The US Food and Drug Administration (FDA) had recently rejected Translarna, a novel small molecule drug known as ataluren to treat genetic disorders due to nonsense mutation such as Duchenne muscular dystrophy (nmDMD). Translarna is marketed by PTC Therapeutics (PTCT), a New Jersey-based company.

The decision was made in view of inconclusive evidence that supported the effectiveness of Translarna for nmDMD, where the agency cited more research is necessary to establish the scientific validity of the treatment. The opinion was endorsed by a landslide majority (10 out of 11 members) of the advisory board on 28 September this year.

A rocky path to securing approval

As it turns out, this is not the first time the agency had rejected PTCT’s application to market Translarna. In 2011 and 2016, FDA had twice refused to file Translarna application.

In response to the decision, PTC issued a press statement on 25 October where the CEO of the company, Stuart Peltz, PhD, remarked that they “are extremely disappointed for the Duchenne community and strongly disagree with the agency’s conclusions”.

“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,” he added.

Among the data reviewed were two clinical trials which attempted to evaluate Translarna efficacy. Both trials, unfortunately, failed to meet the primary endpoint (improvement in the six-minute walk test) in addition to failures to meet some other key secondary endpoints.

In the resultant FDA report, the agency stated that “Ultimately, no positive results from any prospectively planned analyses that are persuasive have been provided with this application. The applicant has presented only the results from numerous post hoc and exploratory analyses that are intended to mitigate two negative clinical trials.”

“Overall, the data intended by the applicant to establish the effectiveness of ataluren for the treatment of nmDMD are not persuasive,” concluded the report.

Ataluren (Translarna) and DMD

DMD is a rare genetic disorder that is associated with a mutation at the X chromosome. The disease is characterised by progressive severe muscle wasting and weakness due to a malfunction in the synthesis of dystrophin. The protein functions as a form of "muscle stabiliser" and protects the muscle fibres. When dystrophin is missing, the muscles are more easily damaged leading to chronic inflammation which worsens over time. The disease is most commonly found in young boys (as it is an X-linked recessive genetic disease) but girls with two copies of the defective DMD gene could develop the disease as well.

Studies have shown that 10% – 15% of DMD patients have the nonsense mutation. Such mutation results in a shorter (truncated), non-functional protein as it introduces a premature stop codon into the dystrophin mRNA. Ataluren is thought to target these nonsense mutations by enabling the ribosome to read through the premature nonsense stop signal, thus producing the fully functional protein.

Approval of Translarna by the EMA

PTC had better fortune with Translarna in Europe. Following the renewal recommendation made by the Committee for Medicinal Products for Human Use (CHMP) of the European's Medicines Agency (EMA) in November last year – PTC is now allowed to continue marketing Translarna for nmDMD children who are at or above the age of five, mobile and living in regions including the EU, Iceland, Liechtenstein and Norway.

The marketing authorisation renewal was conditional, whereby PTC is required to conduct a prospective, 18-month, randomised placebo-controlled trial to evaluate Translarna, followed by another open-label study of similar length.

Peltz, in a press release, expressed that "Duchenne is a rapidly progressive disease and physicians need access to medicines, like Translarna, that have the potential to slow the devastating progression of this disorder." MIMS

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