Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (October 2018)
43 slides from Wave Life Sciences's investor presentation, Oct 9, 2018
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation October 9, 2018 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: Leading a new era of precision medicine
We are leading a new era of precision medicine in which rationally designed nucleic acid therapies are the key to delivering safer, more effective treatments for serious, genetically defined diseases
Slide 4: Architects of transformation
Architects of transformation 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. Wave has reinvented the design, synthesis and
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 Knockdown in Mice Knockdown of Serum hAPOC3 Protein Levels in Mice Two 5 mg/kg doses on Days 1&3 PBS Stereopure Eye MALAT1 Knockdown in Non-Human Primates Single 450 µg IVT injection 10 Weeks after single 100 µg inject
Slide 8: Chemistry affects immune activation
Stereochemistry allows for Human TLR9 activation assay with 5mC modified CpG containing MOE gapmer Cytokine induction in human PBMC assay Chemistry affects immune activation Complement Activation Human TLR9 Activation Cytokine Induction Complement activation in non-human primate serum assay Data rep
Slide 9: Pipeline spanning multiple modalities, novel targets
MUSCLE Pipeline spanning multiple modalities, novel targets CLINICAL CANDIDATE DISCOVERY ESTIMATED U.S. PREVALENCE* TARGET MECHANISM PARTNER WAVE’S COMMERCIAL RIGHTS CNS A Huntington’s disease ~10k / ~35k mHTT SNP1 Phase 1b/2a Takeda 50% Global A Huntington’s disease ~10k / ~35k mHTT SNP2 Phase 1b/2
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: restoration of dystrophin production through exon skipping
Wave approach: meaningful restoration of dystrophin production through Exon skipping Neuro DMD Exon skipping with stereopure oligonucleotides has the potential to enable production of meaningful levels of functional dystrophin Enabling production of meaningful levels of dystrophin is expected to res
Slide 13: WVE-210201 clinical trial
WVE-210201 Phase 1 clinical trial Multicenter, double-blind, placebo-controlled, single ascending dose study with I.V. administration Primary endpoint: Safety and tolerability Inclusion criteria: ages 5 to 18, amenable to Exon 51 skipping Ambulatory and non-ambulatory boys eligible, including those
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: in vivo target engagement of WVE-210201
Exon 51: in vivo target engagement of WVE-210201 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 17: 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 WVE-210201 demonstrated wide tissue distribution in dose dependent fashion No apparent ac
Slide 18: 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 vitro Exp
Slide 19: 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 20: Stereopure surrogate yields dystrophin restoration and CK reduction
Stereopure surrogate yields substantial dystrophin protein restoration and CK reduction *Numbers indicate individual animals Experimental conditions: Tissues collected 96 hours post final dose. Protein expression determined by Western Blot. ALT=alanine aminotransferase; AST=aspartate aminotransferas
Slide 21: Stereopure surrogate restores dystrophin after single dose
Stereopure surrogate restores dystrophin in muscle fibers after single dose 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). Immunohistochemistry:
Slide 22: Stereopure surrogate restores dystrophin after multiple doses
Stereopure surrogate restores dystrophin in muscle fibers after multiple doses 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, Cy3 staini
Slide 23: Huntington's Disease
Huntington’s Disease
Slide 24: Huntington's Disease: a hereditary, fatal disorder
Huntington’s Disease: a hereditary, fatal disorder Autosomal dominant disease, characterized by cognitive decline, psychiatric illness and chorea; fatal No approved disease-modifying therapies Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT); accumula
Slide 25: Novel, allele-specific silencing of expanded CAG repeat
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 26: Two parallel global placebo-controlled multi-ascending-dose trials
Two parallel global placebo-controlled multi-ascending-dose trials for WVE-120101, WVE-120102 Primary objective: assess safety and tolerability of intrathecal doses in early manifest HD patients Additional objectives: exploratory pharmacokinetic, pharmacodynamic, clinical and MRI endpoints Two simul
Slide 27: Selective reduction of mHTT mRNA & protein
Selective reduction of mHTT mRNA & protein Reporter Cell Line* Neuro HD
Slide 28: 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 CIC = cingulate cortex. CN = caudate nucleus. In Situ Hybridization ViewRNA stained tissue Red dots are WVE-1
Slide 29: C9orf72 ALS and FTD
C9orf72 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 30: 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 31: Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis 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 and 8
Slide 32: 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 33: 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 34: 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 35: WVE-3972-01 distributed widely in mouse motor neurons
WVE-3972-01 is distributed widely and taken up in nuclei of motor neurons in mouse spinal cord Neuro C9orf72 Experimental description: C9-BAC mice were administered 50mg of WVE-3972-01 ICV on day 1 and day 8; detection using ViewRNA. Spinal cord: Oligonucleotide visualization (ViewRNA) eight weeks a
Slide 36: 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 Widespread and sustained dist
Slide 37: Ophthalmology
Ophthalmology
Slide 38: 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 39: Partnerships
Partnerships
Slide 40: Collaborations with Takeda and Pfizer
*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 41: 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 42: Upcoming Wave catalysts
Upcoming Wave catalysts Q4 2018: Safety data expected in DMD from Phase 1 trial for WVE-210201 WVE-210201 is the first stereopure oligonucleotide targeting Exon 51 Received EU and US orphan drug designations and US rare pediatric disease designation H1 2019: Data expected in HD from Phase 1b/2a tria
Slide 43: 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
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