PepGen Halts Duchenne Muscular Dystrophy Program After 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 company's lead asset, PGN-EDO51, failed to demonstrate significant clinical benefit, prompting a strategic shift towards other therapeutic areas.

Phase 2 Trial Results and Decision to Discontinue

The phase 2 CONNECT1-EDO51 study, which evaluated PepGen's exon 51-skipping oligonucleotide PGN-EDO51, showed limited efficacy in increasing dystrophin levels in DMD patients. In the 10 mg/kg cohort, dystrophin levels only reached 0.59% of normal levels in four patients, far below the threshold considered necessary for meaningful clinical benefit.

PepGen's community letter stated, "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. We do not believe we can dose at a high enough level to produce an amount of dystrophin that would provide genuine benefit to people with DMD."

As a result, PepGen will cease dosing all patients enrolled in the CONNECT1 trial and abandon its entire DMD pipeline, which included three additional assets beyond PGN-EDO51.

Safety Concerns and Regulatory Challenges

The decision to halt the DMD program follows a series of setbacks for PGN-EDO51. In December 2024, two patients in the 10 mg/kg cohort of CONNECT1 developed asymptomatic magnesium deficiency, leading to an FDA clinical hold on the CONNECT2 trial. Subsequently, PepGen voluntarily paused the U.K. arm of CONNECT2 in March 2025.

These safety concerns, coupled with the limited efficacy observed in the phase 2 trial, ultimately led to the company's decision to discontinue its DMD research efforts.

Strategic Shift to Myotonic Dystrophy 1

With the closure of its DMD program, PepGen will now 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 also faced challenges. The phase 1 FREEDOM-DM1 trial experienced a five-month FDA hold in 2023, reportedly due to dosing issues. Despite these setbacks, PepGen appears committed to advancing its DM1 pipeline as its primary focus moving forward.