The hold was originally placed on part B of the phase 2 MOMENTUM trial in Duchenne muscular dystrophy following a June 2022 report of hypomagnesemia after treatment with high-dose SRP-5051. Going forward, Sarepta will adjust its global trial protocol.
Louise Rodino-Klapac, PhD
The FDA has lifted its clinical hold on part B of the phase 2 MOMENTUM trial (NCT04004065) of SRP-5051, Sarepta Therapeutics’ investigational treatment for patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.1
The hold was originally placed in June 2022, after a patient experienced a serious adverse event (SAE) of hypomagnesemia after treatment with high-dose SRP-5051. Specifically, the patient had grade 3 hypomagnesemia, grade 4 potassium deficiency, muscular cramps, and mild-to-moderate tingling of the extremities. At the time, the FDA requested 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.2
As a result of this lift, Sarepta will now need to adjust the global trial protocol to include expanded monitoring of urine biomarkers as part of the risk mitigation and safety monitoring plan.1
“We would like to thank FDA for working closely with us to expeditiously resolve this clinical hold. We will implement the changes in the protocol to resume dosing in the US as quickly as possible,” Louise Rodino-Klapac, PhD, executive vice president and chief scientific officer, Sarepta Therapeutics, said in a statement.1 “Our monitoring plan is designed to mitigate the risks of hypomagnesemia. MOMENTUM has continued enrolling participants outside the US, and we remain on track to complete enrollment by the end of 2022.”
SRP-5051, also known as vesleteplirsen, is a next-generation peptide conjugated phosphorodiamidate morpholino oligomer (PPMO) designed to bind to exon 51 of dystrophin pre-mRNA. The PPMO therapy showed positive results in part A of MOMENTUM—the data of which were released in May 2021—but there were 3 treatment-related AEs, including 2 cases of hypomagnesemia, reported among those enrolled in the 30-mg/kg cohort. Sarepta noted At the time that, "markers of kidney function have generally been normal and not shown any consistent relationship to the hypomagnesemia."3
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).3
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.
SRP-5051 is one of several RNA products developed by Sarepta, with eteplirsen leading the way, 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.5 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.6