PGN-EDODM1 Nonclinical Data Demonstrate Potential for Meaningful Impact in Myotonic Dystrophy Type 1 (DM1): Support for Phase 1 Clinical Trial Design


Translational Research

Poster Number: 306


Jane Larkindale, PhD, PepGen, Ashling Holland, PhD, PepGen, Arnaud Klein, PhD, Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France, Godfrey Caroline, PhD, PepGen, Niels Svenstrup, PhD, Pepgen, Sonia Bracegirdle, PhD, PepGen, Denis Furling, PhD, Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France, Pallavi Lonkar, PhD, PepGen, Jeff Foy, PhD, PepGen, James McArthur, PhD, Pepgen, Jennifer Cormier, Pepgen, Holly Hand, BA, PepGen, Michelle Mellion, MD, PepGen Inc, Jaya Goyal, PhD, PepGen

Background: PepGen’s EDO cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. Delivery of oligonucleotides to affected tissues is a major challenge that limits their efficacy. PGN-EDODM1 is being evaluated for the treatment of DM1. PGN-EDODM1 binds to the pathogenic trinucleotide repeat expansion in myotonic dystrophy protein kinase (Dmpk) mRNA and reduces sequestration of Muscleblind (MBNL) proteins within nuclear RNA foci through a steric blocking mechanism. Release of MBNL proteins is hypothesized to correct DM1 spliceopathy; a central cause of DM1.

Objectives: A nonclinical dataset, including in vitro and in vivo pharmacology studies, to support initiation of clinical studies of PGN-EDODM1.
Methods: In vitro studies: DM1 donor cells with 2,600 CTG repeats were treated with PGN EDODM1, and nuclear RNA foci profiles and splicing events were evaluated after 24 hours. In vivo studies: PGN-EDODM1 was administered intravenously to wildtype mice and DM1 mouse model HSALR (containing 250 CTG repeats in the HSA gene), and splicing events and myotonia were measured.

Results: PGN-EDODM1 administration resulted in a dose-dependent reduction in toxic RNA foci and correction of mis-splicing in cells. In the HSALR model, a single dose resulted in high muscle concentrations of PGN-EDODM1, dose-dependent correction of mis-splicing persisting over 24 weeks, and resolution of myotonia.

Conclusions: There are no approved therapies for DM1. PGN-EDODM1 shows considerable therapeutic potential. Nonclinical results support a Phase 1 single-ascending dose study (with an open-label extension) in adults with DM1 and will be initiated in 2023. Details of the clinical trial design will be presented.