Study of Ataluren (PTC124) in Nonambulatory Participants With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)

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. Ataluren (PTC124) is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 2a trial that enrolled boys with nonsense mutation DMD/BMD who have lost independent mobility due to the disease. This study evaluated the safety and tolerability of ataluren (PTC124) and also evaluated efficacy outcomes in this participant population.

It was planned that this Phase 2a, open-label, safety and efficacy study to be performed at 5 sites in the US and 1 site in the United Kingdom.

The study was to enroll \~30 boys with nonsense mutation DMD/BMD (nmDBMD) who have been nonambulatory for at least 1 year. Enrollment was to be stratified to ensure evaluation of \~15 participants who were receiving chronic corticosteroid therapy and of \~15 participants who were not receiving chronic corticosteroid therapy. Participants were to take ataluren 3 times per day (at breakfast, lunch, and dinner) for 48 weeks (\~1 year). Study assessments were to be performed at clinic visits during screening, every 6 weeks for 2 visits and then every 12 weeks until the end of the study. Additional safety laboratory testing was to be required 4 times during the course of the study; this could have been performed at the investigational site, at an accredited local laboratory or clinic, or in the participant's home using a nursing service. When the blind for a similar study (PTC124-GD-007-DMD; NCT00592553) was revealed, the results indicated lack of efficacy for the high dose. Therefore, even though an independent data monitoring committee (DMC) agreed that both ataluren dose levels were well tolerated by the participants, the DMC recommended discontinuing ongoing studies with participants with nmDBMD receiving high-dose ataluren.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of DMD or BMD
* Presence of a nonsense mutation in the dystrophin gene
* Unable to ambulate independently for ≥1 year due to DMD/BMD
* Presence of sufficient shoulder and elbow function to perform study-related functional procedures (for example, 9-hole peg test)
* Adequate hepatic, renal, and adrenal function
* Ability to provide evaluable pretreatment echocardiogram and lung function assessments
* Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions
* Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if \<18 years of age)

Exclusion Criteria:

* Initiation of systemic corticosteroid therapy within 6 months prior to start of study treatment or use of systemic aminoglycoside antibiotic within 3 months prior to start of study treatment
* Use of any intermittent systemic corticosteroid therapy regimen (for example, 10 days on followed by 10 days off, weekend dosing, every-other-day dosing); note that participants must have either been receiving a daily dosing regimen of prednisone, prednisolone, or deflazacort at the time of enrollment into the study or must have not been receiving any systemic corticosteroids
* Any change in treatment for congestive heart failure within 3 months prior to start of study treatment
* Ongoing warfarin or phenytoin therapy
* Prior therapy with ataluren
* Known hypersensitivity to any of the ingredients or excipients of ataluren (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 1 month prior to start of study treatment or expectation of major surgical procedure (for example, scoliosis surgery) during the 48-week treatment period of the study
* Ongoing immunosuppressive therapy (other than corticosteroids)
* Ongoing participation in any other clinical trial
* Requirement for daytime ventilator assistance
* Uncontrolled clinical symptoms and signs of congestive heart failure
* Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, 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