This study explored the effects of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO), on exon skipping and dystrophin restoration in Duchenne muscular dystrophy (DMD) patients. The open-label, phase 2, dose-escalation trial enrolled 19 boys aged 5-15, treated with doses ranging from 0.5 to 20 mg/kg weekly for 12 weeks. The main aim was to evaluate safety, with secondary goals to assess pharmacokinetics and the efficacy of exon 51 skipping and dystrophin restoration.

Findings and Results

AVI-4658 was generally well tolerated with no significant adverse events. Dose-dependent dystrophin restoration was observed, with significant protein expression starting at 2 mg/kg and peaking in higher dose groups. In the top dose groups, increased dystrophin levels led to improved localization of associated proteins and reduced muscle inflammation. However, responses varied, potentially due to differences in genetic deletions and pharmacokinetics.

Clinical Implications and Future Directions

The study indicates AVI-4658’s potential as a disease-modifying treatment for DMD, emphasizing the need for long-term trials to confirm clinical benefits. AVI BioPharma sponsored the study, and results highlight the importance of achieving sustained dystrophin expression to slow disease progression.