Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (September 2020)
57 slides from Wave Life Sciences's investor presentation, Sep 9, 2020
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation September 9, 2020 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 Innovative platform Stereopure oligonucleotides Novel backbone modifications (PN chemistry) Allele-selectivity Multiple modalities (silencing, splicing, ADAR editing) Strong IP position1 Foundation of NEUROLOGY programs Huntington’s disease ALS / FTD Atax
Slide 4: PRISM has unlocked novel and proprietary advances in oligonucleotide design
PRISM has unlocked novel and proprietary advances in oligonucleotide design Backbone modifications Sugar modifications Drug approvals (FDA) 1975 2020 2000 Mixtures of 2n molecules1 ~500,000 different molecules per dose fomivirsen pegaptanib Phosphorothioate (PS) mipomersen nusinersen PN backbone che
Slide 5: 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 WVE-003 mHTT SNP3 ~8,000 / ~30,000 Takeda 50:50 option ALS and FTD WVE-
Slide 6: HD portfolio: Huntington's Disease
HD portfolio WVE-120101, WVE-120102, WVE-003 Huntington’s Disease
Slide 7: 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 8: 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 9: Nature publication on importance of wild-type huntingtin
Nature 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 10: 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 11: 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 12: 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 13: WVE-120101: Selective reduction of mHTT mRNA and protein
WVE-120101: Selective reduction of mHTT mRNA and 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 M
Slide 14: 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 15: Safety profile supported addition of higher dose cohorts
Safety profile supported addition of higher dose cohorts PRECISION-HD clinical trials Single Dose Multidose 196 1 Washout CSF sample Dose 28 56 84 112 Study Day* 140 OLE 2 mg 4 mg 8 mg 16 mg 32 mg PRECISION-HD2 and PRECISION-HD1 data, including 32 mg cohorts and OLE data, expected in 1Q 2021 Multido
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 WVE-120101 SNP2 WVE-120102 SNP3 WVE-003 SNP1 SNP2 SNP1 SNP2 SNP3
Slide 17: WVE-003 (SNP3) approaching clinical development
WVE-003 (SNP3) approaching clinical development Knockdown persists for 12 weeks in BACHD mouse model CTA: clinical trial application; wtHTT: wild-type huntingtin; mHTT: mutant huntingtin [Figure on right] Statistics: All oligo treatment groups statistically significantly different from PBS; ***, P<0
Slide 18: WVE-004: ALS and FTD
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 19: C9orf72 repeat expansions: a critical genetic driver of ALS and FTD
C9orf72 repeat expansions: A critical genetic driver of ALS and FTD Normal (non-expanded) Allele < 25 GGGGCC repeats Expanded Allele Sources: DeJesus-Hernandez et al, Neuron, 2011. Renton et al, Neuron, 2011. Zhu et al, Nature Neuroscience, May 2020 Typically 100’s-1000’s of GGGGCC repeats C9orf72 h
Slide 20: C9-ALS and C9-FTD: Manifestations of a clinical spectrum
C9-ALS and C9-FTD: Manifestations of a clinical spectrum Disease C9 specific US population Mean disease duration Standard of care C9-ALS Fatal neurodegenerative disease Progressive degeneration of motor neurons in brain and spinal cord ~2,000 3.1 years Significant unmet need despite two approved the
Slide 21: C9orf72 repeat expansions: Mechanisms of cellular toxicity
C9orf72 repeat expansions: Mechanisms of cellular toxicity 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 C9orf72 protei
Slide 22: C9orf72 targeting strategy spares C9orf72 protein
Normal C9orf72 allele produces three mRNA transcripts (~80% are V2, ~20% are V1 and V3) Pathological allele with expanded repeat leads to healthy V2 and pathological V1 and V3 transcript by-products C9orf72 targeting strategy spares C9orf72 protein Wave C9orf72 candidate targets only V1 and V3 trans
Slide 23: PN backbone chemistry: improved potency among C9orf72 oligonucleotides
PN backbone chemistry: 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 spinal cord and c
Slide 24: WVE-004: Potent and selective knockdown 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 25: WVE-004: Knockdown of repeat transcripts and DPRs in vivo
2 4 8 week 2 4 8 Repeat-containing transcripts WVE-004 PBS Relative fold change C9orf72 V3/mHPRT 2 4 8 week 2 4 8 WVE-004: Potent and selective knockdown of repeat transcripts and DPRs Potent in vivo knockdown of repeat containing transcripts and DPRs Protein preservation Spinal Cord Cortex Repeat-c
Slide 26: WVE-004 reaches target brain regions and cell types in vivo
WVE-004 reaches target brain regions and cell types in vivo In situ hybridization: Red - ViewRNA for WVE-004; Blue – Hematoxylin. 40X magnification. C9 BAC transgenic mice were administered PBS or 50 ug of WVE-004, ICV, on day 0 and day 7. Mice were euthanized at 8 weeks after the first injection. S
Slide 27: Durable knockdown of repeat transcripts after 6 months
4 12 18 12 18 24 4 24 Durable knockdown of repeat transcripts in vivo after 6 months in spinal cord and cortex Spinal cord Cortex 1.0 0.5 0.0 Relative fold change C9orf72 V3/mHPRT1 WVE-004 PBS week 4 12 18 12 18 24 4 24 1.0 0.5 0.0 Relative fold change C9orf72 V3/mHPRT1 WVE-004 PBS week Experimental
Slide 28: Durable knockdown of DPRs in vivo
Durable knockdown of DPRs in vivo after 6 months in spinal cord and cortex 4 12 18 12 18 24 4 24 Spinal cord Cortex 1.5 0.5 0.0 WVE-004 PBS week 4 12 18 12 18 24 4 24 WVE-004 PBS week 1.0 Relative Poly-GP levels (normalized to PBS) 1.5 0.5 0.0 1.0 Experimental description: 2 x 50 ug on day 0 and day
Slide 29: WVE-004 proof-of-concept study to include ALS and FTD patients
WVE-004 proof-of-concept study to include both ALS and FTD patients Patients with documented C9orf72 expansion and confirmed ALS or FTD diagnosis Single and multiple ascending doses to be explored Safety and tolerability Pharmacodynamic effects on key biomarkers while on treatment PolyGP NfL Key exp
Slide 30: Wave's drug discovery and development platform
Wave’s drug discovery and development platform
Slide 31: Design and optimize across multiple modalities
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 Multiple moda
Slide 32: 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 X: backbone chemistry Phosphodiester (PO), phosphorothioate (PS), other backbone modifications Sequence B: bases A, T, C, mC, G, U,
Slide 33: 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 34: In vitro knockdown of PS/PO compared to PS/PN compounds
In vitro knockdown of PS/PO containing compounds compared to PS/PN compounds with same sequence Rational design using PN chemistry backbone modification increases potency on average Presented at Analyst & Investor Research Webcast on August 25, 2020; Left: Experiment was performed in iPSC-derived ne
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
ADAR editing
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: No delivery vehicle or exogenous proteins required
No delivery vehicle required No exogenous proteins necessary Potential for reduced off-target effects 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 Exogen
Slide 40: ADAR amenable diseases represent a sizeable opportunity
ADAR amenable diseases represent a sizeable opportunity Nearly half of known human genetic pathogenic SNPs are G-to-A mutations Tens of thousands of potential disease variants A-to-I(G) editing could target1 ~48% C-to-T C-to-G A-to-T C-to-A A-to-C A-to-G Pathogenic human SNPs by base pair correction
Slide 41: 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 42: PN chemistry improves editing efficiency
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 PN chemistry improves editing efficiency PN backbone modification increased both potency and editing efficiency in vi
Slide 43: Significant ADAR editing 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 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: Sustained editing in vivo in non-human primates
Sustained editing in vivo in non-human primates after 45 days % Editing quantified from Sanger sequencing using EditR program. Efficient and potent editing of ACTB demonstrated with Sanger sequencing T A G T G G T G G Baseline Post-treatment (2 days post-last dose) Post-treatment (45 days post-last
Slide 46: ADAR editing is highly specific
Editing site RNA editing within ACTB transcript (human hepatocytes) RNA editing within transcriptome (human hepatocytes) ADAR editing is highly specific Coverage Genome coordinates ACTB C 0% T 100% C 53.8% T 46.2% ACTB Confidence (LOD score) % Editing Mock Editing oligonucleotide Human hepatocytes w
Slide 47: Efficient and potent editing in neurons and astrocytes
Efficient and potent editing observed in neurons and astrocytes 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, revers
Slide 48: Opening the door to ADAR editing in CNS
Opening the door to ADAR editing in CNS In vivo CNS editing in proprietary hADAR transgenic mouse (1 week) Editing oligonucleotide (100 µg) PBS % Editing UGP2 Cortex Hippocampus Striatum Brain stem Cerebellum Spinal cord hADAR: human ADAR; UGP2: Glucose Pyrophosphorylase 2; CNS: central nervous syst
Slide 49: 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 50: Ophthalmology
Ophthalmology
Slide 51: 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 52: Durable Malat1 knockdown through months with PN chemistry
Durable Malat1 knockdown through 9 months with PN chemistry 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 injection. PBS = phosphate
Slide 53: 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 54: 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 55: Allele-selective reduction for adRP with 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 56: Anticipated upcoming Wave milestones
Anticipated upcoming Wave milestones NEUROLOGY Huntington’s disease 4Q 2020: Initiate clinical development with CTA filing of SNP3 program 1Q 2021: PRECISION-HD2 data from 32 mg cohort and data from OLE trial 1Q 2021: PRECISION-HD1 data, including 32 mg cohort, and data from OLE trial ALS and FTD 4Q
Slide 57: 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
Wave Life Sciences — Investor Presentation (September 2020) on 6ix