PepGen Reports Positive Results from Low-Dose PGN-EDO51 in Phase 2 Duchenne Muscular Dystrophy Trial

PepGen Inc., a biotechnology company focused on developing advanced oligonucleotide therapies, has shared promising clinical results for their lead investigational candidate, PGN-EDO51. This therapy is aimed at treating Duchenne muscular dystrophy (DMD) in patients with mutations amenable to an exon 51-skipping approach. In the CONNECT1-EDO51 Phase 2 open-label trial, PGN-EDO51 at a 5 mg/kg dose showed significant improvements in exon skipping and dystrophin production compared to other therapies.

The trial, which included a cohort of three patients, revealed that the 5 mg/kg dose of PGN-EDO51 was well tolerated over a 13-week period, with no discontinuations or dose interruptions. After three months of treatment, the data showed a mean exon skipping level of 2.15% and a mean muscle-adjusted dystrophin level of 1.49%, representing a 0.70% increase from baseline. Additionally, the mean absolute dystrophin level increased by 0.26% to 0.61%. Impressively, all patients continued into the long-term extension portion of the trial.

James McArthur, Ph.D., President and CEO of PepGen, expressed optimism about these early results, emphasizing the higher levels of exon skipped transcript achieved at lower doses compared to other exon 51 therapies. McArthur highlighted the favorable safety profile of PGN-EDO51 and the ongoing evaluation of a second cohort at a 10 mg/kg dose, aiming for further improvements in dystrophin production.

Dr. Hugh McMillan, a Pediatric Neurologist at the Children’s Hospital of Eastern Ontario and lead investigator for the CONNECT1 trial, also commented positively on the findings. He noted the well-tolerated nature of the 5 mg/kg dose and the observed increase in dystrophin production in all participants, which holds promise for the higher dose trials.

As of late July 2024, the second cohort at the 10 mg/kg dose level included two participants who had received four doses each. Preliminary data suggested that this higher dose was also generally well tolerated. PepGen plans to release initial results from this cohort in early 2025.

In anticipation of these findings, PepGen is optimizing the design of their CONNECT2 Phase 2 double-blind, placebo-controlled multinational trial, set to evaluate PGN-EDO51 over 25 weeks. This trial aims to further investigate the therapy's safety, dystrophin production, exon skipping, and impacts on clinical measures like mobility, pulmonary function, and quality of life. The CONNECT2 trial is currently open in the United Kingdom, with plans to expand to the United States and engage with regulators in the European Union.

PGN-EDO51 leverages PepGen's proprietary Enhanced Delivery Oligonucleotide (EDO) technology, which uses cell-penetrating peptides to improve oligonucleotide delivery to muscle tissue nuclei. This approach aims to restore the reading frame of the dystrophin gene, enabling the production of a functional dystrophin protein. The U.S. Food and Drug Administration has designated PGN-EDO51 as both an Orphan Drug and a Rare Pediatric Disease treatment, underscoring its potential impact on DMD.

DMD, a debilitating and fatal muscle-wasting disease predominantly affecting males, results from mutations in the dystrophin gene. Despite advances in treatment, current therapies have limited efficacy in delivering therapeutic agents to muscle nuclei. PepGen's innovative approach seeks to overcome these limitations and provide a meaningful clinical benefit to patients with this challenging condition.

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