Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation December 15, 2023 Exhibit 99.1
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: Building a leading RNA medicines company
Building a leading RNA medicines company $20 million milestone earned under GSK collaboration and $100 million offering in December 2023 extended cash runway into 4Q 2025* DMD (splicing), HD (silencing), and AATD (RNA editing) clinical programs advancing INHBE, obesity (siRNA), muscle sparing, fat l
Slide 4: Combining best-in-class chemistry with novel biology and genetic insights
Combining potential best-in-class chemistry with novel biology and genetic insights: Opportunities for new high impact medicines Accessing new endogenous enzymes for novel modalities (RNA editing) Opening up new targets, including prevalent diseases
Slide 5: Versatile RNA medicines platform unlocks genetic insights
Wave's versatile RNA medicines platform unlocks genetic insights for rare and common diseases opening up new target opportunities Claussnitzer, et al. Nature (2020) 577, 179; King et al. PLoS Genet (2019) 15, e1008489 Accessing UK Biobank and building proprietary machine learning models to generate
Slide 6: Robust RNA medicines pipeline including first-in-class RNA editing programs
Program Discovery Preclinical Clinical Rights Patient population (US & Europe) RNA EDITING WVE-006 SERPINA1 (AATD) GSK exclusive global license 200K Multiple undisclosed Correction 100% global >20K (multiple) Multiple undisclosed Upregulation 100% global >3M (multiple) SILENCING: siRNA INHBE* (Metab
Slide 7: Strategic collaboration with GSK
Collaboration leverages Wave’s unique stereopure, PN-chemistry containing PRISMTM platform, including editing, splicing, silencing (RNAi and antisense) Strategic collaboration with GSK to develop transformative RNA medicines for genetically defined diseases 1$120 million in cash and $50 million equi
Slide 8: WVE-006 (RNA editing) AATD
WVE-006 (RNA editing) AATD
Slide 9: WVE-006: Designed to correct mutant SERPINA1 transcript
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin
Slide 10: WVE-006 in AATD: First-in-class RNA editing clinical candidate
WVE-006 in AATD: First-in-class RNA editing clinical candidate Potentially comprehensive approach to address both lung and liver manifestations of AATD Increased AAT protein in NSG-PiZ mice Demonstrated functionality of M-AAT protein Confirmed restored wild-type M-AAT protein WVE-006 treatment resul
Slide 11: WVE-006 decreases lobular inflammation and PAS-D globule size
WVE-006 decreases lobular inflammation and PAS-D globule size, prevents increase in hepatocyte turnover Left (Lobular inflammation) and Middle (Mitoses): Scatter plot showing inflammation grade or mitoses score. Each circle represents an individual mouse, (Mean ± SEM); Right (PAS-D Globule Size): 40
Slide 12: AIMer-directed editing is highly specific in mice
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing across transcriptome (mouse liver) AIMer-directed editing is highly specific in mice SERPINA1 (PiZ mutation site) % Editing Dose 3x10 mg/kg (days 0, 2, 4) SC with AATD AIMer (SA1 – 4). Liver biopsies day
Slide 13: Dosing underway in RestorAATion clinical program
Dosing underway in RestorAATion clinical program; proof of mechanism data in patients with AATD expected in 2024 Dose escalation Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels Dosing Underway Multiple assessments of serum AAT throughout cohort HV: healthy volunteer;
Slide 14: AIMers RNA editing capability
AIMers RNA editing capability
Slide 15: The AIMer-targetable Edit-Verse is substantial
The AIMer-targetable ‘Edit-Verse’ is substantial The Edit-verse is the editable gene-disease universe, including upregulation >13,000 genes with a high-probability1 of being amenable to transcriptional regulation with A-to-G editing Model development ongoing to expand access to more protein-coding g
Slide 16: Multiple RNA editing opportunities beyond WVE-006
Multiple RNA editing opportunities to build high-value pipeline beyond WVE-006 The Edit-verse is substantial and still expanding Advancing work for a diverse set of undisclosed targets addressing areas of high unmet need, including both rare and prevalent diseases Hepatic (GalNAc-AIMers) Extra-Hepat
Slide 17: INHBE program (siRNA silencing)
INHBE program (siRNA silencing) Metabolic disorders, including obesity
Slide 18: siRNA silencing is one of multiple Wave modalities
siRNA silencing is one of multiple Wave modalities being advanced in strategic research collaboration with GSK Potential for best-in-class siRNA enabled by Wave’s PRISM platform **** Left, Middle, and right: Mice expressing human HSD17B13 transgene treated with siRNA (3 mg/kg) or PBS, liver mRNA, gu
Slide 19: INHBE: Evolution in treatment for obesity
INHBE: Evolution in treatment for obesity; muscle sparing, sustained fat loss, improved metabolic profile 1. Liang, et al. 2023 Postgraduate Medical Journal 99(1175):985; 2. Lakka, et al. 2002 JAMA 288(21):2709; 3. Sargeant, et al. 2019 Endocrinol Metab (Seoul) 34(3):247-262; 4. Liu, et al. 2022 Fro
Slide 20: GalNAc-siRNA program addresses unmet need in metabolic disorders
Driven by clinical genetics, GalNac-siRNA program addresses high unmet need in metabolic disorders, including obesity Nat Commun 2022. https://doi.org/10.1038/s41467-022-32398-7; 2. Nat Commun 2022. https://doi.org/10.1038/s41467-022-31757-8; 3. PLOS ONE 2018. https://doi.org/10.1371/journal.pone.01
Slide 21: INHBE knockdown of 90% in human hepatocytes
INHBE knockdown of 90% demonstrated in human hepatocytes with GalNAc-siRNA Primary hepatocytes were treated with a cross-reactive siRNA via free uptake. INHBE mRNA was quantified by RT-qPCR. This cross-reactive sequence demonstrates ~90% maximal knock-down in human hepatocytes and ~65% in mouse hepa
Slide 22: INHBE knockdown in mice leads to lower body weight
~62% silencing **** Therapeutic threshold1 INHBE knockdown demonstrated in mice at 5 weeks INHBE silencing achieved in vivo with GalNAc-siRNA exceeds therapeutic threshold and led to lower body weight HFD: high-fat diet. Stats: two-sided Welch’s T Test **** P < 0.0001 1. Adam, RC. et.al. Proc Natl A
Slide 23: INHBE silencing decreases visceral fat
~56% reduction ~34% reduction ~38% reduction **** *** *** Chow, PBS HFD, PBS HFD, Inhbe siRNA Chow, PBS HFD, PBS HFD, Inhbe siRNA Chow, PBS HFD, PBS HFD, Inhbe siRNA INHBE silencing leads to significant decrease in visceral fat, consistent with UK Biobank human data on loss-of-function carriers Adam
Slide 24: Next-generation GalNAc-siRNA demonstrates best-in-class potential
Foster, DJ. et.al. Mol Ther. 2018, 26(3), 708. B6 mice administered PBS or 0.5 mg/kg of siRNA (subcutaneous). Benchmark: Stats: Mixed Two-way ANOVA followed by post hoc test comparing siRNA vs. Next gen siRNA per day derived from linear mixed effects model * P < 0.0001 Wave’s next generation GalNAc-
Slide 25: Platform chemistry enables siRNA extra-hepatic delivery
Wave’s platform chemistry enables siRNA extra-hepatic delivery Chemical impact Introduction of neutral backbone Unique structural feature of PN, specifically guanidine Increased lipophilicity Stereochemistry Extra-hepatic delivery Titrating siRNA lipophilicity tunable PNs (PN variants) Maintaining h
Slide 26: Tunable PN variants enhance potency of non-GalNAc siRNAs
Tunable PN variants enhance potency and alter extra-hepatic delivery of non-GalNAc siRNAs Stats: Three-way ANOVA followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown) * P < 0.05, *** P < 0.001, **** P < 0.0001; B6 mice administered PBS or 5 mg/kg of Sod1 siRNA (no
Slide 27: Next generation siRNA delivers durable CNS target engagement
Single dose of next generation siRNA delivers broad, potent and durable CNS target engagement PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-adjust
Slide 28: Wave siRNA more potent and durable than published state-of-the-art
Wave siRNA demonstrates more potent and durable silencing as compared to published state-of-the-art PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-
Slide 29: WVE-N531 (splicing) Duchenne muscular dystrophy
WVE-N531 (splicing) Duchenne muscular dystrophy
Slide 30: Duchenne muscular dystrophy
Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function Impacts approx. 1 in every 5,000 newborn boys each year; approx. 20,000 new cases annually worldwide Approx. 8-10% are amenable to exon 53 sk
Slide 31: Extended survival in dKO preclinical model
Extended survival in dKO preclinical model supports potential of exon-skipping therapeutics for DMD Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN chemistry improved function and survival in dKO mice 100% survival at time of study termination Restored muscle and respiratory function to wild-typ
Slide 32: Preclinical data supported advancing WVE-N531
Preclinical data supported advancing WVE-N531 to clinical development: enhanced delivery and high levels of dystrophin 26th Annual ASGCT meeting, May 16-20, 2023 WVE-N531 reached high concentrations in heart and diaphragm in NHP WVE-N531: Dystrophin restoration of up to 71% in vitro Western Blot nor
Slide 33: Clinical data from WVE-N531 Part A
Clinical data from WVE-N531 Part A: High exon-skipping & muscle concentrations after three bi-weekly doses
Slide 34: Dosing underway in FORWARD-53 Phase 2 trial
Dosing underway in FORWARD-53, a potentially registrational Phase 2 clinical trial of WVE-N531 in DMD (Exon 53) Design of FORWARD-53: Phase 2, open-label, 10 mg/kg every other week, 10 patients enrolled Endpoints: Dystrophin (powered for >5% of normal), safety/tolerability, pharmacokinetics, digital
Slide 35: Potential to address up to 40% of DMD population
Potential for Wave to address up to 40% of DMD population Exon 45 Exon 44 Exon 52 WVE-N531 Exon 53 Exon 51 Not Amenable to Skipping 11-13% 8-10% 44% Left: Aartsma-Rus, et al. 2009 Hum Mutat 30, 293. DMD Population Exon 52 Exon 51 Exon 44 Protein Restoration Exon skipping and dystrophin restoration d
Slide 36: WVE-003 (Allele-selective antisense silencing) Huntington's Disease
WVE-003 (Allele-selective antisense silencing) Huntington’s Disease
Slide 37: Huntington's disease and mHTT toxic effects
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD Stresses wtHTT Stresses wtHTT mHTT + ~50% decrease in wtHTT Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration Loss of wtHTT functions Hunti
Slide 38: 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 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 39: WVE-003: First-in-class allele-selective candidate for HD
Preservation of wtHTT WVE-003: First-in-class allele-selective candidate for HD mHTT protein levels Placebo WVE-003 (30 and 60 mg pooled*) wtHTT protein levels Reductions in mean CSF mHTT and preservation of wtHTT observed in pooled analysis of single-dose cohorts in SELECT-HD clinical study Single
Slide 40: Anticipated upcoming milestones
Anticipated upcoming milestones
Slide 41: Anticipated upcoming milestones
Anticipated upcoming milestones AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; mHTT: Mutant huntingtin; wtHTT: Wild-type huntingtin WVE-006 (AATD) Most advanced RNA editing candidate & potential best-in-class approach for AATD 2024: Deliver proof-of
Slide 42: Wave is poised for significant and sustained growth
Wave is poised for significant and sustained growth Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients) AATD WVE-006 DMD WVE-N531 Exon 53 HD WVE-003 SNP3 INHBE metabolic disorders, including obesity Clinical candidate expected 4Q 2024;
Slide 43: Thank you
For more information: InvestorRelations@wavelifesci.com Thank you!