NEW YORK – Sarepta Therapeutics announced on Monday that its experimental Duchenne muscular dystrophy therapy SRP-5051 (vesleteplirsen) has shown promising activity in an ongoing Phase II trial that it will discuss with the US Food and Drug Administration.
SRP-5051 is an investigational peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) 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. This results in a shorter, but functional, version of dystrophin.
In Part B of the Phase II MOMENTUM study, Sarepta recruited 40 participants between the ages of 7 and 21, all of whom had previously received SRP-5051 in Part A or in a related study. In Part B, the multi-ascending dose portion, the higher target dose of SRP-5051 — approximately 30 mg/kg every four weeks — resulted in average dystrophin expression of 5.17 percent and mean exon skipping of 11.11 percent at 28 weeks. These changes represent a 12.2-fold increase in dystrophin expression and a 24.6-fold rise in exon skipping, as compared to the same dose of Sarepta's Exondys 51 (eteplirsen) at 24 weeks.
The company also said in a statement that dystrophin expression was consistently seen in approximately 4.76 percent of ambulatory and in 5.67 percent of non-ambulatory patients at 28 weeks.
A lower dose of the candidate therapy — 20 mg/kg — led to average values of 2.81 percent dystrophin expression and 2.47 percent exon skipping, representing 4.3-fold and 4.9-fold increases, respectively, compared to 30 mg/kg of Exondys 51 at 24 weeks.
"The data suggest a favorable benefit-risk profile for SRP-5051, and we look forward to discussing the results and next steps with FDA," Louise Rodino-Klapac, CSO and head of research and development at Sarepta, said in a statement.
Sarepta reported seven serious, treatment-related side effects in MOMENTUM Part B. These consisted of four instances of hypomagnesemia, or low magnesium, and three cases of hypokalemia, or low potassium. Because hypomagnesemia occurred in previous studies of SRP-5051, participants were given supplemental magnesium throughout the study. Sarepta said that no treatment-related events led to participants withdrawing from the study.
"The dystrophin production delivered by SRP-5051 in the MOMENTUM study is very encouraging," said Eugenio Mercuri, head of the neuromuscular unit at Catholic University in Rome, Italy, and a MOMENTUM investigator. "Importantly, with effective supplementation and monitoring, we have not seen additional complications from the hypomagnesemia. The results with SRP-5051 to date suggest it could play an important role in the treatment of Duchenne patients with a confirmed exon 51-amenable mutation."