Background: PepGen’s enhanced delivery oligonucleotide cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen’s clinical candidate for the treatment of people with DMD amenable to exon 51 skipping.
Objectives: In vivo pharmacology studies to support continued development of PGN-EDO51.
Design/Methods: PGN-EDO51 pharmacology was characterized using the mdx model of DMD (using murine analogue PGN-EDO23) and in monkeys.
Results: In mdx mice, single intravenous (IV) dose of 30 or 60 mg/kg PGN-EDO23 resulted in dose-dependent high levels of exon skipping and dystrophin production in biceps; and pharmacological activity was detectable for up to 12 weeks. Four monthly doses in mdx mice (30 mg/kg IV) resulted in significant increase in exon skipping levels (91.5%) and dystrophin production (82.3%) suggesting accumulation of dystrophin with repeat dosing. Immunofluorescence evaluation showed dystrophin was uniformly distributed across muscle and resulted in 97.1% dystrophin positive area following repeat dosing. In monkeys, single IV dose of PGN-EDO51 resulted in dose-dependent exon 51 skipping (by RT-PCR and ddPCR) in biceps. Four monthly doses of PGN-EDO51 also resulted in dose-dependent accumulation of exon 51 skipped transcripts (by ddPCR). Levels of exon 51 skipping (by ddPCR) in biceps observed after a single dose increased by 14-fold with four 20 mg/kg monthly doses.
Conclusions: PGN-EDO51 was generally well tolerated at clinically relevant doses in GLP repeat-dose toxicology studies. Combined, the nonclinical data showed significant accumulation of exon skipping and dystrophin protein after repeat doses in the mdx mouse model and accumulation of exon skipped transcripts in monkeys. These data suggest repeat PGN-EDO51 dosing every 4 weeks may result in dystrophin accumulation, which may potentially support a clinically meaningful benefit in people with DMD amenable to exon 51 skipping. The data informed the design of the Phase 2, multiple-ascending dose studies CONNECT1-EDO51 and CONNECT2-EDO51.