Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (November 2021)
79 slides from Wave Life Sciences's investor presentation, Nov 10, 2021
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation November 10, 2021 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: Biological machinery in our cells can be harnessed to treat genetic diseases
Biological machinery in our cells can be harnessed to treat genetic diseases Silencing Splicing Editing Oligonucleotide-directed delivery of RNA to regulate enzymes Leverages exon skipping machinery to restore a working transcript Efficient editing of RNA bases using endogenous ADAR Endogenous ADAR
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
Seminal 2017 publication from Wave, increasingly recognized by leaders in nucleic acid therapeutics1 Current therapeutics with chiral backbone modifications: Enables design and optimization of fully-characterized, single-isomer RNA therapeutics Wave is the leader in rationally designed stereopure ol
Slide 9: Innovating stereopure backbone chemistry modifications
… … Innovating stereopure backbone chemistry modifications 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 Negative charge
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: 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 12: Improvements in PRISM primary screen hit rates accelerate drug discovery
Improvements in PRISM primary screen hit rates accelerate drug discovery 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 screens used i
Slide 13: 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 SERPINA1 100% global OPHTHALMOLOGY Retinal d
Slide 14: WVE-004 ALS and FTD
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 15: 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 16: 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 17: C9orf72 protein is important for normal regulation of neuronal function
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 18: PN chemistry modifications improved potency 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 19: 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 20: Durable reduction in vivo of Poly-GP 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 21: 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 22: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 23: mHTT toxic effects lead to neurodegeneration, 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 24: Wild-type HTT is a critical protein for important functions in the CNS
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 25: HTT provides BDNF, a growth factor critical for striatal neuron survival
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 26: 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 27: Allele-selective treatments have potential to benefit many at-risk of 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 28: Nature publication 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 29: WVE-003 demonstrates selective, potent, and 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 30: WVE-003 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 31: 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 32: 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 33: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 34: Dramatic increase in effect with PN-modified splicing oligonucleotide in dKO mouse
100 75 50 25 0 Survival probability (%) 0 4 8 12 16 20 24 28 32 36 40 Time (weeks) Dramatic increase in effect with PN-modified splicing oligonucleotide in dKO mouse model dKO; double knockout mice lack dystrophin and utrophin protein. mdx mice lack dystrophin. dKO: PS/PO/PN 150 mg/kg n= 8 (p=0.0018
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: 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 37: ADAR editing
ADAR editing RNA editing capability
Slide 38: 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 39: AIMers: Realizing potential of therapeutic RNA editing
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 40: 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 41: 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 42: 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 43: Sequence space is defined
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 44: RNA-editing design applicable across targets in primary human hepatocytes
ADAR interacts with double-stranded RNA duplex in a sequence independent way RNA-editing design applicable across targets in vitro in primary human hepatocytes Editing achieved across several distinct RNA transcripts Supports potential for technology to be applied across variety of disease targets T
Slide 45: Durable and specific editing out to Day 50 in liver of NHPs
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs 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 editing; plotted circles
Slide 46: Substantial in vivo RNA editing in CNS tissues
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 47: 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 48: Productive editing in multiple NHP tissues with unconjugated systemic AIMer
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 49: Productive editing in multiple immune cell types with AIMers 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 50: 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 51: Alpha-1 antitrypsin deficiency
Alpha-1 antitrypsin deficiency
Slide 52: 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 53: 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 In vivo proof of concept In vitro proof of concept SERPINA1 Z allele mRNA editing AAT protein concentration in media 3-Fold increase Liver AAT aggregation observed in AATD is recapitu
Slide 54: Achieving 40% editing of Z allele mRNA at single time point
Achieving 40% editing of Z allele mRNA at single time point 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 liver of transgeni
Slide 55: RNA editing only detected at PiZ mutation site in 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 56: 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 57: 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 58: Increase in circulating human AAT is durable
Serum AAT mg/mL PBS PBS SA1-4 SA1-4 Dose Days ns *** *** ** *** 11 mM ** Increase in circulating human AAT is durable, with restored M-AAT detected one month post last dose SA1-4: GalNAc AIMer (Left) huADAR/SERPINA1 mice administered PBS or 3 x 10 mg/kg AIMer (days 0, 2, and 4) SC. AAT levels quanti
Slide 59: Optimized AIMers achieve ~50% mRNA editing and restore AAT protein
Optimized AIMers achieve ~50% mRNA editing and restore AAT protein well above therapeutic threshold Left: AIMers administered huADAR/SERPINA1 mice (3x5 mg/kg) on days 0, 2, and 4. Livers collected on day 7, and SERPINA1 editing was quantified by Sanger sequencing (shown as mean ±. sem) Stats: One-wa
Slide 60: Path to AATD development candidate
Demonstrate restoration of functional M-AAT Chemistry optimization to improve potency Path to development candidate ADAR editing is highly specific Restored, circulating wild-type M-AAT in serum at 1-month post-last dose Chemistry optimization of AIMers further increases potency Optimized AIMers res
Slide 61: Ophthalmology
Ophthalmology
Slide 62: Stereopure oligonucleotides for inherited retinal diseases
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 63: Durable Malat1 knockdown through months with PN backbone chemistry
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 64: 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 65: 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 66: Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP eye
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 67: Allele-selective reduction for adRP associated with Rhodopsin P23H
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 68: ADAR editing: up to 50% editing in vivo in posterior of eye
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 69: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 70: PRISM enables precision modulation of RNA therapeutic properties
OMe, MOE, F, other modifications PO, PS, PN 5’ modifications, backbone modifications A, T, C, mC, G, U, other modified bases PRISM enables precision modulation of RNA therapeutic properties using unique chemistry toolkit 2’ modifications Backbone chemistry Bases Chiral control of any stereocenter Po
Slide 71: Keys to delivering therapeutic success in CNS
Keys to delivering therapeutic success in CNS Current and future unmet need Right target for disease Right patient population Selection of relevant biomarkers, clinical endpoints, study duration, dosing regimen PRISM platform PN backbone modifications in the setting of chiral control and other PRISM
Slide 72: PN chemistry improves distribution to CNS
PN chemistry improves distribution to CNS *Isomer 3; 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
Slide 73: 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 74: 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 Target mRNA knockdown 28 days post-dose (WVE-005) Striatum Control NHPs: Non-human primates NHPs were administered 12 mg on day 1 via IT bolus injection; tissue samples were collected from 3 N
Slide 75: 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 76: 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 77: Upcoming milestones
Upcoming milestones
Slide 78: Upcoming milestones throughout 2022 will unlock opportunities
Upcoming milestones throughout 2022 will unlock opportunities Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Liver (Subcutaneous GalNAc) WVE-004 C9orf72 ALS & FTD Clinical data being generated to enable decision making WVE-003 HD SNP3 Clinical data being generated to enable decision m
Slide 79: 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
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