Slide 1: Corporate Presentation March 6, 2024
Corporate Presentation March 6, 2024 Wave Life Sciences 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: Building a leading RNA medicines company
Building a leading RNA medicines company Proof-of-mechanism data from RestorAATion clinical program of WVE-006 for AATD in 2024 Initiate clinical trial of INHBE candidate for obesity in 1Q 2025 Data from FORWARD-53 clinical trial of WVE-N531 for DMD in 3Q 2024 Data from SELECT-HD clinical trial of W
Slide 4: Combining best-in-class chemistry with novel biology and genetic insights
Combining 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 Best-in-class validated chemistry New biology Unlocks new pi
Slide 5: Versatile RNA medicines platform capitalizing on new genetic insights
Claussnitzer, et al. Nature (2020) 577, 179; King et al. PLoS Genet (2019) 15, e1008489 Wave's versatile RNA medicines platform ideal for capitalizing on new genetic insights in rare and common diseases Accessing UK Biobank and building proprietary machine learning models to generate unique genetic
Slide 6: Robust RNA medicines pipeline including first-in-class RNA editing programs
SPLICING WVE-N531 Exon 53 (DMD) 100% global 2.3K Other exons (DMD) 100% global Up to 18K SILENCING: ANTISENSE WVE-003 mHTT (HD) Takeda 50:50 Option 25K Manifest (SNP3) 60K Pre-Manifest (SNP3) Robust RNA medicines pipeline including first-in-class RNA editing programs AATD: Alpha-1 antitrypsin defici
Slide 7: Strategic collaboration with GSK to develop transformative RNA medicines
Strategic collaboration with GSK to develop transformative RNA medicines 1. $120 million in cash and $50 million equity investment received in January 2023, 2. Initiation, development, launch, and commercialization milestones for WVE-006 and programs progressed during initial 4-year research term (8
Slide 8: WVE-006 (RNA editing) AATD
WVE-006 (RNA editing) AATD WWE UFE SCIENCES.
Slide 9: 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 AAT: Alpha-1 antitrypsin Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al., 2017 Int J Chron Obstruct Pulmon Dis 12:561-69; Remih et al., 2021 Curr Opin Pharmacol 59:149-56. 3) Ret
Slide 10: WVE-006 treatment results in serum AAT protein levels up to 30 uM in mice
WVE-006 treatment results in serum AAT protein levels of up to 30 uM in NSG-PiZ mice Overall percentages of serum AAT protein isoforms in NSG-PiZ mice (Week 13) Serum neutrophil elastase inhibition activity in NSG-PiZ mice AATD: Alpha-1 antitrypsin deficiency; M-AAT protein: wild-type AAT protein; W
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: RNA editing only detected at PiZ mutation site in SERPINA1 transcript
RNA editing only detected at PiZ mutation site in SERPINA1 transcript RNA editing across transcriptome Dose 3x10 mg/kg (days 0, 2, 4) SC with AATD AIMer (SA1 – 4). Liver biopsies day 7. RNA-seq to quantify on-target SERPINA1 editing, to quantify off-target editing reads mapped to entire mouse genome
Slide 13: Proof-of-mechanism data from RestorAATion-2 expected in 2024
Proof-of-mechanism data from RestorAATion-2 expected in 2024 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose RestorAATion-2: AATD Patients Informs dose & dose frequency RestorAATion-1: Healthy Volunteers SAD à MAD cohorts Dose escalation Study key objectives Safety and t
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: Innovating on applications of ADAR beyond restoring protein function
Innovating on applications of ADAR beyond restoring protein function mRNA mRNA Decay Cascade Unique RNA motifs Edited mRNA A single edited base permanently disrupts the motif Stable mRNA yields increased protein production Restore or correct protein function Upregulate expression to increase endogen
Slide 17: Multiple RNA editing opportunities to build high-value pipeline 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 18: INHBE program (siRNA silencing) Obesity and other metabolic disorders
INHBE program (siRNA silencing) Obesity and other metabolic disorders
Slide 19: 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, guide strand concentration, Ago2 loading quantified. Stats: Two-way ANOVA with post-hoc test * P<0.05, ****P<0.0001. Liu et al., 2023 Nuc Acids Res doi: 10.1093/nar/gkad268; siRNA silen
Slide 20: INHBE silencing expected to induce fat loss while maintaining muscle mass
Lead to weight loss at the expense of muscle mass1 Associated with poor tolerability profile4 with 68% drop-off after 1 year3 Discontinuation of therapy leads to rapid weight regain Suppress general reward system4 GLP-1 receptor agonists have several reported limitations siRNA to silence INHBE gene
Slide 21: Preclinical results consistent with UK Biobank loss-of-function carrier data
Right: Reduction in fat mass at Week 5 Results of in vivo preclinical study are consistent with UK Biobank human data on loss-of-function carriers First generation INHBE GalNAc-siRNA led to lower body weight and significant decrease in visceral fat in DIO mouse model Chow PBS HFD PBS HFD First gener
Slide 22: Next generation siRNA results in more potent and durable target knockdown
Next generation siRNA results in more potent and durable target knockdown Highly potent silencing (ED50 < 1mg/kg) Durable silencing following one, low-single-digit dose, supporting every-six-month or annual dosing Weight loss with no loss of muscle mass Reduction in fat mass, with preferential effec
Slide 23: 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 high Ago2 loading and intracellular trafficking Titrating plasma
Slide 24: Sustained APP knockdown of at least 75% in mice
Sustained APP knockdown of at least 75% throughout the 16-week study in vivo in mice Single dose of next generation siRNA delivers broad, potent and durable CNS target engagement APP silencing PBS Next gen siRNA Robust target engagement translates to substantial App protein reduction across brain re
Slide 25: Wave siRNA more potent and durable than 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-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly low
Slide 26: WVE-N531 (splicing) Duchenne muscular dystrophy
WVE-N531 (splicing) Duchenne muscular dystrophy
Slide 27: Duchenne muscular dystrophy and exon skipping
1Vyondys: www.fda.gov; viltepso; www.fda.gov; Exondys; www.fda.gov; Amondys: www.fda.gov 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 y
Slide 28: PN chemistry improved function and survival in dKO mice
100% survival at time of study termination Restored muscle and respiratory function to wild-type levels Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 dKO: double knock-out PN chemistry improved function and survival in dKO mice Extended survival in dKO preclinical model supports potential of Wave
Slide 29: PN chemistry yields muscle exposure, exon skipping and dystrophin expression
PBS PS/PO/PN modified oligonucleotides for mouse exon 23 Wave’s PN chemistry yields excellent muscle exposure, exon skipping and dystrophin protein expression in dKO mouse model Kandasamy et al., 2022 Nuc Acids Res doi: 10.1093/nar/gkac018 dose dKO* mouse D37 %Dystrophin Skeletal muscle Diaphragm He
Slide 30: Preclinical data supported advancing WVE-N531 to clinical development
Preclinical data supported advancing WVE-N531 to clinical development WVE-N531 reached high concentrations in heart and diaphragm in NHP 26th Annual ASGCT meeting, May 16-20, 2023 WVE-N531: Dystrophin restoration of up to 71% in vitro in patient-derived myoblasts
Slide 31: Clinical data from WVE-N531 Part A
1: 42 µg/g = 6.1 µM (6,100 nM), WVE-N531 data presented March 22, 2023 at Muscular Dystrophy Association Clinical and Scientific Conference; WVE-N531 biopsies collected ~2 weeks post-last dose (3 biweekly doses of 10 mg/kg); Suvodirsen biopsies collected post-last dose (weekly doses of 5 mg/kg) on w
Slide 32: Design of FORWARD-53 Phase 2 trial
Design of FORWARD-53: Phase 2, open-label, 10 mg/kg every other week Endpoints: Dystrophin (powered for >5% of normal), safety/tolerability, pharmacokinetics, digital and functional assessments (incl. NSAA and others) Muscle biopsies to assess dystrophin expression Fully enrolled (n=11) and dosing u
Slide 33: Potential for Wave to address up to 40% of DMD population
Potential for Wave to address up to 40% of DMD population Left: Aartsma-Rus, et al. 2009 Hum Mutat 30, 293. Exon 45 Exon 44 Exon 52 WVE-N531 Exon 53 Exon 51 Not Amenable to Skipping 11-13% 8-10% 44% DMD Population Exon 52 Exon 51 Exon 44 Exon skipping and dystrophin restoration demonstrated in vitro
Slide 34: WVE-003 (antisense silencing) Huntington's Disease
WVE-003 (antisense silencing) Huntington’s Disease
Slide 35: mHTT toxic effects lead to neurodegeneration
mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD 1 – Sources on wtHTT: 1. Leavitt 2006 2. Cattaneo 2005 3. Kumar 2016 4. Franco-Iborra 2020 5. Hamilton 2015 6. Ochaba 2014 7. Wong 2014 8. Rui 2015 9. Caviston 2007 10. Twelvetrees 2010 11. Strehlow 2007
Slide 36: WVE-003 selective, potent and durable reduction of mHTT in preclinical models
Selectively reduces mHTT mRNA in HD iPSC neurons in vitro Durable striatal mHTT knockdown for 12 weeks in BACHD mouse model Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1. Oligonucleotide or PBS [100 μg ICV injections through ca
Slide 37: WVE-003: First-in-class allele-selective candidate for HD
mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein *Pooled considering no apparent dose response between 2 single-dose cohorts; Data cut-off: August 29, 2022 Data from 30 mg multi-dose cohort with extended follow-up, along with all single-dose data, expected 2Q 2024 WVE-003: First-
Slide 38: Anticipated upcoming milestones
Anticipated upcoming milestones
Slide 39: 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 Obesity INHBE Lead Clinical Candidate Clinical trial initiation expected 1Q 2025 A
Slide 40: Potential for significant cash inflows in 2024 from collaboration milestones
Potential for significant cash inflows in 2024 from collaboration milestones from GSK and Takeda Anticipated milestones in 2024 and beyond AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; mHTT: Mutant huntingtin; wtHTT: Wild-type huntingtin WVE-006 (A
Slide 41: For questions contact: investorrelations@wavelifesci.com
For questions contact: investorrelations@wavelifesci.com