Nonclinical Data Demonstrate the Potential of the Enhanced Delivery Oligonucleotide (EDO) PGN-EDO51 for the Treatment of Duchenne Muscular Dystrophy


Pre-Clinical Research

Poster Number: 242


Ashling Holland, PhD, PepGen, Godfrey Caroline, PhD, PepGen, Pallavi Lonkar, PhD, PepGen, Niels Svenstrup, PhD, Pepgen, Jane Larkindale, PhD, PepGen, James McArthur, PhD, Pepgen, Sonia Bracegirdle, PhD, PepGen, 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-EDO51 is being evaluated for the treatment of Duchenne Muscular Dystrophy (DMD) that is amenable to exon 51 skipping.
Objectives: Pharmacological evaluation of mPGN-EDO23 (murine analogue of PGN-EDO51) was performed in mdx mice. Pharmacological and pharmacokinetic evaluation of PGN-EDO51 in non-human primates (NHPs) consisted of tissue distribution and measurement of exon skipping.

Methods: A single dose of mPGN-EDO23 (0, 30, or 60 mg/kg) was administered intravenously (IV) to mdx mice. Creatine kinase, exon skipping, and dystrophin production were measured. In NHPs, biodistribution and exon skipping were measured following single (20, 40, 60 mg/kg) and repeat (10, 30, 60 mg/kg) IV administration of PGN-EDO51.

Results: Single doses of mPGN-EDO23 reduced levels of creatine kinase in a dose-dependent manner. mPGN-EDO23 induced 93.1%, 86.3%, 76.6%, and 62.3% exon skipping and resulted in the induction of 90.4%, 99.7%, 80.6%, and 25.7% of normal dystrophin levels in the biceps, quadriceps, diaphragm, and heart, respectively.

Following a single PGN-EDO51 dose, broad tissue biodistribution was observed in NHPs. Repeat administration of 30 mg/kg PGN-EDO51 resulted in high levels of exon 51 skipping (biceps: 78%; quadriceps: 73%; diaphragm: 76%; heart: 24%). The skipped transcript accumulated over time with repeat dosing. PGN-EDO51 had an acceptable safety profile at clinically relevant doses.

Conclusions: These data demonstrate that EDOs result in high levels of exon skipping (mPGN EDO23 and PGN-EDO51) and dystrophin production (mPGN-EDO23) and were well tolerated at clinically relevant doses. A Phase 2, multiple-ascending dose study in patients with DMD amenable to exon 51 skipping is planned for 2023.