Months after causing safety concerns that led the FDA to hit a related trial with a clinical hold, a phase 2 trial of PepGen’s lead Duchenne muscular dystrophy (DMD) candidate has resulted in limited evidence for any clinical benefit, prompting the Boston biotech to scrap the asset and end all DMD R&D activities.
In the phase 2 Connect1-EDO51 study, PepGen’s exon 51-skipping oligonucleotide PGN-EDO51 only increased dystrophin levels to 0.59% of normal levels in four patients in the 10-mg/kg cohort, PepGen announced in a May 28 release.
“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 said in a May 28 community letter (PDF). “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.”
PepGen will stop dosing all patients enrolled in Connect1, the company said in the letter. The biotech will instead prioritize its candidate for myotonic dystrophy 1 (DM1), PGN-EDODM1, according to the release. PGN-EDODM1 is currently in a pair of trials, one phase 1 and the other phase 2.
Connect1 in total enrolled seven boys between the ages of 6 and 16. After a 45-day screening period, patients received multiple ascending doses of PGN-EDO51 every four weeks for 16 weeks up to either 5 mg/kg or 10 mg/kg. Patients that completed the ascending doses then entered a long-term extension period that was meant to last 108 weeks, until around April 2027.
PGN-EDO51 first caused trouble last December, when two patients in Connect1’s 10-mg/kg cohort developed asymptomatic magnesium deficiency. This prompted the FDA to put a second trial of the asset, Connect2, on hold, with PepGen later voluntarily pausing the U.K. arm of Connect2 in March 2025.
Along with PGN-EDO51, PepGen’s DMD pipeline—now set to run dry—included three other assets, according to a snapshot of the company’s website archived June 22, 2024.
PepGen’s DM1 program, now the biotech’s primary focus, also has a bumpy history. The phase 1 Freedom-DM1 trial was itself hit with a five-month FDA hold in 2023, seemingly due to issues with dosing.