PepGen Halts Duchenne Muscular Dystrophy Program Following Phase 2 Trial Disappointment

PepGen, a Boston-based biotech company, has announced the termination of its Duchenne muscular dystrophy (DMD) research and development activities following disappointing results from a phase 2 clinical trial. The decision marks a significant setback in the pursuit of effective treatments for this debilitating genetic disorder.

Phase 2 Trial Results Fall Short of Expectations

The CONNECT1-EDO51 study, which evaluated PepGen's lead DMD candidate PGN-EDO51, failed to demonstrate meaningful clinical benefit. The exon 51-skipping oligonucleotide increased dystrophin levels to only 0.59% of normal levels in four patients treated with the 10 mg/kg dose. This outcome fell far short of the threshold believed necessary to provide substantial improvement for DMD patients.

"Unfortunately, we believe that the amount of dystrophin produced by people in the trial is not enough to provide meaningful benefit to people with DMD," PepGen stated in a community letter. The company concluded that it would be unable to administer a sufficiently high dose to produce clinically significant levels of dystrophin.

Safety Concerns and Regulatory Hurdles

PGN-EDO51's development had already faced challenges prior to the phase 2 results. In December, two patients in the 10 mg/kg cohort developed asymptomatic magnesium deficiency, prompting the FDA to place a clinical hold on a related trial, CONNECT2. PepGen subsequently paused the UK arm of CONNECT2 in March 2025.

These safety concerns, coupled with the limited efficacy observed in the phase 2 trial, ultimately led to the decision to discontinue all DMD-related research activities. PepGen will cease dosing patients enrolled in the CONNECT1 trial and withdraw from the DMD therapeutic landscape entirely.

Strategic Pivot to Myotonic Dystrophy 1

In light of the DMD program's termination, PepGen has announced a strategic shift to prioritize its candidate for myotonic dystrophy 1 (DM1), PGN-EDODM1. This asset is currently being evaluated in two clinical trials: a phase 1 study and a phase 2 study.

However, the DM1 program has not been without its own challenges. The phase 1 FREEDOM-DM1 trial experienced a five-month FDA hold in 2023, reportedly due to dosing-related issues. Despite these setbacks, PepGen appears committed to advancing its DM1 pipeline as its primary focus moving forward.