UPDATED: GlaxoSmithKline measures 36-meter leap over placebo in Duchenne walking test

GlaxoSmithKline investigator John Kraus reviewed the long-awaited mid-stage results for its Duchenne muscular dystrophy drug drisapersen this afternoon, revealing that boys taking the experimental therapy benefited with a significant improvement in walking distance compared to a placebo arm. And they did it without any serious signs of the toxicity that has raised questions about how well this drug may compete in the future with a rival therapy from Sarepta ($SRPT).

Looking at the history of the effect of this disease, Kraus tells FierceBiotech, "there is a predictable decline (in patients); the rate accelerates. We would have been happy with results that showed stability in walking distance and further encouraged by any evidence of gain. So when you talk about magnitude of change, 30 meters change from placebo, that is considered clinically meaningful." In addition, he adds, there were no serious adverse events in the study that forced any of the boys to stop taking the medication, though investigators did track mild signs of proteinuria in volunteers.

GlaxoSmithKline ($GSK) randomized 53 subjects for their Phase II study of drisapersen. Of those, 18 were in the placebo arm. Kraus, the project physician leader, noted that in this group of younger boys, some could normally be expected to register an improvement in walking distance without treatment.

For boys in the continuous treatment group after 24 weeks, there was a mean improvement over baseline of 31.5 meters in the 6-minute walking test, says Kraus, who reviewed the data at a scientific meeting at Cold Spring Harbor Labs. In the placebo arm there was an average decline of 3.6 meters at 24 weeks. After 48 weeks of therapy there was an average improved walking distance of 11.2 meters compared to a 24.7 meter mean decline in the placebo arm--a swing of about 36 meters.

In the intermittent treatment group, after 24 weeks the drug arm declined 0.1 meters, reflecting little sign of change. After 48 weeks the intermittent drug arm reflected an improvement in walking distance of 2.4 meters. 

GSK investigators also rated boys using the North Star Ambulatory Assessment scale, a 17-point system on which a score of 34 is normal.

After 48 weeks of continuous treatment, both treatment groups were approximately two points above the placebo arm (the actual mean values were 2.50 continuous, 2.29 intermittent). As a recent natural history study indicates that boys with Duchenne are expected to see a 1.8-point decline over a year, Kraus says they were encouraged to see a 1.6-1.7 point difference from placebo after week 24, though he noted that the study wasn't powered to assess a statistically significant improvement on this score. 

Among the adverse events recorded, investigators noted an injection site reaction, which is not uncommon in drug trials, as well as mild signs of proteinuria, an excess level of protein in the urine. Close observers of drisapersen have paid particularly close attention to the proteinuria cases after GlaxoSmithKline discussed cases in Phase III that required hospitalization.

Kraus notes that of the 12 subjects who have taken drisapersen for more than three years, none have had to withdraw from the study. Now a total of about 300 boys have been randomized in all trials, where the potential safety and efficacy of the compound can be explored for a longer period with significantly increased numbers. It's only after the study was expanded that investigators could see more serious adverse events, "which was not necessarily unexpected," says Kraus.

About the proteinuria in the current study, Kraus noted that "it was not progressive, it didn't get worse over time. In our other trials, there have been two subjects with excessive proteinuria but this resolved after stopping treatment." 

For the Wall Street crowd, these Phase II numbers will quickly be compared to the data Sarepta ($SRPT) has accumulated on eteplirsen, another exon-skipping therapy like drisapersen--which was initially developed by Prosensa. Sarepta's promising Phase II study was significantly smaller, involving 12 boys. At 48 weeks the once-weekly 50 mg treatment arm demonstrated a 21-meter improvement over baseline, which was higher than GSK's results. But the placebo/delayed-treatment group declined 68.4 meters; much, much worse than the placebo arm in GSK's study--offering a much bigger combined advantage of 89.4 meters. Sarepta has also kept track of the boy's ongoing results after 48 weeks, tracking a sustained effect.

A big question here is how regulators are likely to review both sets of data. There's been a frenzy of speculation that Sarepta will go straight to an NDA if they receive some encouragement from the agency, which might allow them to do the Phase III after marketing approval. But if regulators are left dubious about the size of the trial or the potential for detecting adverse events in Phase III, and Sarepta is forced to push ahead with Phase III ahead of an application, a number of analysts expect the stock price to plummet. A green light on the NDA now, though, could push its share price even higher.

A decision from Sarepta should come shortly. GlaxoSmithKline, meanwhile, says it will post Phase III data later this year.

CORRECTION: The original article noted a 27.4 meter decline for the placebo group at 48 weeks. On review, GSK corrected that number to 24.7 meters.