Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)

A Phase 3 Efficacy and Safety Study of Ataluren in Patients With Nonsense Mutation Dystrophinopathy

Dystrophinopathy is a disease continuum that includes Duchenne muscular dystrophy, which develops in boys. It is caused by a mutation in the gene for dystrophin, a protein that is important for maintaining normal muscle structure and function. Loss of dystrophin causes muscle fragility that leads to weakness and loss of walking ability. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of dystrophinopathy in approximately 10-15 percent (%) of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. The main goal of this Phase 3 study is to evaluate the effect of ataluren on walking ability. The effect of ataluren on physical function, quality of life, and activities of daily living will be evaluated. This study will also provide additional information on the long-term safety of ataluren.

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of ataluren in participants with nmDMD.

Inclusion Criteria:

• Ability to provide written informed consent (parental/guardian consent if applicable)/assent per local requirements.
• Phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (for example; proximal muscle weakness, waddling gait, and Gowers' maneuver) by 6 years of age, an elevated serum creatinine kinase level, and ongoing difficulty with walking.
• Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), the Clinical Laboratory Improvement Act/Amendment (CLIA) or an equivalent organization.
• Documentation that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the dystrophin gene.
• Use of systemic corticosteroids (prednisone, prednisolone, or deflazacort) for a minimum of 6 months immediately prior to start of study treatment, with no significant change in dosage or dosing regimen (not related to body weight change) for a minimum of 3 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.
• Valid Screening 6-minute walk distance (6MWD) greater than or equal to (≥) 150 meters. Valid Screening 6MWD must have been less than or equal to (≤) 80% of predicted for age and height.
• Results of the 2 Baseline 6MWD results must be determined as valid and results of the Day 2 Baseline 6MWD must be within 20% of the Day 1 Baseline 6MWD.
• Baseline 6MWD (mean of valid Day 1 and Day 2 values) must be no more than a 20% change from the valid Screening 6MWD.
• Confirmed screening laboratory values within the central laboratory ranges (hepatic, renal, and serum electrolyte parameters).
• Willingness to abstain from sexual intercourse or employ an approved method of contraception during the period of study drug administration and 6-week follow-up period.
• Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions.

Exclusion Criteria:

• Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment.
• Initiation of systemic corticosteroids therapy within 6 months prior to start of study treatment.
• Change in systemic corticosteroid therapy (for example; change in type of drug, dose modification not related to body weight change, schedule modification, interruption, or reinitiation) within 3 months prior to start of study treatment.
• Any change (initiation, change in type of drug, dose modification, schedule modification,interruption, discontinuation, or reinitiation) in prophylaxis/treatment for congestive heart failure (CHF) within 3 months prior to start of study treatment.
• Ongoing use of coumarin-based anticoagulants (for example; warfarin), phenytoin, tolbutamide, or paclitaxel.
• Prior therapy with ataluren.
• Known hypersensitivity to any of the ingredients or excipients of the study drug.
• Exposure to another investigational drug within 3 months prior to start of study treatment.
• History of major surgical procedure within 6 weeks prior to start of study treatment.
• Ongoing immunosuppressive therapy (other than corticosteroids).
• Ongoing participation in any clinical trial (except for studies specifically approved by PTC Therapeutics).
• Expectation of major surgical procedure (for example; scoliosis surgery) during the 12-month treatment period of the study.
• Requirement for daytime ventilator assistance.
• Uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D).
• Prior or ongoing medical condition (for example; concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings (for example; lower limb injury that may affect 6MWT performance), electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.