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.

included serum chemistries (alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, bilirubin) and dystrophin expression (western blot [WB], immunofluorescence [IF]).No treatment-related adverse events were observed, including abnormal histopathology.WB/IF evaluation showed that dystrophin expression and localization at the sarcolemma were not adversely impacted by sequential treatment.These preclinical results support the safety of sequential administration and dystrophin expression consistent with individual treatment, suggesting that patients may be able to receive continuous exonskipping therapy prior to GT.

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.