Wave Life Sciences Ltd. · NASDAQ:WVE

Wave Life Sciences — 26th Annual ASGCT Meeting 2023

13 slides from Wave Life Sciences's conference presentation, May 17, 2023

  1. Slide 1: RNA base editing for the treatment of Alpha-1 antitrypsin deficiency

    RNA base editing for the treatment of Alpha-1 antitrypsin deficiency Prashant Monian Senior Scientist II, Biology May 17, 2023 26th Annual ASGCT meeting, May 16-20, 2023

  2. Slide 2: Disclosures

    Disclosures Prashant Monian, Chikdu Shivalila, Genliang Lu, Keith Bowman, Marissa Bylsma, Michael Byrne, Megan Cannon, Jigar Desai, Alyse Faraone, Frank Favaloro, Anamitra Ghosh, Jack Godfrey, Nidia Hernandez, Naoki Iwamoto, Tomomi Kawamoto, Jayakanthan Kumarasamy, Pachamuthu Kandasamy, Anthony Lama

  3. Slide 3: 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

  4. Slide 4: AIMers: A-to-I RNA editing oligonucleotides

    AIMers: A-to-I RNA editing oligonucleotides GalNAc-mediated delivery Optimize AIMer design  Substrate learnings from biology and structures  Applied to oligonucleotides ASGR Endocytosis Cytoplasm  Applied PRISMTM chemistry Recycling to Endosomal cell surface release Edited RNA RNA ADAR 1Woolf et

  5. Slide 5: SERPINA1 Z mutation: The most common cause of Alpha-1 antitrypsin deficiency (AATD)

    SERPINA1 Z mutation: The most common cause of Alpha-1 antitrypsin deficiency (AATD) Wild-type M-AAT protein AAT is an acute phase protein Serum AAT protects lungs predominately produced against neutrophil elastase by hepatocytes Gain-of-function and loss-of-function disease Liver Disease Lung Diseas

  6. Slide 6: RNA editing is uniquely suited to address the therapeutic goals of AATD

    RNA editing is uniquely suited to address the therapeutic goals of AATD Wave ADAR editing approach potentially addresses all treatment goals: 1) Restore circulating, 2) Reduce Z-AAT protein 3) Retain M-AAT physiological functional wild-type M-AAT aggregation in liver regulation Risk of disease Null

  7. Slide 7: WVE-006 results in circulating AAT protein levels well above established 11 µM threshold in vivo

    WVE-006 results in circulating AAT protein levels well above established 11 µM threshold in vivo WVE-006 treatment results in serum AAT protein SERPINA1 mRNA editing in liver of levels >11 uM in AATD mouse model (NSG-PiZ mice) AATD mouse model (NSG-PiZ mice, week 13) 2000 PBS SERPINA1 RNA Editing 18

  8. Slide 8: WVE-006 restores serum M-AAT protein in mice, increases serum neutrophil elastase inhibition

    WVE-006 restores serum M-AAT protein in mice, increases serum neutrophil elastase inhibition Correction of loss-of-function Serum M-AAT protein Serum neutrophil elastase phenotypes in NSG-PiZ mice, week 13 inhibition activity Z-AAT M-AAT % Relative Elastase inhibition ns ✱✱✱✱ 100 100 % Serum AAT iso

  9. Slide 9: RNA editing preserves expression of SERPINA1 transgene in liver of treated mice

    RNA editing preserves expression of SERPINA1 transgene in liver of treated mice Mutant mRNA; Wild-type (edited) mRNA; Nucleus SERPINA1 mRNA levels PBS (week 13) (NSG-PiZ mice) ns 1.5 ✱✱✱✱ Relative SERPINA1 mRNA (SERPINA1/HPRT) 1.0 Mean, SEM 10X 63X 0.5 WVE-006 (week 13) 0.0 Baseline PBS WVE-006 Week

  10. Slide 10: WVE-006 decreases lobular inflammation and PAS-D globule size, prevents increase in hepatocyte turnover

    WVE-006 decreases lobular inflammation and PAS-D globule size, prevents increase in hepatocyte turnover Correction of gain-of-function liver Fibrosis  Cirrhosis  Hepatocellular Carcinoma phenotypes Lobular inflammation Mitoses PAS-D-positive globule size (NSG PiZ mice, week 13) (NSG PiZ mice, week

  11. Slide 11: WVE-006 supports dose-dependent RNA editing in human preclinical model systems

    WVE-006 supports dose-dependent RNA editing in human preclinical model systems Efficient SERPINA1 editing in donor-derived Editing in iPSC-derived human hepatocytes primary human hepatocytes with WVE-006 with WVE-006 (ZZ genotype) (MZ genotype) 100 80 WVE-006 90 60 % M-AAT RNA (Mean, SEM) % Editing

  12. Slide 12: Conclusions

    Conclusions • We have developed RNA editing oligonucleotides – AIMers – intended to correct homozygous "ZZ" mutations to an "MZ" heterozygous state, and address both lung and liver phenotypes associated with AATD • Investigational lead, WVE-006, drives serum AAT protein levels in AATD mouse model ab

  13. Slide 13: Thanks to all colleagues and contributors from Wave Life Sciences and our collaborators

    Thanks to all colleagues and contributors from Wave Life Sciences and our collaborators Preclinical RNA editing data published in Nature Biotechnology (March 2022) • Foundational AIMer SAR • GalNAc conjugation • In vitro-in vivo translation (NHPs) • Specificity in vitro & in vivo (NHPs) Monian et al

Wave Life Sciences — 26th Annual ASGCT Meeting 2023 on 6ix