Background: 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 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, HSALR mouse), and normalizes myotonia (HSALR mouse).
Objectives: To evaluate safety and tolerability (primary objective) and plasma pharmacokinetics (PK; secondary objective) following a single dose of PGN-EDODM1 in adults with DM1. Exploratory objectives include concentration of PGN-EDODM1 in skeletal muscle, pharmacodynamics (changes in splicing pattern of affected transcripts), PK in urine, as well as person-reported outcome (PRO) measures and functional assessments (including video hand opening time to assess myotonia).
Design/Methods: Adults with a genetically confirmed diagnosis of DM1 will be randomized 3:1 (6 PGN-EDODM1 and 2 placebo) in each dose cohort. A muscle needle biopsy will be performed at baseline, Week 4, and Week 16 for measurement of tissue drug concentrations and splicing of selected transcripts. Clinical assessments including PROs will be explored.
Results: The study design of FREEDOM-DM1 will be presented.
Conclusion: The Phase 1 study FREEDOM-DM1 will inform continued development of PGN-EDODM1 targeting the central cause of DM1.