An experimental drug from Sarepta Therapeutics helped spur production of a crucial muscle-protecting protein that people with Duchenne muscular dystrophy lack, indicating the medicine could be an effective treatment for the degenerative disease.
Notably, the clinical trial results shared by Sarepta Monday suggest the drug, dubbed SRP-5051, may be more potent than an approved medicine, Exondys 51, that the biotechnology company already sells. Yet safety concerns reported in testing might complicate the drug’s path forward.
The new data come from the second part of a small, mid-stage study testing SRP-5051 in people with Duchenne who could still walk, as well as those who couldn’t. In Duchenne, genetic mutations disrupt production of a protein called dystrophin, resulting in progressive weakening that robs people of the ability to walk and eventually damages the heart and lungs.
The 40 study participants received either a high or low dose of SRP-5051 every four weeks. Protein levels in skeletal muscle were assessed at baseline and at week 28 of the trial.
According to Sarepta, treatment with the high-dose led to an average of just over 5% dystrophin production, an increase of 4.5 percentage points from baseline. Participants on the low dose had an average 1.6 percentage point increase to 2.8%. Those levels are, respectively, 12 and four times higher than what was reported for Exondys 51 after 24 weeks of treatment, Sarepta said.
Treatment was associated with low potassium and magnesium levels, however. In seven instances, those side effects were judged to be serious, Sarepta said.
The Food and Drug Administration previously halted Sarepta’s trial after cases of low magnesium levels were reported, but later allowed testing to continue when the company changed its study plan. Participants received preventive magnesium supplements, and there were no treatment-related discontinuations in the trial.
“SRP-5051 dosed every four weeks is showing substantially higher increases in dystrophin and exon-skipping compared to eteplirsen dosed weekly,” said Louise Rodino-Klapac, Sarepta’s chief scientific officer and head of R&D, in the company’s statement Monday. “The data suggest a favorable benefit-risk profile for SRP-5051 and we look forward to discussing the results and next steps with FDA.”
SRP-5051 is built with an improved form of the “exon-skipping” technology Sarepta uses to detour around genetic mutations that halt dystrophin production. When certain exons are skipped in the translation of DNA to protein, cells can produce a shortened, but still functional, form of dystrophin.
In the case of both Exondys 51 and SRP-5051, the exon in the dystrophin gene that’s skipped is called exon 51. About 13% of people with Duchenne have exon 51 mutations and therefore can benefit from such treatments.
FDA drug evaluators expressed doubts about approving Exondys 51 in 2016, in part, because of the tiny amount of dystrophin it produces. To analysts from Stifel and Leerink Partners, the data Sarepta revealed Monday showed the company’s new technology could result in better “biodistribution” to muscles than the older method underpinning Exondys 51.
In a note to clients Monday, Leerink’s Joseph Schwartz wrote that the 5% protein levels seen with the high dose of SRP-5051 cleared a target previously set by the company, but fell short of model forecasts. Past research by his team has indicated other drugs in testing by companies like PepGen and Wave Life Sciences might achieve even higher protein levels.
Raymond James analyst Danielle Brill, meanwhile, predicted the FDA may focus more on SRP-5051’s potassium- and magnesium-related side effects. “
“Given the severe risks related to imbalances in these electrolytes, we believe [Sarepta] has an uphill battle ahead of them in convincing the FDA that the proposed benefits of SRP-5051 outweigh its risks,” she wrote in a Jan. 29 note.
Sarepta specializes in Duchenne and sells two other medicines similar to Exondys 51 that are designed to skip different exons. It also recently won a landmark, but controversial, approval for the first Duchenne gene therapy, and is trying to expand its clearance despite mixed findings from an important trial last year.
Shares in Sarepta rose by about 3% on Monday morning.