RARE Daily

Sarepta Reports Positive Results from Mid-Stage Study of DMD Therapy

December 8, 2020

Rare Daily Staff

Sarepta Therapeutics reported positive results from a phase 2 study of its experimental therapy SRP-5051, its next-generation treatment for patients with the rare neuromuscular condition Duchenne muscular dystrophy who are amenable to exon 51 skipping.

This is the first clinical data from SRP-5051, which uses Sarepta’s peptide phosphorodiamidate morpholino oligomer (PPMO) technology, which is designed to increase cellular uptake of drug in the muscle tissue.

Duchenne muscular dystrophy (DMD) is caused by a 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 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 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. About 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.

Results from Part A of the multi-ascending dose MOMENTUM study found consistently higher tissue exposure, exon-skipping, and dystrophin production in patients taking a monthly dose of SRP-5051 compared to baseline. SRP-5051 was generally well-tolerated across all doses studied, with no clinical or laboratory findings reported. The results support continued dose escalation of SRP-5051 and further clinical development.

“Sarepta’s PMO RNA technology is a vital platform on which we design therapies to treat those with Duchenne muscular dystrophy,” said Doug Ingram, president and CEO of Sarepta. “Our next-generation PPMO technology is designed to increase cell penetration with the goal of offering significantly improved efficacy with more convenient dosing in Duchenne patients amenable to exon skipping.”

When compared to a control group of Duchenne patients from the PROMOVI study who received biopsies at 24 weeks after taking a weekly 30 mg/kg dose of the company’s approved  exon-skipping therapy eteplirsen, once-monthly dosing of SRP-5051 resulted in higher muscle concentration, increased exon-skipping, and dystrophin at 12 weeks. A dose-dependent increase in exon-skipping and dystrophin was observed, with patients in the 20 mg/kg dose group of SRP-5051 seeing a 1.6-fold increase in exon skipping and a 5-fold increase in the percent of normal dystrophin when compared to the group taking eteplirsen at 24 weeks.

The incidence of adverse events in the MOMENTUM study was similar across all dosed cohorts and does not suggest dose dependency. One treatment-emergent event, unrelated to study drug, occurred in the 4 mg/kg dose group. No clinical or laboratory findings were observed. Full results will be presented at a future medical meeting.


Photo: Doug Ingram, president and CEO of Sarepta

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