SRP-5051 Shows Efficacy in DMD Amenable Exon 51 Skipping


Results of the phase 2 study support continued dose escalation of SRP-5051 and further clinical development.

Doug Ingram

Sarepta Therapeutics has announced that SRP-5051, its next-generation treatment for patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping, demonstrated proof-of-concept in the phase 2 MOMENTUM study (Study 5051-201; NCT04004065) with results supporting continued dose escalation.1

This was the first clinical data from SRP-5051, a treatment that uses Sarepta’s peptide phosphorodiamidate morpholino oligomer (PPMO) technology. Consistently higher tissue exposure, exon-skipping and dystrophin production in patients taking a monthly dose of SRP-5051 was observed in Part A from the multi-ascending dose MOMENTUM study.

SRP-5051 was found to be generally well-tolerated across all doses, with no clinical or laboratory findings reported. Sarepta noted its belief that the findings support further clinical development of the agent.

"Sarepta’s PPMO RNA technology is a vital platform on which we design therapies to treat those with Duchenne muscular dystrophy. 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,” Doug Ingram, president and chief executive officer, Sarepta, said in a statement.

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Once-monthly dosing of SRP-5051 resulted in higher muscle concentration, increased exon-skipping and dystrophin at 12 weeks when compared to a control group of patients with DMD from the PROMOVI study (NCT02255552), who received weekly 30 mg/kg doses of eteplirsen (Exondys 51) for 24 weeks.

The group of patients receiving a 20 mg/kg monthly dose of SRP-5051 for 12 weeks yielded a 1.6 times greater increase in exon skipping (n = 4) and a 5-fold increase in functional dystrophin (n = 2) when compared to the group taking eteplirsen at 24 weeks.

Sarepta noted that the incidence of adverse events in the MOMENTUM study were similar across all doses cohorts and did not suggest dose dependency. Furthermore, there was 1 treatment-emergent event in the 4 mg/kg group, but it was deemed unrelated to the study drug.

SRP-5051 is designed to bind to exon 51 of dystrophin pre-RNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping.

The ongoing MOMENTUM phase 2 study was designed to not only investigate the safety and tolerability of SRP-5051 but identify the maximum tolerated dose as well. The study will enroll up to 24 patients, both ambulant and non-ambulant, who will receive monthly intravenous (IV) infusions of SRP-5051, starting at 4 mg/kg and ascending to 40 mg/kg.

MOMENTUM is comprised of 2 parts. Participants in Part A will receive the aforementioned ascending doses of SRP-5051 for 12 weeks. After an optimal dose is established, an additional group of patients will receive that dose for 24 weeks.

"We know from our experience with PPMOs that exon-skipping and dystrophin increase over time, and these results along with our preclinical experience, give us confidence as we dose escalate and continue to advance our PPMO exon-skipping therapies for Duchenne, including another five potential therapies that have already been designed, and explore the utility of the PPMO RNA platform for new disease indications,” Ingram added.

SRP-5051 is among the many RNA technologies in from Sarepta. Eteplirsen became FDA approved for the treatment of patients with DMD in September 2016. At the time, it was the first drug approved for DMD, and is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.2

Sarepta’s second marketed DMD treatment, golodirsen (Vyondys 53), is an antisense oligonucleotide that was approved in December 2019 for the treatment of DMD with genetic mutations subject to skipping exon 53 of the dystrophin gene.3

1. Sarepta Therapeutics announces positive clinical results from MOMENTUM, a phase 2 clinical trial of SRP-5051 in patients with Duchenne muscular dystrophy amenable to skipping exon 51. News release. Sarepta Therapeutics. December 7, 2020. Accessed December 16, 2020.
2. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. News release. FDA. September 19, 2016. Accessed December 16, 2020.
3. Sarepta Therapeutics Announces FDA Approval of VYONDYS 53™ (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53. News release. Sarepta Therapeutics. December 12, 2019. Accessed December 16, 2020.
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