Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — 85th American Diabetes Association Scientific Sessions (ADA 2025)
14 slides from Wave Life Sciences's conference presentation, Jun 20, 2025
Slide 1: siRNA-INHBE Silencing in Mice Recapitulates Human Genetic Data and Demonstrates Improved Healthy Weight Loss Profile
siRNA-INHBE Silencing in Mice Recapitulates Human Genetic Data and Demonstrates Improved Healthy Weight Loss Profile Hsiu-Chiung (Ginnie) Yang, PhD SVP, Translational Medicine June 20, 2025 Presented at the 85th American Diabetes Association Scientific Sessions (ADA 2025)
Slide 2: Disclosures
Disclosures • Hsiu-Chiung (Ginnie) Yang, Wei Liu, Keith Bowman, Michael Byrne, Cynthia Caracta, Jigar Desai, Anamitra Ghosh, Dhiman Ghosh, Joseph Haegele, Naoki Iwamoto, Pachamuthu Kandasamy, Tomomi Kawamoto, Anthony Lamattina, Ken Longo, Khoa Luu, Subramanian Marappan, Padma Narayanan, Lola Owen, P
Slide 3: Forward-looking statements
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, r
Slide 4: Wave's PRISM platform uses genetic insights and modulates RNA expression
Wave’s PRISM® platform uses genetic insights and modulates RNA expression Silencing Splicing RNA Editing Endogenous Endogenous RNase H ADAR RISC Restored Reading Endogenous Frame AGO2 4 Kandasamy et al., 2022, doi: 10.1093/nar/gkac037; Kandasamy et al., 2022, doi: 10.1093/nar/gkac018; Monian et al.,
Slide 5: Human INHBE loss of function variant carriers have a healthy metabolic profile
Human INHBE loss of function (LoF) variant carriers have a healthy metabolic profile Display favorable metabolic traits Lower risk of T2D and CHD Waist to hip ratio T2D adjusted for BMI CHD Serum 0.50 0.75 1 1.25 1.5 triglycerides Odds Ratio HDL-c Lower risk Higher risk (vs. non carriers) (vs. non c
Slide 6: Activin E, a lipolysis suppressor, is upregulated in obesity
Activin E, a lipolysis suppressor, is upregulated in obesity Healthy weight Obesity Circulation Circulation Circulation Overnutrition Albumin-bound Albumin-bound fatty acids fatty acids Liver TG Liver TG INHBE mRNA INHBE mRNA Activin E Activin E Adipocyte Adipocyte Lipolysis Lipolysis 6 TG: triglyce
Slide 7: Human genetics-inspired approach to address obesity-associated metabolic disease
Human genetics-inspired approach to address obesity-associated metabolic disease Activin E Activin E • obesity • abdominal II I I II adiposity • CVD and T2D Adipocyte risk ALK7 • weight loss • abdominal GalNAc-siRNA adiposity • CVD and T2D risk 7 1. Cell Reports (2018) 25, 1193–1203; 2. Biochemical
Slide 8: Weight loss by a single dose of Inhbe GalNAc-siRNA is driven by fat loss with preservation of muscle
Weight loss by a single dose of Inhbe GalNAc-siRNA is driven by fat loss with preservation of muscle Body Weight Tissue Weight 0 14 28 0 28 Days Days siRNA siRNA (3 or 10 Sac (3 or 10 Sac DIO mpk, SC) DIO mpk, SC) Sac EpiWAT Quad 3 mg/kg INHBE-03 PBS % Body weight change 5 10 mg/kg INHBE-03 1.0 0.3
Slide 9: Inhbe knockdown decreases adipocyte size in mesWAT of DIO mice
Inhbe knockdown decreases adipocyte size in mesWAT of DIO mice 0 28 Days Lean or siRNA Sac DIO Lean DIO (10 mpk, SC) Mean Adipocyte Diameter PBS INHBE-03 80 *** Mean adipocyte diameter (μm) 60 40 20 0 DIO DIO Lean PBS INHBE -03 9 At 23 weeks old (D0), DIO C57Bl6 received a single SC injection of 10m
Slide 10: Inhbe GalNAc-siRNA reduces pro-inflammatory macrophage recruitment in epiWAT of DIO mice
Inhbe GalNAc-siRNA reduces pro-inflammatory Mᶲ recruitment in epiWAT of DIO mice Macrophages (Mᶲ) (F4/80) Pro-inflammatory (M1) Anti-inflammatory Mᶲ (CD11c) (M2) Mᶲ (CD163) 3 mpk 10 mpk 3 mpk 10 mpk DIO-PBS 3 mpk 10 mpk INHBE-03 INHBE-03 DIO-PBS INHBE-03 INHBE-03 DIO-PBS INHBE-03 INHBE-03 ✱ ns ✱✱✱ 1
Slide 11: Treatment with Inhbe GalNAc-siRNA augments semaglutide-induced weight loss in DIO mice
Treatment with Inhbe GalNAc-siRNA augments semaglutide-induced weight loss in DIO mice ~2x greater overall weight loss Curtails weight regain after the ✓ when added to GLP-1RA ✓ cessation of GLP1-RA 5 (% of PBS, same time point) Difference in body weight % Body weight change 5 Semaglutide 0 PBS (D0)
Slide 12: Activin E protein is lowered by Inhbe GalNAc-siRNA but minimally affected by GLP1-RA
Activin E protein is lowered by Inhbe GalNAc- siRNA but minimally affected by GLP1-RA 0 28 Days Semaglutide (1, 3, or 10 nM/kg, SC) Daily Inhbe mRNA: Activin E DIO siRNA Single dose Sac protein correlation (10 mpk, SC) Inhbe mRNA Activin E protein 150 (mouse liver) (mouse serum) %Serum Activin E 150
Slide 13: Summary
Summary • Preclinical data show that in DIO mice, Inhbe GalNAc-siRNAs: - Lower Inhbe mRNA and induce weight loss mainly through reduction of fat mass - Reduce pro-inflammatory macrophage recruitment in adipose tissue - Double weight loss, when added on to semaglutide - Curtail weight regain upon ces
Slide 14: Acknowledgements
Acknowledgements • Thanks to all colleagues and contributors from Wave Life Sciences, our collaborators, and INLIGHT participants and study teams • Nicole Neuman and Darienne Myerbeck, Wave Life Sciences, assisted in preparing this presentation Silencing (RNase H and Ago2) Splicing Editing 14 Select
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