PTC Therapeutics has been dealt a blow by the US Food and Drug Administration, which has published a lukewarm background briefing on Duchenne muscular dystrophy (DMD) drug Translarna (ataluren) ahead of a key FDA advisory committee meeting this week.

PTC has submitted it for review for the treatment of the rare, progressive childhood genetic disease, caused by mutations in the gene encoding dystrophin. Life expectancy is 25 years, the last decade of which will typically be spent in a wheelchair.

Ataluren has been developed as a first-in-class, orally bioavailable, small molecule to treat the version of the disease which results from nonsense mutations (nmDMD).

It has conditional approval from the European Commission, but the background information prepared by the FDA for committee members points out that two studies were inconclusive.

A key treatment measure is the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD). But both studies “failed to conclude that ataluren has a treatment effect on the primary endpoint, change in 6MWD at Week 48,” FDA says. “When a trial failed, it means either the treatment had no effect or the study was not able to detect a treatment effect.”

The document highlights several issues with the data. These include: “Opposite trends were observed in the complementary subgroup of patients (i.e. baseline 6MWD <300 or ≥400 metres) in Study 020, suggesting that the treatment effect observed in the baseline ≥300 to <400 metres group might have resulted from excluding subsets of patients with negative results.”

Despite this, the FDA acknowledges that “there appeared to be a signal of treatment effect for the low-dose ataluren”.

“Whether this could be sufficient evidence to support approval of ataluren for the treatment of nonsense mutation-mediated Duchenne Muscular Dystrophy is up for discussion,” the FDA briefing concludes.

PTC’s own submission admits that its randomized clinical trials “did not meet the traditional statistical threshold”, but adds that “the data should be viewed in the context of the disease and the recent understanding of the natural history”.

Whether the committee agrees with that is open to question but PTC has pushed hard to get the drug in front of the experts. Just over a year ago, the company was denied its first appeal contesting the US regulator’s refusal to accept the marketing application for Translarna as a treatment of nmDMD.

The FDA issued a Refusal to File letter in February 2016 on grounds that “the application was not sufficiently complete to permit a substantive review”.