Background: 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. The PGN-EDODM1 clinical development program includes FREEDOM-DM1, a randomized, double-blind placebo-controlled single ascending dose study and FREEDOM2-DM1, a randomized, double-blind placebo-controlled multiple ascending dose study (NCT06204809 and NCT06667453, respectively). Both studies have been approved by regulators and are ongoing.
Objective/methods: The primary objective of FREEDOM-DM1 is to evaluate safety and tolerability, and the secondary objective is measurement of plasma pharmacokinetics following a single dose of PGN-EDODM1. Exploratory measurements include concentration of PGN-EDODM1 in skeletal muscle, pharmacodynamics (changes in splicing pattern of affected transcripts), as well as patient-reported outcome (PRO) measures and functional assessments (including video hand opening time to assess myotonia and measures of muscle strength and function). Key eligibility criteria include genetic diagnosis of DM1, presence of myotonia, and age 18 to 50 years. This study consists of four 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. Participants in cohorts 1 and 2 have received single doses of study drug at 5 mg/kg or 10 mg/kg, respectively.
Results/Conclusion: Interim results from FREEDOM-DM1 will be presented.