Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — 18th Annual Meeting of the Oligonucleotide Therapeutics Society (October 2022)
12 slides from Wave Life Sciences's conference presentation, Oct 5, 2022
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, PhD Senior Scientist I, Biology Oct. 5, 2022 Presented at 18th Annual Meeting of the Oligonucleotide Therapeutics Society
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: Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022)
Proof-of-concept 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., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 S
Slide 4: 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
Slide 5: 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 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 Highest (no
Slide 6: WVE-006 results in circulating AAT protein levels well above established 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 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
Slide 7: Restoration of serum M-AAT protein
Restoration of serum M-AAT protein ~50% Serum M-AAT protein Correction of loss-of-function in NSG-PiZ mice phenotypes (Week 13) 100 % Serum AAT isoform Z-AAT 80 M-AAT (mean, SEM) 60 40 20 Restored M-AAT reaches lungs 0 to protect from proteases GalNAc-conjugated AIMers administered in 7-week old NSG
Slide 8: Restoration of functional serum M-AAT protein that neutralizes protease activity in mice
Restoration of functional serum M-AAT protein that neutralizes protease activity in mice Increased neutrophil elastase Serum Neutrophil Elastase inhibition activity demonstrates Inhibition Activity functionality of AAT protein % Relative Elastase inhibition ns ✱✱✱✱ • Increases in neutrophil elastase
Slide 9: Treatment with WVE-006 maintains SERPINA1 mRNA levels relative to baseline in NSG-PiZ mice
Treatment with WVE-006 maintains SERPINA1 mRNA levels relative to baseline in NSG-PiZ mice Z-AAT aggregation causes loss of hepatocytes SERPINA1 mRNA levels expressing transgene in this mouse model (NSG-PiZ mice) ns Fibrosis Cirrhosis Hepatocellular Carcinoma 1.5 ✱✱✱✱ Relative SERPINA1 mRNA (SER
Slide 10: SERPINA1 AIMer reduces aggregation of Z-AAT and inflammation in mouse liver
SERPINA1 AIMer reduces aggregation of Z-AAT and inflammation in mouse liver PAS-D staining Lobular inflammation (19 weeks) (19 weeks) AATD AIMer Early lead AATD AIMer Early lead PBS PBS PAS-D-positive area PAS-D globule size (19 weeks) Lobular inflammation 15 (19 weeks) 25 **** area PBS * Mean diame
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, s.e.m) (mean, s
Slide 12: CTA submissions for WVE-006 expected in 2023
CTA submissions for WVE-006 expected in 2023 • Our RNA base editing platform capability allows for correction of the most common causative mutation for AATD in preclinical models • We have developed RNA editing oligonucleotides – AIMers – intended to correct homozygous "ZZ" mutations to an "MZ" hete