Sarepta stops development of exon 51-skipping therapy for DMD
Developer cites long-term safety concerns, FDA feedback on SRP-5051
Despite positive trial data, Sarepta Therapeutics has decided to stop the clinical development of SRP-5051 (vesleteplirsen), an exon 51-skipping therapy for some people with Duchenne muscular dystrophy (DMD).
While increases in dystrophin levels seen with the exon-skipping treatment were encouraging, according to the company, concerns over the long-term safety and tolerability of SRP-5051 influenced the ultimate decision. That decision also was based on feedback from the U.S. Food and Drug Administration (FDA), and on the progress seen in recent years in the DMD therapy landscape, Sarepta stated in a company press release.
Accordingly, the Phase 2 MOMENTUM clinical trial (NCT04004065) now testing SRP-5051 has stopped dosing patients, and participants will be scheduling their final visit over the coming months. Sarepta said it plans to present the study’s results in a future scientific forum.
In a letter posted on its website, the company thanked all those who took part in the clinical studies, but stated that “safety is our number one priority.”
“We recognize this news may be deeply disappointing for the Duchenne community, especially those who have participated in studies of SRP-5051,” the patient affairs team stated. “As every one of our programs progresses, we have to check in with ourselves and ask if the data continue to support our belief that this is the best we can do for patients and recognize that the answer may not always be yes.”
Trial testing SRP-5051 exon 51-skipping therapy will also be stopped
Duchenne muscular dystrophy is caused by mutations in the DMD gene, which encodes dystrophin — a protein that normally acts like a shock absorber inside muscle cells, helping prevent muscle damage during movements. Lack of functional dystrophin results in progressive muscle damage that leads to symptoms like muscle weakness and wasting.
Exon skipping is a treatment strategy that aims to skip over the mutated part of the DMD gene, allowing muscle cells to produce a shorter but functional version of dystrophin. Exons are individual sections of genes, which are lined up to produce proteins.
SRP-5051 was a next-generation successor to Exondys 51 (eteplirsen), an older exon 51-skipping therapy also from Sarepta. Exondys 51 is conditionally approved in the U.S. to treat eligible DMD patients.
Both therapies contain a lab-made molecule that masks exon 51 and promotes its removal from messenger RNA, an intermediary molecule needed for protein production.
However, SRP-5051 was modified with a peptide — a string of amino acids, the building blocks of proteins — to improve how much treatment gets inside muscle cells. The therapy was designed to be given once every four weeks by intravenous, or into-the-vein, infusions, compared with weekly infusions of Exondys 51. As such the newer therapy had been expected to reduce the treatment burden for patients.
In announcing the development stop, Sarepta said the company had “made important decisions regarding portfolio prioritization,” adding that this one was “informed by information available to date, including the risk-benefit of the program, feedback from the FDA, and the evolving therapeutic landscape for Duchenne.”
Initial results from the MOMENTUM trial had shown that SRP-5051 could increase dystrophin levels more than Exondys 51 after three and six months. However, despite its efficacy, SRP-5051 was shown to cause low levels of magnesium, known as hypomagnesemia. Magnesium is necessary in the human body for energy production, among other processes.
Such hypomagnesemia was initially considered manageable with magnesium supplementation. Still, in a subset of patients, low magnesium was prolonged and persisted even after discontinuing the treatment. Additionally, some patients experienced a decline in kidney function.
The decision to discontinue this program has no impact on our other approved therapies and/or clinical study programs. … We believe the concerns are related to the specific cell penetrating peptide used in SRP-5051.
Trial participants who want more information are encouraged to reach out to their study site.
“The decision to discontinue this program has no impact on our other approved therapies and/or clinical study programs,” Sarepta’s letter added. “We believe the concerns are related to the specific cell penetrating peptide used in SRP-5051.”
The FDA had placed the trial on hold in 2022 following a severe case of hypomagnesemia. That hold was lifted a few months later and the study resumed with extra safety precautions.
Parent Project Muscular Dystrophy, a nonprofit that seeks to accelerate research and advance care for people with DMD, stated in a separate press release that it was “disappointed” to learn of Sarepta’s decision to stop the therapy’s development.
“We are grateful to all the families who have participated in clinical trials with [SRP-5051], and to the Sarepta team for their work to advance therapy development in Duchenne,” the organization stated. “The discontinuation of a trial is always difficult for our community, but we remain hopeful that the data from this trial will inform other potential treatments and that these experiences will lead us to the day that we end Duchenne.”
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