Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (November 2019)
58 slides from Wave Life Sciences's investor presentation, Nov 5, 2019
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation November 5, 2019 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: Targeting genetically defined diseases with stereopure oligonucleotides
DESIGN & OPTIMIZE SEQUENCE STEREOCHEMISTRY CHEMISTRY Targeting genetically defined diseases with stereopure oligonucleotides Building fully integrated genetic medicines company led by neurology development programs Lead clinical program: Suvodirsen Phase 2/3 trial ongoing for DMD (exon 51); program
Slide 4: Design and optimize: PRISM platform design principles
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 5: Wave rational design: control of stereochemistry
WAVE RATIONAL DESIGN Control of stereochemistry enables the design and manufacture of oligonucleotides with one defined and consistent profile Designing the optimal, stereopure medicine STANDARD OLIGONUCLEOTIDE APPROACHES Pharmacologic properties include >500,000 permutations in every dose Impact: U
Slide 6: Stereochemical diversity
Stereochemical diversity Number of PS linkages in oligonucleotide backbone Antisense, exon skipping, ssRNAi CRISPR guide ADAR oligonucleotide No. diastereomers Exponential diversity arises from uncontrolled stereochemistry (Rp) (Sp) Top view Side view Yellow spheres represent ‘S’ atomsPS: Phosphorot
Slide 7: 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 8: Optimizing potency and durability across multiple tissues
CNS Muscle Liver MALAT1 Transcript Knockdown in Mice Knockdown of Serum hAPOC3 Protein Levels in Mice Two 5 mg/kg SC injections on Days 1&3 PBS Stereopure Eye MALAT1 Knockdown in Non-Human Primates Single 450 µg IVT injection 10 Weeks after single 100 µg ICV injection DMD: Percent Skipped Transcript
Slide 9: Broad tissue distribution and durable target engagement
Broad tissue distribution and durable target engagement Single IV injection of Wave compounds targeting MALAT1 (human equivalent of 1.6 mg/kg) PBS Compound-1 Compound-3 Gastrocnemius Quadriceps Diaphragm Sciatic nerve Lung Heart Mice were dosed with a single IV injection (25 mg/kg) of MALAT1-targeti
Slide 10: Stereochemistry affects immune activation
Stereochemistry allows for Human TLR9 activation assay with 5mC modified CpG containing MOE gapmer Cytokine induction in human PBMC assay Stereochemistry affects immune activation Complement Activation Human TLR9 Activation Cytokine Induction Complement activation in non-human primate serum assay Da
Slide 11: Pipeline
THERAPEUTIC AREA/MODALITY TARGET DISCOVERY CANDIDATE CLINICAL REGISTRATION ESTIMATED U.S. PREVALENCE* PARTNER Duchenne muscular dystrophy Exon-skipping Suvodirsen Exon 51 ~2,000 WVE-N531 Exon 53 ~1,250 Exons 44, 45, 52, 54, 55 ~3,000 Neuromuscular diseases Multiple Huntington’s disease Allele – sele
Slide 12: Suvodirsen: Duchenne Muscular Dystrophy (DMD)
Suvodirsen Duchenne Muscular Dystrophy (DMD)
Slide 13: DMD: a progressive, fatal childhood disorder
DMD: a progressive, fatal childhood disorder Fatal, X-linked genetic neuromuscular disorder characterized by progressive, irreversible loss of muscle function, including heart and lung Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy
Slide 14: Potential benefits of stereopure oligonucleotide approach to DMD
Exon skipping Potential benefits of stereopure oligonucleotide approach to treating Duchenne muscular dystrophy Neuro DMD Sources: Arnett ALH, et al. Mol Ther Methods Clin Dev. 2014;1:14038. doi:10.1038/mtm.2014.38. Counsell JR, et al. Sci Rep. 2017;7:79. doi: 10.1038/s41598-017-00152-5. Duan D. Mol
Slide 15: Exon 51: most frequent mutation among DMD patients
Exon 51: Most frequent mutation among DMD patients ~13% of DMD patients amenable to Exon 51 skipping One exon-skipping therapy conditionally approved by FDA Minimal increase in dystrophin expression over baseline observed after 48 weeks; Mean increase 0.28%, Median increase 0.1%1 Clinical benefit no
Slide 16: Exon 51: improved skipping efficiency
Exon 51: improved skipping efficiency RNA skipping determined by quantitative RT-PCR Wave isomers demonstrated a dose-dependent increase in skipping efficiency in vitro Free uptake at 10 µM concentration of each compound with no transfection agent Same foundational stereopure chemistry for Wave isom
Slide 17: Exon 51: increased dystrophin restoration in vitro
Exon 51: increased dystrophin restoration in vitro *Analogs dystrophin (400-427 kDa) vinculin (120 kDa) Marker Mock drisapersen* eteplirsen* suvodirsen WV-isomer 2 WV-isomer 3 Skeletal Muscle Tissue lysates Marker 0 µM Skeletal Muscle Tissue (2 fold less lysate) 0.1 µM 0.3 µM 1 µM 3 µM 10 µM Skeleta
Slide 18: Exon 51: improved oligonucleotide uptake in the nucleus
Exon 51: improved oligonucleotide uptake in the nucleus where splicing occurs Stereopure oligonucleotides are designed to readily enter the nuclei of cells under free-uptake conditions, which approximates natural delivery in the body Free uptake of stereorandom and stereopure ASOs Experimental condi
Slide 19: Exon 51: in vivo target engagement in non-human primate
Exon 51: in vivo target engagement of suvodirsen in healthy non-human primate 5 doses @ 30 mg/kg /week for 4 weeks healthy NHP by subcutaneous dosing Nested PCR Assay Neuro DMD Experimental conditions: Muscle tissues were collected 2 days after the last dose and fresh frozen. Total RNAs were extract
Slide 20: Exon 51: no apparent tissue accumulation observed
Exon 51: no apparent tissue accumulation observed Standard oligonucleotides tend to accumulate in liver and kidney Wave rationally designed oligonucleotides optimized to allow compound to clear more effectively Suvodirsen demonstrated broad tissue distribution in dose dependent fashion No apparent a
Slide 21: Suvodirsen: path towards US and global approvals
Suvodirsen: Path towards US and global approvals Phase 1 Phase 1 single ascending dose clinical trial (40 patients1) ~20% of patients had received eteplirsen previously (following wash out) Two suvodirsen doses selected for Phase 2/3 clinical trial Suvodirsen had a favorable safety and tolerability
Slide 22: DYSTANCE study selected for FDA CID pilot program
DYSTANCE 51 study selected for FDA Complex Innovative Trial Design (CID) pilot program Phase 2/3 study designed with input from global regulatory communities and DMD patient community DMD historical control data will be leveraged to potentially reduce number of patients required to deliver conclusiv
Slide 23: Building a portfolio to transform the care of DMD
Building a portfolio to transform the care of DMD Neuro DMD Sources: Aartsma-Rus A, et al. Hum Mutat. 2009;30:293-299. Bladen CL, et al. Hum Mutat. 2015;36:395–402. Suvodirsen targeting exon 51 Phase 2/3 trial ongoing for global regulatory submissions Potential FDA accelerated approval filing in 2H
Slide 24: Exon 53: WVE-N531 dose-dependent dystrophin restoration
Exon 53: WVE-N531 in vitro dose-dependent dystrophin restoration Free uptake for 6 days in differentiation media with no transfection agent and no peptide conjugated to the oligonucleotide Wave stereopure exon 53 candidate demonstrated a dose-dependent increase in dystrophin restoration in DMD patie
Slide 25: Exon 53: rapid distribution to muscle within 24 hours
Exon 53: targeting oligonucleotide rapidly distributes to muscle within 24 hours after injection Bright field view 63x oil Nucleus: Hematoxylin; Light Blue Wave oligo: ViewRNA, Fast Red Nucleus: Hoechst33342; Blue Wave oligo: Fast Red/Cy3; Pink Red Fluorescence channel view Z Stack view Data derived
Slide 26: In vivo mdx23 dystrophin protein with oligonucleotides
In vivo mdx23 dystrophin protein with oligonucleotides NT = nontreated mdx mouse; mdx/BL10 = mdx mouse in C57BL/10ScSnJ background; D2-mdx = mdx mouse crossed to DBA/2A background resulting in more severely affected model; CK = creatine kinase Experimental conditions (stereopure surrogate): Tissues
Slide 27: Single dose of surrogate restores dystrophin in muscle fibers
Single dose of surrogate results in restoration of dystrophin in muscle fibers Neuro DMD PBS DMD-1742 Immunohistochemistry of dystrophin in gastrocnemius in mdx23 mice at 4 weeks 10X Experimental conditions: mdx23 mice received a single IV injection of PBS or DMD-1742 (150 mg/kg). Immunohistochemist
Slide 28: Multiple doses of surrogate further restore dystrophin
Multiple doses of surrogate result in further restoration of dystrophin in muscle fibers Experimental conditions: mdx23 mice received 4 weekly IV injections of PBS or DMD-1742 (150 mg/kg). Immunohistochemistry: Blue: Nuclei, Hoechst; Yellow: Rabbit anti-Dystrophin(#ab15277) 1:400 diluent, 555/Cy3, C
Slide 29: WVE-120101 WVE-120102 Huntington's Disease
WVE-120101 WVE-120102 Huntington’s Disease
Slide 30: 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 31: 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 32: Two simultaneous Phase 1b/2a clinical trials
Two simultaneous Phase 1b/2a clinical trials Neuro HD PRECISION-HD is a global clinical program consisting of the PRECISION-HD1 trial evaluating WVE-120101 targeting SNP1 and the PRECISION-HD2 trial evaluating WVE-120102 targeting SNP2 Two parallel, multicenter, double-blind, randomized, placebo-con
Slide 33: Selective reduction of mHTT mRNA and 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 34: 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 35: SNP3 Preclinical Program Huntington's Disease
SNP3 Preclinical Program Huntington’s Disease
Slide 36: Potent mutant HTT knockdown activity
Potent mutant HTT knockdown activity Greater knockdown of mutant HTT as compared to pan-silencing compound Wave allele-selective compounds are more potent than pan-silencing RG6042 analog in preclinical study involving patient-derived neurons ~7-fold shift Pan-silencing RG6042 analog Wave SNP3 Compo
Slide 37: Stereopure oligonucleotides are selective in vitro
Stereopure oligonucleotides are selective in vitro Stereopure isomers targeting a SNP variant promote RNase H-mediated degradation of mutant HTT while sparing wild-type HTT Biochemical RNase H assays RNase H experiments performed with synthetic RNA substrates corresponding to mHTT and wtHTT variants
Slide 38: Demonstration of allele-selective silencing
Demonstration of allele-selective silencing Stereopure compounds selectively deplete mutant HTT mRNA Neurons were derived from GM21756 patient-derived fibroblasts (heterozygous for SNP) and treated with 2.2 mM (left) or 20 mM (right) of the indicated ASO under gymnotic conditions for 7 days. RNA was
Slide 39: In vivo model to assess target engagement and durability
In vivo model to assess target engagement and durability BACHD mouse model Expressed transcript includes SNP3 variant that Wave compounds are targeting Model is homozygous for mutant HTT with SNP3 (only has one type of HTT) Over-expresses mHTT (multiple gene copies) No ability to assess allele selec
Slide 40: Durable in vivo mutant HTT knockdown with SNP3 compounds
Durable in vivo mutant HTT knockdown with stereopure SNP3 compounds Knockdown persists for 12 weeks Oligonucleotide or PBS (3 x 100 mg ICV) was delivered to BACHD mice. Relative percentage of HTT/TUBB3 mRNA in cortex with respect to levels in PBS-treated mice is shown at 2-12 weeks post-injection. S
Slide 41: C9orf72 program: ALS and FTD
C9orf72 program Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 42: 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 43: 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 44: 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 45: C9orf72 program: allele-selective silencing in vivo
C9orf72 program: Allele-selective silencing in vivo C9orf72 genetic mutations are the strongest genetic risk factor found to date for the more common, non-inherited (sporadic) forms of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD); GGGGCC repeat drives the formation and accum
Slide 46: Ophthalmology
Ophthalmology
Slide 47: 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 48: 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 49: Usher Syndrome Type 2A: 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 50: Potent USH2A exon skipping in vitro and ex vivo
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 51: Allele-selective reduction for adRP 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 52: ADAR-mediated RNA editing
ADAR-mediated RNA editing
Slide 53: 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 54: 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 55: Advantages of Wave's ADAR approach
Wave’s ADAR approach has several potential advantages over existing technologies Require AAV or lipid nano particle delivery Require exogenous protein (e.g. CAS13 or chimeric ADAR) Free uptake into tissues Uses endogenous ADAR for editing Use unmodified RNA Fully chemically-modified stereopure oligo
Slide 56: RNA-editing with endogenous ADAR across human cell types
RNA-editing with endogenous ADAR achieved across multiple primary human cell types Stereochemistry significantly increases editing across all cell lines tested, especially for gymnotic delivery GalNAc-conjugated fully-modified stereopure oligonucleotide can be used for targeted editing in hepatocyte
Slide 57: Anticipated upcoming Wave milestones
Anticipated upcoming Wave milestones Neuromuscular 4Q 2019: Interim dystrophin data readout for suvodirsen from OLE in DMD (exon 51) 2H 2020: Accelerated approval filing for suvodirsen in DMD (exon 51) in US, pending positive clinical dystrophin expression data 2H 2020: Topline clinical data for WVE
Slide 58: 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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