Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Oligonucleotides & Precision Therapeutics, March 15-16, 2022
17 slides from Wave Life Sciences's conference presentation, Mar 15, 2022
Slide 1: Chemically optimized stereopure oligonucleotides direct ADAR-mediated RNA editing
Chemically optimized stereopure oligonucleotides direct ADAR- mediated RNA editing Paloma H Giangrande, PhD Vice President, Platform Discovery Sciences Biology Oligonucleotides & Precision Therapeutics March 15-16, 2022
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: 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 predominately Serum AAT protects lungs produced by hepatocytes against neutrophil elastase Strnad et al., 2020 N Engl J Med 382:1443-55; Stoller et al., 1993 Alpha-1 Antitrypsin Deficie
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 predominately Serum AAT protects lungs produced by hepatocytes against neutrophil elastase Gain-of-function and loss-of-function disease Liver Disease Lung Disease Fibrosis Cirrhosis
Slide 5: RNA base editing is uniquely suited to address the therapeutic goals for AATD
RNA base editing is uniquely suited to address the therapeutic goals for AATD Wave ADAR editing approach addresses goals of treatment: 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
Slide 6: Unlocking RNA editing with PRISM to develop GalNAc-AIMers: A-to-I editing oligonucleotides
Unlocking RNA editing with PRISMTM to develop GalNAc-AIMers: A-to-I editing oligonucleotides Optimize AIMer design for endogenous transcripts and GalNAc conjugation GalNAc-mediated uptake ADAR enzymes PRISM-driven gains • First publication (1995) using oligonucleotide to edit RNA with endogenous ADA
Slide 7: AIMers: Realizing potential of therapeutic RNA base editing by harnessing endogenous ADAR
AIMers: Realizing potential of therapeutic RNA base editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Delivery and Efficient ADAR Efficient ADAR recruitment Stability intracellular Beyond liver recruitment trafficking •
Slide 8: Proof-of-concept RNA editing in NHP liver is durable and specific
Proof-of-concept RNA editing in NHP liver is durable and specific AIMers detected in liver of NHP Substantial and durable editing ADAR editing with ACTB AIMer is at day 50 in NHP liver in vivo highly specific pre-dose RNA editing within full transcriptome (primary human hepatocytes) GalNAc AIMers Da
Slide 9: Proof-of-concept preclinical RNA editing data published in Nature Biotechnology
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology Specificity in vitro & in vivo (NHPs) In vitro-in vivo translation (NHPs) GalNAc conjugation Foundational AIMer SAR Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 SAR structure-activity
Slide 10: Robust SERPINA1 RNA base editing in mouse model for AATD restores M-AAT protein in serum
Robust SERPINA1 RNA base editing in mouse model for AATD restores M-AAT protein in serum RNA editing in mice AAT serum protein concentration in mice day 7 (3x5 mg/kg, SC) day 7 (3x10 mg/kg, SC) * 60 1000 1000 MZ (50%) % SERPINA1 editing 800 800 Serum AAT protein (ug/ml) 40 (Mean, s.e.m) 600 11 µM 60
Slide 11: Bi-weekly AIMer treatment results in serum AAT protein levels in mice above anticipated therapeutic threshold
Bi-weekly AIMer treatment results in serum AAT protein levels in mice above anticipated therapeutic threshold GalNAc-AIMer results in serum AAT protein levels >11 uM at week 19 in transgenic mice 1200 18.5 uM Serum AAT protein (µg/mL) 1000 SA1-5 (Mean, SEM) 800 600 11 uM ~5-fold increase 400 in AAT
Slide 12: Bi-weekly AIMer treatment supports robust RNA editing and M-AAT protein expression in mice
Bi-weekly AIMer treatment supports robust RNA editing and M-AAT protein expression in mice GalNAc-AIMer results in serum AAT protein levels >11 uM ~60% RNA editing & ~70% serum M-AAT protein at week 19 in transgenic mice (week 19 data) 1200 18.5 uM Serum AAT protein (µg/mL) 80 SA1-5 100 % Serum AAT
Slide 13: Further analyses suggest functional effects in mouse liver at 19 weeks
Further analyses suggest functional effects in mouse liver at 19 weeks GalNAc-AIMer results in serum AAT protein levels >11 uM ~60% RNA editing & ~70% serum M-AAT protein at week 19 in transgenic mice (week 19 data) 80 100 % Serum AAT Isoform % SERPINA1 editing 1200 PiZ (Mutant) 60 80 PiM (WT) 18.5
Slide 14: AIMer-directed editing is highly specific in mice; no bystander editing observed on SERPINA1 transcript
AIMer-directed editing is highly specific in mice; no bystander editing observed on SERPINA1 transcript RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing across transcriptome (mouse liver) C 0% SERPINA1 PBS (PiZ mutation site) T 100% Coverage Coverage C
Slide 15: Opportunity for novel and innovative AIMer therapeutics
Opportunity for novel and innovative AIMer therapeutics Correct driver mutations with AIMers Free-uptake of chemically modified oligonucleotides Restore or correct protein function Examples AATD Rett syndrome Recessive or dominant genetically defined diseases Examples Haploinsufficient diseases Loss
Slide 16: Efficient and durable editing in mouse CNS with unconjugated AIMer
Efficient and durable editing in mouse CNS with unconjugated AIMer huADAR Peak editing observed 4-weeks post-single ICV dose across tissues mice Cortex Hippocampus Striatum Brain stem Cerebellum Spinal cord Peak editing 30% >40% 25% >40% 50% >65% Transgenic huADAR mice were administered 100 µg AIMer
Slide 17: Acknowledgements
Acknowledgements • Colleagues and contributors from Wave Life Sciences 17
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