Sarepta's Clinical Failings Leave Eteplirsen's Future Bleak

| About: Sarepta Therapeutics, (SRPT)

A tough panel review has left approval of Sarepta’s (NASDAQ:SRPT) Duchenne muscular dystrophy candidate eteplirsen looking unlikely, in spite of the best efforts of patient advocates. The real question is: why did the company resist the FDA’s calls for a placebo-controlled trial, something the agency had asked for six times since 2011?

If Sarepta had carried out such a study yesterday’s panel could have been very different. On the current evidence, though, it is impossible to tell whether eteplirsen works, RBC Capital Markets analysts write, adding that the company will need to carry out a “real trial” to gain approval (Sarepta’s credibility unravels, October 27, 2014).

Such a study would take years, and require another cash injection – and Sarepta might have a hard time convincing investors to finance a project with questionable efficacy, especially in the current climate. The group’s shares opened down 40% this morning.

Sarepta already has an ongoing phase III trial with eteplirsen, Promovi, which does include an untreated group, but it is unclear whether this will satisfy the FDA’s demands, Leerink analysts noted. Data will be available in two to three years, around a year later than previously disclosed.

Emotion vs. evidence

Of course, it is possible that eteplirsen just does not work, and questions about its efficacy could explain Sarepta’s reliance on the testimony of patient advocates.

The fact that the X-linked disease affects young children, mostly boys, some of whom were present at the panel review, made it “one of the most emotional and highly charged advisory committee meetings in memory”, the RBC analysts wrote.

The FDA did well to stick to its guns during the gruelling 11-hour meeting, with the panel voting seven to three that eteplirsen was not effective, based on the available evidence, with three abstentions.

The panel also voted seven to six that the project had not shown that it could increase dystrophin levels to a degree that would lead to a clinical benefit, a blow to eteplirsen’s intended mechanism of action as well as Sarepta’s hopes of accelerated approval.

In asking for more evidence the FDA has often been painted as the bad guy, but agency executives pointed out during the meeting that the DMD community “hasn’t heard the whole story” about eteplirsen’s development.

Sarepta has had plenty of chances to prove efficacy against placebo, but has insisted that a trial would be unethical and unfeasible because patients would not enroll if there was a chance that they might be in the placebo arm – despite the fact that placebo-controlled trials are routinely carried out with other drugs in development for life-threatening conditions.

There is still the very slim chance that the FDA will overrule its panel and approve eteplirsen on May 26, a possibility that some are clinging to. But this would be a rare event: it has only happened twice between 2001 and 2010, according to a 2013 McKinsey analysis.

The more likely outcome is a complete response letter. RBC gives eteplirsen a 25% probability of success but say approval will not come until 2019, after another trial.

So far the FDA has relied on its head rather than its heart, but if it allows emotion to take over there could be a surprise approval of eteplirsen. Whether this will actually help patients with DMD is another matter.

Study Trial ID
Promovi NCT02255552
Click to enlarge
Click to enlarge