PepGen Reports 46.5% Splicing Correction in 10 mg/kg Cohort

Key Facts

PepGen announced positive preliminary results on November 10 for the 10 mg/kg dose cohort in the Phase 2 FREEDOM2-DM1 study, after participants received four monthly doses of the experimental treatment. Mean muscle splicing correction was 46.5% at Week 13, measured across a panel of 22 genes. Five of 6 participants recorded improvement exceeding 20%, while improvement exceeded 50% in 4 participants. The study is evaluating candidate therapy PGN-EDODM1 in people with myotonic dystrophy type 1. The company said in August that data from this cohort were expected in November, following completion of enrollment.

On mobility measures, hand-opening time, a measure of muscle stiffness, improved by 3.9 seconds at Week 16, equivalent to an improvement of about 52.7% from baseline. In the placebo group, the same measure improved by 0.2 seconds. Hand-grip strength also increased by about 16.2% at Week 16. The stand-walk-return test improved by 8.5%, while the 10-meter walk or run test improved by 6.8%. These measures provide a picture of participants' performance on mobility and strength tests during the specified evaluation period.

Participant-reported outcomes, however, were inconclusive at Week 16, according to the company. Scores on the Myotonic Dystrophy Health Index were mixed, with improvement recorded in all groups, including the placebo group. The company said the Patient Global Impression of Change showed a positive trend for the 10 mg/kg cohort compared with placebo. These results differ from the functional measures covering hand opening, grip strength and walking tests. Investigator Hans Lochmüller said longer follow-up would be important to understand the durability and clinical significance of the results.

For comparison with the earlier cohort, PepGen announced results for the 5 mg/kg dose on March 30, with mean splicing correction of 7.3% among treated participants versus 6.8% in the placebo group. The company said the treatment group's mean rose to 22.9% when one outlier was excluded, based on 5 participants in the adjusted calculation. Those figures relate to the lower-dose cohort and the March announcement, while the 46.5% figure is for the 10 mg/kg cohort and the Week 13 measurement. The difference in reported results places the two cohorts at separate stages of dose escalation in the study. The 10 mg/kg cohort included 8 participants, 7 of whom had completed dosing by August 6.

PepGen said all treatment-emergent adverse events in the 10 mg/kg cohort were mild or moderate. The company reported no severe or serious adverse events, events of special interest or dose-limiting toxicities, and no participant withdrew because of treatment. An independent Data and Safety Monitoring Board had reviewed the available safety data from the completed 10 mg/kg cohort and the open-label extension study. Following its review, the board recommended proceeding to the third and highest dose cohort, at 12.5 mg/kg. The company announced in August that this stage of the study had begun.

The FREEDOM2 study comprises three cohorts, each with 8 participants, randomized at a 3-to-1 ratio between treatment and placebo. Planned doses are 5, 10 and 12.5 mg/kg in a multicenter, double-blind, placebo-controlled study. The study is being conducted in Canada, the United Kingdom, New Zealand, Australia and South Korea, and is under a partial clinical hold in the United States. PepGen said in March that the U.S. Food and Drug Administration had imposed the hold because of nonclinical findings in rats, and that it was working on additional studies to discuss the agency's questions. In October, the agency selected PGN-EDODM1 for a pilot program that provides enhanced regulatory interaction on manufacturing and quality development.

The next clinical milestone identified by the company is results from the 12.5 mg/kg cohort, which had completed enrollment and whose participants had received up to 3 doses when the November 10 results were announced. PepGen expects clinical results for this cohort in the first half of 2027. It also said it expects to publish interim clinical data at the 5 mg/kg dose and safety data at the 10 mg/kg dose from the open-label extension study in January 2027. In an earlier announcement, the company had expected to provide an update on the open-label extension study by early January. Lochmüller said longer follow-up is needed to understand how long the results persist and their clinical relevance.