Sarepta Therapeutics is providing the latest evidence suggesting that two similar, experimental gene therapies it’s developing might help treat two deadly genetic diseases.
As with previous updates to the two programs for Duchenne muscular dystrophy and a form of limb-girdle muscular dystrophy, the results, presented at the Annual Congress of the World Muscle Society, aren’t definitive. They come from a handful of patients in two separate early-stage trials. Until Sarepta has data from a randomized, placebo-controlled study, the first of which are expected next year, it won’t truly know whether its gene therapies can change the course of either disease, and if so, for how long.
But the results do show that four boys with Duchenne and six children with limb-girdle have seen either stability or improvement on a test of various motor skills when history suggests that they normally wouldn’t.
Each of the four Duchenne patients treated with the Sarepta gene therapy SRP-9001, for instance, have seen their scores on the North Star Ambulatory Assessment — a 34-point scale that evaluates patients’ ability to sit up, stand, climb stairs and more — increase since the start of the trial.
On average, those scores have increased by 7 points. Those results came after two years of follow-up for three patients, and 18-months post treatment for the fourth; Sarepta previously reported an average 5.5-point increase for all four patients 12 months after treatment. The four boys are each now between 6 and 8 years old.
To put those numbers in context, an analysis of historical Duchenne data published in the journal PLOS One last year found that patients between the ages of 6 and 8 would, on average, be expected to see their NSAA scores peak at 6.3 years of age, plateau, then start to decline.
“Even with the two-year data that we have now, we can confidently say that we’ve altered the course” of the disease, said Louise Rodino-Klapac, Sarepta’s senior vice president of gene therapy, in an interview. “Boys in this age range are in the decline phase.”
Greater proof would be seen if those boys continue to buck historical trends over the next few years. Duchenne is a progressive disease that typically leaves patients in wheelchairs by adolescence and kills them at a young age from heart or lung problems. Though some patients’ disease advances more quickly than others — a reflection of the heterogeneity of Duchenne and the use of steroids to slow its march — NSAA scores are generally expected to plummet between the ages of 8 and 11, according to the PLOS ONE study.
Sarepta also hasn’t done any new muscle biopsies on the Duchenne patients, so it’s unclear whether the gene therapy is still helping them produce the same levels of the key muscle-boosting protein as it was previously. It’s also unclear what changes, if any, patients have seen in a key marker of muscle damage Sarepta had been tracking.
Sarepta hasn’t seen any new treatment-related side effects emerge and has yet to report any serious adverse events. The most common side effect seen so far is vomiting within a week of receiving the gene therapy.
The company is also reporting its latest results for SRP-9003, a gene therapy it is developing for one of the many forms of limb-girdle, which, like Duchenne, leads to a progressive loss of muscle function and an early death. The NSAA scores of three patients who got a low dose of the gene therapy increased by an average of 3 points after six months and 5.7 points after 18 months. The high-dose patients have seen their scores climb by a mean 3.7 points after six months. Four of the six patients were 11 years or older, and thus more likely to see their scores decline.
The company previously reported one serious side effect, a patient who was dehydrated from vomiting. It hasn’t seen any others.
Sarepta has bet heavily on the field of gene therapy over the past few years, amassing one of the industry’s largest pipelines through a series of deals and collaborations. SRP-9001 and SRP-9003 are its most advanced prospects, and could portend success or failure for several others. Both gene therapies have similar components, as do five others the company is developing for other forms of limb-girdle.
SRP-9001 is in a competitive race with a rival gene therapy from Pfizer. Both have said they aim to start, before the end of the year, placebo-controlled trials with product made via a commercial process. The FDA recently slowed Sarepta’s progress, asking for an additional laboratory test before it can start a Phase 3 trial. “We’re confident we can address that request,” said Rodino-Klapac, though the timing will depend on when Sarepta gets a meeting with the agency. Pfizer hasn’t begun enrolling patients in its Phase 3 study yet, according to the clinicaltrials.gov database.
Still, there is more regulatory uncertainty surrounding gene therapy than there was a few months ago, following the surprise rejection of a hemophilia treatment, Roctavian, from BioMarin Pharmaceutical. The FDA asked BioMarin for more longer-term follow-up from clinical studies, indicating that it wants more evidence of how long it’ll last — a key question for all gene therapies.
“Hemophilia is very much different from Duchenne,” Rodino-Klapac said. Unlike Duchenne, there are many other effective drugs available for the chronic blood disease. And gene therapies for hemophilia target liver tissue, which “turns over quite rapidly” compared to muscles that Sarepta’s treatments target, she said, meaning its more likely that its approach could lead to more long-lasting effects.
Sarepta has said that it aims to file for approval based on interim results from the Phase 3 trial and a more complete look at data from an ongoing, placebo-controlled mid-stage test. It expected to have that information by the first quarter of 2021, though that may be more difficult now.
The biotech is currently designing a pivotal trial for its limb-girdle treatment and has said that it expects to be in a position to communicate its plans by early next year.
Ned Pagliarulo contributed reporting.