Myotonic dystrophy type 1 is the most common adult muscular dystrophy, and it kills people slowly. The disease locks muscles in permanent contraction, progressively weakens cardiac and respiratory function, and shortens lifespan. Roughly 40,000 Americans have it, with 75,000 more in Europe and 15,000 in Japan. There are no approved disease-modifying therapies.
PepGen, a Cambridge, Massachusetts biotech, thinks its experimental oligonucleotide drug can change that. On March 30, the company reported topline results from the lowest dose cohort of its Phase 2 FREEDOM2 trial for PGN-EDODM1. The readout was, by any honest read, bleak.
Patients who received 5 mg per kilogram of body weight showed a mean splicing correction of 7.3 percent — versus 6.8 percent in the placebo group, according to BioSpace. The difference between treatment and nothing was half a percentage point. PepGen called the results encouraging and highlighted a clean safety profile. That framing has some merit. It is also insufficient.
Here is why: one patient's splicing got 70.8 percent worse. Excluding that outlier, the other five participants showed a mean correction of 22.9 percent. The entire clinical significance of this trial hinges on that single data point, which PepGen has not explained. Whether the worsening reflects disease progression, a random event, or something drug-related is the unanswered question the company needs to answer before anyone can interpret what this dose actually did.
On safety, there were no serious adverse events and no kidney toxicity signals — the drug was tolerable at this dose. Functional measures did not improve: the 10-meter walk/run test and handgrip strength showed no meaningful change. The ventilatory function score showed early improvement in the treated group versus worsening in placebo, but both converged back to baseline by week 16. Muscle tissue concentrations measured approximately one week after the fourth dose averaged 158 ng per gram in five of the six treated patients, with one readout still pending.
The 5 mg/kg cohort was a starting dose — and a conservative one. Phase 1 data showed a clear dose-response relationship: a single 15 mg/kg dose produced 53.7 percent mean splicing correction, with all six patients responding. The Phase 2 regimen repeated doses every four weeks, which PepGen presumably hoped would match or exceed those results. At 5 mg/kg, it did not.
There is a regulatory complication compounding the picture. The FDA placed a partial clinical hold on U.S. enrollment in the FREEDOM2 trial on March 4, citing questions about preclinical pharmacology and toxicology studies — not patient data, Reuters reported. No U.S. patients had been enrolled at the time of the hold. The study is actively dosing in the United Kingdom and Canada; South Korea, Australia, and New Zealand have received regulatory clearance to initiate, but enrollment has not begun there. The data cutoff for the FREEDOM2 results was also March 4, which raises the question of why the company chose this moment to read out the lowest-dose cohort with a signal that required excluding an outlier to look encouraging.
PepGen is not alone in this disease. Dyne Therapeutics, based in Boston, is already in Phase 3 with z-basivarsen (DYNE-101), showing 27 percent mean splicing correction and what it called robust functional improvements, with plans to submit for accelerated FDA approval in the first half of 2026. Avidity Biosciences, also in San Diego, has its own DM1 drug — del-desiran, branded AOC 1001 — which secured FDA Breakthrough Therapy Designation and has a Phase 3 trial called HARBOR underway. Both competitors are ahead of PepGen. Whether the EDO platform's delivery advantages pan out at higher doses is the question FREEDOM2 is designed to answer.
The 10 mg/kg cohort is more than halfway enrolled, with five of eight patients having received up to three doses. Results are expected in the second half of 2026. PepGen had $148.5 million in cash as of December 31, 2025, Reuters reported, funding operations into the second half of 2027.
The 5 mg/kg data tells us little about whether PGN-EDODM1 will work. Phase 1 already showed the biology is there. The 10 mg/kg readout will determine whether the EDO platform can sustain it at doses that matter clinically — and whether whatever sent one patient's splicing backward is a dose-dependent risk or a one-time anomaly the company simply has not explained yet.
