PepGen’s enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen’s investigational clinical candidate for the treatment of people with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.
Proof of concept studies in mdx mice resulted in dose-dependent high levels of exon skipping and dystrophin production in muscle following a single intravenous (IV) dose of 30 or 60 mg/kg PGN-EDO23 (a mouse analogue of PGN-EDO51). Additionally, four monthly doses in mdx mice (30 mg/kg) resulted in significant increases in both exon skipping levels (91.5%) and dystrophin production (82.2%), suggesting accumulation of dystrophin with repeat dosing. Importantly, dystrophin was uniformly distributed across muscle and resulted in 97.1% dystrophin-positive fibers following repeat dosing. In NHPs, a single IV dose of PGN-EDO51 resulted in dose-dependent exon 51 skipping in muscle. Similar to what was seen in mice, four monthly doses of PGN-EDO51 resulted in dose-dependent accumulation of skipped transcripts. Levels of exon 51 skipping in biceps observed after a single dose were increased by 14-fold following four 20 mg/kg monthly doses in NHPs.
Toxicology studies in NHPs indicated repeat dosing (once every 4 weeks for a total of 11 doses) with PGN-EDO51 was generally safe and well tolerated. Repeat dosing of PGN-EDO51 did not demonstrate any anti-drug antibody (ADA) response in the confirmatory assay. No persistent elevation of kidney biomarkers was observed at doses through 45 mg/kg. Additionally, there were no adverse findings in the kidney after 11 monthly 45 mg/kg doses, no notable hematologic or hepatic effects, and no cardiovascular effects.
Combined, these data suggest monthly repeat dosing of PGN-EDO51 may result in dystrophin accumulation, which may potentially result in a clinically meaningful benefit in people with DMD amenable to exon 51 skipping. These data informed the design of the ongoing Phase 2, multiple-ascending dose studies, CONNECT1-EDO51 and CONNECT2-EDO51.