Phase 2b Study of PTC124 in Duchenne/Becker Muscular Dystrophy (DMD/BMD)

• Activity in the community setting [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Proximal muscle function [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Muscle strength [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Muscle fragility [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Biceps muscle dystrophin expression [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Quality of Life [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Cognitive ability [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Cardiac function [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Frequency of accidental falls during ambulation [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
• Treatment satisfaction [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
• Safety [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Compliance with treatment [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• PTC124 pharmacokinetics [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Duchenne/Becker muscular dystrophy (DMD/BMD) is a genetic disorder that 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 during childhood and teenage years. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of DMD/BMD in approximately 10-15% of boys with the disease. PTC124 is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 2b trial that will evaluate the clinical benefit of PTC124 in boys with DMD/BMD due to a nonsense mutation. The main goals of the study are to understand whether PTC124 can improve walking, activity, muscle function, and strength and whether the drug can safely be given for a long period of time.

This study is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study, designed to document the clinical benefit of PTC124 when administered as therapy of patients with DMD/BMD due to a nonsense mutation (premature stop codon) in the dystrophin gene. It is planned that ~165 boys who are at least 5 years of age and can walk at least 75 meters (80 yards) will be enrolled. Study subjects will be enrolled at sites in North America, Europe, Israel, and Australia. They will be randomized in a 1:1:1 ratio to either a higher dose of PTC124, a lower dose of PTC124, or placebo. Subjects will receive study drug 3 times per day (at breakfast, lunch, and dinner) for 48 weeks. Subjects will be evaluated at clinic visits every 6 weeks. Additional safety laboratory testing, which may be performed at the investigational site or at an accredited local laboratory or clinic, is required every 3 weeks for the first 24 weeks of the study. At the completion of blinded treatment, all compliant participants will be eligible to receive open-label PTC124 in a separate extension study.

• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy

• Drug: PTC124
  PTC124 Low Dose
• Drug: PTC124
  PTC124 High Dose
• Drug: PTC124
  Placebo

• Active Comparator: 1
  Intervention: Drug: PTC124
• Active Comparator: 2
  Intervention: Drug: PTC124
• Placebo Comparator: 3
  Intervention: Drug: PTC124

Inclusion Criteria:

• Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if <18 years of age)
• Male sex.
• Age ≥5 years.
• Phenotypic evidence of DMD/BMD based on the onset of characteristic clinical symptoms or signs (ie., proximal muscle weakness, waddling gait, and Gowers' maneuver) by 9 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.
• Ability to walk ≥75 meters unassisted during the screening 6-minute walk test.
• Documentation that a baseline renal ultrasound has been performed.
• Confirmed screening laboratory values within the central laboratory ranges (adrenal, renal, and serum electrolytes parameters)
• 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 corticosteroid therapy within 6 months prior to start of study treatment or change in systemic corticosteroid therapy (eg, initiation, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, discontinuation, 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 within 3 months prior to start of study treatment.
• Treatment with warfarin within 1 month prior to start of study treatment.
• Prior therapy with PTC124.
• Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P [colloidal silica], magnesium stearate).
• Exposure to another investigational drug within 2 months prior to start of study treatment.
• History of major surgical procedure within 30 days prior to start of study treatment.
• Ongoing immunosuppressive therapy (other than corticosteroids).
• Ongoing participation in any other therapeutic clinical trial.
• Expectation of major surgical procedure (eg, scoliosis surgery) during the 12 month treatment period of the study.
• Requirement for daytime ventilator assistance.
• Clinical symptoms and signs of congestive heart failure (American College of Cardiology/American Heart Association Stage C or Stage D) or evidence on echocardiogram of clinically significant myopathy
• Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, electrocardiogram findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.