Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (January 2023)
68 slides from Wave Life Sciences's investor presentation, Jan 9, 2023
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation January 9, 2023 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: Unlocking the body's own ability to treat genetic disease
UNLOCKING THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE realizing a brighter future for patients and families
Slide 4: Building a leading genetic medicines company
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; HD: Huntington’s disease; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency 1stereopure oligonucleotides and novel backbone chemistry modifications Diversified Pipeline
Slide 5: Rational design of oligonucleotides enables access to unique disease targets
… … Wave’s ability to rationally design oligonucleotides enables access to unique disease targets Chirality None PN backbone Sp PN backbone Rp Chirality … … PS backbone Rp PS backbone Sp Chirality … … PRISM backbone linkages PO: phosphodiester PS: phosphorothioate -O -S N (Rp) (Sp) PO PS PN Negative
Slide 6: Harnessing the biological machinery in our cells to treat genetic diseases
Harnessing the biological machinery in our cells to treat genetic diseases Silencing Splicing RNA Base Editing Degradation of RNA transcripts to turn off protein production Restore RNA transcripts and turn on protein production Efficient editing of RNA bases to restore or modulate protein production
Slide 7: Built-for-Purpose Candidates to Optimally Address Disease Biology
Built-for-Purpose Candidates to Optimally Address Disease Biology Silencing | Splicing | RNA Editing DESIGN Unique ability to construct stereopure oligonucleotides and control three structural features to efficiently engage biological machinery OPTIMIZE Provides the resolution to observe this struct
Slide 8: Robust portfolio of stereopure, PN-modified oligonucleotides
THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NEUROLOGY ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple 100% Global DMD Exon 53 HEPATIC AATD – lung and liver disease SERPINA1 GSK Exclusive Global License Robust portfo
Slide 9: GSK Collaboration and WVE-006 for AATD
GSK Collaboration and WVE-006 for Alpha-1 antitrypsin deficiency (AATD)
Slide 10: Strategic collaboration with GSK for RNA therapeutics
Collaboration leverages Wave’s unique stereopure, PN-chemistry containing PRISM™ platform, including editing, splicing, silencing (RNAi and antisense) Strategic collaboration with GSK to develop transformative RNA therapeutics for genetically defined diseases 1$120 million in cash and $50 million eq
Slide 11: WVE-006: designed to correct mutant SERPINA1 transcript
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin
Slide 12: ~50% RNA editing expected to raise AAT to PI*MZ levels
~50% RNA editing expected to increase PI*ZZ patient serum AAT levels to PI*MZ levels, with low risk of disease 1. Brode, et al. 2012 CMAJ 184:1365-1371; 2. ATS/ERS. 2003 Am J Respir Crit Care Med 168:818–900. Serum AAT Protein Levels and Risk of AATD by Genotype Risk of Emphysema Very High High Low
Slide 13: WVE-006 supports dose-dependent RNA editing in human model systems
WVE-006 supports dose-dependent RNA editing in human preclinical model systems Left: MZ-donor derived primary human hepatocytes treated with WVE-006 at indicated concentrations for 48 hours Right: Patient-iPSC derived hepatocytes (ZZ genotype) plated on day 0 and treated on day 2 with WVE-006 at ind
Slide 14: WVE-006 results in circulating AAT protein 7-fold above control
WVE-006 results in circulating AAT protein levels 7-fold above PBS control, well above established 11µM threshold WVE-006 administered subcutaneously (10 mg/kg bi-weekly) in 7-week old NSG-PiZ mice (n=5 per group); Loading dose: 3 x 10 mg/kg at Day 0. Left: Liver biopsies collected at week 13 (one w
Slide 15: WVE-006 restores wild-type M-AAT protein in serum
WVE-006 leads to restoration of confirmed, wild-type M-AAT protein in serum WVE-006 administered in 7-week old NSG-PiZ mice (n=5 per group). Relative proportion of M- vs. Z-AAT protein in serum collected from animals at week 13 (one week after last dose) was measured by mass spectrometry Overall per
Slide 16: Increased neutrophil elastase inhibition shows restored M-AAT is functional
Significant increase in neutrophil elastase inhibition activity indicates restored M-AAT protein is functional GalNAc-conjugated AIMers administered in 7-week old NSG-PiZ mice (n=5 per group). Serum collected from mice was tested for ability to inhibit fixed concentration of neutrophil elastase in a
Slide 17: AATD AIMer reduces Z-AAT aggregation and inflammation in mouse liver
Early lead pre-optimization AATD AIMer (SA1-5) administered in huADAR/SERPINA1 mice (8–10 wKs old); lower left: 20x liver images PAS-D stained, 19 weeks; Quantification of PAS-D positive staining, Stats 2-way ANOVA; Right: Quantification lobular inflammation grade (Grade based on # of inflammatory f
Slide 18: AIMer-directed editing is highly specific in mice
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing across transcriptome (mouse liver) AIMer-directed editing is highly specific in mice SERPINA1 (PiZ mutation site) % Editing Dose 3x10 mg/kg (days 0, 2, 4) SC with AATD AIMer (SA1 – 4). Liver biopsies day
Slide 19: WVE-006 is a potential first- and best-in-class candidate for AATD
WVE-006 is a potential first- and best-in-class candidate for AATD Correct Z-allele mRNA to replace mutant Z-AAT protein with functional wild-type M-AAT protein RNA editing levels show potential to support conversion of a patient from ZZ to MZ mRNA expression M-AAT protein can address lung disease R
Slide 20: Planning for clinical development for WVE-006 underway
Planning for clinical development for WVE-006 underway Phase 1/2 placebo-controlled study to establish dose and evaluate target engagement CTA submissions for WVE-006 expected in 2023 Single-ascending dose (SAD) cohorts Multiple-ascending dose (MAD) cohorts Initial cohorts healthy volunteers Final c
Slide 21: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 22: Duchenne muscular dystrophy
Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function Impacts approx. 1 in every 5,000 newborn boys each year; approx. 20,000 new cases annually worldwide Approx. 8-10% are amenable to exon 53 sk
Slide 23: PN chemistry improved muscle exposure and survival in mouse models
PN chemistry improved muscle exposure and survival in preclinical mouse models Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN increased muscle concentrations after single dose, which correlated with exon-skipping activity PN PN Treatment with PN-modified molecules led to 100% survival of dKO mi
Slide 24: PS/PO/PN compound restores muscle and respiratory function in dKO mice
PS/PO/PN splicing compound restores muscle and respiratory function to wild-type levels in dKO mice Left: Mdx/utr-/- mice received weekly subQ 150 mg/kg dose of PS/PO/PN stereopure oligonucleotide (postnatal day 10). Age-matched mdx/utr-/- littermates treated with PBS, wild-type C57BL10 mice not tre
Slide 25: WVE-N531: Dystrophin restoration in vitro and muscle distribution in NHPs
WVE-N531: Dystrophin restoration in vitro and enhanced muscle distribution in NHPs Western Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of up to 71% in vitro Plasma and tissue concentrations of WVE-N531 (PS/PO/PN) significantly higher than suvodirsen (first
Slide 26: Multidose portion of study: three biweekly 10 mg/kg doses
In multidose portion of study, patients received three biweekly 10 mg/kg doses Initial cohort Boys with DMD amenable to exon 53 skipping 1 mg/kg 3 mg/kg 6 mg/kg 10 mg/kg Single ascending intra-patient doses Multidosing at 10 mg/kg every other week Weeks Dose WVE-N531 Period before initiating multido
Slide 27: WVE-N531 appeared safe and well-tolerated
WVE-N531 appeared safe and well-tolerated All treatment-emergent adverse events (TEAEs) were mild, except one COVID-19 infection of moderate intensity All adverse events (AEs) related to study drug (headache, pruritic rash) were mild, transient and resolved without sequelae No serious adverse events
Slide 28: Plasma pharmacokinetic profile enabling tissue concentrations
Plasma pharmacokinetic profile enabling meaningful WVE-N531 tissue concentrations Plasma concentrations and other PK parameters following a single dose of 10 mg/kg demonstrate a half-life of 25 days Higher plasma concentrations For 10 mg/kg dose level: Cmax: 191 (+/- 18.1) (µg/mL) AUClast : 933 (+/-
Slide 29: Intracellular WVE-N531 enabling PD effects
Mag: 40x with an enlarged images Myofibers WVE-N531 (in red) in myofiber cytoplasm (stars) and nuclei (yellow arrows) RNAscope (ISH – in situ hybridization) Control Probes: Ubiquitin – Positive DapB – Negative Intracellular WVE-N531 enabling PD effects
Slide 30: High muscle concentration and exon skipping indicate target engagement
High muscle concentration and exon skipping indicate WVE-N531 is engaging target Mean exon skipping: 53% Mean muscle concentration: 42 µg/g Biopsies collected ~2 weeks post-last dose (3 biweekly doses of 10 mg/kg) 42 µg/g = 6.1 µM BLQ: Below level of quantification (1%) Patient Tissue Source Tissue
Slide 31: Conclusions & next steps
Conclusions & next steps Achieved proof-of-concept: High muscle concentrations of WVE-N531 and exon skipping observed following three biweekly doses at 10 mg/kg Planning underway to continue to evaluate dystrophin Evaluating next steps for program in light of evolving regulatory environment
Slide 32: WVE-004 ALS and FTD
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 33: C9orf72 repeat expansions: common genetic cause of ALS and FTD
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Typically 100’s-1000’s of GGGGCC repeats Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD) Hexanucleotide (G4C2)- repeat expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Diff
Slide 34: WVE-004 mechanism and poly(GP) biomarker
Reduced expression RNA variants RAN translation C9orf72 protein RNA foci Dipeptide repeat proteins (DPRs) Sense: poly(GA), poly(GR) Antisense: poly(PR), poly(PA) Sense & Antisense: poly(GP) Toxic RNA aggregation Gain-of-function Loss-of-function Repeat-expanded allele Wild-type C9orf72 allele Geneti
Slide 35: Durable reduction of poly(GP) in spinal cord and cortex
* *** ** *** Spinal cord Relative poly(GP) levels (normalized to PBS) Cortex >90% knockdown of poly(GP) DPR protein Two doses of WVE-004 Six months >80% knockdown of poly(GP) DPR protein Relative poly(GP) levels (normalized to PBS) p≤0.0001 Liu et al., 2022 Molecular Therapy Nucleic Acids doi: 10.10
Slide 36: WVE-004 clinical data show translation of preclinical approach
WVE-004 clinical data demonstrate successful translation of preclinical approach to clinic PK: pharmacokinetic PD: pharmacodynamic; Right: Mixed model for repeated measures used to estimate geometric mean ratio to baseline via least squares mean and to calculate p-values. P-values represented by ast
Slide 37: Dosing ongoing in FOCUS-C9 clinical trial
30 mg n=10 Dosing ongoing in FOCUS-C9 clinical trial with multiple doses of WVE-004 10 mg n=3 60 mg n=4 20 mg n=10 10 mg n=6 4 monthly doses Dose and frequency to be guided by DSMB Target engagement observed in single dose cohorts Single dose Multidose OLE clinical trial initiated in 4Q 2022 10 mg n
Slide 38: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 39: Huntington's disease and mHTT toxic effects
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Stresses wtHTT Stresses wtHTT mHTT + ~50% decrease in wtHTT Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration Loss of wtHTT functions Hunti
Slide 40: wtHTT supports healthy brain function; WVE-003 spares wtHTT
mHTT, mutant HTT; wtHTT, wild-type HTT; PO, phosphodiester; PS, phosphorothioate; PN, phosphoryl guanidine; wtHTT literature sources: 1. Leavitt 2006 2. Cattaneo 2005 3. Kumar 2016 4. Franco-Iborra 2020 5. Hamilton 2015 6. Ochaba 2014 7. Wong 2014 8. Rui 2015 9. Caviston 2007 10. Twelvetrees 2010 11
Slide 41: Allele-selective molecule decreases mHTT, spares wtHTT
Hu97/18 mice administered 3x100 mg intracerebroventricular doses PBS or oligonucleotide. Relative mHTT RNA in cortex (left) striatum (middle) or hippocampus (right) at 4, 8 and 12-weeks post-dosing. Data are mean ± SD, n=8. Stats: ns non-significant, *P<0.05, **P<0.01, ***P<0.0001, ****P<0.0001 vers
Slide 42: WVE-003 shows selective, potent, durable mHTT reduction preclinically
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 43: Initial clinical results indicate allele-selective target engagement
Initial clinical results indicating allele-selective target engagement suggests translation of preclinical data Allele selectivity (Hu97/18 mice) mHTT reduction in cortex and striatum (transgenic mice) Concentrations in NHP brain tissues sufficient for target engagement PK/PD modeling using preclini
Slide 44: Expanding single dose cohorts to optimize dose level
Expanding single dose cohorts to optimize dose level based on initial clinical results 30 mg Expanding cohort 90 mg Expanding cohort Additional single-dose biomarker and safety data are expected in 1H 2023 mHTT protein reductions observed in single dose cohorts wtHTT protein levels appear consistent
Slide 45: AIMers RNA base editing capability
AIMers RNA base editing capability
Slide 46: Unlocking RNA editing with PRISM platform to develop AIMers
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides Endogenous ADAR enzymes 1Woolf et al., PNAS Vol. 92, pp. 8298-8302, 1995; Right: Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site
Slide 47: AIMers: realizing potential of therapeutic RNA editing via ADAR
AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Efficient ADAR recruitment AIMer design principles SAR developed to design AIMers for different targets Systematized AIMer d
Slide 48: Proof-of-concept RNA editing data published in Nature Biotechnology
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022) Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 SAR structure-activity relationship Specificity in vitro & in vivo (NHPs) In vitro-in vivo translation (NHPs) GalNAc conjugat
Slide 49: Potent, durable, specific RNA editing and delivery
Editing: Potent, durable, specific A à I (G) RNA editing Delivery: Efficient RNA editing in preclinical in vivo models: Targeted delivery (GalNAc) Systemic delivery Local delivery (IT, IVT, others) Potential to accelerate timelines to candidate with AIMer pipeline expansion Systemic in vivo editing
Slide 50: Substantial in vivo editing without delivery vehicles in CNS tissues
Substantial in vivo editing without delivery vehicles in CNS tissues Transgenic huADAR mice administered 100 mg AIMer or PBS on day 0 and evaluated for UGP2 editing across CNS tissues at 1, 4, 8, 12, and 16-weeks post dose. Percentage UGP2 editing determined by Sanger sequencing. Stats: 2-way ANOVA
Slide 51: Expanding addressable target space using AIMers
Expanding addressable disease target space using AIMers to activate pathways and upregulate expression Modulate protein-protein interaction Upregulate expression Modify function Post-translational modification Alter folding or processing Restore or correct protein function Achieved POC WVE-006 (GalN
Slide 52: Dose dependent modulation of protein/protein interactions
n=2; Primary hepatocytes 48h of treatment with the indicated dose concentration of AIMers NRF2 is degraded by proteasome NRF2 KEAP1 Transcription is repressed ADAR editing site NRF2 is stabilized KEAP1 NRF2 Transcription is activated Basal conditions ADAR-modified conditions AIMer RNA editing effici
Slide 53: AIMers enable activation of gene pathway in vivo with single edit
Note: Editing percentage for UGP2 control AIMer indicates editing of UGP2 mRNA Methods: hADAR C57BL/6 mice dosed subQ (days 0, 2, 4) at 10mg/kg GalNAc-conjugated AIMers. Livers harvested (day 7), analyzed for editing and NQO1 expression via Sanger sequencing or qPCR, respectively. Data analyzed via
Slide 54: Upregulation: AIMers can edit RNA motifs to upregulate gene expression
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression RNA binding proteins recognize sequence motifs to regulate various mRNA properties Enhance or inhibit mRNA decay Stability Intracellular localization Transport Splicing Capping Processing PolyA usage Translational effi
Slide 55: AIMers upregulate gene expression in hepatocytes and T-cells in vitro
AIMers can edit RNA motifs to upregulate gene expression in hepatocytes and T-cells in vitro Editing RNA Motifs to regulate RNA half-life to upregulate RNA expression is possible for clinically-relevant targets, including both metabolic and immune targets Gene upregulation Primary human hepatocytes
Slide 56: Considerations to translate Target A upregulation results in vivo
Proof-of-concept: Considerations to translate Target A upregulation results in vivo Gene upregulation AIMer Response is greater in human hepatocytes ~14-fold compared to mouse hepatocytes ~2-fold In vitro Target A mRNA fold upregulation (gymnotic 10uM, ~48h) Target A (undisclosed liver target) High
Slide 57: AIMers upregulate mRNA and serum protein in vivo
AIMers upregulate mRNA and downstream serum protein in vivo above anticipated threshold In vitro to in vivo translation of mouse Target A mRNA upregulation In vivo mRNA upregulation corresponds to an upregulation of Target A protein in serum at Day 7 demonstrating proof-of-concept mRNA upregulation
Slide 58: RNA editing of MECP2 nonsense mutation restores functional protein
RNA editing of nonsense mutation found in MECP2 (Rett Syndrome) restores functional protein 293T cells transfected with both nonsense mutation on MECP2 (GFP-fusion construct) and ADAR plasmids. AIMers transfected for 48h prior to RNA extraction and sequencing. Percentage editing determined by Sanger
Slide 59: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 60: Improvements in PRISM primary screen hit rates
Improvements in PRISMTM primary screen hit rates accelerate drug discovery over time Primary screen hit rates with silencing far above industry standard hit rates Stereorandom Chemistry, PN stereochemistry & machine learning optimization Stereopure Chemistry improvements and PRISM advancement All sc
Slide 61: Silencing potency enhanced with PN modifications across modalities
Silencing Potency is enhanced with addition of PN modifications across modalities 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 (Stereorandom) Concen
Slide 62: PN chemistry improved potency of C9orf72-targeting oligonucleotides in vivo
Adding PN chemistry modifications to C9orf72-targeting oligonucleotides improved potency in vivo Exposure (µg/g) Exposure (µg/g) Cortex %C9orf72 V3 transcript remaining Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% confidence intervals (
Slide 63: PN chemistry improves distribution to CNS
PN chemistry improves distribution to CNS NHPs administered 1x12 mg oligonucleotide or PBS by intrathecal injection/lumbar puncture (IT). CNS tissue evaluated 11 or 29 days after injection (n=6 per group). Oligonucleotide was visualized by ViewRNA (red), and nuclei are counterstained with hematoxyli
Slide 64: PRISM PN siRNA led to silencing >3 months after single dose
PRISMTM PN siRNA led to unprecedented silencing >3 months after single dose PBS HSD Reference 2 HSD PN/PS/PO Wk2 Wk 14 Wk 7 Reference 2 HSD PN/PS/PO **** * * Mice expressing a human HSD17B13 transgene were treated with 3 mg/kg of the indicated siRNA or PBS, and liver mRNA, guide strand concentration
Slide 65: Established internal GMP manufacturing
Established internal GMP manufacturing for multiple oligonucleotide modalities Strong technical knowhow and operating expertise Established infrastructure State of the art facilities (90,000 sq ft) and expansion space Process and analytical development labs GMP oligonucleotide (API) manufacturing Es
Slide 66: Upcoming Milestones
Upcoming Milestones
Slide 67: Data updates inform future opportunities, unlock value and cash
Data updates inform future opportunities, unlock value and cash Silencing CNS (Intrathecal) Splicing Muscle (IV) Correction Targeted delivery to liver (Subcutaneous) Multiple modalities Opportunities in a variety of tissues and delivery mechanisms WVE-004 C9orf72 ALS & FTD Delivered clinical target
Slide 68: 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 InvestorRelations@wavelifesci.com 617.949.4827
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