Three years on, another Duchenne showdown beckons

With the US FDA issuing three rare paediatric disease designations – to BioMarin, Sarepta and Santhera – in the space of 24 hours last week the clock is ticking on three Duchenne muscular dystrophy projects in a timeline that should fascinate biotech investors.

It could all culminate with priority review vouchers, which recent form shows carry premium valuations. Before that, of course, investors await further data and highly charged advisory committee and regulatory decisions; three years after Sarepta first wowed the markets the Duchenne battle lines are drawn again.

The potential value of a priority review voucher, with its four-month regulatory advantage, was illustrated by AbbVie’s $350m purchase of United Therapeutics’ one last week, topping the chronological $67.5m, $125m and $245m that the three earlier transactions generated (Why four months is worth $350 to AbbVie and filgotinib, August 21, 2015).

But there is a snag: under the original legislation the FDA could give out three priority vouchers, after which it could issue an unlimited number for the next 12 months, at which point the scheme would end.

That third voucher was issued to Asklepion (before passing to Retrophin, which sold it to Sanofi) in March. This means that – under current rules anyway – approval for any of the three agents must come before March 14, 2016, for them to qualify for a voucher.

The battle

Barring any delays, BioMarin’s drisapersen and Sarepta’s eteplirsen are on track to meet this deadline. Santhera is the odd one out, since its idebenone project has yet to be filed with the FDA; moreover this targets late-stage patients, many of whom are already wheelchair bound.

Meanwhile, drisapersen and eteplirsen are exon-skipping antisense projects positioned for a narrower share of the market: children with the exon 51 genetic deletion, in particular those who are still able to walk.

It is between these two that a curious battle is being fought. On the one hand Sarepta has an arguably positive result, but this is derived from a subgroup of a tiny phase IIb trial; on the other BioMarin can boast a much larger dataset, but this comes from a phase III trial that was ultimately a failure.

Both are now filed with the FDA: drisapersen’s rolling submission began last year and was completed in April, while eteplirsen’s filing was accepted for review just two days ago. Drisapersen’s and eteplirsen’s PDUFA dates are set for December 27 and February 26 respectively.

And before the action dates there is an all-important adcom. This has yet to be confirmed formally, but it seems highly likely that both agents will be reviewed at the Peripheral and CNS Drugs Advisory Committee, set to meet on November 23 and 24.

Against the severe shortcomings of the datasets stands the fact that both projects target a serious childhood condition for which there is a serious unmet need, and have so far shown relative safety. Approval for both seems likely, even if it is on a conditional basis.

After that, while it would still be theoretically possible for the drugs to be pulled from the market, given the hugely emotive patient advocacy campaign that has played out across social media it would seem suicidal for the FDA to revoke approval.

Other triggers

Apart from the prospects of priority review vouchers, investors have another key consideration: additional biopsy data for Sarepta’s project might be presented at October’s World Muscle Society meeting.

While these will not be part of the filing, they will be hard to ignore in the run-up to the likely adcom, especially as a means of backing eteplirsen’s benefit in the six-minute walk test, a far less robust measure (Sarepta offers olive branch to FDA with CEO shuffle, April 1, 2015).

Under an agreement with the FDA eteplirsen started a 160-patient confirmatory trial, Promovi, which Sarepta says should be enrolled by the end of this year. For its part BioMarin says it does not expect any substantial data presentations before the adcom.

And investors banking on a priority review voucher can take heart in one further consideration: the Advancing Hope Act, introduced as a bill in the House of Representatives in March, seeks to make the voucher programme permanent.

The future issuing of unlimited numbers of vouchers would naturally push down their price, but each of the three companies should still look forward to having a valuable asset on their hands.

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