Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (January 2024)
40 slides from Wave Life Sciences's investor presentation, Jan 8, 2024
Slide 1: Wave Life Sciences Corporate Presentation
Exhibit 99.1 Wave Life Sciences Corporate Presentation January 8, 2024
Slide 2: Forward-looking statements
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, r
Slide 3: Building a leading RNA medicines company
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 20
Slide 4: Combining best-in-class chemistry with novel biology and genetic insights
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
Slide 5: Wave's versatile RNA medicines platform for new genetic insights
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
Slide 6: Robust RNA medicines pipeline including first-in-class RNA editing programs
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 (multip
Slide 7: Strategic collaboration with GSK to develop transformative RNA medicines
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 billi
Slide 8: WVE-006 (RNA editing) AATD
WVE-006 (RNA editing) AATD UE SCIENCES.
Slide 9: WVE-006: Designed to correct mutant SERPINA1 transcript
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 aggregatio
Slide 10: WVE-006 in AATD: First-in-class RNA editing clinical candidate
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 r
Slide 11: WVE-006 decreases lobular inflammation and PAS-D globule size
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
Slide 12: AIMer-directed editing is highly specific in mice
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 trans
Slide 13: Proof-of-mechanism data from RestorAATion-2 expected in 2024
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 Multipl
Slide 14: AIMers RNA editing capability
AIMers RNA editing capability 14
Slide 15: The AIMer-targetable 'Edit-Verse' is substantial
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 acc
Slide 16: Innovating on applications of ADAR beyond restoring protein function
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 wi
Slide 17: Multiple RNA editing opportunities beyond WVE-006
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 Upregula
Slide 18: INHBE program (siRNA silencing)
INHBE program (siRNA silencing) Obesity and other metabolic disorders 18
Slide 19: Potential for best-in-class siRNA enabled by PRISM platform
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
Slide 20: Wave's first RNAi program addresses high unmet need in obesity
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 m
Slide 21: INHBE silencing led to lower body weight and decreased visceral fat
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 wee
Slide 22: INHBE candidate expected in 3Q 2024; CTA in 2025
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
Slide 23: Platform chemistry enables siRNA extra-hepatic delivery
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 varian
Slide 24: Single dose of next generation siRNA delivers durable CNS target engagement
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
Slide 25: Wave siRNA more potent and durable than published state-of-the-art
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-do
Slide 26: WVE-N531 (splicing) Duchenne muscular dystrophy
WVE-N531 (splicing) Duchenne muscular dystrophy 26
Slide 27: Duchenne muscular dystrophy
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
Slide 28: Extended survival in dKO preclinical model
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 Stimulatio
Slide 29: Preclinical data supported advancing WVE-N531 to clinical development
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
Slide 30: Clinical data from WVE-N531 Part A
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 i
Slide 31: Dosing underway in FORWARD-53 Phase 2 trial
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
Slide 32: Potential to address up to 40% of DMD population
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
Slide 33: WVE-003 (antisense silencing) Huntington's Disease
WVE-003 (antisense silencing) Huntington’s Disease 33
Slide 34: mHTT toxic effects lead to neurodegeneration
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 hunti
Slide 35: WVE-003 demonstrates selective, potent, durable reduction of mHTT
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-sil
Slide 36: WVE-003: First-in-class allele-selective candidate for HD
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
Slide 37: Anticipated upcoming milestones
Anticipated upcoming milestones 37
Slide 38: Wave is poised for significant and sustained growth
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 unlo
Slide 39: Anticipated milestones in 2024 and beyond
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 geneti
Slide 40: For questions contact investorrelations@wavelifesci.com
For questions contact: investorrelations@wavelifesci.com
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