PGN-EDO51: Preclinical Data Supporting the Development of an Enhanced Delivery Oligonucleotide (EDO) for the Treatment of Duchenne Muscular Dystrophy (DMD) (P3-8.002)

Abstract

<h3>Objective:</h3> 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 <i>mdx</i> mice. Evaluation of PGN-EDO51 in non-human primates (NHPs) consisted of tissue distribution and measurement of exon skipping. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> A single dose of mPGN-EDO23 (0, 30, or 60 mg/kg) was administered intravenously (IV) to <i>mdx</i> 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. <h3>Results:</h3> 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. <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Dr. Holland has received personal compensation for serving as an employee of PepGen Inc.. Dr. Holland has received intellectual property interests from a discovery or technology relating to health care. Caroline Godfrey has nothing to disclose. Pallavi Lonkar has nothing to disclose. Dr. Svenstrup has received personal compensation for serving as an employee of PepGen, Inc. Dr. Svenstrup has stock in PepGen, Inc. Dr. Larkindale has received personal compensation for serving as an employee of PepGen. Dr. McArthur has received personal compensation for serving as an employee of PepGen . Dr. McArthur has stock in PepGen . Dr. Bracegirdle has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for PepGen Inc. Dr. Goyal has received personal compensation for serving as an employee of Pepgen Inc.. Dr. Goyal has received personal compensation for serving as an employee of Wave Life Sciences. Dr. Goyal has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Pepgen Inc.. Dr. Goyal has stock in PepGen Inc..