PepGen reports 46.5% splicing correction in DM1 trial

PepGen said on November 10, 2026, that PGN-EDODM1, its investigational oligonucleotide for myotonic dystrophy type 1, produced a mean splicing correction of 46.5% at Week 13 in the “10 mg/kg” cohort of the Phase 2 FREEDOM2-DM1 trial. The figures are company topline results from six people who received the drug. They have not been published in a peer-reviewed journal.

The company described PGN-EDODM1 as an Enhanced Delivery Oligonucleotide that “leverages cell-penetrating peptides to improve the uptake and activity of conjugated oligonucleotide therapeutics.” FREEDOM2-DM1 (NCT06667453) is a randomized, double-blind, placebo-controlled multiple-ascending-dose study.

What the company measured

The “10 mg/kg” cohort enrolled eight participants, randomized 3:1 to four intravenous doses of PGN-EDODM1 (n=6) or placebo (n=2) every four weeks. PepGen said all eight completed the Week 16 assessment.

Mean splicing correction of 46.5% was observed at Week 13 “as measured by the 22-gene panel.” Five of six treated participants had more than 20% correction, and four had more than 50%. In a pooled placebo group (n=4, combined from cohorts 1 and 2), mean correction was 6.8% at Week 13. PepGen called the treated result “the highest level of splicing correction ever reported in a multiple dose study for DM1.” That comparison is the company’s, not an independent review of other trials.

PepGen also reported functional changes as mean change from baseline. Its investor presentation said percentage improvements for those functional tests were calculated by dividing the mean change at Week 16 by the mean baseline, and that the summary used “10 mg/kg” n=6 and “placebo pooled n=4.” The press release states the cohort itself as n=6 treated and n=2 placebo, and it specifies the pooled placebo only for the 6.8% splicing figure.

On video Hand Opening Time, a measure of myotonia, the company said the “10 mg/kg” group improved 4.3 seconds at Week 13 and 3.9 seconds at Week 16, “an approximately 52.7% improvement at Week 16,” while placebo improved 0.2 seconds at Week 16. PepGen said a “dose-dependent splicing correction of CLCN1,” a muscle chloride channel “believed to be a primary driver of myotonia in DM1,” was also observed. Its presentation added, of a plot of video Hand Opening Time against CLCN1 splicing, “Data illustrate direction only and do not represent a statistical correlation.”

Hand-grip strength “improved by approximately 16.2%” at Week 16, “corresponding to a 6.3-point improvement in maximum predicted percent normal (PPN) from baseline (placebo improved 0.9 PPN).” Timed Up and Go “improved by 8.5%, or 0.6 seconds (placebo worsened 0.5 seconds),” and the 10-Meter Walk/Run Test “improved by 6.8%, or 0.4 seconds (placebo improved 0.2 seconds).”

Patient-reported outcomes “were inconclusive at Week 16.” PepGen said the Patient Global Impression of Change “showed a favorable directional trend” at “10 mg/kg” versus placebo, while Myotonic Dystrophy Health Index total scores were mixed because all groups, including placebo, improved, and baseline measurements differed.

Safety, as reported

PepGen said PGN-EDODM1 “was generally well tolerated at 10 mg/kg.” The company said every treatment-emergent adverse event in that cohort was mild or moderate, and it reported none that were severe or serious, none that were adverse events of special interest, and no dose-limiting toxicities. “No treatment discontinuations were reported.” Nausea was the most common event, PepGen said.

“Four renal TEAEs reported, all were mild.” The company said transient albuminuria was observed after the first dose and decreased with later doses, and that “no evidence of cumulative renal toxicity was observed over the 16-week study period.”

The “12.5 mg/kg” cohort “is fully enrolled, with participants having received up to three doses,” and clinical results are expected in the first half of 2027. PepGen also expects to report interim open-label extension clinical data at “5 mg/kg” and safety data at “10 mg/kg” in January 2027. In the extension, the company said there has been one discontinuation due to a hypersensitivity reaction; that event was not reported as part of the FREEDOM2 “10 mg/kg” cohort safety summary.

FREEDOM2 is being conducted in Canada, the United Kingdom, New Zealand, Australia and South Korea and “is subject to a partial clinical hold in the United States.” PepGen said FDA issued that hold in March 2026, “citing nonclinical findings in mice.” Its November presentation said “no U.S. participants dosed in the FREEDOM2-DM1 study to date.”

Investing.com reported that PepGen shares “rose over 115% in premarket trade Tuesday” after the release. That is the outlet’s market report, not a figure from PepGen’s filing.

What is not known

• How well these changes would hold up in a larger, longer, or independently analyzed study. The efficacy sample is six treated participants. The results are company topline figures, not a peer-reviewed paper, and the releases reviewed here do not report p-values or confidence intervals for the functional comparisons.
• Which placebo group sits behind each functional number. PepGen explicitly pooled placebo participants from cohorts 1 and 2 (n=4) for the 6.8% splicing figure. Its presentation applied “placebo pooled n=4” to a summary that also includes the functional tests. The press release does not repeat that pooling language next to the video Hand Opening Time, grip, Timed Up and Go, or walk/run placebo figures.
• When, or whether, the U.S. partial clinical hold will be lifted. PepGen said it is conducting nonclinical mouse studies and is engaged with FDA. It also said an end-of-Phase 2 meeting is expected in the second half of 2027, “pending removal of the partial clinical hold.”
• Durability beyond Week 16 in this cohort. Longer follow-up is planned in the open-label extension and in an expansion cohort the company said it intends to start in parallel with the “12.5 mg/kg” group.

This story summarizes a company’s clinical topline announcement. It is not medical advice, and PGN-EDODM1 is an investigational therapy that has not been approved for use.