Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (November 2023)
55 slides from Wave Life Sciences's investor presentation, Nov 9, 2023
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation November 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: Building a leading RNA medicines company
Building a leading RNA medicines company Multiple clinical proof-of-concept datasets expected in 2024 DMD (splicing), HD (silencing), and AATD (RNA editing) clinical programs advancing Leader in RNA editing therapeutics, emerging leader in RNAi Multi-modal drug discovery and development platform Pip
Slide 4: Combining novel biology with validated, best-in-class chemistry
Combining novel biology with validated, best-in-class chemistry to open opportunities for first-in-class medicines Accessing new endogenous enzymes for novel modalities (RNA editing) Opening up new targets, including prevalent diseases
Slide 5: Wave has the most versatile RNA medicines platform in the industry
editing splicing siRNA silencing antisense silencing Wave has the most versatile RNA medicines platform in the industry Endogenous RNase H Endogenous AGO2 Endogenous ADAR enzyme RISC Restored Reading Frame Functional Protein Best-in-class nucleic acid chemistry applicable across modalities Ability t
Slide 6: Increasing genetic insights unlocking new target opportunities
Increasing genetic insights for rare and common diseases is unlocking new target opportunities Claussnitzer, et al. Nature (2020) 577, 179; King et al. PLoS Genet (2019) 15, e1008489 Accessing UK Biobank and building proprietary machine learning models to generate unique genetic insights
Slide 7: Proprietary PN chemistry enhances potency across modalities
Silencing Proprietary PN chemistry enhances potency across modalities Improved knockdown Splicing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound PS/PO reference compound PS/PN modified compound % Skipping Target knockdown (% remaining) L
Slide 8: Robust RNA medicines pipeline including first-in-class RNA editing programs
Program Discovery Preclinical Clinical Rights Patient population (US & Europe) RNA EDITING WVE-006 SERPINA1 (AATD) GSK exclusive global license 200K Multiple undisclosed Correction 100% global >20K (multiple) Multiple undisclosed Upregulation 100% global >3M (multiple) SPLICING WVE-N531 Exon 53 (DMD
Slide 9: Strategic collaboration with GSK
Collaboration leverages Wave’s unique stereopure, PN-chemistry containing PRISMTM platform, including editing, splicing, silencing (RNAi and antisense) Strategic collaboration with GSK to develop transformative RNA medicines for genetically defined diseases 1$120 million in cash and $50 million equi
Slide 10: WVE-006 (RNA editing) AATD
WVE-006 (RNA editing) AATD
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: WVE-006 in AATD: First-in-class RNA editing clinical candidate
WVE-006 in AATD: First-in-class RNA editing clinical candidate Potentially comprehensive approach to address both lung and liver manifestations of AATD Increased AAT protein in NSG-PiZ mice Demonstrated functionality of M-AAT protein Confirmed restored wild-type M-AAT protein WVE-006 treatment resul
Slide 13: WVE-006 decreases lobular inflammation and PAS-D globule size
WVE-006 decreases lobular inflammation and PAS-D globule size, prevents increase in hepatocyte turnover Left (Lobular inflammation) and Middle (Mitoses): Scatter plot showing inflammation grade or mitoses score. Each circle represents an individual mouse, (Mean ± SEM); Right (PAS-D Globule Size): 40
Slide 14: 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 15: Proof of mechanism data in patients with AATD expected in 2024
Proof of mechanism data in patients with AATD expected in 2024 Dose escalation Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels Expect to initiate dosing in 4Q 2023 Multiple assessments of serum AAT throughout cohort HV: healthy volunteer; SAD: single-ascending dose;
Slide 16: AIMers RNA editing capability
AIMers RNA editing capability
Slide 17: First-generation AIMer designs published in Nature Biotechnology
First-generation AIMer designs published in Nature Biotechnology 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 conjugation Foundational AIMer SAR A
Slide 18: Innovating on applications of ADAR editing
Innovating on applications of ADAR editing Modulate protein-protein interaction Upregulate expression Modify function Post-translational modification Alter folding or processing Restore or correct protein function Achieved POC WVE-006 (GalNAc AIMer) AATD POC: proof of concept Correct G-to-A driver m
Slide 19: Proprietary base modifications increase editing
Proprietary base modifications increase editing across edit region sequences N3 U: example of proprietary base modifications N3 U consistently improves RNA editing levels, including across sequences Presented at RNA Editing 2023 - Gordon Research Conference Seq 1 (UAU) Seq 2 (GAU) Seq 3 (AAU) Seq 4
Slide 20: Upregulation: AIMers can edit RNA motifs
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression RNA binding proteins recognize sequence motifs to regulate mRNA stability mRNA A I(G) Edited mRNA mRNA Decay Cascade “Dialed up” Gene Expression Attenuated Gene Expression Unique RNA motifs A single edited base permane
Slide 21: Target A: metabolic syndrome target for AIMer upregulation
Edit-verse subnetwork reveals “Target A”: Metabolic syndrome target uniquely suited for AIMer upregulation Target A Liver target for upregulation, non-incretin therapy Strongly implicated in metabolic disease, with indirect causation in familial disorders Few therapies today provide weight loss in t
Slide 22: Substantial upregulation of protein induces weight loss
Substantial upregulation of protein induces weight loss and improves insulin sensitivity ~3-fold upregulation of Target A protein with GalNAc-AIMer led to weight reduction and improved insulin sensitivity in DIO mice Body weight data were analyzed using a linear mixed effects model to assess the fix
Slide 23: Target B upregulation for hyperlipidemia
Target B upregulation offers a first-in-class therapeutic approach for hyperlipidemia >70% editing achieves ~2-fold upregulation with corresponding increase in protein Target B Liver target for upregulation Hyperlipidemia; first-in-class therapeutic approach Estimate ~3 million target patients in US
Slide 24: Upregulation of liver Target X stops decline in kidney function
Upregulation of liver Target X stops decline in kidney function Target X Liver target for upregulation Target X produces a secreted protein to treat kidney disease Estimate ~170K target patients in US and Europe Therapeutic rationale supported by genetic insights, PheWAS, and observational data Plas
Slide 25: Target E correction restores normal metabolism
Building on success of AATD: Target E correction restores normal metabolism in rare genetic disease Target E Liver target for correction Rare genetic disease High unmet need population not addressed with current therapeutic options ~17,000 patients addressable with correction approaches in US and Eu
Slide 26: Upregulation of Target F restores kidney function
Upregulation of Target F restores kidney function in a rare genetic kidney disease Achieved >2-fold upregulation of Target F mRNA in vitro with RNA editing Target F Kidney target for upregulation Rare genetic kidney disease that leads to ESRD and need for dialysis / transplantation; High unmet need
Slide 27: Correction of Target G mutation restores protein function
Correction of Target G mutation restores protein function in patients with a genetic lung disease Target G Lung disease target for correction Genetic lung disease with target patient population not addressed with available therapies ~5K patients amenable to correction approaches in US and Europe Cli
Slide 28: Multiple RNA editing opportunities beyond WVE-006
Multiple RNA editing opportunities to build high-value pipeline beyond WVE-006 The Edit-verse is substantial and still expanding Advancing work for a diverse set of undisclosed targets addressing areas of high unmet need, including both rare and prevalent diseases Hepatic (GalNAc-AIMers) Extra-Hepat
Slide 29: WVE-N531 (splicing) Duchenne muscular dystrophy
WVE-N531 (splicing) Duchenne muscular dystrophy
Slide 30: 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 31: Extended survival in dKO preclinical model
Extended survival in dKO preclinical model supports potential of exon-skipping therapeutics for DMD Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN chemistry improved function and survival in dKO mice 100% survival at time of study termination Restored muscle and respiratory function to wild-typ
Slide 32: Preclinical data supported advancing WVE-N531 to clinical development
Preclinical data supported advancing WVE-N531 to clinical development 26th Annual ASGCT meeting, May 16-20, 2023 WVE-N531 reached high concentrations in heart and diaphragm in NHP WVE-N531: Dystrophin restoration of up to 71% in vitro Western Blot normalized to primary healthy human myoblast lysate
Slide 33: WVE-N531 Part A clinical data
WVE-N531 Part A clinical data: High exon-skipping & muscle concentrations after three bi-weekly doses WVE-N531 data presented March 22, 2023 at Muscular Dystrophy Association Clinical and Scientific Conference; WVE-N531 biopsies collected ~2 weeks post-last dose (3 biweekly doses of 10 mg/kg) 42 µg/
Slide 34: FORWARD-53 Phase 2 clinical trial of WVE-N531
FORWARD-53, a potentially registrational Phase 2 clinical trial of WVE-N531 in DMD (Exon 53) Design of FORWARD-53: Phase 2, open-label, 10 mg/kg every other week, up to 10 patients Endpoints: Dystrophin (powered for >5% of normal), safety/tolerability, pharmacokinetics, digital and functional assess
Slide 35: Potential to address up to 40% of DMD population
Potential for Wave to address up to 40% of DMD population Exon 45 Exon 44 Exon 52 WVE-N531 Exon 53 Exon 51 Not Amenable to Skipping 11-13% 8-10% 44% Left: Aartsma-Rus, et al. 2009 Hum Mutat 30, 293. DMD Population Exon 52 Exon 51 Exon 44 Protein Restoration Exon skipping and dystrophin restoration d
Slide 36: WVE-003 (antisense silencing) Huntington's Disease
WVE-003 (antisense silencing) Huntington’s Disease
Slide 37: Huntington's disease
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 38: WVE-003 demonstrates selective, potent, durable reduction of mHTT
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 39: WVE-003: First-in-class allele-selective candidate for HD
Preservation of wtHTT WVE-003: First-in-class allele-selective candidate for HD mHTT protein levels Placebo WVE-003 (30 and 60 mg pooled*) wtHTT protein levels Reductions in mean CSF mHTT and preservation of wtHTT observed in pooled analysis of single-dose cohorts in SELECT-HD clinical study Single
Slide 40: INHBE program (siRNA silencing)
INHBE program (siRNA silencing) Metabolic disorders, including obesity
Slide 41: siRNA silencing in strategic research collaboration with GSK
siRNA silencing is one of multiple Wave modalities being advanced in strategic research collaboration with GSK Potential for best-in-class siRNA enabled by Wave’s PRISM platform **** Left, Middle, and right: Mice expressing human HSD17B13 transgene treated with siRNA (3 mg/kg) or PBS, liver mRNA, gu
Slide 42: INHBE GalNAc-siRNA: evolution in treatment for metabolic diseases
INHBE GalNAc-siRNA represents an evolution in treatment for metabolic diseases, including obesity 1. Liang, et al. 2023 Postgraduate Medical Journal 99(1175):985; 2. Lakka, et al. 2002 JAMA 288(21):2709; 3. Sargeant, et al. 2019 Endocrinol Metab (Seoul) 34(3):247-262; 4. Liu, et al. 2022 Front. Endo
Slide 43: Wave's first RNAi program addresses unmet need in metabolic disorders
Driven by clinical genetics, Wave’s first RNAi program addresses high unmet need in metabolic disorders, including obesity Nat Commun 2022. https://doi.org/10.1038/s41467-022-32398-7; 2. Nat Commun 2022. https://doi.org/10.1038/s41467-022-31757-8; 3. PLOS ONE 2018. https://doi.org/10.1371/journal.po
Slide 44: INHBE knockdown of 90% in human hepatocytes
INHBE knockdown of 90% demonstrated in human hepatocytes with GalNAc-siRNA Primary hepatocytes were treated with a cross-reactive siRNA via free uptake. INHBE mRNA was quantified by RT-qPCR. This cross-reactive sequence demonstrates ~90% maximal knock-down in human hepatocytes and ~65% in mouse hepa
Slide 45: INHBE knockdown in mice led to lower body weight
~62% silencing **** Therapeutic threshold1 INHBE knockdown demonstrated in mice at 5 weeks INHBE silencing achieved in vivo with GalNAc-siRNA exceeds therapeutic threshold and led to lower body weight HFD: high-fat diet. Stats: two-sided Welch’s T Test **** P < 0.0001 1. Adam, RC. et.al. Proc Natl A
Slide 46: INHBE silencing decreases visceral fat
~56% reduction ~34% reduction ~38% reduction **** *** *** Chow, PBS HFD, PBS HFD, Inhbe siRNA Chow, PBS HFD, PBS HFD, Inhbe siRNA Chow, PBS HFD, PBS HFD, Inhbe siRNA INHBE silencing leads to significant decrease in visceral fat, consistent with phenotype of heterozygous LoF carriers Adam, RC. et.al.
Slide 47: Next-generation GalNAc-siRNA demonstrates best-in-class potential
Foster, DJ. et.al. Mol Ther. 2018, 26(3), 708. B6 mice administered PBS or 0.5 mg/kg of siRNA (subcutaneous). Benchmark: Stats: Mixed Two-way ANOVA followed by post hoc test comparing siRNA vs. Next gen siRNA per day derived from linear mixed effects model * P < 0.0001 Wave’s next generation GalNAc-
Slide 48: Platform chemistry enables siRNA extra-hepatic delivery
Wave’s platform chemistry enables siRNA extra-hepatic delivery Chemical impact Introduction of neutral backbone Unique structural feature of PN, specifically guanidine Increased lipophilicity Stereochemistry Extra-hepatic delivery Titrating siRNA lipophilicity tunable PNs (PN variants) Maintaining h
Slide 49: Tunable PN variants enhance potency of non-GalNAc siRNAs
Tunable PN variants enhance potency and alter extra-hepatic delivery of non-GalNAc siRNAs Stats: Three-way ANOVA followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown) * P < 0.05, *** P < 0.001, **** P < 0.0001; B6 mice administered PBS or 5 mg/kg of Sod1 siRNA (no
Slide 50: Next generation siRNA delivers durable CNS target engagement
Single dose of next generation siRNA delivers broad, potent and durable CNS target engagement PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-adjust
Slide 51: Wave siRNA more potent and durable than published state-of-the-art
Wave siRNA demonstrates more potent and durable silencing as compared to published state-of-the-art PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-
Slide 52: Anticipated upcoming milestones
Anticipated upcoming milestones
Slide 53: Anticipated upcoming milestones
Anticipated upcoming milestones AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; mHTT: Mutant huntingtin; wtHTT: Wild-type huntingtin WVE-006 (AATD) Most advanced RNA editing candidate & potential best-in-class approach for AATD 4Q 2023: Initiate dosi
Slide 54: Wave is poised for significant and sustained growth
Wave is poised for significant and sustained growth Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients) AATD WVE-006 DMD WVE-N531 Exon 53 HD WVE-003 SNP3 INHBE metabolic disorders, including obesity Clinical candidate expected 4Q 2024 F
Slide 55: Thank you!
For more information: InvestorRelations@wavelifesci.com Thank you!
Wave Life Sciences — Investor Presentation (November 2023) on 6ix