Sarepta Therapeutics does not let the grass grow under its feet. With a US FDA nod for Exondys 51 and $300m from a post-approval fund-raising, it has completed a series of business development and clinical milestones that could allow it to become for Duchenne muscular dystrophy (DMD) what Vertex is to cystic fibrosis.
Yesterday’s deal with Summit Therapeutics puts the Massachusetts-based group into three different approaches to treating DMD, giving Sarepta several pipeline plays to follow Exondys. Summit nearly doubled in value on the deal, while Sarepta’s canny post-approval moves have pushed shares 25% above their already lofty levels immediately after the FDA decision (Sarepta, patients win – but what of regulatory oversight?, September 19, 2016).
The speed with which Sarepta has accelerated into its commercial activities could perhaps be accounted for by the long wait for approval while FDA staff fought about the data to support Exondys.
The group had time to lay out a post-decision strategy, and in two weeks the massive equity raise, initiation of a phase III trial of two pipeline assets, SRP-4045 and SRP-4053 for patients with exon 45 and 53 deletions respectively, and a collaboration with Catabasis Pharmaceuticals all took place.
The Catabasis deal focused on another RNA modulation approach, NF-kB inhibition. No terms were disclosed. The deal with Summit, on the other hand, came accompanied with hard cash, bringing European rights to Summit’s utrophin modulator pipeline and the phase II asset ezutromid.
For Summit the $40m is an unexpected windfall, and vindicates its transformation from a drug-screening company and developer of a mixed bag of early-stage projects arising from the University of Oxford, under its former name of Vastox, to its current focus on DMD under a new chief executive, Glyn Edwards, formerly of Antisoma.
Sharp-eyed DMD watchers noted with interest the recent granting to Summit’s ezutromid of US paediatric designation, which the group said could translate into a paediatric priority review voucher (PRV) if ezutromid received FDA approval.
Paediatric PRVs have become prominent because they can be transferred to another company. They have sold for as much as $350m, though the most recent one seems to have gone for around $200m (Priority review vouchers revisited, September 22, 2016).
The legislation governing this scheme was expected to have been renewed last month, but the decision was deferred until December. Sarepta received a paediatric PRV along with Exondys 51 approval – if the legislation is not renewed this could be a highly valuable asset, since it would be one of only four paediatric PRVs in existence.
Summit told EP Vantage that if the legislation is not renewed then it would no longer qualify for a paediatric PRV on potential approval of ezutromid. It has also said that it saw orphan disease designation as a more important accolade in the near term.
Mechanistically ezutromid is an interesting choice for Sarepta. Unlike Exondys 51 it is an oral small molecule designed to modulate utrophin, a protein related to dystrophin; both these proteins play a role in muscle development, but dystrophin gradually takes over this function from utrophin as muscles mature.
The intriguing aspect is that while Sarepta’s exon-skipping approaches target specific subtypes of DMD, a small-molecule utrophin modulator could in theory target the whole patient population.
While at present ezutromid is being studied as monotherapy, on a call yesterday Mr Edwards also spoke at length about the potential for a combination. Even when dystrophin production is stimulated via exon skipping in DMD it does not occupy all binding sites on the muscle fibre; unfilled sites can then be occupied by utrophin to potentiate the effect.
However, designing a surrogate endpoint is more complicated than was the case with Exondys 51, where Sarepta was to an extent able to demonstrate dystrophin production. Typical DMD patient muscle biopsies already show some utrophin production in response to damage, and the aim is to achieve a more uniform distribution of utrophin, which is hard to demonstrate.
Most likely a new surrogate endpoint will be needed – Mr Edwards suggested MRI or muscle fibre maturity data – for accelerated approval, and then confirmatory data would need to show improvement in one of the functional endpoints such as six-minute walk test or an alternative “less noisy” endpoint.
Surprise approval of Exondys has revived interest in the DMD space, and Sarepta’s deal-making has surely spurred others to take a closer look at unpartnered assets. It will be interesting to see if Biomarin, which withdrew its own exon-skipping project after negative FDA reviews, will re-enter the frame now that its rival has shown the way.