Sarepta overheats in a clash of the Duchenne titans

The early publication of arguably positive topline phase II results with GlaxoSmithKline/Prosensa’s Duchenne muscular dystrophy project drisapersen have been interpreted as great news for Sarepta Therapeutics’ rival product, eteplirsen.

Sarepta’s already bloated stock put on another 11% yesterday, valuing the biotech group at $1.3bn. But the fact remains that drisapersen is ahead of eteplirsen, whose data are questionable and come from a tiny phase II trial. Sarepta’s valuation hinges on a US accelerated approval designation, and investors should brace for a sharp correction should this not be forthcoming.

Glaxo had earlier intended to keep the phase II results under wraps until a larger phase III trial reported in the third quarter, but – perhaps seeing the surging interest in the rare, genetic disorder – decided to present them tomorrow at the RNA & Oligonucleotide Therapeutics conference. The abstract was published yesterday by Thestreet.com and on the Cure Duchenne group’s website.

In the 53-patient trial 18 patients were given a drisapersen 6mg/kg continuously once a week, while 17 got the same dose in intermittent twice-weekly amounts, and 18 were on placebo. Those dosed continuously showed a statistically significant difference in the 6-minute walk test (6MWT) versus placebo of 35.1m at week 24, although by week 48 the difference narrowly lost significance, with p=0.051.

The intermittently dosed patients did not separate from placebo at 24 weeks, but by week 48 their mean 6MWT advantage of 27.1m was termed “clinically meaningful” albeit missing statistical significance with p=0.147. No data on dystrophin production have been made available.

Clearly the results are mixed, and reports of side effects continue to dog drisapersen despite the project having been generally well tolerated in the phase II trial. But efficacy is promising, logically favouring longer, continuous dosing; the loss of statistical significance might be put down to the small patient sample.

Reading across

So is this good for Sarepta’s eteplirsen? Granted, both projects work with a broadly similar exon-skipping mechanism, so positive data for one back up the concept of the other.

But the Sarepta bulls need to watch out, especially at the current share price. Hotly touted eteplirsen data come from a study in just 12 patients, two of which the company has retrospectively decided to exclude from its intent-to-treat analysis to make the combined result for both 30mg/kg and 50mg/kg doses tested stack up (Sarepta’s step forwards in muscular dystrophy raises the bar for competitors, October 4, 2012).

The eteplirsen result has been driven by the 50mg/kg dose, which at 36 weeks hit a net 78.0m benefit in 6MWT versus placebo with a p value of under 0.019. Positive effects have been maintained through several iterations of the data, at 48, 62 and, just last Friday, 74 weeks, but the two doses combined only hit statistical significance if two “non-ambulant” outliers are excluded.

By the 62-week data iteration Sarepta was no longer even splitting out the 30mg/kg and 50mg/kg doses, focusing only on its “modified” six-patient population. At 74 weeks this showed a net 6MWT advantage of 65.2m versus a group initially on placebo and then switching to eteplirsen (p≤0.004); without knowing baseline drisapersen numbers a direct 6MWT comparison cannot be made between the two rivals.

A key factor favouring Sarepta has been its ability to show consistently that eteplirsen boosts production of dystrophin – its phase II primary endpoint – and this effect has improved with longer treatment duration. But its study is tiny; in contrast a 180-patient phase III drisapersen trial will end around the mid-year (see table below).

Moreover, much of Sarepta’s near-term value now hinges on its decision to seek, and on the FDA’s willingness to grant, accelerated approval for eteplirsen. Such a designation should permit approval in just 60 days rather than the standard 10 months, and will clearly affect phase III design, as well as speed to market.

With news on this expected imminently, Sarepta’s ability to live up to its overheated valuation rests with the FDA. The company is just one of many US biotechs that need to execute flawlessly or risk seeing a minor hiccup turn into a share price bloodbath.

To contact the writer of this story email Jacob Plieth in London at[email protected]or follow@JacobEPVantageon Twitter