An experimental gene therapy from Sarepta Therapeutics failed to significantly improve motor function in patients with Duchenne muscular dystrophy, the company announced Thursday, dealing a major disappointment to the families and doctors who hope the therapy could be a one-time treatment for the fatal genetic condition.
The result is from one of the most closely watched clinical trials in gene therapy and, more broadly, rare disease research. Sarepta has been racing to prove its gene therapy can help halt and even reverse the steady muscle degeneration brought on by the disease. The Cambridge, Massachusetts-based biotech company's setback came the same day Pfizer announced the treatment of the first patient in a late-stage study of a competing Duchenne gene therapy it's developing.
The trial's negative outcome, which Sarepta sought to mitigate with other data that appeared more positive, could greatly set back the company's plans. Executives had in recent months suggested they could discuss an accelerated approval with the Food and Drug Administration, should this trial and a separate, smaller study now underway succeed.
Sarepta will continue the trial to a second stage, and will wait for that smaller study to read out results before meeting with the FDA. But the unexpectedly negative findings will weigh on the value investors put in Sarepta's gene therapy work. Shares slid by more than 50% in post-marketing trading Thursday, representing a loss in market capitalization of about $6.5 billion if sustained.
The trial of Sarepta's therapy, dubbed SRP-9001, was the first placebo-controlled study of an experimental muscular dystrophy gene therapy. The treatment is designed to work by replacing the faulty gene that causes Duchenne's, enabling patients' bodies to produce a modified version of the key muscle-building protein they lack, called dystrophin.
The study enrolled boys aged 4- to 7-years old, testing whether treatment led to increased dystrophin production and improvement in muscle function.
After 48 weeks, laboratory tests showed the gene therapy did result in higher protein production, but the difference in motor function between treated patients and those given placebo was not statistically significant.
The company blamed the trial's failure on an unlucky randomization process that, among the participants aged 6- to 7-years old, resulted in those with milder disease receiving placebo.
In patients aged 4- to 5-years old, by comparison, treatment led to a significant improvement in motor function, as measured by a series of tests called the North Star Ambulatory Assessment.
Speaking with Wall Street analysts Thursday, CEO Doug Ingram blamed "improbably bad luck in the randomization process" for the mismatched groups of 6- to 7-year old participants in the study.
"It was clear the significant imbalance made it virtually impossible to see a treatment difference in this group," Louise Rodino-Klapac, Sarepta's chief scientific officer, said.
Just last month, however, company executives told analysts from RBC Capital Markets that they had designed the trial to specifically control for variability in patients' muscle function, such as excluding patients whose NSAA scores were too high or low at entry, or whose specific genetic mutations result in slower disease progression.
"We came out reassured that [Sarepta] has incorporated many thoughtful elements to the trial design that should optimize its likelihood of success," RBC analyst Brian Abrahams wrote then.
Pressed by analysts on Thursday, Ingram said, "We don't think there was an inherent flaw in the randomization."
The trial will continue for another year. Patients who initially received placebo will be given the gene therapy, and vice versa, with participants remaining blinded to which they received and when.
Results from that "crossover" portion of the trial, due at the end of 2021, could address the study group imbalances in the first phase, Ingram said.
For now, Sarepta will use the initial data it has in hand to refine the design of a larger Phase 3 trial it's planning. That study would use gene therapy product made from its commercial manufacturing process, which is being tested in the smaller trial as well. Eleven patients have enrolled in that trial and data could come by the second quarter, Sarepta said.
Still, Thursday's results are a significant comedown for Sarepta, which two and a half years ago offered the very first glimpse at its gene therapy's effectiveness. Results from just three patients widely impressed, and the company's market value surged by billions of dollars.
With Sarepta stock's post-market slump Thursday, the company's shares are now worth less than what they were before that June 2018 upswing.