PepGen advances PGN-EDODM1 into the highest-dose Phase 2 FREEDOM2-DM1 cohort after a positive DSMB review. No serious safety concerns were reported.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
PepGen has announced that an independent Data and Safety Monitoring Board (DSMB) has recommended advancing its Phase 2 FREEDOM2-DM1 study (NCT06667453) into the third and highest multiple ascending dose (MAD) cohort, 12.5 mg/kg, with no changes recommended to the study protocol. The trial is evaluating PGN-EDODM1, an investigational oligonucleotide therapy, in participants with myotonic dystrophy type 1 (DM1). The DSMB also recommended escalating the dose in the ongoing open-label extension study, FREEDOM-OLE (NCT07220603), from 5 mg/kg to 10 mg/kg.
Trial Background
PGN-EDODM1 was first evaluated in FREEDOM-DM1 (NCT06204809), a Phase 1 single ascending dose study that established early safety and pharmacodynamic data supporting the current Phase 2 program. FREEDOM2-DM1 builds on those findings as a randomized, double-blind, placebo-controlled, multiple ascending dose study enrolling approximately 24 participants with DM1. Participants who complete a PGN-EDODM1 study are eligible to continue into FREEDOM-OLE, which is tracking long-term safety and pharmacokinetics.
Enrolment and Dosing Progress
The DSMB’s latest recommendation followed a review of available safety data from the fully enrolled 10 mg/kg MAD cohort in FREEDOM2-DM1 and from the OLE study. Seven of eight participants in the 10 mg/kg cohort have now completed dosing. Separately, six of eight participants from the earlier 5 mg/kg FREEDOM2 cohort have chosen to roll over into FREEDOM-OLE, bringing total enrolment in the extension study to 16 participants.
Safety Observations
Across both studies, PGN-EDODM1 has continued to be generally well tolerated. PepGen reported no serious adverse events, no dose-limiting toxicities, no treatment discontinuations, and no evidence of cumulative toxicity in either FREEDOM2-DM1 or FREEDOM-OLE to date. Repeat dosing at both the 5 mg/kg and 10 mg/kg dose levels has shown no evidence of cumulative toxicity, further supporting the favorable safety profile observed following multiple months of treatment.
Expected Clinical Readouts
PepGen expects to report data from the fully enrolled 10 mg/kg FREEDOM2-DM1 cohort in November 2026, including additional safety, RNA splicing, and functional outcome data. Results from the new 12.5 mg/kg cohort are anticipated in the first half of 2027 and are expected to support an end-of-Phase 2 meeting with regulators to discuss the registrational development program. An update from the FREEDOM-OLE study is expected by early January 2027.
Executive Perspective
James McArthur, PhD, President and CEO of PepGen, said the DSMB’s decision to advance the study into its highest planned dose level and increase dosing in the OLE reinforces the encouraging tolerability profile observed to date. He noted that seven of eight participants in the 10 mg/kg FREEDOM2 cohort have completed dosing and that the company looks forward to reporting additional safety, RNA splicing, and functional data as development of PGN-EDODM1 continues.
About PGN-EDODM1
PGN-EDODM1 is built on PepGen’s proprietary Enhanced Delivery Oligonucleotide (EDO) platform, which uses cell-penetrating peptides to improve tissue and nuclear uptake of oligonucleotide therapeutics. The candidate is designed to bind the pathogenic CUG trinucleotide repeat expansion within DMPK transcripts, disrupting its interaction with the RNA-binding protein MBNL1 and allowing normal RNA splicing to resume. Unlike therapeutic approaches that rely on degradation or knockdown of DMPK transcripts, PGN-EDODM1 is designed to preserve the normal cellular function of DMPK while restoring MBNL1 activity and correcting downstream mis-splicing events associated with DM1.
The U.S. Food and Drug Administration (FDA) has granted PGN-EDODM1 both Orphan Drug and Fast Track Designations for the treatment of DM1, while the European Medicines Agency (EMA) has recently granted the therapy Orphan Designation.
What This Means for Patients
DM1 is a progressive genetic disorder with no approved therapies that directly address its underlying molecular cause. The DSMB’s recommendation to progress to the highest planned dose cohort, together with the encouraging safety profile observed after multiple months of repeat dosing, represents an important development for PGN-EDODM1. However, confirmation of the therapy’s clinical potential will depend on the forthcoming safety, RNA splicing, and functional outcome data expected later this year and in 2027.
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About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.