WVE 8-K
Wave Life Sciences, Inc. (WVE)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form
CURRENT REPORT
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| Item 7.01 | Regulation FD Disclosure. |
From time to time, Wave Life Sciences Ltd. (the “Company”) presents and/or distributes slides and presentations to the investment community to provide updates and summaries of its business. On January 13, 2025, the Company updated its corporate presentation, which is available on the “For Investors & Media” section of the Company’s website at http://ir.wavelifesciences.com/. This presentation is also furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information in this Item 7.01 and exhibit 99.1 attached hereto is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that Section, nor shall it be deemed incorporated by reference into any registration statement or other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
| Item 9.01 | Financial Statements and Exhibits. |
| (d) | Exhibits. |
The following exhibit relating to Item 7.01 is furnished and not filed:
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| 99.1 | Corporate Presentation of Wave Life Sciences Ltd. dated January 13, 2025 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| WAVE LIFE SCIENCES LTD. | ||
| By: | /s/ Kyle Moran | |
| Kyle Moran | ||
| Chief Financial Officer | ||
Date: January 13, 2025
Exhibit 99.1 Wave Life Sciences Corporate Presentation January 13, 2025
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, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of Wave Life Sciences Ltd. (the “Company”) to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “aim,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions. The forward- looking statements in this presentation are only predictions. The Company has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company’s business, financial condition and results of operations. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company’s Form 10-K and other filings with the SEC, some of which cannot be predicted or quantified and some of which are beyond the Company’s control. The events and circumstances reflected in the Company’s forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. 2
Our Mission To unlock the broad potential of RNA medicines to transform human health 3
2024 was a year of breakthroughs Achieved first-ever RNA editing in humans, advancing best-in-class treatment for AATD Pioneering RNA editing Expanded GalNAc-AIMer pipeline: unveiled three new wholly owned RNA editing programs targeting PNPLA3, LDLR, APOB Selected and advanced INHBE GalNAc-siRNA clinical candidate, a novel, long acting, muscle sparing approach for obesity grounded in human genetics Innovating in obesity Submitted CTA for Phase 1 INLIGHT clinical trial of WVE-007 Achieved first allele-selective mutant huntingtin silencing, wild-type sparing in clinic with WVE-003 for Huntington’s disease Advancing best-in-class treatments for HD and DMD Delivered positive interim DMD clinical data for WVE-N531 with highly consistent, mean muscle content-adjusted dystrophin expression of 9% Unlocking potential of Demonstrated proprietary PN breakthroughs for intracellular delivery and ability to silence and edit preclinically in high priority extra-hepatic tissues, including CNS PRISM platform Expect to continue momentum with multiple data updates in 2025 and beyond 4 AATD: Alpha-1 antitrypsin deficiency HD: Huntington’s disease DMD: Duchenne muscular dystrophy CTA: clinical trial application CNS: Central nervous system
The powerful convergence of a validated, best-in-class platform with genetics • Multi-modal: RNA editing, RNAi, • Real-time integration of new human antisense, splicing genetic insights into discovery • Best positioned to engage • Proprietary deep learning models Unmatched Data-driven endogenous machinery unveiling novel targets/ toolkit to discovery target sites • Unlocking new, high-impact access novel powered by therapeutic targets • Accelerating time to clinic biology human genetics • Breakthroughs in intracellular delivery • Step-change in potency, distribution, Foundation in durability of effect chemistry innovation • No complex delivery vehicles (AAV, LNP) 5
Differentiated RNA medicines clinical pipeline WVE-007 in Obesity WVE-006 in AATD WVE-N531 in DMD WVE-003 in HD GalNAc-siRNA GalNAc-RNA editing Exon 53 splicing Allele-selective targeting INHBE oligonucleotide oligonucleotide oligonucleotide Multiple CTAs submitted since RestorAATion-2 ongoing in FORWARD-53 trial ongoing; Planning underway for mid-December 2024; proof-of- Pi*ZZ AATD patients; multidose expect feedback from regulators potentially registrational concept clinical data expected data expected in 2025 and 48-week FORWARD-53 data Phase 2/3 study; IND in 2025 in 1Q 2025 submission expected 2H 2025 ~175M people ~2,300 boys with DMD ~85K HD SNP3 patients ~200K patients with AATD living with obesity amenable to exon 53 skipping across all disease stages 6 Patient populations represent US and Europe; WVE-006 is partnered with GSK AATD: Alpha-1 antitrypsin deficiency DMD: Duchenne muscular dystrophy HD: Huntington’s disease
Advancing WVE-007 as a novel, long acting, muscle sparing approach for obesity WVE-007 is a GalNAc-conjugated small interfering RNA (GalNAc-siRNA) that targets INHBE to treat obesity • Adults with obesity have higher risk for many serious health conditions, including heart disease, type 2 1 diabetes, and some forms of cancer • GLP-1s are current standard of care for weight loss, but impact is often limited by: 2 • Loss of muscle mass 3 • Poor tolerability 4 • Frequent dosing 5,6 • High discontinuation rates ~175 million adults with obesity in US and Europe 7 1. CDC.gov; 2. Sargeant, et al. 2019 Endocrinol Metab (Seoul) 34, 247; 3. Ghusn and Hurtado. 2024 Obesity Pillars 12, 100127; 4. Wegovy PI; 5. Leach, et al. 2023 Prime Therapeutics Claims Analysis; 6. Gasoyan, et al. 2024 Obesity (Silver Spring) 32, 486.
Human genetic data demonstrate that heterozygous INHBE LoF 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 INHBE mRNA by ≥50% is expected to recapitulate the healthy metabolic profile of heterozygous INHBE loss of function (LoF) carriers 8 Akbari et al. Nat Commun. 2022 Aug 23;13(1):4844; Deaton et al. Nat Commun. 2022 Jul 27
INHBE GalNAc-RNA expected to address health issues associated with pathogenesis of obesity, associated metabolic disease Reduced release of Diminished activation of Increased adipose GalNAc-siRNA ACVR1C (ALK7) receptor in lipolysis and shrink hepatokine Activin E adipose tissue adipocytes Decreased abdominal adiposity leads to weight loss and reduced risk for CVD and T2D 9 1. Cell Reports (2018) 25, 1193–1203; 2. Biochemical Journal (2024) 481 547–564; 3. PNAS 2023 Vol. 120 No. 32 e2309967120; 4. Nat Commun 2022. https://doi.org/10.1038/s41467- 022-32398-7; 5. Nat Commun 2022. https://doi.org/10.1038/s41467-022-31757-8
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 ✓ ✓ ✓ Quadricep weight (Day 28) Epididymal fat weight (Day 28) * PBS INHBE GalNAc-siRNA (3 mg/kg) INHBE GalNAc-siRNA (10 mg/kg) -23% -40% * * * * * * Single dose INHBE GalNAc-siRNA INHBE GalNAc-siRNA has potential as monotherapy weight loss therapeutic 10 Stats: (left, middle, right) Linear Mixed Effects ANOVA with post hoc comparisons of marginal treatment effects vs. PBS per timepoint (left) or per tissue (middle, right) * p < 0.05
INHBE GalNAc-siRNA can be used synergistically with GLP-1s or to prevent weight regain after the cessation of treatment with GLP-1s ~2x greater overall weight loss when added to Prevents weight regain after the cessation of GLP-1s ✓ ✓ GLP-1s p<0.05 ~2x greater weight loss Not significant Day Day Single dose INHBE GalNAc-siRNA Daily GLP-1 PBS Daily GLP-1 Semaglutide Semaglutide Control for Semaglutide INHBE GalNAc-siRNA Dose INHBE GalNAc-siRNA Semaglutide + Control for siRNA Semaglutide + INHBE GalNAc-siRNA INHBE GalNAc-siRNA 11 Left: 10nmol/kg in mouse is equivalent to therapeutic dose of GLP-1s in human. Stats: Linear Mixed Effects ANOVA with post hoc comparisons of marginal treatment effects of Semaglutide vs. Semaglutide + INHBE GalNAc-siRNA per time point * p < 0.05; Right Stats: Linear Mixed Effects ANOVA with post hoc comparison of Day 28 vs. Day 56 marginal effects per treatment * p < 0.05 Difference in body weight (% of PBS, same time point)
Preclinical data support best-in-class profile and potential to use WVE-007 across multiple treatment settings with 1-2x a year dosing Monotherapy Add-on to GLP-1s Maintenance WVE-007 in addition to GLP-1 WVE-007 for patients who stop WVE-007 as a single agent therapy treatment with GLP-1 therapy ✓ Weight loss similar to semaglutide with a single When administered as an add- ✓ Curtailed rebound weight dose on with semaglutide: gain upon cessation of ✓ No loss of muscle mass semaglutide ✓ A single dose of Wave’s ✓ Reduction in fat mass with ✓ Prevention of weight INHBE GalNAc-siRNA preferential effect to the cycling, which worsens the doubled the weight loss visceral fat outcomes of various observed with semaglutide metabolic diseases ✓ Without suppressing food alone intake 12
INLIGHT: 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 Trial Design SAD Cohort 5 • Objective: Assess dose safety, MAD Cohort 3 tolerability, PK and PD SAD Cohort 4 • Key measurements MAD Cohort 2 - Primary: Safety and Tolerability - Secondary: PK, Activin E SAD Cohort 3 - Exploratory PD: MAD Cohort 1 • Body weight • Body composition SAD Cohort 2 • Metabolic health • Biochemical markers SAD Cohort 1 Expect to initiate dosing in INLIGHT in 1Q 2025; proof-of-concept clinical data expected in 2025 13
Advancing WVE-006 (RNA editing) in AATD WVE-006: GalNAc-conjugated, subcutaneously delivered, designed to address AATD-related lung disease, liver disease, or both • AATD is a rare, inherited genetic disorder that is commonly caused by a G-to-A point mutation in the SERPINA1 gene • Characterized by aggregation of mutant Z-AAT protein in hepatocytes and a lack of functional AAT in lungs • People with AATD typically exhibit progressive lung damage, liver damage, or both • Weekly intravenous augmentation therapy is the only treatment option for AATD in those with the lung pathology • No approved therapies to address AATD liver disease ~200K people in the US and Europe are homozygous for the Z allele 14 Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al. 2017 Int J Chron Obstruct Pulmon Dis 12:561-69
WVE-006 to address both liver and lung manifestations of AATD WVE-006 RNA WVE-006 ADAR editing approach to address editing treatment key goals of AATD treatment: Restore circulating, Reduce Z-AAT Retain M-AAT Subcutaneous 1 2 3 functional wild-type protein aggregation physiological injection M-AAT in liver regulation (GalNAc) Infrequent dosing Z-AAT Highly specific A → I (no M-AAT reaches lungs to RNA correction replaces M-AAT secretion into bystanders) protect from proteases mutant Z-AAT protein with bloodstream wild-type M-AAT protein 15 Strnad et al., 2020 N Engl J Med 382:1443-55; Stoller et al., 1993 Alpha-1 Antitrypsin Deficiency GeneReviews.
RestorAATion-2 clinical trial in Pi*ZZ AATD patients ongoing RestorAATion-2: AATD Patients RestorAATion-1: Healthy Volunteers RestorAATion-1: Healthy Volunteers Single ascending dose (SAD) → Multiple-ascending dose (MAD) cohorts Multi-dosing complete Dose E in RestorAAtion-1 Up to 7 doses Dose D Cohort 3 Dose C Cohort 2 Dose B Cohort 1 200 mg Dose A Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels 16 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose
Achieved proof-of-mechanism for Wave’s RNA editing platform Proof-of-mechanism achieved after a single dose in RestorAATion-2 ✓ Total AAT protein increased to a mean of 10.8 µM at day 15 ✓ Meets level that has been the basis for regulatory approval for AAT augmentation therapies ✓ Circulating wild-type M-AAT protein reached a mean of 6.9 µM at day 15; more than 60% of total AAT ✓ Increases in total AAT from baseline and M-AAT protein were observed as early as day 3 and through day 57 ✓ Increases in neutrophil elastase inhibition from baseline were consistent with production of functional M- AAT ✓ WVE-006 well tolerated with a favorable safety profile; all AEs mild-to-moderate, no SAEs Multidose data from RestorAATion-2 expected in 2025 17 October 16, 2024 Proof-of-mechanism disclosure on first two “ZZ” AATD patients in first dose cohort of RestorAATion-2 to reach day 57
Wholly owned GalNAc-AIMer programs Correction of PNPLA3 Strongly supported by human genetics Genetically defined liver disease ✓ Patient population: ~9 million Leverage unique platform capabilities; GalNAc-AIMers building on learnings ✓ Upregulation of LDLR of WVE-006 HeFH Patient population: ~900,000, with Completely novel ways of treating expansion to ~30 million in follow on indications ✓ diseases with high unmet need Readily accessible biomarkers and Correction of APOB approaches to assess PD, defined ✓ HeFH regulatory paths Patient population: ~70,000 Expect to initiate clinical development of additional RNA editing programs, including PNPLA3, LDLR, and APOB programs in 2026 18 Patient populations are in US and Europe Editing for correction Editing for upregulation HeFH: heterozygous familial hypercholesterolemia
Advancing WVE-N531 in exon 53 amenable DMD WVE-N531: exon skipping oligonucleotide designed to induce production of endogenous, functional dystrophin protein • High unmet need for therapies delivering more consistent dystrophin expression, as few patients today achieve dystrophin >5% of normal • Opportunity to extend dosing intervals beyond weekly standard of care to alleviate burden for patients and caregivers • Need to reach stem cells and distribute broadly to muscle tissues to potentially enable muscle regeneration and impact respiratory and cardiac function • WVE-N531 has Rare Pediatric Disease Designation and Orphan Drug Designation from FDA DMD impacts ~1 / 5,000 newborn boys annually; ~20,000 new cases annually worldwide 19 Duan, D. et al. 2021 Nat Rev Dis Primers 7, 13; Muscular Dystrophy Association; Aartsma-Rus, et al. 2009 Hum Mutat 30, 293.
FORWARD-53: An ongoing potentially registrational open-label Phase 2 clinical trial of WVE-N531 in boys with DMD amenable to exon 53 skipping 10 mg/kg Q2W 10 mg/kg Q4W Screening N = 11 Extension ✓ Interim analysis • Baseline functional • Muscle biopsy after 24 • Muscle biopsy after 48 assessments weeks of treatment weeks of treatment • Functional assessments • Functional assessments Key Assessments: • Safety and tolerability • Muscle biopsies after 24 and 48 weeks of treatment - PK: Drug tissue concentrations - PD: Exon-skipping, Dystrophin level (% of normal) as assessed by Western Blot • Functional outcome measures • 11 participants enrolled, including two from prior Part A clinical trial - Pre-specified analyses in ambulatory patients 20 IV: Intravenous; Q2W: Every 2 Weeks; PK: Pharmacokinetics; PD: Pharmacodynamics
WVE-N531 is the only DMD therapeutic to show uptake in myogenic stem cells WVE-N531 uptake in myofiber nuclei WVE-N531 uptake in myogenic stem cells Myocytes Stars denote an injured myofiber Stem cell containing WVE-N531 Mag: 40x Mag: 20x Myocyte nuclei containing WVE-N531 (red) Mag: 20x Mag: 40x Dual staining utilizing in-situ hybridization for WVE-N531 and PAX7 In-situ hybridization for WVE-N531 immunohistochemistry for stem cells 21 Data from interim analysis clinical results announced September 24, 2024.
Results of interim analysis: WVE-N531 has potential to be the best-in-class therapeutic for DMD amenable to exon 53 skipping Best-in-class dystrophin Evidence supporting Safe and expression and muscle delivery improved muscle health well tolerated • Highly consistent, mean muscle • Improvement in serum biomarkers • No serious adverse events (SAEs) content-adjusted dystrophin for muscle health • No discontinuations expression of 9% • Localization of WVE-N531 in • No oligonucleotide class effects • Muscle tissue concentrations of myogenic stem cells ~41,000 ng/g and tissue half-life of • Improvement in myofiber 61 days (supports monthly dosing) regeneration • Preclinical data suggests higher levels of dystrophin protein expression in heart and diaphragm than skeletal muscle Expect feedback from regulators and the 48-week FORWARD-53 data in 1Q 2025 22 Dystrophin data from prespecified analysis of ambulatory boys; Muscle content adjustment was done using the formula: MHC-normalized dystrophin/(total myofiber area/total area of biopsy section). Interim analysis results announced September 24, 2024.
Unlocking Wave’s best-in-class exon skipping portfolio DMD Population • Data for exons 51, 44, 52, 45 WVE-N531 Exon 53 demonstrate potential for even Not Amenable to Skipping greater dystrophin expression 8-10% Exon 51 17% • Opportunity to address up to 11-13% 40% of population (~10,000 6% Exon 44 patients in US and Europe) 4% Exon 52 • Expect to engage regulators on a 8% platform trial design that Exon 45 44% incorporates multiple exons Other Exons 23 Aartsma-Rus, et al. 2009 Hum Mut 30, 293
Advancing WVE-003 to address HD across all stages of disease WVE-003 is a first-in-class, allele-selective oligonucleotide for the treatment of HD • HD is a monogenic autosomal dominant genetic disease; fully penetrant and affects entire brain • No current disease modifying therapies for HD • Characterized by cognitive decline, psychiatric illness, and chorea; ultimately fatal • Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT) and loss of function in wild-type huntingtin protein (wtHTT) >200,000 patients with HD across all disease states Pre-Symptomatic HD Symptomatic HD (~160K in US and Europe) (~65K in US and Europe) 24 Sources on wtHTT: 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. Strehlow 2007 12. Milnerwood 2010 13. Smith-Dijak 2019 14. Tousley 2019 15. Zhang 2018 16. McAdam 2020 17. Altar 1997 18. Zuccato 2001 19. Gauthier 2004 20. Ferrer 2000 21. Baquet 2004 22. Liu 2011 23. Karam 2015
Wild-type HTT (wtHTT) is critical for normal neuronal function and loss of wtHTT contributes to cellular dysfunction Mutant HTT has a detrimental effect on wild-type Wild-type HTT is crucial for cilia health HTT function • In the absence of wtHTT, ciliogenesis fails, disrupting CSF • Lowering mHTT is expected to restore physiological flow, causing hydrocephalus control over HTT gene expression and relieve its detrimental effect on wtHTT function Ventricle CSF flow Cilia Ependymal cell Brain tissue Sequestered wild-type HTT Only an allele-selective approach can ameliorate both loss-of-function and gain-of-function disruptions driven by mHTT 25 Saudou & Humbert 2016 Neuron; Cason et al., 2022 Nat Rev Cell Biol; Laundos et al., 2023 Front Cell Dev Biol; Kaliszewski et al., 2015 Cell Death Diff; Keryer et al., 2011 J Clin Invest Khoshnan & Patterson, 2011. Neurobiol Dis; Pogoda et al., 2021 Curr Med Chem; Hsiao et al., 2013 Hum Mol Genet
Allele-selective lowering of mutant HTT protein of up to 46% with three doses of WVE-003 and preservation of wild-type HTT Durability of mHTT reductions supports potential for quarterly dosing intervals Mutant HTT protein levels Wild-type HTT protein levels 2.00 2.00 Placebo Placebo WVE-003 30 mg WVE-003 30 mg 1.75 1.75 1.50 1.50 1.25 1.25 1.00 1.00 mHTT Preservation reduction of wtHTT 0.75 0.75 0.50 0.50 1 29 57 85 113 141 169 197 1 29 57 85 113 141 169 197 Dose of Dose of Day Day WVE-003 WVE-003 26 * p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein From June 25, 2024 SELECT-HD disclosure Mutant Huntingtin Protein (fM) - Geometric Mean Ratio to Baseline +/- SE Wild-Type Huntingtin Protein (fM) - Geometric Mean Ratio to Baseline +/- SE
WVE-003 leads to allele-selective mHTT reduction, correlating with slowing of caudate atrophy Allele-selective mHTT Slowing of Caudate Silencing with wtHTT Functional Benefit Atrophy Preservation • mHTT reduction of up to • WVE-003 trended towards • Caudate atrophy is an 46% vs. placebo less caudate atrophy vs. imaging biomarker expected placebo (4.68% vs. 5.10%, to predict clinical • wtHTT preserved/increased not significant) outcomes, including throughout study clinically meaningful worsening of Total Motor Score (TMS) Greater allele-selective mHTT reduction correlated with the slowing of caudate atrophy at 24 weeks (R = -0.50, p=0.047) 27 Liu et al., 2023 Brain Comm
Internal analysis of natural history demonstrates 1% reduction in rate of caudate atrophy would delay onset of disability by ≥7.5-years WVE-003 next steps p<0.001 HR = 0.31 • Planning underway, including key aspects of study design, for a global, potentially registrational Phase 2/3 study in adults with SNP3 and HD Rate of Caudate Atrophy: • Using caudate atrophy as a Fast: -3.04%/year primary endpoint Slow: -2.04%/year Expect to submit IND application for potentially registrational Phase 2/3 study in 2H 2025 28 TRACK-HD (n=366) and PREDICT-HD (n=1,078) are longitudinal HD natural history studies that include MRI brain imaging, clinical outcome assessments. Paulson et al., Neurosci.2014, Tabrizi et al., Lancet Neurol 2009, Tabrizi et al., Lancet Neurol 2012, Tabrizi et al., Lancet Neurol. 2013 IND: Investigational New Drug TFC: Total Functional Capacity Probability of TFC preservation
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 Liver Disease DMD PNPLA3 WVE-N531 Exon 53 HeFH Add’l SNPs LDLR & APOB Add’l Exons Current pipeline has potential to treat well over 100 million patients in US and Europe 29 Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients)
Anticipated upcoming milestones Allele-selective siRNA RNA editing Splicing silencing PNPLA3, LDLR, APOB, WVE-007 (INHBE) WVE-006 WVE-N531 (Exon 53) WVE-003 (SNP3) additional wholly owned Obesity AATD DMD HD programs 1Q 2025: 2025: 2025: 1Q 2025: 2H 2025: Initiate dosing in Deliver multidose Deliver new preclinical Deliver 48-week Submit IND INLIGHT clinical trial data from data from hepatic and FORWARD-53 data & application for RestorAATion-2 extra-hepatic RNA receive feedback from potentially editing programs regulators on registrational Phase 2025: pathway to accelerated 2/3 using caudate Deliver proof-of- 2026: approval atrophy as a primary concept clinical data Initiate clinical endpoint development of additional RNA editing programs Well-capitalized with expected cash runway into 2027 30 AATD: Alpha-1 antitrypsin deficiency; LDLR and APOB programs for treatment of heterozygous familial hypercholesterolemia; PNPLA3 program for treatment of genetically defined liver disease; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; IND: Investigational New Drug
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