1. Several initially promising DMD treatments have stumbled. In 2008, Wyeth -- now Pfizer (PFE) -- halted development of stamulumab (MYO-029), a monoclonal antibody intended to boost muscle strength by blocking an inhibitory protein called myostatin, due to lack of efficacy. Last year, Genzyme (now part of Sanofi (SNY)) abandoned partner PTC Therapeutics after a Phase IIb trial failed to show a meaningful 6MWT benefit for ataluren, a compound intended to make the body ignore so-called "nonsense" mutations like the one that causes DMD. PTC is still developing ataluren, but the prospects appear dim. Although these aren't eteplirsen-specific red flags, it seems prudent to note the tombstones if we hope to successfully navigate the DMD graveyard.
2. Competitors are at least a year ahead. Early last year, GlaxoSmithKline (GSK - Get Report) initiated a 180-patient, randomized Phase III trial of GSK-2402968 in DMD. The drug, formerly known as PRO-051 and licensed from privately held Prosensa, also induces exon 51 skipping and has promising early data. In a small Phase I/II study published in the April 2011 New England Journal of Medicine, GSK-2402968 recipients demonstrated a 35.2-meter absolute improvement in 6MWT from baseline, on average, after 12 weeks. Although this compares well with historical data, the study didn't include a control arm and the authors caution that: "No increase in specific muscle force was noted." To me, that means these results should be viewed with skeptically furrowed brows.
Notably, the FDA required Glaxo to conduct a one-year, placebo-controlled Phase III trial of GSK-2402968 in DMD, which strongly suggests Sarepta has little chance of receiving accelerated approval based on the Phase IIb data. At the very least, the fact that Glaxo successfully enrolled the study proves that complaints about the ethics of a lengthy placebo-controlled trial are completely unfounded.
3. Sarepta's placebo group results may be anomalous. The company's Phase IIb study included 24 weeks of blinded treatment, during which patients were randomized to either drug or placebo. At 24 weeks, patients in the high dose eteplirsen group showed a 28-meter 6MWT difference versus placebo. Investigators unblinded the study at that point and allowed placebo patients to receive drug. After another 12 weeks, those patients that had initially received eteplirsen vastly outperformed those in the placebo-delayed treatment arm, due largely to rapidly declining 6MWT results in the latter group.