Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (April 2021)
60 slides from Wave Life Sciences's investor presentation, Apr 1, 2021
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation April 1, 2021 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: Building a leading genetic medicines company
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia 1stereopure oligonucleotides and novel backbone chemistry modifications Innovative platform Stereopure oligonucleotides Novel backbone modifications (PN chemistry) Allele-selectivity Multipl
Slide 4: PRISM has unlocked novel and proprietary advances in oligonucleotide design
PRISM has unlocked novel and proprietary advances in oligonucleotide design Backbone modifications Sugar modifications Drug approvals (FDA)2 1975 2020 2000 Mixtures of 2n molecules1 ~500,000 different molecules per dose fomivirsen pegaptanib Phosphorothioate (PS) mipomersen nusinersen PN backbone ch
Slide 5: Innovative pipeline led by neurology programs
THERAPEUTIC AREA / TARGET DISCOVERY PRECLINICAL CLINICAL PARTNER ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple† Takeda milestones & royalties DMD Exon 53 100% global ADAR editing Multiple AATD (ADAR editing) SERPINA1 100% global Retinal disea
Slide 6: Platform evolution reflected in three upcoming clinical trials to start in 2021
Platform evolution reflected in three upcoming clinical trials to start in 2021 Variant-selective silencing candidate in ALS and FTD WVE-004 C9orf72 WVE-003 SNP3 Allele-selective silencing candidate in HD WVE-N531 Exon 53 Exon skipping candidate in DMD HD: Huntington’s diseaseALS: amyotrophic latera
Slide 7: WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 8: C9orf72 repeat expansions: A critical genetic driver of ALS and FTD
C9orf72 repeat expansions: A critical genetic driver of ALS and FTD Normal (non-expanded) Allele < 25 GGGGCC repeats Expanded Allele Sources: DeJesus-Hernandez et al, Neuron, 2011. Renton et al, Neuron, 2011. Zhu et al, Nature Neuroscience, May 2020 Typically 100’s-1000’s of GGGGCC repeats C9orf72 h
Slide 9: C9-ALS and C9-FTD: Manifestations of a clinical spectrum
C9-ALS and C9-FTD: Manifestations of a clinical spectrum Disease C9 specific US population Mean disease duration Standard of care C9-ALS Fatal neurodegenerative disease Progressive degeneration of motor neurons in brain and spinal cord ~2,000 3.1 years Significant unmet need despite two approved the
Slide 10: C9orf72 repeat expansions: Mechanisms of cellular toxicity
C9orf72 repeat expansions: Mechanisms of cellular toxicity C9-ALS and C9-FTD may be caused by multiple factors: Insufficient levels of C9orf72 protein Accumulation of repeat-containing RNA transcripts Accumulation of aberrantly translated DPR proteins Recent evidence suggests lowering C9orf72 protei
Slide 11: C9orf72 targeting strategy spares C9orf72 protein
Normal C9orf72 allele produces three mRNA transcripts (~80% are V2, ~20% are V1 and V3) Pathological allele with expanded repeat leads to healthy V2 and pathological V1 and V3 transcript by-products C9orf72 targeting strategy spares C9orf72 protein WVE-004 targets only V1 and V3 transcripts, sparing
Slide 12: PN backbone chemistry modifications: Improved potency among C9orf72-targeting oligonucleotides in vivo
PN backbone chemistry modifications: Improved potency among C9orf72-targeting oligonucleotides in vivo Exposure (µg/g) Exposure (µg/g) C9orf72 compounds Spinal cord Cortex PS/PO backbone PS/PO/PN backbone %C9orf72 V3 transcript remaining Mice received 2 x 50 ug ICV doses on days 0 & 7; mRNA from spi
Slide 13: WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro
WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro V3 Dose (μM) All V WVE-004 NTC Dose (μM) In vitro activity in C9 patient-derived neurons WVE-004 NTC Dose (μM) IC50:201.7nM In vitro selectivity in C9 patient-derived neurons C9 patient-derived motor neurons were treat
Slide 14: WVE-004 demonstrates durable reduction of DPRs in vivo after 6 months
WVE-004 demonstrates durable reduction of DPRs in vivo after 6 months in spinal cord and cortex Spinal cord Cortex Full results presented at the 31st International Symposium on ALS/ MND (December 2020) Top: 2 x 50 ug (day 0, day 7) dosed ICV; DPRs measured by Poly-GP MSD assay. *: p≤ 0.05 **: P ≤ 0.
Slide 15: WVE-004: Adaptive SAD/MAD design to optimize dose level and frequency
WVE-004: Adaptive SAD/MAD design to optimize dose level and frequency Patients with documented C9orf72 expansion and confirmed ALS, FTD, or mixed phenotype (up to 50 patients planned) Starting dose informed by preclinical in vivo models Dose escalation and dosing interval guided by safety committee
Slide 16: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 17: Huntington's disease: mHTT toxic effects and loss of wtHTT functions
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Wild-type HTT is critical for normal neuronal function Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein Huntington’s disea
Slide 18: Wild-type HTT is a critical protein for important functions in the CNS
Plays an essential role in the transport of synaptic proteins—including neurotransmitters and receptors—to their correct location at synapses9-12 Promotes neuronal survival by protecting against stress (e.g., excitotoxicity, oxidative stress, toxic mHTT aggregates)1-8 BRAIN CIRCUITS SYNAPSE NEURON C
Slide 19: HTT provides BDNF, a growth factor critical for survival of striatal neurons
Cerebral cortex Striatum BDNF- containing vesicle To the striatum Microtubule HTT HTT provides BDNF, a growth factor critical for survival of striatal neurons BDNF, brain-derived neurotrophic factor; HD, Huntington’s disease; HTT, huntingtin protein. 1. Altar CA, Cai N, Bliven T, et al. Nature. 1997
Slide 20: Allele-selective approach to treating HD
Target mutant mRNA HTT transcript to reduce mutant HTT protein Preserve wild-type HTT protein reservoir in brain Allele-selective approach to treating HD Wave has only allele-selective clinical program in Huntington’s disease Only an allele-selective approach is designed to address both toxic gain o
Slide 21: Nature publication on importance of wild-type huntingtin
Nature publication contributes to weight of evidence on importance of wild-type huntingtin Source: Poplawski et al., Nature, April 2019 Htt: Huntingtin protein Conditional knock-out of Htt in 4-month old mice (post-neuronal development) Results suggest that: Htt plays a central role in the regenerat
Slide 22: WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in HD iPSC neurons in vitro Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1 Oligonucleotide or PBS [
Slide 23: PK-PD modeling to guide dosing in clinical trial
PK-PD modeling to guide dosing in clinical trial PK: pharmacokinetic PD: pharmacodynamic IC50: the concentration of observed half of the maximal effect mHTT: mutant huntingtin protein BACHD Ascending dose studies PK & mHTT knockdown data IC50 determination Concentrations in cortex and striatum suffi
Slide 24: WVE-003: Clinical trial to leverage experience and learnings in HD
WVE-003: Clinical trial to leverage experience and learnings in HD Adaptive SAD/MAD design Patients with confirmed manifest HD diagnosis with SNP3 mutation (up to 40 patients planned) Dose escalation and dosing interval guided by independent DSMB Safety and tolerability Biomarkers mHTT NfL wtHTT Cli
Slide 25: Assessment of wild-type protein in CSF
Neuro HD Assessment of wild-type protein in CSF Ab: antibodyCSF: cerebrospinal fluidHTT: huntingtin proteinMW1: Wild et al. JCI 2015 CSF sample Total HTT mt wt wt wt mt mt mt mt mt wt wt wt Wild-type HTT wt wt wt wt wt wt wt wt Deplete mutant HTT Add polyQ Ab magnetic beads to CSF sample mt mt mt mt
Slide 26: Wave approach: novel, allele-selective silencing
Wave approach: novel, allele-selective silencing Neuro HD 1 Claassen et al. Neurol Genet Jun 2020; Carroll et al. Mol Ther. 2011 Dec; HDSA.org : 2000 patients ~30,000 people with manifest HD in US ~40% of HD Patients Carry SNP3 Allele-selective Treatments Have Potential to Benefit Many of Those At-r
Slide 27: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 28: WVE-N531 in vitro dose-dependent dystrophin restoration
WVE-N531 in vitro dose-dependent dystrophin restoration WVE-N531 contains novel PN backbone chemistry modifications Free uptake for 6 days in differentiation media with no transfection agent and no peptide conjugated to the oligonucleotide Demonstrated a dose-dependent increase in dystrophin restora
Slide 29: PN chemistry led to overall survival benefit in dKO model
PN chemistry led to overall survival benefit in dKO model dKO; double knockout mice lack dystrophin and utrophin protein. mdx mice lack dystrophin. Left: Mice with severe disease were euthanized. dKO: PS/PO/PN 150 mg/kg n= 8 (p=0.0018); PS/PO/PN 75 mg/kg n=9 (p=0.00005); PS/PO n=9 (p=0.0024), PBS n=
Slide 30: Clinical trial of WVE-N531
Clinical trial of WVE-N531 Unmet need in DMD remains high Planned clinical trial designed to evaluate change in dystrophin production, drug concentration in muscle, and initial safety Open-label study; targeting every-other-week administration in up to 15 boys with DMD Potential to apply PN chemistr
Slide 31: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 32: Iterative analysis and machine learning define design principles across programs
Through iterative analysis of in vitro and in vivo outcomes and machine learning-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 Multiple modalities
Slide 33: PRISM platform enables rational drug design
Sequence Stereochemistry Chemistry PRISM platform enables rational drug design Chemistry R: 2’ modifications OMe, MOE, F, other modifications 5’ 2’ 3’ 5’ 3’ 2’ R X B B X: backbone chemistry Phosphodiester (PO), phosphorothioate (PS), Phosphoramidate diester (PN) Sequence B: bases A, T, C, mC, G, U,
Slide 34: Expanding repertoire of backbone modifications with novel PN chemistry
Backbone modification (X) Phosphodiester Phosphorothioate Phosphoramidate diester Stereochemistry Not chiral Chiral Chiral Charge Negative Negative Neutral Depiction PRISM backbone modifications Expanding repertoire of backbone modifications with novel PN backbone chemistry Molecule structure illust
Slide 35: PN chemistry increases potency in silencing, splicing, and editing
Silencing PN chemistry increases potency in silencing, splicing, and editing preclinical studies Improved knockdown Splicing Editing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stere
Slide 36: Lead program in Takeda collaboration reinforces potential of PN chemistry in the CNS
Lead program in Takeda collaboration reinforces potential of PN chemistry in the CNS Single IT dose of 12 mg (n=3) Therapeutic candidate widely distributed across brain and spinal cord ~90% mRNA knockdown one-month following single dose Substantial and widespread target mRNA reduction following sing
Slide 37: PRISM enables optimal placement of backbone stereochemistry
PRISM enables optimal placement of backbone stereochemistry Crystal structure confirms phosphate-binding pocket of RNase H binds 3’-SSR-5’ motif in stereopure oligonucleotide – supports design strategy for Wave oligonucleotides ASO/RNA duplex Yellow spheres represent ‘S’ atoms Phosphate binding pock
Slide 38: Importance of controlling stereochemistry
Importance of controlling stereochemistry (Rp) (Sp) Top view Side view Yellow spheres represent ‘S’ atomsPS: Phosphorothioate Number of PS linkages in oligonucleotide backbone No. diastereomers 80T 60T 40T 20T 30B 22M 12M 2M 1M 500K 0 0 10 20 30 40 50 Antisense, exon skipping, ssRNAi ADAR oligonucle
Slide 39: ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
Slide 40: PRISM platform has unlocked ADAR editing
PRISM platform has unlocked ADAR editing A-to-I editing is one of most common post-transcriptional modifications ADAR is ubiquitously expressed across tissues, including liver and CNS ADAR Target RNA I(G) A Edited RNA Oligonucleotide establishes double-stranded RNA complex Oligonucleotide Modificati
Slide 41: PRISM enables practical approach to RNA editing without viruses or exogenous protein
PRISM enables practical approach to RNA editing without need for viruses or exogenous protein Intracellular Extracellular space Endogenous ADAR Unedited RNA Wave ADAR-editing Oligonucleotides Exogenous ADAR or other base editors Edited RNA Protein release/ expression Delivery vehicles Alternative Ba
Slide 42: Advantages of Wave ADAR editing platform
Wave platform Fully chemically modified to increase stability in vivo Chirally-controlled backbone to maximize in vitro activity PN backbone chemistry modification improves editing efficiency No requirement for AAV / nanoparticles GalNAc-conjugated for targeted delivery into liver Avoids permanent o
Slide 43: ADAR amenable diseases represent a sizeable opportunity
ADAR amenable diseases represent a sizeable opportunity Nearly half of known human SNPs associated with disease are G-to-A mutations A-to-I(G) editing could target tens of thousands of potential disease variants1 ~48% C-to-T C-to-G A-to-T C-to-A A-to-C A-to-G Potentially pathogenic human SNPs by bas
Slide 44: RNA editing opens many new therapeutic applications
RNA editing opens many new therapeutic applications Fix nonsense and missense mutations that cannot be splice-corrected Remove stop mutations Prevent protein misfolding and aggregation Alter protein processing (e.g. protease cleavage sites) Protein-protein interactions domains Modulate signaling p
Slide 45: Significant ADAR editing demonstrated in vitro in NHP and primary human hepatocytes
Significant ADAR editing demonstrated in vitro in NHP and primary human hepatocytes NHP: non-human primate; ACTB: Beta-actin; nd= not determined Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR. In vitro dose-response human hepatocytes I
Slide 46: Efficient ADAR editing translated in vivo in non-human primate study
Efficient ADAR editing translated in vivo in non-human primate study NHP: non-human primate; ACTB: Beta-actin; Left: 5mg/kg SC: Day 1,2,3,4,5; Liver Biopsy for mRNA (ACTB Editing) & eASO Exposure: Day 7 Up to 50% editing efficiency observed at Day 7, 2 days post last dose Substantial and durable edi
Slide 47: Wave ADAR editing oligonucleotides are highly specific
Editing site RNA editing within ACTB transcript (human hepatocytes) RNA editing within transcriptome (human hepatocytes) Wave ADAR editing oligonucleotides are highly specific Coverage Genome coordinates ACTB C 0% T 100% C 53.8% T 46.2% ACTB Confidence (LOD score) % Editing Mock Editing oligonucleot
Slide 48: Advancing Wave's first ADAR editing program in alpha-1 antitrypsin deficiency
Advancing Wave’s first ADAR editing program in alpha-1 antitrypsin deficiency (AATD) Sources: Strnad 2020; Blanco 2017 AAT: Alpha-1 antitrypsin Most common cause is a single G-to-A point mutation on the “Z” allele ~200K people in US and EU with homozygous ZZ genotype, most common form of severe AATD
Slide 49: SERPINA1 Z allele mRNA editing increases edited AAT protein concentration in vitro
SERPINA1 Z allele mRNA editing increases edited AAT protein concentration in vitro AAT (alpha-1 antitrypson); Mouse primary hepatocytes that express SERPINA1 Z allele mRNA were transfected with 25 nanomolar (nM) of SERPINA1 (SA1-1 and SA1-2) targeting antisense oligonucleotides (ASOs) and a control
Slide 50: Proprietary humanized mouse model developed to support ADAR platform
Proprietary humanized mouse model developed to support ADAR platform Model validation and in vivo data expected 1H 2021 SERPINA1-Pi*Z/huADAR Protein ü Human ADAR Expressed in all tissues huADAR mouse Protein Pathology ü huADAR Liver pathology, lower huSERPINA1 serum ü SERPINA1 SERPINA1 mouse Protein
Slide 51: Multiple opportunities for ADAR editing in neurology
Multiple opportunities for ADAR editing in neurology ACTB editing in iCell Neurons ACTB editing in human iCell Astrocytes Concentration (µM) % Editing % Editing Compound 2 (PS / PN) Compound 1 (PS / PN) Compound 3 (PS / PN) EC50: ~200-250nM Gymnotic uptake; Total RNA was harvested, reverse transcrib
Slide 52: Ophthalmology
Ophthalmology
Slide 53: Stereopure oligonucleotides for inherited retinal diseases (IRDs)
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 54: Durable Malat1 knockdown through months with PN backbone chemistry modifications
Durable Malat1 knockdown through 9 months with PN backbone chemistry modifications Compound or PBS (1 x 50 ug 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, 20 and 36 weeks post-single inj
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: Potent USH2A exon skipping with stereopure compound in vitro and ex vivo
Potent USH2A exon 13 skipping with stereopure compound in vitro and ex vivo Oligonucleotides 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. Stereorandom: Compound identified in v
Slide 57: Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP eye in vivo
Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP eye in vivo Oligonucleotide is complementary to NHP USH2A exon 12* Evaluated 1-week post-single IVT injection Dose-dependent activity of stereopure oligonucleotides Substantial exposure in retina Exon-skipping integrity confirmed
Slide 58: Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H
Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation Left: Reporter assays on a sequence described in WO2016138353A1. Oligonucleotide and luciferase reporter plasmids (wild-type and mutant RHO) are transfected into Cos7 cells. Cells are harvested after
Slide 59: Expected upcoming milestones
THERAPEUTIC AREA / TARGET Milestone Huntington’s disease mHTT SNP3 2021: Dosing of first patient in clinical trial of WVE-003 ALS and FTD C9orf72 2021: Dosing of first patient in clinical trial of WVE-004 DMD Exon 53 2021: Dosing of first patient in clinical trial of WVE-N531 ADAR editing Multiple 1
Slide 60: Realizing a brighter future for people affected by genetic diseases
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations krausch@wavelifesci.com 617.949.4827
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