Company: Sarepta Therapeutics
Used for: Duchenne muscular dystrophy
Est. 2026 sales: $1.88 billion
Sarepta Therapeutics already has two marketed Duchenne muscular dystrophy drugs: Exondys 51 and Vyondys 53 for specific patient subgroups. But those approvals previously raised eyebrows because they were based on a surrogate endpoint in single-arm trials.
The company hopes to change that with gene therapy SRP-9001. But by the look of phase 2 data, it’s going to be a tough road ahead.
DMD is caused by a gene mutation that disrupts the expression of the dystrophin protein, which is critical for muscle functions.
Exondys 51 and Vyondys 53 work by skipping specific exons near the mutation to partially restore dystrophin production. In their respective clinical trials, the meds showed they could indeed increase dystrophin but offered no evidence that they could improve symptoms or slow disease progression.
These two antisense drugs are also limited by their ability to target mutations that are amenable to specific exon skipping. Enter SRP-9001. It uses an adeno-associated virus to deliver a gene that encodes for microdystrophin to the muscle tissue.
Sarepta designed SRP-9001’s phase 2 trial in a placebo-controlled manner, and besides microdystrophin protein expression improvement from baseline, it also set the change on a 17-point motor function scale called the North Star Ambulatory Assessment (NSAA) as its co-primary endpoint.
However, data unveiled in January showed the gene therapy, in short, failed. But Sarepta management tried to paint a more complicated picture, which CEO Doug Ingram said made him “more confident than ever” about the program.
Among children who got SRP-9001, investigators recorded a mean 1.7-point NSAA improvement from baseline at week 48, versus a 0.9-point increase in the placebo group. The difference was too small to cross the statistical significance bar.
But Sarepta pointed to an imbalance in the fitness of patients at baseline to explain the failure. In the small, 42-subject study, Sarepta grouped patients into two cohorts by age. And it was among the older 6- to 7-year-olds that baseline NSAA scores weren't too different, according to Sarepta. In children aged 4 and 5, SRP-9001 was linked to a mean NSAA change of 4.3, significantly larger than the placebo arm’s 1.9.
Sarepta hopes learnings from the phase 2 study will guide it to a better phase 3 design, and the company’s not fighting solo in this pursuit. In late 2019, Roche paid up $1.15 billion upfront—including a $400 million equity investment—for ex-U.S. rights to SRP-9001, with potential milestones reaching $1.7 billion.
The hefty dollar amount of the deal reflects the market potential of a successful DMD drug given the lack of treatment options. In the third quarter of 2020, Exondys 51 and Vyondys 53 together brought in sales of $121.4 million, and that came from them being able to target only about 20% of all DMD patients.
Right now, Sarepta’s closest rival is Pfizer’s PF-06939926, which was given to its first phase 3 patient in January. At least before SRP-9001’s phase 2 flop, the Sarepta drug was considered superior to the Pfizer candidate based on their safety profiles. Three of six patients in Pfizer’s phase 2 were hospitalized because of serious side effects, including two immune-related events, while SRP-9001’s side effects looked benign.
Sarepta is running a separate trial using commercial process material before moving into phase 3, but the company could go to drug regulators with the phase 2 data and phase 1 results, which involve a mean microdystrophin expression of 95.8% in muscle fibers of four patients and a mean 7.0-point improvement on NSAA from baseline after two years.