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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 November 20, 2024, the Company updated its corporate presentation, which is available on the “Investors” section of the Company’s website at https://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. |
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| 99.1 | Corporate Presentation of Wave Life Sciences Ltd. dated November 20, 2024 | |
| 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: November 20, 2024
Exhibit 99.1 Wave Life Sciences Corporate Presentation November 20, 2024
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
Building a leading RNA medicines company Novel RNA medicines platform (PRISM®) • Multi-modal: RNA editing, RNAi, splicing, allele-selective silencing • Best-in-class, clinically-validated oligonucleotide chemistry (PN, stereochemistry) Differentiated RNA medicines pipeline WVE-N531 in DMD WVE-006 in AATD WVE-007 in Obesity WVE-003 in HD Well-capitalized with cash In-house GMP manufacturing Strong and broad IP runway into 2027* 3 AATD: Alpha-1 antitrypsin deficiency DMD: Duchenne muscular dystrophy HD: Huntington’s disease *Cash runway does not include potential future milestones or opt-in payments under GSK collaboration
Wave’s best-in-class multi-modal platform Clinically-validated oligonucleotide chemistry (including PN, stereochemistry) Editing Silencing Splicing Efficient editing of RNA bases to Degradation of RNA transcripts to Restore RNA transcripts and turn on restore or modulate protein turn off protein production protein production production Antisense siRNA RISC Spliceosome Machinery (>300 proteins) Endogenous RNase H Restored Reading Frame Endogenous for Functional Protein ADAR enzyme Endogenous AGO2 WVE-006 (AATD) WVE-003 (HD) WVE-007 (obesity) WVE-N531 (DMD) PNPLA3 (Liver disease), LDLR, APOB (HeFH) 4
Wave has driven foundational advances in nucleic acid chemistry to expand platform technologies and develop next generation of RNA therapeutics Further information can be found in recent platform publications Silencing (RNase H and Ago2) Splicing Editing 5 Full list of Wave publications: https://ir.wavelifesciences.com/events-publications/publications
Three clinical updates in 2024 demonstrate continued platform translation Clinical Clinical Therapeutic Preclinical translation trial results modalities publication 53% exon skipping, 9.0% mean muscle-adjusted Splicing 42 µg/g muscle tissue dystrophin; safe and tolerable ✓ ✓ ✓ (WVE-N531 for DMD) concentrations in 6 weeks (interim analysis) Proprietary PRISM platform 46% allele-selective mHTT Stereopure oligonucleotides 35% allele-selective Allele-selective silencing; correlation with mHTT silencing with single silencing ✓ ✓ ✓ slowing of caudate (WVE-003 for HD) dose atrophy Novel backbone modifications (including PN chemistry) First ever RNA editing GalNAc-RNA Multidose data expected achieved; 11 µM total AAT editing in 2025 ✓ ✓ protein, >60% (6.9 µM ) M- Novel base and sugar (WVE-006 for AATD) AAT with single dose chemistry modifications GalNAc-RNAi Clinical trial initiation ✓ expected 1Q 2025 (WVE-007 for obesity) 6 Full list of Wave publications: https://ir.wavelifesciences.com/events-publications/publications *mHTT reductions compared to placebo
Robust, diversified RNA medicines pipeline including first-in-class RNA editing programs IND / CTA Enabling Patient population Program Discovery Clinical Rights Studies (US & Europe) R N A E D I T I N G GSK exclusive WVE-006 RestorAATion Clinical Program 200K SERPINA1 (AATD) global license GalNAc-AIMer 100% global 9M PNPLA3 (liver disease) GalNAc-AIMer 100% global 900K (30M expansion) LDLR (HeFH) GalNAc-AIMer 100% global 70K APOB (HeFH) R N A i WVE-007 (GalNAc) INHBE (Obesity and other 100% global 47M metabolic disorders) GalNAc-siRNA 100% global -- Undisclosed S PLI C I N G WVE-N531 FORWARD-53 Trial (Phase 2) 100% global 2.3K Exon 53 (DMD) Other exons (DMD) 100% global Up to 18K A LLE LE - S E LE C T I V E S I LE N C I N G 25K Symptomatic (SNP3) WVE-003 100% global SELECT-HD Trial (Phase 1b/2a) - Trial Completed mHTT (HD) 60K Pre-Symptomatic (SNP3) Editing for correction Editing for upregulation 7 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; HeFH: heterozygous familial hypercholesterolemia
WVE-006 RNA editing (AIMers) Alpha-1 antitrypsin deficiency (AATD) 8
WVE-006: GalNAc-conjugated AIMer designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD WVE-006 for AATD Wild-type M-AAT protein A SERPINA1 Z allele mRNA encodes Z-AAT protein with E342K mutation AAT is an acute phase protein Serum AAT protects lungs predominantly produced against neutrophil elastase by hepatocytes I(G) Gain of Loss of Function: Function: Liver Edited SERPINA1 mRNA enables wild-type Lung Disease M-AAT protein production Disease Misfolded Z-AAT Hepatocellular Emphysema Bronchiectasis protein with Fibrosis → Cirrhosis → Carcinoma E342K mutation A → I Subcutaneous Infrequent Highly specific ✓✓✓ injection dosing (No bystanders) Polymerization Z protein causes AAT proteotoxic Low serum AAT (GalNAc) stress, leading to progressive leads to lung disease liver disease 9 Strnad et al., 2020 N Engl J Med 382:1443-55; Stoller et al., 1993 Alpha-1 Antitrypsin Deficiency GeneReviews. AATD Healthy
RestorAATion-1 and RestorAATion-2 ongoing RestorAATion-2: AATD Patients RestorAATion-1: Healthy Volunteers RestorAATion-1: Healthy Volunteers 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 Cohort 1 200 mg Dose A Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels 10 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose
Achieved proof-of-mechanism for Wave’s RNA editing platform Proof-of-mechanism after a single dose in RestorAATion-2 • Circulating wild-type M-AAT protein in plasma: Mean of 6.9 µM at day 15; more than 60% of total AAT • Increases in neutrophil elastase inhibition from baseline: Consistent with production of functional M- AAT • Mean total AAT protein: Increased from below level of quantification at baseline to 10.8 µM at day 15 – Meets level that has been the basis for regulatory approval for AAT augmentation therapies • Increases in total AAT from baseline and M-AAT protein: Observed as early as day 3 and through day 57 • WVE-006 well tolerated with a favorable safety profile; all AEs mild-to-moderate, no SAEs Wave expects to share multidose data from RestorAATion-2 in 2025 11 October 16, 2024 Proof-of-mechanism disclosure on first two “ZZ” AATD patients in first dose cohort of RestorAATion-2 to reach day 57;
Strategic collaboration with GSK to develop transformative RNA medicines Maximize global Advance up to eight Collaboration Expand Wave’s potential for GSK collaboration Highlights pipeline WVE-006 for AATD programs 1 • $170 million upfront Wave to advance up to Up to $525 million in Up to $2.8 billion in three wholly owned • Additional research total milestones and total milestones and collaboration programs funding tiered royalties on net tiered royalties on (or more with GSK’s sales net sales 3 consent) • Potential for up to $3.3 billion in 2 milestones✓ ✓ ✓ $20 million milestone $12 million aggregate INHBE is Wave’s first with first individual dosing initiation payment for wholly owned program • Leverage GSK’s emerging from GSK GSK’s selection of two expertise in genetics RestorAATion-2 trial collaboration programs to advance and genomics underway (AATD patients) 12 1. $120 million in cash and $50 million equity investment; 2. Initiation, development, launch, and commercialization milestones for WVE-006 and programs progressed during initial 4- year research term (8 GSK collaboration programs); 3. GSK eligible to receive tiered royalty payments and commercial milestones from Wave Recent Highlights
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; Upregulation of LDLR ✓ GalNAc-AIMers building on learnings of WVE-006 Familial hypercholesterolemia Completely novel ways of treating diseases ✓ with high unmet need Correction of APOB Readily accessible biomarkers and approaches ✓ to assess PD, defined regulatory paths Familial hypercholesterolemia PNPLA3, LDLR, APOB clinical candidates expected in 2025 13 Editing for correction Editing for upregulation
WVE-007 (INHBE program) GalNAc-siRNA silencing Obesity and other metabolic disorders 14
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 INHBE mRNA by ≥50% is expected to recapitulate the healthy metabolic profile of heterozygous INHBE loss of function (LoF) carriers 15 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 Release of dimerized INHBE Binds to and activates Block adipose subunits creates hepatokine ACVR1C (ALK7) receptor in lipolysis Activin E adipose tissue Activin E Activin E Increased abdominal adiposity leads to obesity, II II I CVD and T2D I Adipocyte ALK7 Decreased abdominal adiposity leads to weight loss and reduced risk for GalNAc-siRNA CVD and T2D Diminished activation of Reduced release of Increased adipose ACVR1C (ALK7) receptor in hepatokine Activin E lipolysis and shrink adipose tissue adipocytes 16 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 17 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 18 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: 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 fat, and without suppressing food intake ✓ Add-on to GLP-1s: WVE-007 in addition to GLP-1 therapy. When administered as an add-on with semaglutide, a single dose of Wave’s INHBE GalNAc-siRNA doubled the weight loss observed with semaglutide alone ✓ Maintenance: for patients who stop treatment with GLP-1 therapy. Curtailed rebound weight gain upon cessation of semaglutide and prevention of weight cycling, which worsens the outcomes of various metabolic diseases 19
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 MAD Cohort 2 SAD Cohort 4 • Key measurements - Primary: Safety and Tolerability MAD Cohort 1 - Secondary: PK, Activin E SAD Cohort 3 - Exploratory PD: • Body Weight • Body compositions SAD Cohort 2 • Metabolic health • Biochemical markers SAD Cohort 1 Expect to initiate clinical trial for WVE-007 in 1Q 2025 20
WVE-N531 Splicing Duchenne muscular dystrophy 21
Urgent need for improved therapeutic options for the treatment of DMD Duchenne is a devastating and fatal disease • Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function • Impacts ~1 / 5,000 newborn boys annually; ~20,000 new cases annually worldwide - ~8–10% are amenable to exon 53 skipping - Potential for Wave to address up to 40% of DMD with additional exon skipping therapeutics Multiple urgent unmet needs • 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 Boy living with DMD cardiac function 22 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 Screening Safety Follow-up N = 11 • Baseline functional • Muscle biopsy after 24 • Muscle biopsy after 48 Interim weeks of treatment weeks of treatment assessments analysis • 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 23 IV: Intravenous; Q2W: Every 2 Weeks; PK: Pharmacokinetics; PD: Pharmacodynamics
Results of interim analysis: WVE-N531 has potential to be the best-in-class therapeutic for exon 53 DMD Highly consistent dystrophin expression Muscle delivery and extended dosing across patients intervals • 9.0% muscle-content adjusted dystrophin (5.5% • Skeletal muscle tissue concentrations of WVE-N531: unadjusted), quantified from two isoforms that are ~41,000 ng/g consistent with Becker patients who display milder • WVE-N531 tissue half-life of 61 days supports disease monthly dosing • 89% of patients over 5% of normal (muscle-content • Preclinical data suggests WVE-N531 is translating in adjusted) heart and diaphragm Evidence supporting improved Safe and well tolerated muscle health Safe and well tolerated profile • Improvement in serum biomarkers for muscle health • No SAEs • Localization of WVE-N531 in myogenic stem cells • No discontinuations • Improvement in myofiber regeneration • No oligonucleotide class effects Expect to receive feedback from regulators on pathway to accelerated approval and deliver 48-week FORWARD-53 data in 1Q 2025 24 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.
WVE-N531 was localized in myofiber nuclei and 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 25
Dystrophin expression of up to ~14% with high consistency across participants Percentage dystrophin expression across each patient after 24 weeks of treatment 13.9% Dystrophin Adjusted for Muscle Content • Mean 9.0% absolute muscle content 12.2% 11.6% Dystrophin Unadjusted for Muscle Content adjusted dystrophin 11.2% • Mean 5.5% absolute unadjusted dystrophin 8.3% 7.6% 7.3% 6.7% • Dystrophin expression was 6.3% 6.0% 5.9% 5.8% 5.7% quantified from two isoforms 5.3% 5% threshold 4.8% 4.6% consistent with those observed in 3.9% Becker patients who display milder 3.3% disease * 1.2% 1.0% Subject 89% of ambulatory participants achieve muscle content-adjusted dystrophin levels of at least 5% 26 *Excluded from prespecified mean analysis of ambulatory patients; Muscle content adjustment was done using the formula: MHC-normalized dystrophin/(total myofiber area/total area of biopsy section); Graph shows all patients (including non-ambulatory) with appropriate biopsy sample; dystrophin measured by Western Blot (AB15277); Data as of August 19, 2024 MHC Normalized Dystrophin (% normal)
Unlocking Wave’s best-in-class exon skipping portfolio DMD Population WVE-N531 • Data for exons 51, 44, 52, 45 Exon 53 Not Amenable to demonstrate potential for even Skipping greater dystrophin expression 8-10% Exon 51 17% • Opportunity to address up to 11-13% 40% of population 6% Exon 44 4% Exon 52 • Expect to engage regulators on a 8% platform trial design that Exon 45 incorporates multiple exons 44% Other Exons 27 Aartsma-Rus, et al. 2009 Hum Mut 30, 293
WVE-003 Allele-selective silencing Huntington’s Disease 28
Huntington's disease is a devastating neurological disorder caused by a toxic gain of function and concurrent loss of function HD-ISS stage probability and predicted clinical landmark • HD is a monogenic autosomal changes as a function of age dominant genetic disease; fully penetrant and affects entire brain IS TFC Putamen TMS volume SDMT • No current disease modifying Caudate therapies for HD volume • 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 Adapted from Tabrizi 2022 function in wild-type huntingtin >200,000 patients with HD across all disease states protein (wtHTT) Pre-Symptomatic HD Symptomatic HD (~160K in US and Europe) (~65K in US and Europe) An allele-selective, wtHTT-sparing approach is uniquely suited to address HD across all stages of disease 29 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; IS, Independence Scale; SDMT, Symbol Digit Modalities Test; TFC, Total Functional Capacity; TMS, Total Motor Score
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 30 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 31 * 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) 32 Liu et al., 2023 Brain Comm
Regularity of caudate change makes it an ideal biomarker for more efficient clinical development in HD • Caudate volume has a more regular, • HD-ISS Stage 2 linear change at individual level versus variability in individual trajectories with cUHDRS 1 • Wave analysis of PREDICT and TRACK-HD reinforces the relationship between caudate volume loss and clinical outcomes - Difference of 1% reduction in rate of caudate atrophy results in ≥6-year delay in loss of function (i.e. reduction from TFC 13) • Using caudate volume as a primary endpoint will enable smaller, faster and more efficient clinical trials 33 “Using the HD-ISS for Planning Clinical Trials”, Long, J; presented at EHDN & Enroll-HD Conference, Strasbourg, France, Sept 2024 1 – internal analysis conducted by Wave
Preservation of caudate volume offers an efficient pathway for potential accelerated approval for HD • Received supportive initial feedback from FDA: - Recognize the severity of HD - Receptive to and engaged with Wave regarding a potential pathway to accelerated approval - Open to Wave’s plan to evaluate biomarkers, including vMRI for caudate atrophy, as an endpoint to assess HD progression with the potential to predict clinical outcome • Planning is underway for a global, potentially registrational Phase 2/3 study in adults with SNP3 and HD, including finalization of key aspects of design Wave expects to submit an IND for WVE-003 in 2H 2025 34 vMRI: volumetric MRI
Reimagining RNA medicines 35
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 patients in the US and Europe 36 Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients)
Anticipated upcoming milestones Allele-selective GalNAc-RNA editing GalNAc-siRNA Splicing silencing WVE-006 PNPLA3 - Liver disease WVE-007 (INHBE) WVE-N531 (Exon 53) WVE-003 (SNP3) AATD LDLR, APOB - HeFH Obesity DMD HD 2025: 2025: Year-end 2024: 1Q 2025: 2H 2025: Deliver multidose Select clinical Deliver 48-week Submit an Submit CTA data from candidates FORWARD-53 data & Investigational 1Q 2025: RestorAATion-2 receive feedback from New Drug (“IND”) Initiate clinical trial regulators on application pathway to accelerated approval Well-capitalized with cash runway into 2027 37 AATD: Alpha-1 antitrypsin deficiency; HeFH: Heterozygous familial hypercholesterolemia; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; mHTT: Mutant huntingtin; wtHTT: Wild-type huntingtin; CTA: clinical trial application
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