FDA Places Clinical Hold on Phase 2 Study of PGN-EDO51 in Duchenne Muscular Dystrophy

Author(s):

As of July 2024, 2 participants in the ongoing CONNECT1 study have received 4 doses of PGN-EDO51 at 10 mg/kg, which has been generally well tolerated, with initial results expected in early 2025.

Paul Streck, MD, MBA

(Credit: PepGen)

According to a recent announcement, the FDA has placed a clinical hold on PepGen’s investigational new drug application for its phase 2 CONNECT2-EDO51 study, assessing PGN-EDO51 in patients with Duchenne muscular dystrophy (DMD), and will issue an official clinical hold letter within 30 days. The company noted that CONNECT2, a 25-week multinational, double-blind, placebo-controlled trial with multiple ascending doses, is currently open in the United Kingdom.

“We intend to work closely with the FDA to address their questions on our application to initiate CONNECT2 as expeditiously as possible,” Paul Streck, MD, MBA, head of R&D at PepGen, said in a statement.¹ “Our open-label CONNECT1-EDO51 multiple ascending dose study of PGN-EDO51 in boys and young men living with DMD continues as planned in Canada. We have completed enrollment of the 10 mg/kg dose cohort; all four patients in this cohort have received at least one dose.”

Earlier this year in July, PepGen reported data from the first dose cohort (5 mg/kg) of its ongoing phase 2 CONNECT1-EDO51 study (NCT06079736) evaluating PGN-EDO51 in patients DMD amendable to an exon 51 skipping therapy. In the trial, PGN-EDO51 showed higher levels of exon skipping and had a comparable, or higher, change from baseline in total dystrophin production and muscle-adjusted dystrophin production compared with reports from prior studies with other oligonucleotide therapies at similar PMO dose levels in patients with DMD.²

CONNECT1-EDO51 is an open-label study enrolling approximately 10 patients at least 8 years old with DMD amenable to an exon 51 skipping approach to investigate the safety and tolerability of PGN-EDO51. The trial will also assess oligonucleotide muscle concentrations, exon skipping and dystrophin protein production in muscle at week 12 following 4 monthly doses of PGN-EDO51. Following protocol, the starting dose for patients will increase from 5 mg/kg to 10 mg/kg and further escalation will be determined based on evaluation of safety data from prior cohorts.

In the 5 mg/kg starting dose cohort (n = 3), PGN-EDO51 revealed promising efficacy in exon 51 skipping and dystrophin production. At week 13, PGN-EDO51 produced a mean exon skipping level of 2.15% in biceps tissue, suggesting potentially greater potency compared with other receptor-mediated oligonucleotide delivery technologies at comparable dosing levels. Additionally, PGN-EDO51 achieved a mean muscle-adjusted dystrophin level of 1.49% of normal and a 0.70% change from baseline after 4 doses. Western blot analysis showed a mean absolute dystrophin level of 0.61% of normal and a 0.26% change from baseline, further supporting its efficacy in increasing dystrophin production.

As for safety data, the 5 mg/kg dose of PGN-EDO51 was well tolerated through week 13, with no discontinuations, dose interruptions, or dose reductions reported. Safety findings included only 1 treatment-related adverse event, which was mild and resolved. Importantly, there were no sustained elevations in kidney biomarkers, no cases of hypomagnesemia or hypokalemia, and no changes in electrolytes, hepatic function, anemia, or thrombocytopenia. All 3 participants have continued treatment with PGN-EDO51 at 5 mg/kg in the long-term extension (LTE) phase, where the therapy remains well tolerated as of July 29, 2024.

“People with DMD and their families constantly hope for effective therapies with the potential to change the course of this relentlessly progressive neuromuscular disease. I was pleased to see that the 5 mg/kg dose was well tolerated and that all three participants demonstrated an increase in dystrophin production and exon skipping after only three months of treatment with PGN-EDO51. I look forward to seeing the results of exon skipping and dystrophin production at 10 mg/kg in both CONNECT1 and CONNECT2,” Hugh McMillan, MD, MSc, pediatric neurologist at the Children’s Hospital of Eastern Ontario, and professor of pediatrics at the University of Ottawa, said in a statement.²

REFERENCES
1. PepGen Announces Clinical Hold in the U.S. on IND Application to Initiate CONNECT2-EDO51 Phase 2 Study of PGN-EDO51 for Duchenne Muscular Dystrophy. News Release. PepGen. Published December 16, 2024. Accessed December 17, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-clinical-hold-us-ind-application-initiate
2. PepGen Announces Positive Data from Low-Dose Cohort of PGN-EDO51 in Ongoing CONNECT1-EDO51 Phase 2 Clinical Trial for Treatment of Duchenne Muscular Dystrophy. News Release. PepGen. Published July 30, 2024. Accessed December 17, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-positive-data-low-dose-cohort-pgn-edo51-ongoing