Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (January 2022)
45 slides from Wave Life Sciences's investor presentation, Jan 10, 2022
Slide 1: Wave Life Sciences Investor Presentation
Wave Life Sciences Investor Presentation January 10, 2022 Exhibit 99.1
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 genetic medicines company
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; HD: Huntington’s disease; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency 1stereopure oligonucleotides and novel backbone chemistry modifications Diversified Pipeline
Slide 4: Biological machinery in our cells can be harnessed to treat genetic diseases
Biological machinery in our cells can be harnessed to treat genetic diseases Silencing Splicing RNA Base Editing Degradation of RNA transcripts to turn off protein production Restore RNA transcripts and turn on protein production Efficient editing of RNA bases to restore or modulate protein function
Slide 5: PRISM enables precision modulation of RNA therapeutic properties
OMe, MOE, F, other modifications PO, PS, PN 5’ modifications, backbone modifications A, T, C, mC, G, U, other modified bases PRISM enables precision modulation of RNA therapeutic properties using unique chemistry toolkit 2’ modifications Backbone chemistry Bases Chiral control of any stereocenter Po
Slide 6: Innovating stereopure backbone chemistry modifications
… … Innovating stereopure backbone chemistry modifications Chirality None PN backbone Sp PN backbone Rp Chirality … … PS backbone Rp PS backbone Sp Chirality … … PRISM backbone linkages PO: phosphodiester PS: phosphorothioate -O -S N (Rp) (Sp) PO PS PN Negative charge Neutral charge Negative charge
Slide 7: Improvements in PRISM primary screen hit rates accelerate drug discovery
Improvements in PRISM primary screen hit rates accelerate drug discovery Primary screen hit rates with silencing far above industry standard hit rates Stereorandom Chemistry, PN stereochemistry & machine learning optimization Stereopure Chemistry improvements and PRISM advancement All screens used i
Slide 8: Silencing potency is enhanced with addition of PN modifications across modalities
Silencing Potency is enhanced with addition of PN modifications across modalities Improved knockdown Splicing Editing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) Concen
Slide 9: Adding PN chemistry to C9orf72-targeting oligonucleotides improved potency in vivo
Adding PN chemistry modifications to C9orf72-targeting oligonucleotides improved potency in vivo Exposure (µg/g) Exposure (µg/g) Cortex %C9orf72 V3 transcript remaining Target knockdown: Liu, TIDES poster 2021; Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best
Slide 10: PN chemistry improves distribution to CNS
PN chemistry improves distribution to CNS NHPs administered 1x12 mg oligonucleotide or PBS by intrathecal injection/lumbar puncture (IT). CNS tissue evaluated 11 or 29 days after injection (n=6 per group). Oligonucleotide was visualized by ViewRNA (red), and nuclei are counterstained with hematoxyli
Slide 11: Single intrathecal dose in NHP leads to widespread target mRNA reduction in CNS
Single intrathecal dose in NHP leads to substantial and widespread target mRNA reduction throughout the CNS Target mRNA knockdown 28 days post-dose (WVE-005) Striatum Control NHPs: Non-human primates NHPs were administered 12 mg on day 1 via IT bolus injection; tissue samples were collected from 3 N
Slide 12: Robust portfolio of stereopure, PN-modified oligonucleotides
THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NEUROLOGY Takeda 50:50 option ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple 100% global DMD Exon 53 100% global HEPATIC AATD SERPINA1 100% global OPHTHALMOLOGY Retinal d
Slide 13: Dramatic increase in effect with PN-modified splicing oligonucleotide in dKO mouse model
100 75 50 25 0 Survival probability (%) 0 4 8 12 16 20 24 28 32 36 40 Time (weeks) Dramatic increase in effect with PN-modified splicing oligonucleotide in dKO mouse model dKO; double knockout mice lack dystrophin and utrophin protein. mdx mice lack dystrophin. dKO: PS/PO/PN 150 mg/kg n= 8 (p=0.0018
Slide 14: PS/PO/PN splicing compound restores respiratory function in dKO mice
PS/PO/PN slicing compound restores respiratory function to wild-type levels in dKO mice Manuscript in press. 10 day old dKO mice received weekly subcutaneous 150 mg/kg doses of PS/PO/PN splicing compound or PBS. Age-matched C57BI/6 wild-type mice were also included in study. Data are presented as me
Slide 15: PS/PO/PN compound restores muscle function to wild-type levels in dKO mice
PS/PO/PN compound restores muscle function to wild-type levels in dKO mice dKO / PBS (6 week old) dKO PS/PO/PN, QW 150mpk (38-41 week old) Wild-type (6 week old) Specific Force (EDL) Eccentric Contraction (EDL) Mdx/utr-/- mice received weekly subQ 150 mpk dose of PS/PO/PN stereopure oligonucleotide
Slide 16: Clinical trial of WVE-N531 underway
Clinical trial of WVE-N531 underway Unmet need in DMD remains high Open-label clinical trial of up to 15 boys with DMD amenable to exon 53 skipping Powered to evaluate change in dystrophin expression Possible cohort expansion driven by assessment of drug distribution in muscle and biomarkers, includ
Slide 17: C9orf72 repeat expansions: one of the most common genetic causes of ALS and FTD
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Typically 100’s-1000’s of GGGGCC repeats Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD) Hexanucleotide (G4C2)- repeat expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Diff
Slide 18: C9orf72 protein is important for normal regulation of neuronal function and immune system
C9orf72 protein is important for normal regulation of neuronal function and the immune system WVE-004 targets hexanucleotide repeat containing transcript variants that lead to loss of normal C9orf72 function and production of pathological mRNA products and toxic dipeptide repeat (DPR) proteins Poly-
Slide 19: Durable reduction in vivo of Poly-GP in spinal cord and cortex after 6 months
* *** ** *** Spinal cord Relative Poly-GP levels (normalized to PBS) Cortex >90% knockdown of Poly-GP DPR protein Two doses of WVE-004 Six months >80% knockdown of Poly-GP DPR protein Relative Poly-GP levels (normalized to PBS) p≤0.0001 Full results presented at the 31st International Symposium on A
Slide 20: FOCUS-C9 clinical trial design
Day 1-3 15 29 57 85 Dose q PK / Biomarker Samples l l l l l Clinical Evaluations l l l l FOCUS-C9 clinical trial: Dose level and dosing frequency guided by independent committee Dose level and dosing frequency guided by independent committee Single ascending dose Dose Level Cohort 1 Cohort 1 Additio
Slide 21: Allele-selective approach to treating HD
Target mutant mRNA HTT transcript to reduce mutant HTT protein Preserve wild-type HTT protein reservoir in brain Allele-selective approach to treating HD Wave has only allele-selective clinical program in Huntington’s disease Only an allele-selective approach is designed to address both toxic gain o
Slide 22: WVE-003 demonstrates selective, potent, and durable reduction of mHTT in preclinical models
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in HD iPSC neurons in vitro Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1. Oligonucleotide or PBS
Slide 23: SELECT-HD clinical trial design
Day 1-3 15 29 57 85 Dose q PK / Biomarker Samples l l l l l Clinical Evaluations l l l l SELECT-HD clinical trial: Dose level and dosing frequency guided by independent committee Dose level and dosing frequency guided by independent committee Single ascending dose Dose Level Cohort 1 Cohort 1 Additi
Slide 24: Unlocking RNA editing with PRISM platform to develop AIMers
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides ADAR enzymes Catalyze conversion of A-to-I (G) in double-stranded RNA substrates A-to-I (G) edits are one of the most common post-transcriptional modifications ADAR1 is ubiquitously expressed across tissues,
Slide 25: AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR
AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Efficient ADAR recruitment AIMer design principles SAR developed to design AIMers for different targets Systematized AIMer d
Slide 26: Opportunity for novel and innovative AIMer therapeutics
Opportunity for novel and innovative AIMer therapeutics SNP: single nucleotide polymorphism A: Adenosine I: Inosine G: Guanosine 1ClinVar database 2Gaudeli NM et al. Nature (2017) 3Keeling KM et al., Madame Curie Bioscience Database 2000-2013 4Luck, K et al. Nature (2020) 5Prasad, TSK et al. Nucleic
Slide 27: Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers
Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR and quantified by Sanger sequencing Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers ACTB editing in primary human hepat
Slide 28: Optimization of every dimension to inform rational design of AIMers
XAX NNN AIMer mRNA target Sequence space is defined >300 unique AIMers tested containing different base pair combinations Identified base modification combinations with high editing efficiency to optimize sequence Optimization of every dimension to inform future rational design of AIMers Motif on ta
Slide 29: Stability of AIMers enables durable and specific editing out to Day 50 in NHP liver
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs Manuscript in press. Left: AIMer PK C: 5mg/kg SC: Day 1,2,3,4,5; Liver biopsy; Right: Dosed 1um AIMer, 48 hrs later RNA collected, RNAseq conducted using strand-specific libraries to quantify on / off-target edit
Slide 30: Substantial in vivo RNA editing out to months post-single dose in CNS tissues
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues Transgenic huADAR mice administered 100 mg AIMer or PBS on day 0 and evaluated for UGP2 editing across CNS tissues at 1, 4, 8, 12, and 16-weeks post dose. Percentage UGP2 editing determined by Sanger sequencing.
Slide 31: RNA editing of MECP2 nonsense mutation restores functional protein
RNA editing of nonsense mutation found in MECP2 (Rett Syndrome) restores functional protein 293T cells transfected with both nonsense mutation on MECP2 (GFP-fusion construct) and ADAR plasmids. AIMers transfected for 48h prior to RNA extraction and sequencing. Percentage editing determined by Sanger
Slide 32: Up to 50% editing in vivo in posterior of eye after single IVT dose
AIMers in retina at 4 weeks ADAR editing: Up to 50% editing in vivo in posterior of eye one month post-single IVT dose Mice received a single IVT injection (10 or 50 ug AIMer), and eyes were collected for RNA analysis and histology 1 or 4 weeks later. Left: editing evaluated by Sanger sequencing, an
Slide 33: Productive editing in multiple NHP tissues with unconjugated systemic AIMer delivery
Achieving productive editing in multiple NHP tissues with unconjugated systemic AIMer delivery NHP study demonstrated productive editing in kidney, liver, lung and heart with single subcutaneous dose PBS ACTB AIMer GalNAc-conjugated (Targeted - subcutaneous) Unconjugated (Local – IVT, IT) Unconjugat
Slide 34: Productive editing in multiple immune cell types with AIMers in vitro
Achieving productive editing in multiple immune cell types with AIMers in vitro Human peripheral blood mononuclear cell (PBMC) CD4+ T-cell CD19 B-cell CD14 Monocytes Tregs T-cell CD8+ T-cell NK NK-cell Human PBMCs dosed with 10 uM ACTB AIMers, under activating conditions (PHA). After 4 days, differe
Slide 35: Expanding addressable disease target space using ADAR editing
Expanding addressable disease target space using ADAR editing to modulate proteins Correction Protein- protein interaction Upregulation Processing Folding (stability) Post-translational modification ADAR editing of mRNA Restore or modify protein function Impact diseases Examples: Familial epilepsies
Slide 36: ADAR to modify protein-protein interactions
Nrf2 activated genes {A:B:C:D} ADAR to modify protein-protein interactions ADAR modified pathway KEAP1 ADAR editing to change one amino acid in KEAP1 or Nrf2 could allow for stabilization of Nrf2 and activation of Nrf2 mediated gene transcription Nrf2 Nrf2 is stabilized Nrf2 translocates to nucleus
Slide 37: ADAR editing activates multiple genes confirming disrupted protein-protein interaction in vitro
Nrf2 mediated gene transcription {A:B:C:D} ADAR editing activates multiple genes confirming disrupted protein-protein interaction in vitro KEAP1 Nrf2 ADAR editing of either KEAP1 or Nrf2 directs gene activation NQO1/mRNA-A Fold increase over control Control Control Fold increase over control Fold in
Slide 38: RNA editing is uniquely suited to address the therapeutic goals for AATD
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver RNA editing is uniquely suited to address the therapeutic goals for AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin; Sources: Strnad 2020; Blanco 2017; R
Slide 39: RNA editing of 40% results in meaningful increases in circulating AAT protein
RNA editing of 40% results in therapeutically meaningful increases in circulating AAT protein SERPINA1 Z allele mRNA editing levels nearing correction to heterozygote (MZ) huADAR/SERPINA1 mice administered PBS or 3 x 10 mg/kg AIMer (days 0, 2, and 4) SC. Samples collected day 7. Stats: One-way ANOVA
Slide 40: RNA editing only detected at PiZ mutation site in SERPINA1 transcript
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing within transcriptome (mouse liver) ADAR editing is highly specific; no bystander editing observed on SERPINA1 transcript SERPINA1 (PiZ mutation site) % Editing Dose 3 x 10mg/kg days (0, 2, 4) SC. Liver bi
Slide 41: ADAR editing restores circulating, functional M-AAT
ADAR editing restores circulating, functional M-AAT Human wild-type M-AAT AAT protein increase Wild-type M-AAT functional Z allele mRNA editing in vivo Wild-type M-AAT detected with ADAR editing ~2.5-fold increase Significant increase in neutrophil elastase inhibition with ADAR editing 3-fold increa
Slide 42: Increase in circulating human AAT is durable
Serum AAT mg/mL PBS PBS SA1-4 SA1-4 Dose Days ns *** *** ** *** 11 mM ** Increase in circulating human AAT is durable, with restored M-AAT detected one month post last dose SA1-4: GalNAc AIMer (Left) huADAR/SERPINA1 mice administered PBS or 3 x 10 mg/kg AIMer (days 0, 2, and 4) SC. AAT levels quanti
Slide 43: Optimized AIMers achieve ~50% mRNA editing and restore AAT protein
Optimized AIMers achieve ~50% mRNA editing and restore AAT protein well above therapeutic threshold Left: AIMers administered huADAR/SERPINA1 mice (3x5 mg/kg) on days 0, 2, and 4. Livers collected on day 7, and SERPINA1 editing was quantified by Sanger sequencing (shown as mean ±. sem) Stats: One-wa
Slide 44: Upcoming milestones throughout 2022 will unlock opportunities
Upcoming milestones throughout 2022 will unlock opportunities Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Liver (Subcutaneous GalNAc) WVE-004 C9orf72 ALS & FTD Clinical data being generated to enable decision making WVE-003 HD SNP3 Clinical data being generated to enable decision m
Slide 45: Realizing a brighter future for people affected by genetic diseases
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations krausch@wavelifesci.com 617.949.4827
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