Pepgen pulls plug on exon-skipping therapy for Duchenne MD
Company will instead focus on development of investigational therapy for DM1
Following lackluster data from a Phase 2 clinical trial, Pepgen will discontinue developing PGN-ED051, its experimental exon 51-skipping therapy for Duchenne muscular dystrophy (DMD).
The company said it will wind down all DMD-related research and development activities, focusing instead on an investigational therapy for myotonic dystrophy type 1 (DM1) that’s in clinical testing.
“As we wind down our DMD program, we would like to thank the patients, families, caregivers, investigators, and study staff for their support and participation in this research. I also want to acknowledge our team’s hard work and commitment to advancing new potential treatments for DMD patients,” Pepgen President and CEO James McArthur, PhD, said in a company press release.
DMD is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein that’s vital for maintaining muscle health. People with DMD produce little to no dystrophin, which leads to the muscle weakness and wasting that characterize the disease.
Like other protein-coding genes, DMD is composed of sections called exons. Multiple exons come together to form the full gene, sort of how words are put together to make a sentence. The basic idea behind exon-skipping therapies for DMD is to skip over one or more exons, letting cells produce a shortened, but functional, version of dystrophin. PGN-ED051 was designed to skip over exon 51 of the DMD gene.
The therapy was being tested in a Phase 2 clinical trial called CONNECT1-EDO51 (NCT06079736). The new data come from four trial participants who were given PGN-ED051 at a dose of 10 mg/kg. The treatment was well tolerated, with no serious side effects reported, but the increase in total dystrophin levels with the therapy was less than 1% of what’s seen in people without DMD.
“We are disappointed by the dystrophin results observed in the 10 mg/kg dose cohort in CONNECT1, as it was our hope that we could improve upon existing therapies for patients in a more profound way,” McArthur said.
Switching gears
With the conclusion of its DMD program, Pepgen will turn its attention to PGN-EDODM1, its experimental treatment for DM1.
DM1 is caused by mutations in the DMPK gene. When the mutated gene is read, it produces an abnormal messenger RNA, which is an intermediary molecule produced when genes are read to make protein, that forms clumps in cells and interferes with normal cellular processes. PGN-EDODM1 is designed to target the mutated messenger RNA to restore normal splicing (RNA processing), allowing production of the DMPK protein.
“Mis-splicing is the primary driver of DM1 pathology and currently patients have no approved treatment options for this disabling, life-shortening disorder,” said Paul Streck, MD, executive vice president and head of research and development at Pepgen.
PGN-EDODM1 has been tested in a Phase 1 study called FREEDOM-DM1 (NCT06204809) and results from the participants who took the 15 mg/kg dose are expected this year.
A Phase 2 study called FREEDOM2-DM1 (NCT06667453) is recruiting in Canada and the U.K., and data from it are expected in early 2026. Initial findings from the studies have been promising, according to Pepgen. Both trials feature DM1 patients who receive either PGN-EDODM1 or a placebo, with the main goal being to assess the therapy’s safety profile.
“PGN-EDODM1, PepGen’s investigational drug in development for DM1, has already demonstrated robust target engagement after a single 10 mg/kg dose in patients that resulted in mean mis-splicing correction of 29% with a favorable emerging safety profile.” Streck said. “Going forward, we will focus our resources on advancing the company’s ongoing DM1 clinical program, along with our research pipeline.”
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