Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (January 2019)
44 slides from Wave Life Sciences's investor presentation, Jan 3, 2019
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation January 3, 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: Clinical-stage genetic medicines company with proprietary chemistry platform
Wave Life Sciences is a clinical-stage, genetic medicines company unlocking the potential of a proprietary chemistry platform that enables the precise design, optimization and production of stereopure nucleic acid therapies. We are leading a new era of precision medicine in which rationally designed
Slide 4: Architects of transformation
Architects of transformation Wave has reinvented the design, synthesis and manufacture of nucleic acid therapies to potentially optimize potency, durability and safety PRECISION Ability to design nucleic acid compounds that have one defined and consistent profile SCALE Platform potential across mult
Slide 5: Wave rational design: building the optimal stereopure medicine
WAVE RATIONAL DESIGN Stereochemistry enables precise control, ability to optimize critical constructs into one defined and consistent profile Building the optimal, stereopure medicine STANDARD OLIGONUCLEOTIDE APPROACHES Pharmacologic properties include >500,000 permutations in every dose Impact: Unr
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
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 s
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 spanning multiple modalities, novel targets
Pipeline spanning multiple modalities, novel targets CLINICAL CANDIDATE DISCOVERY ESTIMATED U.S. PREVALENCE* TARGET MECHANISM PARTNER WAVE’S COMMERCIAL RIGHTS *Estimates of U.S. prevalence and addressable population by target based on publicly available data and are approximate; for Huntington’s dis
Slide 10: Duchenne Muscular Dystrophy (DMD)
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: Wave approach: stereopure exon skipping oligonucleotide
Wave approach: stereopure exon skipping oligonucleotide Neuro DMD Potential benefits of an oligonucleotide approach to treating a lifelong disease Chronic administration may better address high muscle cell turnover and need for broad and durable distribution Entry into cells, including progenitor ce
Slide 13: Exon 51: suvodirsen clinical program
Exon 51: suvodirsen (WVE-210201) clinical program Neuro DMD PHASE 2/3 Open-Label Extension (OLE) PHASE 1 OBJECTIVE Determine safety and tolerability profile and select dose(s) for OLE and Phase 2/3 STUDY DESCRIPTION Phase 1 single ascending dose clinical trial KEY MILESTONES Safety and tolerability
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
Dystrophin protein restoration in vitro was quantified to be between 50-100% of normal skeletal muscle tissue lysates, as compared to about 1% by drisapersen and eteplirsen analogs Exon 51: increased dystrophin restoration *Analogs dystrophin (400-427 kDa) vinculin (120 kDa) Marker Mock drisapersen*
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 wide tissue distribution in dose dependent fashion No apparent ac
Slide 19: 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 20: 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 21: Stereopure surrogate yields dystrophin restoration and CK reduction
Stereopure surrogate yields substantial dystrophin protein restoration and CK reduction *Numbers indicate individual animals Note: DMD-1742 is a stereopure oligonucleotide designed to induce exon 23 skipping in the mdx23 mouse model and is a surrogate of suvodirsen, which is designed to induce exon
Slide 22: 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 23: 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, Hoechest; Yellow: Rabbit anti-Dystrophin(#ab15277) 1:400 diluent, 555/Cy3,
Slide 24: Expansion of stereopure exon skipping DMD portfolio
Expansion of stereopure exon skipping DMD portfolio Applying learnings from ongoing DMD development efforts and platform advances to explore additional exons for candidate development, including exons 44, 45, 52, 54, 55 Early leads demonstrate similar in vitro exon skipping efficiency as suvodirsen
Slide 25: Huntington's Disease
Huntington’s Disease
Slide 26: 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 27: 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 28: 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 29: 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 30: 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 31: C9orf72 ALS and FTD
C9orf72 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 32: 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 33: 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 34: 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 35: Selective silencing in vivo of expanded C9orf72 repeat transcripts
Selective silencing in vivo of expanded C9orf72 repeat transcripts Wave has developed a series of highly optimized antisense compounds which selectively silence the repeat containing transcript in C9orf72 transgenic mice These compounds show target engagement across cell types and regions of the ner
Slide 36: WVE-3972-01 produces durable reduction in dipeptides in vivo
WVE-3972-01 produces durable reduction in dipeptides in vivo Neuro C9orf72 PolyGP (Relative expression, means+SEM) Spinal Cord Cortex Durable reduction of dipeptide in spinal cord and cortex in C9-BAC mice for at least 12 weeks Stereopure Stereopure Stereorandom Stereorandom Experimental design: C9-
Slide 37: WVE-3972-01 in nuclei of neurons in NHP CNS
NHP = non-human primate. Experimental design: Cynomolgus monkeys were administered 3 weekly IT doses of ASO; tissues were collected 48 hours after last injection. WVE-3972-01 in nuclei of neurons in NHP CNS Blue: Nuclear, Hematoxylin; Pink Red: ASO/ViewRNA, Fast Red/Cy3 Spinal cord: Oligonucleotide
Slide 38: Ophthalmology
Ophthalmology
Slide 39: 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 all IRDs Approximately 200,000 affected in the U.S. and millions world-wide RHO P23H Retinitis pigmentosa ~1,800 USH2A Usher syndrome
Slide 40: Partnerships
Partnerships
Slide 41: Collaborating to maximize portfolio and platform
*Assuming Takeda advances six programs that achieve regulatory approval and commercial sales, Wave will be eligible to receive up to $2 billion in cash milestone payments, of which more than $1 billion would be in precommercial milestone payments. $230+ million in committed cash; eligible for milest
Slide 42: Intellectual property strength: breadth and depth of patent portfolio
Intellectual property strength: breadth and depth of patent portfolio Programs HD candidates DMD candidates Platform Designs Compositions Stereochemistry Process development Improved activity, stability, specificity, immunogenicity Oligonucleotide compositions Monomers, key reagents Methods of synth
Slide 43: Upcoming Wave catalysts
Upcoming Wave catalysts H1 2019: Data expected in HD from Phase 1b/2a trials for WVE-120101 and WVE-120102 Potential to be first two allele-specific disease-modifying therapies selectively lowering mHTT 2019: Initiate Phase 2/3 clinical trial for suvodirsen (WVE-210201) in DMD Protocol selected for
Slide 44: Realizing the potential of nucleic acid therapeutics
Realizing the potential of nucleic acid therapeutics For more information: Graham Morrell, Investor Relations gmorrell@wavelifesci.com 781.686.9600
Wave Life Sciences — Investor Presentation (January 2019) on 6ix