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FDA Places Clinical Hold on Duchenne Muscular Dystrophy Drug SRP-5051 Amid Safety Concerns

The decision to stop clinical testing of SRP-5051 in DMD follows a serious adverse event of hypomagnesemia in part B of the phase 2 MOMENTUM trial.

According to an announcement by Sarepta Therapeutics, the FDA has placed a clinical hold on testing for their investigational agent SRP-5051, a next-generation peptide conjugated phosphorodiamidate morpholino oligomer (PPMO) to treat patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.1

The decision was made based off a patient in part B of the phase 2 MOMENTUM trial (NCT04004065) who suffered a serious adverse event of low magnesium, otherwise known as hypomagnesemia, after treatment with high-dose SRP-5051. More specifically, the patient had grade 3 hypomagnesemia, grade 4 potassium deficiency, muscular cramps, and mild-to-moderate tingling of the extremities. Notably, the FDA will request information on all cases of hypomagnesemia, including a small number of nonserious grade 2 cases, and to assess the adequacy of the risk mitigation and safety monitoring plan.

"Patient safety is always our top priority. The hypomagnesemia was identified through lab tests conducted as part of the monitoring outlined in the protocol of the MOMENTUM study and is similar to previously observed cases of hypomagnesemia in clinical trials of SRP-5051,” Louise Rodino-Klapac, PhD, executive vice president and chief executive officer, Sarepta Therapeutics said in a statement.1 "The hypomagnesemia was transient and patients’ magnesium levels returned to normal following additional supplementation."

She added, "globally, we have enrolled approximately half of the planned patients in Part B of MOMENTUM. The study is ongoing, and we remain on track to complete enrollment by the end of the year. We will work to share information with FDA with the goal of resuming screening and dosing in the US as quickly as possible."

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SRP-5051 is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in the exclusion of this exon during the mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. The agent showed positive results in part A of MOMENTUM, released in May 2021, but with 3 treatment-related AEs, including 2 cases of hypomagnesemia, reported among those enrolled in the 30 mg/kg cohort. At the time, Sarepta noted that "markers of kidney function have generally been normal and not shown any consistent relationship to the hypomagnesemia."2

In the multiascending 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-fold 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).2

In response to the FDA, Sarepta hosted an investor conference call on Thursday to discuss the update, where it assured those in attendance that the trial will get back on track soon. “We are confident that we can provide clarifying information to satisfy the FDA’s requests in the next few days and to resume dosing in the US very expeditiously,” Doug Ingram, chief executive officer of Sarepta, said on the call. “The study remains ongoing outside of the US and we remain on track to complete dosing in the second half of the year as previously guided."

REFERENCES
1. Sarepta Therapeutics provides update on SRP-5051 for the treatment of Duchenne muscular dystrophy. News release. Sarepta. June 23, 2022. Accessed June 24, 2022. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-update-srp-5051-treatment-duchenne
2. 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 June 24, 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