Sarepta’s bubble bursts


When Prosensa’s muscular dystrophy project drisapersen flunked its phase III study two months ago, even Sarepta’s cult of bullish followers knew deep down that the odds of their company’s similarly acting project eteplirsen getting early approval had lengthened. What they had not bargained for was an even worse scenario.

Today’s shock announcement that the US FDA viewed a possible early eteplirsen filing as “premature” confirms the bear case; but the agency has not only slammed the validity of dystrophin as a surrogate marker, it has also called into serious question the metric on which Sarepta had based its efficacy claim.

As such, Sarepta’s comments on a call today that the setback did not increase the risk to eteplirsen’s ultimate approval, and just pushed this out by “two years or more”, seem like extreme optimism.

Sarepta bulls had argued that the group would file eteplirsen based solely on its tiny phase II study, using the dystrophin benefit as a surrogate endpoint to gain accelerated approval. Change in dystrophin had been the trial’s primary endpoint, while its benefit in the more robust efficacy measure of the six-minute walk test (6MWT) came from a post hoc analysis.

Today the company revealed that in a meeting with the FDA last Friday the US agency had told it that drisapersen’s failure raised “considerable doubt” about the biomarker.

Expression and efficacy disconnect

Prosensa’s drisapersen had shown some increases in dystrophin but failed to show an effect on the 6MWT in its 186-patient trial, highlighting what the FDA now says is a disconnect between dystrophin expression and efficacy (Prosensa's phase III flop could have broad implications for exon-skipping, September 20, 2013).

The agency also cited the failure in muscular dystrophy of PTC Therapeutics’ ataluren, another project thought to act by increasing dystrophin.

But what is even worse, the FDA has told Sarepta to re-examine its enrolment criteria and study endpoints. This is because, although the agency says it would still accept a 6MWT benefit in an “appropriately powered study”, this endpoint excludes younger boys and those who can no longer walk.

It says motor scales that measure a broader range of function could be used, and suggests combining an ambulation endpoint in less advanced patients with findings from an upper-limb or respiratory endpoint in more advanced ones. It has also asked for a placebo-controlled study.

Until now many had thought that in the worst case scenario the FDA would refuse to deem dystrophin a surrogate marker, and Sarepta would simply need to run a new, prospectively designed study to duplicate the 6MWT benefit it had seen in a post hoc analysis of the 12-patient phase II.

Back to the drawing board

Now the company will have to go back to the drawing board, raising additional doubts about eteplirsen's ability to show a benefit in new study endpoints. However, Sarepta has rejected the suggestion that a confirmatory phase II study will be necessary before the phase III is run, and at present hopes to start a pivotal trial in the second quarter of next year.

Sarepta’s stock opened down almost 60% this morning, valuing it at a still impressive $520m. Though there have been hiccups along the way, today marks the first really bad news day for the company since it changed its name from AVI Biopharma and reported 36-week eteplirsen data in the middle of last year.

If there is any saving grace it is that Sarepta is well funded. Today it reported a third-quarter cash balance of $274m, meaning that it will not need to go back to the market any time soon.

To contact the writer of this story email Jacob Plieth in London at or follow @JacobEPVantage on Twitter

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