Wave Life Sciences (WVE) investor relations material

Novel obesity treatment mechanism

• GalNAc-conjugated siRNA targets INHBE, a genetically validated liver protein, to induce fat loss while preserving muscle, aiming for healthy, sustainable weight reduction without CNS or GI side effects.

• The approach leverages improved oligonucleotide chemistry for enhanced potency and duration, enabling potential once or twice yearly dosing.

• INHBE inhibition increases lipolysis in visceral fat, with preclinical models showing weight loss comparable to semaglutide, all from fat, and no muscle loss.

• Combination with semaglutide doubles the effect, and INHBE siRNA prevents weight rebound after GLP-1 cessation in animal models.

• The mechanism is orthogonal to GLP-1s, acting peripherally and not suppressing appetite or hedonic eating.

Clinical development and trial updates

• Phase 1 trial includes healthy overweight volunteers, with subtherapeutic and therapeutic dose cohorts; significant activin reduction and favorable safety observed at both 75mg and 240mg doses.

• The 240mg cohort expanded to 32 patients, and a 400mg cohort is underway, with six-month follow-up data expected in Q4 and Q1.

• Regulatory progress includes IND acceptance for U.S. expansion, with ongoing safety and target engagement reviews.

• Biomarker analysis will include cardiometabolic health indicators, with a focus on fat loss, muscle preservation, and potentially liver fat reduction.

• The trial aims to distinguish between fat and total body weight loss, aligning with regulatory emphasis on healthy weight loss and muscle preservation.

Market positioning and future outlook

• The therapy is positioned as a monotherapy or maintenance treatment, offering an alternative to GLP-1s with fewer side effects and less frequent dosing.

• Manufacturing efficiency and low dosing frequency could enable broader global access and cost advantages over current weekly injectables.

• No genetic testing is required for patient selection; the target population is all individuals with obesity, similar to the approach with PCSK9 inhibitors.

• The company anticipates Q4 data as a key milestone, with the potential to redefine healthy, sustainable weight loss in the obesity market.