Sarepta Therapeutics has announced the discontinuation of its vesleteplirsen (SRP-5051) program, an antisense oligonucleotide (ASO) treatment for Duchenne muscular dystrophy (DMD). The decision, revealed alongside the company's third-quarter results, stems from an updated risk-benefit analysis, feedback from the U.S. Food and Drug Administration (FDA), and the shifting therapeutic landscape for DMD.
Sarepta's pipeline focuses on RNA-based therapies, including exon-skipping ASOs, gene therapies, and gene editing, primarily for DMD and other inherited neurological conditions like limb-girdle muscular dystrophy and Charcot-Marie-Tooth disease. The company currently markets three exon-skipping ASOs for DMD symptom management: eteplirsen, golodirsen, and casimersen. These therapies target exons 51, 53, and 45 of the dystrophin mRNA, respectively. Eteplirsen received FDA approval in 2016 after considerable debate, while golodirsen and casimersen were approved in 2019 and 2021.
Vesleteplirsen's Development Challenges
Vesleteplirsen was conceived as an improved version of eteplirsen, targeting exon 51 skipping to enhance dystrophin production in DMD patients. While the drug demonstrated increased dystrophin expression, the Phase 2 Momentum trial encountered significant safety issues. In 2022, the FDA placed the trial on hold after a patient experienced severely low magnesium levels, a condition that can lead to muscle weakness, seizures, and irregular heart rhythms. Subsequent observations revealed similar side effects in other patients, along with decreased kidney function as measured by estimated glomerular filtration rate (eGFR).
In a communication to the Duchenne community, Sarepta emphasized that safety was the primary concern driving the decision to halt vesleteplirsen's development. "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," the company stated.
Sarepta will now concentrate on advancing other molecular candidates, including two late-stage gene therapies for limb-girdle muscular dystrophy. One of these gene therapies is anticipated to be submitted for regulatory approval in the coming year. This strategic shift underscores Sarepta's commitment to addressing unmet needs in neuromuscular disorders while prioritizing patient safety and long-term therapeutic efficacy.
