Slides
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2026
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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 Presentation Speaker Opening remarks Paul Bolno, MD, MBA President and Chief Executive Officer From genetic risk to genetic correction: The future of PNPLA3 liver disease Arun J. Sanyal, MD, FAASLD Professor of Medicine, Physiology, and Molecular Pathology at VCU Medical Center WVE-008: PNPLA3 AIMer for liver disease Erik Ingelsson, MD, PhD Chief Scientific Officer RNAi (SpiNA design) differentiation and clinical translation Chandra Vargeese, PhD Chief Technology OfficerUnlocking extra-hepatic delivery with PN conjugates Bifunctional modalities: Silence, edit or upregulate Closing remarks Paul Bolno, MD, MBA President and Chief Executive Officer Q&A All Today’s agenda RNA editing for PNPLA3 liver disease Wrap-up PRISM® platform innovations
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Paul Bolno, MD, MBA President and CEO Opening Remarks
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To unlock the broad potential of RNA medicines to transform human health Our Mission
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6 Unlocking the potential of RNA medicines • Wave is developing a toolbox of therapeutic modalities that target the transcriptome to turn on, switch off, modulate the expression of genes, or modulate multiple targets • We are in the midst of a revolution in human genetics bringing a greater understanding of the genetic and molecular drivers of disease • There are over 6,000 genetically defined diseases, comprised of both rare diseases and a rapidly growing number of strong targets for common diseases • An increase in genetic testing has enabled identification of individuals likely to benefit from treatment with precision RNA medicines Gene-Disease Network A network of rare and common diseases and associated phenotypes with strong genetics support (Data source: GWAS Catalog)
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7 1975 2000 • Mixtures of 2n molecules1 • Potential for >1 million different molecules per dose Phosphorothioate (PS) 2’-4’-cEt2’-O-methyl 2’-F 2’-4’-LNA2’-MOE Phosphorodiamidate Morpholino (PMO) 1. n=number of chiral centers PRISM® platform has unlocked novel and proprietary advances in oligonucleotide design that are now translating in the clinic Present Backbone stereochemistry SpiNA (siRNA)PN N3U (editing) Standard Chemistry Clinical Translation PN conjugates (extra -hepatic)
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8 Pair the modality that best addresses the target Design & optimize with PRISM chemistry: Advance clinical candidates rapidly and reproducibly Scalable, cost-effective manufacturing Select targets strongly supported by human genetics PRISM® platform is continuously improving Design principles refined program after program, applied across the pipeline Model-guided design Models score millions of candidate chemistries to prioritize those for synthesis Design Test Predict AI/ML across the workflow… Human genetics (UK Biobank, FinnGen, All of Us, others) Analyze target biology, delivery, biomarkers, and feasibility Predictive models of sequence and chemistry Cross-program modeling of design principles Synthesis models predict and design more efficiently Learning across programs Standard backbones build shared training data across programs
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9 Arun J. Sanyal, MD, FAASLD PNPLA3 liver disease and opportunity for RNA editing WVE-008 (GalNAc-AIMer) PNPLA3 RNA editing program advancing towards clinic siRNA SpiNA design: innovations are translating in clinic PN conjugates Beyond GalNAc: Unlocking extra-hepatic delivery to multiple tissues Bifunctional modalities Silence, edit, upregulate two unique targets What you will hear today: RNA editing PRISM® platform innovations
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10 Guest speaker: Arun J. Sanyal, MD, FAASLD • Arun J. Sanyal, MD, is ranked in the top 0.1% of all biomedical scientists by Stanford University rankings. • Dr. Sanyal serves as Chairman of the NIH NASH Clinical Research Network, the NIMBLE and MASH track projects of FNIH, and the Liver Forum for NASH and fibrosis. • He chaired the hepatobiliary pathophysiology study section of the NIH and was a founding member of the Hepatology committee of the American Board of Internal Medicine. • He has also served as Secretary as well as President of the American Association for the Study of Liver Diseases. • Dr. Sanyal has authored more than 500 articles in the highest tier journals such as the New England Journal of Medicine, Lancet, and Nature Medicine. He has an H- index of 163 and his work was cited almost 18,000 times in previous year alone. • He has pioneered the development of diagnostics and therapeutics for end stage liver disease and fatty liver disease and currently leads multiple global trials for this condition. • He is the recipient of the American Liver Foundation (ALF) 2026 National Legacy Gala Leadership Award, Distinguished Mentorship Award from the American Gastroenterological Association, and the Distinguished Scientific Achievement Award from the American Liver Foundation in 2017 and the Distinguished Achievement Award from the AASLD in 2018. Professor of Medicine, Physiology, and Molecular Pathology in the Division of Gastroenterology at Virginia Commonwealth University (VCU) Medical Center Professor of Medicine, Physiology, and Molecular Pathology in the Division of Gastroenterology at VCU Director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health
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From Genetic Risk to Genetic Correction: The Future of PNPLA3 Liver Disease Arun J. Sanyal M.D. Z Reno Vlahcevic Professor of Medicine Director, Stravitz-Sanyal Institute for Liver Disease and Metabolic Health Virginia Commonwealth University School of Medicine
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Discovery of PNPLA3 I148M (rs738409) association with liver disease transformed hepatology through human genetics PNPLA3 I148M & steatosis PNPLA3 I148M & MASH / fibrosis PNPLA3 I148M & cirrhosis / HCC PNPLA3- multiple roles in maintaining lipid droplet health PNPLA3- HSC retinyl esterase PNPLA3 I148M in ALD PNPLA3 I148M increase liver - related death PNPLA3 I148M as a driver for steatotic liver disease PNPLA3 I148M in overall liver health Multiple clinical trials on PNPLA3 GalNAc-silencing agents Announcement of WVE -008: First RNA-editing to address root cause of PNPLA3-liver diseases Failure of the first phase 2 PNPLA3 silencing (FORTUNA)
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PNPLA3 I148M demonstrates strong association with liver cirrhosis (GWAS analyses) Ghouse, J. et al. Nature Genetics 2024, 56, 827 Chromosomal location of SNPs
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PNPLA3 I148M is the clearest genotype-defined MASLD/MASH target
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Global prevalence of PNPLA3 rs738409 variant in MASLD / MASH patients by world region Souza, M., et al. Journal of Clinical and Experimental Hepatology 2025, 15, 102495 Younossi, Z., et al. Hepatology 2023, 77, 1335 G-allele Frequency of PNPLA3 I148M among MASLD Patients Country / Region Est Prevalence of MASLD with Homozygous PNPLA3 I148M United States 18M Europe (Germany, France, Italy, Spain, UK) 12M China 75M Japan 10M Mexico 15M
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PNPLA3 I148M is the strongest genetic risk factor for fibrosis and HCC Bruschi, F., et al. Hepatic Medicine: Evidence and Research 2017:9 55–66
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Homozygous PNPLA3 I148M leads to faster MASLD disease progression and worse outcome Effect of PNPLA3 G-allele on risk of MALO at strata of exposures Effect of age on the risk of MALO at strata of PNPLA3 genotypes Chalasani et al, 2024 Vilar Gomez et al, 2025
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PNPLA3 I148M is associated with poorer prognosis Thrift, A. et al. Clin Gastroenterol Hepatol. 2024 22(9): 1858 NHANES data: Unalp-Arida, et al. Hepatology 2020 Swedish cohort study: Ekstedt, et al. Liver Intl 2022 PNPLA3 GG is associated with decompensation or composite end point, after adjusting for age, gender, diabetes, and BMI (aOR 1.64, 95% CI 1.19-2.25) in the IU cohort of ~ 800 NAFLD patients prospectively followed NASH CRN analyses are ongoing Heterozygous I148M Homozygous I148 Homozygous 148M Multivariate-adjusted cumulative liver disease mortality by PNPLA3 I148M genotype Homozygous 148M Cirrhosis-free survival time in NAFLD patients without advanced fibrosis Homozygous I148 Heterozygous I148M
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Effect of PNPLA3 I148M is amplified with obesity and alcohol use Thrift, A. et al. Clin Gastroenterol Hepatol. 2024 22(9): 1858 PNPLA3 risk allele noncarrier PNPLA3 risk allele carrier Hazard Ratio No Current Heavy Alcohol Current Heavy Alcohol BMI < 30 BMI > 30 1 1.54 0.86 1 1.83 1.51 2.4
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How PNPLA3 I148M mutation worsens fibrosis and exacerbates MASH progression PUFA-rich VLDL Retinyl ester Retinol Issues with I148M mutation: Disrupts lipid-droplet remodeling in hepatocytes, retains triglycerides and promotes steatosis & inflammation Impairs retinyl ester hydrolysis in hepatic stellate cells and accelerates fibrosis Attenuates proteosome autophagy and further exacerbates MASH progression PNPLA3 biology supports RNA editing over silencing approach
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MASH resolution with Tirzepatide was weaker in G-allele (mutant) carriers than in CC (wild-type) carriers Overall CC CG GG CG+GG 0 20 40 60 80 100Proportion of participants *** ** ** *** n N 2 23 55 83 17 18 0 8 2 13 26 43 0 2 12 22 2 15 38 65 Placebo Tirzepatide pooled *p<0.05; **p<0.01; ***p<0.001 for comparison vs. placebo. N=total number with measure; n=participants achieving the endpoint. Significantly more participants achieved MASH resolution without worsening of fibrosis with tirzepatide vs. placebo in the overall population, CC, CG and CG+GG combined The placebo-corrected treatment effect of tirzepatide was significantly higher with CC vs CG+GG combined (p=0.033)† †Interaction between the treatment effect of tirzepatide and genotype (CC versus CG + GG); p = 0.033 Sanyal et al. (2024) TLM24
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Why is mutation correction through RNA editing an optimal solution for PNPLA3 I148M liver disease ? PNPLA3 interacts with regulatory proteins and enzymes on lipid droplet to maintain hepatic lipid homeostasis. Mutation correction restores lipid homeostasis, reduces steatosis and prevents liver injury. PNPLA3 plays critical roles in control of hepatic retinol homeostasis, inflammation and oxidative stress. In turn, the I148M mutation promotes fibrosis and MASH progression. Mutation correction attenuates hepatic inflammation and oxidative stress. Consequently, it will lead to lowering of fibrosis and MASH resolution.
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Erik Ingelsson, MD, PhD Chief Scientific Officer WVE-008: PNPLA3 AIMer for Liver Disease
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24 Clinical translation of WVE -006 unlocks broad opportunity in RNA editing ✓ ✓ ✓ ✓ Efficient and consistent editing Restore dynamic physiological response Durable RNA editing supporting infrequent dosing Generally safe and well tolerated WVE-006 for AATD Wave is the leading RNA editing company
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25 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 WVE-008 for PNPLA3 I148M liver disease GalNAc-RNA editing approach uniquely aims to restore PNPLA3 function to fully address genetic liver disease Over nine million homozygous PNPLA3 I148M individuals with genetic liver disease in US and Europe 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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26 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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27 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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28 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 scale Potent editing with WVE-008 Proprietary chemistry✓ Subcutaneous delivery (GalNAc) ✓ Potential for infrequent dosing ✓ Highly specific editing ✓
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29 PNPLA3 AIMers achieve efficient editing of PNPLA3, leading to reduction of fat accumulation in hepatocytes 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 0 500 1000 1500 ( ) ns ✱✱✱✱ PBS PNPLA3 siRNA PNPLA3 AIMer Lipid Droplet Density (pixel2/cell) (mean + SE) Day 3 Day 7 Day 14 0 50 100 150Percent Normalized Lipid Droplet Density (%) PBS NTC WVE-008 NTC 100 µm 100 µm 100 µm Percent Normalized Lipid Droplet Density (%) WVE-008 NTC PBS
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30 PNPLA3 AIMers distribute evenly across all three zones of liver Human PNPLA3 I148M transgenic mice were dosed with a single subcutaneous injection of 10, 30 or 100 mg/kg PNPLA3 AIMer or PBS . PNPLA3 AIMer was detected by in situ hybridization in liver tissues collected at 7 days following the initial dose. Red signal: RNAscope ISH probe for detecting PNPLA3 AIMer; Blue signal: DAPI nuclear counterstain Zone 1 Zone 2 Zone 3 Zone 1: Periportal hepatocytes Zone 2: Intermediate hepatocytes Zone 3: Pericentral hepatocytes Portal triad Central vein 100 µm
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31 PNPLA3 AIMer presence in hepatic stellate cells supports a direct anti - fibrotic mechanism of RNA editing Human PNPLA3 I148M transgenic mice were injected with a single (10, 30 and 100mg/kg) subcutaneous dose (n=4) of AIMer-3 or PBS. Immunofluorescence was performed in liver collected at 7 days after the initial dose, PNPLA3 AIMer (red), DAPI (blue, cell nuclei), desmin (green, HSC). The colocalization of PNPLA3 AIMer and desmin was shown in yellow signal. Representative images (20X) from the 10mg/kg and PBS treatment groups were shown here. Images were quantified by HALO, digital pathology image-analysis platform. Each bar represents mean ± SEM of n=4. The %editing in HSC was analyzed by Sanger sequencing of liver tissue collected 7 days after 30mg/kg Q2W for 10 weeks in human PNPLA3 I148M transgenic mice. PNPLA3 AIMer AIMer+Desmin+DAPI Desmin PBS PNPLA3 AIMer 10 mg/kg % Editing (G%) Over 60% editing observed in hepatic stellate cells HSCsPBS 0 20 40 60 80
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32 WVE-008 has potential to reduce steatosis, inflammation, and fibrosis, and improve MASH resolution in patients homozygous for PNPLA3 I148M WVE-008 corrects I148M mutation and restores its normal function in hepatocytes and hepatic stellate cells
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33 • Large addressable patient population with no treatment options directly targeting PNPLA3 I148M-driven liver disease • Preclinical data demonstrate: - Substantial editing expected to reverse MASH progression - Restoration of lipid regulation for improvement of liver health and decreases in liver fat - Broad distribution across all three zones of the liver, and in hepatic stellate cells, which supports a direct anti-fibrotic mechanism of RNA editing • Clinical development planning underway for a first-in-human clinical study - Leveraging previously genotyped populations to efficiently identify homozygous I148M carriers - Initial study to enroll homozygous carriers to assess safety, tolerability, pharmacokinetics, and pharmacodynamic endpoints Expect to file Clinical Trial Application (CTA) for WVE-008 in 4Q 2026 Potential best -in-class, disease modifying treatment for homozygous PNPLA3 I148M carriers with liver disease
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Chandra Vargeese, PhD Chief Technology Officer PRISM® Platform Innovations
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35 Today’s PRISM® platform update: RNAi (SpiNA design) differentiation and clinical translation1 Unlocking extra-hepatic delivery with PN conjugates2 Bifunctional modalities: Silence, edit or upregulate3
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36 Single well-defined compounds Novel backbone modifications Novel base and sugar chemistry 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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37 Wave’s leading chirally-controlled rationally designed stereopure oligonucleotides are translating in clinic Chirality matters: Backbone stereochemistry affects pharmacology PRISM® platform controls stereochemistry Several Nobel Prizes featured stereochemistry, including the 2026 prize in Chemistry Oligonucleotide isomers with same target engagement can have opposite tolerability profiles Design and optimization of fully- characterized, single-isomer oligonucleotides can improve pharmacology including potency, duration, and tolerability Chirality enhances Ago2 loading Dominant IP portfolio Unique ability to manufacture and screen stereopure oligonucleotides, without significant increase to cost 2021 OTS presentation; nobelprize.org/prizes/chemistry/2026/press -release/
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38 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 NAR SpiNA-1 SpiNA-2Ref SpiNA-1 SpiNA-2 SpiNA: Stereopure interfering Nucleic Acid % mRNA remaining (mTTR / mHPRT) Serum Ttr +SEM (rel to PBS) PBSDay 7Day 28Day 56 Day 7Day 28Day 56 Day 7Day 28Day 56 Day 7Day 28Day 56 0 100 50 25 Dose
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39 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 7Day 28Day 56Day 7Day 28Day 56Day 7Day 28Day 56Day 7Day 28Day 56 0 10 20 30 ug of siRNA/g of tissue (Mean ± SEM) Ref NAR SpiNA1 SpiNA2Ref NAR SpiNA-1 SpiNA-2 Ref NAR SpiNA-2 ug of siRNA /g of tissue (Mean + SEM) Relative TTR guide strand /miR-143/Ref (fold change, + SE)
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40 PCSK9 protein reduction following single dose LDLR protein upregulation downstream of PCSK9 knockdown Transgenic mice expressing human PCSK9 were dosed subcutaneously with a single 3 mg/kg dose of indicated GalNAc -siRNA. Serum was collected at indicated timepoints for PCSK9 protein analysis by ELISA. Liver punches were collected at day 56 to analyze hepatic LDLR protein content by ELISA. All resul ts were normalized to PBS treated animals; Bar graph stats: Ordinary one-way ANOVA with Dunnett’s multiple comparisons test relative to PBS group. (*) p ≤ 0.05 Substantial improvements in duration and efficacy achieved with PCSK9 SpiNA LDLR Protein in Liver as a % of PBS %PCSK9 Protein Remaining (relative to pre-bleed) PBS Reference SpiNA 1 SpiNA 2 0 7 14 21 28 35 42 49 56 0 50 100 Days 0 50 100 150 * * Dose
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41 WVE-007: Clinical -stage INHBE-siRNA leveraging proprietary chemistry for enhanced interactions with Ago2, better silencing Potent and durable Activin E reductions achieved following a single dose Liu et al., 2023 Nucleic Acids Research doi: 10.1093/nar/gkad268 Rational design Chirality enhances Ago2 loading Phosphoryl guanidine (PN) WVE-007 (INHBE GalNAc-siRNA) Proprietary, clinically validated chemistry✓ Subcutaneous delivery (GalNAc)✓ Potential for infrequent dosing (1 – 2x year) ✓ MID-PIWI domain Guide Strand PO g1-g7
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42 INLIGHT interim Phase 1 data reported March 26, 2026; Left: figure shows sample means and SEMs. All MMRM baseline and placebo comparisons from Day 8 onwards are p<0.003. Right: *p<0.05. All reductions are placebo-adjusted % change from baseline were estimated using an MMRM model with fixed effects for treatment group, visit, treatment-by-visit interaction, and baseline as a covariate; estimates were based on geometric mean ratios. Phase 2a multidose INLIGHT clinical trial enrolling population with higher baseline adiposity and comorbidities with expectations for greater fat loss SpiNA clinical translation: Potent and durable Activin E reductions observed leading to improvements in body composition following single dose Activin E change in INLIGHTTM trial Placebo (N=26) WVE-007 75 mg (N=6) WVE-007 400 mg (N=24) Dose WVE-007 240 mg (N=24) WVE-007 600 mg (N=24) Single dose WVE-007 (GalNAc-siRNA) Improved body composition six months following single 240 mg dose: - Significant reduction in visceral fat (-14%*) - Reduction in waist circumference (-3%) - Reduction in total fat (-5%) - Stabilization of lean mass (+2%) - Reduction in body weight (-1%) • 400 mg three-month data emphasize impact of baseline body composition on therapeutic effect • Durable and dose-dependent suppression of Activin E sustained through at least 7 months continues to support 1-2x yearly dosing • Generally safe and well tolerated Phase 1 otherwise healthy (SAD) Lower BMI of ~32 kg/m²
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43 Greater weight loss observed with increased baseline adiposity support Phase 2a design Presented at American Diabetes Association 2026 Scientific Sessions June 2026 Single dose of INHBE SpiNA results in weight loss and reduction in visceral fat, without affecting muscle mass, in DIO mice Single dose drove weight loss on par with semaglutide in mice on high-fat diet INHBE SpiNA showed no weight loss in lean mice on chow diet INHBE SpiNA Semaglutide Difference in baseline-corrected body weight (vs. control per time point, mean + SE) DIO mice (high adiposity) Lean mice (low adiposity) Days PBS INHBE SpiNA Difference in baseline-corrected body weight (vs. control per time point, mean + SE) Days Single dose INHBE SpiNA Single dose INHBE SpiNA
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44 WVE-007 has potential for use synergistically with GLP -1s or to curtail weight regain after the cessation of treatment with GLP -1, based on preclinical data Data from preclinical studies conducted in mice fed with 60% high fat diet; Left: semaglutide10 nmol/kg daily SC in mouse is equivalent to therapeutic dose of 2.4mg weekly SC in human. Left Stats: Linear Mixed Effects ANOVA with post hoc comparisons of marginal treatment effects of Semaglutide vs. Semaglu tide + 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 Not significant PBS Semaglutide + INHBE SpiNA Semaglutide Difference in body weight (% of PBS, same time point) Daily GLP-1 Dose INHBE SpiNA Semaglutide Control for Semaglutide INHBE SpiNA Control for siRNA Semaglutide + INHBE SpiNA Daily GLP-1 Single dose INHBE SpiNA ~2x greater weight loss After cessation of GLP-1: Curtails weight regain✓ Day Combined with GLP-1: Greater weight loss✓ Day
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45 The color scale of the heatmap is standard normal (mean 64.4%, SD = 25.1%). Unique chemical properties of different PN backbones allow for the tunability of delivery Conjugates beyond GalNAc: Ability to tune extra -hepatic delivery using SpiNA PN conjugates Adjusting chemical properties of PN conjugates with proprietary chemistry PN conjugates enable delivery to kidney, adipose, liver, or a combination of tissues Same sequence with different PN conjugates Kidney Liver White Adipose O O P O N N N R1 R2 PN conjugate SpiNA
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46 GalNAc conjugates for liver PN conjugates for adipose PN conjugates for adipose + liver Durable silencing at 8 weeks in vivo following a single dose Directing silencing to high -priority extrahepatic tissues in mice using SpiNA Achieved by changes in physicochemical properties without requirement for LNP or other delivery agents 0 25 50 75 100 125Relative expression siRNA silencing siRNA silencing 0 25 50 75 100 125Relative expression 0 25 50 75 100 125Relative expression siRNA silencing
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47 Directing silencing to both liver and adipose in mice using PN conjugates and SpiNA design for cardiometabolic Target A Human genetics data support that silencing Target A may improve insulin sensitivity Epididymal WAT Inguinal WAT Durability out to three months in both liver and adipose in mice following a single dose D ay 28 D ay 56 D ay 84 0 75 100 %mRNA remaining 50 25 %mRNA remaining %mRNA remaining D ay 28 D ay 56 D ay 84 0 75 100 %mRNA remaining 50 25 %mRNA remaining D ay 28 D ay 56 D ay 84 0 75 100 50 25 Liver Target A mRNA silencing in liver and adipose tissue Target A • Strong association between LoF and risk reduction for CAD and insulin resistance • Addresses historical challenge in addressing insulin resistance, a key driver of type 2 diabetes • Current insulin sensitizers have modest efficacy or carry significant safety concerns • No insulin sensitizer has been approved by FDA in over 25 years
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48 PN conjugate + SpiNA: 75% mRNA knockdown and sustained 50% knockdown up to 3 months post single dose; 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 Broad distribution and protein reduction 1 month 2 months 3 months 0 25 50 75 100 125Relative mRNA expression PBS 5 mg/kg 10 mg/kg SOD1 mRNA knockdown siRNA SOD1 protein Cell nuclei 1 month 2 months 3 months
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49 Bifunctional modalities: Silencing two distinct transcripts with a dual guide single oligonucleotide construct Dual RNAi silencing with a single construct Silence expression of two transcripts simultaneously in the same cell in tissue Requires unique chemistry design Enabled by best-in-class SpiNA design Potential to drive efficiencies in drug development and deliver value to patients, providers, and payers AGO2 AGO2 siRNA siRNA
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50 0 20 40 60 80 0 50 100 Day Serum Lp(a) Percent Remaining (Normalized to Prebleed) 0 20 40 60 80 0 50 100 Day Serum PCSK9 Percent Remaining (Normalized to Prebleed) Serum Lp(a) knockdown Transgenic mice expressing either hLPA or hPCSK9 were subcutaneously injected with equimolar concentration of the indicated c ompounds. Overnight-fasted serum was collected biweekly starting with a pre-bleed on D0. Serum protein was analyzed via ELISA, normalized to the pre -bleed concentration of each animal, and plot ted as mean ± SEM. Note: serum Lp(a) concentrations at days 14, 28, 42, and 56 include values below the LLOQ of the ELISA assay; these values are represented as the samples’ maximum potenti al concentration based on the sample dilution used and the LLOQ. Bifunctional SpiNAs have robust and durable activity comparable to mono SpiNA in mice Serum PCSK9 knockdown Lp(a) mono SpiNA Bifunctional Lp(a)-PCSK9PCSK9 mono SpiNA Dose Lp(a) PCSK9 Durable activity supports potential for once or twice-yearly dosing Dose
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51 Reimagining RNA medicines: Combining modalities to simultaneously edit, upregulate or silence RNA with a single oligonucleotide construct AGO2 Edit, upregulate, or silence with a single construct Engage both endogenous Ago2 and ADAR enzymes Silence one target, while simultaneously editing or upregulating another unique target Potential to drive efficiencies in drug development and deliver value to patients, providers, and payers May continue to increase durability of editing ADAR EDIT AIMer siRNA
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52 0.0 0.5 1.0 1.5 Day 28 **** **** 7 14 21 28 0.0 0.5 1.0 1.5 Days **** **** Potent UGP2 mRNA editing 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 Bifunctional construct demonstrates more durable editing with comparable knockdown in vivo Bifunctional construct improves durability of RNA editing, while preserving mRNA silencing with a single dose in vivo PBS TTR SpiNA UGP2 AIMer Bifunctional UGP2-TTR RNA Editing Fold Change Rel. to UGP2 AIMer TTR mRNA Rel. to PBS EDIT UGP2 TTR
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53 Upregulators: Engaging ADAR to upregulate gene expression mRNA mRNA Decay Cascade Unique RNA motifs Edited mRNA A single edited base permanently disrupts the motif Stable mRNA yields increased protein production Upregulate expression to increase endogenous protein activity “Dialed up” Gene Expression Attenuated gene expression Upregulate siRNA AGO2Loading on Ago2 potentially extends duration
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54 0.0 0.5 1.0 1.5 0 50 100 150 **** **** Bifunctional LDLR - PCSK9: upregulates and silences simultaneously, without losing efficacy in vitro 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: PCSK9 transcript was measured by qPCR using the ΔΔCt method Bifunctional construct: Upregulate + silence two distinct targets with a single GalNAc-conjugated oligonucleotide PCSK9 mRNA LDLR protein (pg)/ Total protein (ug) PCSK9 mRNA ref. to PBS (Mean, SEM) PBS PCSK9 siRNA LDLR upregulator Bifunctional LDLR-PCSK9 LDLR protein LDLR PCSK9
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55 WT C57BL/6J mice were subcutaneously injected with equimolar concentrations of indicated compounds on Days 0,2, 4 and liver biop sies were collected at day 11. Relative amounts of transcript X and Y in the liver were measured by qPCR using the ΔΔCt method. Stats: One -way ANOVA with Dunnett’s test adjustment for multiple comparisons vs. PBS Synergistic effect enables bifunctional construct to upregulate Target Y >5-fold, while achieving potent siRNA silencing of Target X Bifunctional construct demonstrates synergistic effects in vivo Target Y mRNA Target X transcript (Fold change vs. mock) Target Y transcript fold change Target X mRNA 0.0 0.5 1.0 1.5 2.0 ✱✱✱ ✱✱✱ 0 1 2 3 4 5 6 7 8 9 10 ✱✱✱ PBS Target Y (upregulator) Target X (siRNA) Bifunctional Target Y-Target X Target Y Target X
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Paul Bolno, MD, MBA President and CEO Closing Remarks
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57 Delivering on our mission to unlock the broad potential of RNA medicines • Wave’s multi-modal platform combines genetic insights and proprietary chemistry - Oligonucleotide center of excellence: in-house large-dataset integration, rational drug design, multi- model platform, and manufacturing • Advancing WVE-008 for PNPLA3 liver disease - Strong support from human genetics, with advantages over siRNA approach - CTA filing expected in 4Q 2026 • SpiNA design translating in the clinic and PN conjugates enabling extra-hepatic targets - WVE-007 has delivered potent and durable target engagement in clinic, supporting potential once or twice-yearly dosing, with a safe and well-tolerated profile - PN conjugates enable delivery beyond liver, including to adipose and kidney • Bifunctional modalities - Simultaneously silence, edit or upregulate two unique targets with a single construct; potential to increase durability of editing - Potential to drive efficiencies in development and deliver value to patients, providers, and payers
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58 Q&A Research Day 2026
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