PepGen’s DM1 Trial Shows Early Functional Improvements as Safety and FDA Questions Remain

PepGen’s experimental treatment for myotonic dystrophy type 1 produced a 46.5% average correction in a muscle RNA measure in six patients in a Phase 2 study. The same group showed improvements in hand opening and other measures of muscle function after four doses of PGN-EDODM1. The findings provide a basis for continued development and a closer look at whether the changes persist with longer treatment.

In its November 10 update, PepGen compared the six patients receiving 10 milligrams per kilogram with four placebo patients pooled from two dose cohorts. The small groups make the results difficult to interpret, and patient-reported outcomes were inconclusive. Earlier kidney-related findings and a U.S. partial clinical hold are additional considerations as the company advances the program.

A treatment aimed at faulty RNA

Myotonic dystrophy type 1, or DM1, is an inherited, progressive condition that affects muscles and other body systems. Patients can experience muscle weakness and myotonia, a delayed relaxation of muscles after contraction. Difficulty releasing a grip is one example of a symptom that can interfere with daily activities. There is no approved therapy directed at the underlying cause; care addresses symptoms and complications.

The disease is caused by an expanded genetic sequence in the DMPK gene. The resulting abnormal RNA can trap proteins needed for normal RNA splicing, the process by which cells prepare genetic instructions for making proteins. When splicing goes wrong across multiple genes, normal muscle function is disrupted.

PGN-EDODM1 is an investigational oligonucleotide, a short strand designed to bind the abnormal RNA. PepGen attaches it to a cell-penetrating peptide intended to improve delivery into cells and their nuclei. As described in PepGen’s quarterly filing, the treatment is designed to release splicing-regulating proteins and improve the processing of other RNA messages. Measuring splicing correction can therefore help show whether the drug is engaging its intended target.

PepGen estimates that more than 110,000 people in the United States and European Union have DM1. That is a broad disease estimate, not the number immediately eligible for treatment: any eventual label, diagnosis, clinical severity, delivery requirements and payer coverage would determine the reachable population. The medicine is given intravenously in the study, which also makes treatment-center access and administration part of its potential commercial profile.

What the six-patient cohort showed

FREEDOM2 is a randomized, double-blind, placebo-controlled, multiple-dose Phase 2 study. In the 10 mg/kg cohort, six participants received the drug and two received placebo, with four infusions given every four weeks. All eight completed the week 16 assessment. PepGen reported placebo outcomes pooled across the 5 mg/kg and 10 mg/kg cohorts, giving four placebo participants for the comparisons below.

Source: PepGen’s November 10 results. The treated group had six participants and the pooled placebo group four. The measures use different scales and time points.

The 46.5% figure is average correction on a panel of 22 splicing events in muscle at week 13, not the percentage of patients whose disease was corrected. Five of six treated participants exceeded 20% correction and four exceeded 50%, according to the company.

Hand opening time measures how quickly a person can release a grip; a shorter time indicates less myotonia. Although the treated group improved on that measure and on grip strength, the patient-reported Myotonic Dystrophy Health Index produced mixed results, including improvement in the placebo group. Longer follow-up can help establish how the observed changes relate to patients’ daily lives.

In the earlier single-dose study, PepGen reported molecular correction at several doses but no meaningful functional improvements. The company also reported limited functional change at the lowest 5 mg/kg multiple-dose level. Functional improvements were observed after repeated dosing in the new 10 mg/kg cohort; the small groups do not establish the cause of the differences between studies or the best dose and duration for treatment.

Safety and the dose decision

PepGen reported no serious or severe adverse events, dose-limiting toxicities or treatment discontinuations in the 10 mg/kg cohort through week 16. It also reported four mild kidney-related adverse events and transient increases in urine protein after the first dose that decreased with later doses. The company said it observed no evidence of cumulative kidney toxicity over that period.

In an earlier single-dose study, a dose-limiting toxicity was identified at 15 mg/kg, alongside transient kidney-related biomarkers at the 10 and 15 mg/kg levels. PepGen says the clinical significance of some laboratory findings remains incompletely understood and that it is monitoring kidney markers and electrolytes as dosing continues.

An independent monitoring board recommended advancing to 12.5 mg/kg. That cohort is fully enrolled, with results expected in the first half of 2027. Its results will add evidence on molecular activity and tolerability as PepGen considers a dose for a larger trial.

The regulatory and competitive context

In March 2026, the FDA placed the U.S. FREEDOM2 study on a partial clinical hold over questions arising from preclinical pharmacology and toxicology. PepGen says the questions relate to nonclinical findings in mice and that it is conducting studies and engaging with the agency. FREEDOM2 continues in other countries. The company expects data from the trial and its extension to support an end-of-Phase 2 meeting in the second half of 2027, contingent on removal of the partial hold.

A separate DM1 program illustrates the difficulty of translating a treatment’s intended mechanism into a measurable clinical benefit. In September, Novartis reported that its investigational therapy, delpacibart etedesiran, did not show a statistically significant improvement over placebo on hand opening time in the Phase 3 HARBOR trial. Novartis reported evidence of activity on secondary and exploratory measures and said it would review the full dataset and discuss next steps with regulators.

HARBOR followed approximately 150 patients over 54 weeks, compared with PepGen’s six treated patients and 16-week functional observation. Novartis’s candidate uses an antibody to deliver an RNA designed to degrade the disease-causing message; PepGen’s candidate is designed to bind the abnormal RNA without degrading it. The studies differ in treatment, design and population, so they cannot establish which drug is more effective. For PepGen, a larger controlled study must establish whether the functional improvements are sustained and measurable on an agreed clinical endpoint.

Resources and the next evidence

At September 30, PepGen held $104.8 million in cash, cash equivalents and marketable securities. Management expects those resources to fund planned operations into 2028. The cost and timing of a larger trial will depend on the development plan and regulatory discussions.

For the first nine months of 2026, operating activities used $47.4 million of cash, compared with $65.8 million a year earlier. The 2026 figure began with a $55.0 million net loss, adjusted for noncash items including $9.1 million of stock compensation and changes in operating assets and liabilities. Future spending will depend on trial design, manufacturing and regulatory work.

PepGen expects interim extension-study clinical data at 5 mg/kg and safety data at 10 mg/kg in January 2027. It also plans a separate 10 mg/kg expansion cohort to collect up to nine months of data, with the 12.5 mg/kg cohort results expected in the first half of 2027. The extension has enrolled 19 participants; PepGen reports one discontinuation due to a hypersensitivity reaction.

The next results will show whether functional changes persist as more patients receive treatment and how kidney findings develop with repeated dosing. If longer follow-up supports the hand-function signal and the FDA hold is resolved, PepGen will be better positioned to agree on a larger controlled study. Demonstrating a sustained benefit on a clinical endpoint would bring the company closer to a potential treatment for patients with DM1.