Today’s US setback for Sarepta’s eteplirsen probably came as a surprise to those investors who had got drawn into an emotionally charged debate that has raged across social media, involving Duchenne muscular dystrophy patient advocates, over the past two years.
On the other hand those who have taken a hard, dispassionate look at data generated by Sarepta and its rival Prosensa might be less shocked. The additional FDA requests, apparently made some time last week but only disclosed by Sarepta today, cast major doubts on eteplirsen’s approvability.
They centre on three key points: the need for Sarepta to provide a new, independent assessment of dystrophin-positive fibres from the project’s phase II study; a request for 120-day safety data; and a strong suggestion that MRI data, with appropriate natural history controls, need to be submitted too.
The immediate effect is that an NDA filing for eteplirsen can no longer be made this year, as bullish investors had expected, but instead will be pushed at least to mid-2015.
On the face of it this hands Sarepta’s rival, Prosensa, a win. Prosensa has already started a rolling NDA process for its own exon-skipping project, drisapersen, and so in theory it is now at least six months ahead of Sarepta.
In practice things are far more complex, since both projects have struggled to demonstrate a real clinical benefit. Sarepta has shown an arguably positive effect in a tiny, single-centre study, while Prosensa has a failed 233-patient phase III trial, and its abandonment by GlaxoSmithKline as partner, under its belt.
Indeed, the jury is still out on the concept of treating Duchenne with exon skipping. But expectations behind Sarepta were clearly far greater than Prosensa’s, so it is clear which company has underdelivered; Sarepta stock plummeted 33% this morning, while Prosensa was up 7% in early trade.
The issue of management credibility is also important. While Prosensa has been more restrained with its rhetoric and more open with disclosure, for instance publishing in full a not entirely positive FDA letter on drisapersen’s approvability, Sarepta has done little to cool bullish expectations.
Sarepta insisted, for instance, that it already had an excellent dialogue with the FDA, based on which it did not see the need to apply for breakthrough therapy designation. After today’s disclosure, which apparently came out of the blue, investors must wonder how accurate this and several other claims were.
A key pillar in Sarepta’s bull case was its claim to relate the expression of dystrophin to eteplirsen’s efficacy. In fact, the FDA was particularly scathing as regards to this, stating: “Clinical site inspection... uncovered marked disparities in the immunohistochemistry methodology [of measuring dystrophin] and concerns about the reproducibility of the data.”
Interestingly, doubts over the quantification and relevance of dystrophin expression was something that Prosensa’s chief executive, Hans Schikan, had raised with EP Vantage in an interview a year ago (EP Vantage interview – Prosensa braces itself for Glaxo verdict, November 22, 2013).
Until its latest meeting with the FDA Sarepta had been banking on submitting much of the eteplirsen dataset after an NDA filing, but behind the scenes there were signs that all was not going well.
Eteplirsen had made little progress since Sarepta touted results of its 12-patient trial over two years ago, and the sudden departure in July of the group’s chief scientific officer, Art Krieg, hinted at discord in the C-suite.
It must have been clear to the dispassionate observer that a tiny study, with efficacy based on a retrospective analysis to boot, would cut little ice with the FDA, however much pressure patient advocacy groups were seeking to exert on the regulator.
It now looks like the FDA at last has told Sarepta to go and generate some real data.