PepGen (NASDAQ:PEPG) reported top-line results from the lowest-dose cohort of its Phase II FREEDOM2 multiple ascending dose (MAD) study evaluating PGN-EDO-DM1 in myotonic dystrophy type 1 (DM1), highlighting what management characterized as encouraging safety, splicing, and functional trend data.
FREEDOM2 design and baseline cohort characteristics
Paul Streck, executive vice president and head of research and development, said FREEDOM2 is a three-cohort, four-dose study in which patients receive four monthly doses. Each cohort includes eight patients randomized 3-to-1 active to placebo. The update focused on the 5 mg/kg starting-dose cohort; the company said it is currently enrolling the 10 mg/kg cohort.
Safety: mild-to-moderate adverse events and no kidney-related treatment AEs
James McArthur, PepGen’s president and CEO, said that at 5 mg/kg, “all adverse events were mild or moderate with no serious adverse events, no treatment-related adverse events related to the kidney, and no cumulative dose toxicity through the four doses.” Streck added that the company did not observe a cumulative increase in safety signals with multiple doses and reported no dose-limiting toxicities.
Streck said nausea was the most common adverse event and “did not get worse with multiple doses.” He also said there were no signs of hypersensitivity following administration.
On renal monitoring, Streck said eGFR and creatinine measurements “remained within the normal range,” and that transient albuminuria was observed in two subjects without a cumulative signal after four doses. In response to an analyst question on how PepGen evaluates whether safety developments warrant disclosure, McArthur said the company would disclose events that required materially changing the study, stopping dosing, or a regulatory hold, adding that what the company observed at 5 mg/kg was “very mild in nature,” transient, and not worsening over four doses.
On questions related to hypomagnesemia, McArthur said PepGen has seen no hypomagnesemia in its Phase I study or in the FREEDOM2 update presented. Streck said the company’s view is that safety findings that are transient, reversible, and manageable would be consistent with an acceptable long-term safety profile given the disease burden in DM1.
Splicing correction and the impact of an outlier
To assess splicing correction, tibialis anterior (TA) muscle needle biopsies were taken about seven days after the fourth dose and compared to baseline TA biopsies taken prior to dosing, Streck said.
In the 5 mg/kg cohort, mean splicing correction in the treatment group improved 7.3% versus 6.8% in placebo. However, Streck highlighted one treatment patient as a “notable outlier” who showed a 70.8% worsening of splicing. Excluding that outlier, the mean splicing correction across the remaining five DM1 treatment samples increased to 22.9% seven days after the last dose, compared with 6.8% in placebo.
McArthur said the outlier patient had “relatively significant levels of drug on board,” but the company does not understand why the patient did not improve in splicing. He added that PepGen reviewed potential procedural or analytical errors—such as sample mix-ups, RNA extraction fidelity, or calculation issues—and said the company does not believe the result was due to an error. McArthur said outside experts told the company that such a large worsening is rare, described as a low single-digit percentage event in their experience across large sample sets. Because the study remains blinded, PepGen said it cannot yet evaluate whether baseline characteristics (such as repeat size) may explain the response.
Streck also noted that the day-seven biopsies from treated patients showed high mean TA muscle concentrations of EDO-DM1 of 158 nanograms per gram.
Functional measure trends: vHOT signal, limited movement in 10-meter walk/run
On myotonia, Streck said vHOT improved in the EDO-DM1 treatment group while worsening in placebo from week four through week 13. He reported that vHOT improved by up to 4.1 seconds through week 13 in an analysis of six treated patients, before returning to baseline at week 16. Excluding the splicing outlier, Streck said vHOT improved by up to three seconds at all time points through week 16.
Asked why both placebo and treatment measures moved back toward baseline near the end of the study window, McArthur said the company does not know whether this reflects assay variability, though he emphasized that PepGen observed separation between groups for “over three-plus months.” He also said the splicing outlier showed the greatest variability in the vHOT assay.
McArthur said PepGen did not see “meaningful movement” in the 10-meter walk/run test at 5 mg/kg, describing the cohort as the program’s starting dose. He said the company is assessing additional functional endpoints but does not plan to report broader functional data until it has more placebo patients and has explored higher dose levels.
Next steps: 10 mg/kg cohort underway, open-label extension enrollment, and cash runway
McArthur said PepGen has started dosing the 10 mg/kg cohort and “expect[s] to report clinical data from this next cohort in the H2 of 2026.” As of the call, he said five of eight patients in the 10 mg/kg cohort had been dosed, with subjects having received up to three doses. He also said PepGen anticipates moving to a third cohort at 12.5 mg/kg, with results from that cohort expected in 2027.
McArthur added that 12 patients have progressed into an open-label extension at 5 mg/kg, including five patients from FREEDOM2.
On regulatory matters, McArthur said PepGen continues to engage with the FDA regarding an existing hold but could not provide a timeline for lifting it. He also reiterated prior guidance that PepGen’s cash runway extends into the second half of 2027, which he said should be sufficient to reach the 10 mg/kg readout later in 2026 and the 12.5 mg/kg cohort results in 2027.
About PepGen (NASDAQ:PEPG)
PepGen, Inc (NASDAQ: PEPG) is a clinical-stage biotechnology company headquartered in San Diego, California. The company is developing precision gene editing therapies to address rare genetic diseases by combining advanced prime editing modalities with proprietary delivery technologies. PepGen’s platform is designed to achieve targeted and durable correction of disease-causing mutations in vivo, with the goal of providing long-lasting therapeutic benefit after a single administration.
The company’s lead development programs include PPG-001 for mucopolysaccharidosis type II (Hunter syndrome) and PPG-002 for mucopolysaccharidosis type I (Hurler syndrome).
