Eteplirsen, a Phosphorodiamidate Morpholino Oligomer (PMO) for the Treatment of Duchenne Muscular Dystrophy (DMD): 168 Week Update on Six-Minute Walk Test (6MWT), Pulmonary Function Testing (PFT), and Safety

Background/Objective: DMD is a rare, degenerative, X-linked recessive genetic disease that results in progressive muscle loss and premature death. DMD is caused by mutations in the dystrophin gene that lead to a reading frame shift and premature translation termination. Exon skipping, a promising disease-modifying approach for DMD, can be induced by eteplirsen, a charge neutral PMO that selectively binds to exon 51 of dystrophin pre-mRNA, restoring the open reading frame and enabling production of an internally truncated yet functional dystrophin protein as found in the less severe dystrophinopathy, Becker muscular dystrophy (BMD). Methods: Twelve eligible boys, aged 7-13 years were randomized 1:1:1 to eteplirsen 30 or 50 mg/kg/wk, or placebo for 24 weeks. All patients transitioned into the ongoing open-label extension trial at Week 25 taking eteplirsen 30 or 50 mg/kg. Initial placebo-treated were denoted “placebo-delayed” after starting the PMO. Efficacy endpoints included 6MWT, PFT, and %-dystrophin positive fibers. Safety assessments included AE recording, ECG, ECHO, and safety laboratory testing. Results: After more than 3 years of treatment, all patients previously evaluable on 6MWT (mITT; n=10) showed continued ambulation. The boys on continuous eteplirsen from Week 1 (n=6) declined 76.7 meters in walking ability through week 168. This was 65 meters better than placebo-delayed (n= 4; p≤0.017), starting eteplirsen at Week 25. Of particular interest, the placebo-delayed declined 68 meters through Week 36 and then showed a course almost identical to the eteplirsen cohort (placebo-delayed declined 73 meters; continuous eteplirsen declined 76 meters). This is most likely related to the time needed for the production of meaningful levels of dystrophin (∼12 weeks post-treatment). All patients, even those age 12-15, continue to demonstrate an ability to climb stairs, to rise from supine, and to raise a hand to the mouth at a rate higher than what was observed in a natural history study of glucocorticoid-naïve or steroid-treated boys with DMD (Henricson et al., 2013). All 12 patients, including the two non-ambulatory patients, demonstrated PFT stability from baseline through Week 168, including MIP (+11.1%, p=NS), MEP (+13.5%, p=NS), and MIP/MEP %-predicted (-2.4%/-6.3%, p=NS).