SRP-5051 Builds Momentum in Duchenne Muscular Dystrophy With Positive Phase 2 Data

Results showed that SRP-5051 30 mg/kg is likely to deliver greater than 10% dystrophin over time with monthly dosing in Duchenne muscular dystrophy.

SRP-5051, Sarepta Therapeutics’ next generation peptide phosphorodiamidate morpholino oligomer (PPMO) treatment for patients with Duchenne muscular dystrophy (DMD), demonstrated positive results in Part A of the phase 2 MOMENTUM study (Study 5051-201; NCT04004065), according to a recent announcement.1

In the multi-ascending dose clinical trial, biopsies taken at a median of 12 weeks after receiving 30 mg/kg of SRP-5051 monthly showed a mean exon skipping of 10.79% (n = 4), measured by digital drop polymerase chain reaction (ddPCR). When compared with the 20 mg/kg cohort at 12 weeks (mean exon skipping, 2.57%; n = 2), the 30 mg/kg dose resulted in more than a 4-fold increase in exon skipping.

Notably, the 30 mg/kg monthly dose resulted in an 18-times increase in exon skipping compared with a weekly 30 mg/kg dose of eteplirsen (Exondys 51; Sarepta) at 24 weeks (mean exon skipping, 0.59%; n = 16).

"We are pleased to report strong, dose-dependent exon-skipping and dystrophin expression results with monthly dosing of SRP-5051—in ambulant and non-ambulant patients. Even at an early time point of 12 weeks and after as few as only 3 doses, these data confirm the potential of Sarepta’s next-generation PPMO platform to be a step order improvement over our current PMO platform, and to profoundly impact the course of Duchenne,” Doug Ingram, president and chief executive officer, Sarepta, said in a statement.1

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"While we saw exceptional expression after only a few initial doses, our models predict that we will exceed dystrophin expression levels of 10% of normal or greater over time with SRP-5051,” Ingram added. "This was calculated using predictive modeling that included assumptions of known turnover of dystrophin in the muscle and an analysis of data generated with the PPMO platform."

The investigational DMD treatment is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in the exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping.

Patients in the SRP-5051 30 mg/kg group had a mean dystrophin production of 6.55% of normal at a median of week 12, which was twice as much compared with the 20 mg/kg cohort at week 12 (mean expression, 3.06%) and 8 times that of the eteplirsen comparison group (mean expression, 0.82%). Dystrophin expression was measured by western blot.

Notably, 3 serious, treatment-emergent adverse events (TEAEs), including 2 cases of hypomagnesemia, were reported among patients enrolled in the 30 mg/kg cohort. The company noted that “markers of kidney function have generally been normal and not shown any consistent relationship to the hypomagnesemia.”

"We are excited to have chosen our target dose for further development. Part A of MOMENTUM is now complete and Sarepta will work with great urgency to discuss the results with regulatory agencies and gain their insights, including the development path to support an accelerated approval of SRP-5051 in the United States,” Ingram said.

The first clinical data from SRP-5051 from the MOMENTUM study was published in December 2020, showing that the treatment demonstrated proof-of-concept, with results supporting continued dose escalation.2 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.

SRP-5051 is among the many RNA technologies under development from Sarepta. Eteplirsen was approved for the treatment of DMD in September 2016. At the time, it was the first drug approved for DMD for patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.3 Sarepta’s second DMD treatment, golodirsen (Vyondys 53), is an antisense oligonucleotide that was approved in December 2019 for the treatment of DMD in patients with genetic mutations amenable to 53 skipping.4

REFERENCES
1. Sarepta Therapeutics reports positive clinical results from phase 2 MOMENTUM study of SRP-5051 in patients with Duchenne muscular dystrophy amenable to skipping exon 51. News release. Sarepta Therapeutics. May 3, 2021. Accessed May 4, 2021. https://www.globenewswire.com/news-release/2021/05/03/2221411/0/en/Sarepta-Therapeutics-Reports-Positive-Clinical-Results-from-Phase-2-MOMENTUM-Study-of-SRP-5051-in-Patients-with-Duchenne-Muscular-Dystrophy-Amenable-to-Skipping-Exon-51.html
2. 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 May 4, 2021. http://www.globenewswire.com/news-release/2020/12/07/2140613/0/en/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-5.html
3. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. News release. FDA. September 19, 2016. Accessed May 4, 2021. fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-drug-duchenne-muscular-dystrophy
4. 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 May 4, 2021. sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-vyondys-53tm