCLUSION CRITERIA

The presence of any of the following conditions will exclude a patient from study enrollment:

• Patient is mentally or legally incapacitated at the time of the screening visit or during the conduct of the study.
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.
• History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients.
• Positive urine drug or alcohol results at screening.
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
• Patients with baseline ALT levels three times above the upper limits of normal (ULN) or baseline AST levels five times the ULN (isolated elevations of total bilirubin 10 years prior to the screening where in the judgment of the investigator has revealed no evidence of recurrence from the time of treatment through the time of the