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: 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 whether the micro-dystrophin delivered by Sarepta’s gene therapy is as beneficial as actual dystrophin. Sarepta is offering positive but inconclusive evidence today that it might. Each of the four patients has shown an improvement on what’s known as the North Star Ambulatory Assessment, a 17-item rating scale that assesses motor function in patients with Duchenne. The average improvement in NSAA scores for the four boys at their last examinations was 6.5 points, or 33 percent.
Patients have also shown improvements in the time it takes to climb four stairs (31 percent faster), rise from the floor (13 percent), and walk either 100 meters (14 percent) or 10 meters (10 percent).
There are caveats to these results. Sarepta’s study is an open-label trial with no control, so there is no comparator other than historical, recorded results from similar types of patients. As JMP Securities analyst Liisa Bayko wrote in a recent research note, function generally begins to decline in Duchenne patients at the age of seven. What’s more, a 2015 study on NSAA scores published in the Journal of Neurology, Neurosurgery & Psychiatry noted the motor function of boys under 7 can improve, particularly if treated with steroids at a young age. The fact that the patients in Sarepta’s trial were on steroids could “cloud the picture” a bit, says UPenn’s Elman.
Still, Ingram, citing discussions Sarepta has had about the results with Duchenne experts around the world, says the numbers are “significantly better than you would ever expect to see” for four- to six-year-old boys with Duchenne.
Sarepta hasn’t reported any serious safety problems. Three patients saw levels of a particular enzyme spike, a common gene therapy reaction, but extra steroids helped lower those levels within a week. Patients had temporary nausea from the steroids.
Possible safety issues have been important to watch ever since gene therapy pioneer James Wilson and his colleagues at the University of Pennsylvania published a paper sounding an alarm about the safety of gene therapy for diseases like Duchenne. They cited results from animal tests of a potential gene therapy for the rare disease spinal muscular atrophy. And the FDA temporarily halted a study of a gene therapy from Sarepta’s rival Solid Biosciences (NASDAQ: SLDB) after a patient’s platelet and red blood cell counts dropped dangerously low.
Sarepta’s gene therapy study was temporarily suspended, too, but because of a manufacturing issue, not safety concerns, the company said. Ingram says the expectation is that if a treatment-related health problem were to arise, it would happen very quickly after Sarepta’s therapy is administered, not down the road, given it’s a one-time dose.
Additionally, Sarepta hasn’t seen any signs so far of the therapy wearing off, he says. But it’s only been a matter of months since patients have been treated, not years.
“Looking at short term clinical outcomes is exciting and what we all want to look at, but I don’t think it’s the endgame,” Elman says. “We’re unfortunately going to have to be patient and wait and see because I don’t think at this point anybody knows how long the expression is going to last.”
Sarepta is now prepping for a key meeting with the FDA. It wants to begin enrolling patients, by the end of the year or in early 2019, in a 24-person study in which half of the patients would get the gene therapy initially and the other half a year later. Sarepta hopes to file for approval off of that data, and Ingram talks ambitiously of bringing the treatment to market in late 2020 if all goes well. But regulators have to agree with those plans first.
Sarepta is ahead of a cluster of companies developing gene therapy or gene editing techniques for Duchenne. Solid Bio and Pfizer (NYSE: PFE) are also developing gene therapies that shuttle micro-dystrophin into patients’ cells. Gene editing treatments, which use CRISPR technology to snip out Duchenne-causing genetic mutations, are advancing toward human trials as well at companies like Exonics Therapeutics and Editas Medicine (NASDAQ: EDIT).