Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation March 3, 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 single isomers and control three structural features of oligonucleotides to efficiently engage biological machinery OPTIMIZE Provides the resolution to observe this
Slide 8: 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, single-isomer RNA therapeutics Wave is the leader in rationally designed stereopure oligonucleotides Stereochemistry is a reality of chemically-modified nuclei
Slide 9: 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 10: 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 11: PN chemistry improved potency of C9orf72-targeting oligonucleotides 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 Target knockdown: Liu, TIDES poster 2021; Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best
Slide 12: 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 13: Single intrathecal dose in NHP leads to widespread target mRNA reduction
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 14: 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 15: 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 16: 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 17: 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 18: WVE-004 ALS and FTD
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 19: 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 20: C9orf72 repeat expansions: mechanisms of cellular toxicity
C9orf72 repeat expansions: Mechanisms of cellular toxicity in ALS and FTD C9-ALS and C9-FTD may be caused by multiple factors: Insufficient levels of C9orf72 protein Accumulation of repeat-containing RNA transcripts Accumulation of aberrantly translated DPR proteins Recent evidence suggests lowering
Slide 21: C9orf72 protein is important for normal neuronal function and immune system
C9orf72 protein is important for normal regulation of neuronal function and the immune system WVE-004 targets hexanucleotide repeat containing transcript variants that lead to loss of normal C9orf72 function and production of pathological mRNA products and toxic dipeptide repeat (DPR) proteins Poly-
Slide 22: WVE-004 treatment resulted in 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 Full results presented at the 31st International Symposium on A
Slide 23: FOCUS-C9 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 FOCUS-C9 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 Additio
Slide 24: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 25: Huntington's disease: mHTT toxic effects and loss of wtHTT functions
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Wild-type HTT is critical for normal neuronal function Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein Huntington’s disea
Slide 26: Wild-type HTT is a critical protein for central nervous system functions
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 27: WVE-003: allele-selective approach to treating HD
Target mutant mRNA HTT transcript to reduce mutant HTT protein Preserve 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 approach is designed to address both
Slide 28: WVE-003 demonstrates 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 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 29: WVE-003 in vivo distribution to cortex and striatum in BACHD and NHPs
WVE-003: In vivo studies support distribution to cortex and striatum in BACHD 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 30: 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 31: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 32: PN chemistry improved muscle exposure and survival in 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 33: PS/PO/PN splicing compound restores respiratory function in dKO mice
PS/PO/PN slicing compound restores respiratory function to wild-type levels in dKO mice Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 Neuro DMD Wild-type dKO / PBS dKO (PS/PO/PN oligonucleotide) **** **** **** ****
Slide 34: PS/PO/PN compound restores muscle function to wild-type levels
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 35: WVE-N531: first splicing candidate to use PN chemistry
WVE-N531: First splicing candidate to use PN chemistry Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function. Current disease modifying treatments have demonstrated minimal dystrophin expression
Slide 36: PN chemistry enhances muscle distribution and exon-skipping in NHPs
WVE-N531: PN chemistry enhances muscle distribution and exon-skipping in NHPs Non-human primates (NHPs) received 6 x weekly IV infusions of PBS or 3, 7, or 25 mg WVE-N531 (n=2 per dose); necropsied on day 38. Exon 53 skipping quantified by RT-PCR; W, week; HED: Human equivalent dose WVE-N531 leads t
Slide 37: WVE-N531 plasma concentrations 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 38: 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 39: AIMers RNA base editing capability
AIMers RNA base editing capability
Slide 40: Unlocking RNA editing with PRISM platform to develop AIMers
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides ADAR enzymes Catalyze conversion of A-to-I (G) in double-stranded RNA substrates A-to-I (G) edits are one of the most common post-transcriptional modifications ADAR1 is ubiquitously expressed across tissues,
Slide 41: 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 42: Opportunity for novel and innovative AIMer therapeutics
Opportunity for novel and innovative AIMer therapeutics SNP: single nucleotide polymorphism A: Adenosine I: Inosine G: Guanosine 1ClinVar database 2Gaudeli NM et al. Nature (2017) 3Keeling KM et al., Madame Curie Bioscience Database 2000-2013 4Luck, K et al. Nature (2020) 5Prasad, TSK et al. Nucleic
Slide 43: Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers
Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR and quantified by Sanger sequencing Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers ACTB editing in primary human hepat
Slide 44: 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 45: Sequence space is defined; optimization informs AIMer design
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 46: AIMers enable durable and specific editing out to Day 50 in NHP liver
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs Manuscript in press. 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 using strand-specific libraries to quantify on / off-target edit
Slide 47: Substantial in vivo RNA editing in CNS tissues months 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 48: RNA editing of MECP2 nonsense mutation 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 49: Productive editing in multiple NHP tissues with unconjugated systemic delivery
Achieving productive editing in multiple NHP tissues with unconjugated systemic AIMer delivery NHP study demonstrated productive editing in kidney, liver, lung and heart with single subcutaneous dose PBS ACTB AIMer GalNAc-conjugated (Targeted - subcutaneous) Unconjugated (Local – IVT, IT) Unconjugat
Slide 50: ADAR editing in retina after single IVT dose
AIMers in retina at 4 weeks ADAR editing: Up to 50% editing in vivo in posterior of eye one month post-single IVT dose Mice received a single IVT injection (10 or 50 ug AIMer), and eyes were collected for RNA analysis and histology 1 or 4 weeks later. Left: editing evaluated by Sanger sequencing, an
Slide 51: Productive editing in multiple immune cell types in vitro
Achieving productive editing in multiple immune cell types with AIMers in vitro Human peripheral blood mononuclear cell (PBMC) CD4+ T-cell CD19 B-cell CD14 Monocytes Tregs T-cell CD8+ T-cell NK NK-cell Human PBMCs dosed with 10 uM ACTB AIMers, under activating conditions (PHA). After 4 days, differe
Slide 52: Expanding addressable disease target space using ADAR editing
Expanding addressable disease target space using ADAR editing to modulate proteins Correction Protein- protein interaction Upregulation Processing Folding (stability) Post-translational modification ADAR editing of mRNA Restore or modify protein function Impact diseases Examples: Familial epilepsies
Slide 53: ADAR to modify protein-protein interactions: KEAP1 and Nrf2
Nrf2 activated genes {A:B:C:D} ADAR to modify protein-protein interactions ADAR modified pathway KEAP1 ADAR editing to change one amino acid in KEAP1 or Nrf2 could allow for stabilization of Nrf2 and activation of Nrf2 mediated gene transcription Nrf2 Nrf2 is stabilized Nrf2 translocates to nucleus
Slide 54: ADAR editing activates multiple Nrf2 genes in vitro
Nrf2 mediated gene transcription {A:B:C:D} 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/mRNA-A Fold increase over control Control Control Fold increase over control Fold in
Slide 55: Alpha-1 antitrypsin deficiency
Alpha-1 antitrypsin deficiency
Slide 56: 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; Sources: Strnad 2020; Blanco 2017; R
Slide 57: ADAR editing is highly specific on 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 58: AIMer treatment results in circulating AAT protein 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 59: Histological analysis shows reduction of liver aggregates
Histological analysis indicates reduction of liver aggregates at 19 weeks with AIMer treatment PBS AIMer treatment (SA1-5) Preliminary histological analysis of transgenic mouse liver aggregates (Week 19) PAS-D, 4X PAS-D, 40X AAT Polymer, 40X Representative images from liver biopsies stained with PAS
Slide 60: GalNAc-AIMers are uniquely suited to address key AATD treatment goals
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 61: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 62: PRISM enables optimal placement of backbone stereochemistry
PRISM enables optimal placement of backbone stereochemistry Crystal structure confirms phosphate-binding pocket of RNase H binds 3’-SSR-5’ motif in stereopure oligonucleotide – supports design strategy for Wave oligonucleotides ASO/RNA duplex Yellow spheres represent ‘S’ atoms Phosphate binding pock
Slide 63: Importance of controlling stereochemistry
Importance of controlling stereochemistry (Rp) (Sp) Top view Side view Yellow spheres represent ‘S’ atomsPS: Phosphorothioate Number of PS linkages in oligonucleotide backbone No. diastereomers 80T 60T 40T 20T 30B 22M 12M 2M 1M 500K 0 0 10 20 30 40 50 Antisense, exon skipping, ssRNAi ADAR oligonucle
Slide 64: 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 65: PRISM PN siRNA silencing of HSD17B13 mRNA in vivo
*** **** 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 66: Upcoming milestones
Upcoming milestones
Slide 67: Data generated in 2022 expected to inform future opportunities and unlock value
Data generated in 2022 expected to inform future opportunities and unlock value Success with any current program validates platform and unlocks modalities and tissues Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Targeted delivery Liver (Subcutaneous) WVE-004 C9orf72 ALS & FTD Clinic
Slide 68: 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