Slide 1: Corporate Presentation August 8, 2024
Corporate Presentation August 8, 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
AATD: Alpha-1 antitrypsin deficiency DMD: Duchenne muscular dystrophy HD: Huntington’s disease Building a leading RNA medicines company Multi-modal: RNA editing, RNAi, splicing, allele-selective silencing Best-in-class, clinically-validated oligonucleotide chemistry (PN, stereochemistry) Novel RNA m
Slide 4: PRISM platform: Unlocking the broad potential of RNA medicines
PRISM platform: Unlocking the broad potential of RNA medicines Wave is uniquely positioned to harness human genetic insights and biological machinery in our body to deliver powerful ways to treat both rare and prevalent human diseases Best-in-class, rationally designed oligonucleotides enabled by pr
Slide 5: Foundational advances in nucleic acid chemistry
Full list of Wave publications: https://ir.wavelifesciences.com/events-publications/publications Wave has driven foundational advances in nucleic acid chemistry to expand platform technologies and develop next generation of RNA therapeutics Further information can be found in recent platform publica
Slide 6: Proprietary chemistry continues to translate in clinic across modalities
Full list of Wave publications: https://ir.wavelifesciences.com/events-publications/publications *mHTT reductions compared to placebo Proprietary chemistry continues to translate in clinic across modalities, enabling first-in-class and best-in-class therapies Preclinical publication Clinical transla
Slide 7: Robust, diversified RNA medicines pipeline
SPLICING WVE-N531 Exon 53 (DMD) 100% global 2.3K Other exons (DMD) 100% global Up to 18K ALLELE-SELECTIVE SILENCING WVE-003 mHTT (HD) Takeda 50:50 Option 25K Symptomatic (SNP3) 60K Pre-Symptomatic (SNP3) Robust, diversified RNA medicines pipeline including first-in-class RNA editing programs AATD: A
Slide 8: WVE-006 + AIMers RNA editing Alpha-1 antitrypsin deficiency (AATD)
WVE-006 + AIMers RNA editing Alpha-1 antitrypsin deficiency (AATD)
Slide 9: WVE-006: GalNAc-conjugated AIMer to correct mutant SERPINA1 transcript
WVE-006: GalNAc-conjugated AIMer 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 Pha
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
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: RestorAATion-2 underway, proof-of-mechanism data expected 4Q 2024
RestorAATion-2 underway, proof-of-mechanism data expected in 4Q 2024 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose RestorAATion-2: AATD Patients Informs dose & dose frequency RestorAATion-1: Healthy Volunteers Single ascending dose (SAD) à Multiple-ascending dose (MAD)
Slide 14: Multiple RNA editing opportunities beyond WVE-006
Multiple RNA editing opportunities to build high-value, wholly-owned 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-AIMer
Slide 15: 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 2. Initiation, development, launch, and commercialization milestones for WVE-006 and programs progressed during initial 4-year research term (8 GSK collaboration program
Slide 16: WVE-007 (INHBE program) GalNAc-siRNA silencing Obesity
WVE-007 (INHBE program) GalNAc-siRNA silencing Obesity and other metabolic disorders
Slide 17: Potential for best-in-class siRNA enabled by PRISM platform
Left and Middle: 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; Right: Benchmark: F
Slide 18: Silencing INHBE by ≥50% expected to recapitulate healthy metabolic profile
Silencing INHBE gene by ≥ 50% is expected to recapitulate the healthy metabolic profile of INHBE loss of function (LoF) carriers, including:1,2,3 INHBE (Inhibin βE) expressed primarily in liver and gene product (activin E) acts on its receptor in adipose tissue4 Lowering of INHBE mRNA promotes fat b
Slide 19: INHBE program: Data from DIO mouse model supports best-in-class profile
Highly potent (ED50 < 1mg/kg) and durable silencing following one, low-single-digit dose, supporting every-six-month or annual dosing Monotherapy: Weight loss similar to semaglutide with no loss of muscle mass and a reduction in fat mass, with preferential effect to the visceral fat (consistent with
Slide 20: WVE-N531 Splicing Duchenne muscular dystrophy
WVE-N531 Splicing Duchenne muscular dystrophy
Slide 21: Genetic mutation in dystrophin gene prevents dystrophin production
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 skipping In 2023, exon skippin
Slide 22: 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 23: PN chemistry yields excellent muscle exposure 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 24: 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 25: 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 26: 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 27: WVE-003 Allele-selective silencing Huntington's Disease
WVE-003 Allele-selective silencing Huntington’s Disease
Slide 28: Huntington's disease is a devastating neurological disorder
HD is a monogenic autosomal dominant genetic disease; fully penetrant and affects entire brain No current disease modifying therapies for HD Characterized by cognitive decline, psychiatric illness, and chorea; ultimately fatal Expanded CAG triplet repeat in HTT gene results in production of mutant h
Slide 29: Wild-type HTT is critical for normal neuronal function
Saudou & Humbert 2016 Neuron; Cason et al., 2022 Nat Rev Cell Biol; Laundos et al., 2023 Front Cell Dev Biol; Kaliszewski et al., 2015 Cell Death Diff; Keryer et al., 2011 J Clin Invest Khoshnan & Patterson, 2011. Neurobiol Dis; Pogoda et al., 2021 Curr Med Chem; Hsiao et al., 2013 Hum Mol Genet Wil
Slide 30: Allele-selective lowering of mutant HTT protein of up to 46%
* p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein Allele-selective lowering of mutant HTT protein of up to 46% with three doses of WVE-003 and preservation of wild-type HTT Durability of mHTT reductions supports potential for quarterly
Slide 31: WVE-003 mHTT reduction correlating with slowing of caudate atrophy
WVE-003 leads to allele-selective mHTT reduction, correlating with slowing of caudate atrophy Allele-Selective mHTT KD with wtHTT Preservation Slowing of Caudate Atrophy Functional Benefit mHTT reduction of up to 46% vs. placebo wtHTT preserved/increased throughout study Caudate atrophy is an imagin
Slide 32: Draft study design: Registrational study powered to show impact on caudate atrophy
Draft study design: Registrational study powered to show impact on caudate atrophy Randomized, placebo controlled clinical study Adults with SNP3 and HD Stage 1-2 N = ~150 12-18 months duration vMRI: volumetric MRI Expect feedback from regulators on path to accelerated approval by year-end 2024 Alle
Slide 33: Anticipated upcoming milestones
Anticipated upcoming milestones
Slide 34: 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 Add’l AIMer Programs (GalNAc liver and extra-hepatic) Wave’s platform is translati
Slide 35: Anticipated milestones in 2024 and beyond
Potential for GSK and Takeda collaboration milestones in 2024 R&D Day expected in the Fall 2024 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 (AA
Slide 36: For questions contact investorrelations@wavelifesci.com
For questions contact: investorrelations@wavelifesci.com