Muscle biopsies were repeated for all patients at 48 weeks. As reported by Sarepta, there was a statistically significant increase in dystrophin-positive fibers to 47% of normal in the six patients treated with eteplirsen since the start of the study. The placebo/delayed treatment patients also showed a significant increase of dystrophin-positive fibers to 38.3% of normal after just 24 weeks of therapy. This is surprising as it's nearly double the dystrophin increase observed after 24 weeks of treatment for the active treatment patients (which was only 22.5%.)
However, when we look at the relationship between percentage of dystrophin-positive fibers and mean change in the six-minute walk test (6MWT), there is no clear correlation between eteplirsen dose, percentage of dystrophin-positive fibers and 6MWT performance.
Patients treated at the lower 30 mg eteplirsen dose produced more dystrophin-positive fibers, but this benefit in the surrogate or biomarker endpoint did not translate to improved physical performance on the 6MWT.
Similarly, Prosensa and GlaxoSmithKine (GSK - Get Report) published results of a phase I/II dose-escalation study demonstrating treatment with their DMD drug PRO051 that resulted in 20-100% dystrophin-positive fibers after only two weeks of treatment in some patients, with levels maintained at greater than 70% after seven weeks of treatment for higher doses of the drug. As with eteplirsen, there was no correlation between percent dystrophin-positivity and 6MWT performance. Obviously, the argument can be made that the dystrophin is not fully functional as early as seven weeks, which is why Glaxo is conducting a phase III multi-center, double-blind, randomized controlled study of PRO051 to investigate the effects of treatment for 48 weeks in 180 DMDpatients. The results of this phase III study should report in the second half of the year.The point I'm making is there is insufficient clinical evidence from human studies to conclude with reasonable confidence that dystrophin-positive fiber counts predict clinical outcomes (6MWT performance) in DMD patients. To that end, it is entirely unknown what the correct dose or dosing frequency should even be for eteplirsen based on early study results. I doubt FDA will be persuaded otherwise. Furthermore, if Glaxo was required to demonstrate efficacy of PRO015 under blinded, controlled conditions, why should the regulatory hurdle be any lower for Sarepta? Bulls argue Glaxo is conducting the phase 3 study due to concerns about PRO015's safety profile. FDA requires a drug demonstrate both safety and efficacy. A review of PRO051's phase I/II data do not suggest there are any concerning safety signals compared with eteplirsen's safety early data. The fact remains that eteplirsen's open-label "placebo-adjusted" benefit has never been demonstrated by Sarepta under blinded, controlled conditions. If Sarepta were to repeat this trial with adequate power for 48 weeks under double-blind conditions, it's possible the absolute benefit of eteplirsen in DMD patients could be modest.