PepGen’s Phase 2 FREEDOM2 clinical trial for myotonic dystrophy type 1 has been partially paused by the U.S. Food and Drug Administration (FDA) following concerns about preclinical data. The company is investigating its therapeutic oligonucleotide PGN-EDODM1, which aims to restore the function of a disrupted RNA splicing protein in patients with DM1. This asset had previously received orphan drug and fast track designations from the FDA.
Analysts at Stifel described the study pause as “a surprise” and noted that dosing continues outside the United States, including escalated dosing at international sites. "The timing here is confusing," Stifel analysts said, "and clouds things a bit" for PepGen.
The company stated in its press release that the partial hold was related to questions about “previously submitted preclinical pharmacology and toxicology studies.” The FDA did not raise issues with previously submitted Phase 1 clinical data prior to launching FREEDOM2.
Stifel obtained additional information indicating that the FDA’s concerns stemmed from a subchronic mouse study filed by PepGen in mid-2024, where mice experienced reduced blood pressure linked to the investigational drug. PepGen also provided mouse data showing slower infusion did not cause such changes, and non-human primate studies as well as Phase 1 single-ascending dose trials did not reveal safety signals associated with hypotension.
“The timing of this partial hold is odd,” Stifel wrote. According to PepGen’s statement, further analyses have been submitted to the FDA, including recently unblinded Phase 1 data.
Despite this setback in the U.S., FREEDOM2 continues enrolling and dosing participants in countries such as the United Kingdom and Canada, with recent regulatory clearance allowing expansion into South Korea, Australia, and New Zealand. Multiple-ascending dose data for FREEDOM2 are still expected later this month.
“Any FDA setback, even one that seems surmountable, does increase the risk for any stock,” Stifel commented. However, they remain positive on PepGen’s prospects because “the biotech can make the case that this was a mouse-specific finding, and they can share actual clinical data with FDA.”
PepGen shares fell over 17% in pre-market trading after news of the partial hold became public.
