FDA Pauses PepGen’s DMD Drug Trial in the US

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Key Takeaways

The FDA placed a clinical hold on PGN-EDO51's phase 2 trial.
PGN-EDO51 targets exon 51 skipping in the dystrophin gene, showing promising results in earlier trials.
Ongoing studies outside the US, including in the UK and Canada, remain unaffected by the clinical hold.
PepGen previously faced a similar regulatory hold for PGN-EDODM1, which was lifted after safety data reviews and protocol adjustments.

The CONNECT2-EDO51 phase 2 trial looks at PGN-EDO51, an investigational therapy for Duchenne muscular dystrophy (DMD), and is still ongoing in the United Kingdom.

The FDA has issued a clinical hold notice on PepGen’s phase 2 trial for PGN-EDO51, an investigational treatment for Duchenne muscular dystrophy (DMD), delaying its US launch.¹

The therapy was being evaluated in ascending doses in the 25-week, multinational, double-blind, placebo-controlled CONNECT2-EDO51 trial. According to a PepGen news release, the decision was tied to questions arising during the regulatory review and does not impact ongoing studies outside the US, such as the mid-stage trial in the United Kingdom and the open-label CONNECT1-EDO51 trial enrolling in Canada.

Gene therapy | Image credit: Treecha – stock.adobe.com

PepGen expected to open the phase 2 CONNECT2-EDO51 trial in the US by end of year. | Image credit: Treecha – stock.adobe.com

PepGen did not mention a specific reason for the decision; the FDA is expected to issue an official clinical hold letter to the company within 30 days of the notice.

“We intend to work closely with the FDA to address their questions on our application to initiate CONNECT2 as expeditiously as possible,” said Paul Streck, MD, MBA, executive vice president and head of research and development at PepGen.

PGN-EDO51 is an investigational therapy that has not been approved for use in the US or any other country, though it was previously granted Orphan Drug and Rare Pediatric Disease designations, reflecting the unmet need in this patient population. The therapy is designed to skip exon 51 of the dystrophin gene, which is mutated in approximately 13% of patients with DMD.

Earlier this year, PepGen shared results from the first dose cohort (5 mg/kg) of the ongoing phase 2 CONNECT1-EDO51 study.² The data revealed that PGN-EDO51 achieved greater levels of exon skipping and showed comparable or higher increases in total and muscle-adjusted dystrophin production compared with outcomes from earlier studies of other oligonucleotide therapies at similar PMO dose levels.

PepGen had expected to open the phase 2 CONNECT2-EDO51 trial in the US by the end of 2024 subject to regulatory approval, according to the company’s third quarter earnings report.³

This clinical hold marks a familiar challenge for PepGen. In May 2023, the company’s phase 1 trial of PGN-EDODM1 for myotonic dystrophy type 1 also faced a US regulatory hold. The FDA ultimately lifted that hold in October 2023 following safety data reviews and protocol adjustments, allowing the study to proceed 2 months later.⁴

DMD is a rare genetic disorder that causes progressive muscle degeneration and weakness, affecting roughly 1 in 3600 male births worldwide.⁵ Over time, the condition leads to loss of mobility, respiratory complications, and heart issues. While there is no cure, treatments like physical therapy, medications, and emerging therapies aim to slow progression and improve quality of life. Newer therapies like PGN-EDO51 that target exon skipping are considered promising pathways to slow disease progression by restoring partial dystrophin function.

References

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. December 16, 2024. Accessed December 18, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-clinical-hold-us-ind-application-initiate
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. July 30, 2024. Accessed December 18, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-positive-data-low-dose-cohort-pgn-edo51-ongoing
PepGen reports third quarter 2024 financial results and recent corporate highlights. News release. PepGen. November 7, 2024. Accessed December 18, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-reports-third-quarter-2024-financial-results-and-recent
PepGen Inc. Announces FDA has lifted the clinical hold on its investigational new drug application for FREEDOM-DM1 Phase 1 Study of PGN-EDODM1 for myotonic dystrophy type 1 (DM1). News release. PepGen. October 12, 2023. Accessed December 18, 2024. https://investors.pepgen.com/news-releases/news-release-details/pepgen-inc-announces-fda-has-lifted-clinical-hold-its
Duchenne muscular dystrophy (DMD). Cleveland Clinic. Updated July 25, 2022. Accessed December 18, 2024. https://my.clevelandclinic.org/health/diseases/23538-duchenne-muscular-dystrophy-dmd