PepGen (PEPG) Study update summary

Study design and objectives

• FREEDOM2 is a multinational, randomized, double-blind, placebo-controlled, multiple-ascending dose Phase 2 study for DM1, with sites in Canada, UK, New Zealand, Australia, and South Korea.

• The study evaluates PGN-EDODM1 in myotonic dystrophy type 1 (DM1) with dose escalation up to 12.5 mg/kg, using proprietary EDO technology to restore normal splicing of MBNL1.

• The 5 mg/kg cohort included eight patients randomized 3:1 or 6:2 to drug or placebo, dosed every four weeks for 12 weeks, with all completing four doses.

• Participants receive IV PGN-EDODM1 or placebo every 4 weeks for 12 weeks, with key endpoints including safety, pharmacokinetics, splicing correction, and functional assessments such as vHOT, hand grip, and 10-meter walk/run test.

• PGN-EDODM1 has received Orphan Drug and Fast Track designations from the FDA and Orphan Designation from the EMA.

Safety and tolerability

• At 5 mg/kg, all adverse events were mild or moderate, with no serious adverse events, dose-limiting toxicities, withdrawals, or kidney-related issues, and no cumulative toxicity observed over four doses.

• Nausea was the most common adverse event; transient albuminuria occurred in some subjects but resolved without intervention and did not worsen with repeat dosing.

• No hypomagnesemia, hypersensitivity, or treatment-related discontinuations were observed.

• The adverse event profile was consistent with previous single ascending dose studies.

• Safety profile supports dose escalation to 10 mg/kg and potentially 12.5 mg/kg.

Efficacy and biomarker results

• Mean splicing correction in the 5 mg/kg group was 7.3% versus 6.8% in placebo; excluding one outlier, mean correction rose to 22.9%.

• One treatment patient showed a 70.8% worsening in splicing, considered a rare outlier event, with significant drug levels and no assay errors identified.

• High muscle concentrations of PGN-EDODM1 were observed in treated patients, with mean tissue concentration of 158 ng/g after four doses.

• vHOT (video hand opening time) improved up to 4.1 seconds through week 13 in the treatment group, returning to baseline by week 16; excluding the outlier, vHOT improved up to three seconds at all time points through week 16.

• No meaningful improvements were observed in the 10-meter walk/run test or handgrip strength at 5 mg/kg.