Phase 3 Trial of Translarna’s Long-term Efficacy Enrolling Duchenne MD Patients with Nonsense Mutations

PTC Therapeutics is recruiting Duchenne muscular dystrophy (DMD) patients ages 5 and older and with a nonsense mutation for a long-term Phase 3 study to characterize the effects of Translarna (ataluren) on disease progression.

The trial (NCT03179631) opened in July 2017 and enrolling patients at eight sites across the U.S., and at others in Australia, Korea and Hong Kong.

PTC will likely use data from this new trial, if positive, combined with analyses of previous trial results, to resubmit a New Drug Application (NDA) to the U.S. Food and Drug Administration requesting that Translarna be approved for use in nonsense mutation Duchenne muscular dystrophy (nmDMD) patients.

The FDA has rejected previous applications for Translarna, most recently in October, stating the results supporting them were insufficient and further evidence of the therapy’s efficacy was required.

But the agency’s Office of New Drugs recently left the door open for a new submission. In a statement released this week, it said a “possible path forward” for Translarna would be an NDA that included new data supporting its efficacy in nmDMD patients’ muscles, as well as current data. The re-submission would be based on the FDA’s accelerated approval pathway, and make use of “newer technologies” to measure efficacy as well as procedures agreed upon by the company and regulatory agency.

Patients enrolled in this Phase 3 trial will be randomized to receive Translarna or a placebo orally three times a day – morning, midday, and evening – for a total of 72 weeks (16.5 months), after which all patients will receive Translarna for an additional 72 weeks (the study’s open-label phase). In total, the trial will run through 144 weeks (2.8 years) and expects to recruit 250 patients, more than half of whom will be between the ages of 7 and 16 years old.

Researchers will administer Translarna or placebo in three daily doses of 10, 10, 20 mg/kg.

The study’s primary objective (endpoint) is to evaluate patients’ performance in the six-minute walk test, a measure of physical function, after 72 weeks of treatment. Additional (secondary) endpoints include timed function tests, and assessing Translarna safety and patients’ upper limbs performance in those 7 or older at the study’s start.

Both primary and secondary endpoints will be performed at clinic visits every 12 weeks (first phase of the study), and at visits every 24 weeks in the open-label period.

PTC had appealed the FDA decision of October 2017, which the agency said was due a lack of substantial evidence of Translarna’s efficacy and a need for additional well-controlled clinical trials to demonstrate effectiveness.

In its recent statement, the FDA rejected that appeal and stood by its decision, but noted that the long-term Phase 3 trial now underway could serve as the “confirmatory post-approval trial required in connection with the accelerated approval framework.”

Translarna showed promise as an nmDMD treatment in a Phase 2b study (NCT00592553) that finished collecting data in late 2009. Patients given 40 mg/kg of the treatment daily showed a significant difference in their ability to walk compared to the placebo group after 48 weeks. Complete trial results were published in the journal Muscle and Nerve.

However, two later trials – a Phase 2b extension study (NCT00847379) of the earlier trial, and a new Phase 3 study (NCT01826487) — failed to meet their primary goal and key secondary outcome measures.

In Phase 2b extension study all patients received Translarna three times a day (breakfast, lunch, and dinner) for 96 weeks (about 2 years). The primary outcome was to assess long-term safety, secondary measures looked at ambulation and proximal (those closest to the chest) muscle function.

The Phase 3 study included a placebo control arm and tested Translarna delivery in the same regimen — three times a day — again for 48 weeks. The primary outcome measured the therapy’s efficacy as changes in the six-minute walk test from baseline.

Nonsense mutations introduce a stop signal — read by the protein-making machinery — in a gene. This mutation leads to the production of a truncated, and nonfunctional, form of dystrophin. Translarna works by bypassing the stop sign to produce a functional dystrophin protein.

In Europe, Translarna was granted a conditional approval and is being used to treat ambulatory patients ages 5 and older with nmDMD. However, the EU required PTC Therapeutics to conduct a new randomized, long-term placebo-controlled trial of Translarna in nmDMD patients. The study will include a first randomized 18-month phase, followed by an equal open-label extension period where all patients will be treatment with Translarna. Results are expected by early 2021.

An observational, registry trial (NCT02369731) is currently recruiting nmDMD patients across Europe to assess the long-term safety of Translarna’s use.