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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 8, 2024, 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. |
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| 99.1 | Corporate Presentation of Wave Life Sciences Ltd. dated January 8, 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: January 8, 2024
Exhibit 99.1 Wave Life Sciences Corporate Presentation January 8, 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 Anticipated Upcoming Milestones DMD (splicing), HD (silencing), and AATD (RNA editing) clinical programs advancing • Proof-of-mechanism data from RestorAATion clinical program of INHBE program, obesity (siRNA), muscle sparing, fat loss, WVE-006 for AATD in 2024 improved metabolic profile • Select INHBE clinical Multi-modal drug discovery and development platform candidate for obesity in 3Q 2024 and submit CTA in 2025 Leader in RNA editing with best-in-class oligonucleotide chemistry • Data from FORWARD-53 clinical trial of WVE-N531 for DMD in 3Q 2024 In-house GMP manufacturing; Strong and broad IP portfolio • Data from SELECT-HD clinical trial of WVE-003 for HD in 2Q Strategic collaborations to expand and advance pipeline 2024 Well-capitalized with cash runway into 4Q 2025* 3 *Cash runway does not include potential future milestones or opt-in payments under GSK and Takeda collaborations
Combining best-in-class chemistry with novel biology and genetic insights: Opportunities for new high-impact medicines • Accessing new endogenous enzymes for novel modalities Best-in-class Unlocks (RNA editing) validated new pipeline New biology chemistry programs • Opening up new targets, including prevalent diseases 4
Wave's versatile RNA medicines platform ideal for capitalizing on new genetic insights in rare and common diseases Accessing UK Biobank and building proprietary machine learning models to generate unique genetic insights 5 Claussnitzer, et al. Nature (2020) 577, 179; King et al. PLoS Genet (2019) 15, e1008489
Robust RNA medicines pipeline including first-in-class RNA editing programs Patient population Program Discovery Preclinical Clinical Rights (US & Europe) RNA EDITING WVE-006 GSK exclusive RestorAATion Clinical Program 200K SERPINA1 (AATD) global license Multiple undisclosed 100% global >20K (multiple) Correction Multiple undisclosed 100% global >3M (multiple) Upregulation SILENCING: siRNA INHBE (Obesity and other 100% global 47M metabolic disorders) SPLICING WVE-N531 100% global 2.3K FORWARD-53 Trial (Phase 2) Exon 53 (DMD) Other exons (DMD) 100% global Up to 18K SILENCING: ANTISENSE 25K Manifest (SNP3) WVE-003 SELECT-HD Trial (Phase 1b/2a) Takeda 50:50 Option mHTT (HD) 60K Pre-Manifest (SNP3) Editing for correction Editing for upregulation 6 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease
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 $505 million in Up to $2.8 billion in three wholly owned • Additional research additional milestones total milestones and collaboration programs funding and tiered royalties on tiered royalties on (or more with GSK’s net sales net sales 3 consent) • Potential for up to $3.3 billion in 2 milestones ✓ ✓ ✓ $20 million milestone Advancing work on INHBE is Wave’s first achieved with first multiple targets wholly owned program • Leverage GSK’s individual dosing in spanning multiple emerging from GSK expertise in genetics 4Q 2023 modalities beyond RNA collaboration and genomics editing, including siRNA 7 1. $120 million in cash and $50 million equity investment received in January 2023, 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-006 (RNA editing) AATD 8
WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD WVE-006 for AATD WVE-006 ADAR editing approach to address key goals of AATD treatment: 1) Restore circulating, 2) Reduce Z-AAT protein 3) Retain M-AAT A functional wild-type M-AAT aggregation in liver physiological regulation SERPINA1 Z allele mRNA encodes Z-AAT protein with E342K mutation Z-AAT WVE-006 (GalNAc-conjugated AIMer) I(G) RNA correction replaces M-AAT reaches lungs to M-AAT secretion into mutant Z-AAT protein with protect from proteases bloodstream wild-type M-AAT protein Edited SERPINA1 mRNA enables wild-type M-AAT protein production 200,000 Pi*ZZ patients in US and Europe 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 5 1 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 SERPINA1 C 0% PBS (PiZ mutation site) T 100% C 48.2% AATD AIMer T 51.8% Editing site (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
Proof-of-mechanism data from RestorAATion-2 expected in 2024 Informs dose & dose frequency R Res estto orA rAA AT Tiio on n--1: 1: H Healt ealthy hy V Volunteers olunteers RestorAATion-2: AATD Patients SAD → MAD cohorts Dose E Up to 7 doses Dose D High dose Dose C Medium dose Dose B Low dose Multiple assessments of serum AAT throughout cohort Dose A Study key objectives Dosing Safety and tolerability Underway Pharmacokinetics Serum M-AAT levels 13 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose
AIMers RNA editing capability 14
The AIMer-targetable ‘Edit-Verse’ is substantial Gene-Disease Network • The Edit-verse is the editable gene-disease universe, including upregulation 1 • >13,000 genes with a high-probability of being amenable to transcriptional regulation with A-to-G editing • Model development ongoing to expand access to more protein-coding genes and expand the Edit-verse • AIMers are expected to be able to target ~50% of the transcriptome 15 1 (score >95th p-tile)
Innovating on applications of ADAR beyond restoring protein function Restore or correct Upregulate expression to increase endogenous protein activity protein function Attenuated gene expression mRNA mRNA Decay Cascade Unique RNA motifs “Dialed up” Gene Expression • Correct G-to-A driver mutations with AIMers WVE-006 (GalNAc-AIMer) Edited mRNA AATD A single edited base permanently disrupts the motif Stable mRNA yields increased protein production 16
Multiple RNA editing opportunities to build high-value 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) • The Edit-verse is substantial and still expanding • Advancing work for a diverse set of undisclosed targets addressing areas of high unmet need, including both rare and prevalent diseases 17
INHBE program (siRNA silencing) Obesity and other metabolic disorders 18
Potential for best-in-class siRNA enabled by Wave’s PRISM platform • Unprecedented Ago2 loading increases potency and durability of silencing following administration of single subcutaneous dose Ago2 loading Antisense strand Ago2 loading HSD17B13 mRNA (liver, transgenic mice) (Liver, transgenic mice) 25 (liver, transgenic mice) (liver, transgenic mice) 5 125 Wk 2 Wk 7 Wk 14 Wk 2 Wk 7 Wk 14 4 20 100 3 2 15 75 1 11 .0 1 50 10 25 * 0.5 * 5 0 0 2 4 6 8 10 12 14 16 0.0 0 Time (weeks) PBS Reference Wave siRNA Reference Wave siRNA siRNA silencing is one of multiple Wave modalities being advanced in strategic research collaboration with GSK 19 Left, Middle, and right: Mice expressing human HSD17B13 transgene treated with siRNA (3 mg/kg) or PBS, liver mRNA, guide strand concentration, Ago2 loading quantified. Stats: Two-way ANOVA with post-hoc test * P<0.05, ****P<0.0001. Liu et al., 2023 Nuc Acids Res doi: 10.1093/nar/gkad268; % mRNA remaining (HSD17B13/Hprt) ug of oligo/g of tissue (mean± sem) Fold change relative to Reference 2
Driven by clinical genetics, Wave’s first RNAi program addresses high unmet need in obesity INHBE program (GalNAc siRNA) is Wave’s first wholly owned program emerging from GSK collaboration GLP-1 receptor agonists have several INHBE silencing expected to induce fat reported limitations loss, while maintaining muscle mass • siRNA to silence INHBE gene is expected to recapitulate 1 × Lead to weight loss at the expense of muscle mass the healthy metabolic profile of INHBE loss of function 1,2,3 (LoF) heterozygous human carriers, including: 4 × Suppress general reward system 4 ✓ Reduced waist-to-hip ratio ✓ Reduced serum × Associated with poor tolerability profile with 68% drop- 3 ✓ Reduced odds ratio of type 2 triglycerides off after 1 year diabetes and coronary artery ✓ Elevated HDL-c × Discontinuation of therapy leads to rapid weight regain disease by >25% • INHBE expressed primarily in liver and gene product 4 (activin E) acts on its receptor in adipose tissue Wave’s INHBE siRNA program may address these • Lowering of INHBE mRNA or blocking of its receptor limitations and / or work synergistically with GLP-1s promotes fat burning (lipolysis) and decreases fat 5,6 accumulation (adiposity) ≥50% reduction of INHBE in patients expected to restore and maintain a healthy metabolic profile 20 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/
INHBE silencing achieved in vivo with GalNAc-siRNA led to lower body weight and significant decrease in visceral fat INHBE mRNA silencing INHBE silencing led to INHBE silencing leads to demonstrated at 5 weeks 16% lower body weight as significant decrease in compared to control visceral fat at 5 weeks Results of in vivo preclinical study are consistent with UK Biobank human data on loss-of-function carriers 21 HFD: high-fat diet. Stats: two-sided Welch’s T Test **** P < 0.0001 1. Adam, RC. et.al. Proc Natl Acad Sci USA. 2023. Data plotted by body weight difference as a % of PBS treated young DIO mice; Coskun, T. et. al. Mol. Metab. 2018, 18, 3. Stats: Repeated Measures ANOVA; Inhbe siRNA vs. Control sig. different at P < 0.05 level weeks 2 - 5; Stats: white-adj. Two-way ANOVA with Bonferroni-adj post hoc comparisons per tissue type allowing heteroscedasticity (only HFD, Inhbe siRNA vs. HFD, PBS shown) ***P < 0.001, ****P < 0.0001
INHBE candidate for obesity expected in 3Q 2024; CTA expected in 2025 Next generation siRNA results in more Applying next-generation siRNA chemistry potent and durable target knockdown to INHBE program ✓ Potent and highly specific INHBE leads 125 PBS identified 100 Benchmark First gen siRNA ✓ GalNAc-conjugated for targeted delivery to 75 Next gen siRNA liver * 50 * ✓ Potential for infrequent administration Next generation 25 * * siRNA 0 0 5 10 15 20 25 30 35 40 45 50 Day Wave’s next generation GalNAc-siRNA demonstrates best-in-class potential 22 Foster, DJ. et.al. Mol Ther. 2018, 26(3), 708. B6 mice administered PBS or 0.5 mg/kg of siRNA (subcutaneous). Benchmark: Stats: Mixed Two-way ANOVA followed by post hoc test comparing siRNA vs. Next gen siRNA per day derived from linear mixed effects model * P < 0.0001 Serum Ttr±SEM (rel to PBS)
Wave’s platform chemistry enables siRNA extra-hepatic delivery • Chemical impact - Introduction of neutral backbone - Unique structural feature of PN, specifically guanidine - Increased lipophilicity - Stereochemistry • Extra-hepatic delivery PN - Titrating siRNA lipophilicity tunable PNs (PN variants) - Maintaining high Ago2 loading and intracellular trafficking - Titrating plasma protein binding - Altered delivery, enhanced potency and durability in various tissues PN can tune extra-hepatic delivery of siRNA using rational design, including placement, number of modifications and PN variants 23
Single dose of next generation siRNA delivers broad, potent and durable CNS target engagement Robust target engagement translates to substantial App protein reduction across brain Next gen siRNA wk8 Next gen siRNA wk16 regions 8-weeks post single dose 125 100 PBS 75 50 25 Next gen siRNA 0 Sustained APP knockdown of at least 75% throughout the 16-week study in vivo in mice 24 PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly lower than PBS at both time points for all tissues at P < 0.0001 level; Immunohistochemical nd analysis of FFPE Mouse Brain tissue labeling App protein (Color Brown) with CS#19389 followed by a ready to use Polymer-HRP 2 Detection antibody. Nuclei were counterstained with Hematoxylin (Color Blue). Single 100 ug ICV injection Cortex Striatum Cerebellum Hippocampus Brainstem Spinal cord APP silencing %mRNA remaining (SEM) (App/Hprt)
Wave siRNA demonstrates more potent and durable silencing as compared to published state-of-the-art Wave (APP – Cortex) Alnylam (APP – Cortex) Nat Biotechnol 40, 1500–1508 (2022) Single dose 100 μg Single dose by ICV 120 μg by ICV 125 Knockdown < 90 days 100 post-dose Knockdown 75 > 112 days post-dose 50 25 0 Cortex Next gen siRNA wk8 Next gen siRNA wk16 Next gen siRNA wk8 Next gen siRNA wk16 125 125 25 PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by 100 100 Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly lower than PBS at both time points for all tissues at P < 0.0001 level. Source: Brown, K.M., Nair, J.K., Janas, M.M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat Biotechnol 40, 1500–1508 (2022). 75 75 50 50 25 25 0 0 Cortex Cortex Striatum Striatum Cerebellum Cerebellum Hippocampus Hippocampus Brainstem Brainstem Spinal cord Spinal cord %mRNA remaining (SEM) (App/Hprt) %mRNA remaining (SEM) (App/Hprt) %mRNA remaining (SEM) %mRNA remaining (SEM) (App/Hprt) (App/Hprt) % message remaining (relative to aCSF)
WVE-N531 (splicing) Duchenne muscular dystrophy 26
Duchenne muscular dystrophy • Genetic mutation in dystrophin gene prevents Disease State Restored State the production of dystrophin protein, a critical Dysfunctional Splicing Exon Skipping Oligo component of healthy muscle function Mutant pre-mRNA Mutant pre-mRNA • Impacts approx. 1 in every 5,000 newborn boys 50 51 53 54 55 50 51 53 54 55 each year; approx. 20,000 new cases annually Skip worldwide – Approx. 8-10% are amenable to exon 53 50 51 53 54 55 50 51 54 55 skipping mRNA with disrupted reading frame Restored mRNA • Dystrophin protein established by FDA as surrogate endpoint reasonably likely to predict 1 Translation halted Translation continues benefit in boys for accelerated approval in DMD • Increasing amount of functional dystrophin expression over minimal amount shown with approved therapies is expected to result in greater benefit for boys with DMD Functional No dystrophin protein dystrophin produced produced 27 1 Vyondys: www.fda.gov; viltepso; www.fda.gov; Exondys; www.fda.gov; Amondys: www.fda.gov
Extended survival in dKO preclinical model supports potential of Wave’s PN-modified exon-skipping therapeutics for DMD 100% survival at time of study termination Restored muscle and respiratory function to wild-type levels 300 dKO: PBS 200 Wild-type dKO: PS/PO/PN 100 0 20 40 60 80 100 120 Stimulation Frequency (Hz) Wild-type dKO: PBS dKO (PS/PO/PN oligonucleotide) PS/PO/PN 150 mg/kg weekly PS/PO/PN 75 mg/kg bi-weekly PS/PO 150 mg/kg weekly PBS Note: Untreated, age-matched mdx mice had 100% survival at study termination [not shown] PN chemistry improved function and survival in dKO mice 28 Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 dKO: double knock-out 2 Specific Force (Nm )
Preclinical data supported advancing WVE-N531 to clinical development WVE-N531: Dystrophin restoration of up to WVE-N531 reached high concentrations in 71% in vitro heart and diaphragm in NHP 29 th 26 Annual ASGCT meeting, May 16-20, 2023
Clinical data from WVE-N531 Part A: High exon-skipping & muscle concentrations after three doses every other week WVE-N531 uptake in myocyte stem cells suvodirsen WVE-N531 Mean muscle 0.7 µg/g 42 µg/g concentration Mean exon Not detectable 53% skipping Half-life in WVE-N531 18 hours 25 days uptake in plasma myogenic stem cells 3 doses of 10 mg/kg 22 weekly doses of 5 mg/kg Dose every other week Important for potential muscle regeneration 30 WVE-N531 data presented March 22, 2023 at Muscular Dystrophy Association Clinical and Scientific Conference; WVE-N531 biopsies collected ~2 weeks post-last dose (3 biweekly doses of 10 mg/kg) 42 µg/g = 6.1 µM; Suvodirsen biopsies collected post-last dose (weekly doses of 5 mg/kg) on week 22; Half-life as indicated by PK analysis; suvodirsen: discontinued first-generation non-PN chemistry compound; Right: Dual staining utilizing in-situ hybridization for WVE-N531 and PAX7 immunohistochemistry for stem cells. Suvodirsen N= 8; WVE-N531 N=3 boys
Dosing underway in FORWARD-53, a potentially registrational Phase 2 clinical trial of WVE-N531 in DMD (Exon 53) Screening Every other week IV dosing Safety Follow-up • Biopsy after 24 weeks of • Functional • Biopsy after 48 weeks of assessment treatment treatment • Functional assessment • Functional assessment • Design of FORWARD-53: Phase 2, open-label, 10 mg/kg every other week • Endpoints: Dystrophin (powered for >5% of normal), safety/tolerability, pharmacokinetics, digital and functional assessments (incl. NSAA and others) • Muscle biopsies to assess dystrophin expression • Fully enrolled and dosing underway Potentially registrational 24-week dystrophin expression data are expected in 3Q 2024 31 IV: intravenous; NSAA: North star ambulatory assessment
Potential for Wave to address up to 40% of DMD population Exon skipping and dystrophin restoration demonstrated in vitro Exon Skipping DMD Population 1.1 µM 2.5 µM 2.5 µM 3.3 µM 5 µM 5 µM 100 100 100 10 µM 10 µM 10 µM WVE-N531 Exon 53 Not Amenable to Skipping 50 50 50 8-10% Exon 51 17% 11-13% 0 0 0 Ex51 Ex51 mock Ex52 Ex52 mock Ex44 Ex44 mock SSO-1 SSO-2 SSO-1 SSO-2 SSO-1 SSO-2 6% Exon 44 Protein Restoration 1.1 µM 2.5 µM 2.5 µM 150 150 4% 3.3 µM 5 µM 5 µM Exon 52 100 10 µM 10 µM 10 µM 8% 100 100 Exon 45 44% 50 50 50 Other Exons 0 0 0 Ex51 Ex51 mock Ex52 Ex52 mock Ex44 Ex44 mock SSO-1 SSO-2 SSO-1 SSO-2 SSO-1 SSO-2 Exon 51 Exon 52 Exon 44 32 Left: Aartsma-Rus, et al. 2009 Hum Mutat 30, 293. % Dystrophin Relative to WT % Exon 51 Skipping Rel to Total DMD % Dystrophin Relative to WT % Exon 52 Skipping Rel to Total DMD % Dystrophin Relative to WT % Exon 44 Skipping Rel to Total DMD
WVE-003 (antisense silencing) Huntington’s Disease 33
mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD Healthy individual Huntington’s disease (HD) • Wild-type HTT (wtHTT) is critical for normal neuronal function • Expanded CAG triplet repeat in HTT gene wtHTT Stresses results in production of mutant huntingtin protein (mHTT) • HD is a monogenic autosomal dominant Huntington’s disease genetic disease; fully penetrant and affects entire brain • Fatal disease characterized by cognitive decline, psychiatric illness, and chorea ~50% decrease in wtHTT Stresses mHTT + wtHTT • 30,000 people with HD in the US and more Loss of wtHTT functions than 200,000 at risk of developing HD Synaptic dysfunction | Healthy CNS function Cell death | Neurodegeneration 34
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in Durable striatal mHTT knockdown for 12 HD iPSC neurons in vitro weeks in BACHD mouse model Striatum Similar results in cortex *** **** **** **** **** **** Weeks Pan-silencing WVE-003 PBS Pan-silencing WVE-003 reference compound reference compound NHP study demonstrating significant tissue exposure levels of WVE-003 in deep brain regions resulted in $7 million milestone payment from Takeda in 4Q 2023 35 Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1. Oligonucleotide or PBS [100 μg ICV injections through cannula on days 1, 3, 5] delivered to BACHD transgenic. Mean ± SD (n=8, *P<0.0332, ***P<0.0002, ****P<0.0001 versus PBS unless otherwise noted). HPRT1, hypoxanthine-guanine phosphoribosyl transferase; iPSC, induced pluripotent stem cell; ICV, intracerebroventricular; PBS, phosphate-buffered saline
WVE-003: First-in-class allele-selective candidate for HD Reductions in mean CSF mHTT and preservation of wtHTT observed in pooled analysis of single-dose cohorts in SELECT-HD clinical study wtHTT protein levels mHTT protein levels Placebo WVE-003 (30 and 60 mg Reduction in mHTT protein: pooled*) 22% from baseline 35% vs. placebo Preservation of wtHTT Single dose of WVE-003 Single dose of WVE-003 Data from 30 mg multi-dose cohort with extended follow-up, along with all single-dose data, expected 2Q 2024 36 mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein *Pooled considering no apparent dose response between 2 single-dose cohorts; Data cut-off: August 29, 2022 Reductions in mHTT
Anticipated upcoming milestones 37
Wave is poised for significant and sustained growth AATD WVE-006 INHBE Obesity and other metabolic disorders HD WVE-003 Clinical candidate SNP3 expected 3Q 2024; CTA in 2025 DMD Add’l AIMer Programs WVE-N531 Add’l SNPs Exon 53 Add’l Exons Clinical data in 2024 and advancement of INHBE candidate unlock potential to address > 50M patients in US and Europe 38 Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients)
Anticipated milestones in 2024 and beyond WVE-006 (AATD) 2024: Deliver proof-of-mechanism data from RestorAATion clinical Most advanced RNA editing candidate & program potential best-in-class approach for AATD INHBE Program (Obesity) 3Q 2024: Select INHBE clinical candidate Driven by clinical genetics, with potential to be 2025: Submit a clinical trial application (CTA) next-generation therapeutic for obesity WVE-N531 (DMD) 3Q 2024: Deliver potentially registrational 24-week dystrophin Potential best-in-class approach with highest expression data from FORWARD-53 exon skipping reported WVE-003 (HD) 2Q 2024: Deliver data from 30 mg multi-dose cohort with extended First-in-class mHTT lowering, wtHTT-sparing follow up, along with all single-dose data approach Potential for significant cash inflows in 2024 from collaboration milestones from GSK and Takeda 39 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; mHTT: Mutant huntingtin; wtHTT: Wild-type huntingtin
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