PepGen Announces Positive Results from FREEDOM-DM1 Trial in DM1 Patients
PepGen Inc. (Nasdaq: PEPG), a clinical-stage biotechnology company focused on advancing next-generation oligonucleotide therapies, recently announced promising early results from the ongoing FREEDOM-DM1 Phase 1 trial. The trial is investigating PGN-EDODM1, a novel treatment for myotonic dystrophy type 1 (DM1), a severe neuromuscular disorder. These initial data from the 5 mg/kg and 10 mg/kg dose cohorts suggest that PGN-EDODM1 has the potential to correct splicing defects, a key underlying cause of DM1 pathology, showing significant promise as a therapeutic option for patients suffering from this challenging disease.
James McArthur, PhD, President and CEO of PepGen, expressed his optimism, stating, “These results far exceeded our expectations for splicing correction following a single dose of PGN-EDODM1. Mis-splicing is central to DM1 pathology, and we believe the observed mean splicing correction at 28 days after a single dose of PGN-EDODM1 at 10 mg/kg in the FREEDOM clinical trial surpasses those reported to date in multi-dose clinical trials of up to nine months in duration in DM1 patients. We believe this strong splicing correction is a powerful indicator of our Enhanced Delivery Oligonucleotide (EDO) technology’s ability to effectively deliver therapeutic oligonucleotides to the nucleus, addressing the root cause of the disease.”
In the FREEDOM-DM1 trial, patients in the 5 mg/kg and 10 mg/kg cohorts were treated with PGN-EDODM1, and their blood was assessed for splicing correction and muscle tissue concentrations at 28 days post-dose. Results revealed a dose-dependent improvement in splicing correction: 12.3% for the 5 mg/kg cohort and 29.1% for the 10 mg/kg cohort, as measured using a 22-gene panel. These results suggest a significant therapeutic potential, as splicing defects are directly linked to the pathology of DM1. Furthermore, muscle tissue concentrations of PGN-EDODM1 increased with the higher dose, indicating effective delivery of the drug to the muscle.
While single-dose studies typically do not show major functional improvements in DM1 patients, PepGen observed early positive trends in some functional outcome measures. These trends suggest that with repeated dosing over time, PGN-EDODM1 may lead to meaningful functional improvements. The company remains optimistic that the observed robust splicing correction could translate into enhanced clinical outcomes as treatment continues.
Regarding safety, PGN-EDODM1 exhibited a favorable profile in both dose cohorts, with most treatment-emergent adverse events being mild or moderate in severity. Notably, there were no adverse events related to renal biomarkers or electrolyte imbalances. However, there was one treatment-related serious adverse event of abdominal pain in the 10 mg/kg cohort, which was potentially influenced by the use of a prohibited, off-label drug taken by the patient on the day of dosing. This isolated incident has not raised concerns regarding the overall safety of PGN-EDODM1.
Dr. Johanna Hamel, Associate Professor of Neurology, Pathology, and Laboratory Medicine at the University of Rochester Medical Center, commented on the results, saying, “These initial results are highly encouraging. The dose-dependent splicing correction suggests that the drug is effectively binding to the target and getting into muscle tissue. Since mis-splicing is central to DM1, correcting this could potentially lead to functional improvements for patients over time. The levels of splicing correction observed after just a single dose are particularly exciting, and I believe these effects will strengthen with repeated doses.”
The company expects to report additional results from the FREEDOM trial’s 15 mg/kg cohort in the second half of 2025, followed by data from the FREEDOM2-DM1 multiple ascending dose study in the first quarter of 2026.
PGN-EDODM1, PepGen’s investigational therapeutic, uses the company’s proprietary EDO technology to deliver oligonucleotides designed to restore normal RNA splicing function in patients with DM1. This treatment directly targets the toxic CUG-repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene, which disrupts the activity of the key RNA splicing protein MBNL1. By binding to this repeat expansion, PGN-EDODM1 releases MBNL1, allowing it to correct downstream mis-splicing events. This approach offers a promising alternative to other therapies that rely on RNA knockdown or degradation.
The U.S. Food and Drug Administration has granted Orphan Drug and Fast Track Designations to PGN-EDODM1 for the treatment of DM1, reflecting the urgency and unmet need for effective treatments for this debilitating disease.
The FREEDOM-DM1 trial is a Phase 1, randomized, double-blind, placebo-controlled study aimed at evaluating the safety, tolerability, and pharmacodynamics of PGN-EDODM1 in adult patients with DM1. In addition to splicing correction, the study also measures muscle concentrations of PGN-EDODM1 and functional outcomes. Following the successful single-dose phase, the trial is progressing into multiple ascending doses, with results expected to provide more comprehensive data on the long-term effects of the drug.
Myotonic dystrophy type 1 is a progressive, monogenic disorder that primarily affects skeletal and cardiac muscles, along with other systems. It is caused by expanded CUG repeats in the DMPK gene, which disrupt normal RNA splicing, leading to the various symptoms of DM1, including muscle weakness, cardiac abnormalities, and cognitive impairments. There are currently no approved treatments that address the root cause of the disease, making PGN-EDODM1 a potentially transformative option for patients with DM1.
PepGen’s ongoing efforts aim to provide new therapeutic options for patients with DM1 and other neuromuscular disorders by advancing oligonucleotide therapies with improved delivery capabilities. The company’s proprietary EDO platform has the potential to transform the treatment of a range of severe, life-altering diseases.
