PTC Therapeutics’ Translarna at risk of losing EU approval after failing to impress FDA for DMD

Duchenne muscular dystrophy, PTC Therapeutics, European Medicines Agency, Translarna, Committee for Medicinal Products for Human Use

PTC Therapeutics is facing a significant setback as it seeks to maintain approval for its Duchenne muscular dystrophy (DMD) therapy, Translarna, in the European market. The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) has declined to convert Translarna’s conditional marketing authorization into a full approval for the treatment of nonsense mutation DMD, a decision that has left PTC Therapeutics “surprised and extremely disappointed.”

In response to this unfavorable review, PTC plans to contest the decision, and Translarna (ataluren) will remain available on the market during the re-examination process. A second opinion on the matter is expected in January 2024. However, if the European Commission ultimately adopts the negative review, PTC may be forced to withdraw Translarna from the European market.

“We are surprised and extremely disappointed by the CHMP decision, given the well-established and favorable safety and efficacy profile of Translarna. Of course, this decision is most devastating for the hundreds of boys and young men in Europe with nonsense mutation DMD, for whom no other approved therapies are available. We will be submitting a request for re-examination to the CHMP to reverse this opinion, as we have done previously in the regulatory history of Translarna in Europe.”

– Matthew B. Klein, M.D., Chief Executive Officer, PTC Therapeutics

The CHMP based its evaluation of Translarna on data from the placebo-controlled Study 041, the same trial that recently faced criticism from the FDA for lacking sufficient evidence to support a new drug application re-submission. Translarna initially received conditional approval in Europe in 2014, primarily based on the results of Study 007, which demonstrated Translarna’s superiority over placebo in a six-minute walk test at week 48, the trial’s primary endpoint. However, neither Study 007 nor the subsequent Study 020 produced statistically significant results in this walk test.

In 2017, as part of the EMA’s renewal of Translarna’s conditional clearance, PTC agreed to leverage data from a third trial, Study 041, to further establish the drug’s benefit-risk profile. Unfortunately, Study 041 also failed to achieve statistical significance on the primary endpoint in the selected patient subgroup. However, it did reach a “nominally statistically significant” threshold when considering all enrolled patients.

In the United States, PTC has faced multiple FDA rejections, beginning with a refusal to file letter in early 2016. The company now aims to re-submit its application, armed with the data from Study 041. Nevertheless, the FDA has expressed doubts about the study’s efficacy data, prompting PTC to request a formal meeting with the agency to comprehensively review all data collected to date.

Translarna functions by enabling ribosomes to read through premature stop signals in mRNA, known as nonsense mutations, thereby facilitating the production of functional dystrophin protein for DMD patients. Notably, around 10% to 15% of individuals with DMD have a nonsense mutation, making Translarna the only approved therapy for these patients in Europe.

In addition to the three clinical trials, PTC has analyzed real-world data from the STRIDE registry, which includes approximately 300 boys with an average treatment duration of about 5.5 years. During the EMA’s re-examination, PTC intends to address concerns raised about the strength of the STRIDE data in supporting long-term treatment benefits.

Despite these regulatory challenges, Translarna performed well financially, generating $77 million in revenue during the second quarter, marking a 46% increase compared to the same period last year.

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