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Today's agenda PRESENTATION SPEAKER Paul Bolno, MD, MBA Opening

Remarks President and CEO Chandra Vargeese, PhD Applying PRISM Principles for Rational Oligonucleotide Design Chief Technology Officer Chandra Vargeese, PhD Building a Best-in-Class ADAR Editing Capability: Introducing AIMers Chief Technology

Officer Ken Rhodes, PhD Advancing ADAR Editing in the CNS SVP, Therapeutics Discovery Paloma Giangrande, PhD Restoring Functional AAT Protein with ADAR Editing: Program Update VP, Platform & Discovery Sciences Biology Q&A Paul Bolno, MD, MBA

Closing Remarks President and CEO 3

Opening Remarks Paul Bolno, MD, MBA President and CEO 4

We are taking part in a genetic revolution Greater understanding

of genetic Wave is developing therapeutics to drug drivers of disease and definition at the transcriptome to turn on, switch molecular level off, or modulate expression of faulty genes >6,000 genetically defined diseases

Increase in genetic testing enabling identification of individuals likely to DNA benefit from treatment Many diseases beyond RNA the reach of traditional treatments Protein Sources: Shen et al, Genetics Research, 2015; Hopkins et al, Nat Rev Drug

Discov, 2002; geneticdiseasefoundation.org 5

Strategic decision to intervene at RNA level RNA-targeting therapeutics

offer ideal balance of precision, durability, potency, and safety Address underlying genetic Defined path to drivers of disease commercialization Durable effects to enable Simplified delivery infrequent dosing 6

Biological machinery in our cells can be harnessed to treat genetic

diseases Editing Silencing Splicing Oligonucleotide- Leverages exon skipping Efficient editing of RNA directed delivery of RNA machinery to restore a bases using endogenous to regulate enzymes working transcript ADAR

Endogenous RNase H Endogenous AGO2 RISC Endogenous Restored Reading ADAR enzyme Frame 7

Unlocking the body's own ability to treat genetic disease DESIGN

OPTIMIZE Chemistry Unique ability to construct Provides the resolution to Sequence single isomers and control observe this structural three structural features of interplay and understand how oligonucleotides to efficiently it impacts key

pharmacological engage biological machinery properties Stereochemistry Built-for-Purpose Candidates to Optimally Address Disease Biology Silencing | Splicing | RNA Editing 8

Wave is the leader in chirally-controlled rationally designed stereopure

oligonucleotides Stereochemistry is a Chirality matters: affects PRISM controls reality of chemically- pharmacology of stereochemistry modified nucleic acid oligonucleotides in throughout drug discovery therapeutics vitro and in vivo and development

process Current therapeutics with chiral Increasingly recognized by leaders Enables design and optimization backbone modifications: in nucleic acid therapeutics: of fully-characterized, single- isomer RNA therapeutics Antisense siRNA

oligonucleotides Exon-skipping mRNA oligonucleotides therapeutics RNA guide strands Dominant IP portfolio and unique ability to manufacture and screen stereopure oligonucleotides 9 Jahns et al., NAR, 2021; Hansen, et al. 2021; Funder, Albaek et al.

PRISM platform is continuously improving Design & optimize PN

chemistry Stereochemistry Choose Machine modality to learning Rapidly Genetic code Predictive best address develop modeling carried by Scalable, genetic target clinical RNA to cost-effective candidates in predict manufacturing Silencing reproducible

sequence Splicing way In vivo Editing models Iterative analysis of Platform in vitro and improves as in vivo learnings outcomes from each program are applied Continuous definition of design principles deployed across programs 10

Improvements in PRISM primary screen hit rates accelerate drug

discovery Primary screen hit rates with silencing far above industry standard hit rates Chemistry, PN stereochemistry & machine learning optimization 100 80 80.0% (2020 - current) 60 55.4% (2019) 40 Stereopure 32.9% 20 Stereorandom 12.2% 0

Chemistry improvements and PRISM advancement All screens used iPSC-derived neurons; Data pipeline for improved standardization. Hit rate = % of oligonucleotides with target 11 knockdown greater than 50%. Each screen contains >100

oligonucleotides. ML: machine learning % Hit Rate

Data sciences enable prediction of new potential therapeutic

exon-skipping targets Model trained on millions of Predicts skippable exons that Identifies clinically relevant known protein sequences are currently undiscovered genes with skippable exons Is an exon amenable Identified ~2,500 potential exon-

Identified >10,000 exons that to exon-skipping skipping targets with are predicted to be skippable but oligonucleotides? oligonucleotide therapeutics as are currently unannotated compared ~100 identified skippable in literature Experimentally

Exon ByPASS predicted Many predicted confirmed skippable but (PubMed) unannotated exons are validated in public data ~2500 genes ~100 genes Exon ByPASS: predicting Exon-skipping Based on Protein Amino acid SequenceS; Data presented at OTS 2021.

Manuscript submitted 12

Advancing programs using multiple modalities Silencing Skipping Editing

ALS and FTD DMD AATD C9orf72 (WVE-004) Exon 53 (WVE-N531) SERPINA1 Huntington's disease mHTT SNP3 (WVE-003) Neurology Multiple undisclosed targets ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; DMD: Duchenne muscular

dystrophy; AATD: Alpha-1 antitrypsin deficiency 13

Building a leading genetic medicines company Scientific

approach focused on unlocking the body's own ability to treat genetic disease PRISM platform enables multiple modalities for built-for-purpose therapeutics Leading the way in rationally designed stereopure oligonucleotides with

innovative backbone chemistry Robust portfolio of PN-modified, stereopure oligonucleotides, including three programs in clinic and multiple ADAR editing discovery programs 14

Applying PRISM Principles for Rational Oligonucleotide Design Chandra

Vargeese, PhD Chief Technology Officer 15

PRISM platform enables rational drug design Sequence Chemistry 5'

B B: bases R: 2' modifications A, T, C, mC, G, U, OMe, MOE, F, 3' 2' other modified bases other modifications X R 5' B Stereochemistry X: backbone chemistry 2' PO, PS, PN3' Chiral control of R any stereocenter

5' modifications, backbone modifications 16

Optimization framework compatible across different modalities Interplay

between key structural ..to modulate key and apply to multiple components of oligonucleotides aspects of activity therapeutic modalities Silencing Potency Tissue exposure Splicing (exon-skipping) Duration of

activity ADAR editing 17

Innovating new backbone chemistry modifications PRISM backbone linkages

PO PS PN B B B O O O O O O (Sp) (Rp) O O O R R R O O O P P P - - O S N B B B O O O O O O O O O R R R Phosphoryl guanidine Chirality Chirality Chirality x-ray structure None PN backbone Rp PS backbone

Rp PN backbone Sp PS backbone Sp Negative Negative Neutral example charge charge charge PO: phosphodiester PS: phosphorothioate 18

Rationally placed stereopure PN modifications enhance pharmacology

across modalities example and improves key pharmacological Adding PN linkages benefits all drivers of translation PRISM modalities Efficient engagement Target knockdown, Silencing Potency of RNase H or Ago2 splicing or

editing In the right tissues, Efficient uptake in Splicing Exposure cells and cellular the cell nucleus compartments Enabling infrequent Efficient engagement Editing Durability administration of ADAR 19

Potency is enhanced with addition of PN modifications across modalities

Silencing Splicing Editing Target knockdown (% remaining) % Skipping % Editing 100 80 60 40 20 0 -8 -6 -4 -2 0 2 10 10 10 10 10 10 Concentration ( M) Concentration ( M) Ranked by potency of reference PS/PO compound Ranked by potency of

reference PS/PO compound PS/PO/PN PS/PO (Stereopure) PS/PO reference compound PS/PN modified compound PS/PO (Stereorandom) Left: Experiment was performed in iPSC-derived neurons in vitro; target mRNA levels were monitored using qPCR against a

control gene (HPRT1) using a 20 linear model equivalent of the DDCt method; Middle: DMD patient-derived myoblasts treated with PS/PO or PS/PO/PN stereopure oligonucleotide under free-uptake conditions. Exon-skipping efficiency evaluated by qPCR.

Right: Data from independent experiments Improved knockdown Improved skipping % Editing Improved editing

Adding PN chemistry modifications to C9orf72- targeting

oligonucleotides improved potency in vivo Cortex Spinal Cord C9orf72-targeting oligonucleotides PS/PO backbone chemistry PS/PO/PN backbone chemistry Exposure ( g/g) Exposure ( g/g) Improved tissue exposure Target knockdown: Liu, TIDES

poster 2021; Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% 21 confidence intervals (shading) for PK-PD analysis. Manuscript submitted. %C9orf72 V3 transcript remaining Improved

Adding PN chemistry modifications led to overall survival benefit in

dKO model PN-containing molecules led to 100% dKO survival 100 PS/PO/PN, 150 mg/kg weekly PS/PO/PN, 75 mg/kg bi-weekly PS/PO, 150 mg/kg weekly 75 PBS 50 25 Note: Untreated, age-matched mdx mice had 100% survival at study termination [not shown] 0 0

4 8 12 16 20 24 28 32 36 40 Time (weeks) dKO; double knockout mice lack dystrophin and utrophin protein. mdx mice lack dystrophin. Left: Mice with severe disease were euthanized. dKO: 22 PS/PO/PN 150 mg/kg n= 8 (p=0.0018); PS/PO/PN 75 mg/kg n=9

(p=0.00005); PS/PO n=9 (p=0.0024), PBS n=12 Stats: Chi square analysis with pairwise comparisons to PBS using log-rank test. Manuscript submitted. Survival probability (%)

PN chemistry improves exposure and target engagement in key tissues

p 0.0001 p 0.0001 p 0.0001 Exon-skipping oligonucleotides PS/PO p 0.0001 backbone chemistry p 0.0001 PS/PO/PN p 0.01 backbone chemistry p 0.0001 p 0.0001 p 0.0001 6x weekly 75 mg/kg subcutaneous

doses; Sample collected 2 days after last dose. Manuscript submitted 23

PRISM principles applied to another class of silencers: siRNA PRISM

siRNA AGO2 RISC Complex 24

Application of PRISM principles to siRNA improves another class of

silencers PN chemistry improves potency and durability of ESC format Potency Durability Ago2-loading mTtr mRNA (liver) mTTR protein (serum) Guide strand-Ago2 IP (liver) Dose (2 mg/kg) Dose (6 mg/kg) **** 15 125 35x 100 100 ~2-fold 75 10 75 **** **

50 50 5x 25 5 25 -5 p < 1.0 x 10 0 0 0.6 10 20 30 40 0 2 6 0 Time (days) Dose (mg/kg) siRNA chemistry PBS ESC Ref PS/PO PN/PS/PO Ttr-targeted siRNA (Left) C57Bl/6 mice administered single 0.2, 2 or 6 mg/kg subcutaneous dose on day 1. Tissue

harvested on day 8. Stats: 2-way ANOVA with post-hoc comparison to ESC. (Middle) Mice received single 6 mg/kg subcutaneous dose on day 1. Serum collected weekly. Stats: 2-way mixed ANOVA with post hoc comparisons PN vs Reference. (Right) As

described for 25 left panel (2 mg/kg); Ago2 loading measured by qPCR after immunoprecipitation (IP) and normalized to miR-122; Stats: 1-way ANOVA followed by Tukey's honest significance test. ** P<0.01, *** P<0.001****, P<0.0001. All

post-hoc P values Bonferroni-corrected for multiple hypotheses. Reference: Enhanced Stabilization Chemistry ESC Ref PS/PO PN/PS/PO % Ttr mRNA remaining % Serum Ttr (relative to pre-dose) Relative Guide strand loading (Ttr/miR-122)

Application of PN chemistry to siRNA: Improving on the state-of-the-art

PN chemistry extends duration of GalNAc-conjugated Advanced ESC format Enhanced duration of activity with PN Dose mTTR protein (serum) (1 mg/kg) PBS Adv ESC Ref PN/PS/PO PN extends 50% knockdown period for GalNAc-conjugated Adv ESC 100

siRNAs 75 Further optimization studies are in progress 50 50% increase in duration of activity 25 -12 p < 1.0 x 10 0 0 20 40 60 80 Time (days) Mice received a single 1 mg/kg subcutaneous dose on day 1. Serum was collected weekly. Stats:

2-way mixed ANOVA with post hoc comparisons PN vs 26 Reference. P value is Bonferroni corrected for multiple hypotheses. % Serum Ttr (relative to PBS)

PRISM provides visibility into effects of backbone stereochemistry

within every sequence Backbone stereochemistry impacts pharmacologic properties PRISM enables stereochemical control to fully characterize and investigate structure activity relationship (SAR) of each therapeutic candidate

Standard in small molecule and antibody development Backbone stereochemistry can be a tool to modulate pharmacologic properties, including tolerability 27

A single stereoisomeric change can dramatically alter the tolerability

profile in vivo GalNAc conjugated Isomer1 Same sequence and chemical oligonucleotide administered modifications, but different stereochemistry subcutaneously Isomer2 Stereoisomers have similar Changing backbone stereochemistry leads to different

hepatotoxicity profiles in vivo pharmacodynamic effects Target knockdown ALT AST Tnfrsf10b **** (liver) *** **** 1500 10000 150 15000 125 10000 5000 1000 100 5000 1000 75 1500 ns 750 500 50 1000 500 500 25 250 0 0 0 0 C57Bl/6 mice were administered

5 mg/kg oligonucleotide or PBS by subcutaneous injection on days 1, 3, 5 and 8. Liver tissue was collected on day 11. 28 Target mRNA was normalized to Hprt1. Data are presented as mean sem (n=5). Stats: One-way ANOVA ns not significant, PBS

phosphate buffered saline, NTC non-targeting control Undisclosed target Percentage mRNA remaining ALT (U/L) AST (U/L) Tnfrsf10b (normalized to PBS)