Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation May 12, 2022 Exhibit 99.2
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
Slide 4: Building a leading genetic medicines company
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; HD: Huntington’s disease; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency 1stereopure oligonucleotides and novel backbone chemistry modifications Diversified Pipeline
Slide 5: RNA-targeting therapeutics offer ideal balance of precision, durability, potency, and safety
Established regulatory, manufacturing, access and reimbursement pathways Continued progress towards longer dosing intervals while still being reversible and titratable Freely taken up by cells in multiple tissues or compatible with simple ligands – no need for complex delivery vehicles Changes erron
Slide 6: Harnessing the biological machinery in our cells to treat genetic diseases
Harnessing the biological machinery in our cells to treat genetic diseases Silencing Splicing RNA Base Editing Degradation of RNA transcripts to turn off protein production Restore RNA transcripts and turn on protein production Efficient editing of RNA bases to restore or modulate protein production
Slide 7: Built-for-Purpose Candidates to Optimally Address Disease Biology
Built-for-Purpose Candidates to Optimally Address Disease Biology Silencing | Splicing | RNA Editing DESIGN Unique ability to construct stereopure oligonucleotides and control three structural features to efficiently engage biological machinery OPTIMIZE Provides the resolution to observe this struct
Slide 8: Robust portfolio of stereopure, PN-modified oligonucleotides
THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NEUROLOGY Takeda 50:50 option ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple 100% global DMD Exon 53 100% global HEPATIC AATD – lung and liver disease SERPINA1 100% globa
Slide 9: WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 10: C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Typically 100’s-1000’s of GGGGCC repeats Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD) Hexanucleotide (G4C2)- repeat expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Diff
Slide 11: WVE-004 targets repeat-containing transcript variants
WVE-004 targets repeat-containing transcript variants that lead to production of pathological mRNA products and toxic DPR proteins and loss of normal C9orf72 function, which is important for normal regulation of neuronal function and the immune system Wave selected the poly(GP) DPR because it is a s
Slide 12: Preclinical studies with WVE-004 demonstrated durable reduction of poly(GP)
* *** ** *** Spinal cord Relative poly(GP) levels (normalized to PBS) Cortex >90% knockdown of poly(GP) DPR protein Two doses of WVE-004 Six months >80% knockdown of poly(GP) DPR protein Relative poly(GP) levels (normalized to PBS) p≤0.0001 Liu et al., 2022 Molecular Therapy Nucleic Acids doi: 10.10
Slide 13: WVE-004 clinical data demonstrate successful translation of preclinical models to clinic
WVE-004 clinical data demonstrate successful translation of preclinical models to clinic PK: pharmacokinetic PD: pharmacodynamic; Right: *p=0.020, **p=0.008, ***p=0.001, ****p<0.001, % change from baseline. Mixed model for repeated measures used for all statistical testing PK/PD modeling using precl
Slide 14: Optimizing dose level and frequency to enable discussions with regulatory authorities
30 mg Optimizing dose level and frequency to enable discussions with regulatory authorities later in 2022 10 mg n=3 60 mg n=4 20 mg 10 mg n=6 4 monthly doses Dose and frequency to be guided by DSMB Expanding n=10 Given poly(GP) reduction with single 30 mg doses that does not appear to have plateaued
Slide 15: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 16: Huntington's disease: mHTT toxic effects lead to neurodegeneration
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Wild-type HTT (wtHTT) is critical for normal neuronal function Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT) Hun
Slide 17: HD: Wild-type HTT is a critical protein for important functions in the central nervous system
Plays an essential role in the transport of synaptic proteins—including neurotransmitters and receptors—to their correct location at synapses9-12 Promotes neuronal survival by protecting against stress (e.g., excitotoxicity, oxidative stress, toxic mHTT aggregates)1-8 BRAIN CIRCUITS SYNAPSE NEURON C
Slide 18: WVE-003: Allele-selective approach to treating HD
Target SNP3 on mutant mRNA HTT transcript to potentially reduce mutant HTT protein Potential to reserve wild-type HTT protein reservoir in brain WVE-003: Allele-selective approach to treating HD Wave has the only allele-selective clinical program in Huntington’s disease Only an allele-selective appr
Slide 19: WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in HD iPSC neurons in vitro Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1. Oligonucleotide or PBS
Slide 20: WVE-003: In vivo studies support distribution to cortex and striatum in mice and NHPs
WVE-003: In vivo studies support distribution to cortex and striatum in mice and NHPs PK: pharmacokinetic PD: pharmacodynamic IC50: the concentration of observed half of the maximal effect mHTT: mutant huntingtin protein NHP: non-human primate Achieved sufficient concentrations of WVE-003 in cortex
Slide 21: SELECT-HD clinical trial design
Day 1-3 15 29 57 85 Dose q PK / Biomarker Samples l l l l l Clinical Evaluations l l l l SELECT-HD clinical trial: Dose level and dosing frequency guided by independent committee Dose level and dosing frequency guided by independent committee Single ascending dose Dose Level Cohort 1 Cohort 1 Additi
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 patients1 fo
Slide 24: PN chemistry improved muscle exposure and survival in preclinical mouse models
PN chemistry improved muscle exposure and survival in preclinical mouse models Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN boosted muscle concentrations after single dose, which correlated with exon-skipping activity PN PN Treatment with PN-modified molecules led to 100% survival of dKO mice
Slide 25: PS/PO/PN splicing compound restores respiratory function to wild-type levels in dKO mice
PS/PO/PN splicing compound restores respiratory function to wild-type levels in dKO mice Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 Wild-type dKO / PBS dKO (PS/PO/PN oligonucleotide) **** **** **** ****
Slide 26: PS/PO/PN compound restores muscle function to wild-type levels in dKO mice
PS/PO/PN compound restores muscle function to wild-type levels in dKO mice dKO / PBS (6 week old) dKO PS/PO/PN, QW 150mpk (38-41 week old) Wild-type (6 week old) Specific Force (EDL) Eccentric Contraction (EDL) Mdx/utr-/- mice received weekly subQ 150 mpk dose of PS/PO/PN stereopure oligonucleotide
Slide 27: WVE-N531: Dystrophin restoration in vitro and enhanced muscle distribution in NHPs
WVE-N531: Dystrophin restoration in vitro and enhanced muscle distribution in NHPs Western Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of up to 71% in vitro Plasma and tissue concentrations of WVE-N531 (PS/PO/PN) significantly higher than suvodirsen (1st-g
Slide 28: Dose escalation ongoing in clinical trial of WVE-N531
Cohort expansion to be guided by assessment of muscle biopsies: (drug distribution in muscle and biomarkers) 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
Slide 29: WVE-N531 plasma concentrations at starting dose significantly improved over suvodirsen
WVE-N531 plasma concentrations at starting dose significantly improved over suvodirsen WVE-N531 is designed with PN chemistry backbone modifications. Suvodirsen (first-generation Exon 51 candidate) did not include PN chemistry. NHP: non-human primates; AUC: Area under curve; Cmax: Maximum plasma con
Slide 30: AIMers RNA base editing capability
AIMers RNA base editing capability
Slide 31: Unlocking RNA editing with PRISM platform to develop AIMers
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides Endogenous ADAR enzymes 1Woolf et al., PNAS Vol. 92, pp. 8298-8302, 1995; Right: Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site
Slide 32: AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR
AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Efficient ADAR recruitment AIMer design principles SAR developed to design AIMers for different targets Systematized AIMer d
Slide 33: Wave's AIMers have potential to uniquely address wide array of genetically-defined diseases
AATD and additional hepatic diseases Neurological disorders (e.g. Rett syndrome) Recessive or dominant genetically defined diseases Cardiometabolic, oncology, immunology AIMer opportunity Correct tens of thousands of pathogenic human SNPs potentially amenable to ADAR editing correction1 Modulate pro
Slide 34: Proof-of-concept preclinical RNA editing data published in Nature Biotechnology
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022) Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 SAR structure-activity relationship Specificity in vitro & in vivo (NHPs) In vitro-in vivo translation (NHPs) GalNAc conjugat
Slide 35: Levels of endogenous ADAR enzyme are not rate limiting for editing
Levels of endogenous ADAR enzyme are not rate limiting for editing Percentage A-to-I editing detected on the indicated transcripts in presence of 20 nM each of a single (Isolated) or multiple (Multiplex) AIMers after transfection of primary human hepatocytes (left). Data are presented as mean ± SEM,
Slide 36: Sequence space is defined; optimization of every dimension
XAX NNN AIMer mRNA target Sequence space is defined >300 unique AIMers tested containing different base pair combinations Identified base modification combinations with high editing efficiency to optimize sequence Optimization of every dimension to inform future rational design of AIMers Motif on ta
Slide 37: Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 Left: AIMer PK C: 5mg/kg SC: Day 1,2,3,4,5; Liver biopsy; Right: Dosed 1um AIMer, 48 hrs later RNA collected, RNAseq conducted usi
Slide 38: Substantial in vivo RNA editing in CNS tissues post-single dose
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues Transgenic huADAR mice administered 100 mg AIMer or PBS on day 0 and evaluated for UGP2 editing across CNS tissues at 1, 4, 8, 12, and 16-weeks post dose. Percentage UGP2 editing determined by Sanger sequencing.
Slide 39: RNA editing of nonsense mutation found in MECP2 restores functional protein
RNA editing of nonsense mutation found in MECP2 (Rett Syndrome) restores functional protein 293T cells transfected with both nonsense mutation on MECP2 (GFP-fusion construct) and ADAR plasmids. AIMers transfected for 48h prior to RNA extraction and sequencing. Percentage editing determined by Sanger
Slide 40: Productive editing beyond liver and CNS with unconjugated AIMers
(left): non-human primate (NHP) 50 mg/kg beta-Actin (ACTB) AIMer, SC (subcutaneous) on day 1; Necropsy for editing day 8; (top right): Mice received 10 or 50 mg UGP2 AIMer intravitreal (IVT), eye collected for analysis 1 or 4 weeks later. (lower right): Human PBMCs dosed with 10 mM ACTB AIMers, unde
Slide 41: Apply AIMers to modify protein-protein interactions
Apply AIMers to modify protein-protein interactions AIMer 1 Control AIMer 2 AIMer 3 AIMer 4 Amino acid substitution Cys Gly Cys Asp Tyr Arg Tyr Asn KEAP1 Edited Percentage editing (293T cells) AIMer 10 Control AIMer 11 AIMer 12 AIMer 13 Percentage editing (293T cells) Arg Val Gly Gly Gln Ile Asp Glu
Slide 42: ADAR editing activates multiple genes, confirming disrupted protein-protein interaction in vitro
NRF2-mediated gene transcription ADAR editing activates multiple genes, confirming disrupted protein-protein interaction in vitro KEAP1 NRF2 ADAR editing of either KEAP1 or NRF2 directs gene activation NQO1 Fold increase over control Control Control Fold increase over control Fold increase over cont
Slide 43: Alpha-1 antitrypsin deficiency (AATD)
Alpha-1 antitrypsin deficiency (AATD)
Slide 44: RNA editing is uniquely suited to address the therapeutic goals for AATD
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver RNA editing is uniquely suited to address the therapeutic goals for AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin Strnad et al., 2020 N Engl J Med 382:
Slide 45: RNA editing only detected at PiZ mutation site in SERPINA1 transcript
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing within transcriptome (mouse liver) ADAR editing is highly specific; no bystander editing observed on SERPINA1 transcript SERPINA1 (PiZ mutation site) % Editing Dose 3 x 10mg/kg days (0, 2, 4) SC. Liver bi
Slide 46: Preclinical AIMer treatment results in circulating AAT protein levels above therapeutic threshold
PBS Week Preclinical AIMer treatment results in circulating AAT protein levels well above anticipated therapeutic threshold AIMers (SA1-5) administered in huADAR/SERPINA1 mice (8 – 10 weeks old) Left : Total AAT protein quantified by ELISA. Right: Liver biopsies collected at week 19 (one week after
Slide 47: AATD AIMer restores functional M-AAT protein and alleviates liver aggregation
AATD AIMer restores functional M-AAT protein and alleviates liver aggregation in preclinical model GalNAc AIMer (SA1-5) administered bi-weekly (10 mg/kg) following initial loading dose (3 x 10 mg/kg) in huADAR/SERPINA1 mice (8–10 weeks old); Left: Neutrophil elastase inhibition assay (pre-dose, week
Slide 48: GalNAc-AIMers are uniquely suited to address the key treatment goals for AATD
GalNAc-AIMers are uniquely suited to address the key treatment goals for AATD https://www.labiotech.eu AIMers RNAi AAT augmentation therapy Restore circulating functional wild-type AAT ü ü Reduce Z-AAT protein aggregation in liver ü ü Retain M-AAT physiological regulation ü Recruit endogenous ADAR e
Slide 49: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 50: Wave is the leader in rationally designed stereopure oligonucleotides
Wave publications: Current therapeutics with chiral backbone modifications: Enables rational design and optimization of fully-characterized, stereopure RNA therapeutics Wave is the leader in rationally designed stereopure oligonucleotides Stereochemistry is a reality of chemically-modified nucleic a
Slide 51: Innovating stereopure backbone chemistry modifications: PN chemistry
… … Innovating stereopure backbone chemistry modifications: PN chemistry Chirality None PN backbone Sp PN backbone Rp Chirality … … PS backbone Rp PS backbone Sp Chirality … … PRISM backbone linkages PO: phosphodiester PS: phosphorothioate -O -S N (Rp) (Sp) PO PS PN Negative charge Neutral charge Ne
Slide 52: Improvements in PRISM primary screen hit rates accelerate drug discovery
Improvements in PRISM primary screen hit rates accelerate drug discovery over time Primary screen hit rates with silencing far above industry standard hit rates Stereorandom Chemistry, PN stereochemistry & machine learning optimization Stereopure Chemistry improvements and PRISM advancement All scre
Slide 53: Potency is enhanced with addition of PN modifications across modalities
Silencing Potency is enhanced with addition of PN modifications across modalities Improved knockdown Splicing Editing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) Concen
Slide 54: Adding PN chemistry to C9orf72-targeting oligonucleotides improved potency in vivo
Adding PN chemistry modifications to C9orf72-targeting oligonucleotides improved potency in vivo Exposure (µg/g) Exposure (µg/g) Cortex %C9orf72 V3 transcript remaining Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% confidence intervals (
Slide 55: PN chemistry improves distribution to CNS
PN chemistry improves distribution to CNS NHPs administered 1x12 mg oligonucleotide or PBS by intrathecal injection/lumbar puncture (IT). CNS tissue evaluated 11 or 29 days after injection (n=6 per group). Oligonucleotide was visualized by ViewRNA (red), and nuclei are counterstained with hematoxyli
Slide 56: Rational design to achieve target engagement and preclinical tolerability
Rational design to achieve target engagement and preclinical tolerability Isomer 1 Isomer 2 ns Stereoisomers have similar pharmacodynamic effects in vivo Changing backbone stereochemistry leads to different tolerability profiles in vivo Same sequence, but different backbone stereochemistry Unconjuga
Slide 57: Single intrathecal dose in NHP leads to widespread target mRNA reduction throughout the CNS
Single intrathecal dose in NHP leads to substantial and widespread target mRNA reduction throughout the CNS NHPs: Non-human primates; NHPs (n=3) received a single 12 mg IT dose of WVE-005. ASO and mRNA quantified by ELISA and qPCR, respectively. Striatum was evaluated in a separate experiment. CTX c
Slide 58: PRISM PN siRNA led to unprecedented silencing after single dose
*** **** Single dose (3 mg/kg) PRISM PN siRNA loaded in RISC is significantly greater than Adv. ESC siRNA PBS PRISM PN siRNA led to unprecedented silencing as compared to state-of-art >3 months after single dose Adv. ESC siRNA (stereorandom) PRISM PN siRNA (stereopure) ~80% silencing HSD17B13 mRNA i
Slide 59: PRISM platform is continuously improving
Choose modality to best address genetic target Rapidly develop clinical candidates in reproducible way Scalable, cost-effective manufacturing Genetic code carried by RNA to predict sequence PRISM platform is continuously improving Continuous definition of design principles deployed across programs D
Slide 60: Established internal GMP manufacturing for multiple oligonucleotide modalities
Established internal GMP manufacturing for multiple oligonucleotide modalities Strong technical knowhow and operating expertise Established infrastructure State of the art facilities (90,000 sq ft) and expansion space Process and analytical development labs GMP oligonucleotide (API) manufacturing Es
Slide 61: Upcoming milestones
Upcoming milestones
Slide 62: Key anticipated upcoming milestones
Key anticipated upcoming milestones Additional data generated in 2022 expected to further inform future opportunities and unlock value Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Targeted delivery liver (Subcutaneous) WVE-004 C9orf72 ALS & FTD Delivered clinical target engagement d
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