Use of the Six-Minute Walk Distance (6MWD) Across Duchenne Muscular Dystrophy (DMD) Studies (P3.121)

Objective: Evaluate optimal ranges of 6MWD for inclusion in ambulatory DMD trials.Background: 6MWD is a validated clinical outcome for ambulatory DMD studies and the primary endpoint in trials of ataluren, drisapersen, tadalafil, and eteplirsen. Decline in 6MWD is predictive of disease progression, time to loss of ambulation, and subsequent onset of disease milestones. Over time, there has been an effort to tighten 6MWT inclusion criteria, thereby excluding ambulatory patients with near-normal walking ability and those with severely impaired ambulation.Design/Methods: Recent DMD studies were reviewed to determine how the 6MWT has evolved as a sensitive clinical endpoint.Results: 6MWT inclusion criteria for DMD clinical trials have evolved since 2008 from the original criteria of 75m with no ceiling value for the first two trials which used the 6MWT as a clinical endpoint. These baseline 6MWT criteria have narrowed to a floor value as high as 300m for the eteplirsen open-label Phase 3 study (Sarepta 4658-301 initiated 2015) and ceiling values as low as 400m in the tadalafil Phase 3 trial (Eli Lilly H6D-MC-LVJJ initiated 2013). The Phase 3 ataluren study (ACT DMD; initiated 2013) included patients with a baseline ≥150m and u003c80[percnt] predicted, with a pre-specified subgroup of 300-400m baseline. In the ACT DMD study, the benefit of ataluren over placebo observed in the overall population (48-week difference=15m; p=0.213) was enhanced in the pre-specified 300-400m subgroup (47m; p=0.007). Sensitivity analyses confirmed an ataluren effect with 6MWD ≥250 to u003c400m (29.5m; p=0.035); ≥200 to u003c400m (26.6m; p=0.0501); and ≥300 to u003c450m (24.4m; p=0.0504).Conclusions: When evaluating drugs expected to slow progression in DMD, narrower 6MWD ranges are being used as inclusion criteria. For ataluren, a pre-specified range of 300-400m demonstrated the greatest treatment effect. Meaningful effects were seen with 6MWD from 200-450m.Supported By: PTC Therapeutics Inc. Disclosure: Dr. McDonald has nothing to disclose. Dr. Sweeney has received personal compensation for activities with PTC Therapeutics as a consultant. Dr. Luo has received personal compensation for activities with PTC Therapeutics as an employee. Dr. Elfring has received personal compensation for activities with PTC Therapeutics as an employee. Dr. Kroger has received personal compensation for activities with PTC Therapeutics, Inc. as an employee. Dr. Riebling has received personal compensation for activities with PTC Therapeutics, Inc. Dr. Ong has received personal compensation for activities with a pharmaceutical company as an employee. Dr. Spiegel has received personal compensation from PTC Therapeutics. Dr. Peltz has nothing to disclose. Dr. Mercuri has nothing to disclose.