Sarepta Drug Helps Boys With Duchenne to Walk; Shares Boom

[Updated 9:42 am ET] Sarepta Therapeutics looked like road kill last spring when researchers pored over early results from a clinical trial of its drug for Duchenne Muscular Dystrophy. But now, as long-term follow-up data has arrived, the company looks like it is onto something big and important in the treatment of this crippling genetic disease. Shares of the company doubled to more than $30 a share after the company released an update today on a key clinical trial.

Cambridge, MA-based Sarepta (NASDAQ: SRPT), the company formerly known as AVI Biopharma, said today that patients on its experimental drug for Duchenne were able to walk an average of 89 meters further than those on a placebo, when both groups of boys took a standard 6-minute walk test after 48 weeks of study. Much of that difference can be explained by the rapid decline of patients on the placebo, but the boys who got the drug actually improved, and were able to walk an average of 21 meters further after 48 weeks than they could at the start of the study. The 89-meter difference between drug and placebo is about three times greater in magnitude as the difference seen in a separate clinical trial of Duchenne patients who got PTC Therapeutics’ adaluren.

While these new Sarepta results come from a small sample size of just 12 patients, researchers can see that the clinical improvement is matching up with what is happening in these boys at the molecular level. When researchers took muscle biopsies from the boys at the start of the study, they were producing almost none of the dystrophin proteins their muscles need to function properly. By the end of 48 weeks on the once-weekly infusion drug, boys on a low dose of Sarepta’s eteplirsen were able to produce about 52 percent of what is considered a normal amount of dystrophin. Researchers haven’t yet seen any serious treatment-related adverse events, and the boys are continuing to get the drug on an experimental basis. Sarepta plans to release more details at the World Muscle Society symposium Oct. 13 in Perth, Australia.

“These data represent a significant milestone and a defining moment of progress and hope for patients with Duchenne Muscular Dystrophy and their families, as well as for those of us in the scientific community who have been pursuing potential treatments for this devastating and deadly disease for decades,” said Jerry Mendell, director of the Centers for Gene Therapy and Muscular Dystrophy at Nationwide Children’s Hospital and principal investigator of study, in a Sarepta statement. He added that the drug has shown “unparalleled effects.”

“This was really beyond all expectations,” says Sarepta CEO Chris Garabedian. “This is the best controlled study with favorable outcomes that has ever been conducted in Duchenne.”

Chris Garabedian, CEO of Sarepta Therapeutics

The results represent a stunning reversal of fortune for Sarepta. The company, which closed at $14.99 a share yesterday in the run-up to today’s announcement, saw its stock fall below $1 a share in April after early results from this study were released. Back then, Sarepta could only say that its drug was able to help boys produce 22.5 percent of their normal dystrophin levels after 24 weeks of analysis, but that didn’t translate into any improvement in six-minute walking distance. Still Sarepta clung to the hope that its RNA-based treatment just needed a little more time to help the boys start producing more dystrophin, and for that protein to help the muscles start functioning better. Sure enough, Sarepta’s drug started to show it could help boys walk farther when an interim 36-week analysis was conducted in July. Although those results were intriguing, researchers didn’t have any biopsy samples at that point that could draw a clear connection between dystrophin production and improvement in walking distance. That was the kind of evidence Sarepta didn’t have until today.

Sarepta’s program is clearly going to stir much attention among patient advocates, and generate renewed interest among scientists. The drug is designed to work in a novel way, by functioning at the level of RNA in cells, and helping patients skip past a faulty section of the gene for making dystrophin, so that they can make enough of the critical protein to keep their muscles working.

Like any set of data, there is room for interpretation of the results, and doubt. The study included only 12 boys at a single site in the U.S.. Boys on a low dose of 30 milligrams per kilogram of body weight were able to make even more dystrophin (52.1 percent of normal vs. 41.7 percent of normal) than those who got a higher dose. And there was variability in individual responses, as boys on the drug produced dystrophin at between 30 to 60 percent of normal levels, Garabedian says.

Much as scientists might want the data, clinical trials can’t be designed to take muscle biopsy samples for analysis every couple weeks because of the invasiveness of the procedure. So researchers were only able to take snapshots of what was happening to the dystrophin at the start of the study, at either a 12 or 24 week analysis, and then ultimately after 48 weeks, Garabedian says.

Even though researchers can’t see what’s happening at the molecular level in real-time, they can see that dystrophin production rose significantly over time, and that it clearly exceeded the 30 percent of normal threshold that researchers think is necessary to show clinical improvement. The 6-minute walk test, on the other hand, is easy to administer consistently and is a standard goal for FDA-approved clinical trials. That test showed that boys on the Sarepta drug remained pretty stable in their walking ability through 36 weeks, and then started to show stronger walking ability after 48 weeks. Boys in the placebo group were allowed to “cross over” and start taking the experimental drug after 24 weeks, when many of them started to decline in their walking ability. When researchers looked at the muscle biopsies from those boys after 48 weeks, they saw that this group was also able to produce significant amounts of dystrophin (about 38 percent of normal), and that was able to help stop the decline in their walking distances.

Sarepta plans to discuss this latest batch of clinical trial results with the FDA, probably in early 2013, Garabedian says. The company said back in April that it believed its results were good enough to advance the drug into the third and final phase of clinical trials. But since then, Garabedian has suggested he thinks it might be feasible for the company to seek FDA approval based on this small 12-patient study, under the agency’s “accelerated approval” pathway for groundbreaking new medicines.

Regardless of what regulatory pathway is used, Garabedian says the key question will be “what it will take to get this drug approved the most rapidly.”

One key variable will be how much pressure patients put on the FDA to get access to the new medicine, based on this preliminary glimpse at the data. Some parents of boys in this study were so emotionally moved by the improvement they saw, they told local media outlets tales about how their boy could suddenly climb the stairs on the bus by himself after getting the Sarepta drug. In another case, parents talked about how a boy could twist open a milk carton by himself.

Sarepta didn’t encourage the parents to seek media attention on behalf of the drug, and wants to make sure the anecdotes don’t overshadow an evidence-based scientific reading of the data, Garabedian says. But at the same time, those parents and their supporters at patient advocacy groups could end up being powerful allies for Sarepta in its quest to start selling its first marketed product.

“We were already getting demand and requests from patients asking us how quickly we can help them get their hands on this drug,” Garabedian says. “I can’t imagine what the demand for this drug will be from the advocacy community after they see this data.”

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