Sarepta’s step forwards in muscular dystrophy raises the bar for competitors

A strong result from one of two doses of Sarepta Therapeutics’ eteplirsen in a small phase IIb Duchenne muscular dystrophy study has raised the bar for competitors, in particular GlaxoSmithKline and Prosensa, whose similarly acting drisapersen is in phase III.

However, with Sarepta’s stock up 200% yesterday, taking its market cap over $1bn and making it the best performing biotech stock of the year, the company now has an awful lot to live up to. Given that there are no specific treatments for the rare disease the excitement is probably justified. But the tiny study size – 12 patients – and lack of a dose response are two niggling doubts that Sarepta will have to overcome as it seeks to take eteplirsen into phase III in 2014.

The latest data, from an extension phase of a 12-patient trial taken out to 48 weeks of treatment, build on previously reported findings from the 36-week point (Therapeutic focus – Sarepta success signals antisense progress in muscular dystrophy, July 25, 2012). The earlier findings had prompted 146% share price pop, and in the extra 12 weeks of treatment an added benefit is seen.

Six-minute walk

At 48 weeks the four patients on 50mg/kg eteplirsen (AVI-4658) had an average 21m improvement in the six-minute walk test versus a 68m decline for the four who were on placebo for 24 weeks before switching to the drug, hitting statistical significance with p≤0.016. The net 89m (22%) improvement was unprecedented, Sarepta said. At 36 weeks the 50mg/kg dose had shown a net 66m improvement.

However, the other eteplirsen dose, 30mg/kg, failed to hit statistical significance at either 36 or 48 weeks. Sarepta said two of the four patients in this group had declined quickly after dosing, and were “non-ambulant” at 48 weeks; but even excluding these outliers, the numerical 30m improvement at 48 weeks was not statistically significant. The two doses combined do reach statistical significance with p≤0.001 – but only if the two outliers are excluded.

Notwithstanding this discrepancy, Sarepta hopes that the killer blow will be dealt by improvements seen in patient biopsies, a surrogate marker for a clinical benefit. Both the high and low eteplirsen dose showed strongly significant increases in dystrophin-positive fibres – 41.7% and 52.1% over baseline respectively – including the two outlying patients.

The anomaly of the lower dose doing better is likely irrelevant given that the difference between the doses was not statistically significant. However, Sarepta admitted that it had not yet decided which dose to take into phase III.

Improving dataset

The improving dataset does back up the central belief that eteplirsen needs to be dosed for longer to exert an action. Not only did the walk test results improve over time, so did the biopsy data, with the 30mg/kg dose rising from a 22.5% increase at 24 weeks, and 50mg/kg becoming significant after a meaningless effect at 12 weeks.

The results were lauded by Sarepta-covering analysts like those at Piper Jaffray, which had already described the 36-week results as “nothing short of remarkable”. However, Bryan, Garnier & Co, which covers GlaxoSmithKline, was more restrained, cautioning that while the data represented a big step forward doubts remained over the lack of dose response and small number of patients treated.

GlaxoSmithKline, in partnership with Prosensa, is running a 220-patient phase III trial of drisapersen, the most advanced Duchene muscular dystrophy project in development. This, like eteplirsen, acts as to silence a faulty exon in the dystrophin gene, potentially targeting a 13% subset of the estimated 10,000 Duchenne boys in the US.

Sarepta said a 60-patient phase III eteplirsen study, perhaps without a placebo arm for ethical reasons, might be sufficient to provide confirmatory evidence, and has started scaling up manufacturing for this. Analysts expect a first launch in 2015, with sales reaching a modest $158m in 2018.

The company had $24m of cash at the mid-year, and subsequently signed a deal to raise up to $40m at its discretion. It says it will reengage with potential licensees whose interest had been whetted by the 36-week data.

No doubt some investors now have dollar signs in their eyes, but as Sarepta moves to start phase III discussions with the US FDA they should think carefully and ask themselves precisely what is now priced into the shares.

To contact the writer of this story email Jacob Plieth in London at [email protected]