Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation August 17, 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: Unlocking the body's own ability to treat genetic disease
UNLOCKING THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE realizing a brighter future for patients and families
Slide 4: 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 5: Rational design of oligonucleotides enables access to unique disease targets
… … Wave’s ability to rationally design oligonucleotides enables access to unique disease targets 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
Slide 6: Harnessing biological machinery to treat genetic diseases
Harnessing the biological machinery in our cells 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 production
Slide 7: Built-for-purpose candidates to optimally address disease biology
Built-for-Purpose Candidates to Optimally Address Disease Biology Silencing | Splicing | RNA Editing DESIGN Unique ability to construct stereopure oligonucleotides and control three structural features to efficiently engage biological machinery OPTIMIZE Provides the resolution to observe this struct
Slide 8: 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 – lung and liver disease SERPINA1 100% globa
Slide 9: WVE-004 ALS and FTD
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 10: C9orf72 repeat expansions: 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 11: WVE-004 mechanism targeting C9orf72 variants
Reduced expression RNA variants RAN translation C9orf72 protein RNA foci Dipeptide repeat proteins (DPRs) Sense: poly(GA), poly(GR) Antisense: poly(PR), poly(PA) Sense & Antisense: poly(GP) Toxic RNA aggregation Gain-of-function Loss-of-function Repeat-expanded allele Wild-type C9orf72 allele Geneti
Slide 12: Preclinical durable reduction of poly(GP) in spinal cord and cortex
* *** ** *** 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 Liu et al., 2022 Molecular Therapy Nucleic Acids doi: 10.10
Slide 13: WVE-004 clinical data demonstrate translation of preclinical approach
WVE-004 clinical data demonstrate successful translation of preclinical approach to clinic PK: pharmacokinetic PD: pharmacodynamic; Right: Mixed model for repeated measures used to estimate geometric mean ratio to baseline via least squares mean and to calculate p-values. P-values represented by ast
Slide 14: FOCUS-C9 clinical trial underway
30 mg n=10 FOCUS-C9 clinical trial underway 10 mg n=3 60 mg n=4 20 mg n=10 10 mg n=6 4 monthly doses Dose and frequency to be guided by DSMB Target engagement observed in single dose cohorts Single dose Multidose Open-label extension (OLE) clinical trial Initiation anticipated in 2H 2022 Additional
Slide 15: WVE-003 Huntington's Disease
WVE-003 Huntington’s Disease
Slide 16: Huntington's disease and loss of wtHTT functions
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Stresses wtHTT Stresses wtHTT mHTT + ~50% decrease in wtHTT Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration Loss of wtHTT functions Hunti
Slide 17: WVE-003 targets mHTT SNP3 while sparing wtHTT
mHTT, mutant HTT; wtHTT, wild-type HTT; PO, phosphodiester; PS, phosphorothioate; PN, phosphoryl guanidine; wtHTT literature sources: 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
Slide 18: Allele-selective molecule decreases mHTT, spares wtHTT
Hu97/18 mice administered 3x100 mg intracerebroventricular doses PBS or oligonucleotide. Relative mHTT RNA in cortex (left) striatum (middle) or hippocampus (right) at 4, 8 and 12-weeks post-dosing. Data are mean ± SD, n=8. Stats: ns non-significant, *P<0.05, **P<0.01, ***P<0.0001, ****P<0.0001 vers
Slide 19: WVE-003 selective, potent, durable reduction of mHTT preclinically
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 20: WVE-003 achieves concentrations in patient CSF expected to engage target
WVE-003 (allele-selective compound in HD) achieves concentrations in patient CSF expected to engage target Blinded CSF WVE-003 concentrations compared to CSF WVE-120102/WVE-120101 concentrations Demonstrated allele selectivity for mHTT mHTT reduction in cortex and striatum in transgenic mice with WV
Slide 21: 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 22: WVE-N531 Duchenne muscular dystrophy
WVE-N531 Duchenne muscular dystrophy
Slide 23: Duchenne muscular dystrophy
Duchenne muscular dystrophy Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function. Dystrophin protein established by FDA as surrogate endpoint reasonably likely to predict benefit in patients1 fo
Slide 24: PN chemistry improved muscle exposure and survival in mouse models
PN chemistry improved muscle exposure and survival in preclinical mouse models Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN boosted muscle concentrations after single dose, which correlated with exon-skipping activity PN PN Treatment with PN-modified molecules led to 100% survival of dKO mice
Slide 25: PS/PO/PN compound restores muscle and respiratory function in dKO mice
PS/PO/PN splicing compound restores muscle and respiratory function to wild-type levels in dKO mice Left: Mdx/utr-/- mice received weekly subQ 150 mg/kg dose of PS/PO/PN stereopure oligonucleotide (postnatal day 10). Age-matched mdx/utr-/- littermates treated with PBS, wild-type C57BL10 mice not tre
Slide 26: WVE-N531 dystrophin restoration and enhanced muscle distribution in NHPs
WVE-N531: Dystrophin restoration in vitro and enhanced muscle distribution in NHPs Western Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of up to 71% in vitro Plasma and tissue concentrations of WVE-N531 (PS/PO/PN) significantly higher than suvodirsen (1st-g
Slide 27: WVE-N531 dosing in dKO model and plasma concentrations
dKO mouse model Currently dosing at human equivalent doses in the range explored in preclinical dKO model Plasma WVE-N531 concentrations compared to plasma suvodirsen concentrations Treatment with PN-modified molecules led to 100% survival of dKO mice at time of study termination Dosing underway at
Slide 28: Dose escalation ongoing in clinical trial of WVE-N531
Cohort expansion to be guided by assessment of muscle biopsies: (drug distribution in muscle and biomarkers) Dose escalation ongoing in clinical trial of WVE-N531 Open-label clinical trial of boys with DMD amenable to exon 53 skipping Dose level and dosing frequency guided by tolerability and plasma
Slide 29: WVE-006 Alpha-1 antitrypsin deficiency (AATD)
WVE-006 Alpha-1 antitrypsin deficiency (AATD)
Slide 30: WVE-006 designed to correct mutant AATD transcript
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver WVE-006: designed to correct mutant AATD transcript to address both liver and lung manifestations of AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin Strn
Slide 31: AATD AIMer restores M-AAT protein and alleviates liver aggregation
AATD AIMer restores functional M-AAT protein and alleviates liver aggregation in preclinical model GalNAc AIMer (SA1-5) administered bi-weekly (10 mg/kg) following initial loading dose (3 x 10 mg/kg) in huADAR/SERPINA1 mice (8–10 weeks old); Left: Neutrophil elastase inhibition assay (pre-dose, week
Slide 32: WVE-006 yields AAT levels above 11µM threshold in vivo
WVE-006 results in circulating AAT protein levels well above established 11µM threshold in vivo WVE-006 treatment results in serum AAT protein levels >11 uM in AATD mouse model (NSG-PiZ mice) Restored AAT protein WVE-006 is a GalNAc-conjugated AIMer (A to I(G) RNA base editing oligonucleotide); WVE-
Slide 33: RNA editing only detected at PiZ mutation site
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 34: WVE-006 efficient editing in primary human hepatocytes
WVE-006 results in efficient editing in primary human hepatocytes, further supporting strong candidate profile Primary human hepatocytes from an MZ donor treated with WVE-006 (GalNAc AIMer) at indicated doses for 48 hrs; SERPINA1 editing was quantified by Sanger sequencing Note: Due to MZ genotype,
Slide 35: AIMers RNA base editing capability
AIMers RNA base editing capability
Slide 36: PRISM platform to develop AIMers
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides Endogenous ADAR enzymes 1Woolf et al., PNAS Vol. 92, pp. 8298-8302, 1995; Right: Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site
Slide 37: AIMers: realizing potential of therapeutic RNA editing
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 38: Preclinical RNA editing data published in Nature Biotechnology
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022) Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 SAR structure-activity relationship Specificity in vitro & in vivo (NHPs) In vitro-in vivo translation (NHPs) GalNAc conjugat
Slide 39: Potent, durable, specific editing and efficient delivery
Editing: Potent, durable, specific A à I (G) RNA editing Delivery: Efficient RNA editing in preclinical in vivo models: Targeted delivery (GalNAc) Systemic delivery Local delivery (IT, IVT, others) Potential to accelerate timelines to candidate with AIMer pipeline expansion Systemic in vivo editing
Slide 40: Expanding addressable disease target space using AIMers
Expanding addressable disease target space using AIMers to activate pathways and upregulate expression Correct G-to-A driver mutations with AIMers Modulate protein-protein interaction Upregulate expression Modify function Post-translational modification Alter folding or processing Restore or correct
Slide 41: Dose-dependent gene upregulation following Nrf2 editing
n=2; Primary hepatocytes 48h of treatment with the indicated dose concentration of AIMers NRF2 is degraded by proteasome NRF2 KEAP1 Transcription is repressed ADAR editing site NRF2 is stabilized KEAP1 NRF2 Transcription is activated Basal conditions ADAR-modified conditions AIMer RNA editing effici
Slide 42: AIMers enable activation of gene pathway in vivo
Note: Editing percentage for UGP2 control AIMer indicates editing of UGP2 mRNA Methods: hADAR C57BL/6 mice dosed subQ (days 0, 2, 4) at 10mg/kg GalNAc-conjugated AIMers. Livers harvested (day 7), analyzed for editing and NQO1 expression via Sanger sequencing or qPCR, respectively. Data analyzed via
Slide 43: AIMers can edit RNA motifs to upregulate gene expression
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression mRNA RNA binding proteins recognize sequence motifs to regulate various mRNA properties Stability Inhibit or enhance mRNA decay Processing Splicing PolyA usage Capping Transport Intracellular localization Protein produ
Slide 44: 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 45: Wave's discovery and drug development platform
Wave’s discovery and drug development platform
Slide 46: Improvements in PRISM primary screen hit rates
Improvements in PRISM primary screen hit rates accelerate drug discovery over time 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 scre
Slide 47: Silencing potency enhanced with 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 48: PN chemistry improved potency of C9orf72-targeting oligonucleotides 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 Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% confidence intervals (
Slide 49: 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 50: PRISM PN siRNA silencing of HSD17B13
*** **** Single dose (3 mg/kg) PRISM PN siRNA loaded in RISC is significantly greater than Adv. ESC siRNA PBS PRISM PN siRNA led to unprecedented silencing as compared to state-of-art >3 months after single dose Adv. ESC siRNA (stereorandom) PRISM PN siRNA (stereopure) ~80% silencing HSD17B13 mRNA i
Slide 51: Established internal GMP manufacturing
Established internal GMP manufacturing for multiple oligonucleotide modalities Strong technical knowhow and operating expertise Established infrastructure State of the art facilities (90,000 sq ft) and expansion space Process and analytical development labs GMP oligonucleotide (API) manufacturing Es
Slide 52: Upcoming milestones
Upcoming milestones
Slide 53: Pipeline with multiple clinical datasets expected in 2H 2022
Differentiated RNA therapeutics pipeline with multiple clinical datasets expected in 2H 2022 Additional data generated in 2022 expected to further inform future opportunities and unlock value Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Targeted delivery liver (Subcutaneous) WVE-004
Slide 54: 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