Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Day (October 2024)
89 slides from Wave Life Sciences's investor day presentation, Oct 30, 2024
Slide 1: Wave Life Sciences Research Day
Wave Life Sciences Research Day October 30, 2024
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: Agenda
Agenda Presentation Speaker Welcome & Introduction Kate Rausch Vice President, Investor Relations & Corporate Affairs Reimagining RNA Medicines Paul Bolno, MD, MBA President and Chief Executive Officer PRISM Platform: Best-in-Class Oligonucleotide Chemistry Chandra Vargeese, PhD Chief Technology Off
Slide 4: Reimagining RNA Medicines
Reimagining RNA Medicines Paul Bolno, MD, MBA President and CEO 4
Slide 5: Wave today: Making history in oligonucleotides
Wave today: Making history in oligonucleotides • Best-in-class, clinically differentiated oligonucleotide platform (PRISM®) - Proprietary chemistry - Multi-modal (editing, silencing and splicing) • First-ever to unlock RNA editing- enabled by unique and proprietary capabilities • HD and DMD clinical
Slide 6: Three clinical updates in 2024 demonstrate continued translation
Three clinical updates in 2024 demonstrate continued translation Therapeutic Preclinical Clinical Clinical modalities publication translation trial results 53% exon skipping, 9.0% mean muscle-adjusted Proprietary PRISM platform Splicing (WVE-N531 for DMD) ✓ ✓ 42 µg/g muscle tissue concentrations in
Slide 7: The future of Wave: Leader in oligonucleotide therapeutics
The future of Wave: Leader in oligonucleotide therapeutics • Multiple late-stage clinical programs: - Potential for significant milestones and royalties from first-in-class RNA editing therapeutic for AATD - Opportunity for accelerated paths to registration for HD and DMD • Robust, differentiated em
Slide 8: Five GalNAc clinical programs expected in 2026
Five GalNAc clinical programs expected in 2026 2026 WVE-006 for AATD (GalNAc-AIMer) 2025 • Multidose data from AATD further derisking AIMer portfolio PNPLA3 (GalNAc-AIMer) WVE-006 for AATD • Dosing in obesity clinical trial • Synergies in cardiometabolic LDLR (GalNAc-AIMer) WVE-007 for Obesity indic
Slide 9: Poised for significant and sustained growth driven by GalNAc editing and siRNA
Poised for significant and sustained growth driven by GalNAc editing and siRNA GalNAc siRNA GalNAc Editing Obesity HD WVE-007 (INHBE) WVE-003 AATD SNP3 WVE-006 DMD WVE-N531 Exon 53 Add’l SNPs Add’l Exons Wave’s platform is translating in the clinic and has potential to treat >90M patients in the US
Slide 10: PRISM Platform: Best-in-Class Oligonucleotide Chemistry
PRISM Platform: Best-in-Class Oligonucleotide Chemistry Chandra Vargeese, PhD Chief Technology Officer 10
Slide 11: Building the best-in-class oligonucleotide platform
Building the best-in-class oligonucleotide platform Stereochemistry PN backbone, N3U and more Apply the principles of Expand medicinal Improve silencing, rational drug design chemistry splicing, and unlock editing Structure-activity Increased potency, From nucleases to relationships from single dura
Slide 12: Shared learning enables rapid, predictable and efficient clinical translation
Shared learning enables rapid, predictable and efficient clinical translation Platform Shared Across Intracellular delivery learning platform Tissue distribution Modalities Enzymes Complexes Within Editing Silencing Silencing Splicing modality ADARp110 Ago2 RNase H Spliceosome 12 Full list of Wave p
Slide 13: Wave's chemistry is a breakthrough for intracellular delivery
Wave’s chemistry is a breakthrough for intracellular delivery Addition of PN modification increases: 1. Cellular uptake 2. Endosomal release 3. Cellular residency 4. Nuclear uptake 5. Target engagement 13
Slide 14: PN modifications increase cellular uptake and endosomal release
PN modifications increase cellular uptake and endosomal release 1 Cellular Uptake 2 Endosomal Release PS PS/PN Released >2-fold increase in uptake after 5- ~4-fold increase in endosomal hour dose pulse release 14
Slide 15: PN modifications increase cellular residency, nuclear uptake and target engagement
PN modifications increase cellular residency, nuclear uptake and target engagement 3 Cellular Residency 4 Nuclear Uptake 5 Target Engagement ~2-fold increase in cellular ~5-fold increase in nuclear 30-fold increase in target residency uptake engagement 15
Slide 16: Directing silencing to high priority extrahepatic tissues
Directing silencing to high priority extrahepatic tissues Achieved by changes in physicochemical properties without requirement for LNP or other delivery agents GalNAc + PN Non-GalNAc + PN variants Liver Targeting Liver and Adipose Targeting Adipose Targeting Muscle Targeting (siRNA 1) (siRNA 2) (si
Slide 17: Directing editing across high priority extrahepatic tissues
Directing editing across high priority extrahepatic tissues Achieved by changes in physicochemical properties without requirement for LNP or other delivery agents Lung Adipose Heart Pancreas 1 x 100mpk IV 3 x 10mpk IV 60 60 30 25 Percent UGP2 Percent UGP2 20 Percent UGP2 Percent UGP2 40 Editing Edit
Slide 18: Potent and durable silencing across regions of the CNS
Potent and durable silencing across regions of the CNS Frontal Cortex Striatum Hippocampus Cerebellum Brain Stem Average PBS across regions 100 %mRNA remaining (SEM) 75 PBS (App/Hprt) Silencing 50 25 App siRNA 0 x m m s m rd o rte ia tu e llu m pu s te l co IHC staining Brown: App C r b a in a St e
Slide 19: Broad RNA editing in CNS observed following a single dose in mouse and NHP
Editing %Ugp2 mRNA Editing 0 20 40 60 80 C or H te ip x po ca m pu s St ria PBS tu m B ra in St em C er ICV injection eb el lu m AIMer Sp in al C or d %ACTB mRNA Editing 0 20 40 60 80 C or H te ip x po ca C m or pu pu s s C al aCSF lo su m B ra in St em IT delivery C er eb el lu m Sp in al co rd ACT
Slide 20: Unique and proprietary chemistry space to drive RNA editing
Wave has unique and proprietary chemistry space to drive potent, specific and durable RNA editing • Removal of any hairpin ADAR recruiting domain • Pioneered the use of fully modified short oligonucleotides for highly efficient RNA editing including in human • Proprietary base modifications (includi
Slide 21: Proprietary N3U chemistry substantially enhances AIMer editing efficiency
Proprietary N3U chemistry substantially enhances AIMer editing efficiency in a sequence independent manner Liver Enhanced RNA Editing hADAR-p110 micewith N3U Base 100 Proprietary Base Rational design of base, sugar and backbone modifications improves ADAR-mediated RNA editing ✱✱✱✱ editing mRNA editi
Slide 22: RNA editing can address an unmet need for nonsense mutation-induced diseases
RNA editing can address an unmet need for patients with nonsense mutation- induced diseases Protein Restoration with RNA Editing Rett Syndrome → MECP2 Protein aa STOP aa Trp aa • Female-dominant neurodevelopmental disorder affecting walking, talking, breathing and mRNA xxx UGA xxx xxx UGG xxx intell
Slide 23: MECP2 RNA editing and protein rescue detected in vivo
MECP2 RNA editing and protein rescue detected in vivo 6 weeks post single neonatal ICV injection Cortex Brain Stem Hippocampus MECP2 RNA Editing MECP2R168X ADAR-P110 WT AIMer PBS PBS PBS AIMer 1 ✱✱✱ 2000 MECP2 Mecp2-positive cells/ mm2 ✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ 1500 Protein 1000 Rescue 500 0 ha s
Slide 24: AIMer treatment in bronchial epithelial cells produces up to 75% editing
AIMer treatment in bronchial epithelial cells produces up to 75% editing, translating to a 50% recovery of wild-type CFTR protein 75% W1282X editing in 3-fold increase in CFTR 50% recovery of wild-type human bronchial epithelial transcript expression CFTR protein cells (gymnotic delivery) Relative C
Slide 25: Spotlight: WVE-003: Allele-Selective Treatment for Huntington's Disease
Spotlight: WVE-003: Allele-Selective Treatment for Huntington’s Disease 25
Slide 26: WVE-003: First-in-class allele-selective oligonucleotide
WVE-003: First-in-class allele-selective oligonucleotide, enabled by Wave’s unique and proprietary chemistry WVE-003 suppresses mHTT protein expression Recruit by promoting degradation of the transcript RNase H SNP3 mHTT transcript Expanded CAG repeat mHTT allele ‘003 Transcript degradation Reduced
Slide 27: SELECT-HD results: allele-selective mHTT reduction and slowing of caudate atrophy
SELECT-HD results: WVE-003 led to allele-selective mHTT reduction, correlating with slowing of caudate atrophy Allele-Selective mHTT Slowing of Caudate KD with wtHTT Functional Benefit Atrophy Preservation • mHTT reduction of up to • WVE-003 trended towards • Caudate atrophy is an 46% vs. placebo le
Slide 28: Guest speaker: Jeffrey D. Long, PhD
Guest speaker: Jeffrey D. Long, PhD Professor of Psychiatry & Biostatistics at the University of Iowa • Dr. Long is Professor in the departments of Psychiatry and Biostatistics at the University of Iowa and works primarily in Huntington’s disease (HD). • He is the co-chair of the C-PATH HD Regulator
Slide 29: Caudate Volume and Clinical Trials in Huntington's Disease
Caudate Volume and Clinical Trials in Huntington’s Disease JEFFREY D. LONG, PHD PROFESSOR, PSYCHIATRY AND BIOSTATISTICS, UNIVERSITY OF IOWA Wave Research Day, October 30, 2024 CHANGING MEDICINE. CHANGING LIVES.®
Slide 30: Overview
Overview • Why consider caudate volume in HD clinical trials? • Sample size considerations • Caudate volume and the prediction of clinical variables • Tutorial • Ongoing research 30
Slide 31: Why Consider Caudate Volume?
Why Consider Caudate Volume? • (1) HD-specific biomarker • HD is caused by a CAG expansion on HTT gene • Loss of medium spiny neurons in the striatum • (2) Enables earlier clinical trials • (3) Enables smaller clinical trials • Due to favorable characteristics 31
Slide 32: Regularity of Caudate Change
Regularity of Caudate Change • HD-ISS Stage 2 Caudate Volume cUHDRS • Image-HD • Predict-HD • Track- HD/ON • Enroll-HD (PDS6) 32
Slide 33: Required Sample Size
Required Sample Size • HD-ISS Stage 2 inclusion • Standard 2-year randomized controlled trial (2 arms) Caudate Volume Caudate cUHDR cUHDRS Volume S 33
Slide 34: Caudate Volume & Clinical Variables
Caudate Volume & Clinical Variables • Regulators: does caudate volume predict clinical change? • Time precedence is important (caudate → clinical change) • HD-ISS based on associations in the extent HD literature • Prediction analysis (in collaboration with Jim Mills, University of Iowa) • Use earli
Slide 35: Tutorial Slides
Tutorial Slides • Earlier caudate volume predicting later functioning • Level of caudate volume • Rate of atrophy • Total Functional Capacity (TFC) • TFC = 13 is normal functioning • TFC < 13 is functional loss • First loss in TFC • Job modification: some change in occupation due to disease • Consid
Slide 36: Caudate Change and TFC Loss
Caudate Change and TFC Loss Normal functioning (TFC = 13 during this period) Risk of functional loss (TFC < 13) Probability of preserving Prob of Preserving Functioning functioning (with 95% CI) After 5th year is when TFC starts to decrease for at least one patient Imagine a cohort of After 3 years
Slide 37: Comparing Caudate Profiles
Comparing Caudate Profiles 80% with normal functioning Worse Profile Better Profile Prob of Preserving Functioning Prob of Preserving Functioning Higher level & Lower level & slower decline faster decline 40% with normal functioning Year on Study Year on Study 37
Slide 38: Efficacy Trial: Delay functional loss
TFC = 13 TFC < 13 Efficacy Trial Delay functional loss 80% normal functioning at 8y Recruit a cohort Prob of Preserving Functioning with a relatively fast rate of atrophy Slow down 40% normal functioning at 8y caudate atrophy Year on Study 38
Slide 39: Ongoing Research
Ongoing Research • Determine how much slowing in caudate atrophy is required for a meaningful delay in HD onset • Clinical meaningfulness • Delay functioning loss by 1 year, for example • Define the treatment effect • 1 year delay in functioning loss requires 40% slowing of caudate atrophy, for exam
Slide 40: Spotlight: WVE-007: GalNAc-siRNA for obesity
Spotlight: WVE-007: GalNAc-siRNA for obesity 40
Slide 41: Guest speaker: Mehmet Furkan Burak, MD
Guest speaker: Mehmet Furkan Burak, MD Instructor in Medicine, Harvard Medical School & Endocrinologist and Obesity Specialist, Brigham and Women’s Hospital • Dr. Burak is an endocrinologist and faculty member, leading translational immunometabolism research group at Brigham and Women’s Hospital / H
Slide 42: Paradigm Shift in Obesity Treatment
Paradigm Shift in Obesity Treatment Dr. Mehmet Furkan Burak Division of Endocrinology, Diabetes and Hypertension Brigham and Women’s Hospital Harvard Medical School Department of Molecular Metabolism Harvard T.H. Chan School of Public Health
Slide 43: Obesity and Dysmetabolism
Obesity and Dysmetabolism Prevalence of Overall Obesity (BMI ≥ 30) Hotamisligil et al. Nature, 2006 Ward et al. N Engl J Med, 2019
Slide 44: History, Revolution of the Biologics!
History, Revolution of the Biologics! Courtesy of Caroline Apovian, modified
Slide 45: Energy Regulation and Current Anti-Obesity Medications
Energy Regulation and Current Anti-Obesity Medications Lipid spillover Modified from Rosen et al. Cell, 2014 Adipogenic peripheral pathways become pathological in obesity -INHBE -GPR75 -Myostatin (GDF8), ALK7 Burak et al. 2023. Handbook of Obesity – Volume 2: Clinical Applications (5th ed.) CRC Pres
Slide 46: Energy Regulation and Current Anti-Obesity Medications
Energy Regulation and Current Anti-Obesity Medications Lipid spillover Modified from Rosen et al. Cell, 2014 Lipolysis Adipogenic peripheral pathways become pathological in obesity Inhibition of these pathways would be beneficial with switching back to more lipolysis and less muscle breakdown -INHBE
Slide 47: GLP-1 Agonists: Pros
GLP-1 Agonists: Pros -14.9% -21.1% Semaglutide Tirzepatide ▪ Paradigm shift in obesity treatment ▪ The efficacy of weight loss medications Wilding et al. NEJM, 2021 Wadden et al. Nat Med, 2023 is closing the gap with bariatric surgery ▪ Cardiovascular benefits Lincoff et al. NEJM, 2023
Slide 48: GLP-1 Agonists: Cons
GLP-1 Agonists: Cons ▪ Despite high obesity rate, only 2- 3% is getting obesity treatment ▪ Discontinuation is high, only ~35% +60% +70% continues treatment over 1 year ▪ Decrease in energy expenditure ▪ Weight regain after discontinuation Wilding et al. Diabetes Obes Metab, 2022 ▪ GI side effects,
Slide 49: Current Unmet Needs in Era of GLP-1 Agonists
Current Unmet Needs in Era of GLP-1 Agonists Oral form of medications & Access to medications convenient dosing for chronic treatment Novel biological MoA for GLP-1 intolerant patients, Prevention of muscle mass loss Gentle drugs for maintenance and weight regain Higher efficacy drug combinations, N
Slide 50: WVE-007: A Novel Obesity Therapeutic for Healthy, Sustainable Weight Loss
WVE-007: A Novel Obesity Therapeutic for Healthy, Sustainable Weight Loss Ginnie Yang, PhD SVP, Translational Medicine 50
Slide 51: Human genetic data show INHBE carriers have a healthy metabolic profile
Human genetic data demonstrate that INHBE heterozygous carriers have a healthy metabolic profile Heterozygous INHBE LoF carriers have favorable traits: Heterozygous INHBE LoF carriers have lower risk of Type 2 lower abdominal obesity, lower triglycerides, higher HDL-c diabetes and CHD Silencing INHB
Slide 52: Role of INHBE in obesity associated metabolic diseases
Role of INHBE in the pathogenesis of obesity associated metabolic diseases and how INHBE GalNAc-siRNA would address these health issues Release of dimerized INHBE Binds to and activates subunits creates hepatokine ACVR1C (ALK7) receptor in Block adipose Activin E adipose tissue lipolysis Activin E A
Slide 53: ~43% decrease of adipocyte size with INHBE siRNA treatment
Significant ~43% decrease of adipocyte size in mesenteric adipose tissues with INHBE siRNA treatment *** 43% 100% Mesenteric PBS DIO Day28 0% (baseline) INHBE siRNA DIO Day28 Lean Control Supports peripheral mechanism of WVE-007 – distinct from GLP-1s with central mechanism 53 10 m/kg INHBE siRNA, S
Slide 54: Potent and sustained change in body weight with a single dose
Potent and sustained change in body weight up to 12 weeks with a single dose of INHBE GalNAc-siRNA, supporting 1-2x a year dosing Potent knockdown of INHBE Potent and durable effect on Sustained reductions of mRNA with a single dose body weight mesenteric fat mass at 12 weeks PBS INHBE GalNAc-siRNA
Slide 55: Single doses result in dose-dependent weight loss and visceral fat reduction
Single doses of INHBE GalNAc-siRNA result in dose-dependent weight loss and reduction of visceral fat, without affecting muscle mass ✓ Reduction in body weight ✓ Reduction in visceral fat ✓ No muscle loss Epididymal fat weight (Day 28) Quadricep weight (Day 28) PBS * INHBE GalNAc-siRNA (3 mg/kg) INH
Slide 56: INHBE GalNAc-siRNA added to GLP-1 drives synergistic weight loss
Single dose INHBE GalNAc-siRNA added to daily GLP-1 drives a synergistic effect on weight loss, resulting in ~2x greater overall weight loss Control for Semaglutide Control for siRNA Semaglutide INHBE GalNAc-siRNA Semaglutide + INHBE GalNAc-siRNA * ~2x greater weight loss * * * * * Daily GLP-1 Add-o
Slide 57: Adding INHBE siRNA prevents weight regain after GLP-1 cessation
Adding INHBE siRNA to GLP-1 treatment course prevents weight regain after the cessation of GLP-1 Weight Change 5 DIO Mice (% of PBS, same time point) Difference in body weight 0 PBS Semaglutide p<0.05 Semaglutide + INHBE GalNAc-siRNA -5 Not -10 significant Treatment period -15 0 20 40 60 Maintenance
Slide 58: Preclinical data support best-in-class profile of WVE-007
Preclinical data support best-in-class profile and potential to use WVE-007 across multiple treatment settings with 1-2x a year dosing ✓ Monotherapy: as a single agent. Weight loss similar to semaglutide with no loss of muscle mass and a reduction in fat mass with preferential effect to the visceral
Slide 59: CTA expected before year-end for Phase 1 trial of WVE-007
CTA expected before year-end for Phase 1 trial of WVE-007 in adults living with overweight or obesity, otherwise healthy Randomized, double-blind, placebo-controlled study of ascending doses of WVE-007 MAD Cohort 3 Trial Design SAD Cohort 5 • Objective: Assess dose safety, tolerability, PK and PD MA
Slide 60: Spotlight: WVE-006: First-ever RNA Editor
Spotlight: WVE-006: First-ever RNA Editor Unlocking New Wholly Owned Programs Erik Ingelsson, MD, PhD Chief Scientific Officer 60
Slide 61: WVE-006: GalNAc-conjugated AIMer designed to correct mutant SERPINA1 transcript
WVE-006: GalNAc-conjugated AIMer designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD Wild-type WVE-006 for AATD M-AAT protein A Healthy SERPINA1 Z allele mRNA encodes Z-AAT protein with E342K mutation AAT is an acute phase protein Serum AAT protects l
Slide 62: RestorAATion-1 and RestorAATion-2 ongoing
RestorAATion-1 and RestorAATion-2 ongoing RestorAATion-1: HealthyHealthy RestorAATion-1: Volunteers Volunteers RestorAATion-2: AATD Patients Single ascending dose (SAD) → Multiple-ascending dose (MAD) cohorts Multidosing Dose E ongoing in Dose E Up to 7 doses Dose D Cohort 3 Dose C Cohort 2 Dose B C
Slide 63: WVE-006 has been well-tolerated with a favorable safety profile
WVE-006 has been well-tolerated with a favorable safety profile to date RestorAATion-1: HealthyHealthy RestorAATion-1: Volunteers Volunteers RestorAATion-2: AATD Patients RestorAATion-1: Healthy Volunteers Single ascending dose (SAD) → Multiple-ascending dose (MAD) cohorts • WVE-006 has been well-to
Slide 64: Achieved proof-of-mechanism for Wave's RNA editing platform
Achieved proof-of-mechanism for Wave’s RNA editing platform First two patients among first dose cohort in RestorAATion-2 with “ZZ” AATD (Pi*ZZ AATD) to reach day 57: • Circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT •
Slide 65: AATD market estimated to grow to ~$3B by 2030
AATD market estimated to grow to ~$3B by 2030 Global AATD Market Value ($, Billions) AATD Market Overview (2023 – 2030)1 • AATD market today is estimated at ~$1.5B worldwide1 $3.5 despite limitations of current treatment $3.2B - Market consists entirely of plasma-derived $3.0 augmentation therapy fo
Slide 66: Building the pipeline: New programs informed by human genetics
Building the pipeline: New programs informed by human genetics 66
Slide 67: Wave is uniquely positioned to leverage human genetics
Wave is uniquely positioned to develop first- and best-in-class therapies that leverage growing insight in human genetics Unique chemistry required Genetic rationale instrumental to address untapped targets in drug development and mechanisms ✓ Strong foundation in human genetics First or best-in cla
Slide 68: Human genetics dramatically increases probability of success in drug development
Human genetics dramatically increases probability of success in drug development and can accelerate development of new medicines Evidence from human genetics increases probability of 50 approved medicines driven by human genetics successful drug development at least 2x Fold probability of success Wa
Slide 69: Wave's AI-driven approach to pipeline growth, quality & sustainability
Wave’s AI-driven approach to pipeline growth, quality & sustainability Target • Leverage genetic evidence Discovery through UK Biobank collaboration and public data resources • Insight synthesis using LLMs and retrieval augmented generation Selection, Mechanism prioritization of action & & tracking
Slide 70: Introducing new, wholly-owned GalNAc-AIMer programs
Introducing new, wholly-owned GalNAc-AIMer programs New targets meet key criteria, expected to improve probability of success: Correction of PNPLA3 Genetically defined liver disease ✓ Strongly supported by human genetics ✓ Leverage unique platform capabilities; GalNAc-AIMers building on learnings of
Slide 71: Homozygous PNPLA3 I148M are at high-risk for liver diseases
Homozygous PNPLA3 I148M are at high-risk for liver diseases Over 9 million homozygous PNPLA3-I148M patients who are predisposed to liver diseases in US and Europe Homozygous PNPLA3-I148M patients Heterozygous I148M patients have lower risk of liver diseases and a >5- have significantly higher risk o
Slide 72: Functional PNPLA3 is imperative for liver health
Functional PNPLA3 is imperative for liver health beyond improvements in steatosis Knockout (KO) of PNPLA3 in normal liver may worsen basal physiological functions, i.e. steatosis or inflammation-induced cell death Multiple histological endpoints Silencing PNPLA3 worsens Silencing PNPLA3 increases of
Slide 73: AIMers achieve efficient editing of PNPLA3, leading to reduction of liver fat
AIMers achieve efficient editing of PNPLA3, leading to reduction of liver fat Potent editing of PNPLA3 in homozygous Significant decrease in liver fat with PNPLA3 editing in human HEPATOPAC® I148M human primary hepatocytes with homozygous I148M EC50 = 15nM EC50 = 16nM **** AIMer 73 Significant reduc
Slide 74: PNPLA3 I148M AIMer candidate selection expected in 2025
PNPLA3 I148M AIMer candidate selection expected in 2025 • PNPLA3 preclinical data demonstrates ability to restore functional PNPLA3, decreasing lipid uptake for improvement of liver health • In vivo studies ongoing to support candidate selection in 2025 • Clinical development planning underway for a
Slide 75: GalNAc-AIMer LDLR and APOB: Heterozygous familial hypercholesterolemia
GalNAc-AIMer LDLR (upregulation) GalNAc-AIMer APOB (correction) Heterozygous familial hypercholesterolemia 75
Slide 76: AIMer editing unlocks opportunity for best-in-class LDL-c lowering
AIMer editing unlocks opportunity to deliver best-in-class LDL-c lowering with first-in-class LDLR and APOB RNA editing approaches High unmet need remains for effective LDL-c AIMer editing to enhance clearance and lower lowering therapies LDL-c through two different approaches • Cardiovascular disea
Slide 77: Initial focus on HeFH with expansion opportunities for LDLR upregulation
Initially focused on comprehensive treatment approach for HeFH, with multiple potential opportunities for expansion with LDLR upregulation Lead Indication Potential Expansion Opportunities for LDLR HeFH with CAD Statin-Intolerant Population ASCVD Population ~900K HeFH individuals in the Estimate 10M
Slide 78: Opportunity to directly upregulate LDLR with AIMers
Opportunity to directly upregulate LDLR with AIMers to bring majority of HeFH patients to goal LDLR-AIMer Proportion HeFH (LDLR) patients achieving goal LDL-c levels I(G) 90% Edited LDLR mRNA ~50% Editing yields stable mRNA leading to 6% ~0% increased LDLR production Untreated High Intensity Max the
Slide 79: ~2.5-fold upregulation of LDLR protein exceeds target threshold
~2.5-fold upregulation of LDLR protein exceeds target threshold Up to 70% LDLR mRNA editing in ~2.5x increase LDLR protein in ~4-fold increase LDL-c uptake to primary human hepatocytes primary human hepatocytes hepatocytes by AIMers 100 2500 **** LDLc Positive Pixels2/Cell 8000 % LDLR mRNA Editing *
Slide 80: Correction of APOB point mutation with AIMer editing
Correction of APOB point mutation with AIMer editing to address genetically-defined subset of familial hypercholesterolemia patients APOB AIMer for HeFH APOB editing approach A LDL-c LDL-c APOB R3527Q WT APOB APOB mRNA with R3527Q mutation LDLR Edit mutant APOB Hepatocyte APOB mutation Restoring WT
Slide 81: Increasing wild type APOB from 50% to 75% expected to provide benefit
Increasing amount of wild type APOB from 50% in heterozygous patients to 75% is expected to provide therapeutic benefit Restoration of wild-type APOB in APOB R3527Q+/- iPSC-derived hepatocytes Mock ApoB AIMer 1 ApoB AIMer 2 50 60 70 80 90 100 Note: Due to heterozygous genotype, Y-axis ranges from %
Slide 82: Potent in vivo editing supports benefit to FH patients
Potent editing in vivo support potential to provide therapeutic benefit to FH patients Potent in vivo editing with GalNAc-AIMers 60 • ~50% in vivo editing in transgenic mouse model expressing human ApoB, which would translate % ApoB Surrogate (Mean ± SEM) to ~75% circulating functional protein in Si
Slide 83: LDLR and APOB clinical candidates expected in 2025
LDLR and APOB clinical candidates expected in 2025 • LDLR and APOB are first-in-class approaches to achieve best-in-class LDL-c lowering • HeFH patients offer a genetically-defined population to address a high unmet need with AIMers and represent ~1M patients in US and Europe • In vivo studies under
Slide 84: Closing remarks
Closing remarks Paul Bolno, MD, MBA President and CEO 84
Slide 85: Wave is reimagining RNA medicines
Wave is reimagining RNA medicines ✓ Best-in-class, clinically validated platform: Breakthroughs in oligonucleotide chemistry with shared learnings that enable rapid and predictable clinical translation ✓ Clinical programs with potential paths to accelerated approval: Caudate atrophy is a promising b
Slide 86: Robust, diversified RNA medicines pipeline
Robust, diversified RNA medicines pipeline including first-in-class RNA editing programs IND / CTA Enabling Patient population Program Discovery Clinical Rights Studies (US & Europe) RNA EDITING WVE-006 GSK exclusive RestorAATion Clinical Program 200K SERPINA1 (AATD) global license GalNAc-AIMer 100%
Slide 87: Poised for significant and sustained growth driven by editing and siRNA
Poised for significant and sustained growth driven by editing and siRNA GalNAc-siRNA GalNAc-Editing Obesity HD WVE-007 (INHBE) WVE-003 AATD SNP3 WVE-006 PNPLA3 DMD WVE-N531 Exon 53 LDLR & APOB Add’l SNPs Add’l Exons Wave’s platform is translating in the clinic and has potential to treat >90M patient
Slide 88: Q&A
Q&A Paul Bolno, MD, MBA Erik Ingelsson, MD, PhD Chandra Vargeese, PhD President and CEO Chief Scientific Officer Chief Technology Officer Ginnie Yang, PhD Mehmet Furkan Burak, MD Anne-Marie Li-Kwai-Cheung, Senior Vice President, Instructor in Medicine, Harvard MChem, MTOPRA, RAPS Translational Medic
Slide 89: InvestorRelations@wavelifesci.com
InvestorRelations@wavelifesci.com