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.