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Analyst & Investor Day Spotlight on RNA editing and RNAi AATD, obesity and beyond October 29, 2025
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2 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, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of Wave Life Sciences Ltd. (the “Company”) to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “aim,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions. The forward- looking statements in this presentation are only predictions. The Company has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company’s business, financial condition and results of operations. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company’s Form 10-K and other filings with the SEC, some of which cannot be predicted or quantified and some of which are beyond the Company’s control. The events and circumstances reflected in the Company’s forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
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3 Today’s agenda Presentation Speaker Welcome and introduction Kate Rausch Vice President, Investor Relations & Corporate Affairs Opening remarks Paul Bolno, MD, MBA President and Chief Executive Officer RNA Editing WVE-006: RNA Editing (AIMer) for AATD Chris Wright, MD, PhD Chief Medical Officer WVE-008: PNPLA3 AIMer for liver disease Erik Ingelsson, MD, PhD Chief Scientific Officer RNAi WVE-007: INHBE siRNA for obesity Erik Ingelsson, MD, PhD Chief Scientific Officer Chris Wright, MD, PhD Chief Medical Officer PRISM platform innovations Chandra Vargeese, PhD Chief Technology Officer Closing remarks Paul Bolno, MD, MBA President and Chief Executive Officer Q&A All
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4 Opening remarks Paul Bolno, MD, MBA President and CEO
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To unlock the broad potential of RNA medicines to transform human health Our Mission
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6 AATD: Alpha-1 antitrypsin deficiency DMD: Duchenne muscular dystrophy HD: Huntington’s disease Leveraging best -in-class chemistry and genetic insights to build a leading RNA medicines company Clinical translationT arget selection Best-in-class oligonucleotide platform Clinically-validated oligonucleotide chemistry (including PN, stereochemistry) Human genetic or clinical support Select suitable modality and tissue delivery that leverages unique Wave chemistry Translational path Focus on first/ best-in-class opportunities Novelty and unmet need Pioneering RNA editingWVE-006 AATD Novel approach to reduce fat, preserve muscle WVE-007 Obesity Potential best-in-class profile WVE-N531 DMD Leading in allele-selective silencing WVE-003 HD In-house GMP manufacturingAI-driven continuous learnings Strong and broad IP Leverage genetic databases and clinical data
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7 Positive INHBE target engagement data update demonstrates rapid acceleration from target to successful clinical translation What you’ll hear today: Spotlight on RNA editing and RNAi Platform innovationRNA editing RNAi • First-ever clinical translation of RNA editing achieved with WVE-006 for AATD, including restoration of dynamic protein production • WVE-008, a wholly-owned RNA editing candidate for PNPLA3 liver disease, building on successful clinical translation of Wave’s editing capability • INLIGHT: Dose-dependent mean Activin E reductions post-single WVE-007 dose in clinic; exceeding levels that led to weight loss in preclinical studies; durability supports once or twice per year dosing • Multiple upcoming INLIGHT clinical data updates expected, including body composition and body weight starting in 4Q 2025 • Extra-hepatic capabilities: enable tuning of siRNA to achieve potent and durable silencing across multiple extra- hepatic tissues; RNA editing also achieved across multiple tissues • Novel therapeutic modality: capability to simultaneously edit and silence two unique targets with a single oligonucleotide construct
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8 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease Robust, diversified RNA medicines pipeline including first -in-class RNA editing and RNAi programs Program Discovery IND / CTA Enabling Studies Clinical Rights Patient population (US & Europe) R N A E D I T I N G WVE-006 (GalNAc) SERPINA1 (AATD) GSK exclusive global license 200K WVE-008 (GalNAc) PNPLA3 (liver disease) 100% global 9M GalNAc / extra-hepatic Multiple 100% global -- R N A i WVE-007 (GalNAc) INHBE (Obesity) 100% global 175M (>1 billion globally) GalNAc / extra-hepatic Multiple 100% global -- S P L I C I N G WVE-N531 Exon 53 (DMD) 100% global 2.3K Other exons (DMD) 100% global Up to 18K A L L E L E- S E L E C T I V E S I L E N C I N G WVE-003 mHTT (HD) 100% global 25K Symptomatic (SNP3) 60K Pre-Symptomatic (SNP3)
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9 WVE-006: RNA editing (AIMer) for AATD Chris Wright, MD, PhD Chief Medical Officer
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10 Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al. 2017 Int J Chron Obstruct Pulmon Dis 12:561-69 • AATD is a rare, inherited genetic disorder; commonly caused by G-to-A point mutation in SERPINA1 gene • Aggregation of mutant Z-AAT protein in hepatocytes and lack of functional, wild-type M-AAT drives liver and lung pathology, respectively • ~200,000 people in US and Europe are homozygous (Pi*ZZ genotype), which is the leading type of severe AATD with high risk of lung and/or liver pathology Correcting mutation with RNA editing is expected to address risk for both lung and liver pathology Alpha-1 antitrypsin deficiency impacts multiple organ systems Lung damage occurs during exacerbations that induce an inflammatory acute phase response, when more AAT protein is needed for protection Progressive liver disease results from Z-AAT-induced proteotoxic stress Lung pathology Liver pathology
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11 AATD has limited treatment options Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al. 2017 Int J Chron Obstruct Pulmon Dis 12:561-69 Treatment options that prevent lung pathology Treatment options that address liver pathology Weekly IV augmentation therapy is only approved treatment option ▪ No protective increase in AAT protein levels during acute phase response without additional IV infusions No approved therapies to prevent or reverse liver pathology • IV augmentation therapy does not decrease Z-AAT protein aggregation in liver Treatment goal Minimize episodic exacerbations and associated lung damage Treatment goal Decrease Z-AAT protein
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12 Strnad et al., 2020 N Engl J Med 382:1443-55; Stoller et al., 1993 Alpha -1 Antitrypsin Deficiency GeneReviews. M-AAT: Wild-type alpha-1 antitrypsin protein Z-AAT: mutant alpha-1 antitrypsin protein WVE-006: Potential first -in-class, convenient therapy for AATD that addresses both liver and lung manifestations of the disease RNA correction replaces mutant Z-AAT protein with wild-type M-AAT protein to reduce risk of liver pathology Z-AAT M-AAT reaches lungs to protect from proteases and reduce risk of lung pathology 1 2 M-AAT Restore circulating M-AAT and physiological AAT protein production✓ Reduce Z-AAT protein aggregation in liver ✓ WVE-006 (RNA editing) Proprietary chemistry✓ Infrequent dosing✓ Subcutaneous injection (GalNAc)✓ Highly specific (no bystanders)✓
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13 Heterozygous Pi*MZ AAT protein of >11uM, >50% M-AAT RNA editing aims to increase M -AAT and restore physiological AAT production during acute phase response Yes Low Low ✓Goal: ~50% editing to shift Pi*ZZ individuals to AAT function consistent with Pi*MZ genotype Homozygous Pi*ZZ No healthy M-AAT AAT levels increase during acute phase response No Risk of lung pathology High Risk of liver pathology High
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14 0 100 200 300 400 500 600 700 800 900 0 7 14 21 Days AAT protein Inflammatory stimulus CRP 30,000 30,100 Left: Mantovani A, Garlanda C. N Engl J Med, 2023;388:439-452; Right: Sanders et al., J COPD, 2018 RNA editing has potential to restore dynamic AAT response to inflammation RNA editing aims to restore production of dynamic and therapeutically relevant levels of AAT protein in Pi*ZZ individuals during acute phase response Percent change in plasma concentration (%) 0 100 200 300 400 500 600 700 800 900 0 7 14 21 Days AAT protein Inflammatory stimulus 30,000 30,100 Pi*ZZ CRP Lung damage occurs during exacerbations, when more AAT protein is needed for protection AAT protein has protective functions and is produced during acute phase response Pi*MZ
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15 WVE-006 achieved key treatment goals of restoring MZ phenotype Circulating M-AAT, Z-AAT, and total (M + Z) AAT protein in the serum were measured by highly selective and sensitive LC -MS/MS assays (LLOQ: 0.096 µM (M), 0.029 µM (Z)) and reported as mean participant SAD and MAD maximums Right: from 200 mg SAD cohort Total AAT levels exceeded 11 µM, production of wild-type M-AAT of greater than 50%, restored physiological AAT production Wild-type M-AATMutant Z-AAT AAT reached >20 μM during an acute phase response Plasma AAT of ~13 µM Wild-type M-AAT protein of 64% of total, reduction in Z-AAT• Protein levels associated with lower risk of AATD liver and lung diseases 400 mg single dose 12.8 µM total AAT 200 mg multidose 11.9 µM total AAT Acute phase response due to a kidney stone CRP (mg/L) 200 mg multidose cohort:
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16 WVE-006 enables endogenous AAT production during an acute phase response while augmentation therapy leaves patients at risk WVE-006 therapeutic goal is to restore dynamic AAT physiology; augmentation therapy goal is to maximize AAT levels as dynamic response is not enabled Illustrative model of impact of acute phase response Serum AAT RNA editing dose Protected lungs Endogenous AAT levels increase during acute phase response without need for add’l doses Serum AAT IV dosing Lung damage Exogenous AAT levels are depleted before next scheduled IV dose Augmentation therapy WVE-006 treatment approach • Augmentation therapy has no impact on liver disease • WVE-006 also reduces levels of Z-AAT
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17 RestorAATion-2 clinical trial ongoing; 400 mg MAD data expected in 1Q 2026 and 600 mg SAD and MAD data expected in 2026 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose RestorAATion-2: AATD PatientsRestorAATion-1: Healthy Volunteers 30 mg 100 mg 200 mg 400 mg 600 mg RestorAATion-1: Healthy Volunteers SAD → MAD Multi-dosing complete SAD Cohort 3 600 mg SAD Cohort 1 200 mg MAD Cohort 3 600 mg; Q4W SAD Cohort 2 400 mg MAD Cohort 2 400 mg; Q4W MAD Cohort 1 200 mg Q2W Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels
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18 WVE-008: PNPLA3 AIMer for liver disease Erik Ingelsson, MD, PhD Chief Scientific Officer
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19 RNA editing program: WVE -008 (PNPLA3 AIMer) for liver diseases Clinically-validated RNA editing ✓ ✓ ✓ ✓ Efficient and consistent RNA editing Restore dynamic physiological response Durable RNA editing supporting infrequent dosing Safe and well-tolerated • Strong foundation in human genetics • Over 9 million homozygous PNPLA3-I148M patients with liver disease in US and Europe • GalNAc-RNA editing approach uniquely aims to restore PNPLA3 function to fully address disease WVE-008 for PNPLA3 I148M
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20 1. Carlsson, B., et al. 2020 Aliment Pharmacol Ther.; 2. Unalp-Arida and Ruhl 2020 Hepatology; 3. Dong, XC, 2019 Front. Med. 4. Liver International, 2025; 45:e16133 MAFLD, Metabolic dysfunction-associated fatty liver disease; MASH, Metabolic dysfunction-associated steatohepatitis; ALD, alcoholic liver disease; AH, Alcohol-associated hepatitis; HCC, hepatocellular carcinoma People homozygous for PNPLA3 I148M are at high risk for liver disease Over 9 million homozygous PNPLA3-I148M patients with liver disease in US and Europe >50% RNA editing would support restoration of heterozygous phenotype with lower risk of liver complications and death Heterozygous carriers have 80% lower risk of liver-related death as compared to homozygous carriers Homozygous PNPLA3-I148M carriers have significantly higher risk of multiple liver diseases 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Years of follow-up Survival (%) of liver-related death 0 92 94 96 98 100 Homozygous I148 Heterozygous I148M Homozygous I148M HR = 8.61 (3.28–22.60) HR = 1.70 (0.78–3.71) AIMer editing to restore heterozygous phenotype MASH MAFLD
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21 Homozygous PNPLA3 I148M carriers with MASH tend to have more severe disease and urgent need for effective treatment options • Enrichment for metabolic cofactors including: - Obesity - Type 2 Diabetes - Hypertension • Polygenetic background and strongly influenced by environmental factors • Only treatment options are non-precision medicines primarily targeting steatosis and earlier stages of MASH MASH in PNPLA3 I148M non-carriers MASH in Homozygous PNPLA3 I148M carriers • Subset of MASH population with more severe disease - Faster progression to advanced fibrosis and end-stage liver disease • Account for ~90% of lean (normal weight) MASH • Up to 25% of all MASH are homozygous for PNPLA3 I148M, even higher in lean MASH and advanced MASH • No treatment options targeted to this population
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22 PNPLA3 has a critical role in lipid metabolism in the liver Johnson Nature Comms 2024 Tg: triglyceride; VLDL very low-density lipoprotein; LDL low-density lipoprotein; HDL high-density lipoprotein; ATGL Triglyceride with 3 fatty acids Phospholipid with 2 fatty acids PNPLA3 Tg-rich VLDL released into circulation, supply lipids to peripheral tissues Lipid droplet PNPLA3 balances triglyceride storage and secretion PNPLA3 supports lipid remodeling, lipid mobilization, and retinol metabolism VLDL PNPLA3 supports lipid remodeling PNPLA3 drives lipid mobilization from liver LDs store neutral lipids; lipolytic enzymes remodel lipids to provide cellular energy, lipid building blocks PNPLA3 expression on LDs is dynamic, increases in response to food Sterol ester Triglyceride PNPLA3 Phospholipid packaging PNPLA3 regulates retinol balance in liver
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23 RNA editing is expected to restore PNPLA3 function to treat across the stages of liver diseases ATGL: adipose triglyceride lipase; CGI-58: co-factor for ATGL; ER endoplasmic reticulum; LDs: lipid droplets; CGI-58 also called ABHD5 Liver International, 2025; 45:e16117; Human Molecular Genetics, (2014) 23(15): 4077 –4085 PNPLA3 I148M CGI-58 ATGL PNPLA3 I148M aggravates steatosis and fibrosis through gain-of-function Silencing PNPLA3 may only partially address disease PNPLA3 correction expected to restore function, counter liver disease • PNPLA3 I148M accumulates on LDs, sequesters CGI-58, inhibits ATGL’s lipase activity and lipid mobilization from ER • Suppresses retinol metabolism in liver and worsens inflammation and fibrosis • Promotes liver fat accumulation and fibrosis through activation of stellate cells • Creates PNPLA3 loss of function • ATGL partial rescue for loss PNPLA3 • Silencing will not restore retinol metabolism • Fibrosis, ballooning, and inflammation persist • Restores full PNPLA3 activity • Restores lipid mobilization, reverses steatosis, fibrosis, ballooning, and inflammation RNA editing approach ✓ PNPLA3
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24 1. Rady, B, et al. 2021 PLoS ONE 2021; 2. Hendriks, D, et al. 2023 Nat Biotechnol; 3. Tilson, SG, et al. 2021 Hepatology Functional PNPLA3 is imperative for liver health beyond improvements in steatosis Silencing of PNPLA3 in normal liver may worsen basal physiological functions Worsening Silencing PNPLA3 worsens steatosis in iPSC-derived human liver organoids2 Silencing PNPLA3 increases inflammation-induced liver cell death in human primary hepatocytes3Worsening KOUC UC KOI148MI148M Control OA PNPLA3 siRNA exacerbates the fibrotic response in hepatic stellate cells1
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25 Left: 4-parameter log-logistic dose response curve; Middle: Analysis utilized RNA-sequencing with two separate primary human hep atocyte cell lines (PH1/2). Variant calling utilized GATK best practices for RNA variant calling using Mutect2 and display A->G evidence found when filtering for variants found in b oth cell lines and all doses. WVE-008 builds on the clinical translation of Wave’s RNA editing capability WVE-008: Potential first -in-class, disease modifying therapy, for treatment of PNPLA3 I148M -driven liver disease Tissue exposure supports excellent delivery Highly specific editing with WVE-008 0 5 10 15 20 25 10 100 1000 Time (day) Liver Tissue Conc (μg/g) Semi-log scalePotent editing with WVE-008 WVE-008 (RNA editing) Proprietary chemistry✓ Subcutaneous injection (GalNAc)✓ Potential for infrequent dosing✓ Highly specific editing✓
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26 AIMers achieve efficient editing of PNPLA3, leading to reduction of liver fat One-way ANOVA with Dunnett post hoc test comparisons to Mock **** P< 0.0001 PNPLA3 siRNA Significant decrease in liver fat with PNPLA3 editing in human HEPATOPAC® model with homozygous I148M Decrease in liver fat with WVE-008 in monolayer model Mock PNPLA3 siRNA PNPLA3 AIMer 0 500 1000 1500 Lipid Droplet Density (pixel2/cell) (mean ± SE) ns ✱✱✱✱ PBS PNPLA3 siRNA PNPLA3 AIMer PBS PNPLA3 siRNA WVE-008 Lipid Droplet Density (pixel2/cell) (mean + SE)% Lipid Droplet Density vs. PBS (mean + SE)
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27 • Large addressable patient population with no disease modifying treatment options targeting PNPLA3 I148M-driven liver disease • PNPLA3 preclinical data demonstrates ability to restore functional PNPLA3 with RNA editing, restoring lipid regulation for improvement of liver health • WVE-008 candidate selected, builds on successful clinical translation of Wave’s RNA editing capability • Clinical development planning underway for a first-in-human clinical study - Leveraging previously genotyped populations to identify homozygous I148M carriers - Initial study to enroll homozygous carriers to assess safety, tolerability, pharmacokinetics and pharmacodynamic endpoints Potential best-in-class disease modifying treatment for homozygous PNPLA3 I148M carriers with liver disease CTA filing for WVE -008 expected in 2026
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28 Robust AIMer pipeline, including extra -hepatic targets AIMers
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29 WVE-007: INHBE GalNAc-siRNA Erik Ingelsson, MD, PhD Chief Scientific Officer
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30 • Adults with obesity have higher risk for many serious health conditions, including heart disease, type 2 diabetes, and some forms of cancer1 • GLP-1s are current standard of care for weight loss, but impact is often limited by: • Loss of muscle mass2 • Poor tolerability3 • Frequent dosing4 • High discontinuation rates5,6 Obesity is a metabolic disease with a treatment paradigm ripe for disruption 1. CDC.gov; 2. Sargeant, et al. 2019 Endocrinol Metab (Seoul) 34, 247; 3. Ghusn and Hurtado. 2024 Obesity Pillars 12, 100127; 4. Wegovy PI; 5. Leach, et al. 2023 Prime Therapeutics Claims Analysis; 6. Gasoyan, et al. 2024 Obesity (Silver Spring) 32, 486.; GalNAc-siRNA: GalNAc-conjugated small interfering RNA Advancing WVE-007, a GalNAc-siRNA, as a novel, long acting, muscle sparing approach for obesity > 1 billion people living with obesity globally
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31 Silencing INHBE mRNA by ≥50% is expected to recapitulate the healthy metabolic profile of heterozygous INHBE loss of function (LoF) carriers Akbari et al. Nat Commun. 2022 Aug 23;13(1):4844; Deaton et al. Nat Commun. 2022 Jul 27 Waist to hip ratio: waist to hip ratio adjusted for BMI; HDL-c: high-density lipoprotein cholesterol; ALT: alanine transaminase; ApoB: apolipoprotein B; cT1: corrected T1 Human genetic data demonstrate that heterozygous INHBE LoF carriers have a healthy metabolic profile Heterozygous INHBE LoF carriers have favorable traits: lower abdominal obesity, lower triglycerides, higher HDL-c Heterozygous INHBE LoF carriers have lower risk of Type 2 diabetes and CHD Favorable association with liver traits Odds Ratio Standard Deviations Standard Deviations
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32 Silencing of INHBE mRNA is expected to lead to fat loss and restore metabolic health Lower INHBE mRNA levels are associated with better metabolic health Adiposity is associated with INHBE mRNA1 Insulin resistance is associated with INHBE mRNA1 MAFLD is associated with INHBE expression2 1. PLoS ONE 13(3): e0194798. 2. Nature Communications | ( 2022) 13:4844 NAS = NAFLD activity score
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33 1. Cell Reports (2018) 25, 1193–1203; 2. Biochemical Journal (2024) 481 547–564; 3. PNAS 2023 Vol. 120 No. 32 e2309967120; 4. Nat Commun 2022. https://doi.org/10.1038/s41467- 022-32398-7; 5. Nat Commun 2022. https://doi.org/10.1038/s41467 -022-31757-8 Release of dimerized INHBE subunits creates hepatokine Activin E Binds to and activates ACVR1C (ALK7) receptor in adipose tissue Block adipose lipolysis Increased abdominal adiposity leads to obesity, CVD and T2D Diminished activation of ACVR1C (ALK7) receptor in adipose tissue Increased adipose lipolysis and shrink adipocytes Decreased abdominal adiposity leads to weight loss and reduced risk for CVD and T2D Adipocyte ALK7 I III II Activin E Activin E Reduced release of hepatokine Activin E Silencing INHBE mRNA has potential to treat obesity and associated metabolic diseases Reduction of INHBE mRNA with GalNAc-siRNA
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34 WVE-007: Potential best -in-class INHBE -siRNA that leverages proprietary chemistry for enhanced interactions with Ago2, better silencing Wave’s siRNA has demonstrated >10x improvement in Ago2 loading versus reference compounds Liu et al., 2023 Nucleic Acids Research doi: 10.1093/nar/gkad268 Builds beyond siRNA NAR publication Rational design Ago2 MID-PIWI Domain Guide Strand PO g1-g7 Phosphoryl guanidine (PN) WVE-007 (siRNA) Proprietary, clinically validated chemistry✓ Subcutaneous injection (GalNAc)✓ Potential for infrequent dosing (1 – 2x year)✓
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35 Data from preclinical studies conducted in DIO mice; Stats: (left, middle, right) Linear Mixed Effects ANOVA with post hoc co mparisons of marginal treatment effects vs. PBS per timepoint (left) or per tissue (middle, right) * p < 0.05 Single doses of INHBE GalNAc -siRNA result in dose -dependent weight loss and reduction of visceral fat, without affecting muscle mass, in DIO mice Preclinical data support INHBE GalNAc-siRNA as a single agent for healthy weight loss Quadricep weight (Day 28)Epididymal fat weight (Day 28) * -23% -40% Reduction in body weight✓ Reduction in visceral fat✓ No muscle loss✓ INHBE GalNAc-siRNA (3 mg/kg) PBS INHBE GalNAc-siRNA (10 mg/kg) Single dose INHBE GalNAc-siRNA * * * * * *
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36 INHBE GalNAc -siRNA can be used synergistically with GLP -1s or to curtail weight regain after the cessation of treatment with GLP -1 Data from preclinical studies conducted in DIO mice; Left: 10nmol/kg in mouse is equivalent to therapeutic dose of GLP -1s in human. Left Stats: Linear Mixed Effects ANOVA with post hoc comparisons of marginal treatment effects of Semaglutide vs. Semaglutide + INHBE GalNAc -siRNA per time point * p < 0.05; Right Stats: Linear Mixed Effects ANOVA with post hoc comparison of Day 28 vs. Day 56 marginal effects per treatment * p < 0.05 p<0.05 Not significant PBS Semaglutide + INHBE GalNAc-siRNA Semaglutide Difference in body weight (% of PBS, same time point) Daily GLP-1 Dose INHBE GalNAc-siRNA Semaglutide Control for Semaglutide INHBE GalNAc-siRNA Control for siRNA Semaglutide + INHBE GalNAc-siRNA Daily GLP-1 Single dose INHBE GalNAc-siRNA ~2x greater weight loss After cessation of GLP-1: Curtails weight re-gain✓ Day Combined with GLP-1: Greater weight loss✓ Day
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37 Potent and durable Activin E reduction of greater than 70% in preclinical models delivers weight loss similar to GLP -1 Semaglutide 10 nmol/kg in mouse is equivalent to therapeutic dose of GLP-1s in human PBS semaglutide INHBE GalNAc-siRNA INHBE siRNA semaglutide Single dose INHBE GalNAc-siRNA Weight loss with INHBE GalNAc-siRNA more gradual versus semaglutide 0 50 100 150 %Activin E (%Control) Durable Activin E reduction one-month following a single dose
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38 Treatment with INHBE GalNAc -siRNA expected to improve key measures of cardiometabolic health Measures of metabolic improvements ↓ Fat reduction Improved cardiometabolic outcomes Risk of CVD Risk of T2D Reduction of INHBE mRNA and circulating Activin E Adipocyte lipolysis Adipocyte size Proinflammatory macrophages in adipose Fibrosis Insulin sensitivity
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39 Suppressing adipose remodeling and fibrosis in inguinal subcutaneous adipose INHBE siRNA improves insulin sensitivity, cellular energetics, and beiging of white adipose tissue Upregulation Insulin sensitivity Fatty acid utilization for energy production Adaptive thermogenesis (beiging of white adipose) Downregulation Adipose remodeling and fibrosis pathways Log2FC Log2FC Adjusted p-value
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40 INHBE siRNA improves cellular energetics while suppressing inflammation and fibrosis in mesenteric visceral adipose Upregulation Innate immunity Cytokine release Downregulation Extracellular matrix remodeling (fibrosis) Glucose utilization, thermogenesis, and lipid metabolism (consistent with inguinal subcutaneous adipose) Anticipated improvement in plasticity of adipose tissues with downregulation Log2FC Log2FC Log2FC Adjusted p-value
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41 A single dose of INHBE GalNAc -siRNA led to shrinkage of adipocytes in DIO mice Data presented at ADA Scientific Sessions June 2025 ***p<0.001; Day 28 LeanDIO PBS INHBE GalNAc-siRNA Mean adipocyte diameter (μm) 0 20 40 60 80 ✱✱✱ DIO Lean PBS INHBE GalNAc- siRNA DIO
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42 Macrophages (Mᶲ) (F4/80) Pro-inflammatory (M1) Mᶲ (CD11c) Anti-inflammatory (M2) Mᶲ (CD163) Data presented at ADA Scientific Sessions June 2025 ***p<0.001, *p<0.05, ns=non-significant A single dose of INHBE siRNA led to a lower inflammatory state of visceral adipose tissues in DIO mice, with strong suppression of pro -inflammatory M1 macrophages in visceral fat PBS PBS INHBE GalNAc siRNA 10 mg/kg3 mg/kg INHBE GalNAc siRNA 10 mg/kg3 mg/kg PBS 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kgPBS 0.0 0.2 0.4 0.6 0.8 1.0 %F4/80 positive area ✱ PBS 3 mg/kg 10 mg/kg PBS INHBE GalNAc siRNA 10 mg/kg3 mg/kg
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43 Lowering of inflammatory state of epiWAT visceral fat induced by single dose of INHBE siRNA resulted in 58% reduction of adipose fibrosis Data are means ± SEM of 6 mice. Each dot represents an individual mouse. Kruska-Wallis test with Dunn’s multiple comparisons. *P<0.05 0 5 10 15 ✱ PBS 3 mg/kg 10 mg/kg Reduced staining illustrates decreased tissue fibrosis Fibrosis in mouse adipose (Day 56) Trichrome % Trichrome positive area PBS 3 mg/kg 10 mg/kg
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44 WVE-007 has potential to be a convenient therapeutic option to drive fat loss, while preserving muscle • Human genetic data of INHBE LoF carriers support potential for INHBE-siRNA to drive healthy metabolic outcomes • WVE-007 siRNA includes proprietary chemistry, including PN-chemistry and unique design to support highly potent and durable silencing • Potent and durable INHBE mRNA reduction of >70% observed in preclinical studies • Treatment with INHBE GalNAc-siRNA expected to improve key measures of cardiometabolic health based on preclinical data • WVE-007 is currently being evaluated as monotherapy in ongoing INLIGHT clinical study
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45 INLIGHT clinical study and target engagement update Chris Wright, MD, PhD Chief Medical Officer
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46 INLIGHT: Dose escalation continues in single -dose portion, follow -up ongoing from multiple therapeutic cohorts SAD: single-ascending dose; MAD: multi-ascending dose Randomized, double-blind, placebo-controlled (3:1) study of ascending doses of WVE-007 SAD Cohort 5 SAD Cohort 4 600 mg (Expanding to n=32) SAD Cohort 3 400 mg (Expanded to n=32) SAD Cohort 2 240 mg (Expanded to n=32) SAD Cohort 1 75 mg (n=8) • Objective: Assess dose safety, tolerability, PK and PD • Key study criteria: - HbA1c: <5.9 - BMI: 28 – 35 kg/m2 (SAD) • Key measurements - Primary: Safety and tolerability - Secondary: PK, Activin E - Exploratory PD: • Body weight • Body composition (including DEXA) • Biomarkers • Multiple clinical trial sites, including US MAD Cohort 3 MAD Cohort 2 MAD Cohort 1
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47 WVE-007 is safe and well tolerated to date; no discontinuations Today’s update: Activin E biomarker data from single -dose Cohorts 1, 2 and 3 Cohort 3 400 mg Cohort 2 240 mg Cohort 1 75 mg Activin E biomarker data includes - 1 month of follow-up (Day 29) from Cohort 3 (n=8) - 1 month of follow-up (Day 29) from Cohort 2 (n=32) - 6 months of follow-up (Day 169) from Cohort 1 (n=8)
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48 -85% -75% -56% Highly significant, dose dependent Activin E reductions following a single dose of WVE -007 Figure shows sample means and SEMs. All MMRM baseline and placebo comparisons from Day 8 onwards are p<0.007. For change fro m baseline at day 29 all dose groups were p<0.0001. Placebo includes one individual from 400 mg expansion. Single dose WVE-007 (GalNAc-siRNA) Activin E change in INLIGHT
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49 Figure shows sample means and SEMs. All MMRM baseline and placebo comparisons from Day 8 onwards are p<0.007. Placebo include s one individual from 400 mg expansion. Single dose WVE-007 (GalNAc-siRNA) Highly durable Activin E reductions with WVE -007 supporting dosing once or twice per year Activin E change in INLIGHT
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50 Clinical Activin E reductions after single dose of WVE -007 exceed levels leading to weight loss in preclinical studies Left: semaglutide 10nmol/kg in mouse is equivalent to therapeutic dose of GLP-1s in humans INHBE siRNA semaglutide Single dose INHBE GalNAc-siRNA Preclinical studies >70% Activin E reductions led to weight loss INLIGHT clinical trial >70% Activin E reductions achieved Daily GLP-1 Single dose WVE-007 (GalNAc-siRNA) Placebo WVE-007 75 mg WVE-007 240 mg WVE-007 400 mg
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51 Estimated from Wilding, et al. NEJM 2021, 384, 989. Assumes 34% of weight loss at each timepoint is from lean mass loss (Kin g, et al, Impact of Semaglutide on Body Composition in Adults with Overweight or Obesity: Exploratory Analysis of the STEP 1 Study , Association of British Clinical Diabetologists (ABCD), 14 October 2021, virtual meeting [poster presentation]) INLIGHT includes evaluations across multiple cohorts and follow -up periods to detect metabolic, body composition improvements, and weight loss Weekly doses of semaglutide Placebo-adj. weight loss due to fat or lean mass loss Single dose cohorts 3 months 6 months -1.6% -2.5% -3.4% -4.4% -10% -8% -6% -4% -2% 0% 4 8 12 16 20 28 36 44 52 60 68 Follow-up WVE-007 aims to achieve fat loss on par with semaglutide by 6 months post-single dose Fat Mass Lean Mass Semaglutide Clinical Study (STEP-1): Placebo-Adjusted Weight Loss from Fat and Lean Mass Reduction Activin E Potent, durable reductions achieved Associated biomarkers Signals of metabolic improvement Fat mass Reductions Lean mass No reductions (preservation) Body weight Reductions INLIGHT initial clinical data updates aim to achieve: Weight loss from:
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52 Multiple near -term clinical anticipated data updates for WVE -007, including body weight and body composition Clinical target engagement update: • WVE-007 led to dose-dependent, potent and durable Activin E reductions in INLIGHT clinical study - Activin E reductions exceed levels that led to weight loss in preclinical models - Potential for once or twice yearly dosing • Safe and well-tolerated to date; 600 mg ongoing (Cohort 4) • Follow-up ongoing with multiple clinical data updates expected starting in 4Q 2025 600 mg 400 mg 75 mg 240 mg 2Q 20261Q 20264Q 2025 Follow-up (n=8) 3 month follow-up (n=32) 6 month follow-up (n=32) 9 month follow-up (n=32) 3 month follow-up (n=32) 3 month follow-up (n=32) 6 month follow-up (n=32)
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53 SpiNA: Advancing a best-in-class siRNA capability Chandra Vargeese, PhD Chief Technology Officer
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54 Single well-defined compounds Novel base and sugar chemistry modifications Novel backbone modifications https://wavelifesciences.com/science/publications/ For over a decade Wave has been extending the frontiers of RNA therapies through advances in nucleic acid chemistry Addition of PN modification increases: Cell uptake, endosomal release, residency, nuclear uptake, target engagement Optimize pharmacological profiles✓ Optimize sequence✓ Optimize stereochemistry✓ Addition of base modifications led to dramatic increase RNA editing efficiency
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55 mRNA silencing following single dose Protein reduction following single dose Left: single subcutaneous dose of 2 mg/kg in C57BL/6 mice; Right: single subcutaneous dose of 0.5 mg/kg in C57BL/6 mice Ref, NAR: Liu et al., 2023 Nucleic Acids Research doi: 10.1093/nar/gkad268 Substantial improvements in duration of activity and potency achieved through chemistry optimization with SpiNA GalNAc-siRNAs 0 0 25 50 75 100 125 Days Serum Ttr SEM (rel to PBS) PBS Ref SpiNA1NAR SpiNA2 30 60 90 120 PBS Day 7 Day 28 Day 56 Day 7 Day 28 Day 56 Day 7 Day 28 Day 56 Day 7 Day 28 Day 56 0 100 %mRNA remaining (mTTR / mHPRT) 50 25 PBS NAR SpiNA-1 SpiNA-2Ref SpiNA-1 SpiNA-2 SpiNA: Stereopure interfering Nucleic Acid
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56 siRNA pharmacokinetics siRNA Ago2 loading Left: single subcutaneous dose of 2 mg/kg in C57BL/6 mice; Right: single subcutaneous dose of 0.5 mg/kg in C57BL/6 mice; Ref+NAR: Liu et al., 2023 Nucleic Acids Research doi: 10.1093/nar/gkad268 SpiNA GalNAc-siRNAs demonstrate >10 -fold improvement in Ago2 loading versus reference siRNAs Day 7 Day 28 Day 56 Day 7 Day 28 Day 56 Day 7 Day 28 Day 56 Day 7 Day 28 Day 56 0 10 20 30 ug of siRNA/g of tissue (Mean ± SEM) Ref NAR SpiNA1 SpiNA2 Ref NAR SpiNA-1 SpiNA-2 Ref NAR SpiNA-2
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57 SpiNA Targeting White Adipose Tissue SpiNA Targeting Heart SpiNA Targeting Skeletal Muscle PN variants in SpiNA achieve robust and durable target engagement in extrahepatic tissues Silencing was durable out to at least 3 months following single, subcutaneous dose
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58 In vivo silencing at 8 weeks following a single dose Directing silencing to high priority extrahepatic tissues in mice using siRNA Liver and Adipose Targeting siRNA Liver Targeting siRNA Adipose Targeting siRNA Non-GalNAc + PN variantsGalNAc + PN Achieved by changes in physicochemical properties without requirement for LNP or other delivery agents Liver WAT Muscle Heart 0 25 50 75 100 125 Relative expression Liver WAT 0 25 50 75 100 125 Relative expression siRNA silencing siRNA silencing 0 25 50 75 100 125 Relative expression
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59 Robust and consistent knockdown of mRNA and protein in liver and adipose achieved with a single dose Left Stats: Linear Mixed Effects ANOVA on log2-transformed values Z-scored per tissue type with post hoc comparisons of marginal treatment effects vs. PBS per tissue Right Stats: Linear Mixed Effects ANOVA with post hoc comparisons of marginal time point effects vs. Week -1 per treatment group, * p<0.05 EpiWAT - epididymal white adipose tissue, mesWAT - mesenteric white adipose tissue, iBAT - interscapular brown adipose tissue % mRNA remaining (mean + SE) Liver epiWAT mesWAT iBAT PBS SpiNA variant SpiNA variant B % protein remaining (mean + SE) >50% reduction in serum triglycerides Effectively reduce fasting serum triglycerides in mice
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60 Early generation SOD1 mRNA knockdown Broad distribution in kidney Single 10 mg/kg SC dose Early generation SpiNA variants drove durable 50% knockdown with broad distribution and activity across cell types with a single dose Sod1-3 Sod1-2 Sod1-1 Cell nucleisiRNA Work performed in collaboration with GSK
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61 Single cell RNA -seq analysis demonstrates knockdown in various cell types in the kidney Work performed in collaboration with GSK Distal tubule cells Endothelial cells Intercalated cells Macrophages Proximal tubule cells PodocytesEndothelial cellsDistal tubule cells Mesangial cells Podocytes Principal cells Proximal tubule cells
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62 SpiNA variant drove 75% mRNA knockdown and sustained 50% knockdown up to 3 months post single dose with broad distribution and protein reduction in kidney Left side: Single subcutaneous administration of 5 or10 mg/kg to C57BL/6 mice on D0, necropsy 1,2 -,or 3-months post dose. SOD1 mRNA expression assessed in the kidney. Right side: Hematoxylin staining was performed to identify cell nuclei, followed by Immunohistochemistry and miRNAscope staining for SOD1 protein and SOD1 siRNA, respectively. C: cortex; OM: outer medulla; IM: inner medulla; P: papilla. PBS treatedSOD1-4 treated C OM IM OM IM C PP Broad distribution and Protein Reduction 1 month 2 months 3 months 0 25 50 75 100 125 Relative mRNA expression PBS 5 mg/kg 10 mg/kg PBS 5 mg/kg 10 mg/kg SOD1 mRNA knockdown siRNA SOD1 protein Cell nuclei 1 month 2 months 3 months C OM IM P
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63 SpiNA variant achieves broad distribution in kidney with corresponding protein reduction through 3 months post single 5 mg/kg dose Protein Reduction siRNA SOD1 protein Cell nuclei PBS treated SOD1-4 treated 1 month 2 months 3 months 10x 10x 10x 40x 40x Single subcutaneous administration of 5 mg/kg to C57BL/6 mice on D0, necropsy 1,2 -,or 3-months post dose. Hematoxylin staining was performed to identify cell nuclei, followed by Immunohistochemistry and miRNAscope staining for SOD1 protein and SOD1 siRNA, respectively.
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64 ~50% editing 1 week post dose Broad distribution Initial AIMer optimization leads to improved editing, duration, and distribution in kidney PBS ADR-0101520 ADR-0102506 ADR-0102535 PBS ADR-0101520 ADR-0102506 ADR-0102535 0 20 40 60 Percent Editing (UGP2) Week 1 Week 2 PBS NTC AIMer-1 AIMer-2 % Editing (UGP2) PBS Cell nuclei AIMer AIMer-2 AIMer-1
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65 Non-targeting control AIMer-1 AIMer-2 Work performed in collaboration with GSK Single cell RNA -seq analysis shows efficient editing in multiple cell types in the kidney 0.00 0.25 0.50 0.75 0.00 0.25 0.50 0.75 0.00 0.25 0.50 0.75 Proportion of edited base Proportion of edited base Proportion of edited base
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66 Reimagining RNA medicines: Combining modalities to simultaneously knockdown and edit RNA with single oligonucleotide construct SpiNA AGO2 ✓ Engage both endogenous Ago2 and ADAR enzymes ✓ Silence one target, while simultaneously editing or upregulating another unique target ✓ Unlock complex indications that require engaging multiple targets ✓ May continue to increase durability of editing AIMer ADAR Single Oligonucleotide Construct
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67 Single oligo construct achieves higher UGP2 mRNA editing Single oligo construct achieves robust TTR mRNA silencing WT C57BL/6J mice were subcutaneously injected with equimolar concentration of indicated compounds, and liver biopsies were co llected at indicated timepoints Left: UGP2 RNA editing was measured by Sanger sequencing and normalized to % editing for UGP2 AIMer at day 7. Stats: 2-way ANOVA with Dunnett post-hoc comparison to AIMer Right: TTR transcript knockdown was measured by qPCR using the ΔΔCt method . Stats: Welch's One-Way ANOVA with Dunnett's T3 post hoc-comparison ****<0.0001 Single GalNAc-conjugate oligonucleotide construct demonstrate more durable editing than traditional AIMers with comparable knockdown in vivo Increased editing and knockdown engaging both ADAR and Ago2 with single oligonucleotide construct in vivo with single dose PBS TTR SpiNA UGP2 AIMer Single oligo construct 7 14 21 28 0.0 0.5 1.0 1.5 Days RNA Editing Fold Change Relative to UGP2 AIMer (Mean, SEM) **** **** 0.0 0.5 1.0 1.5 Day 28 TTR mRNA Rel. to PBS (Mean, SEM) **** **** PBS TTR SpiNA UGP2 AIMer Single oligo construct Editing Silencing
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68 Primary human hepatocytes were treated in vitro with indicated compounds for 96 hours. Left: LDLR protein was measured using an ELISA; Stats: Welch's One-Way ANOVA with Dunnett's T3 post hoc-comparison. Right: PCKS9 transcript was measuring by qPCR using the ΔΔCt method Demonstrates potential to address complex indications that require engaging multiple targets Single GalNAc -conjugated oligonucleotide construct can simultaneously upregulate and silence protein in vitro LDLR Protein upregulation PCSK9 mRNA knockdown LDLR protein (pg)/ Total protein (ug) PBS PCSK9 SpiNA LDLR AIMer Single oligo construct PCSK9 mRNA ref. to PBS (Mean, SEM) 0 50 100 150 **** **** 0.0 0.5 1.0 1.5 PBS PCSK9 SpiNA LDLR AIMer Single oligo construct
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69 Closing remarks Paul Bolno, MD, MBA President and CEO
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70 Reimagining RNA medicines: Today’s updates • Rapidly advancing WVE-006: first-in-class RNA editing therapeutic for AATD — RestorAATion-2 Cohort 3 underway at 600 mg; 400 mg multidose data expected in 1Q 2026, 600 mg single and multidose data expected 2026 • Building on successful translation of RNA editing with WVE-008 for PNPLA3 liver disease — Potential first-in-class, disease modifying therapy; large patient population with high unmet need — CTA filing on track for 2026 • Highly significant, dose-dependent mean reductions of Activin E up to 85% with WVE-007 in INLIGHT — Exceeding Activin E reductions that led to weight loss in preclinical studies; potential for dosing 1 – 2x per year; safe and well tolerated to date — WVE-007 aims to achieve fat loss on par with semaglutide by 6 months post-single dose — Multiple clinical data updates expected, including body composition and body weight, starting 4Q 2025 • Platform innovations: extra-hepatic delivery and an emerging new modality — PN variants enable tuning of SpiNA (potential best-in-class siRNA format) for extra-hepatic silencing — Emerging modality adds capability to simultaneously edit and silence two unique targets with a single oligonucleotide construct
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71 WVE-006 AATD WVE-008 PNPLA3 Liver Disease Other hepatic targets Extra-hepatic targetsRNA Editing WVE-007 Obesity RNAi Other hepatic targets Extra-hepatic targets Poised for significant and sustained growth driven by editing and siRNA
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72 Q&A Spotlight on RNA editing and RNAi Research Day 2025
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