Promising data with Sarepta’s lead gene therapy project have carried other players in the space up with the tide. But they dealt a blow to Wave Life Sciences, whose stock has sunk this week amid fears that a potential once-and-done treatment could make its next-generation exon-skipping candidates for Duchenne muscular dystrophy obsolete.
As would be expected Wave insists that there is still a place for its stereopure oligonucleotides, which it claims could be much more effective than Sarepta’s current DMD drug, Exondys 51. But many investors now see Wave being relegated to the sidelines if Sarepta’s gene therapy efforts succeed, and the argument boils down to which of the competing treatments would be used first.
Worryingly for Wave, 90% of investors surveyed by Mizuho analysts think that, if both technologies are eventually approved, gene therapy would be used first line, with Wave’s candidates reserved for later use if a boost in efficacy is needed.
Several respondents were particularly pessimistic about Wave’s future, essentially saying that the company was now finished.
Wave’s head of neurology, Mike Panzara, contested this view, telling EP Vantage that there was “absolutely” room for both projects on the market: “We’re going to have a very specific approach to patients who have a certain deletion – and oligonucleotides could be the optimal way to start in those patients, because it’s the most specific and efficient [approach].”
Still, he unwittingly highlighted a big problem for Wave: its lead DMD project, WVE-210201 – like Exondys 51 – targets only the 13% of patients amenable to exon 51 skipping.
Sarepta’s gene therapy projects, meanwhile, could be effective in all DMD patients. The group has several shots on goal here and on Tuesday reported promising results with its most advanced candidate, AAVrh74.MHCK7.micro-dystrophin – which added $3bn to Sarepta’s market cap, despite the data only coming from three patients, and with no placebo comparator (Sarepta investors party like it’s 2015, June 19, 2018).
While it is undoubtedly early days for DMD gene therapy, Mr Panzara described the Sarepta data as “preliminary but encouraging”.
But he cited various unanswered questions, including uncertainty over the durability of gene therapy and the ability of AAV vectors – like the one used in Sarepta’s project – to get into immature muscle cells.
The latter point could be particularly important in DMD as the disease primarily affects young boys, whose muscles are regenerating. If the effect of gene therapy does wane, immunogenicity concerns would prevent re-dosing, Mr Panzara pointed out.
He also highlighted the unproven nature of microdystrophin, the shortened version of dystrophin used in Sarepta’s project, necessitated by the large size of the dystrophin gene.
While the link between increased dystrophin levels and improved clinical outcomes is generally accepted, no similar correlation has yet been proven for microdystrophin. “It doesn’t mean it won’t happen, it just means it’s yet to be established,” Mr Panzara said.
As far as dystrophin goes, he is confident that WVE-210201 has the edge, claiming that Wave’s stereopure candidate leads to more efficient exon skipping than Exondys 51. Sarepta’s drug increases dystrophin levels to around 1% of normal, while WVE-210201 has shown greater than 50% dystrophin restoration – albeit in cell line studies, so Wave still has a lot to prove.
The first clinical efficacy data with WVE-210201 are due next year, and Wave will no doubt hope to come close to this figure; if it does not, its future will look even bleaker.
And, even if WVE-210201 is as good as Wave says, there could soon be yet more competition from Sarepta in the form of the latter’s next-generation PPMO exon-skipping candidates.
Of course, Sarepta’s gene therapy still has a long way to go – it will need to show safety in more patients, as well as efficacy. And the huge dose of vector used raises questions about the timeliness of treatment, as well as its cost.
Sarepta has the potential to corner the DMD market with multiple options. Though Wave has other irons in the fire, the problem is that its first-line DMD market, which was already small, might disappear entirely.