PGN-EDO51: Preclinical Data Supporting the Development of an Enhanced Delivery Oligonucleotide (EDO) for the Treatment of Duchenne Muscular Dystrophy (DMD)
Ashling Holland1, Caroline Godfrey1, Pallavi Lonkar1, Niels Svenstrup1, Jane Larkindale1, James McArthur1, Sonia Bracegirdle1, Jaya Goyal1
1PepGen Inc.
Objective:
Pharmacological evaluation of mPGN-EDO23 (murine analogue of PGN-EDO51) was performed via assessment of serum biomarkers of muscle damage, exon skipping, and dystrophin production in mdx mice. Evaluation of PGN-EDO51 in non-human primates (NHPs) consisted of tissue distribution and measurement of exon skipping.
Background:
PepGen’s EDO cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO51 is being evaluated for the treatment of DMD amenable to exon 51 skipping.
Design/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, and 60 mg/kg) and repeat (10, 30, and 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 biodistribution was observed in NHPs. Repeat administration of 30 mg/kg PGN-EDO51 resulted in high levels of exon 51 skipping (78% in biceps, 73% in quadriceps, 76% in diaphragm, and 24% in heart). Exon skipping was higher with PGN-EDO51 than R6G-PMO51 (the most clinically advanced PPMO [peptide phosphorodiamidate morpholino oligomer] for exon 51 skipping) and the skipped transcript accumulated over time with repeat dosing. PGN-EDO51 was generally well tolerated 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.