For the first time, a gene therapy—a one-time, long-lasting treatment—has shown it may improve the lives of kids with Duchenne muscular dystrophy, a deadly genetic disease with no cure. Patients in a small trial showed improved motor function, such as walking and climbing stairs, and near-normal levels of a key muscle protein.
But the data Sarepta Therapeutics (NASDAQ: [[ticker:SRPT]]) is presenting this afternoon at the World Muscle Society meeting in Argentina are rife with caveats: The results are from just four patients, and must be confirmed through further testing. The improvements so far could be due to random chance.
“At this age, most boys will be getting slowly worse, and some will be plateauing. But a few could be making gains,” says Lauren Elman, the associate director of the Muscular Dystrophy Association Clinic at the University of Pennsylvania Medical Center. “To see any improvement is great, but I think you have to interpret this with cautious optimism.” Elman is not associated with Sarepta.
It’s also unclear how long the treatment will last, whether any problems will arise, or if other patients will respond the same way.
Nonetheless, the results are noteworthy. Duchenne afflicts some 300,000 boys worldwide, puts them in wheelchairs by their teenage years, and typically kills them at a young age from lung or heart problems. The only available treatments are steroids and, for a subgroup of patients, another product from Sarepta called eteplirsen (Exondys 51). These treatments can slow progression but do not change the course of the disease. That’s where, ideally, gene therapy may be different.
“I don’t want to look unscientific by taking just four patients and then extrapolating in perpetuity,” says Sarepta CEO Doug Ingram. But Sarepta has seen “a very strong potential signal of functional benefit. And you’re seeing it across all of the measures.”
With its gene therapy, Sarepta uses an engineered virus to deliver, via a one-time infusion, “micro” dystrophin, which is a smaller version of dystrophin, the muscle-protecting protein that Duchenne patients lack. The goal is to boost production of micro-dystrophin, which is meant to function the same way as dystrophin.
The four patients in the study, boys age 4 to 6, all have levels of micro-dystrophin approaching normal, three to nine months after receiving the gene therapy. (Officially the therapy is called AAVrh74.MHCK7.micro-Dystrophin.) The therapy helped these four patients produce an average of either 74.3 percent or 95.8 percent, as measured by two different diagnostic tests, of normal levels of micro-dystrophin after three months, numbers that are higher than what Sarepta reported in June. At that time, Sarepta reported the first three patients produced an average of either 38.2 percent or 53.7 percent of normal levels after three months.
The reason for the increase is the fourth patient after three months produced levels of micro-dystrophin far higher than normal: an average of either 182.7 percent or 222 percent compared to a healthy patient. Ingram says when it comes to dystrophin, “more is better” and there is no known safety issue with above-normal levels. And though the improvements in micro-dystrophin levels varied patient to patient, all of the variability has been “significantly above” a threshold that should be meaningful for patients, he says.
“Before we saw any of the kids, we were hoping we would get [micro-dystrophin] expression levels that would be as high as 10 or 15 percent,” Ingram says. “All of the kids are significantly above that.”
The patients are also producing an average of 78 percent less of an enzyme called creatine kinase (CK), compared to baseline levels when the trial began. High CK levels are an indicator of muscle damage and are used to diagnose a patient with Duchenne. “The pathology looks extremely promising,” says UPenn’s Elman. “These muscle biopsies look spectacular.”
But will the reported improvements in these markers lead to better outcomes over time in a larger swath of patients? There is an open question
