The hold was related to a serious adverse event of hypomagnesemia in an ongoing phase 2 clinical trial.
The FDA has placed a clinical hold on SRP-5051 (vesleteplirsen), Sarepta Therapeutics’ next-generation peptide-conjugated phosphorodiamidate morpholino oligomer, which is intended for the treatment of Duchenne muscular dystrophy (DMD) in patients amenable to exon 51 skipping.1 The hold is related to a serious adverse event of hypomagnesemia that occurred in part B of the ongoing 2-part, phase 2 MOMENTUM clinical trial (NCT04004065).
The FDA is requesting additional information to determine whether the risk mitigation and safety monitoring plans are adequate, in addition to requesting information on all cases of hypomagnesemia from the study, including non-serious grade 2 cases.1
“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 scientific officer, Sarepta Therapeutics, said in a statement regarding the clinical hold.1 “The hypomagnesemia was transient and patients’ magnesium levels returned to normal following additional supplementation.”
Data from the first part of the clinical trial reported in 2021 showed that at a median of week 12, 30 mg/kg of SRP-5051 dosed monthly resulted in mean exon skipping of 10.79% (n=4) and mean dystrophin production of 6.55% of normal.2 This correlated to a more than 4-times increase in exon skipping and twice the dystrophin expression compared to the 20 mg/kg cohort at week 12. At the time, 3 serious treatment-emergent adverse events in 2 patients were reported, which included 2 cases of hypomagnesemia. Both cases were asymptomatic and resolved with magnesium supplementation.
Part B of the clinical trial is open to male patients between the ages of 7 and 21. Patients must have a genetic diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51-skipping treatment. Treatment-naïve patients that have a history of hypomagnesemia within 12 weeks prior to screening will be excluded from part B.
“We believe that the SRP-5051 may transiently interfere with magnesium reabsorption by the kidney,” Rodino-Klapac said in an investor conference call regarding the hold on June 23, 2022.3 “Importantly, we have not seen worsening of the hypomagnesemia over time or evidence of acute or chronic renal damage or evidence of persistent renal-tubular injury associated with the hypomagnesemia. Furthermore, the cases of hypomagnesemia have improved or resolved while patients remain on treatment and do not appear to worsen over time.”
Sarepta Therapeutics plans to respond to the FDA with the requested information and proposed changes to the monitoring plan within the next few days.1