Slide 1: Wave Life Sciences Corporate Presentation
Exhibit 99.1 Wave Life Sciences Corporate Presentation October 4, 2022
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: Unlocking the body's own ability to treat genetic disease
UNLOCKING THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE realizing a brighter future for patients and families 3
Slide 4: Building a leading genetic medicines company
Building a leading genetic medicines company LEVERAGING THE ONGOING TARGETING THE TRANSCRIPTOME TO UNLOCK THE GENETIC REVOLUTION BODY’S OWN ABILITY TO TREAT GENETIC DISEASE >6,000 monogenic Increase in Innovative Platform Diversified Pipeline diseases; genetic vastly more Stereopure oligonucleotides
Slide 5: Rational design of oligonucleotides enables access to unique disease targets
Wave’s ability to rationally design oligonucleotides enables access to unique disease targets 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 No
Slide 6: Harnessing biological machinery in our cells to treat genetic diseases
Harnessing the biological machinery in our cells to treat genetic diseases RNA Base Editing Silencing Splicing • Degradation of RNA transcripts • Restore RNA transcripts and • Efficient editing of RNA bases to turn off protein production turn on protein production to restore or modulate protein prod
Slide 7: 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 stereopure oligonucleotides observe this structural and control three structural interplay and understand how features to efficiently engage it impacts
Slide 8: Robust portfolio of stereopure, PN-modified oligonucleotides
Robust portfolio of stereopure, PN-modified oligonucleotides THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NE NE UROL UROL O O G G YY ALS and FTD WVE-004 (FOCUS-C9) C9orf72 Takeda 50:50 option Huntington’s disease WVE-003 (SELECT-HD) mHTT SNP3 SCA3 ATXN3 CNS diseases Multi
Slide 9: WVE-004 ALS and FTD
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 10: C9orf72 repeat expansions: common genetic causes of ALS and FTD
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Hexanucleotide (G C )- repeat 4 2 expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Typically 100’s- 1000’s of GGGGCC repeats Different manifestations across a clinical spectrum Amyotrophic L
Slide 11: WVE-004 addresses each biological aspect of C9orf72-associated ALS and FTD
WVE-004 addresses each biological aspect of C9orf72- associated ALS and FTD RNA variants Disease drivers C9orf72 protein V1 V2 V3 C9orf72 Poly(GP) biomarker 1 Decrease in Genetic mutation Loss-of- selected as preferred beneficial function protein Reduced DPR biomarker Repeat- Wild-type expression ex
Slide 12: Preclinical WVE-004 durable reduction of poly(GP)
ug of oligo / g of tissue ug of oligo / g of tissue Preclinical studies with WVE-004 demonstrated durable reduction of poly(GP) in spinal cord and cortex 6 months after two doses Preclinical in vivo results: C9orf72 protein Six months unchanged at 6 months Spinal Spinal cord 8 150 1.5 1.5 cord ns 6
Slide 13: WVE-004 clinical data demonstrate translation of preclinical approach
WVE-004 clinical data demonstrate successful translation of preclinical approach to clinic Target engagement confirmed in patients PK/PD modeling using preclinical in vivo supports advancing FOCUS-C9 clinical study models predicted pharmacodynamically active starting dose ✓ Poly(GP) reduction in cor
Slide 14: FOCUS-C9 clinical trial underway
FOCUS-C9 clinical trial underway Single dose Multidose 60 mg n=4 Target 30 mg engagement n=10 Dose and frequency to observed in be guided by DSMB 20 mg single dose n=10 cohorts 10 mg 10 mg Open-label extension (OLE) clinical trial n=6 n=3 Initiation anticipated in 2H 2022 4 monthly doses Additional
Slide 15: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 16: mHTT toxic effects lead to neurodegeneration
mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Huntington’s disease (HD) Healthy individual • Wild-type HTT (wtHTT) is critical * for normal neuronal function • Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein
Slide 17: WVE-003: Allele-selective oligonucleotide designed to lower mHTT
WVE-003: Allele-selective oligonucleotide designed to lower mHTT while sparing wtHTT wtHTT supports healthy brain function, especially in the context of stress Promotes neuronal Supports synaptic Regulates synaptic Supports cilia and CSF survival protein transport plasticity circulation Only wtHTT-s
Slide 18: Allele-selective molecule decreases mHTT, spares wtHTT
Allele-selective molecule decreases mHTT, spares wtHTT; Pan-silencer uniformly decreases both Allele-selective activity in CNS of Hu97/18 mice mHTT wtHTT Cortex Striatum 150 150 **** * *** **** *** **** **** **** 100 100 50 50 0 0 4 8 12 4 8 12 4 8 12 4 8 12 4 8 12 4 8 12 Time (weeks) Time (weeks) P
Slide 19: WVE-003 selective, potent, durable reduction of mHTT preclinically
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in Durable striatal mHTT knockdown for 12 weeks in BACHD mouse model HD iPSC neurons in vitro *** **** **** **** **** **** Weeks PBS Pan-silencing WVE-003 reference compou
Slide 20: Initial results indicating allele-selective target engagement with WVE-003
Initial results indicating allele-selective target engagement with WVE-003 suggests translation of preclinical data Reductions in mean CSF mHTT and preservation of wtHTT observed in PK/PD modeling using preclinical in pooled analysis of single dose cohorts in SELECT-HD clinical study vivo models pre
Slide 21: Expanding single dose cohorts to optimize dose level
Expanding single dose cohorts to optimize dose level based on initial results • mHTT protein reductions • Adapting 90 mg Expanding cohort observed in single dose clinical trial to cohorts optimize dose Adding additional level 60 mg • wtHTT protein levels appear patients to each Expanding cohort cons
Slide 22: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 23: Duchenne muscular dystrophy
Duchenne muscular dystrophy Duchenne muscular dystrophy • Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function. • Dystrophin protein established by FDA as surrogate endpoint reasonably likely to predict benefit in 1 patien
Slide 24: PN chemistry improved muscle exposure and survival in mouse models
PN chemistry improved muscle exposure and survival in preclinical mouse models PN boosted muscle concentrations after Treatment with PN-modified molecules led to 100% single dose, which correlated with survival of dKO mice at time of study termination exon-skipping activity 100 Better tissue exposur
Slide 25: PS/PO/PN compound restores muscle and respiratory function in dKO mice
PS/PO/PN splicing compound restores muscle and respiratory function to wild-type levels in dKO mice Muscle Function Respiratory Function Minute Volume Tidal Volume Specific Force (EDL) 300 150 0.3 200 100 **** 0.2 **** 50 100 0.1 0 0 0.0 21 28 35 42 49 Wild-type 20 40 60 80 100 120 21 28 35 42 49 Ag
Slide 26: WVE-N531: Dystrophin restoration in vitro and muscle distribution in NHPs
WVE-N531: Dystrophin restoration in vitro and enhanced muscle distribution in NHPs Dystrophin protein restoration of up to 71% in vitro Enhanced muscle distribution in NHPs Western Blot normalized to Plasma and tissue concentrations of primary healthy human myoblast lysate WVE-N531 (PS/PO/PN) signif
Slide 27: Dosing at human equivalent doses explored in dKO model
Currently dosing at human equivalent doses in the range explored in preclinical dKO model dKO mouse model Plasma WVE-N531 concentrations compared to plasma suvodirsen concentrations 1000 100 Dose 1 - WVE-N531 (PS/PO/PN) Dose 2 - WVE-N531 (PS/PO/PN) 10 Dose 3 - WVE-N531 (PS/PO/PN) 5 mg/kg - Suvodirse
Slide 28: Dose escalation ongoing in clinical trial of WVE-N531
Dose escalation ongoing in clinical trial of WVE-N531 • Open-label clinical trial of boys with DMD amenable to exon 53 skipping • Dose level and dosing frequency guided by tolerability and plasma PK Initial cohort Possible cohort expansion (up to 15 boys) - Ascending intra-patient doses of - Additio
Slide 29: WVE-006 Alpha-1 antitrypsin deficiency (AATD)
WVE-006 Alpha-1 antitrypsin deficiency (AATD)
Slide 30: WVE-006: Designed to correct mutant SERPINA1 transcript
WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD WVE-006 designed to correct WVE-006 ADAR editing approach to address key goals of AATD treatment: Z allele mRNA to enable M-AAT protein to be produced 2) Reduce Z-AAT 1) Restore circulating,
Slide 31: ~50% RNA editing expected to increase serum AAT to PI*MZ levels
~50% RNA editing expected to increase PI*ZZ patient serum AAT levels to PI*MZ levels, with low risk of disease Serum AAT Protein Levels and Risk of AATD by Genotype 100% M-AAT protein 50 ~2.5-7-fold higher 25 100% Z-AAT protein 0 Null ZZ SZ MZ MM Risk of Very High High Low Very Low No Emphysema Risk
Slide 32: WVE-006 supports dose-dependent RNA editing in human model systems
WVE-006 supports dose-dependent RNA editing in human preclinical model systems iPSC-derived human hepatocytes Efficient SERPINA1 editing in donor-derived (ZZ genotype) primary human hepatocytes with WVE-006 (MZ genotype) 80 100 60 WVE-006 90 40 80 20 70 60 0 0.08 0.31 1.25 5.0 50 Mock treated Concen
Slide 33: WVE-006 results in circulating AAT protein 7-fold above PBS
WVE-006 results in circulating AAT protein levels 7-fold above PBS control, well above established 11µM threshold WVE-006 treatment results in serum AAT protein SERPINA1 mRNA editing in liver of levels >11 uM in AATD mouse model (NSG-PiZ mice) AATD mouse model (NSG-PiZ mice) (Week 13) ns 2000 60 PBS
Slide 34: WVE-006 restores wild-type M-AAT protein in serum
WVE-006 leads to restoration of confirmed, wild- type M-AAT protein in serum Overall percentages of serum AAT protein isoforms in NSG-PiZ mice (Week 13) Z-AAT 100 • Mass spectrometry confirms restoration of circulating 80 healthy M-AAT protein in vivo 60 after WVE-006 treatment Wild-type 40 M-AAT pr
Slide 35: Increased neutrophil elastase inhibition indicates functional M-AAT protein
Significant increase in neutrophil elastase inhibition activity indicates restored M-AAT protein is functional Serum neutrophil elastase Increased neutrophil elastase inhibition activity inhibition activity demonstrates ns ✱✱✱✱ functionality of AAT protein 100 • Increases in neutrophil elastase, 80
Slide 36: Early lead AATD AIMer reduces Z-AAT aggregation and inflammation
Early lead (pre-optimization) AATD AIMer reduces aggregation of Z-AAT and inflammation in mouse liver Lobular inflammation (19 weeks) 15 25 **** PBS 5 * Early lead AATD AIMer p<0.0001 20 p=0.03 4 10 15 p<0.01 3 5 10 ** 2 5 1 0 4 8 19 0 0 Weeks following first dose AIMer PBS PBS AIMer Early lead pre-
Slide 37: AIMer-directed editing is highly specific in mice
AIMer-directed editing is highly specific in mice No bystander editing observed on SERPINA1 transcript RNA editing only detected at PiZ mutation site in SERPINA1 transcript RNA editing across transcriptome (mouse liver) (mouse liver) C 0% SERPINA1 PBS (PiZ mutation site) T 100% C 48.2% AATD AIMer T
Slide 38: WVE-006 potential first- and best-in-class candidate for AATD
WVE-006 is a potential first- and best-in-class candidate for AATD • Correct Z-allele mRNA to replace mutant Z-AAT protein with functional wild- type M-AAT protein – RNA editing levels show potential to support conversion of a patient from ZZ to MZ mRNA expression – M-AAT protein can address lung di
Slide 39: Planning for clinical development for WVE-006 underway
Planning for clinical development for WVE-006 underway Phase 1/2 placebo-controlled study to establish dose and evaluate target engagement Single-ascending dose (SAD) cohorts Multiple-ascending dose (MAD) cohorts Final cohort in Pi*ZZ patients • Assess dose & frequency • Effective dose to be selecte
Slide 40: AIMers RNA base editing capability
AIMers RNA base editing capability
Slide 41: 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 Stereochemistry and PN chemistry enhance oligonucleotides potency and editing efficiency of GalNAc ADAR enzymes (No need for LNPs or viral vectors) AIMers in primary human
Slide 42: AIMers: Realizing potential of therapeutic RNA editing
AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Delivery and Efficient ADAR Stability intracellular Beyond liver ✓ Efficient ADAR recruitment trafficking recruitment • AIMe
Slide 43: Preclinical RNA editing data published in Nature Biotechnology
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022) • Specificity in vitro & in vivo (NHPs)• GalNAc conjugation • In vitro-in vivo translation (NHPs)• Foundational AIMer SAR AIMers detected in liver of NHP at Day 50 Substantial and durable editing in NHP ADAR
Slide 44: Systemic in vivo editing without delivery vehicles
Systemic in vivo editing without delivery vehicles Substantial RNA editing across multiple tissues following single subcutaneous dose of UGP2 AIMer Control Specific liver associated cells UGP2 AIMer (unconjugated) T cell Cholan- Macro- NK cell LSEC giocyte phage subset Editing: Potent, durable, spec
Slide 45: Substantial in vivo editing without delivery vehicles in CNS tissues
Substantial in vivo editing without delivery vehicles in CNS tissues UGP2 AIMer-1 Peak RNA editing observed one-month post-single dose across tissues PBS Peak 30% >40% 25% >40% 50% >65% editing Potential CNS editing targets to benefit from learnings taken from clinical CNS silencing programs Transge
Slide 46: Expanding addressable disease target space using AIMers
Expanding addressable disease target space using AIMers to activate pathways and upregulate expression Correct G-to-A driver mutations with AIMers Modulate protein interactions with AIMers Modulate protein- Restore or correct Achieved protein interaction protein function POC Upregulate expression WV
Slide 47: Dose dependent modulation of protein/protein interactions
Dose dependent modulation of protein/protein interactions Dose-dependent gene upregulation (NQO1) in vitro following Nrf2 editing to disrupt protein/protein interaction KEAP1 RNA editing efficiency Gene upregulation NQO1 qPCR NRF2 % Editing 0.0016uM NRF2 is 0.0016uM 0.008uM degraded by 0.008uM prote
Slide 48: AIMers enable activation of gene pathway in vivo with single edit
AIMers enable activation of gene pathway in vivo with single edit NRF2 downstream gene upregulation following GalNAc AIMer Nrf2 liver editing in vivo Nrf2 mRNA editing in vivo in liver of mRNA editing in vivo in liver of mice mice with GalNAc AIMers Nrf2 activation Nrf2 activation of of NQO1 express
Slide 49: Upregulation: AIMers can edit RNA motifs to upregulate gene expression
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression RNA binding proteins recognize sequence motifs to regulate various mRNA properties Stability Transport Processing Protein production • Enhance or inhibit • Intracellular localization • Splicing • Translational efficien
Slide 50: AIMers upregulate gene expression in hepatocytes and T-cells in vitro
AIMers can edit RNA motifs to upregulate gene expression in hepatocytes and T-cells in vitro Editing RNA Motifs to regulate RNA half-life to upregulate RNA expression is possible for clinically-relevant targets, including both metabolic and immune targets Target A Target B Target C Target D 15 5 8 8
Slide 51: Considerations to translate Target A upregulation results in vivo
Proof-of-concept: Considerations to translate Target A upregulation results in vivo Mouse model may underpredict potential Target A (undisclosed liver target) translation of Target A upregulation • High unmet need with potential for multiple large indications Human 15 • Preserves endogenous protein
Slide 52: AIMers upregulate mRNA and downstream serum protein in vivo
AIMers upregulate mRNA and downstream serum protein in vivo above anticipated threshold Target A mRNA editing mRNA upregulation Protein upregulation (undisclosed liver 7 days post-initial dose 7 days post-initial dose 7 days post-initial dose target) GalNAc AIMer GalNAc AIMer GalNAc AIMer 20 • High
Slide 53: RNA editing of MECP2 nonsense mutation 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 54: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 55: Improvements in PRISM primary screen hit rates
Improvements in PRISM primary screen hit rates accelerate drug discovery over time 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 Stereora
Slide 56: Potency enhanced with 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) Ranked by potency of reference Concentration (mM) PS/PO compound Ranked by pot
Slide 57: 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 Oligonucleotide concentrations quantif
Slide 58: PN chemistry improves distribution to CNS
PN chemistry improves distribution to CNS Distribution of oligonucleotides in non-human primate CNS 1-month post single IT dose Cerebral Cortex Striatum Oligonucleotide (red staining) Backbone PS/PO chemistry PS/PO/PN Midbrain Cerebellum Hippocampus Spinal cord 58 NHPs administered 1x12 mg oligonucl
Slide 59: PRISM PN siRNA led to silencing >3 months after single dose
PRISM PN siRNA led to unprecedented silencing >3 months after single dose Ag Ao2 go2 lloa oadindin g g (liver, transgenic mice) (liver, transgenic mice) 25 HSD17B13 mRNA Wk2 Wk 7 Wk 14 (liver, transgenic mice) 20 125 15 100 75 10 50 * * 5 **** 25 0 0 0 2 4 6 8 10 12 14 16 Time (weeks) Reference 2 PB
Slide 60: Established internal GMP manufacturing for multiple oligonucleotide modalities
Established internal GMP manufacturing for multiple oligonucleotide modalities Strong technical knowhow Established and operating expertise infrastructure • Experienced team led by Sridhar • State of the art facilities (90,000 Vaddeboina, PhD (SVP sq ft) and expansion space Chemistry, Manufacturing,
Slide 61: Upcoming milestones
Upcoming milestones 61
Slide 62: Continued clinical validation of PRISM platform and PN stereochemistry
Continued clinical validation of PRISM platform and PN stereochemistry ✓ Delivered clinical target engagement data with single doses • Additional single and multidose data in 2H 2022 WVE-004 C9orf72 ALS & • Discussions with regulatory authorities regarding next phase of CNS Silencing FTD development
Slide 63: 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 63 63