PepGen’s lead candidate for myotonic dystrophy type 1 barely beat the placebo in a Phase 2 trial in terms of fixing incorrect gene splicing, but the biotech attributed the poor result to an outlier.
It’s a rough start to the week for PepGen—and patients with a rare muscle-wasting disease—as the company’s lead asset produced mixed data in a mid-stage trial. PepGen shares were down 59% after the opening bell on Tuesday.
In the 5 mg/kg multiple ascending dose cohort of the FREEDOM2 study, treatment with PGN-EDODM1 led to a mean 7.3% splicing correction in six patients with myotonic dystrophy type 1 (DM1) compared to 6.8% in the two-person placebo control group, according to the company’s Tuesday announcement. PepGen noted that when excluding one outlier who saw a 70.8% worsening in splicing correction, the mean splicing correction for the treated cohort was 22.9%.
In addition to there being “minimal separation from placebo” in patients receiving multiple ascending doses, that cohort also saw inferior splicing correction compared to the single ascending dose portion, in which PGN-EDODM1 elicited a 12.3% correction, William Blair wrote in a Tuesday note to investors. Both results likely contributed to PepGen’s falling shares, the analysts said.
The firm added that the “splicing response rate is 50% at 5 mg/kg, which leaves room for improvement.”
FREEDOM2 included eight patients who were given either PGN-EDODM1 or placebo every four weeks over a 12-week period. The study’s key endpoints included safety, splicing correction and functional outcome measures.
On the functional side, PepGen noted a “positive trend of improvement” on a hand-opening time test—delayed release of handgrip is a common symptom in DM1—compared to a worsening in placebo comparators. Both groups returned to baseline at 16 weeks. No meaningful improvements were observed in 10-meter walk/run test or handgrip strength with the 5 mg/kg dose, according to PepGen.
The company is also testing PGN-EDODM1 in the multiple ascending dose cohort of the FREEDOM2 study, in which five of eight patients have been given up to three 10 mg/kg doses of PGN-EDODM1. PepGen plans to report data from this cohort in the second half of this year.
DM1 is caused by a mutation in the dystrophia myotonica protein kinase (DMPK) gene that effectively traps the RNA-binding protein MBNL1, preventing it from doing its job. With PGN-EDODM1, PepGen is hoping to address the negative effects of this mutation by delivering a therapeutic oligonucleotide designed to restore the normal splicing function of MBNL1.
Other players tackling DM1 include Dyne Therapeutics and Avidity Biosciences, which was snapped up by Novartis in October 2025 for around $12 billion. Sarepta Therapeutics is also working with Arrowhead on a treatment for DM1, SRP-1003. In a cruel twist of fate, the biotech’s longtime CEO Doug Ingram stepped down in February after two members of his immediate family were diagnosed with the disease.
William Blair said in its Tuesday note that, like PepGen, Dyne and Avidity have seen high variability in splicing data in small cohorts of DM1 patients.
