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-EDODM1, in clinical trials for the treatment of myotonic dystrophy type 1 (DM1), is designed to bind pathogenic CUG repeat expansions in DMPK mRNA and liberate MBNL1 protein without degrading DMPK transcripts. Liberation of sequestered MBNL1 is expected to restore the normal splicing of multiple downstream transcripts; a central cause of DM1 pathology. Indeed, in vitro treatment of DM1 myotubes showed PGN-EDODM1 delivery to the nucleus, and treatment of DM1 patient myotubes with both low-CUG and high-CUG repeats demonstrated similar dose-dependent reduction of pathogenic myonuclear foci, liberation of MBNL1 from foci, and correction of mis-splicing without DMPK RNA degradation. A single intravenous (IV) dose of PGN-EDODM1 to HSALR mice resulted in dose-dependent correction of mis-splicing and improvement in myotonia. Following repeat-dosing of PGN-EDODM1 once every 4 weeks, near complete resolution of DM1 pathology including correction of mis-splicing and resolution of myotonia was observed. Toxicology studies in NHPs indicate repeat dosing with PGN-EDODM1 was generally safe and well tolerated. No persistent elevation of kidney biomarkers was observed at doses through 60 mg/kg. Additionally, there were no adverse findings in the kidney after 4 monthly doses of 60 mg/kg, nor notable hematologic or hepatic or cardiovascular effects. Currently, there are no approved therapies for DM1. Nonclinical pharmacology and safety studies with PGN-EDODM1 showed meaningful therapeutic potential on splicing correction and myotonia correction and support the ongoing Phase 1 single-ascending dose study FREEDOM-DM1 in adults with DM1.

PepGen's enhanced delivery oligonucleotide (EDO) 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. In the mdx mouse model of DMD, a single intravenous (IV) dose of 30 or 60 mg/kg of mPGN EDO23 (mouse analogue of PGN-EDO51) resulted in exon skipping levels of 52.5% and 82.8% and dystrophin protein production of 22.5% and 51.7% in biceps. Pharmacological activity was detectable in biceps for up to 12 weeks after the single dose. Repeat dosing (30 mg/kg mPGN EDO23 once every 4 weeks for 4 doses) in mdx mice resulted in higher levels of exon skipping (91.5%) and dystrophin protein (82.3%) suggesting accumulation in biceps with repeat dosing. A single IV dose of PGN-EDO51 in non-human primates (NHP) resulted in dose-dependent exon 51 skipping (by RT-PCR and ddPCR) in biceps. Repeat dosing every 4 weeks resulted in dose-dependent accumulation of exon 51 skipping (by ddPCR) in biceps. Levels of exon 51 skipping (by ddPCR) in biceps observed after a single dose increased by 14-fold at 20 mg/kg and 3.4-fold at 30mg/kg with repeat dosing. Comparative pharmacology data show 5.9- to 12.9-fold higher levels of exon skipping in biceps following single IV doses of mPGN-EDO23 (mdx) and PGN-EDO51 (NHP) compared to comparator compounds PPMOs R6G-PMO23 (mdx) and R6G-PMO51 (NHP). Combined, the nonclinical studies show significant accumulation of exon skipping and dystrophin protein after repeat doses in the mdx mouse model and accumulation of exon skipping in NHPs. These data suggest repeat PGN-EDO51 dosing every 4 weeks may result in dystrophin accumulation potentially resulting in a clinically meaningful benefit in people with DMD amenable to exon 51 skipping and informed the design of CONNECT-EDO51 Phase 2, multiple-ascending dose studies. PepGen's enhanced delivery oligonucleotide (EDO) 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. In the mdx mouse model of DMD, a single intravenous (IV) dose of 30 or 60 mg/kg of mPGN EDO23 (mouse analogue of PGN-EDO51) resulted in exon skipping levels of 52.5% and 82.8% and dystrophin protein production of 22.5% and 51.7% in biceps. Pharmacological activity was detectable in biceps for up to 12 weeks after the single dose. Repeat dosing (30 mg/kg mPGN EDO23 once every 4 weeks for 4 doses) in mdx mice resulted in higher levels of exon skipping (91.5%) and dystrophin protein (82.3%) suggesting accumulation in biceps with repeat dosing. A single IV dose of PGN-EDO51 in non-human primates (NHP) resulted in dose-dependent exon 51 skipping (by RT-PCR and ddPCR) in biceps. Repeat dosing every 4 weeks resulted in dose-dependent accumulation of exon 51 skipping (by ddPCR) in biceps. Levels of exon 51 skipping (by ddPCR) in biceps observed after a single dose increased by 14-fold at 20 mg/kg and 3.4-fold at 30mg/kg with repeat dosing. Comparative pharmacology data show 5.9- to 12.9-fold higher levels of exon skipping in biceps following single IV doses of mPGN-EDO23 (mdx) and PGN-EDO51 (NHP) compared to comparator compounds PPMOs R6G-PMO23 (mdx) and R6G-PMO51 (NHP). Combined, the nonclinical studies show significant accumulation of exon skipping and dystrophin protein after repeat doses in the mdx mouse model and accumulation of exon skipping in NHPs. These data suggest repeat PGN-EDO51 dosing every 4 weeks may result in dystrophin accumulation potentially resulting in a clinically meaningful benefit in people with DMD amenable to exon 51 skipping and informed the design of CONNECT-EDO51 Phase 2, multiple-ascending dose studies.