Early Phase 1 Trial Data Suggests Therapeutic Potential for PGN-EDODM1 in Myotonic Dystrophy Type 1

Author(s):

Isabella Ciccone, MPH

Fact checked by:

Marco Meglio

Key Takeaways

Initial data from the FREEDOM-DM1 trial showed dose-dependent splicing correction in DM1 patients, with 12.3% and 29.1% mean corrections for 5 mg/kg and 10 mg/kg doses, respectively.
The emerging safety profile of PGN-EDODM1 was favorable, with most adverse events being mild or moderate, and no significant issues related to electrolytes or renal biomarkers.
Although single-dose trials did not improve functional outcomes, early trends suggest potential benefits with repeat dosing, indicating the drug's potential to address DM1's underlying cause.
Further studies, including the FREEDOM2-DM1 multiple ascending dose study, are planned to evaluate PGN-EDODM1's long-term efficacy and potential functional benefits for DM1 patients.

Initial data reported from the FREEDOM-DM1 trial suggest PGN-EDODM1 has dose-dependent effects in patients with DM1, with further results from study cohorts expected in 2025 and 2026.

Johanna Hamel, MD

(Credit: University of Rochester Medical Center)

Initial data from the 5 and 10 mg/kg dose cohorts in the ongoing FREEDOM-DM1 phase 1 trial investigating PGN-EDODM1 (PepGen), an investigational antisense oligonucleotide (ASO), demonstrated positive findings in patients with myotonic dystrophy type 1 (DM1). The company noted that it anticipates reporting results from the FREEDOM 15 mg/kg cohort in the second half of 2025 and from the FREEDOM2 5 mg/kg cohort in the first quarter of 2026.¹

In the 5 mg/kg (n = 8) and 10 mg/kg (n = 8) dose cohorts of FREEDOM-DM1, findings from evaluable participants showed a mean splicing correction of 12.3% and 29.1% at 5 mg/kg (n = 6) and 10 mg/kg (n = 4) doses, respectively, as measured by the 22-gene panel² at 28 days post-dosing. Additional results also revealed a dose-dependent increase in muscle tissue concentrations of PGN-EDODM1 in the 5 mg/kg (n = 6) and 10 mg/kg (n = 5) cohorts at day 28.

“Unlike degraders that eliminate all DMPK RNA, our CUG targeted blocking approach selectively targets only the pathogenic portion, preserving healthy DMPK and potentially leading to superior long-term outcomes for DM1 patients," James McArthur, PhD, president and CEO at PepGen, told NeurologyLive^® in a recent interview. "The splicing correction numbers we observed in FREEDOM-DM1—12.3% at 5 mg/kg and 29.1% at 10 mg/kg—exceeded our expectations, especially after just a single dose of PGN-EDODM1. We look forward to sharing 15 mg/kg data from FREEDOM in the second half of 2025 and 5 mg/kg data from FREEDOM2-DM1 in the first quarter of 2026."

Although data from the single-dose portions of the trial did not demonstrate improved functional outcomes in patients with DM1, the collected data from these cohorts revealed positive early trends in some functional outcome measures. Overall, PepGen noted that it believes robust splicing correction with PGN-EDODM1 has the potential to lead to meaningful functional improvements with repeat dosing over time.

In the trial, PGN-EDODM1 had a favorable emerging safety profile in the 5 and 10 mg/kg cohorts through the data cut-off date of December 3, 2024, which continued through the date of this release. The company reported no adverse events (AEs) related to electrolytes or renal biomarkers and that most of the treatment emergent AEs were considered mild or moderate in severity. Notably, 1 treatment-related serious AE of abdominal pain reported in the 10 mg/kg cohort was potentially confounded by use of a prohibited, off-label drug taken on the morning of PGN-EDODM1 dosing.

“These initial results from the FREEDOM clinical trial are highly encouraging. The emerging safety profile is very promising. The dose-dependent splicing correction may suggest that the drug gets into the muscle and effectively binds to the target. Mis-splicing is central to the cause of DM1, and correcting mis-splicing may improve functional outcomes for DM1 patients over time. With this in mind, I am particularly excited by the levels of splicing correction seen after only a single dose of PGN-EDODM1. Based on previous work, I believe that these effects could be stronger as levels of the drug build up with repeat dosing,” Johanna Hamel, MD, associate professor of neurology, pathology and laboratory medicine at the University of Rochester Medical Center, said in a statement.¹

REFERENCES
1. PepGen Announces Positive Initial Results, Including Robust Splicing Correction, from Ongoing FREEDOM-DM1 Trial in Patients with DM1. News Release. Published February 24, 2025. Accessed February 24, 2025. https://investors.pepgen.com/news-releases/news-release-details/pepgen-announces-positive-initial-results-including-robust
2. Provenzano M, Ikegami K, Bates K, et al. The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1. J Clin Invest. 2025;135(4):e185426. Published 2025 Jan 7. doi:10.1172/JCI185426