MDA 2026: Early trial of PGN-EDODM1 shows biomarker activity in DM1
Splicing correction seen in Phase 1 study as Phase 2 trial launches
Written by |
PGN-EDODM1, Pepgen’s experimental therapy for myotonic dystrophy type 1 (DM1), was generally well tolerated in an early clinical trial, with biomarker data suggesting that the treatment is affecting its intended molecular target.
Based on these early findings, Pepgen is now sponsoring a Phase 2 trial, FREEDOM2-DM1 (NCT06667453), to evaluate the safety of repeated doses of PGN-EDODM1. The study aims to enroll 24 people with DM1 ages 16 to 60. Participants will be randomly assigned to receive monthly infusions of the therapy at several dose levels or a placebo for 12 weeks (about three months). The trial is currently recruiting at sites in Canada and the U.K.
How faulty RNA splicing drives myotonic dystrophy type 1
DM1 is a genetic disorder caused by mutations in the DMPK gene, which lead to the production of an abnormal messenger RNA (mRNA), an intermediary molecule cells use when genes are read to make proteins.
The abnormal DMPK mRNA forms clumps inside cells and interferes with a key type of RNA processing called splicing, the process by which parts of a gene are cut and joined together to form functional proteins. Problems with splicing lead to widespread genetic dysregulation, ultimately damaging muscle cells and driving DM1 symptoms. PGN-EDODM1 is designed to target hairpin structures formed by the mutated mRNA and prevent it from trapping RNA-binding proteins, helping correct splicing and lessen muscle damage.
Pepgen sponsored a Phase 1 trial called FREEDOM-DM1 (NCT06204809) to test single doses of PGN-EDODM1 in adults with DM1. The study enrolled 24 patients who received a single infusion of a placebo or PGN-EDODM1 at doses of 5, 10, or 15 mg/kg.
Johanna Hamel, MD, of the University of Rochester, discussed findings from FREEDOM-DM1 at the Muscular Dystrophy Association (MDA) Conference 2026, in a talk titled, “FREEDOM-DM1: Final results from a Phase 1, placebo-controlled SAD study to evaluate PGN-EDODM1 in people with myotonic dystrophy type 1 (DM1).”
Phase 1 trial primarily assessed safety of PGN-EDODM1
The study’s main goal was to assess safety, and the results were generally positive. The most commonly reported side effects included nausea, headache, and the common cold. One serious adverse event — severe abdominal pain — was reported in a participant who was also taking another medication known to cause abdominal pain, meaning the event may have been related to that medication rather than PGN-EDODM1.
Safety data also showed that at the highest tested dose, some participants experienced worsening in markers of kidney health after PGN-EDODM1 treatment. These changes resolved without additional treatment but were considered a dose-limiting toxicity, which indicates the 15 mg/kg dose may be too high for repeated dosing. The ongoing multiple-dose study of PGN-EDODM1 is evaluating doses ranging from 5 mg/kg up to 12.5 mg/kg, pending safety reviews.
As a preliminary assessment of the therapy’s efficacy, researchers collected muscle biopsies about one month after treatment. A 22-gene panel was tested to look for splicing correction, with results showing correction of 12.3%, 29.1%, and 53.7% at the low, medium, and high doses, respectively. These levels are “substantially higher than any previously reported splicing correction in people with DM1,” the researchers wrote in their abstract. Overall, 87.5% of patients given PGN-EDODM1 showed improved splicing, Hamel noted.
Biomarker data show dose-dependent splicing correction
“High levels of splicing correction after single doses of PGN-EDODM1 demonstrate PGN-EDODM1’s potential to affect the symptoms of DM1,” the scientists wrote, adding that the increase in splicing correction was accompanied by increasing levels of the active drug detectable in muscle tissue.
“This safety data and the initial splicing assessment does support evaluation of [PGN-EDODM1] further in an optimized dose regimen in a multiple ascending dose study, which is underway,” Hamel said. Results from the ongoing Phase 2 study are expected later this year, with findings from the 5 mg/kg-dose group anticipated in the coming months.
The researchers also noted that, in animal models, repeated dosing of PGN-EDODM1 produced greater correction of abnormal splicing and was associated with larger reductions in myotonia, a hallmark symptom of myotonic dystrophy in which muscles become stiff and have difficulty relaxing after contraction. “Correction of mis-splicing over time with repeat dosing is therefore anticipated to improve functional measures in people with DM1,” the researchers wrote in their abstract.
Note: The Muscular Dystrophy News Today team is providing live coverage of the 2026 MDA Clinical & Scientific Conference March 8-11 in Orlando, Florida. Go here to see the latest stories from the conference.
