Slide 1: Analyst & Investor Research Webcast
Exhibit 99.1 Analyst & Investor Research Webcast September 28, 2021 1
Slide 2: Forward-looking statements
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, r
Slide 3: Today's agenda
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 Tech
Slide 4: Opening Remarks
Opening Remarks Paul Bolno, MD, MBA President and CEO 4
Slide 5: We are taking part in a genetic revolution
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 • Increa
Slide 6: Strategic decision to intervene at RNA level
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
Slide 7: Biological machinery in our cells can be harnessed to treat genetic diseases
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
Slide 8: Unlocking the body's own ability to treat genetic disease
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
Slide 9: Wave is the leader in chirally-controlled stereopure oligonucleotides
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 i
Slide 10: PRISM platform is continuously improving
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 r
Slide 11: Improvements in PRISM primary screen hit rates accelerate drug discovery
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%
Slide 12: Data sciences enable prediction of new exon-skipping targets
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 e
Slide 13: Advancing programs using multiple modalities
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 m
Slide 14: Building a leading genetic medicines company
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
Slide 15: Applying PRISM Principles for Rational Oligonucleotide Design
Applying PRISM Principles for Rational Oligonucleotide Design Chandra Vargeese, PhD Chief Technology Officer 15
Slide 16: PRISM platform enables rational drug design
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, backbo
Slide 17: Optimization framework compatible across different modalities
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 • AD
Slide 18: Innovating new backbone chemistry modifications
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 S
Slide 19: Rationally placed stereopure PN modifications enhance pharmacology across modalities
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
Slide 20: Potency is enhanced with addition of PN modifications across modalities
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 (µM) Concentration (mM) Ranked by potency of reference PS/PO compound Ranked by pot
Slide 21: PN chemistry improved potency of C9orf72-targeting oligonucleotides in vivo
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 (µg/g) Exposure (µg/g) Improved tissue exposure Target knockdown: Liu, TIDES poster 20
Slide 22: PN chemistry led to overall survival benefit in dKO model
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 terminatio
Slide 23: PN chemistry improves exposure and target engagement in key tissues
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
Slide 24: PRISM principles applied to another class of silencers: siRNA
PRISM principles applied to another class of silencers: siRNA PRISM siRNA AGO2 RISC Complex 24
Slide 25: Application of PRISM principles to siRNA improves another class of silencers
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
Slide 26: Application of PN chemistry to siRNA: Improving on the state-of-the-art
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 Ad
Slide 27: PRISM provides visibility into effects of backbone stereochemistry
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 • Stan
Slide 28: A single stereoisomeric change can alter tolerability in vivo
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 le
Slide 29: Stereoisomeric changes can alter tolerability profile in the CNS
Stereoisomeric changes can dramatically alter the tolerability profile in the CNS in vivo Unconjugated Isomer 1 Same sequence and chemical oligonucleotide administered modifications, but different stereochemistry ICV Isomer 2 Changing backbone stereochemistry leads to Stereoisomers have similar diff
Slide 30: PRISM enables novel advances in oligonucleotide design
PRISM enables novel advances in oligonucleotide design for optimization of RNA therapeutics • PRISM uses deep understanding of interplay between sequence, chemistry and stereochemistry • Rationally placed PN backbone chemistry modifications improve potency, durability of effect and distribution in v
Slide 31: Building a Best-in-Class RNA Editing Capability: Introduction of AIMers
Building a Best-in-Class RNA Editing Capability: Introduction of AIMers Chandra Vargeese, PhD Chief Technology Officer 31
Slide 32: Unlocking RNA editing with PRISM platform to develop AIMers
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides Free-uptake of chemically modified oligonucleotides • First publication (1995) ✓ Learnings from using oligonucleotide to biological concepts AIMer: edit RNA with 1 endogenous ADAR ✓ Applied to ASO structural
Slide 33: Building best-in-class ADAR editing capability
Building best-in-class ADAR editing capability Topics of discussion 1 2 3 Applications Design & Optimize Translation in vivo • Restore protein expression • Modulate protein activity 33
Slide 34: ADAR editing enables correction of single-point mutations to restore functional protein
ADAR editing enables correction of single-point mutations to restore functional protein Restore functional protein Example therapeutic areas AIMer • AATD A I(G) • Rett syndrome Restore or • Recessive or correct dominant expression genetically defined diseases DNA 2 • >32,000 pathogenic human SNPs –
Slide 35: ADAR editing to modulate proteins opens wide range of therapeutic applications
ADAR editing to modulate proteins at transcript level opens wide range of large therapeutic applications Modulate downstream protein interactions with single RNA base edit Example therapeutic areas AIMer Upregulate expression • Haploinsufficient Modify function diseases A I(G) • Loss of function Mod
Slide 36: Building best-in-class ADAR editing capability
Building best-in-class ADAR editing capability Topics of discussion 1 2 3 Applications Design & Optimize Translation in vivo • Restore protein expression• Applying unique chemistry capabilities to AIMers enhances • Modulate protein activity editing • Optimization of chemistry and SAR informs design
Slide 37: Unique chemistry platform enables rational design of AIMers
Unique chemistry platform enables rational design of AIMers to efficiently recruit ADAR enzymes AIMers • RNA base editing oligonucleotides • Short, single-stranded • Fully chemically modified • Modified nucleobases • Stereopure PS and PN backbone modifications • Compatible with targeting ligands 37
Slide 38: Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers
Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers ACTB editing in primary human hepatocytes using GalNAc-mediated uptake 100 80 AIMer chemistry PS / PO / PN 60 PS / PO 40 (Stereopure) 20 PS / PO (Stereorandom) 0 -8 -6 -4 -2 0 2 10 10 10 10 10 10 Concentration (µM) Dat
Slide 39: Levels of endogenous ADAR enzyme are not rate limiting for editing
Levels of endogenous ADAR enzyme are not rate limiting for editing Primary Human Hepatocytes • Endogenous ADAR enzyme (transfection) supports editing on multiple independent targets ns 80 Single AIMer • Editing efficiency comparable Multiple AIMers targeting 60 even when additional AIMers different
Slide 40: Optimization of every dimension to inform future rational design of AIMers
Optimization of every dimension to inform future rational design of AIMers Motif on target Sequence is one of multiple dimensions for optimization NNN AIMer Sequence space is defined XAX mRNA target • >300 unique AIMers tested containing different base pair combinations • Identified base modificatio
Slide 41: ADAR interacts with dsRNA duplex in a sequence independent way
ADAR interacts with double-stranded RNA duplex in a sequence independent way RNA-editing design applicable across targets in vitro in primary human hepatocytes AIMer 80 60 A 40 I(G) 20 0 • Editing achieved across several distinct RNA transcripts • The intrinsic function of ADAR is to recognize dsRNA
Slide 42: Building best-in-class ADAR editing capability
Building best-in-class ADAR editing capability Topics of discussion 1 2 3 Applications Design & Optimize Translation in vivo • Restore protein expression• Applying unique chemistry • GalNAc-conjugated AIMers: liver capabilities to AIMers enhances • Modulate protein activity• Unconjugated AIMers: CNS
Slide 43: huADAR mouse enables optimization of AIMers to human ADAR
huADAR mouse enables optimization of AIMers to human ADAR Human ADAR expression in hepatocytes huADAR mouse Genotype Human ADAR1 ✓ huADAR/mADAR GAPDH Human ADAR expressed in all tissues • Transgenic mouse expressing Human ADAR expression in neurons human ADAR1 C57Bl/6 hADAR1 mouse mouse Human • Expr
Slide 44: GalNAc-conjugated AIMers demonstrate proof-of-concept of RNA editing in liver
GalNAc-conjugated AIMers demonstrate proof-of concept of RNA editing in liver Rapidly advancing first therapeutic program Routes of Delivery administration Tissue types GalNAc-conjugated Subcutaneous Liver AATD program Unconjugated IVT Ophthalmology Intrathecal (IT) Central nervous system (CNS) PN-m
Slide 45: GalNAc-conjugated AIMers support efficient, durable, specific ADAR editing in NHPs
GalNAc-conjugated AIMers support efficient, durable and highly specific ADAR editing in NHPs Dose-dependent editing in Substantial and durable ADAR editing with ACTB AIMer is highly specific NHP hepatocytes in vitro editing in NHP liver in vivo RNA editing within full transcriptome (primary human he
Slide 46: Unconjugated AIMers expand tissues amenable to ADAR editing
Unconjugated AIMers expand tissues amenable to ADAR editing Opportunity for future pipeline programs Routes of Delivery administration Tissue types GalNAc-conjugated Subcutaneous Liver Unconjugated MECP2 and IVT Ophthalmology undisclosed exploratory Intrathecal (IT) Central nervous system (CNS) prog
Slide 47: Up to 50% editing in vivo in the posterior of eye
Up to 50% editing in vivo in the posterior of eye one month post-single IVT dose AIMers in retina Durable, dose-dependent editing post- at 4 weeks single intravitreal dose of UGP2 AIMer-1 80 80 60 60 50 ug 40 40 20 20 10 ug 0 0 PBS 10 ug 50 ug PBS 10 ug 50 ug 1 week 4 weeks Mice received a single IV
Slide 48: AIMers direct editing in multiple CNS cell types and throughout CNS
AIMers direct editing in vitro in multiple CNS cell types and throughout CNS in vivo Editing in CNS of hADAR mouse In vitro dose-response (Single ICV injection, 100 mg) 80 100 UGP2 AIMer-1 *** *** 80 UGP2 AIMer-1 60 PBS *** 60 *** 40 40 ** ** 20 20 0 0 0.01 0.1 1 10 100 1 2 3 4 5 6 Concentration (mM
Slide 49: Substantial in vivo RNA editing out to at least months post-single dose in CNS
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues UGP2 AIMer-1 Peak RNA editing observed one-month post-single dose across tissues PBS Cortex Hippocampus Striatum Brain stem Cerebellum Spinal cord 80 80 80 80 80 80 **** ** ** 60 60 60 60 60 60 ** **** * *** * *
Slide 50: UGP2 AIMer-1 distributes throughout CNS
UGP2 AIMer-1 distributes throughout CNS Spinal cord Frontal cortex Hippocampus Cerebellum 50 Sections from treated mice 12-weeks after a single 100 mg dose of UGP2-AIMer or PBS (bottom). ViewRNA (red, Fast red) was used to detect oligonucleotides; sections are counterstained with hematoxylin (blue n
Slide 51: Productive editing in multiple NHP tissues with unconjugated systemic AIMer delivery
Achieving productive editing in multiple NHP tissues with unconjugated systemic AIMer delivery ✓ GalNAc-conjugated (Targeted - subcutaneous) Editing in NHP 1-week post-single dose ✓ Unconjugated (Local – IVT, IT) SC administration 60 ✓ Unconjugated (Systemic) 40 • NHP study demonstrated productive e
Slide 52: Productive editing in multiple immune cell types with AIMers in vitro
Achieving productive editing in multiple immune cell types with AIMers in vitro ACTB AIMer Mock Human peripheral blood CD4+ T-cell ***** mononuclear cell CD4 (PBMC) CD8+ ***** T-cell CD8 CD14 ***** CD14 Monocytes CD19 ***** CD19 B-cell NK NK ***** NK-cell Tregs ***** Treg T-cell Activate (PHA) → Dos
Slide 53: Ongoing chemistry optimization continues to drive potency gains
Ongoing chemistry optimization continues to drive potency gains In vitro dose-response in iCell neurons 80 60 ~75% more efficient editing 40 with optimized AIMers 20 0 1.0 3.0 1.0 3.0 Concentration (mM) Initial Optimized chemistry chemistry iCell neurons treated with 1 or 3 mM UGP2 AIMer with old (l
Slide 54: Rapidly advancing best-in-class ADAR editing capability
Rapidly advancing best-in-class ADAR editing capability Principles of PRISM rational chemistry capabilities design Efficient, Leverages durable and AIMers endogenous highly specific RNA editing ADAR editing in oligonucleotides enzymes multiple tissues Compatible In vivo with GalNAc for models editin
Slide 55: Advancing ADAR Editing in the CNS
Advancing ADAR Editing in the CNS Ken Rhodes, PhD SVP, Therapeutics Discovery 55
Slide 56: Substantial in vivo RNA editing out to at least months post-single dose in CNS
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues UGP2 AIMer-1 Peak RNA editing observed one-month post-single dose across tissues PBS Cortex Hippocampus Striatum Brain stem Cerebellum Spinal cord 80 80 80 80 80 80 **** ** ** 60 60 60 60 60 60 ** **** * *** * *
Slide 57: Expanding addressable disease target space using ADAR editing
Expanding addressable disease target space using ADAR editing to modulate proteins ADAR editing of Impact diseases Restore or modify protein function mRNA Post- Examples: Correction translational modification • Familial epilepsies • Neuropathic pain I(G) • Neuromuscular disorders Folding Upregulatio
Slide 58: Correct a nonsense mutation using ADAR editing to restore protein expression
Correct a nonsense mutation using ADAR editing to restore protein expression and function ADAR editing of Downstream protein interactions mRNA Post- Correction translational modification I(G) Folding Upregulation (stability) Protein- Processing protein interaction 58
Slide 59: RNA editing of nonsense mutation in MECP2 (Rett Syndrome) restores functional protein
RNA editing of nonsense mutation found in MECP2 (Rett Syndrome) restores functional protein Nonsense mutations found in Rett Syndrome can occur in multiple locations on RNA transcript: Normal: … CGA… wild type protein Variant base Rett Syndrome: … TGA… premature stop codon ADAR editing site ADAR edi
Slide 60: Restored MECP2 retains proper nuclear localization
Restored MECP2 retains proper nuclear localization Functional domains on MECP2 Cytoplasm Nucleus R168W R168W 125 Mock WT 90 FLAG MECP2 70 GAPDH 38 (Loading Control Cytoplasm) 30 25 Histone H3 DAPI FLAG (Loading Control Nucleus) 15 293T cells transfected with plasmids containing either wildtype or R1
Slide 61: Restored MECP2 binds coregulatory proteins and recruits HDAC3
Restored MECP2 binds to coregulatory proteins and recruits HDAC3, further suggesting functional restoration Functional domains on MECP2 90 FLAG 70 R168W MECP2 NCoR/SMRT complex NCoR1 260 90 TBLR1 70 IgG Heavy Chain HDAC3 50 NCoR1 - Transcriptional coregulatory proteins that facilitates the recruitme
Slide 62: ADAR editing to modulate protein-protein interactions
ADAR editing to modulate protein-protein interactions: upregulating gene expression ADAR editing of Downstream protein interactions mRNA Post- Restore translational modification I(G) Folding Upregulation (stability) Protein- Processing protein interaction 62
Slide 63: ADAR to modify protein-protein interactions: basal conditions
ADAR to modify protein-protein interactions Basal conditions KEAP1 Nrf2 Nrf2 is degraded Transcription is repressed Nrf2-mediated gene transcription program KEAP1 binds Nrf2, targeting Nrf2 for proteosomal degradation and repressing Nrf2 mediated gene transcription 63
Slide 64: ADAR to modify protein-protein interactions: ADAR modified pathway
ADAR to modify protein-protein interactions Basal conditions ADAR modified pathway ADAR editing KEAP1 KEAP1 sites Nrf2 Nrf2 is stabilized Nrf2 is degraded Nrf2 translocates to nucleus and activates gene expression Transcription is repressed Nrf2 mediated gene Nrf2 activated genes Nrf2 transcription
Slide 65: ADAR editing alters multiple amino acids on two different proteins in vitro
ADAR editing alters multiple amino acids on two different proteins in vitro Amino acid targets Changed amino acid 10 Control 9 Tyr Cys AIMer 1 8 Arg Gly AIMer 2 → Evaluated gene 7 Tyr Cys AIMer 3 KEAP1 transcription 6 Asn Asp AIMer 4 ADAR 5 Tyr base Cys AIMer 5 editing 4 Asn Asp AIMer 6 Ser Gly AIMe
Slide 66: ADAR editing activates multiple genes confirming disrupted protein-protein interaction
ADAR editing activates multiple genes confirming disrupted protein-protein interaction in vitro ADAR editing of either KEAP1 or Nrf2 directs gene activation Control SLC7a11/mRNA-B Contro 1l0 Contro 1l0 NQO1/mRNA-A Control Control Control 9 9 AIMer 1 AIMer 18 8 AIMer 2 AIMer 2 7 7 AIMer 3 AIMer 3 6 6
Slide 67: ADAR editing expands target universe in CNS
ADAR editing expands target universe in CNS • PN chemistry expands addressable CNS disease target space, enabling protein restoration and protein modulation by leveraging shared learnings across ADAR programs – Editing of UGP2 in vivo in CNS tissues is durable out to 4 months – Discovery-stage MECP2
Slide 68: Restoring Functional AAT Protein with ADAR Editing: Program Update
Restoring Functional AAT Protein with ADAR Editing: Program Update Paloma Giangrande, PhD VP, Platform Discovery Sciences 68
Slide 69: Leading RNA editing program provides optimal approach for treatment of AATD
Leading RNA editing program provides optimal approach for treatment of AATD 1) Restore circulating, 2) Reduce Z-AAT protein 3) Retain M-AAT physiological functional wild-type M-AAT aggregation in liver regulation Risk of disease Highest Null risk (lung) (no AAT) Z-AAT High PI*ZZ (lung + liver) PI*SZ
Slide 70: Today's update on AATD program
Today’s update on AATD program Demonstrate restoration of Assess specificity and Chemistry optimization to Path to development functional M-AAT candidate duration of effect improve potency 70
Slide 71: Focused on restoring wild-type M-AAT in vivo
3-Fold increase Focused on restoring wild-type M-AAT in vivo In vitro proof of concept In vivo proof of concept SERPINA1 Z allele mRNA editing 1 0 0 8 0 6 0 4 0 2 0 0 NT SA1-1 SA1-2 Liver AAT aggregation observed in AATD is recapitulated in AAT protein concentration in media mouse model * * *** * 6
Slide 72: Achieving 40% editing of Z allele mRNA at single time point
Achieving 40% editing of Z allele mRNA at single time point SERPINA1 Z allele mRNA editing levels nearing correction to heterozygote (MZ) SERPINA1 editing huADAR SERPINA1 editing huADAR mouse hepatocytes SA1-3 100 50 SA1-4• GalNAc-conjugated compounds **** 80 40 **** • Up to 40% editing of Z allele
Slide 73: ADAR editing is highly specific; no bystander editing on SERPINA1
ADAR editing is highly specific; no bystander editing observed on SERPINA1 transcript RNA editing only detected at PiZ mutation site in SERPINA1 transcript RNA editing within transcriptome (mouse liver) (mouse liver) C 0% SERPINA1 PBS (PiZ mutation site) T 100% C 48.2% SA1-4 AIMer T 51.8% % Editing
Slide 74: Therapeutically meaningful increases in circulating human AAT protein
Achieving therapeutically meaningful increases in circulating human AAT protein 3-fold increase in circulating human AAT as compared to PBS at initial timepoint Human AAT concentration in serum AAT serum levels by genotype 800 3-fold increase at day 7 PI*MZ ~3 to 5-fold increase 600 **** 11µM PI*SZ
Slide 75: ADAR editing restores circulating, functional M-AAT
ADAR editing restores circulating, functional M-AAT Significant increase in neutrophil Wild-type M-AAT detected with ADAR editing elastase inhibition with ADAR editing 3-fold increase in total AAT 100 ~2.5-fold increase 600 Pre-dose **** 80 Day 7 Human *** 60 wild-type 300 M-AAT n.s 40 20 0 0 PBS UG
Slide 76: Increase in circulating human AAT is durable
Increase in circulating human AAT is durable, with restored M-AAT detected one month post last dose Human AAT serum concentration ≥3-fold Restored wild-type M-AAT detected over higher over 30 days post-last dose 30 days post-last dose 800 M-AAT production 800 *** *** Elevated Z-AAT at Day 35 600 11
Slide 77: Optimization further improves potency
Optimization further improves potency 50% mean editing observed with half dose in mice at Day 7 SERPINA1 RNA editing huADAR mouse with GalNAc AIMers Chemistry optimization: (3x5 mg/kg, SC) ✓ Increases Z allele mRNA * editing efficiency * 60 50% editing 40 20 0 PBS SA1-4 SA1-5 SA1-6 Initial Optimized
Slide 78: Optimization further improves M-AAT restoration
Optimization further improves M-AAT restoration 4-fold increase in AAT protein (>15uM) relative to PBS at Day 7 with optimized AIMer Initial chemistry Opti Opti mimi zed zed che che mimi strsy try AAT concentration in serum AAT concentration in serum Chemistry optimization: 4-fold increase in 1000 1
Slide 79: AATD development candidate expected in 2022
AATD development candidate expected in 2022 Demonstrate restoration of Path to development Assess specificity and Chemistry optimization to functional M-AAT duration of effect improve potency candidate ✓ GalNAc-conjugated ✓ ADAR editing is highly ✓ Chemistry optimization of • Ongoing and planned AIM
Slide 80: Closing Remarks
Closing Remarks Paul Bolno, MD, MBA President and CEO 80
Slide 81: Q&A
Q&A Dr. Paul Bolno Dr. Chandra Vargeese President and Chief Technology Officer Chief Executive Officer Dr. Paloma Giangrande Dr. Ken Rhodes VP, Platform Discovery SVP, Therapeutics Discovery Sciences, Biology 81 81
Slide 82: Realizing a brighter future for people affected by genetic diseases
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations krausch@wavelifesci.com 617.949.4827 82 82