Prosensa's phase III flop could have broad implications for exon-skipping


It cannot be denied that today’s failure of Prosensa and GlaxoSmithKline’s exon-skipping project drisapersen in a phase III Duchenne muscular dystrophy study is a major disappointment, with no hint of activity and a big miss in terms of statistical significance.

What is less certain, however, is what the setback means for Prosensa’s rival, Sarepta Therapeutics. While Prosensa stock crashed 70% in early trading, Sarepta’s was up in pre-market trading on the failure of its competitor, before some of these gains were erased as realisation of the negative effect on the exon-skipping concept sank in.

Prosensa’s data came from Demand 3, drisapersen’s first phase III study, in 186 patients. Drisapersen recipients’ 48-week results showed an average six-minute walk test (6MWT) decline of 42 metres – just 10 metres better than the placebo group’s and a big miss on statistical significance, with p=0.415.

Prosensa also said key secondary endpoint measures had failed to show a benefit for drisapersen, and did not tout any potential subgroup analyses.

The extent of the miss came as a big shock given a phase II study, Demand 2, that had yielded arguably positive topline results earlier this year. This had shown a 35-metre 6MWT benefit for drisapersen at 24 weeks, although by week 48 the difference narrowly lost statistical significance.

Prosensa today also revealed topline results from a US phase II trial, Demand 5, that were previously to have been kept back for scientific meetings in the coming weeks. These also failed to hit statistical significance, but the numerical 6MWT benefit favouring the 6mg drisapersen dose – 27 metres (p=0.069) – suggested evidence of some activity where the result of Demand 3 showed none.

Leerink Swann analysts are touting the possibility of Prosensa salvaging the situation by pooling the results of the studies. Still, for this to hold water would require phase II data to have been overwhelming, which they hardly were.

Prosensa ahead... until now

Until now Prosensa was thought to boast more robust results than Sarepta thanks to running far bigger and better-designed studies. Sarepta’s eteplirsen has arguably shown a 6MWT benefit in a phase II trial, but this is in just 12 patients – two of whom have retrospectively been excluded from the final analysis.

Even before today Sarepta’s eteplirsen had shown benefits in dystrophin production that Prosensa’s drisapersen had struggled to emulate, though there have been questions over the robustness of its method for measuring the changes (Prosensa’s turn to wobble on limited Duchenne results, August 19, 2013).

This is important because the bull case for Sarepta is that it will file eteplirsen with the US FDA based solely on its tiny phase II study, using the dystrophin benefit as a surrogate endpoint to gain accelerated approval; whether the agency will agree to such a surrogate endpoint will only become clear after a filing is made.

Prosensa says it has not yet analysed dystrophin levels in the Demand 3 and 5 studies, so the resounding 6MWT failure of the former adds little to the understanding of Sarepta’s chances of accelerated approval.

However, it undoubtedly increases eteplirsen’s risk – especially at Sarepta’s $1.2bn market cap. Both eteplirsen and drisapersen work by a broadly similar exon-skipping mechanism to restore production of dystrophin.

Cross-trial comparisons are notoriously unreliable, but failure of the largest study to date of exon-skipping in Duchenne cannot be good news; this mechanistic concept just took a major knock.

Study Design Trial ID Result
Demand 2 53-pt phase II NCT01153932 6MWT numerically favoured drisa (p=0.051); some dystrophin benefit 
Demand 3 186-pt phase III NCT01254019 6MWT failed to benefit drisa (p=0.415)
Demand 5 54-pt US phase II NCT01462292 6MWT numerically favoured drisa (p=0.069)
Demand 4 220-pt phase III extension NCT01480245 Ends Dec 2014

(This story was corrected to reflect the status of Demand 4 as a phase III extension trial.)

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

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