Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Day (October 2019)
63 slides from Wave Life Sciences's investor day presentation, Oct 7, 2019
Slide 1: Analyst and Investor Research Day
Analyst and Investor Research Day OCTOBER 7, 2019 BOSTON, MASSACHUSETTS Exhibit 99.1
Slide 2: Welcome
Welcome Paul Bolno, MD, MBA President and CEO Wave Life Sciences
Slide 3: 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 4: Our purpose at Wave
Our purpose at Wave Genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox I II III
Slide 5: Our purpose at Wave
Our purpose at Wave Genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases I One tool appears suitable from a distance Building a genetic toolbox for a lifetime of treatment
Slide 6: Our purpose at Wave
Our purpose at Wave Genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases Target variability requires a comprehensive toolkit I Building a genetic toolbox for a lifetime of treatment
Slide 7: Our purpose at Wave
Our purpose at Wave Genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox I II III Splicing, silencing, editing Non-viral delivery to nucleus Optimized, stereopure oligonucleotides
Slide 8: Our purpose at Wave
Our purpose at Wave Genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox Designing precision medicines for complex diseases I II III Restoring functional protein Selectively reducing toxic protein Pursuing broa
Slide 9: Our purpose at Wave
Our purpose at Wave Genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox Designing precision medicines for complex diseases Committed to patients in need I II III Restoring functional protein Selectively reduci
Slide 10: Today's Agenda
Today’s Agenda Gregory Verdine, Ph.D. Co-founder / Board Member | Wave Life Sciences Chandra Vargeese, Ph.D. SVP, Head of Drug Discovery | Wave Life Sciences Elena Cattaneo, Ph.D. University of Milano Frédéric Saudou, M.Sc., Ph.D. Grenoble Institute of Neurosciences (GIN) Chandra Vargeese, Ph.D. SVP
Slide 11: Chirality Matters in Biology
Chirality Matters in Biology Gregory Verdine, Ph.D. Co-founder and Board Member Wave Life Sciences
Slide 12: Chirality in biology
Chirality in biology carvone R-carvone S-carvone H Chirality Matters
Slide 13: Stereochemistry Matters in Drugs – Case of Thalidomide
Stereochemistry Matters in Drugs – Case of Thalidomide Vargesson et al., 2015. Thalomide-induced teratogenesis: History and mechanisms. Birth Defects Res C Embryo Today 105:140-156. ACS Molecule of the week archive: Sept. 1, 2014. Thalidomide was prescribed for the treatment of morning sickness in p
Slide 14: Oligonucleotides: phosphorothioate modifications introduce chiral centers
Oligonucleotides Phosphorothioate (PS) modifications introduce chiral centers Nucleoside Enormous number of permutations exist (2n) à Resulting in thousands of different molecules in every dose Stereopure ASO 1 diastereoisomer 215 = 32,768 diastereoisomers Stereorandom ASO Phosphodiester Stereorando
Slide 15: Stereochemical diversity
Stereochemical diversity No. PS linkages Antisense, exon skipping, ssRNAi CRISPR guide ADAR oligonucleotide No. diastereomers Exponential diversity arises from uncontrolled stereochemistry (Rp) (Sp) Top view Side view
Slide 16: Mipomersen
Mipomersen Iwamoto et al., 2017. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat. Biotechnol. 35:845-851. 524,288 diastereomers Stereopure diastereomers of mipomersen (WV-1-WV-6) Mipomersen Chirality Matters
Slide 17: Overall ASO/RNA/RNase H complex structure
Overall ASO/RNA/RNase H complex structure Yellow spheres represent ‘S’ atoms + Target RNA + ASO drug ASO/RNA duplex RNase H Phosphate Binding Pocket RNA Cleavage site Chirality Matters
Slide 18: Phosphate binding pocket
Phosphate binding pocket 1.3 Å resolution RNase H1 Phosphate Binding Pocket 5’ 3’ Rp Sp Sp Scissile Phosphate R179 W225 I239 N240 ASO RNA T181 S223 Chirality Matters
Slide 19: Precision RNase H-mediated RNA degradation
Precision RNase H-mediated RNA degradation In RNase H1 assay, ASOs were pre-annealed to surrogate MALAT1 mRNA (1:1, Cf=5 mM). RNase H (250:1, E:S) was added and quenched with EDTA at the indicated times. Products were quantified, and V0 was calculated from the best-fit line (n=3 per time point). In
Slide 20: PRISM
PRISM Chandra Vargeese, Ph.D. SVP, Head of Drug Discovery Wave Life Sciences
Slide 21: PRISM: Wave's proprietary discovery and drug development platform
PRISM: Wave’s proprietary discovery and drug development platform PRISM Platform progress Applied learnings New modality: ADAR-mediated RNA editing
Slide 22: PRISM Continuous Learning
PRISM Continuous Learning PRISM platform enables rationale drug design
Slide 23: PRISM platform advancing
PRISM platform advancing Stereopure Stereorandom ~5-fold improvement in primary screen hit rates Advancement of PRISM platform PRISM All screens used iPSC-derived neurons; Data pipeline for improved standardization
Slide 24: PRISM: Wave's proprietary discovery and drug development platform
PRISM: Wave’s proprietary discovery and drug development platform PRISM Platform progress Applied learnings New modality: ADAR-mediated RNA editing
Slide 25: 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 PRISM Mice were dosed with a single IV injection (25 mg/kg) of MALAT1-t
Slide 26: CNS: Potent and durable targeting with PRISM designed oligonucleotides
CNS: Potent and durable targeting with PRISM designed oligonucleotides MALAT1 knockdown in mouse CNS 10-weeks post-dose Compound-2 Broad distribution >80% knockdown of MALAT1 in multiple regions and cell types Knockdown observed 10-weeks after single 100µg dose PRISM Mice received a single 100 mg IC
Slide 27: CNS: Allele-selective silencing of expanded C9orf72 repeat transcripts
CNS: Allele-selective silencing of expanded C9orf72 repeat containing transcripts 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
Slide 28: PRISM enables resolution of stereoisomer toxicity profiles
PRISM enables resolution of different stereoisomer toxicity profiles Single Rp to Sp shift increases biomarkers for hepatotoxicity Compound-4 and Compound-5 have identical: Sequence Chemical modifications Backbone modifications In vitro potency In vivo potency GalNAc GalNAc Wave Compound-4 Wave Comp
Slide 29: Stereopure oligonucleotides designed to enter nuclei
Bright field view Nucleus: Hematoxylin; Light Blue Wave oligo: ViewRNA, Fast Red Nucleus: Hoechst33342; Blue Wave oligo: Fast Red/Cy3; Pink Red 63x oil Fluorescence channel view Z Stack view Stereopure 51, n=82 Stereorandom 5, n=132 # of oligo foci/nuclei 0 50 100 150 200 250 P < 0.001 Stereopure St
Slide 30: PRISM exon-skipping programs restore significant dystrophin in vitro
PRISM exon-skipping programs restore significant dystrophin 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 Dystrophin protein restoration of up to 71% in vitro Western Blot normalize
Slide 31: PRISM: Wave's proprietary discovery and drug development platform
PRISM: Wave’s proprietary discovery and drug development platform PRISM Platform progress Applied learnings New modality: ADAR-mediated RNA editing
Slide 32: RNA-editing can be used for several therapeutic applications
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 33: 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 34: Wave's ADAR approach has several advantages over existing technologies
Wave’s ADAR approach has several 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 oligonucleotide
Slide 35: RNA-editing with endogenous ADAR across multiple primary 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 36: Portfolio
Portfolio Paul Bolno, MD, MBA President and CEO Wave Life Sciences
Slide 37: Pipeline by therapeutic area and modality
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 38: Biology of Huntingtin (HTT)
Biology of Huntingtin (HTT) Elena Cattaneo, Ph.D. University of Milano Frédéric Saudou, M.Sc., Ph.D. Grenoble Institute of Neurosciences (GIN)
Slide 39: Speaker biography
Prof. of pharmacology, director of Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases Director of UniStem (Centre for Stem Cell Research of the University of Milan) Earned PhD in biotechnology applied to pharmacology at University of Milan Completed first post-doc at MIT
Slide 40: Huntington's disease (Elena Cattaneo placeholder)
[Placeholder] Elena Cattaneo slides Huntington’s disease
Slide 41: Huntington's disease (Frédéric Saudou placeholder)
Huntington’s disease [Placeholder] Frédéric Saudou slides
Slide 42: Advancing HD Portfolio with mHTT SNP3
Advancing HD Portfolio with mHTT SNP3 Chandra Vargeese, Ph.D. SVP, Head of Drug Discovery Wave Life Sciences
Slide 43: Huntington's disease allele-selective silencing
wt SNP1 SNP3 SNP2 Huntington’s disease Allele-selective silencing Aims to lower mHTT transcript while leaving healthy HTT relatively intact RNase H and ASO:RNA Allele-selectivity possible by targeting SNPs associated with expanded long CAG repeat in HTT gene
Slide 44: Broadening reach in Huntington's disease with SNP3 program
Broadening reach in Huntington’s disease with SNP3 development program Due to overlap, ~80% of the total HD patient population carry SNP1 and/or SNP2 and/or SNP3 In vivo models for SNP3 available for preclinical development SNP3 % Huntington’s Disease Patient Population with SNP SNP1 SNP2 SNP3 SNP1
Slide 45: SNP3 program
SNP3 program Potency in homozygous iCell neurons as compared to pan-silencing compound Allele-selectivity in vitro as compared to pan-silencing compound Biochemical assay Heterozygous patient neurons Target engagement and durability in vivo in BACHD models Huntington’s disease
Slide 46: 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 patient-derived neurons ~7-fold shift Pan-silencing RG6042 analog Wave SNP3 Compound-1 Wave SNP3 Compound-2 H
Slide 47: 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 48: 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 49: 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 50: Durable in vivo mutant HTT knockdown with stereopure 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 51: Lead Inherited Retinal Disease Program: USH2A
Lead Inherited Retinal Disease Program: USH2A Michael Byrne, Ph.D. Director In Vivo Biology and Ophthalmology Wave Life Sciences
Slide 52: 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 53: Stereopure compounds durably deplete MALAT1 for months in vivo
Stereopure compounds durably deplete MALAT1 for 9 months in vivo ~50% MALAT1 knockdown at 9 months in the posterior of the eye Ophthalmology 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-tr
Slide 54: Potent and durable MALAT1 knockdown in the eye
Stereopure compound induces potent and durable MALAT1 knockdown in the eye Ophthalmology Oligonucleotide or PBS (1 x 450 mg IVT) was delivered to NHP. Relative percentage of MALAT1 RNA in the retina to PBS-treated is shown at 1 week, 2 and 4 months, post-single injection. Compound-1 is a stereopure
Slide 55: 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 56: Productive USH2A exon skipping with stereopure compound
Productive USH2A exon 13 skipping with stereopure compound Ophthalmology 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. Primers mapping to exons 8 and 17 were used to a
Slide 57: Potent USH2A exon skipping ex vivo in NHP and human retinas
Potent USH2A exon skipping ex vivo in NHP and human retinas Ophthalmology Whole NHP and human eyes were enucleated (n=4 and n=2, respectively) and compounds (1–20 µM) were added to extracted retinas under free-uptake conditions. Exon skipping was evaluated by Taqman assays on RNA. USH2A transcript l
Slide 58: Autosomal dominant retinitis pigmentosa with Rhodopsin P23H mutation
Autosomal dominant retinitis pigmentosa (adRP) associated with Rhodopsin P23H mutation Retinitis pigmentosa (RP) is a group of rare, genetic disorders of the eye resulting in progressive photoreceptor cell death and gradual functional loss Currently no cure for RP ~10% of US autosomal dominant RP ca
Slide 59: Allele-selective reduction of SNP-containing allele
adRP associated with Rhodopsin P23H mutation Stereopure oligonucleotides achieve allele-selective reduction of SNP-containing allele Reporter assays on a Wave stereopure sequence as well as a sequence described in WO2016138353A1: ASO and luciferase reporter plasmids (wild-type and mutant rhodopsin)
Slide 60: Summary
Summary Wave stereopure compounds induce potent and durable MALAT1 knockdown in the eye USH2A is Wave’s lead ophthalmology program Productive USH2A exon 13 skipping in cellular models Confirmed skipping at the sequence level Potent exon skipping demonstrated ex vivo in NHP and human retinas USH2A in
Slide 61: Conclusion
Conclusion Paul Bolno, MD, MBA President and CEO Wave Life Sciences
Slide 62: Q&A
Q&A
Slide 63: Analyst and Investor Research Day
Analyst and Investor Research Day OCTOBER 7, 2019 BOSTON, MASSACHUSETTS