FDA Rejects New Drug Application for Translarna to Treat DMD

The U.S. Food and Drug Administration decided not to approve Translarna (ataluren), by PTC Therapeutics, as a treatment for specific types of Duchenne muscular dystrophy caused by “nonsense” mutations.

Although not entirely unexpected, the decision was disappointing to many in the Duchenne community.

On Sept. 28, an FDA advisory panel concluded that evidence to support Translarna’s effectiveness as a therapy was lacking, and more research was needed. That opinion was endorsed by 10 of the panel’s 11 members and echoed by an FDA briefing document given to the advisory panel in advance of the meeting. The brief highlighted problems with research data presented to support the treatment’s marketing application.

The FDA’s Office of Drug Evaluation noted in its recent complete response letter (CRL) that PTC had failed to clearly demonstrate that the treatment worked — a stronger condemnation than that of the advisory group, whose majority voiced its dissatisfaction with inconclusive data.

“Ultimately, no positive results from any prospectively planned analyses that are persuasive have been provided with this application,” the agency memo stated. The CRL calls for additional adequate and well-controlled and clinical trials, at a minimum, to provide substantial evidence of the effectiveness of the treatment.

PTC is in the process of addressing other nonclinical and chemistry, manufacturing, and controls (CMC) matters that were brought up in the CRL.

“We are extremely disappointed for the Duchenne community and strongly disagree with the agency’s conclusions,” Stuart W. Peltz, PhD, chief executive officer of PTC Therapeutics, said in a press release. “We believe that this decision fails to consider the benefit-risk of ataluren and the high unmet medical need. Therefore, we plan to file a formal dispute resolution request next week.”

Results of two Translarna clinical trials (NCT00847379 and NCT01826487), both of which failed to meet their primary goal of improvements in the six-minute walk test and failed at key secondary outcome measures, were among the data reviewed by the FDA and its panel.

PTC had also given the advisory board additional information regarding the regulatory history of Translarna, opting to use a “file-over-protest” approach. This rarely used regulatory pathway allows a developer to file a new drug application (NDA) against the recommendations of the FDA.

Twice in recent years, the agency has refused to file applications sent in support of Translarna’s approval. PTC’s filed-over-protest application came after two unsuccessful appeals to those rejections, in 2011 and 2016.

Translarna is designed to bypass a stop signal caused by a mutation in the dystrophin gene, called a nonsense mutation. The mutation halts the production of dystrophin protein. By overriding the effect of the mutation, Translarna is expected to allow dystrophin to be produced normally. But, to date, it is not clear if this actually happens in patients treated with the drug.

Europe has taken a different approach to Translarna compared to its regulatory turns in the U.S. In the EU, the treatment was given conditional approval, and that approval status was renewed in January. As a result, Translarna may be used in Europe to treat ambulatory patients ages 5 and older who have nonsense mutation Duchenne muscular dystrophy (nmDMD).