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 Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotide resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. The collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes over time. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada, and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in an open-label, long-term extension. The primary objectives of CONNECT2-EDO51 are to evaluate the safety and tolerability of PGN-EDO51 and to determine dystrophin levels following repeat dosing in male participants with DMD amenable to exon 51 skipping. Secondary objectives are plasma pharmacokinetics (PK) and concentration of PGN-EDO51 in muscle tissue. Muscle biopsies occur at Baseline and Week 25. Main inclusion criteria are age ≥6 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will be randomized 3:1 to receive either PGN-EDO51 or placebo in multiple ascending doses across 3 cohorts. All participants (N=20) will receive 7 doses at approximately 4-week intervals over 24 weeks. The study design will be presented.

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 candidate for the treatment of people with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In mdx mice, a single intravenous (IV) dose of 30 or 60 mg/kg PGN-EDO23 (a murine analogue of PGN-EDO51) resulted in dose-dependent high levels of exon skipping and dystrophin production in biceps. Additionally, four monthly doses in mdx mice (30 mg/kg) resulted in significant increase in 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 biceps. 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 with PGN-EDO51 was generally safe and well tolerated. 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.

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 Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotides resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. Collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada (NCT06079736), and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in a long-term extension. The CONNECT1-EDO51 study objective is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (dystrophin, exon skipping) of PGN-EDO51 following repeat dosing in male participants with DMD amenable to exon 51 skipping. Muscle biopsies are taken at Baseline and Week 13. Main inclusion criteria are age ≥8 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will receive PGN-EDO51 in ascending doses across 3 cohorts. All participants (N=10) will receive 4 doses of PGN-EDO51 at approximately 4-week intervals over 12 weeks. Participants in the first cohort have received repeat doses of 5 mg/kg PGN-EDO51. Safety and initial dystrophin results from this cohort will be presented.

In Duchenne Muscular Dystrophy (DMD) a lack of dystrophin protein results in severe, progressive muscle atrophy, eventual loss of ambulation, respiratory insufficiency, cardiomyopathy, and premature death. Despite advances, there remains a substantial unmet need for treatments that reach cardiac and respiratory muscles, where restoration of dystrophin may be essential to improve respiratory and cardiac function and extend survival. WVE-N531 is a stereopure exon 53 skipping antisense oligonucleotide that contains PN (phosphoryl guanidine) chemistry. WVE-N531 was designed to address the limitations of first-generation exon-skipping oligonucleotides that had poor exposure in non-human primate (NHP) muscle tissue, including in the heart and diaphragm, and poor stability. This study evaluated the concentrations of WVE-N531 in cardiac, diaphragm, and skeletal muscle tissue of NHPs. WVE-N531 was administered every other week via intravenous infusion to cynomolgus monkeys for 6 weeks at 5, 15, or 45 mg/kg (n=2 per dose group). Muscle concentrations of WVE-N531 were measured at 2 days post-last dose using hybridization-ligation enzyme-linked immunosorbent assay. The mean tissue concentrations of WVE-N531 were 12.1, 57.2, and 93.1 µg/g in heart; 2.3, 10.8, and 15.9 µg/g in diaphragm; 0.263, 2.17, and 18.0 µg/g in skeletal muscle (tibialis anterior); after administration of four doses of 5, 15, and 45 mg/kg, respectively. The 15 mg/kg dose level in the monkey study was approximately equivalent to 10 mg/kg in patients based on plasma AUC values. These data suggest that chemical modifications to WVE-N531, including PN chemistry, have profoundly affected its pharmacology. WVE-N531 achieved high mean concentrations in skeletal muscle in NHPs, with even higher general exposure observed in the heart and diaphragm. Together, these data illustrate WVE-N531's excellent tissue uptake and distribution in both skeletal and non-skeletal muscles. In Duchenne Muscular Dystrophy (DMD) a lack of dystrophin protein results in severe, progressive muscle atrophy, eventual loss of ambulation, respiratory insufficiency, cardiomyopathy, and premature death. Despite advances, there remains a substantial unmet need for treatments that reach cardiac and respiratory muscles, where restoration of dystrophin may be essential to improve respiratory and cardiac function and extend survival. WVE-N531 is a stereopure exon 53 skipping antisense oligonucleotide that contains PN (phosphoryl guanidine) chemistry. WVE-N531 was designed to address the limitations of first-generation exon-skipping oligonucleotides that had poor exposure in non-human primate (NHP) muscle tissue, including in the heart and diaphragm, and poor stability. This study evaluated the concentrations of WVE-N531 in cardiac, diaphragm, and skeletal muscle tissue of NHPs. WVE-N531 was administered every other week via intravenous infusion to cynomolgus monkeys for 6 weeks at 5, 15, or 45 mg/kg (n=2 per dose group). Muscle concentrations of WVE-N531 were measured at 2 days post-last dose using hybridization-ligation enzyme-linked immunosorbent assay. The mean tissue concentrations of WVE-N531 were 12.1, 57.2, and 93.1 µg/g in heart; 2.3, 10.8, and 15.9 µg/g in diaphragm; 0.263, 2.17, and 18.0 µg/g in skeletal muscle (tibialis anterior); after administration of four doses of 5, 15, and 45 mg/kg, respectively. The 15 mg/kg dose level in the monkey study was approximately equivalent to 10 mg/kg in patients based on plasma AUC values. These data suggest that chemical modifications to WVE-N531, including PN chemistry, have profoundly affected its pharmacology. WVE-N531 achieved high mean concentrations in skeletal muscle in NHPs, with even higher general exposure observed in the heart and diaphragm. Together, these data illustrate WVE-N531's excellent tissue uptake and distribution in both skeletal and non-skeletal muscles.