Eteplirsen, a Phosphorodiamidate Morpholino Oligomer (PMO) for Duchenne Muscular Dystrophy (DMD): Clinical Update and Longitudinal Comparison to External Controls on Six-Minute Walk Test (6MWT) (S28.001)

Abstract

Objective: DMD, a rare, degenerative, X-linked genetic disease results in progressive muscle loss and premature death, occurring in ~1:3500-5000 males worldwide. DMD is primarily caused by frameshift-causing whole-exon mRNA deletions that prevent production of dystrophin protein. Eteplirsen, a PMO, is designed to induce production of internally-shortened dystrophin in patients amenable to exon 51-skipping. Methods: In a 24-week double-blind placebo-controlled study, twelve 12 boys aged 7-13 years were randomized to weekly intravenous infusions of 30/50 mg/kg eteplirsen or placebo, rolling-over to an ongoing open-label extension study (1:1 30/50 mg/kg). Clinical outcome measures included 6MWT and dystrophin expression. Routine safety assessments and cardiac monitoring were conducted. External control (EC) data were obtained from the DMD Italian Network and the Leuven Neuromuscular Research Center. A cohort (N=13) comparable to the eteplirsen-treated boys was defined based on age at baseline, corticosteroid use, and genotype. 3 year longitudinal data were used for comparative analysis of 6MWT performance. Results: At Year 3, a statistically-significant treatment benefit of 151 meters on 6MWT was observed in eteplirsen-treated patients compared with EC (p<0.01). 2/12 (16.6[percnt]) eteplirsen patients lost ambulation by Year 1 with no additional losses observed, compared with 6/13 (46[percnt]) EC at Year 3. Muscle biopsy analysis demonstrated exon 51-skipping in consented eteplirsen-treated patients (N=11) by RT-PCR and statistically significant increases (p<0.001) of dystrophin intensity and [percnt] dystrophin-positive fibers by immunohistochemistry over untreated DMD controls (N=9). Western blot confirmed dystrophin production in 9/11 patients. No deaths, discontinuations due to AEs, or treatment-related SAEs were reported. LVEF on ECHO was stable over 3 years. AEs were generally mild and unrelated to study-drug. Conclusions: After 3 years of eteplirsen-treatment, DMD patients had a mean 6MWT that was 151m higher (p<0.01) than the comparable external cohort and de novo dystrophin was detected using 3 complementary methods in nearly all eteplirsen-treated patients.

Disclosure: Dr. Mendell has nothing to disclose. Dr. Goemans has nothing to disclose. Dr. Rodino-Klapac has nothing to disclose. Dr. Sahenk has received research support from Sarepta Therapeutics. Dr. Lowes has received personal compensation for activities with Sarepta Pharmaceuticals, Eli Lilly, and Pfizer as a consultant. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Peterson has nothing to disclose. Dr. Lewis has nothing to disclose. Dr. Shontz has nothing to disclose. Dr. Shao has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Duda has received personal compensation for activities with Sarepta Therapeutics as an FTE. Dr. Donoghue has received personal compensation for activities with Sarepta Therapeutics as an FTE. Dr. Schnell has received personal compensation for activities with Sarepta Therapeutics as a full time employee. Dr. Dworzak has received personal compensation for activities with Sarepta Therapeutics as an FTE. Dr. Wentworth has nothing to disclose. Dr. EM has received personal compensation for activities with Sarepta Therapeutics. Dr. Mercuri has nothing to disclose. Dr. Italian Network has nothing to disclose.