Sarepta Therapeutics' SRP-5051 Demonstrates Ability to Increase Dystrophin Expression in Patients With Duchenne Muscular Dystrophy

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SRP-5051 is an investigational peptide-conjugated phosphorodiamidate morpholino oligomer.

Louise Rodino-Klapac, PhD, the executive vice president, chief scientific officer, and head of research and development at Sarepta Therapeutics

Louise Rodino-Klapac, PhD

Sarepta Therapeutics' SRP-5051 (vesleteplirsen), an investigational peptide-conjugated phosphorodiamidate morpholino oligomer intended for the treatment of Duchenne muscular dystrophy (DMD) in patients amenable to exon 51 skipping, has demonstrated efficacy in the phase 2 MOMENTUM (NCT04004065, Study SRP-5051-201) clinical trial.1

Among 20 patients in Part B of the trial who were treated at the study’s high dose (approximately 30 mg/kg, dosed every 4 weeks), 5.17% mean dystrophin expression with a 4.53% mean change from baseline (P < .0001) and 11.11% mean exon skipping with a 10.07% mean change from baseline were observed at 28 weeks posttreatment. Furthermore, compared to a weekly 30 mg/kg dose of Sarepta’s FDA-approved product eteplirsen (EXONDYS 51) at 24 weeks, SRP-5051 here showed a 12.2-fold increase in dystrophin expression and a 24.6-fold increase in exon skipping in the previously stated changes from baseline. The eteplirsen data is representative of 16 patients who achieved a 0.37% mean change from baseline in dystrophin expression and a 0.41% mean change from baseline in exon skipping.

“SRP-5051 dosed every 4 weeks is showing substantially higher increases in dystrophin and exon skipping compared to eteplirsen dosed weekly,” Louise Rodino-Klapac, PhD, the executive vice president, chief scientific officer, and head of research and development at Sarepta Therapeutics, 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.”

Among the 20 patients treated at the low dose in Part B of MOMENTUM (approximately 20 mg/kg, dosed every 4 weeks) 2.81% mean dystrophin expression with a 1.60% mean change from baseline (P = .0012) and 2.47% mean exon skipping with a 2.00% mean change from baseline were observed at 28 weeks posttreatment. Compared to the aforementioned data from patients treated with eteplirsen, SRP-5051 here showed a 4.3-fold increase in dystrophin expression and a 4.9-fold increase in exon skipping in the previously stated changes from baseline.

Key Takeaways

  • Sarepta Therapeutics' investigational peptide-conjugated phosphorodiamidate morpholino oligomer, SRP-5051, has shown efficacy in Part B of the phase 2 MOMENTUM trial (NCT04004065, Study SRP-5051-201) for Duchenne muscular dystrophy.
  • Among 20 patients in Part B of the trial who were treated at the study’s high dose (approximately 30 mg/kg, dosed every 4 weeks), 5.17% mean dystrophin expression with a 4.53% mean change from baseline (P < .0001) and 11.11% mean exon skipping with a 10.07% mean change from baseline were observed at 28 weeks posttreatment.
  • In terms of safety, 7 treatment-emergent serious adverse events (SAEs) occurred among the 40 patients treated in Part B of MOMENTUM, although no patients discontinued participation in the study in relation to the treatment.

In terms of safety, 7 treatment-emergent serious adverse events (SAEs) occurred among the 40 patients treated in Part B of MOMENTUM, although no patients discontinued participation in the study in relation to the treatment. The SAEs included 4 cases of hypomagnesemia and 3 cases of hypokalemia. Sarepta noted that hypomagnesemia had been observed in earlier clinical trials for SRP-5051 and that patients were receiving prophylactic supplemental magnesium in MOMENTUM Part B.

“The dystrophin production delivered by SRP-5051 in the MOMENTUM study is very encouraging,” Eugenio Mercuri, MD, PhD, the head of the Neuromuscular Unit at Catholic University in Rome, Italy, and an investigator in MOMENTUM, added to the statement.1 “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.”

MOMENTUM previously received a clinical hold from the FDA in June 2022 in relation to one of the SAEs of hypomagnesemia that occurred in part B.2 The clinical hold was later lifted in September 2022 after discussions between the company and the FDA and Sarepta’s agreement to expand monitoring of urine biomarkers in MOMENTUM’s protocol.3

In addition to SRP-5051, Sarepta is also developing several gene therapies, including SRP-9003 (bidridistrogene xeboparvovec), an investigational adeno-associated virus vector-based gene therapy intended to treat limb-girdle muscular dystrophy Type 2E (also known as beta sarcoglycanopathy).4 Just earlier this month, the company announced that it had begun screening patients for EMERGENE, a phase 3 clinical trial (NCT identifier pending) that will evaluate SRP-9003.

REFERENCES
1. Sarepta Therapeutics Announces Positive Data from Part B of MOMENTUM, a Phase 2 Study of SRP-5051 in Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 51. News release. Sarepta Therapeutics, Inc. January 29, 2024. Accessed January 29, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-positive-data-part-b-momentum
2. Sarepta Therapeutics provides update on SRP-5051 for the treatment of Duchenne muscular dystrophy. News release. Sarepta Therapeutics, Inc. June 23, 2022. Accessed January 29, 2024. https://www.globenewswire.com/news-release/2022/06/23/2468415/36419/en/Sarepta-Therapeutics-Provides-Update-on-SRP-5051-for-the-Treatment-of-Duchenne-Muscular-Dystrophy.html
3. Sarepta Therapeutics announces that FDA has lifted its clinical hold on SRP-5051 for the treatment of Duchenne muscular dystrophy. News release. Sarepta Therapeutics, Inc. September 6, 2022. Accessed January 29, 2024. Accessed January 29, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-has-lifted-its-clinical-hold
4. Sarepta Therapeutics initiates screening in EMERGENE, a phase 3 clinical study of SRP-9003 for the treatment of limb-girdle muscular dystrophy type 2E/R4. News release. Sarepta Therapeutics, Inc. January 16, 2024. Accessed January 29, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-initiates-screening-emergene-phase-3?_ga=2.7071793.2083102767.1706027313-1116878115.1706027313
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