Abstract Details

Title PGN-EDO51, an Enhanced Delivery Oligonucleotide (EDO) for the Treatment of Duchenne Muscular Dystrophy (DMD): Results of a Phase 1 Study in Healthy Volunteers

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-004

Objective Evaluate the safety, tolerability, pharmacokinetics (plasma and muscle), and pharmacodynamics (exon skipping) of single-ascending doses of PGN-EDO51 administered intravenously (IV) to healthy male volunteers (HV).

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 Thirty-two HVs (18-55 years of age) were randomized 3:1 to receive a single dose of PGN-EDO51 (1, 5, 10, or 15 mg/kg) or placebo (n=8 per cohort). Biceps needle biopsies were performed on Days 10 and 28.

Results All HVs completed the study. The majority of treatment-related adverse events were mild and resolved without intervention, including transient, reversible changes in kidney biomarkers (n=9) and hypomagnesemia (n=2) at the highest doses; with no significant clinical sequelae. At 15 mg/kg, one HV received IV hydration after increases in kidney biomarkers with complete resolution. At Days 10 and 28, respectively, there were dose-dependent and sustained concentrations of PGN-EDO51 measured in biceps biopsies: 9.7nM and 3.8nM (5 mg/kg); 19nM and 11nM (10 mg/kg); and 50nM (both days) at 15 mg/kg; and dose-dependent increases in mean exon skipping of 0.14% and 0.35% (5 mg/kg); 1.1% and 1.4% (10 mg/kg); and 1.4% and 2.0% (15 mg/kg).

Conclusions The Phase 1 study results demonstrate that PGN-EDO51 has a generally tolerable profile at clinically relevant doses. PGN-EDO51 exhibited high levels of muscle oligonucleotide delivery and exon 51 skipping following a single dose. Oligonucleotide concentrations and levels of exon skipped transcripts in muscle at Day 28 indicate the potential accumulation of exon 51 skipped transcripts and dystrophin protein with repeat dosing in people with DMD amenable to exon 51 skipping. Based on these results, a Phase 2a, multiple-ascending dose study in people with DMD will be initiated in the first half of 2023.

Authors/Disclosures
Michelle L. Mellion, MD PRESENTER	Dr. Mellion has received personal compensation for serving as an employee of PepGen. Dr. Mellion has stock in PepGen.
Jane Larkindale, PhD (Muscular Dystrophy Association)	Dr. Larkindale has received personal compensation for serving as an employee of PepGen.
	No disclosure on file
	No disclosure on file
Ashling Holland, PhD (PepGen)	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.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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