PepGen Reports 46.5% Splicing Correction with PGN-EDODM1 in DM1 Trial

PepGen reported positive topline results on November 10, 2026, from the 10 mg/kg cohort of its Phase 2 FREEDOM2-DM1 study evaluating PGN-EDODM1 in patients with myotonic dystrophy type 1 (DM1). The investigational Enhanced Delivery Oligonucleotide (EDO) achieved mean muscle splicing correction of 46.5% at Week 13 following four monthly doses, which the company described as the highest reported in a multiple-dose DM1 study.

The molecular findings were accompanied by improvements in myotonia, hand grip strength and mobility. PGN-EDODM1 was generally well tolerated, with no serious or severe adverse events or dose-limiting toxicities reported.

PGN-EDODM1 Targets the Underlying Molecular Defect

PGN-EDODM1 uses PepGen’s proprietary cell-penetrating peptide technology to enhance cellular uptake and nuclear delivery of therapeutic oligonucleotides. It selectively binds expanded CUG repeats in pathogenic dystrophia myotonica protein kinase (DMPK) RNA, releasing MBNL1, a key regulator of RNA splicing, to restore normal splicing patterns.

Unlike approaches that degrade DMPK RNA, PGN-EDODM1 is designed to disrupt pathogenic RNA structures while preserving normal DMPK function. It has received Orphan Drug and Fast Track designations from the US Food and Drug Administration (FDA) and Orphan Designation from the European Medicines Agency (EMA). The candidate remains investigational.

FREEDOM2-DM1 Study Design

FREEDOM2-DM1 (NCT06667453) is a randomized, double-blind, placebo-controlled Phase 2 multiple ascending dose study. It enrolled three cohorts of eight participants each, randomized 3:1 to receive PGN-EDODM1 or placebo at 5, 10 or 12.5 mg/kg.

In the 10 mg/kg cohort, six participants received active treatment and two received placebo through four intravenous doses administered every four weeks. All eight completed the Week 16 assessment. The study is being conducted in Canada, the United Kingdom, New Zealand, Australia and South Korea, while a partial clinical hold remains in place in the United States.

Splicing Correction Accompanied by Functional Improvements

Mean splicing correction reached 46.5% at Week 13, measured using a 22-gene panel in muscle tissue. Five of six treated participants demonstrated greater than 20% correction, while four achieved more than 50%. The pooled placebo group from Cohorts 1 and 2 (n=4) showed mean correction of 6.8%.

Myotonia: Video Hand Opening Time (vHOT) improved by 4.3 seconds at Week 13 and 3.9 seconds at Week 16, representing approximately 52.7% improvement from baseline at Week 16, compared with 0.2 seconds in the placebo group. Dose-dependent correction of CLCN1 splicing was also observed. CLCN1 encodes a muscle chloride channel implicated in myotonia.

Muscle strength: Hand grip strength improved by approximately 16.2% at Week 16, corresponding to a 6.3-point improvement in maximum predicted percent normal from baseline, compared with 0.9 points in the placebo group.

Mobility: The Timed Up and Go assessment improved by 8.5% (0.6 seconds) at Week 16, while placebo recipients worsened by 0.5 seconds. The 10-Meter Walk/Run Test improved by 6.8% (0.4 seconds), compared with a 0.2-second improvement with placebo.

Patient-reported outcomes were inconclusive. The Patient Global Impression of Change showed a favorable directional trend, while Myotonic Dystrophy Health Index scores were mixed, partly reflecting improvements in placebo recipients and baseline differences.

Safety and Development Plans

PGN-EDODM1 was generally well tolerated at 10 mg/kg. All treatment-emergent adverse events were mild or moderate, with no serious or severe events, adverse events of special interest, dose-limiting toxicities or treatment discontinuations. Nausea was the most frequently reported event.

Four mild renal events were reported, including transient albuminuria after the first dose, which decreased with subsequent doses. No evidence of cumulative renal toxicity was observed during the 16-week assessment period.

The 12.5 mg/kg cohort is fully enrolled, with participants having received up to three doses. PepGen expects results in the first half of 2027. Interim 5 mg/kg clinical data and 10 mg/kg safety data from the FREEDOM-OLE extension study are expected in January 2027. The extension has exceeded 135 administered doses.

Clinical Interpretation

The 46.5% splicing correction demonstrates substantial molecular activity following repeated PGN-EDODM1 administration, accompanied by encouraging improvements in myotonia, strength and mobility. The CLCN1 findings provide a potential mechanistic link to improved myotonia. However, the small treated cohort, absence of reported statistical testing and confidence intervals, inconclusive patient-reported outcomes and 16-week observation period limit conclusions about clinical efficacy and durability. Longer-term extension data and results from the 12.5 mg/kg cohort will be important to establish sustained benefit and further characterize renal safety.

Reference

PepGen Announces Positive Phase 2 FREEDOM2-DM1 10 mg/kg Results Demonstrating Highest Reported Splicing Correction and Improvements Across Multiple Functional Measures, PepGen, 10 November 2026

A Clinical Study of PGN-EDODM1 in People with Myotonic Dystrophy Type 1 (FREEDOM2-DM1), ClinicalTrials.gov ID NCT06667453