PepGen reports Phase 2 FREEDOM2 data showing favorable safety and early splicing correction signals with PGN-EDODM1 in patients with myotonic dystrophy type 1
Written By: Mahathi Palivela, PharmD
Reviewed By: Pharmacally Editorial Team
PepGen has announced topline results from the lowest-dose cohort (5 mg/kg) in its ongoing Phase 2 FREEDOM2 trial, highlighting promising safety and early efficacy signals for its investigational therapy PGN-EDODM1 in patients with myotonic dystrophy type 1 (DM1).
The multiple ascending dose (MAD), randomized, placebo-controlled cohort (n=8; 6 treated, 2 placebo) demonstrated a favorable safety and tolerability profile, with no serious adverse events or treatment discontinuations reported and no dose-limiting toxicities observed. All treatment-emergent adverse events were mild, with nausea being the most common, and no renal toxicity or signs of cumulative toxicity were identified. These findings are particularly important given the chronic nature of DM1 and the need for therapies suitable for long-term use.
In addition to safety, the study showed encouraging biological activity. Patients receiving the 5 mg/kg dose exhibited a mean splicing correction of 7.3% compared to 6.8% in placebo-treated patients. Excluding a single outlier, splicing correction reached 22.9%, suggesting a stronger pharmacodynamic effect across most treated individuals. These findings indicate that PGN-EDODM1 is engaging its intended target and may be addressing the underlying molecular defect of DM1.
Further supporting these results, patients demonstrated a positive trend in middle finger video hand opening time (vHOT), while placebo patients showed worsening over the same period, although both groups returned to baseline by Week 16. Improvements in variant of high clinical interest transcripts (vHOT) reinforce the alignment between molecular activity and potential functional benefit. However, no meaningful changes were observed in 10-meter walk/run test or handgrip strength at this dose level.
Pharmacokinetic data showed mean muscle tissue concentrations of PGN-EDODM1 at 158 ng/g (n=5) measured approximately one week after the fourth dose, confirming drug delivery to target tissue.
PGN-EDODM1 is designed to bind pathogenic CUG repeat expansions in DMPK transcripts and release sequestered MBNL1 protein, restoring normal RNA splicing without degrading the transcript. This mechanism aims to preserve normal cellular function while correcting downstream mis-splicing events.
The FREEDOM2 study is evaluating PGN-EDODM1 across escalating dose levels up to 12.5 mg/kg.
Paul Streck, MD, EVP Research and Development, said, “Overall, we are encouraged by the favorable safety and tolerability profile, and the positive trends exhibited with splicing improvement and vHOT.”
The current safety and splicing findings follow an earlier regulatory update in which the U.S. Food and Drug Administration placed a partial clinical hold on the FREEDOM2-DM1 trial on March 4, 2026, citing concerns from preclinical pharmacology and toxicology studies. Against this backdrop, the emerging 5 mg/kg data provide important clinical context, suggesting a favorable safety profile and early biological activity at the evaluated dose, while discussions with the FDA on dose escalation and further development remain ongoing.
PepGen also noted that enrollment in the 10 mg/kg cohort is ongoing, with more than half of patients already dosed and data expected in the second half of 2026. In parallel, 12 patients have enrolled in the open-label extension study at the 5 mg/kg dose.
The topline data from the 5 mg/kg cohort underscore the potential of PepGen’s platform to deliver targeted therapies with a balance of safety, tissue exposure, and early biological activity supporting continued dose escalation and further clinical development in DM1.
References
PepGen Announces Topline Results from Lowest Dose (5 mg/kg) MAD Cohort in the Ongoing Phase 2 FREEDOM2 Study Demonstrating Favorable Safety, Splicing and vHOT Data, 30 March 2026, PepGen Announces Topline Results from Lowest Dose (5 mg/kg) MAD Cohort in the Ongoing Phase 2 FREEDOM2 Study Demonstrating Favorable Safety, Splicing and vHOT Data | PepGen
About the Writer
Mahathi Palivela is pursuing a PharmD and has a strong interest in clinical pharmacy and patient safety. She is passionate about handling and analyzing patient data, and translating clinical insights into clear, meaningful summaries. She aims to apply this interest in medical writing and pharmacovigilance, focusing on improving patient outcomes through careful data interpretation and communication