PepGen (PEPG) Study result summary

Study design and mechanism

• FREEDOM2 is a multinational, randomized, double-blind, placebo-controlled Phase 2 MAD study; the 10 mg/kg cohort had 8 participants (6 active, 2 placebo) receiving four IV doses every four weeks. All completed Week 16.

• PGN-EDODM1 targets expanded CUG repeats in pathogenic DMPK RNA to restore splicing; its EDO platform is designed for broad tissue delivery and nuclear uptake.

• Final-biopsy mean muscle concentrations were 153.4 ng/g at 5 mg/kg and 222.0 ng/g at 10 mg/kg; biopsies were taken seven days after dose four.

Splicing and functional results

• At 10 mg/kg, mean muscle splicing correction was 46.5% at Week 13/day 7 after dose four; 5 of 6 participants exceeded 20% and 4 of 6 exceeded 50%, versus 6.8% in pooled placebo.

• Video Hand Opening Time improved 4.3 seconds at Week 13 and 3.9 seconds (52.7%) at Week 16; placebo improved 0.2 seconds at Week 16. CLCN1 splicing correction and VHOT gains showed a dose-dependent directional relationship, not statistical correlation.

• At Week 16, hand grip strength improved 16.2% (6.3 maximum predicted percent-normal points), Timed Up and Go improved 8.5% (0.6 seconds), and 10-Meter Walk/Run improved 6.8% (0.4 seconds).

• Patient-reported outcomes were inconclusive at Week 16: PGI-C showed a favorable directional trend, while MDHI results were mixed.

Safety and tolerability

• All participants in the 5 and 10 mg/kg cohorts completed dosing; treatment-emergent adverse events were mild or moderate, with no SAEs, severe events, AESIs, DLTs or discontinuations. Nausea was the most common event.

• Four mild renal events involved transient albuminuria that diminished with repeat dosing; eGFR and creatinine remained stable, with no cumulative renal toxicity observed over 16 weeks.

• No notable liver or hematologic changes, cardiovascular events or anti-drug antibodies were observed in the cohorts discussed.

• In the open-label extension, one participant discontinued after a hypersensitivity reaction; no SAEs or DLTs were reported.