Gene therapy offers the potential to correct the genetic problems that cause the disease, and Sarepta Therapeutics is one of the companies vying to bring this treatment option to people with Duchenne muscular dystrophy. new clinical data Show that Sarepta’s gene therapy resulted in improvements in various measures of muscular dystrophy. Regulatory submissions are almost certain, but the question is when.
Sarepta has had “very intense discussions” with the FDA, CEO Doug Ingram said on a conference call Wednesday. The agency has the latest data from three Phase 1 and Phase 2 studies. Ingram said that while a 120-patient Phase 3 study already offers a pathway to regulatory approval, he expects discussions with regulators to shed light on whether it is possible to use current data to seek accelerated approval.
“We’re excited about either pathway, but obviously the pathway that brings this therapy to patients the fastest is our ultimate goal,” Ingram said.
Duchenne muscular dystrophy results from mutations in the gene encoding dystrophin, a protein important for muscle function. Without enough dystrophin, a patient’s skeletal muscle gradually weakens, reducing mobility. Over time, the disease can affect heart and lung function and become fatal. Sarepta’s gene therapy SRP-9001 provides a functional version of the gene encoding dystrophin. Sarepta has marketed three long-term medications to treat certain genetic subpopulations of Duchenne patients. Gene therapy offers the prospect of a one-time treatment.
Sarepta presented results from the latest clinical trial of its gene therapy on Wednesday at the International Congress of Neuromuscular Diseases in Brussels. The company highlighted one-year results from a study that tested a commercially representative version of Duchenne’s gene therapy at a target commercial dose. In the first group of 20 study participants, the gene therapy treatment resulted in a 3.8-point improvement, according to a rating scale used to assess exercise capacity in Duchenne patients. In addition, study participants showed, on average, improvements in measures including wake-up time, 10-meter walk/run test, time to climb four steps, and 100-meter walk/run test.
The open-label study compared participants to an external control group using data from three independent Duchenne studies, two of which were randomized controlled studies. These external controls only analyze measurements of ascent time and 10m walk/run.
Sarepta gene therapy has long-term data from another open-label study, albeit with a smaller patient sample. Four years later, four patients (aged 4 to 7 years old at the time of treatment) had an average improvement of 7 points compared to baseline. Compared to the external control, the difference was even greater, with an average of 9.9 points.
“These are elderly patients around the age of nine at four years of age, and since Duchenne is a progressive disease, these patients will now be in a deep, declining phase of the disease,” said Sarepta chief scientific officer Louise Rodino-Klapac. “However, they Instead of declining, their functionality increased and, importantly, maintained this increase, demonstrating a unique therapeutic effect that increases over time, supporting the durability of SRP-9001.”
Sarepta gene therapy is also being evaluated in a 41-patient, placebo-controlled Phase 2 trial. After 48 weeks, patients in the placebo group will switch to active treatment. All study participants will be followed for five years.
The safety of Duchenne’s gene therapy remains an issue, and the FDA has been closely monitoring clinical development programs. Solid Biosciences persevered through two clinical trials of its gene therapy candidate. The death of a patient last year led the FDA to suspend testing of Pfizer’s gene therapy.that keep is Changes to study, including hospitalizing patients for a week, were canceled in April After administration, it can be monitored. By contrast, Sarepta’s gene therapy is delivered on an outpatient basis.
The most serious adverse event reported by Sarepta from gene therapy was myocarditis or inflammation of the heart in one patient. The 11-year-old boy showed no signs of impaired heartbeat, Rodino-Clapak said. MRI at one month showed normal function with partial resolution of inflammation; at four months, echocardiography showed normal cardiac function. Vomiting is the most common side effect of Sarepta gene therapy. There is no indication that SRP-9001 activates the immune system’s complement pathway, a potential adverse effect of adenovirus-delivered gene therapy such as Sarepta’s.
In a research note to investors Wednesday, William Blair analyst Tim Lugo wrote that Sarepta’s latest data provides the company’s most comprehensive gene therapy candidate to date. Results so far show strong efficacy and a favorable safety and tolerability profile, Lugo said. But he questioned whether it was possible to speed up the approval pathway given the agency’s recent conservative approach to gene therapy. The FDA may question Sarepta’s use of external controls, he said. In addition, the myocarditis case could also cause the FDA to drop a faster review, given safety concerns observed in other Duchenne gene therapy studies. Still, Lugo is optimistic about Sarepta’s gene therapy.
“While we believe that an application for accelerated approval is unlikely, we continue to believe that SRP-9001 has a path to market and represents the most promising treatment for DMD (Duchenne muscular dystrophy) patients in the history of the disease and Sarepta great opportunity,” he said.
photo: Blackjack 3DGetty Images
