Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (May 2020)
44 slides from Wave Life Sciences's investor presentation, May 11, 2020
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation May 11, 2020 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 genetic medicines company
Building a leading genetic medicines company Innovative platform Stereopure oligonucleotides Backbone modifications Allele-selectivity Novel modalities (ADAR) Foundational stereochemistry IP Foundation of NEUROLOGY programs Huntington’s disease ALS / FTD Ataxias Parkinson’s Alzheimer’s Clinical deve
Slide 4: Innovative pipeline led by neurology programs
THERAPEUTIC AREA TARGET DISCOVERY PRECLINICAL CLINICAL ESTIMATED U.S. PREVALENCE* PARTNER Huntington’s disease WVE-120101 mHTT SNP1 ~10,000 / ~35,000 Takeda 50:50 option WVE-120102 mHTT SNP2 ~10,000 / ~35,000 Takeda 50:50 option mHTT SNP3 ~8,000 / ~30,000 Takeda 50:50 option ALS and FTD C9orf72 ~1,8
Slide 5: HD portfolio: Huntington's Disease
HD portfolio Huntington’s Disease
Slide 6: Huntington's disease: a hereditary, fatal disorder
Huntington’s disease: a hereditary, fatal disorder Sources: Auerbach W, et al. Hum Mol Genet. 2001;10:2515-2523. Dragatsis I, et al. Nat Genet. 2000;26:300-306. Leavitt BR, et al. J Neurochem. 2006;96:1121-1129. Nasir J, et al. Cell. 1995;81:811-823. Reiner A, et al. J Neurosci. 2001;21:7608-7619. W
Slide 7: Evidence suggests wild-type HTT is neuroprotective in an adult brain
Evidence suggests wild-type or healthy HTT is neuroprotective in an adult brain Transport of key neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are regulated by wtHTT levels Relative proportion of wild-type to mutant protein is critical Increased amount of wild-type protein re
Slide 8: Recent publication on importance of wild-type huntingtin
Recent publication contributes to weight of evidence on importance of wild-type huntingtin 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 regenerating tra
Slide 9: Increasing evidence on the importance of wtHTT in HD
Increasing evidence on the importance of wtHTT in HD pathogenesis, CNS and systemic health Striatum-specific defect in synaptic vesicle endocytosis that was not corrected by total lowering of HTT Corrected by overexpression of wild-type protein Striatal projection neurons require HTT for motor regul
Slide 10: Wild-type HTT in the cortex appears critical for striatal health
Wild-type HTT in the cortex appears critical for striatal health Presented by Dr. Frederic Saudou at Wave’s Analyst and Investor Research Day on October 7, 2019 Virlogeux et al., Cell Reports 2018 Neuro HD Neuron Type Genetic Status Compartment Cortical Striatal Network Status Functional Dysfunction
Slide 11: Wave approach: novel, allele-selective silencing
Utilize association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including Huntington’s disease (HD) Potential to provide treatment for up to 80% of HD population Wave approach: novel, allele-selective silencing Source: Kay,
Slide 12: Selective reduction of mHTT mRNA & protein
Selective reduction of mHTT mRNA & protein Reporter Cell Line* Neuro HD Source: Meena, Zboray L, Svrzikapa N, et al. Selectivity and biodistribution of WVE-120101, a potential antisense oligonucleotide therapy for the treatment of Huntington’s disease. Paper presented at: 69th Annual Meeting of the
Slide 13: Demonstrated delivery to brain tissue
Demonstrated delivery to brain tissue WVE-120101 and WVE-120102 distribution in cynomolgus non-human primate brain following intrathecal bolus injection In Situ Hybridization ViewRNA stained tissue Red dots are WVE-120102 oligonucleotide Arrow points to nuclear and perinuclear distribution of WVE-12
Slide 14: PRECISION-HD clinical trial design
PRECISION-HD clinical trial design Two parallel, multicenter, double-blind, randomized, placebo-controlled Phase 1b/2a clinical trials for WVE-120101 and WVE-120102 Single Dose (3:1) Multidose Randomization 3:1 196 1 Washout CSF sample Dose 28 56 84 112 Study Day* 140 OLE 2 mg 4 mg 8 mg 16 mg 32 mg
Slide 15: PRECISION-HD2 topline results
PRECISION-HD2 topline results Clinical trial ongoing Neuro HD Doses Safety Biomarker Effects Topline results announced December 30. 2019; mHTT: mutant huntingtinwtHTT: wild-type HTTtHTT: total HTT 1 Hodges-Lehmann non-parametric shift estimates of the difference between treatment and placebo; 2 Wilc
Slide 16: Three allele-selective HD programs
Three allele-selective HD programs Intend to explore efficacy in early manifest and pre-manifest HD patient populations Neuro HD Potential to address ~80% of HD patient population % Huntington’s Disease Patient Population with SNP SNP1 SNP2 SNP3 SNP1 SNP2 SNP1 SNP2 SNP3 ~50% ~50% ~40% ~70% ~80% +10%
Slide 17: SNP3 program approaching clinical development
SNP3 program approaching clinical development Knockdown persists for 12 weeks in BACHD mouse model Data presented at CHDI Foundation’s 15th Annual HD Therapeutics Conference Feb 24-27, 2020; See poster for full dataset. [Figure on right] Statistics: All oligo treatment groups statistically significa
Slide 18: C9orf72 program: ALS and FTD
C9orf72 program Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 19: C9orf72: a critical genetic risk factor
C9orf72: a critical genetic risk factor C9orf72 gene provides instructions for making protein found in various tissues, with abundance in nerve cells in the cerebral cortex and motor neurons C9orf72 genetic mutations are the strongest genetic risk factor found to date for the more common, non-inheri
Slide 20: Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis Fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord Affects approximately 15,000-20,000 people in the US with a median survival of three years C9orf72 is present in approximately 40% of familial ALS
Slide 21: Frontotemporal dementia
Frontotemporal dementia Progressive neuronal atrophy with loss in the frontal and temporal cortices characterized by personality and behavioral changes, as well as gradual impairment of language skills Affects approximately 55,000 people in the US Second most common form of early-onset dementia afte
Slide 22: C9orf72 program: selective silencing in vivo
2 4 8 week 2 4 8 Repeat-containing transcripts C9orf72 candidate PBS Relative fold change C9orf72 V3/mHPRT 2 4 8 week 2 4 8 C9orf72 program: Selective silencing in vivo of expanded C9orf72 repeat transcripts Clinical development expected to initiate in 2H 2020 C9orf72 genetic mutations are the most
Slide 23: PRISM Platform
PRISM Platform
Slide 24: PRISM design and optimization of stereopure oligonucleotides
Through iterative analysis of in vitro and in vivo outcomes and artificial intelligence-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 DESIGN Unique
Slide 25: 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 26: 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 27: PRISM platform enables rational drug design
Continuous Learning PRISM platform enables rational drug design Source: Iwamoto N, et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol. 2017;35:845-851.
Slide 28: Optimizing potency and durability across multiple tissues
Liver Knockdown of Serum APOC3 Protein Levels in Mice Two 5 mg/kg SC injections on Days 1&3 Stereorandom Stereopure Data represented in this slide from in vivo studies. CNS: Central nervous system; PBS = phosphate buffered saline; Ctx = cortex; Str = striatum; Cb = cerebellum; Hp = hippocampus; SC =
Slide 29: ADAR-mediated RNA editing
ADAR-mediated RNA editing
Slide 30: RNA editing: a promising new therapeutic modality
RNA editing: A promising new therapeutic modality for treatment of genetic diseases Potential benefits versus gene editing A-to-I(G) RNA editing opportunity is significant >32,000 pathogenic human SNPs1 Ability to use endogenous proteins (e.g. ADAR) Ease of delivery Titratable, repeatable dosing Rev
Slide 31: RNA editing supplements Wave's existing modalities
RNA editing can be used for several therapeutic applications and supplement Wave’s existing modalities Silence protein expression Reduce levels of toxic mRNA/protein ü ü Alter mRNA splicing Exon skipping/inclusion/ restore frame ü ü Fix nonsense mutations that cannot be splice-corrected Restore prot
Slide 32: Using PRISM to unlock ADAR-mediated RNA editing
Structure of ADAR deaminase domain bound to dsRNA substrate Using PRISM to unlock ADAR-mediated RNA editing Target mRNA Oligonucleotide ADAR makes multiple contacts with oligonucleotide backbone, sugar and bases Using PRISM platform, rationally designed and screened oligonucleotides to optimize: 2'
Slide 33: Advantages of Wave ADAR-mediated RNA-editing platform
Wave platform Advantages of Wave ADAR-mediated RNA-editing platform Fully chemically modified to increase stability in vivo Chirally-controlled backbone to maximize in vitro activity GalNAc-conjugated for targeted delivery into liver No requirement for AAV / nanoparticles No immunogenicity from exog
Slide 34: In vitro RNA editing in NHP and human hepatocytes
NHP Hepatocytes Human Hepatocytes In vitro RNA editing demonstrated in non-human primate and 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. Potent, dose-de
Slide 35: First non-human primate RNA editing
First non-human primate RNA editing 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 Right: % Editing quantified from Sanger sequencing using EditR program. In vivo – NHP Liver biopsies conducted at baseline and 2
Slide 36: RNA-editing design applicable across targets
RNA-editing design applicable across targets Data presented at 1st International Conference on Base Editing – Enzymes and Applications (Deaminet 2020); See poster for full dataset Editing achieved across several distinct RNA transcripts Supports potential for technology to be applied across variety
Slide 37: Ophthalmology
Ophthalmology
Slide 38: 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 39: Potent and durable MALAT1 knockdown in the eye
Stereopure compound induces potent and durable MALAT1 knockdown in the eye ~50% MALAT1 knockdown at 9 months Mouse: Compound or PBS (1 x 50 mg 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
Slide 40: 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 41: Potent USH2A exon skipping with stereopure compound
Potent USH2A exon 13 skipping with stereopure compound in vitro and ex vivo Left: Compounds 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. Reference Compound: van Diepen et al. 2
Slide 42: Allele-selective reduction for Rhodopsin P23H mutation
Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation Ferrari et al., Current Genomics. 2011;12:238-249.; Reporter assays on a Wave stereopure sequence as well as a sequence described in WO2016138353A1: ASO and luciferase reporter plasmids (wild-type an
Slide 43: Anticipated upcoming Wave milestones
Anticipated upcoming Wave milestones Neurology 2H 2020: PRECISION-HD2 data from 32 mg cohort in Huntington’s disease 2H 2020: PRECISION-HD1 topline data, including 32 mg cohort, in Huntington’s disease 2H 2020: Initiate clinical development of SNP3 program in Huntington’s disease 2H 2020: Initiate c
Slide 44: Realizing the potential of genetic medicines
Realizing the potential of genetic medicines For more information: Kate Rausch, Investor Relations krausch@wavelifesci.com 617.949.4827
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