The U.S. Food and Drug Administration placed a clinical hold on Sarepta Therapeutics SRP-5051, the company’s next-generation experimental therapy to treat patients with the rare neuromuscular condition Duchenne muscular dystrophy who are amenable to exon 51 skipping.

Photo: Louise Rodino-Klapac, executive vice president and chief scientific officer of Sarepta
The hold in Part B of Study 5051-201, also known as MOMENTUM, follows a serious adverse event of hypomagnesemia. FDA is requesting information on all cases of hypomagnesemia, including a small number of non-serious grade 2 cases, and to assess the adequacy of the risk mitigation and safety monitoring plan. The company said it will respond to the agency in the next few days with this information and proposed changes to the monitoring plan.
Duchenne muscular dystrophy (DMD) is a rare, fatal neuromuscular genetic disease that occurs in approximately one in every 3,500-5,000 males worldwide. DMD is caused by a change or mutation in the gene that encodes instructions for dystrophin. Symptoms of DMD usually appear in infants and toddlers. Affected children may experience developmental delays such as difficulty in walking, climbing stairs or standing from a sitting position. As the disease progresses, muscle weakness in the lower limbs spreads to the arms, neck, and other areas. Most patients require full-time use of a wheelchair in their early teens, and then progressively lose the ability to independently perform activities of daily living such as using the bathroom, bathing, and feeding. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and patients usually succumb to the disease in their twenties.
SRP-5051 (vesleteplirsen) is an investigational agent using Sarepta’s peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. SRP-5051 is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally shortened functional dystrophin protein. PPMO is Sarepta’s next-generation chemistry platform designed around a proprietary cell-penetrating peptide conjugated to the PMO backbone, with the goal of increasing tissue penetration, increasing exon skipping, and significantly increasing dystrophin production. Around 13 percent of DMD patients have mutations that make them amenable to skipping exon 51. If successful, the PPMO offers the potential for improved efficacy and less frequent dosing for patients.
MOMENTUM is phase 2, multi-arm, ascending dose study of SRP-5051, infused monthly and will assess dystrophin protein levels in skeletal muscle tissue following SRP-5051 treatment. The study will enroll up to 60 participants, both ambulant and non-ambulant, between the ages of 7 to 21 at sites in the U.S., Canada, and the European Union. The study will also assess safety and tolerability.
In 2021, the Company announced results from Part A of MOMENTUM showing that after 12 weeks, 30 mg/kg of SRP-5051 dosed monthly resulted in 18 times the exon skipping and eight times the dystrophin production as eteplirsen, dosed weekly for 24 weeks. Reversible hypomagnesemia was identified in patients taking SRP-5051. The protocol for Part B of MOMENTUM includes magnesium supplementation and monitoring of magnesium levels.
“Patient safety is always our top priority. The hypomagnesemia was identified through lab tests conducted as part of the monitoring outlined in the protocol of the MOMENTUM study and is similar to previously observed cases of hypomagnesemia in clinical trials of SRP-5051. The hypomagnesemia was transient and patients’ magnesium levels returned to normal following additional supplementation,” said Louise Rodino-Klapac, executive vice president and chief scientific officer of Sarepta. “Globally, we have enrolled approximately half of the planned patients in Part B of MOMENTUM. The study is ongoing, and we remain on track to complete enrollment by the end of the year. We will work to share information with FDA with the goal of resuming screening and dosing in the U.S. as quickly as possible.”
Author: Rare Daily Staff

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