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 October 1, 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 October 1, 2024 | |
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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: October 1, 2024
Exhibit 99.1 Wave Life Sciences Corporate Presentation October 1, 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 Strategic collaborations Well-capitalized with cash In-house GMP manufacturing Strong and broad IP runway into 2027* (GSK and Takeda) 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 and Takeda collaborations
Wave’s best-in-class multi-modal platform Clinically-validated oligonucleotide chemistry (PN, stereochemistry) Splicing Editing Silencing Restore RNA transcripts and turn on Efficient editing of RNA bases to Degradation of RNA transcripts to protein production restore or modulate protein turn off 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-N531 (DMD) WVE-003 (HD) WVE-007 (obesity) Additional wholly owned editing programs 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
Proprietary chemistry continues to translate in clinic across modalities, enabling first-in-class and best-in-class therapies 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 ✓ ✓ ✓ (WVE-N531 for DMD) concentrations in 6 weeks tolerable 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) GalNAc-RNA Proof-of-mechanism data RestorAATion trial editing ✓ expected 4Q 2024 completion Novel base and sugar (WVE-006 for AATD) 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 / Preclinical Clinical Rights Studies (US & Europe) R NA E D I T I NG GSK exclusive WVE-006 RestorAATion Clinical Program 200K SERPINA1 (AATD) global license Multiple undisclosed 100% global >20K (multiple) Correction Multiple undisclosed 100% global >3M (multiple) Upregulation R N A i WVE-007 Obesity and 100% global 47M other metabolic disorders 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 Takeda 25K Symptomatic (SNP3) WVE-003 SELECT-HD Trial (Phase 1b/2a) - Trial Completed mHTT (HD) 50:50 Option 60K Pre-Symptomatic (SNP3) Editing for correction Editing for upregulation 7 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease
WVE-006 + AIMers RNA editing 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 aims to address the large unmet need in AATD • 200,000 Pi*ZZ patients in US and Europe WVE-006 for AATD • Current standard of care is weekly IV augmentation therapy • No therapies address AATD liver disease A WVE-006 ADAR editing approach to address key goals of AATD treatment: SERPINA1 Z allele mRNA encodes Z-AAT protein 1) Restore circulating, 2) Reduce Z-AAT protein 3) Retain M-AAT with E342K mutation functional wild-type M-AAT aggregation in liver physiological regulation Z-AAT I(G) Edited SERPINA1 mRNA enables wild-type M- RNA correction replaces AAT protein production M-AAT reaches lungs to M-AAT secretion into mutant Z-AAT protein with wild- protect from proteases bloodstream type M-AAT protein 9 AAT: Alpha-1 antitrypsin Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al., 2017 Int J Chron Obstruct Pulmon Dis 12:561-69; Remih et al., 2021 Curr Opin Pharmacol 59:149-56.
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 Confirmed restored Demonstrated functionality ✓ ✓ ✓ in NSG-PiZ mice wild-type M-AAT protein of M-AAT protein WVE-006 treatment results in serum AAT Overall percentages of serum AAT Serum neutrophil elastase protein levels of up to 30 uM in NSG-PiZ mice protein isoforms in NSG-PiZ mice inhibition activity in NSG-PiZ mice (Week 13) 2000 PBS 1800 WVE-006 1600 WVE-006 (NO LOADING DOSE) 1400 1200 ~7-fold 1000 increase 800 600 11μM 400 200 0 Week ≥50% editing supports restoration of MZ phenotype 10 AATD: Alpha-1 antitrypsin deficiency; M-AAT protein: wild-type AAT protein; WVE-006 administered subcutaneously (10 mg/kg bi-weekly) in 7-week old NSG-PiZ mice (n=5 per group); Loading dose: 3 x 10 mg/kg at Day 0. Left: Liver biopsies collected at wk 13 (1 wk after last dose) and SERPINA1 editing quantified by Sanger sequencing; Right: Total serum AAT protein quantified by ELISA; Stats: Two-Way ANOVA with adjustment for multiple comparisons (Tukey) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Serum AAT protein (ug/ml) (Mean, s.e.m)
WVE-006 decreases lobular inflammation and PAS-D globule size, prevents increase in hepatocyte turnover Fibrosis → Cirrhosis → Hepatocellular Carcinoma Correction of gain-of-function liver phenotypes Lobular inflammation Mitoses PAS-D-positive globule size (NSG PiZ mice, week 13) (NSG PiZ mice, week 13) (NSG PiZ mice, week 13) ✱✱✱✱ ns ns ✱✱✱✱ 5 ✱✱✱ 40 ns 25✱✱✱✱ ✱ 4 20 30 3 15 20 2 10 10 1 5 0 0 0 Week 0 Week 13 11 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 largest globules in each of 5 mice were measured. Each circle represents a single PAS-D globule, (Mean ± SEM). Baseline: week 0 (7 weeks old); Treated week 13 (20 weeks old); Stats: Kruskal-Wallis followed by Dunn’s test Baseline PBS WVE-006 Baseline PBS WVE-006 Baseline PBS WVE-006 Score (0-4) Number of mitotic figures/10 MPF + Mean PAS-D globule diameter (μm)
AIMer-directed editing is highly specific in mice RNA editing only detected at PiZ mutation RNA editing across transcriptome site in SERPINA1 transcript PBS SERPINA1 C 0% (PiZ mutation site) T 100% AATD AIMer C 48.2% T 51.8% Editing site % Editing (PiZ mutation) No bystander editing observed on SERPINA1 transcript 12 Dose 3x10 mg/kg (days 0, 2, 4) SC with AATD AIMer (SA1 – 4). Liver biopsies day 7. RNA-seq to quantify on-target SERPINA1 editing, to quantify off-target editing reads mapped to entire mouse genome; plotted circles represent sites with LOD>3 (N=4), SERPINA1 edit site is indicated Coverage Coverage
RestorAATion-2 underway, proof-of-mechanism data expected in 4Q 2024 Informs dose & dose frequency RestorAATion-1: Healthy Volunteers RestorAATion-2: AATD Patients RestorAATion-1: Healthy Volunteers Single ascending dose (SAD) → Multiple-ascending dose (MAD) cohorts Dose E Up to 7 doses Dose D Cohort 3 Dose C Cohort 2 Dose B Cohort 1 Multiple assessments of serum AAT throughout cohort Dose A Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels 13 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose
Multiple RNA editing opportunities to build high-value, wholly owned pipeline beyond WVE-006 Potential to advance any combination of targets into preclinical development Hepatic (GalNAc-AIMers) Extra-Hepatic (AIMers) Target A Target B Target X Target E Target F Target G Approach Upregulation Upregulation Upregulation Correction Upregulation Correction Tissue Liver Liver Liver Liver Kidney Lung Therapeutic Area Metabolic Metabolic Renal Rare Renal Rare Estimated Patients (US and ~90M ~3M ~170K ~17K ~85K ~5K Europe) • Identifying new targets using proprietary “Edit-Verse”, which is powered by genetic datasets and deep learning models • Advancing work for a diverse set of undisclosed targets addressing areas of high unmet need, including both rare and prevalent diseases 14
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) 15 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
WVE-007 (INHBE program) GalNAc-siRNA silencing Obesity and other metabolic disorders 16
Potential for best-in-class siRNA enabled by Wave’s PRISM® platform • Unprecedented Ago2 loading increases potency and Next-generation siRNA results in durability of silencing following administration of more potent and durable silencing single subcutaneous dose Ago2 loading Next generation siRNA enhances Ago2 loading HSD17B13 mRNA (liver, transgenic mice) knockdown of serum Ttr protein (liver, transgenic mice) 25 (liver, transgenic mice) 125 125 Wk 2 Wk 7 Wk 14 PBS 20 100 100 Benchmark First gen siRNA 15 75 75 Next gen siRNA 50 50 10 25 * Next-gen * 25 5 siRNA 0 0 0 2 4 6 8 10 12 14 16 125 0 0 5 10 15 20 25 30 35 40 45 50 PBS Time (weeks) Benchmark 100 Day 125 PBS Reference Wave first gen PBS First gen siRNA Reference Wave first gen siRNA 75 100 Benchmark Next gen siRNA siRNA First gen siRNA 50 75 Next gen siRNA siRNA silencing is one of multiple Wave modalities being advanced in strategic research collaboration with GSK 25 50 0 25 0 5 10 15 20 25 30 35 40 45 50 17 Day Left and Middle: Mice expressing human HSD17B13 transgene treated with siRNA (3 mg/kg) or PBS, liver mRNA, guide strand concentration, Ago2 loading quantified. Stats: Two-way 0 ANOVA with post-hoc test * P<0.05, ****P<0.0001. Liu et al., 2023 Nuc Acids Res doi: 10.1093/nar/gkad268; Right: Benchmark: Foster, DJ. et.al. Mol Ther. 2018, 26(3), 708. B6 mice 0 5 10 15 20 25 30 35 40 45 50 administered PBS or 0.5 mg/kg of siRNA (subcutaneous). Stats: Mixed Two-way ANOVA followed by post hoc test comparing siRNA vs. Next gen siRNA per day derived from linear mixed Day effects model * P < 0.0001 % mRNA remaining (HSD17B13/Hprt) Fold change relative to Reference 2 Serum Ttr±SEM (rel to PBS) Serum Ttr±SEM (rel to PBS) Serum Ttr±SEM (rel to PBS)
Supported by human genetics, WVE-007 (INHBE GalNAc-siRNA) expected to drive healthy, sustainable weight loss INHBE silencing expected to induce fat loss, Distinct pathway as compared to GLP-1s while maintaining muscle mass 1 ✓ Weight loss with no impact on muscle mass • Silencing INHBE gene by ≥ 50% is expected to recapitulate the healthy metabolic profile of INHBE loss of function ✓ Preferential reduction of visceral fat 1,2,3 (LoF) carriers, including: 3 ✓ No suppression of general reward system ✓ Reduced waist-to-hip ratio ✓ Reduced serum ✓ No loss of appetite ✓ Reduced odds ratio of type 2 triglycerides diabetes and coronary artery ✓ Elevated HDL-c ✓ GalNAc-siRNA enables infrequent dosing; 1 – 2x/year disease by >25% • INHBE (Inhibin βE) expressed primarily in liver and gene Wave’s INHBE siRNA program may address these 4 product (activin E) acts on its receptor in adipose tissue limitations and / or work complementarily with GLP-1s • Lowering of INHBE mRNA promotes fat burning (lipolysis) 5,6 and decreases fat accumulation (adiposity) Obesity is estimated to impact 174M adults in the US and Europe 18 1. Sargeant, et al. 2019 Endocrinol Metab (Seoul) 34(3):247-262; 2. Prime Therapeutics Claims 1. Nat Commun 2022. https://doi.org/10.1038/s41467-022-32398-7; 2. Nat Commun 2022. Analysis, July 2023; 3. Müller, et al. 2019 Molecular Metabolism 30: 72-130. https://doi.org/10.1038/s41467-022-31757-8; 3. PLOS ONE 2018. https://doi.org/10.1371/journal.pone.0194798; 4. Adam, RC. et.al. Proc Natl Acad Sci USA. 2023, 120(32): e2309967120. 5. Yogosawa et al. 2013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526038/ 6. Zhao et al. 2023 https://pubmed.ncbi.nlm.nih.gov/36626233/
WVE-007 has Wave’s next generation siRNA format and best-in-class profile with infrequent dosing INHBE program: Data from DIO mouse model supports best-in-class profile and potential use of WVE-007 in multiple treatment settings ✓ Highly potent (ED50 < 1mg/kg) and durable silencing following one, low-single-digit dose, supporting every-six-month or annual dosing ✓ Monotherapy: Weight loss similar to semaglutide with no loss of muscle mass and a reduction in fat mass, with preferential effect to the visceral fat (consistent with profile of INHBE LoF carriers in human genetics) ✓ Add-on to GLP-1s: 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 and this effect was sustained throughout the duration of the study ✓ Maintenance: Curtailed rebound weight gain upon cessation of semaglutide Expect to initiate clinical trial for WVE-007 in 1Q 2025 19
WVE-N531 Splicing Duchenne muscular dystrophy 20
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 21 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 22 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 23 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 safe and well tolerated WVE-N531 10 mg/kg TEAE Category n=11 Patients (%) Any TEAE 10 (90.9) Any drug-related TEAE 3 (27.3) Mild 3 (27.3) Moderate 0 Severe 0 Any serious TEAE 0 Any severe TEAE 0 Any TEAE leading to discontinuation 0 Any TEAE leading to death 0 No Serious Adverse Events and no oligonucleotide class-related events 24 TEAE: Treatment emergent adverse event; Data as of August 19, 2024
Industry-leading muscle tissue concentrations and exon skipping Muscle tissue concentrations Exon skipping ~41,000 ng/g 57% Tissue half-life of 61 days supports monthly dosing 25 Muscle tissue concentrations and exon skipping n=11; ~41,000 ng/g = ~5,900 nM WVE-N531 muscle concentration (ng/g, mean + SD) % Exon skipping (mean + SD)
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 26
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% 27 *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) MHC Normalized Dystrophin (% normal)
WVE-N531 in skeletal muscle likely to underrepresent activity in heart and diaphragm Preclinical data: → Higher dystrophin in heart dKO: Dystrophin restoration ~9% ~12% ~17% and diaphragm, survival benefit cardiac and respiratory functional improvements WVE-N531 muscle tissue → Greater exposure in heart NHP: 2.17 57.2 10.8 and diaphragm concentration (µg/g) 28 Kandasamy et al., 2022 Nuc Acids Res doi: 10.1093/nar/gkac018 Skeletal Heart Diaphragm
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 29 Aartsma-Rus, et al. 2009 Hum Mut 30, 293
WVE-003 Allele-selective silencing Huntington’s Disease 30
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 31 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 32 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 33 * p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein 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 KD 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) 34 Liu et al., 2023 Brain Comm
Preservation of caudate volume offers an efficient pathway for potential accelerated approval for HD Draft study design:• Randomized, placebo controlled clinical study Adults with SNP3 and HD Stage 1-2 Registrational study powered to show impact on • N = ~150 caudate atrophy• 12-18 months duration Allele-selective mHTT Clinical outcomes Slowing caudate atrophy reductions vMRI imaging marker for accelerated approval Expect feedback from regulators on path to accelerated approval by year-end 2024 35 vMRI: volumetric MRI
Anticipated upcoming milestones 36
Wave is poised for significant and sustained growth AATD WVE-006 DMD Obesity WVE-N531 WVE-007 (INHBE) Exon 53 HD Add’l GalNAc liver WVE-003 Add’l AIMer Programs Add’l Exons siRNA programs SNP3 (GalNAc liver and extra-hepatic) Add’l SNPs Wave’s platform is translating in the clinic; AATD proof-of-mechanism data expected in 4Q 2024 and initiation of clinical trial for WVE-007 (INHBE) expected in 1Q 2025 37 Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients)
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