it works in a novel way, at the level of RNA in cells. This compound, given as a once-weekly infusion, is designed to work on machinery inside cells which skips past a faulty section of the gene for making dystrophin, so they can make enough of the critical protein to keep their muscles working.
Netherlands-based Prosensa—a company that AVI has fought with over intellectual property— has also shown an ability in clinical trials to boost production of dystrophin. But Garabedian noted that AVI is the first to accomplish that goal in a blinded, placebo-controlled fashion, which eliminates a lot of the potential for biased results. Patients agreed to have muscle biopsies taken from their biceps before and after treatment, to get a clear sense of how much improvement they were getting in their dystrophin levels.
Details from the trial will be presented later this month at the American Academy of Neurology meeting in New Orleans, but AVI has already released much of the meaningful data to investors. Garabedian noted that the company is still analyzing some of the data itself, on key secondary goals of the trial, but he noted that the primary goal was an unequivocal success. The average patient saw a 22.5 percent increase in their dystrophin levels, and there wasn’t a huge amount of variability from patient to patient. The lowest level of dystrophin seen in a patient was 15.9 percent improvement, while the largest improvement was 29 percent, Garabedian says.
The study was small, however, with just four patients on the placebo, four on a low dose of 30 milligrams per kilogram of body weight, and four more on 50 milligrams per kilogram of body weight. Now the company will have to wait for the analysis of patients after 48 weeks of follow-up to see how much dystrophin the patients produce, whether it increases or plateaus, and whether they do better on the 6-minute walk test as time goes on. Whatever those results say, they will have a big impact on conversations AVI has with the FDA about the next proper steps in development, and the size, scope, and cost of trials to prove AVI has a real drug.
Everything would have been simpler, of course, if AVI had shown what it did on dystrophin levels, and that finding neatly aligned with an improvement in the 6-minute walk test. Had that happened, you can bet the stock would have jumped, and manuscripts would have been prepared for the New England Journal of Medicine.
But drug development rarely provides such black-and-white answers, especially early in the game. So AVI will have to live with ambiguity this year, both in terms of how its drug is doing clinically, and what its future holds as a business. In the best case, Garabedian says, he can imagine getting positive 48-week data in the fourth quarter, having a meeting to discuss it soon after with the FDA, and starting a pivotal study of eteplirsen in 2013.
“While we’d prefer to have a stronger signal of clinical benefit to accelerate the program, we’ll use this period to think about how to design and execute our pivotal program,” Garabedian says. “There’s a lot to do.”
