1792-P: Interim Results from INLIGHT, a Phase 1 Study of Investigational WVE-007, an INHBE Galnac siRNA for the Treatment of Overweight and Obesity

Introduction and Objective: Evidence from heterozygous INHBE loss-of-function carriers suggests that lowering INHBE expression by ≥50% may restore a healthy metabolic profile in people living with overweight and obesity. Wave Life Sciences is evaluating WVE-007, an investigational INHBE GalNAc-conjugated siRNA, for the treatment of adults with overweight or obesity in the INLIGHT clinical study (NCT06842186). Methods: INLIGHT is a randomized (3:1), double-blind, placebo-controlled Phase 1 study of single ascending doses of WVE-007. Four dose levels administered subcutaneously are being evaluated: 75, 240, 400, and 600 mg. Key criteria include HbA1c <5.9% and BMI 28-40 kg/m2. Interim (as of December 2025) safety, tolerability, pharmacokinetics, and pharmacodynamics data, including serum Activin E (the protein product of INHBE), and body composition measured by DEXA, are reported. Results: Baseline characteristics were generally balanced across groups. WVE-007 was safe and well tolerated up to 600 mg, with no discontinuations. All treatment-related AEs were mild. Robust, dose-dependent, and durable target engagement (TE) was demonstrated: on Day 29, the mean reduction in Activin E from baseline was 56% for 75 mg WVE-007 (n=8), 75% for 240 mg (n=24), and 85% for 400 mg (n=24). In the 240 mg WVE-007 group, mean Activin E reductions of >75% were maintained to at least Day 85, the last available time point. A single 240 mg dose of WVE-007 (n=24) led to a 9.4% reduction in visceral fat mass (p=0.02) relative to baseline, a 4.5% reduction in total fat mass (3.5 lbs; p=0.07) and a 3.2% increase in lean mass (4.0 lbs; p=0.01) at Day 85. No statistically significant changes from baseline were observed in the placebo group (n=8). Conclusion: Durable Activin E reductions support the potential for once or twice-yearly dosing of WVE-007. Interim safety, TE and body composition data support continued evaluation of WVE-007 for the treatment of overweight and obesity in the ongoing Phase 1 INLIGHT clinical trial. Disclosure C. Caracta: Employee; Current; Wave Life Sciences. D. Ghosh: None. V. Goel: Employee; Current; Wave Life Sciences, Lexington, MA, USA. J. Haegele: Employee; Current; Wave Life Sciences. A. Hart: None. P. Narayanan: None. K. Singh: None. A. Strahs: Stock/Shareholder; Ended; Alnylam Pharmaceuticals, Inc. Employee; Current; Wave Life Sciences. C.I. Wright: None.