Eteplirsen, a Phosphorodiamidate Morpholino Oligomer (PMO) for Duchenne Muscular Dystrophy (DMD): Longitudinal Comparison to External Controls on Six-Minute Walk Test (6MWT) and Loss of Ambulation (LOA) (S42.004)

Objective: PMO eteplirsen is designed to skip exon 51, restore the reading frame, and induce production of internally-shortened dystrophin in patients amenable to exon 51-skipping. Background: DMD, a rare, degenerative, X-linked disease occurring in ~1:5000 males worldwide results in progressive muscle loss and premature death. DMD is primarily caused by whole exon deletions resulting in a shift of the dystrophin mRNA reading frame that prevents production of functional dystrophin protein. Design/Methods: Analysis of 6MWT performance over 4 years compared boys treated with 30 or 50 mg/kg/wk eteplirsen IV (N=12) versus a group of comparable, untreated external controls (N=13) as defined by age, corticosteroid use, and genotype. Results: At Year 4, a statistically significant treatment benefit of 162 meters on 6MWT was observed in eteplirsen-treated patients versus external controls (p=0.0005). Sensitivity analyses of 6MWT with covariates including baseline 6MWT, age and glucocorticoid use resulted in differences >150 meters between the groups that were statistically significant (p Kaplan-Meier estimates of Loss of Ambulation (LOA) showed that 85% of the external control patients lost ambulation versus 17% of eteplirsen-treated patients at Year 4 (log-rank p=0.011). Median age to LOA in the external cohort was 12.9 years. The eteplirsen-treated patients had not reached median age of LOA as 10/12 were still ambulatory at Year 4; however, the median age of eteplirsen-treated patients at this time point was 13.4. No major safety signal was observed. Data from the final study time-point will be presented. Conclusions: Eteplirsen slowed DMD progression as evidenced by a 162 meter advantage on the 6MWT compared to external control patients (p=0.0005) at Year 4. In addition, there was a reduction in risk of loss of ambulation in the eteplirsen treated patients (p=0.011). The 6MWT and LOA data reported here were not included in the US prescribing information for eteplirsen by the Food & Drug Administration. Study Supported by: Sarepta Therapeutics, Inc. DMD Italian Network University Hospitals, Leuven Disclosure: Dr. Mendell has received personal compensation for activities with Sarepta Therapeutics, Inc. Dr. Goemans has received personal compensation for activities with PRC, Biomarin, Biogen, and Italofarmaca as a consultant, speaker, and advisory board member. Dr. Rodino-Klapac has nothing to disclose. Dr. Lowes has received personal compensation for activities with AveXis, Inc., Bristol-Myers Squibb, Sarepta Therapeutics, and Pfizer as a consultant. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Moody has received personal compensation for activities with Sarepta Therapeutics, Inc. Ms. Naughton has received personal compensation for activities with Sarepta Therapeutics. Dr. Mercuri has nothing to disclose. Dr. Italian Network has nothing to disclose.