Sarepta Therapeutics has ended development of a late-phase Duchenne muscular dystrophy (DMD) drug candidate over a safety problem. The safety signal deprived Sarepta of a near-term shot at accelerated approval—and took down the biotech’s entire PPMO franchise.
Development of the exon 51 skipping DMD candidate SRP-5051 ran into difficulties in 2022, when the FDA imposed and then lifted a hold on a study in response to a case of low magnesium, clinically known as hypomagnesemia. Sarepta kept going, reported phase 2 data in January and began talking to the FDA about a confirmatory study it would need to start to seek accelerated approval.
However, Sarepta gave up on the program Wednesday. Louise Rodino-Klapac, Ph.D., chief scientific officer at Sarepta, said on an earnings call that “long-term safety in a chronic treatment setting does not support further development.” The safety concerns overrode encouraging dystrophin expression results.
“Our initial hypothesis was that the hypomagnesemia was manageable and monitorable,” Rodino-Klapac said. “Although events thus far have remained medically manageable in a small number of patients, we saw persistent hypomagnesemia despite treatment discontinuation, and our risk-benefit analysis led us to end the study.”
Rodino-Klapac said the risk-benefit analysis was the primary driver of the decision to stop development of SRP-5051. Talks with the FDA were another factor, the CSO said, because the agency told Sarepta “the accelerated approval pathway was not open based on the current profile.” The biotech also looked at the evolving DMD treatment landscape.
Sarepta CEO Doug Ingram provided more details of the talks with the FDA. While phosphorodiamidate morpholino oligomers, like SRP-5051, have won accelerated approval in the past, the discontinued asset was different because it had a delivery component. Ingram said the component changed safety, “and, I think, the agency wasn't comfortable with the concept of accelerated approval in light of this change.”
The impact of the news extends beyond SRP-5051. Rodino-Klapac said Sarepta is discontinuing its entire PPMO franchise. PPMO is the chemistry platform behind SRP-5051 and the factor that differentiated the candidate from Sarepta’s approved exon 51 skipper Exondys 51.
Like Sarepta’s Exondys 51, SRP-5051 was designed to bind to exon 51 and thereby enable DMD patients to produce a form of the dystrophin protein. The difference, which came from the PPMO platform, is that SRP-5051 had a cell-penetrating peptide designed to increase dystrophin production. All Sarepta’s PPMO assets use the same cell-penetrating peptide, so the biotech is stopping all the programs.