Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation September 10, 2021 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 genetic medicines company
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia 1stereopure oligonucleotides and novel backbone chemistry modifications Innovative platform Stereopure oligonucleotides Novel backbone modifications (PN chemistry) Allele-selectivity Multipl
Slide 4: Robust portfolio of stereopure, PN-modified oligonucleotides
THERAPEUTIC AREA / TARGET DISCOVERY PRECLINICAL CLINICAL PARTNER ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple† Takeda milestones & royalties DMD Exon 53 100% global ADAR editing Multiple AATD (ADAR editing) SERPINA1 100% global Retinal disea
Slide 5: WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 6: 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 7: C9orf72 repeat expansions: Mechanisms of cellular toxicity in ALS and FTD
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 8: C9orf72 protein is important for normal regulation of neuronal function and the 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 9: PN backbone chemistry modifications: Improved potency among C9orf72-targeting oligonucleotides in vivo
PN backbone chemistry modifications: Improved potency among C9orf72-targeting oligonucleotides in vivo Exposure (µg/g) Exposure (µg/g) C9orf72 compounds Spinal cord Cortex PS/PO backbone PS/PO/PN backbone %C9orf72 V3 transcript remaining Mice received 2 x 50 ug ICV doses on days 0 & 7; mRNA from spi
Slide 10: WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro
WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro V3 Dose (μM) All V WVE-004 NTC Dose (μM) In vitro activity in C9 patient-derived neurons WVE-004 NTC Dose (μM) IC50:201.7nM In vitro selectivity in C9 patient-derived neurons C9 patient-derived motor neurons were treat
Slide 11: Durable reduction in vivo of Poly-GP in spinal cord and cortex after 6 months
* *** ** *** 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 12: FOCUS-C9: Adaptive trial designed to assess target engagement
Single-ascending dose (SAD) Multi-ascending dose (MAD) Phase 1b/2a global, multicenter, randomized, double-blind, placebo-controlled trial Dose escalation and MAD dosing frequency guided by independent committee Safety and tolerability Primary objectives Plasma and CSF PK profile PolyGP in CSF Secon
Slide 13: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 14: mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD
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 15: 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 16: HTT provides BDNF, a growth factor critical for survival of striatal neurons
Cerebral cortex Striatum BDNF- containing vesicle To the striatum Microtubule HTT HTT provides BDNF, a growth factor critical for survival of striatal neurons BDNF, brain-derived neurotrophic factor; HD, Huntington’s disease; HTT, huntingtin protein. 1. Altar CA, Cai N, Bliven T, et al. Nature. 1997
Slide 17: Allele-selective approach to treating HD
Target mutant mRNA HTT transcript to reduce mutant HTT protein Preserve wild-type HTT protein reservoir in brain Allele-selective approach to treating HD Wave has only allele-selective clinical program in Huntington’s disease Only an allele-selective approach is designed to address both toxic gain o
Slide 18: Allele-selective approach to treating HD
Allele-selective approach to treating HD Neuro HD 1 Claassen et al. Neurol Genet Jun 2020; Carroll et al. Mol Ther. 2011 Dec; HDSA.org : 2000 patients ~30,000 people with manifest HD in US ~40% of HD Patients Carry SNP3 Allele-selective Treatments Have Potential to Benefit Many of Those At-risk of H
Slide 19: Nature publication contributes to weight of evidence on importance of wild-type huntingtin
Nature publication contributes to weight of evidence on importance of wild-type huntingtin Source: Poplawski et al., Nature, April 2019 Htt: Huntingtin protein Conditional knock-out of Htt in 4-month old mice (post-neuronal development) Results suggest that: Htt plays a central role in the regenerat
Slide 20: 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 21: WVE-003: In vivo studies support 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 Achieved sufficient concentrations of WVE-003 in cortex and striatum for targe
Slide 22: SELECT-HD: Adaptive trial designed to assess target engagement
Single-ascending dose (SAD) Multi-ascending dose (MAD) Day 1-3 15 29 57 85 Dose q Biomarker Samples l l l l l Clinical Evaluations l l Week 1 2 4 8 12 16 20 24 l l l l l l l l l l l Phase 1b/2a global, multicenter, randomized, double-blind, placebo-controlled trial Safety and tolerability Primary ob
Slide 23: Assessment of wild-type protein in CSF
Neuro HD Assessment of wild-type protein in CSF Ab: antibodyCSF: cerebrospinal fluidHTT: huntingtin proteinMW1: Wild et al. JCI 2015 CSF sample Total HTT mt wt wt wt mt mt mt mt mt wt wt wt Wild-type HTT wt wt wt wt wt wt wt wt Deplete mutant HTT Add polyQ Ab magnetic beads to CSF sample mt mt mt mt
Slide 24: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 25: Dramatic increase in effect in dKO mouse model with PN-modified backbone
100 75 50 25 0 Survival probability (%) 0 4 8 12 16 20 24 28 32 36 40 Time (weeks) Dramatic increase in effect in dKO mouse model with stereopure ASO with PN-modified backbone versus stereopure compound with PS/PO modifications dKO; double knockout mice lack dystrophin and utrophin protein. mdx mice
Slide 26: 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 27: Clinical trial of WVE-N531 underway
Clinical trial of WVE-N531 underway Unmet need in DMD remains high Open-label clinical trial of up to 15 boys with DMD amenable to exon 53 skipping Powered to evaluate change in dystrophin production Includes assessment of drug concentration in muscle and initial safety Study planned for every-other
Slide 28: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 29: Rational drug design: Evolution of PRISM platform
Silencing & splicing capabilities PN backbone chemistry modifications In vivo target engagement, including NHP ADAR editing capability Learnings of first-generation programs Establish PK/PD and toxicology relationships Novel in vivo models Stereopure oligonucleotides Rational drug design: Evolution
Slide 30: Design principles deployed across programs
Through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, Wave continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles Multiple modalities
Slide 31: PRISM platform enables rational drug design
Sequence Stereochemistry Chemistry PRISM platform enables rational drug design Chemistry R: 2’ modifications OMe, MOE, F, other modifications 5’ 2’ 3’ 5’ 3’ 2’ R X B B R X: backbone chemistry PO, PS, PN Sequence B: bases A, T, C, mC, G, U, other modified bases Stereochemistry Chiral control of any s
Slide 32: PRISM backbone modifications
Backbone modification (X) Phosphodiester Phosphorothioate Phosphoramidate diester Stereochemistry Not chiral Chiral Chiral Charge Negative Negative Neutral Depiction PRISM backbone modifications Expanding repertoire of backbone modifications with novel PN backbone chemistry Molecule structure illust
Slide 33: PN chemistry increases potency in silencing, splicing, and editing in preclinical studies
Silencing PN chemistry increases potency in silencing, splicing, and editing in preclinical studies 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 (St
Slide 34: Lead program in Takeda collaboration reinforces potential of PN chemistry in the CNS
Lead program in Takeda collaboration reinforces potential of PN chemistry in the CNS Single IT dose of 12 mg (n=3) Therapeutic candidate widely distributed across brain and spinal cord ~90% mRNA knockdown one-month following single dose Substantial and widespread target mRNA reduction following sing
Slide 35: 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 36: 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 37: ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
Slide 38: PRISM platform has unlocked ADAR editing
PRISM platform has unlocked ADAR editing A-to-I editing is one of most common post-transcriptional modifications ADAR is ubiquitously expressed across tissues, including liver and CNS ADAR Target RNA I(G) A Edited RNA Oligonucleotide establishes double-stranded RNA complex Oligonucleotide Modificati
Slide 39: PRISM enables practical approach to RNA editing without need for viruses or exogenous protein
PRISM enables practical approach to RNA editing without need for viruses or exogenous protein Intracellular Extracellular space Endogenous ADAR Unedited RNA Wave ADAR-editing Oligonucleotides Exogenous ADAR or other base editors Edited RNA Protein release/ expression Delivery vehicles Alternative Ba
Slide 40: Advantages of Wave ADAR editing platform
Wave platform Fully chemically modified to increase stability in vivo Chirally-controlled backbone to maximize in vitro activity PN backbone chemistry modification improves editing efficiency No requirement for AAV / nanoparticles GalNAc-conjugated for targeted delivery into liver Avoids permanent o
Slide 41: ADAR amenable diseases represent a sizeable opportunity
ADAR amenable diseases represent a sizeable opportunity Nearly half of known human SNPs associated with disease are G-to-A mutations A-to-I(G) editing could target tens of thousands of potential disease variants1 ~48% C-to-T C-to-G A-to-T C-to-A A-to-C A-to-G Potentially pathogenic human SNPs by bas
Slide 42: RNA editing opens many new therapeutic applications
RNA editing opens many new therapeutic applications Fix nonsense and missense mutations that cannot be splice-corrected Remove stop mutations Prevent protein misfolding and aggregation Alter protein processing (e.g. protease cleavage sites) Protein-protein interactions domains Modulate signaling p
Slide 43: Significant ADAR editing demonstrated in vitro in NHP and primary human hepatocytes
Significant ADAR editing demonstrated in vitro in NHP and primary human hepatocytes NHP: non-human primate; ACTB: Beta-actin; nd= not determined Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR. In vitro dose-response human hepatocytes I
Slide 44: Efficient ADAR editing translated in vivo in non-human primate study
Efficient ADAR editing translated in vivo in non-human primate study NHP: non-human primate; ACTB: Beta-actin; Left: 5mg/kg SC: Day 1,2,3,4,5; Liver Biopsy for mRNA (ACTB Editing) & eASO Exposure: Day 7 Up to 50% editing efficiency observed at Day 7, 2 days post last dose Substantial and durable edi
Slide 45: Wave ADAR editing oligonucleotides are highly specific
Editing site RNA editing within ACTB transcript (human hepatocytes) RNA editing within transcriptome (human hepatocytes) Wave ADAR editing oligonucleotides are highly specific Coverage Genome coordinates ACTB C 0% T 100% C 53.8% T 46.2% ACTB Confidence (LOD score) % Editing Mock Editing oligonucleot
Slide 46: Multiple opportunities for ADAR editing in neurology
Multiple opportunities for ADAR editing in neurology ACTB editing in iCell Neurons ACTB editing in human iCell Astrocytes Concentration (µM) % Editing % Editing Compound 2 (PS / PN) Compound 1 (PS / PN) Compound 3 (PS / PN) EC50: ~200-250nM Gymnotic uptake; Total RNA was harvested, reverse transcrib
Slide 47: Leading RNA editing program provides optimal approach for treatment of AATD
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver Leading RNA editing program provides optimal approach for treatment of AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin; Sources: Strnad 2020; Blanco 2017
Slide 48: Focused on restoring wild-type M-AAT in vivo
AAT Protein ng/ml SA1-1 NT SA1-2 % Z allele mRNA editing SA1-1 NT SA1-2 Focused on restoring wild-type M-AAT in vivo AATD: Alpha-1 antitrypsin deficiency, Z-AAT: mutated protein, M-AAT: wild-type human AAT protein In vivo proof of concept In vitro proof of concept SERPINA1 Z allele mRNA editing AAT
Slide 49: Achieving 40% editing of Z allele mRNA at initial timepoint
Achieving 40% editing of Z allele mRNA at initial timepoint SA1 - 3 SA1 - 4 SERPINA1 Z allele mRNA editing levels nearing correction to heterozygote (MZ) AAT protein increase Wild-type M-AAT functional Z allele mRNA editing in vivo GalNAc-conjugated compounds Up to 40% editing of Z allele mRNA in li
Slide 50: Achieving therapeutically meaningful increases in circulating human AAT protein
Statistics (ELISA): Matched 2-way ANOVA with correction for multiple comparisons (Bonferroni) was used to test for differences in AAT abundance in treated samples compared to PBS Statistics; de Serres et al., J Intern Med. 2014; NTC: non-targeting control Achieving therapeutically meaningful increas
Slide 51: ADAR editing restores circulating, functional M-AAT
ADAR editing restores circulating, functional M-AAT Human wild-type M-AAT AAT protein increase Wild-type M-AAT functional Z allele mRNA editing in vivo Wild-type M-AAT detected with ADAR editing ~2.5-fold increase Significant increase in neutrophil elastase inhibition with ADAR editing 3-fold increa
Slide 52: ADAR editing successfully corrects Z allele mRNA in vivo to restore functional M-AAT protein
ADAR editing successfully corrects Z allele mRNA in vivo to restore functional M-AAT protein Up to 40% editing of SERPINA1 Z allele mRNA in liver at initial timepoint, nearing correction to heterozygotes (MZ) Initial Z allele mRNA editing resulted in therapeutically meaningful increase in circulatin
Slide 53: Ophthalmology
Ophthalmology
Slide 54: Stereopure oligonucleotides for inherited retinal diseases (IRDs)
Stereopure oligonucleotides for inherited retinal diseases (IRDs) Wave ophthalmology opportunity Oligonucleotides can be administered by intravitreal (IVT) injection; targeting twice per year dosing Stereopure oligonucleotides open novel strategies in both dominant and recessive IRDs; potential for
Slide 55: Durable Malat1 knockdown through months with PN backbone chemistry modifications
Durable Malat1 knockdown through 9 months with PN backbone chemistry modifications Compound or PBS (1 x 50 ug IVT) was delivered to C57BL6 mice. Relative percentage of Malat1 RNA in the posterior of the eye (retina, choroid, sclera) to PBS-treated mice is shown at 12, 20 and 36 weeks post-single inj
Slide 56: Usher Syndrome Type 2A: a progressive vision loss disorder
Usher Syndrome Type 2A: a progressive vision loss disorder Autosomal recessive disease characterized by hearing loss at birth and progressive vision loss beginning in adolescence or adulthood Caused by mutations in USH2A gene (72 exons) that disrupt production of usherin protein in retina, leading t
Slide 57: Potent USH2A exon skipping with stereopure compound in vitro and ex vivo
Potent USH2A exon 13 skipping with stereopure compound in vitro and ex vivo Oligonucleotides were added to Y79 cells under free-uptake conditions. Exon skipping was evaluated by Taqman assays. USH2A transcripts were normalized to SRSF9. Data are mean±s.d., n=2. Stereorandom: Compound identified in v
Slide 58: Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP eye in vivo
Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP eye in vivo Oligonucleotide is complementary to NHP USH2A exon 12* Evaluated 1-week post-single IVT injection Dose-dependent activity of stereopure oligonucleotides Substantial exposure in retina Exon-skipping integrity confirmed
Slide 59: Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation
Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation Left: Reporter assays on a sequence described in WO2016138353A1. Oligonucleotide and luciferase reporter plasmids (wild-type and mutant RHO) are transfected into Cos7 cells. Cells are harvested after
Slide 60: Upcoming milestones
Upcoming milestones
Slide 61: Clinical data to unlock the potential of PN chemistry across different modalities and tissues
Clinical data to unlock the potential of PN chemistry across different modalities and tissues GalNAc-conjugated subcutaneous Liver Systemic delivery Muscle IT delivery CNS C9orf72 Exon 53 SERPINA1 SNP3 Advanced to clinic ALSFTD HD CNS collaboration programs DMD Other exons AATD New editing targets S
Slide 62: Upcoming milestones 2021-2022
WVE-004: Dose first patient in FOCUS-C9 trial for patients with ALS/FTD in 2021 Continuous flow of data to enable program decisions through 2022 WVE-003: Dose first patient in SELECT-HD trial for patients with HD in 2021 WVE-N531: Clinical trial recruitment ongoing Dose first patient in clinical tri
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