Two of Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) candidates have failed to reach their primary endpoint in a Phase III confirmatory trial.
In the ESSENCE study, AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen) failed to show statistical benefit compared to placebo, achieving a difference of 0.05 steps/second in least square means (LSM) after 96 weeks. Sarepta added, however, that there were numerical trends that favoured treatment over placebo.
The study has taken nine years, with Sarepta stating data was “confounded” by the Covid-19 pandemic. Even when taking that into consideration, treatment led to a 30% reduction (LSM 0.11 steps/second, which is still not statistically significant, but is a clinically meaningful change.
Despite not reaching statistical significance, Sarepta said that armed with data from ESSENCE, real-world evidence, and the positive safety profile of AMONDYS 45 and VYONDYS 53, it intends to schedule a meeting with the US Food and Drug Administration (FDA) to discuss the possibility of converting from accelerated to traditional approval.
Sarepta R&D and technical operations president Dr Louise Rodino-Klapac said: “While the ESSENCE study did not meet statistical significance on its primary endpoint, we believe the results demonstrated a clear treatment effect, showing clinically meaningful functional outcomes for people with Duchenne who have mutations amenable to skipping exons 45 or 53.
“These top line findings reinforce the potential impact of these therapies to slow muscle weakness and other symptoms. The results of the study are consistent with the growing body of real-world evidence accumulated over several years. These data, which we have shared with the FDA, strengthen our confidence in the benefit of added dystrophin over time.”
Sarepta’s stock is set to be impacted by the ESSENCE failure, with pre-market analysis predicting a market open price of $15.30 on 4 November, down 37.42% on the 3 November market close of $24.45.
The confirmatory trial enrolled 225 patients aged between six and 13 years, with DMD amenable to exon 45 or 53 skipping.
There were no new safety signals identified in the trial, with adverse events (AEs) remaining mostly mild or moderate.
Full results from ESSENCE will be shared at future medical meetings, and publication will be pursued in a medical journal.
Sarepta received accelerated approval for VYONDYS 53 and AMONDYS 45 in 2019 and 2021, respectively. According to GlobalData’s patient-based forecasts, VYONDYS 53 is set to reach peak sales of $148m in 2027 while AMONDYS 45 is set to reach peak sales of $308m in 2031.
GlobalData is the parent company of Clinical Trials Arena.
Sarepta has contended with the FDA several times in recent months over the safety profile of its flagship gene therapy Elevidys (delandistrogene moxeparvovec), following the death of two patients attributed to liver failure. The agency put a number of pauses on Sarepta's trials involving the DMD therapy, as well as temporarily stopping sales and adding a black box label to the gene therapy.
The company has also culled some of its pipeline after a 51-year-old man with limb-girdle muscular dystrophy (LGMD) type 2D/R3 died after being treated with Sarepta’s gene therapy candidate SRP-9004 in a Phase I trial.
