Over a 28-week treatment period, the investigational agent demonstrated significantly greater increase in dystrophin expression and exon skipping than previously approved eteplirsen, Sarepta’s first therapy for Duchenne muscular dystrophy.
Sarepta Therapeutics has announced new data from part B of its phase 2 MOMENTUM study (NCT04004065) with results showing that treatment with SRP-5051 (vesleteplirsen) resulted in increased dystrophin expression and exon skipping among patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.1
After 28 weeks of treatment, those on high-dose SRP-5051 (30 mg/kg every 4 weeks; n = 20) demonstrated a 5.17% mean dystrophin expression as measured by western blot and mean exon-skipping of 11.11%, as measured by digital drop polymerase chain reaction. Notably, there were a number of treatment-emergent cases of hypomagnesemia, which had been previously identified, and were subsequently managed and monitored through prophylactic magnesium supplementation as part of the study protocol.
Part B of the study enrolled 40 participants, both ambulant and non-ambulant, between the ages of 8 to 21 at sites in the US, Canada, and Europe. Overall, patients in the high-dose group showed a 4.53% mean change in dystrophin expression (P <.001) and a 10.07% mean change in exon skipping at 28 weeks. In addition, consistent dystrophin expression was observed regardless of whether patients were ambulatory (4.76%; n = 11) or non-ambulatory (5.67%; n = 11).
"SRP-5051 dosed every four weeks is showing substantially higher increases in dystrophin and exon skipping compared to eteplirsen (Exondys 51) dosed weekly," Louise Rodino-Klapac, PhD, executive vice president, chief scientific officer, and head of research and development at Sarepta, said in a statement.1 "The data suggest a favorable benefit-risk profile for SRP-5051 and we look forward to discussing the results and next steps with FDA. As the leader in Duchenne, Sarepta is committed to advancing meaningful treatments for those with Duchenne and other rare diseases where there is unmet need."
In the high-dose group, investigators recorded a 12.2-fold increase in dystrophin expression and a 24.6-fold increase in exon skipping compared with a weekly 30 mg/kg dose of eteplirsen at 24 weeks (n = 16). Eteplirsen became the first of the class of exon-skipping therapies to be approved in 2016 under the accelerated approval pathway as a treatment for those with DMD amenable to exon 51 skipping. It is currently being assessed in a confirmatory trial, MIS51ON (NCT0399243), that is expected to conclude towards the end of 2024.
In MOMENTUM part B, there were 4 serious events of hypomagnesemia and 3 serious cases of hypokalemia, which did not result in any discontinuations. The FDA originally placed a clinical hold on part B in June 2022 because of issues with hypomagnesemia and requested further information from Sarepta on the findings. Months later, the agency lifted its hold, with the belief that Sarepta would adjust the global trial protocol to include expanded monitoring of urine biomarkers as part of the risk mitigation and safety monitoring plan.2
In terms of the low-dose group from MOMENTUM part B, results showed a 2.81% mean dystrophin expression and a mean exon skipping of 2.47% over the 28-week period. This group, which received 20 mg/kg every 4 weeks, had a 4.3-fold increase in dystrophin expression and a 4.9-fold increase in exon skipping in comparison with weekly 30 mg/kg dose of eteplirsen at 24 weeks.
"The dystrophin production delivered by SRP-5051 in the MOMENTUM study is very encouraging. Importantly, with effective supplementation and monitoring, we have not seen additional complications from the hypomagnesemia," study investigator Eugenio Mercuri, MD, PhD, head of the Neuromuscular Unit at Catholic University in Rome, Italy, said in a statement.1 "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."
The original clinical data on SRP-5051 from the MOMENTUM study were published in December 2020. Those data revealed that the treatment demonstrated proof-of-concept, with results supporting continued dose escalation.4 In that analysis, patients receiving a 20 mg/kg monthly dose of SRP-5051 for 12 weeks yielded 1.6 times greater increase in exon skipping (n = 4) and a 5-fold increase in functional dystrophin (n = 2) when compared with the group taking eteplirsen at 24 weeks.3