Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (October 2023)
56 slides from Wave Life Sciences's investor presentation, Oct 2, 2023
Slide 1: Wave Life Sciences Corporate Presentation
Exhibit 99.1 Wave Life Sciences Corporate Presentation October 2, 2023
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: Wave today is well positioned for significant and sustained growth
Wave today is well positioned for significant and sustained growth DMD, HD, and AATD clinical programs advancing Collaborations & access to genetic insights DMD, HD, and AATD clinical programs advancing Clinical proof-of- Leader in RNA editing therapeutics, emerging concept leader in RNAi Opened new
Slide 4: RNA medicines allow matching disease target to therapeutic modality
RNA medicines allow matching disease target to therapeutic modality Most versatile RNA medicines Restored platform (PRISM™) in the Reading Frame industry Endogenous ADAR enzyme Functional Best-in-class nucleic acid Protein chemistry applicable editing splicing across modalities Ability to access nov
Slide 5: Proprietary PN chemistry enhances potency across modalities
Proprietary PN chemistry enhances potency across modalities RNA Editing Splicing Silencing % Editing % Skipping Target knockdown (% remaining) 100 80 60 40 20 0 -8 -6 -4 -2 0 2 10 10 10 10 10 10 Concentration (µM) Concentration (mM) Ranked by potency of reference PS/PO compound Ranked by potency of
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 200K SERPINA1 (AATD) global license Multiple undisclosed 100% global >20K (multiple) Correction Multiple undisc
Slide 7: Strategic collaboration with GSK to develop transformative RNA medicines
Strategic collaboration with GSK to develop transformative RNA medicines for genetically defined diseases Multiple value drivers to Wave Milestone / royalties Milestone / royalties Genetic targets ✓ $170 million upfront to Wave to leverage GSK granted exclusive global GSK to advance up to eight 1 GS
Slide 8: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 9: Duchenne muscular dystrophy
Duchenne muscular dystrophy • Genetic mutation in dystrophin gene Disease State Restored State prevents the production of dystrophin Dysfunctional Splicing Exon Skipping Oligo protein, a critical component of healthy Mutant pre-mRNA Mutant pre-mRNA muscle function 50 51 53 54 55 50 51 53 54 55 • Imp
Slide 10: Extended survival in dKO preclinical model supports potential of exon-skipping
Extended survival in dKO preclinical model supports potential of exon-skipping therapeutics for DMD PN chemistry improved function and survival in dKO mice dKO survival studies in literature Restored muscle and respiratory 100% survival at time of study termination function to wild-type levels 300 2
Slide 11: Preclinical data supported advancing WVE-N531 to clinical development
Preclinical data supported advancing WVE-N531 to clinical development WVE-N531 reached high concentrations in heart and WVE-N531: Dystrophin diaphragm in NHP restoration of up to 71% in vitro Western Blot normalized to primary healthy human myoblast lysate Conc (uM) % Dystrophin Dystrophin Vinculin
Slide 12: WVE-N531 Part A clinical data: High exon-skipping & muscle concentrations
WVE-N531 Part A clinical data: High exon-skipping & muscle concentrations after three bi-weekly doses WVE-N531 uptake in WVE-N531 uptake in myocyte stem cells myocyte stem cells suvodirsen WVE-N531 Mean muscle 0.7 µg/g 42 µg/g concentration Mean exon Not detectable 53% skipping WVE-N531 uptake in Ha
Slide 13: FORWARD-53, a potentially registrational Phase 2 clinical trial of WVE-N531
FORWARD-53, a potentially registrational Phase 2 clinical trial of WVE-N531 in DMD (Exon 53) Screening Biweekly Dosing (10 mg/kg IV) Safety Follow-up • Functional • Biopsy after 24 weeks of • Biopsy after 48 weeks of treatment assessment treatment • Functional assessment • Functional assessment • De
Slide 14: Potential for Wave 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 1.1 µM 2.5 µM 2.5 µM DMD Population 3.3 µM 5 µM 5 µM 100 100 100 10 µM 10 µM 10 µM WVE-N531 Exon 53 Not Amenable 50 50 50 to Skipping 8-10% Exon 51 17% 0 0 0 11-13%
Slide 15: WVE-006 for Alpha-1 antitrypsin deficiency (AATD)
WVE-006 for Alpha-1 antitrypsin deficiency (AATD)
Slide 16: 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 designed to correct WVE-006 ADAR editing approach to address key goals of AATD treatment: Z allele mRNA to enable M-AAT protein to be produced 2) Reduce Z-AAT 1) Restore circulating,
Slide 17: 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 resul
Slide 18: 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 19: AIMer-directed editing is highly specific in mice
AIMer-directed editing is highly specific in mice No bystander editing observed on SERPINA1 transcript RNA editing only detected at PiZ mutation site in SERPINA1 transcript RNA editing across transcriptome (mouse liver) (mouse liver) C 0% SERPINA1 PBS (PiZ mutation site) T 100% C 48.2% AATD AIMer T
Slide 20: Proof of mechanism data in patients with AATD expected in 2024
Proof of mechanism data in patients with AATD expected in 2024 Informs dose & RestorAATion-2: AATD Patients RestorAATion-1: Healthy Volunteers dose frequency SAD → MAD cohorts Dose E Up to 7 doses High dose Dose D Dose C Medium dose Dose B Low dose Multiple assessments of serum AAT throughout cohort
Slide 21: AIMers RNA base editing capability
AIMers RNA base editing capability
Slide 22: First-generation AIMer designs published in Nature Biotechnology
First-generation AIMer designs published in Nature Biotechnology • Specificity in vitro & in vivo (NHPs)• GalNAc conjugation • In vitro-in vivo translation (NHPs)• Foundational AIMer SAR AIMers detected in liver of NHP at Day 50 Substantial and durable editing in NHP ADAR editing with ACTB AIMer is
Slide 23: Innovating on applications of ADAR editing
Innovating on applications of ADAR editing Correct G-to-A driver mutations with AIMers Modulate protein interactions with AIMers Achieved POC Restore or correct Modulate protein- protein function protein interaction Upregulate expression WVE-006 Modify function (GalNAc AIMer) AATD Post-translational
Slide 24: Proprietary base modifications increase editing across edit region sequences
Proprietary base modifications increase editing across edit region sequences N3 U AIMer 5’ 3’ Edit Site Proprietary base modification (N3 U) increases UGP2 RNA editing across sequences in vitro ns ns * ** ** ** ** ** *** ** ** ** 100 • N3 U: example of proprietary base modifications 80 • N3 U consis
Slide 25: Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression RNA binding proteins recognize sequence motifs to regulate mRNA stability Attenuated “Dialed up” Catalytically Efficient AIMer Gene Expression Gene Expression RNA-binding protein AIMer edits and durably stabilizes mRNA
Slide 26: Edit-verse subnetwork reveals Target A for AIMer upregulation
Edit-verse subnetwork reveals “Target A”: Metabolic syndrome target uniquely suited for AIMer upregulation Target A • Liver target for upregulation, non-incretin therapy • Strongly implicated in metabolic disease, with indirect causation in familial disorders • Few therapies today provide weight los
Slide 27: Substantial upregulation of protein induces weight loss and improves insulin sensitivity
Substantial upregulation of protein induces weight loss and improves insulin sensitivity • ~3-fold upregulation of Target A protein with GalNAc-AIMer led to weight reduction and improved insulin sensitivity in DIO mice Significant Weight Loss Improved Insulin Sensitivity Fasting glucose Fasting insu
Slide 28: Target B upregulation offers a first-in-class approach for hyperlipidemia
Target B upregulation offers a first-in-class therapeutic approach for hyperlipidemia >70% editing achieves ~2-fold upregulation with corresponding increase in protein Target B • Liver target for upregulation • Hyperlipidemia; first-in-class therapeutic approach • Estimate ~3 million target patients
Slide 29: Upregulation of liver Target X stops decline in kidney function
Upregulation of liver Target X stops decline in kidney function Renal Insufficiency Target X Network • Liver target for upregulation • Target X produces a secreted protein to treat kidney disease • Estimate ~170K target patients in US and Europe • Therapeutic rationale supported by genetic insights,
Slide 30: Building on success of AATD: Target E correction restores normal metabolism
Building on success of AATD: Target E correction restores normal metabolism in rare genetic disease Proof-of-concept RNA editing in human primary Target E hepatocytes AIMer-1 Target E AIMer-2 Target E • Liver target for correction • Rare genetic disease • High unmet need population not addressed wit
Slide 31: Upregulation of Target F restores kidney function
Upregulation of Target F restores kidney function in a rare genetic kidney disease Achieved >2-fold upregulation of Target F mRNA in vitro with RNA editing Target F • Kidney target for upregulation • Rare genetic kidney disease that leads to ESRD and need for dialysis / transplantation; High unmet n
Slide 32: Correction of Target G mutation restores protein function in a genetic lung disease
Correction of Target G mutation restores protein function in patients with a genetic lung disease Target G In vitro • Lung disease target for correction Target G mRNA editing 80 • Genetic lung disease with target patient population not addressed with available therapies 60 • ~5K patients amenable to
Slide 33: Multiple RNA editing opportunities to build high-value pipeline beyond WVE-006
Multiple RNA editing opportunities to build high-value pipeline beyond WVE-006 • 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 Potential to advance any combin
Slide 34: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 35: mHTT toxic effects lead to neurodegeneration
mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD Huntington’s disease (HD) Healthy individual • Wild-type HTT (wtHTT) is critical for normal neuronal function • Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (
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 Reduction in mHTT mg pooled*) protein: 22
Slide 37: INHBE and siRNA
INHBE and siRNA
Slide 38: Potential for best-in-class RNAi enabled by Wave's PRISM platform
Potential for best-in-class RNAi enabled by Wave’s PRISM platform • Unprecedented Ago2 loading increases potency and durability of silencing following administration of single subcutaneous dose Ago2 Ago2 ll ooa adindi g ng Antisense strand HSD17B13 mRNA (liver, transgenic mice) (liver, transgenic mi
Slide 39: Wave's first RNAi program addresses high unmet need in metabolic disorders
Driven by clinical genetics, Wave’s first RNAi program addresses high unmet need in metabolic disorders, including obesity INHBE program is Wave’s first wholly owned program emerging from GSK collaboration • Leverages novel genetic insights accessed through GSK collaboration 1,2,3 • INHBE loss-of-fu
Slide 40: INHBE GalNAc-siRNA represents an evolution in treatment for metabolic diseases
INHBE GalNAc-siRNA represents an evolution in treatment for metabolic diseases, including obesity • Metabolic syndrome* is associated with type 2 diabetes, cardiovascular disease, hypertension, stroke, 1,2 cancer, and increased mortality • Estimate ~47M people in US and Europe with metabolic disorde
Slide 41: INHBE knockdown of 90% demonstrated in human hepatocytes
INHBE knockdown of 90% demonstrated in human hepatocytes with GalNAc-siRNA Human hepatocytes Mouse hepatocytes 100 100 75 75 50 50 25 25 0 0 2 nM 8 nM 30 nM 125 nM 0.1 nM 1.6 nM 10 nM 25 nM • This cross-reactive sequence demonstrates ~90% maximal knock-down in human hepatocytes and ~65% in mouse hep
Slide 42: INHBE silencing achieved in vivo exceeds therapeutic threshold
INHBE silencing achieved in vivo with GalNAc-siRNA exceeds therapeutic threshold INHBE knockdown demonstrated in mice at 5 weeks ~62% 125 silencing 100 75 1 Therapeutic threshold **** 50 25 0 HFD: high-fat diet. Stats: two-sided Welch’s T Test **** P < 0.0001 42 1. Adam, RC. et.al. Proc Natl Acad Sc
Slide 43: INHBE knockdown led to 16% lower body weight
INHBE knockdown led to 16% lower body weight Similar effect seen in semaglutide preclinical studies Control Inhbe siRNA (HFD, PBS) 5 0 -5 -10 -15 -20 1 2 3 4 5 Weeks Data plotted by body weight difference as a percentage of PBS treated young DIO mice; Coskun, T. et. al. Mol. Metab. 2018, 18, 3. Stat
Slide 44: INHBE reduction leads to significant decrease in visceral fat
INHBE reduction leads to significant decrease in visceral fat at 5 weeks • INHBE knockdown in young DIO mice resulted in less fat mass across multiple types of white adipose tissue, without loss of brown fat Changes in white adipose tissue after 5 weeks inguinal mesenteric epididymal **** *** 1.5 1.
Slide 45: >50% reduction of INHBE mRNA recapitulates phenotype of LoF carriers
>50% reduction of INHBE mRNA recapitulates phenotype of heterozygous LoF carriers • Subsequent 8-week study demonstrates further reduction in excess visceral fat Changes in white adipose tissue after 8 weeks epididymal inguinal mesenteric **** ** ~40% reduction * ~56% reduction 1.5 2.5 1.5 ~45% redu
Slide 46: Wave's next generation GalNAc-siRNA demonstrates best-in-class potential
Wave’s next generation GalNAc-siRNA demonstrates best- in-class potential Next generation siRNA results in more potent and durable knockdown of serum Ttr protein 125 PBS • Applying next-generation Benchmark 100 siRNA chemistry to siRNA INHBE program 75 Next gen siRNA * • Potential for infrequent 50
Slide 47: Wave's 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 48: Tunable PN variants enhance potency and alter extra-hepatic delivery
Tunable PN variants enhance potency and alter extra- hepatic delivery of non-GalNAc siRNAs Non-GalNAc siRNA with PN variants improve silencing in liver and adipose tissue 14 and 28 days post single dose • Reaching adipose tissue Day in addition to liver with siRNA is important for certain metabolic
Slide 49: Single dose of next generation siRNA delivers broad CNS target engagement
Single dose of next generation siRNA delivers broad, potent and durable CNS target engagement Sustained APP knockdown of at least 75% throughout the 16-week study in vivo in mice Next gen siRNA wk8 Next gen siRNA wk16 125 100 75 50 25 0 PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7)
Slide 50: Wave siRNA demonstrates more potent and durable silencing than 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 Single dose 120 μg by ICV 100 μg by ICV Next gen siRNA wk8 Next gen siRNA wk16 125 Knockdown < 90 days 100 po
Slide 51: Robust target engagement translates to substantial App protein reduction
Robust target engagement translates to substantial App protein reduction across brain regions Reductions observed 8-weeks post single-dose Frontal Cortex Striatum Hippocampus Cerebellum Brain Stem PBS Next gen siRNA Immunohistochemical analysis of FFPE Mouse Brain tissue labeling App protein (Color
Slide 52: First siRNA clinical candidate (INHBE) expected in 4Q 2024
First siRNA clinical candidate (INHBE) with proprietary chemistry expected in 4Q 2024 • INHBE GalNAc-siRNA program is driven by clinical genetics, with potential to be next- generation therapeutic for obesity – ≥50% silencing of INHBE is expected to improve metabolic health – INHBE siRNA silencing a
Slide 53: Anticipated upcoming milestones
Anticipated upcoming milestones
Slide 54: Anticipated upcoming milestones
Anticipated upcoming milestones RNA ANTISENSE SPLICING RNAi EDITING SILENCING WVE-006 for AATD WVE-N531 for DMD WVE-003 for HD INHBE program for Most advanced RNA editing Potential best-in-class First-in-class metabolic disorders, candidate & potential best-in- approach with highest exon wild-type h
Slide 55: Wave is poised for significant and sustained growth
Wave is poised for significant and sustained growth INHBE Four additional metabolic AATD clinical disorders, WVE-006 candidates HD including obesity by year-end 2025 WVE-003 SNP3 Clinical candidate expected 4Q 2024 DMD WVE-N531 Add’l SNPs Exon 53 Add’l Exons ~$12B >$65B Value of US Total Addressable
Slide 56: For more information: InvestorRelations@wavelifesci.com
For more information: InvestorRelations@wavelifesci.com 56
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