In an announcement for its third quarter developments and results, Sarepta said it was cancelling the program due to an updated risk-benefit analysis, feedback from the US FDA, and the “evolving therapeutic landscape for Duchenne.”
Sarepta has a focus on RNA-based therapies such as exon skipping antisense oligonucleotide (ASO) therapies, gene therapies and gene editing, primarily for Duchenne muscular dystrophy, but also other inherited neurological conditions such as limb-girdle muscular dystrophy and Charcot-Marie-Tooth disease.
The company has three exon-skipping ASO’s on the market, which can treat symptoms of Duchenne but cannot cure the disease. The first of these, eteplirsen, targeting exon 51 of the dystrophin mRNA was approved by the FDA after much debate in 2016, although it was rejected by the EMA due to doubts about the extent of the clinical evidence and the high price tag.
After eteplirsen was approved, the company followed up with two further ASOs golodirsen and casimersen, which were approved by the FDA in 2019 and 2021, respectively. Golodirsen is designed to skip exon 53 and casimersen exon 45.
This summer Sarepta finally achieved full FDA approval for its Duchenne gene therapy Elevidys (delandistrogene moxeparvovec-rokl), although it missed its primary goal in an earlier phase 3 trial.
End of a difficult road
Vesleteplirsen (also known as SRP-5051) was designed as an updated version of eteplirsen to treat patients amenable to exon 51 skipping in the dystrophin gene. It was supposed to be a more potent version of the original ASO, with better tissue penetration and increased production of dystrophin.
Although it did show increased dystrophin expression, the phase 2 Momentum trial was placed on hold by the FDA in 2022, because one patient developed very low magnesium levels due to the treatment, which can result in muscle weakness, seizures, and irregular heart rhythms.
This side effect was seen in other patients as well and some also had a decrease in kidney function, as measured by eGFR.
In a letter to the Duchenne community involved in the trial, the company stated: “Safety is our number one priority. Considerations about long-term safety and tolerability led to the decision to discontinue development of SRP-5051… We recognize this news may be deeply disappointing for the Duchenne community, especially those who have participated in studies of SRP-5051.”
Sarepta will continue to develop other molecular candidates including two late-stage gene therapies for limb-girdle muscular dystrophy, one of which is likely to be submitted for approval next year.