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 Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. Nonclinical data from mdx mice and monkeys support the hypothesis that accumulation of exon skipping and dystrophin protein will be observed with repeat PGN-EDO51 dosing. Phase 1 study demonstrated a generally tolerable profile at clinically relevant PGN-EDO51 doses with high levels of muscle oligonucleotide delivery and exon 51 skipping. When compared to publicly available clinical data for other approaches, these are the highest levels measured in a clinical study after a single dose of oligonucleotide in healthy adult volunteers, supporting the hypothesis of enhanced delivery and the design of Phase 2 studies.
Objectives: Phase 2 studies to evaluate safety and explore efficacy of PGN-EDO51 for DMD.
Design/Methods: In the multiple-ascending dose (MAD) study CONNECT1-EDO51, males with DMD amenable to exon 51 skipping will receive repeat PGN-EDO51 dosing every 4 weeks. The primary outcome will be safety and tolerability; secondary outcomes include dystrophin production, the concentration of PGN-EDO51 in skeletal muscle, and PGN-EDO51 pharmacokinetics. CONNECT2-EDO51 is a placebo-controlled MAD study that will also evaluate PGN-EDO51 in males with DMD amenable to exon 51 skipping.
Results: Study designs of CONNECT1-EDO51 and CONNECT2-EDO51 will be presented.
Conclusions: CONNECT1-EDO51 is an open-label trial in Canada and CONNECT2-EDO51 is a multinational, randomized, placebo-controlled trial designed to support development of PGN-EDO51 for the treatment of DMD. Based on nonclinical data, monthly repeat PGN-EDO51 dosing may result in accumulation of skipped transcripts and dystrophin production, which would be anticipated to result in clinical efficacy.