Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (March 2021)
62 slides from Wave Life Sciences's investor presentation, Mar 4, 2021
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation March 4, 2021 Exhibit 99.2
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 Huntington’s disease mHTT SNP1 Takeda 50:50 option Huntington’s disease mHTT SNP2 Huntington’s disease mHTT SNP3 ALS and FTD C9orf72 SCA3 ATXN3 CNS diseases Multiple† Takeda milestones & royalties DMD Exon 53 100% global ADAR editing M
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 Oligonucleotide optimization Stereopure backbone PN backbone chemistry modifications In vivo disease models Insight into PK / PD relationships Novel model generation Leverage learnings of first generation programs Transl
Slide 7: Huntington's Disease Portfolio
WVE-120101 WVE-120102 WVE-003 Huntington’s Disease Portfolio
Slide 8: 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 9: mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute
Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Healthy individual Stresses wtHTT Huntington’s disease Stresses Toxic effects of mHTT + Loss of wtHTT functions ~50% decrease in
Slide 10: HD: Wild-type HTT is a critical protein for important functions in the central nervous system
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 11: Nature publication contributes to weight of evidence 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 12: Wave approach: novel, allele-selective silencing
Utilize association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including Huntington’s disease (HD) Potential to provide treatment for up to 80% of HD population Wave approach: novel, allele-selective silencing Source: Kay,
Slide 13: WVE-120101: Selective reduction of mHTT mRNA and protein
WVE-120101: Selective reduction of mHTT mRNA and 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 M
Slide 14: 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 In Situ Hybridization ViewRNA stained tissue Red dots are WVE-120102 oligonucleotide Arrow points to nuclear and perinuclear distribution of WVE-12
Slide 15: PRECISION-HD clinical trials
PRECISION-HD clinical trials Single Dose Multidose 196 1 Washout CSF sample Dose 28 56 84 112 Study Day* 140 OLE 2 mg 4 mg 8 mg 16 mg 32 mg Multidose Cohorts (N = 12 per cohort) OLE: Open label extension; CSF: cerebrospinal fluid; mHTT: mutant huntingtin; NfL: neurofilament light chain; wtHTT: wild-
Slide 16: 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 17: WVE-003 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 18: 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 19: Three allele-selective HD programs
Three allele-selective HD programs Intend to explore efficacy in early manifest and pre-manifest HD patient populations Neuro HD Potential to address ~80% of HD patient population % Huntington’s Disease Patient Population with SNP SNP1 WVE-120101 SNP2 WVE-120102 SNP3 WVE-003 SNP1 SNP2 SNP1 SNP2 SNP3
Slide 20: WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 21: 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 22: 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 23: 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 24: 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 25: 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 26: 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 27: 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 28: 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 independent DSMB
Slide 29: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 30: 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 31: 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 32: Clinical trial of WVE-N531 to initiate in 2021
Clinical trial of WVE-N531 to initiate in 2021 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
Slide 33: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 34: 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 35: 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 36: Expanding repertoire of backbone modifications with novel PN backbone 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 37: PN chemistry increases potency in silencing, splicing, and editing preclinical studies
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 38: 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 39: 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 40: 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 41: ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
Slide 42: 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 43: PRISM enables practical approach to RNA editing without need for 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 44: 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 45: 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 46: 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 47: 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 48: 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 49: 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 50: 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 51: 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 52: 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 53: 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 54: Ophthalmology
Ophthalmology
Slide 55: 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 56: 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 57: 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 58: 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 59: 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 60: Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation
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 61: Expected upcoming milestones
THERAPEUTIC AREA / TARGET Milestone Huntington’s disease mHTT SNP2 End of 1Q 2021: PRECISION-HD2 data, including complete 32 milligram cohort, and initial data from OLE trial Huntington’s disease mHTT SNP1 End of 1Q 2021: PRECISION-HD1 data, including complete 16 milligram cohort, and initial data f
Slide 62: 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
Wave Life Sciences — Investor Presentation (March 2021) on 6ix