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PTC Therapeutics, Inc. announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has given a negative opinion on the conversion of the conditional marketing authorization to full marketing authorization of Translarna (ataluren) for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). The negative opinion also applies to the renewal of the existing conditional authorization. PTC plans to submit a request for re-examination per EMA guidelines. Translarna will remain on the market and available to patients with nmDMD until the re-examination process is completed. Based on CHMP procedural guidance, the opinion following the re-examination process would be expected to occur in January 2024, with EC ratification of the opinion within the following 67 days.
"We are surprised and extremely disappointed by the CHMP decision, given the well-established and favourable safety and efficacy profile of Translarna," said Matthew B. Klein, M.D., chief executive officer, PTC Therapeutics. "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."
Translarna received conditional marketing authorization in Europe in 2014 based on the results of Study 007, and the conditional authorization was renewed in 2017. As part of the renewal of the conditional marketing authorization, PTC agreed to a specific obligation to conduct a third placebo-controlled trial, Study 041. PTC shared the results of Study 041, which included nominally statistically significant results on several key endpoints in the overall enrolled Intent-to-Treat population of 359 boys even though it did not meet statistical significance in the primary analysis subgroup.
The data from Study 041, as well as data from the two previous placebo-controlled trials—Studies 007 and 020 — formed the basis of the CHMPs review and decision. Additional supportive evidence of efficacy included robust meta-analyses demonstrating highly statistically significant benefit on several key disease endpoints capturing different aspects of DMD, including the Six-Minute Walk Distance test (6MWD), North Star Ambulatory Assessment, and Timed Function Tests. In addition, analyses of the real-world STRIDE registry, which includes 300 boys with an average treatment duration of over 5.5 years, demonstrating that long-term Translarna therapy delays the time to loss of ambulation by 3.5 years were included as part of the data package to confirm long-term meaningful treatment benefit. In addition, Translarna has shown a favourable safety profile, with over 3,000 patients treated to date.
In the re-examination, PTC plans to focus on the clear and consistent evidence of benefit recorded in the overall population of 700 boys included in all studies (007, 020 and 041). In addition, PTC will address the decision to designate a different primary analysis subgroup in Study 041 than the subgroup previously demonstrated to be most responsive to a treatment effect on 6MWD in Studies 007 and 020. PTC will also address concerns raised regarding the robustness of the STRIDE data in supporting long-term treatment benefit.
Translarna (ataluren), discovered and developed by PTC Therapeutics, is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne. Translarna, the tradename of ataluren, is licensed in multiple countries including Great Britain, Northern Ireland and the European Economic Area for the treatment of nonsense mutation Duchenne muscular dystrophy in ambulatory patients aged 2 years and older. Ataluren is an investigational new drug in the United States.
Primarily affecting males, Duchenne is a rare and fatal genetic disorder that results in progressive muscle weakness from early childhood and leads to premature death in the mid-20's due to heart and respiratory failure. It is a progressive muscle disorder caused by the lack of functional dystrophin protein. Dystrophin is critical to the structural stability of all muscles, including skeletal, diaphragm, and heart muscles. Patients with Duchenne can lose the ability to walk (loss of ambulation) as early as 10 years old, followed by loss of the use of their arms. Duchenne patients subsequently experience life-threatening lung complications, requiring the need for ventilation support, and heart complications in their late teens and 20s.
PTC is a global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders.
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