Sarepta Halts Progress on Duchenne ASO Therapy Vesleteplirsen

Sarepta Halts Progress on Duchenne ASO Therapy Vesleteplirsen

Sarepta Halts Progress on Duchenne ASO Therapy Vesleteplirsen

In a recent update regarding its financial performance for the third quarter of 2024, Sarepta Therapeutics revealed that it has decided to discontinue its development of vesleteplirsen. This decision comes in light of a revised risk-benefit evaluation, input from the US FDA, and the shifting therapeutic environment for Duchenne muscular dystrophy (DMD).

Sarepta is focused on RNA-centric therapies, including exon skipping antisense oligonucleotide (ASO) treatments, in addition to gene therapies and gene editing strategies, primarily targeting DMD and other inherited neurological disorders such as limb-girdle muscular dystrophy and Charcot-Marie-Tooth disease.

Currently, Sarepta has three market-approved exon-skipping ASOs that address the symptoms of DMD but do not offer a cure. The first among these, eteplirsen, which targets exon 51 of dystrophin mRNA, received FDA approval after extensive discussions in 2016, although it was not approved​ by the EMA due to concerns about the clinical evidence and the high cost.

Following the approval of eteplirsen, Sarepta introduced two additional ASOs, golodirsen and casimersen, which gained FDA approval in 2019 and 2021, respectively. Golodirsen is intended to skip exon 53, while casimersen is designed for exon 45.

This past summer, Sarepta secured full FDA approval for its gene therapy, Elevidys (delandistrogene moxeparvovec-rokl), despite it missing its primary objective in a previous phase 3 trial.

Conclusion of a challenging journey​

Vesleteplirsen, also referred to as SRP-5051, was developed as a more advanced iteration of eteplirsen aimed at patients who are suitable for exon 51 skipping within the dystrophin gene. It was expected to demonstrate improved potency, enhanced tissue penetration, and greater dystrophin production.

Although increased dystrophin expression was noted, the phase 2 Momentum trial was placed on hold​ by the FDA in 2022 due to one patient experiencing significantly low magnesium levels from the treatment, which may lead to muscle weakness, seizures, and irregular heartbeats.

This adverse effect was observed in other patients as well, with some also experiencing decreased kidney performance, as indicated by eGFR metrics.

In communication with the Duchenne community involved in the study, Sarepta emphasized, “Safety is our number one priority. Considerations around long-term safety and tolerability contributed to the decision to halt SRP-5051 development… We understand this news will be profoundly disappointing for the Duchenne community, particularly those who have contributed to the SRP-5051 studies.”

Looking forward, Sarepta plans to persist with the advancement of other molecular candidates, including two advanced-stage gene therapies for limb-girdle muscular dystrophy, with one expected to seek approval in the coming year.