Gene therapy offers the potential to correct a genetic problem causing disease and Sarepta Therapeutics is among the companies vying to bring this treatment option to patients who have Duchenne muscular dystrophy. New clinical data indicate that Sarepta’s gene therapy led to improvement on a variety of measures of the muscle-wasting disorder. A regulatory submission is almost certain, but the question is when.
Sarepta has had ”very robust discussions” with the FDA, company CEO Doug Ingram said Wednesday, speaking during a conference call. The agency has the latest data available from three Phase 1 and 2 studies. Ingram said that while a 120-patient Phase 3 study already underway offers one pathway to regulatory approval, he expects the discussions with regulators will clarify whether seeking accelerated approval with the current data is a possibility.
“We’re excited about any of the pathways, but obviously the pathway that can bring this therapy to patients the quickest is our ultimate goal,” Ingram said.
Duchenne muscular dystrophy stems from mutations to the gene that codes for dystrophin, a protein that’s important for muscle function. Without sufficient dystrophin, patients develop a progressive weakening of their skeletal muscles that diminishes mobility. In time, the disease affects heart and lung function, becoming fatal. Sarepta’s gene therapy, SRP-9001, delivers a functional version of the gene that encodes dystrophin. Sarepta already markets three drugs taken chronically for treating certain genetic subsets of Duchenne patients. A gene therapy offers the prospect of a one-time treatment.
Sarepta presented the latest clinical trial results for its gene therapy on Wednesday, during the the International Congress on Neuromuscular Diseases in Brussels. The company highlighted one-year results from a study testing a commercially representative version of the Duchenne gene therapy at the target commercial dose. In the first group of 20 study participants, treatment with the gene therapy led to a 3.8 point improvement according to a rating scale used to assess motor abilities in Duchenne patients. Furthermore, study participants showed, on average, improvements in measures that include time to rise, a 10 meter walk/run test, time to climb four steps, and a 100-meter walk/run test.
The open-label study compared participants to an external control group that used data from tree separate Duchenne studies, two of which were randomized-controlled studies. These external controls only had analyses for the time to rise and the 10 meter walk/run measures.
The gene therapy has longer-term data from a different open-label study, albeit a smaller sample of patients. After four years, the four patients (who were between the ages of 4 and 7 when they received the treatment) are showing an average 7-point improvement in scores compared to baseline. When compared to the external control, the difference is even greater at an average of 9.9 points.
“These are older patients around 9 years of age at year four, and because Duchenne is a disease that gets progressively worse, these patients would now be in the deep decline phase of their disease,” said Louise Rodino-Klapac, Sarepta’s chief scientific officer. “However, instead of declining, they’ve increased their function and importantly, maintained that increase, thereby demonstrating a distinct treatment effect that increases over time, supporting the durability of SRP-9001.”
The Sarepta gene therapy is also still being evaluated in a 41-patient, placebo-controlled Phase 2 test. After 48 weeks, those in the placebo-group will cross over to active treatment. All study participants will be followed for five years.
Safety for Duchenne gene therapies remains a concern and the FDA has kept a watchful eye on the programs in clinical development. Solid Biosciences has persevered through two clinical holds placed on its gene therapy candidate. A patient death last year led to an FDA hold placed on tests of a Pfizer gene therapy. That hold was lifted in April with study changes that include keeping patients hospitalized for one week after dosing so that they can be monitored. By contrast, Sarepta’s gene therapy is dosed on an outpatient basis.
The most serious adverse event that Sarepta reported for its gene therapy was myocarditis, or heart inflammation, in one patient. Rodino-Klapac said that this 11-year-old boy had no signs of impaired heart pumping. An MRI at one month showed normal function and partial resolution of the inflammation; at four months, an echocardiogram showed normal heart function. Vomiting was the most common side effect of the Sarepta gene therapy. There were no signs that SRP-9001 activated the complement pathway of the immune system, which is a potential adverse effect of gene therapies, such as Sarepta’s, that are delivered by adenoviruses.
In a research note sent to investors Wednesday, William Blair analyst Tim Lugo wrote that Sarepta’s latest data provide the most comprehensive look at the company’s gene therapy candidate to date. The results so far show strong efficacy along with good safety and tolerability, Lugo said. But he questioned whether an accelerated approval pathway is likely given the agency’s conservative approach to gene therapies lately. The FDA may raise questions about Sarepta’s use of external controls, he said. Also, the myocarditis case could also lead the FDA away from a speedier review in light of safety problems observed in other Duchenne gene therapy studies. Nevertheless, Lugo expressed optimism for Sarepta’s gene therapy.
“While we view filing for an accelerated approval unlikely, we continue to believe SRP-9001 has a path to market and represents the most promising therapy for DMD (Duchenne muscular dystrophy) patients in the history of the disease and a major opportunity for Sarepta,” he said.
Photo: BlackJack3D, Getty Images
