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-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 binds to pathogenic CUG trinucleotide repeat expansions in DMPK mRNA, thereby liberating MBNL1 protein through steric blocking without degrading DMPK transcripts. Liberation of sequestered MBNL1 is hypothesized to restore splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology. Nonclinical data demonstrate that PGN-EDODM1 reduces the number of myonuclear foci (DM1 cells), liberates MBNL1 (DM1 cells), corrects mis-splicing (DM1 cells, HSA-LR mouse), and normalizes myotonia (HSA-LR mouse). FREEDOM-DM1, a randomized, double-blind placebo-controlled single ascending dose study is underway (NCT06204809). The objective of the study is to evaluate safety and tolerability (primary objective) and plasma pharmacokinetics (secondary objective) following a single dose of PGN-EDODM1 in adults with DM1. Exploratory measurements include concentration of PGN-EDODM1 in skeletal muscle, pharmacodynamics (changes in splicing pattern of affected transcripts), as well as person-reported outcome (PRO) measures and functional assessments (including video hand opening time to assess myotonia). This study consists of three dose-ascending cohorts of participants (N=8), each randomized 3:1 investigational drug to placebo. A muscle needle biopsy will be performed at Baseline, Week 4, and Week 16 to measure tissue drug concentrations and evaluate splicing of selected transcripts. The design of this study and the subsequent FREEDOM2-DM1 multiple ascending dose study will be presented. The FREEDOM-DM1 and FREEDOM2-DM1 studies are designed to support and advance the clinical development of PGN-EDODM1.

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.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 binds to toxic CUG repeat expansion (CUGexp) in DMPK mRNA and acts to liberate sequestered MBNL1 protein without degrading DMPK transcript. Release of MBNL1 protein is hypothesized to restore the splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology. Men and women, 18-50 years of age, inclusive, with genetically confirmed diagnosis of DM1 will be randomized 3:1 (6 active, 2 placebo) to receive PGN EDODM1 or placebo in each dose cohort. The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1. Secondary and exploratory objectives include pharmacokinetics (PK), concentration of PGN-EDODM1 in skeletal muscle, and pharmacodynamics (changes in splicing pattern of affected transcripts). A muscle needle biopsy (tibialis anterior) will be performed at baseline and at Weeks 4 and 16 post-dosing for measurement of tissue drug concentrations and splicing of selected transcripts. Exploratory measures such as video hand opening time to assess myotonia and functional measures will be included to inform future studies. This Phase 1 SAD clinical study will support continued development of PGN-EDODM1 for the treatment of the root cause of DM1. PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 binds to toxic CUG repeat expansion (CUGexp) in DMPK mRNA and acts to liberate sequestered MBNL1 protein without degrading DMPK transcript. Release of MBNL1 protein is hypothesized to restore the splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology. Men and women, 18-50 years of age, inclusive, with genetically confirmed diagnosis of DM1 will be randomized 3:1 (6 active, 2 placebo) to receive PGN EDODM1 or placebo in each dose cohort. The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1. Secondary and exploratory objectives include pharmacokinetics (PK), concentration of PGN-EDODM1 in skeletal muscle, and pharmacodynamics (changes in splicing pattern of affected transcripts). A muscle needle biopsy (tibialis anterior) will be performed at baseline and at Weeks 4 and 16 post-dosing for measurement of tissue drug concentrations and splicing of selected transcripts. Exploratory measures such as video hand opening time to assess myotonia and functional measures will be included to inform future studies. This Phase 1 SAD clinical study will support continued development of PGN-EDODM1 for the treatment of the root cause of DM1.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides.PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1).PGN-EDODM1 binds to toxic CUG repeat expansion (CUGexp) in DMPK mRNA and acts to liberate sequestered MBNL1 protein without degrading DMPK transcript.Liberation of MBNL1 is hypothesized to restore splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology.PGN-EDODM1 pharmacology was characterized using human immortalized myoblasts and the HSALR transgenic mouse model of DM1, and nonhuman primates (NHPs) were used to evaluate DMPK levels.Control and DM1 myoblasts ( ∼2600 CTGexp) were differentiated and treated with PGN EDODM1, which resulted in dose-dependent reduction in pathogenic myonuclear foci, liberation of MBNL1 from foci, and correction of mis-splicing in DM1 cells, while DMPK levels remained unchanged.Single intravenous (IV) dose of PGN-EDODM1 or control administered to HSALR mice resulted in high muscle concentrations of PGN-EDODM1, resolution of myotonia, dose-dependent correction of mis-splicing, and no significant impact on HSA expression when evaluated 2-weeks postdose.Splicing correction in HSALR mice persisted up to 24 weeks.Additional data from a repeat-dose study in HSALR mice with low PGN EDODM1 doses will be presented.Repeat IV doses of PGN-EDODM1 or control administered to NHPs every 2 weeks (10, 30, or 60mg/kg) or every 4 weeks (60mg/kg) did not result in decreases in DMPK transcript levels when evaluated 1 week after the final dose.Currently, there are no approved therapies for DM1.Nonclinical pharmacology studies with PGN-EDODM1 showed considerable therapeutic potential.Nonclinical data support the Phase 1 single-ascending dose study in adults with DM1.

Delandistrogene moxeparvovec (SRP-9001) is an investigational rAAV vectorbased gene therapy, designed to compensate for missing functional dystrophin in Duchenne muscular dystrophy (DMD) by delivering a transgene encoding SRP-9001 dystrophin, an engineered dystrophin protein that retains key functional domains of the wild-type protein.Drawing on delandistrogene moxeparvovec clinical trial experience (Study 101 [SRP-9001-101; NCT03375164], Study 102 [SRP-9001-102; NCT03769116], and ENDEAVOR [Study 103; NCT04626674]), we outline several practical considerations for delandistrogene moxeparvovec administration in patients with DMD, including the observed time course of events, monitoring for and management of adverse events, and mitigation strategies.Considerations for initiating delandistrogene moxeparvovec treatment in patients with DMD include: (1) screening for elevated levels of anti-rAAVrh74 total binding antibodies before infusion; (2) assessing liver function, platelet count, and troponin I levels before administration; (3) monitoring liver function weekly (first 3 months post-infusion) and, if indicated, continuing monitoring until results are unremarkable; (4) postponing administration for patients with acute liver disease until disease control/resolution; (5) monitoring troponin I levels weekly (first month post-infusion), and continuing monitoring if indicated; and (6) administering corticosteroids starting 1 day prior to infusion (for patients already on corticosteroids), and maintaining the corticosteroid regimen for at least 60 days post-infusion, unless earlier tapering is indicated.Though the safety profile of delandistrogene moxeparvovec to date has been relatively consistent, monitorable, and manageable, clinical trial experience has led to important learnings and practical considerations that may mitigate the risk of adverse events following administration of delandistrogene moxeparvovec.