Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (June 2019)
42 slides from Wave Life Sciences's investor presentation, Jun 5, 2019
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation June 5, 2019 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: 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 initiation expected in July 2019 fo
Slide 4: Design and optimize: sequence, stereochemistry, chemistry
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 of stereopure medicines
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: Creating a new class of oligonucleotides
Source: Iwamoto N, et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol. 2017;35:845-851. Creating a new class of oligonucleotides INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY D
Slide 7: 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 8: 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 9: 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 10: Suvodirsen Duchenne Muscular Dystrophy (DMD)
Suvodirsen Duchenne Muscular Dystrophy (DMD)
Slide 11: 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 12: Potential benefits of stereopure oligonucleotide approach to DMD
Potential benefits of stereopure oligonucleotide approach to treating Duchenne muscular dystrophy Exon skipping 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 13: 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 14: 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 10uM concentration of each compound with no transfection agent Same foundational stereopure chemistry for Wave isome
Slide 15: 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 16: 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 17: 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 18: 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 19: Suvodirsen: Phase 1 and OLE clinical trials
Suvodirsen: Phase 1 and OLE clinical trials 136 patients randomized in Phase 1 and four screened patients expected to enroll directly into Phase 1 OLE OLE: Open-label Extension; Full Phase 1 Results presented at MDA 2019 Scientific and Clinical Conference. Open-Label Extension Trial Ongoing Phase 1
Slide 20: Suvodirsen: path towards US and global approvals
Suvodirsen: Path towards US and global approvals Phase 1 Phase 1 single ascending dose clinical trial Based on in vitro and in vivo preclinical studies and Phase 1 clinical results, two suvodirsen doses selected for Phase 2/3 clinical trial Study complete Phase 2/3 Phase 2/3 clinical trial to assess
Slide 21: Phase 2/3 study selected for FDA CID pilot program
Phase 2/3 study selected for FDA Complex Innovative Trial Design (CID) pilot program Designed with input from global regulatory communities and DMD patient community DMD historical control data will be leveraged to help reduce number of patients required to deliver conclusive clinical efficacy resul
Slide 22: 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 expected to initiate in July 2019 for global regulatory submissions Potential FDA accelera
Slide 23: Exon 53: WVE-N531 in vitro 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 24: Exon 53: oligonucleotide rapidly distributes to muscle
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 25: 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 26: 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 27: Multiple doses of surrogate result in further dystrophin restoration
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, Hoechest; Yellow: Rabbit anti-Dystrophin(#ab15277) 1:400 diluent, 555/Cy3,
Slide 28: Huntington's Disease
WVE-120101 WVE-120102 Huntington’s Disease
Slide 29: 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 30: Wave approach: novel, allele-specific silencing
Utilize association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including HD Allele-specificity possible by targeting SNPs associated with expanded long CAG repeat in mHTT gene Approach aims to lower mHTT transcript while l
Slide 31: 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 32: 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 33: 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 Demonstrated delivery to brain tissue In Situ Hybridization ViewRNA stained tissue Red dots are WVE-120102 oligonucleotide Arrow points to nuclear
Slide 34: WVE-C092 ALS and FTD
WVE-C092 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 35: 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 36: 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 37: 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 38: WVE-C092 selective and potent silencing of C9orf72 repeat transcripts
WVE-C092 demonstrated selective and potent silencing of expanded C9orf72 repeat transcripts in vitro experimental methods: C9 ALS patient derived MNs were treated with ASO gymnotically (free-uptake) for 1 week. Cell were harvested with Trizol reagent for RNA extraction. Taqman qPCR assays were used
Slide 39: Ophthalmology
Ophthalmology
Slide 40: Building a portfolio for inherited retinal diseases
Building a portfolio for inherited retinal diseases Rare eye disorders caused by genetic mutations leading to progressive vision loss No approved therapies for almost any IRDs Approximately 200,000 affected in the U.S. and millions world-wide RHO P23H Retinitis pigmentosa ~1,800 USH2A Usher syndrome
Slide 41: Anticipated upcoming Wave milestones
Anticipated upcoming Wave milestones Neuromuscular July 2019: Initiation of DYSTANCE 51 Phase 2/3 clinical trial for suvodirsen in DMD (exon 51) 2H 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 U
Slide 42: 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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