Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — 18th Annual Meeting of the Oligonucleotide Therapeutics Society (October 2022)
24 slides from Wave Life Sciences's conference presentation, Oct 4, 2022
Slide 1: Phosphoryl-guanidine backbone chemistry: understanding its impact on stereopure oligonucleotides
Phosphoryl-guanidine backbone chemistry: understanding its impact on stereopure oligonucleotides Chandra Vargeese, PhD Chief Technology Officer, Head of Platform Discovery Sciences October 4, 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: PRISM platform enables rational drug design
PRISM platform enables rational drug design Sequence Chemistry O 5’ B B B: bases R: 2’ modifications O A, T, C, mC, G, U, OMe, MOE, F, - 3’ 2’ other modified bases R other modifications XX O R P O O 5’ B X: backbone chemistry O PO, PS, PN 3’ 2’ O R R Stereochemistry Chiral control of any stereocente
Slide 4: Wave's ability to rationally design oligonucleotides enables access to unique disease targets
Wave’s ability to rationally design oligonucleotides enables access to unique disease targets PRISM backbone linkages PO PS PN (Sp) (Rp) -O -S N … … … … … … Phosphoryl guanidine Chirality Chirality Chirality x-ray structure None PS backbone Rp PN backbone Rp PS backbone Sp PN backbone Sp Negative Ne
Slide 5: PN backbone and monomer library for stereopure oligonucleotide synthesis
PN backbone and monomer library for stereopure oligonucleotide synthesis Chiral monomers Candidate Stereorandom O O – Tunable ‘R’ groups Optimization P – Std base protecting groups and Selection S O O BPG – Various 2’-modifications O – Manufactured in multi kilos Rp PS O O O O R S P O PS P O BPG O O
Slide 6: Harnessing the biological machinery in our cells to treat genetic diseases
Harnessing the biological machinery in our cells to Silencing Splicing treat genetic diseases Editing Silencing Splicing RNA Base Editing • Degradation of RNA transcripts • Restore RNA transcripts and • Efficient editing of RNA bases to turn off protein production turn on protein production to resto
Slide 7: Potency is enhanced with addition of PN modifications across modalities
Potency is enhanced with addition of PN Silencing Splicing modifications across modalities Editing Silencing Splicing Editing Target knockdown (% remaining) % Skipping % Editing 100 Improved knockdown 80 Improved skipping Improved editing % Editing 60 40 20 0 10 -8 10 -6 10 -4 10 -2 10 0 10 2 Ranked
Slide 8: WVE-004 treatment resulted in durable reduction of poly-GP biomarker in mouse spinal cord & cortex
WVE-004 treatment resulted in durable reduction Silencing of poly-GP biomarker in mouse spinal cord & cortex1 Silencing – RNase H • WVE-004 leads to variant-selective silencing of C9orf72 transcripts Endogenous Contains PN chemistry RNase H Lowers expansion-containing transcripts Preserves hea
Slide 9: Potent, durable and allele-selective knockdown demonstrated in preclinical studies
Potent, durable and allele-selective knockdown Silencing demonstrated in preclinical studies Durable mHTT knockdown for 12 weeks with Multiple doses of allele-selective molecule multiple doses of WVE-003 in cortex* decreases mHTT, spares wtHTT in cortex* (BACHD mouse) (Hu97/18 mouse) Relative mHTT R
Slide 10: Durable HSD17B13 silencing is driven in part by Ago2 loading advantage
Durable HSD17B13 silencing is driven in part by Silencing Ago2 loading advantage • ~80% silencing HSD17B13 mRNA 14-weeks Silencing – RNAi post-single dose with PN-containing siRNA Endogenous AGO2 3 mg/kg SC dose mRNA (day 1) • Significantly more Ago2-loading than (liver) Human HSD17B13 RISC transgen
Slide 11: PN-containing molecule restores dystrophin expression and prolongs survival in severe mouse model for DMD
PN-containing molecule restores dystrophin expression and Splicing prolongs survival in severe mouse model for DMD Increased survival in dKO mice Splicing R2: 75 mg/kg, bi-weekly SC PBS PS/PO utr/mdx23 dKO mice PN/PS/PO PS/PO R1 Dosing regimens PN/PS/PO R2 R1: 150 mg/kg weekly Restored Reading Frame
Slide 12: PN-containing molecule restored healthy respiratory function in severe mouse model for DMD
PN-containing molecule restored healthy respiratory Splicing function in severe mouse model for DMD Respiratory profiles in DMD-2788-treated dKO mice matched wild-type mice in 6-week study Dosing regimen (150 mg/kg weekly) Plethysmography recording day 21 35 47 10 17 24 31 38 45 Dosing day PBS (dKO)
Slide 13: Expanding addressable disease target space using AIMers to activate pathways and upregulate expression
Expanding addressable disease target space using AIMers to activate pathways and upregulate expression Correct G-to-A driver mutations with AIMers Modulate protein interactions with AIMers Restore or correct Modulate protein- protein function protein interaction Achieved POC Upregulate expression WV
Slide 14: Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs Editing AIMers detected in liver Substantial and durable ADAR editing with ACTB of NHP at Day 50 editing in NHP liver in vivo AIMer is highly specific (PK) (PD) RNA editing within full transcriptome (primary huma
Slide 15: Dose-dependent modulation of protein-protein interactions
Dose-dependent modulation of protein-protein interactions Dose-dependent gene upregulation (NQO1) in Editing vitro following Nrf2 editing to disrupt protein/protein interaction KEAP1 RNA editing efficiency Gene NQO1upregulation NRF2 % Editing qPCR UGP2 (Control) 0.0016uM NRF2 is 0.0016uM degraded by
Slide 16: AIMers enable activation of gene pathway in vivo with single edit
AIMers enable activation of gene pathway in vivo with single edit Editing Nrf2 downstream gene upregulation following GalNAc-AIMer Nrf2 Nrf2 mRNA liver editing editing in vivo in vivo in liver of mRNA editing in vivo in liver of mice mice with GalNAc AIMers Nrf2 activation Nrf2 activation of of NQO1
Slide 17: Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression Editing RNA binding proteins recognize sequence motifs to regulate various mRNA properties Stability Transport Processing Protein production • Enhance or inhibit • Intracellular localization • Splicing • PolyA usage •
Slide 18: AIMers can edit RNA motifs to upregulate gene expression in hepatocytes and T cells in vitro
AIMers can edit RNA motifs to upregulate gene expression in hepatocytes and T cells in vitro Editing RNA motifs to regulate RNA half-life to upregulate RNA expression is possible for clinically-relevant targets, including both metabolic and immune targets Target A Target B Target C Target D 15 5 8 8
Slide 19: AIMers upregulate mRNA and downstream serum protein in vivo in mice
AIMers upregulate mRNA and downstream serum protein in vivo in mice Editing Target A mRNA editing mRNA upregulation Protein upregulation (undisclosed liver 7-days post-initial dose in mice 7-days post-initial dose in mice 7-days post-initial dose in mice target) GalNAc-AIMer GalNAc-AIMer GalNAc-AIMe
Slide 20: Systemic in vivo editing without delivery vehicles
Systemic in vivo editing without delivery vehicles Editing Substantial RNA editing across multiple tissues in mice following single subcutaneous dose of UGP2 AIMer Control Specific liver associated cells UGP2 AIMer (unconjugated) T cell Cholan- Macro- NK cell LSEC giocyte phage subset Editing: Poten
Slide 21: Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues Editing UGP2 AIMer-1 Peak RNA editing observed one-month post-single dose across mouse tissues PBS Peak editing 30% >40% 25% >40% 50% >65% Transgenic huADAR mice administered 100 µg AIMer or PBS on day 0 and eva
Slide 22: PN modification improves cellular uptake and target engagement for AIMers
PN modification improves cellular uptake and target engagement for AIMers Editing Increases AIMer abundance following 6-hr Increases % editing independent of delivery, treatment pulse, suggesting improved suggesting improved target engagement cellular uptake Ranking of AIMer Editing Efficiency (prim
Slide 23: Summary
Summary • We’ve developed methods that support stereopure oligonucleotide synthesis – Scalable (high-throughput to commercial manufacture) – Stereopure – Enables chimeric backbone structure – Excellent yields • Backbone chemistry and stereochemistry profoundly impact oligonucleotide pharmacology • P
Slide 24: Impact of PN chemistry highlighted in three high-impact publications this year
Impact of PN chemistry highlighted in three high- impact publications this year Silencing Splicing RNA Editing Thanks to all colleagues and contributors from Wave Life Sciences and our collaborators 24