Background: PepGen’s Enhanced Delivery Oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. Delivery of oligonucleotides to affected tissues is a major challenge that limits their efficacy. PGN-EDO51 is being evaluated for the treatment of DMD amenable to exon 51 skipping.
Objectives: Evaluate the safety, tolerability, pharmacokinetics (plasma and muscle), and pharmacodynamics (exon skipping) of single-ascending doses of PGN-EDO51 administered intravenously (IV) to healthy male volunteers (HV).
Methods: Thirty-two adult HVs were randomized to receive a single dose of PGN-EDO51 (1, 5, 10, or 15 mg/kg; n=6 per cohort) or placebo (n=2 per cohort). Biceps needle biopsies were performed on Days 10 and 28.
Results: All HVs completed the study. The majority of treatment-emergent adverse events were mild and resolved without intervention, including transient, reversible changes in kidney biomarkers (n=9) and hypomagnesemia (n=2) at the highest doses, with no significant clinical sequelae. At Days 10 and 28, respectively, there were dose-dependent and sustained concentrations of PGN-EDO51 measured in biceps biopsies: 9.7nM and 3.8nM (5mg/kg); 19nM and 11nM (10mg/kg); and 50nM (both days at 15mg/kg); and dose-dependent increases in mean exon skipping of 0.14% and 0.35% (5mg/kg); 1.1% and 1.4% (10mg/kg); and 1.4% and 2.0% (15mg/kg).
Conclusions: The Phase 1 study results demonstrate that PGN-EDO51 has a generally tolerable profile at clinically relevant doses. PGN-EDO51 exhibited high levels of muscle oligonucleotide delivery and exon 51 skipping following a single dose. Oligonucleotide concentrations and levels of exon skipped transcripts in muscle at Day 28 indicate the potential for accumulation of exon 51 skipped transcripts and dystrophin protein with repeat dosing in people with DMD amenable to exon 51 skipping. Based on these results, a Phase 2, multiple-ascending dose study in people with DMD will be initiated in the first half of 2023.