Wave Life Sciences Ltd. · NASDAQ:WVE

Wave Life Sciences — Oligonucleotide Therapeutics Society 2021

12 slides from Wave Life Sciences's conference presentation, September 2021

  1. Slide 1: Chemically-optimized stereopure oligonucleotides direct ADAR-mediated RNA editing of SERPINA1 transcripts

    Chemically-optimized stereopure oligonucleotides direct ADAR-mediated RNA editing of SERPINA1 transcripts, yielding functional α1-antitrypsin protein in a mouse model for α1-antitrypsin deficiency Prashant Monian Oligonucleotide Therapeutics Society Sept. 26-29, 2021

  2. 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

  3. Slide 3: PRISM enables practical approach to RNA editing without need for viruses or exogenous protein

    PRISM enables practical approach to RNA editing without need for viruses or exogenous protein Wave ADAR-editing oligonucleotides Extracellular space GalNAc Intracellular Endogenous ADAR Unedited Edited RNA RNA 3 No delivery vehicle required No exogenous proteins necessary Potential for reduced of

  4. Slide 4: An ADAR editing approach to correct alpha-1 antitrypsin deficiency

    An ADAR editing approach to correct alpha-1 antitrypsin deficiency Alpha-1 antitrypsin deficiency (AATD) No M-AAT Risk of disease Null Highest risk Most common cause is (no AAT) (lung) mutation in SERPINA1 Z allele (PI*ZZ) Z-AAT PI*ZZ High misfolded protein Inability to secrete (lung + liver) prone

  5. Slide 5: Species differences in ADAR activity necessitate transgenic human ADAR mouse model

    Species differences in ADAR activity necessitate transgenic human ADAR mouse model Mouse hepatocytes huADAR mouse hepatocytes 100 (UGP2) 100 (UGP2) huADAR mouse 80 80 Genotype % Editing % Editing 60 60  huADAR 40 40 Human ADAR expressed 20 20 in all tissues 0 0 0.001 0.01 0.1 1 10 0.001 0.01 0.1 1

  6. Slide 6: Focused on restoring wild-type M-AAT in vivo

    Focused on restoring wild-type M-AAT in vivo NSG-PiZ Genotype huADAR/AATD mouse huADAR/AATD mouse  huSERPINA1-Pi*Z Genotype Pathology Human Z-AAT protein expressed in  huADAR Liver pathology, liver Z-AAT protein huSERPINA1-  in serum and liver Pi*Z huADAR mouse AATD mouse Genotype huADAR Genotype

  7. Slide 7: Achieving 40% editing of Z allele mRNA at single time point

    Achieving 40% editing of Z allele mRNA at single time point SERPINA1 Z allele mRNA editing levels nearing correction to heterozygote (MZ) SERPINA1 editing, in vitro SERPINA1 editing, mouse (Primary hepatocytes) (3x10 mpk, SC) 50 • GalNAc-conjugated huADAR/AATD 100 SA1-3 **** 40 compounds % Editing 8

  8. Slide 8: Achieving therapeutically meaningful increases in circulating human AAT protein

    Achieving therapeutically meaningful increases in circulating human AAT protein 3-fold increase in circulating human AAT as compared to PBS at initial timepoint Human AAT concentration in serum 800 AAT serum levels by genotype 3-fold increase at day 7 Serum AAT (µg/ml) 600 **** PI*MZ ~3 to 5-fold in

  9. Slide 9: ADAR editing restores circulating, functional M-AAT

    ADAR editing restores circulating, functional M-AAT Wild-type M-AAT detected with ADAR editing Significant increase in neutrophil elastase inhibition with ADAR editing % Relative Elastase Inhibition 600 3-fold increase in total AAT 100 ~2.5-fold increase Serum AAT protein (ug/ml) Pre-dose 80 **** Da

  10. Slide 10: Durable increase in serum AAT in mouse model

    Durable increase in serum AAT in mouse model Serum AAT with loading dose Serum AAT (3x10 mpk, SC) (3x10 mpk, SC) 800 M-AAT production 800 Serum AAT µg/mL *** *** 11 µM Serum AAT µg/mL 600 ** 600 Z-AAT ** (E342K mutant) 400 ns *** 400 M-AAT ≥3-fold (wild type) 200 increase 200 0 0 7 14 21 28 35 0 0 7

  11. Slide 11: Optimization further improves mean editing

    Optimization further improves mean editing 50% mean editing observed with 50% lower dose in mice SERPINA1 RNA editing in vitro SERPINA1 RNA editing huADAR mouse (3x5 mpk, SC) 100 * 80 * 60 % Editing 60 40 % Editing 40 20 0 0.001 0.01 0.1 1 10 20 Concentration (µM) 0 SA1-4 SA1-5 SA1-6 PBS SA1-4 SA1-5

  12. Slide 12: Summary

    Summary • Up to 50% editing of SERPINA1 Z allele mRNA in liver, nearing correction to heterozygotes (MZ) • Z allele mRNA editing results in therapeutically meaningful increase in circulating functional wild-type M-AAT protein in vivo • Restoration of wild-type M-AAT is durable • Production of M-AAT

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