RARE Daily

FDA Lifts Clinical Hold on Sarepta’s PPMO for DMD

September 6, 2022

The U.S. Food and Drug Administration lifted the clinical hold on Sarepta Therapeutics’ SRP-5051, the company’s experimental, next-generation peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) to treat patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping.

Photo: Louise Rodino-Klapac, executive vice president and chief scientific officer for Sarepta Therapeutics

As part of the lift, Sarepta will adjust the global trial protocol to include expanded monitoring of urine biomarkers. ​

The hold in Part B of Study 5051-201, also known as MOMENTUM, followed a serious adverse event of hypomagnesemia. Information was provided by the company to the FDA to assess the adequacy of the risk mitigation and safety monitoring plan.

“We will implement the changes in the protocol to resume dosing in the U.S. as quickly as possible,” said Louise Rodino-Klapac, executive vice president and chief scientific officer for Sarepta Therapeutics. “Our monitoring plan is designed to mitigate the risks of hypomagnesemia.”

Rodino-Klapac said the company has continued enrolling participants outside the United States in the study and remains on track to complete enrollment by the end of 2022.

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. Disease progression leads to muscle weakness in the lower limbs that 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 restroom, 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 uses Sarepta’s proprietary 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 truncated dystrophin protein. Around 13 percent of DMD patients have mutations which make them amenable to skipping exon 51.

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 a phase 2, multi-arm, ascending dose trial of SRP-5051, infused monthly and will assess dystrophin protein levels in skeletal muscle tissue following SRP-5051 treatment. The trial 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 trial 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.

Author: Rare Daily Staff

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