T.I.2 Exon skipping and PRO044 in Duchenne muscular dystrophy: Extending the program

Abstract

Patients with Duchenne muscular dystrophy (DMD) suffer from progressive muscle degeneration due to DMD gene mutations and resulting absence of dystrophin. Antisense oligonucleotides (AONs) have potential to modulate premRNA splicing so that a specific exon is skipped and the disrupted dystrophin reading frame restored. This allows production of internally deleted, partially functional dystrophins like those produced in Becker muscular dystrophy, which may lead to improvements in DMD skeletal muscle function through improved membrane stability and cell signaling. The first AON, currently in late phase clinical trials, is drisapersen (PRO051; GSK), a 2′-O-methyl phosphorothioate (2OMePS) RNA molecule inducing specific exon 51 skipping. Recently, a second AON was developed to target a different DMD patient population. PRO044, also a 2OMePS RNA molecule, applies to 6% of the DMD population and induces specific exon 44 skipping in dystrophin premRNA and dystrophin expression in cultured muscle cells of DMD patients. A Phase 1/2 open-label study of systemic PRO044 in 18 boys with DMD (5–15 years) is close to completion, exploring safety pharmacokinetics and molecular efficacy at different dose levels with five once-weekly sc administrations (0.5, 1.5, 5, 8, 12 mg/kg). Nine of these boys have also received 5 additional weekly doses at different dose levels by iv infusion (1.5, 5, 12 mg/kg). Preliminary data are encouraging. No clinical response was expected after 5 weeks’ treatment; however, the safety profile is consistent with the class of compound and a molecular response has been observed. Due to high degrees of spontaneous skipping, giving rise to revertant fibers in this DMD population, a new and robust, reproducible dystrophin detection methodology has been developed. Data will be presented to show effects on safety and plasma/tissue drug levels, putative biomarkers and muscle dystrophin expression, which will be used to support subsequent long-term PRO044 studies.