Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — American Society for Gene & Cell Therapy 27th Annual Meeting (May 2024)
15 slides from Wave Life Sciences's conference presentation, May 10, 2024
Slide 1: Potent, Durable mRNA Knockdown in Extrahepatic Tissues Using siRNAs With Novel Phosphoryl Guanidine Backbone Variants
Potent, Durable mRNA Knockdown in Extrahepatic Tissues Using siRNAs With Novel Phosphoryl Guanidine Backbone Variants Wei Liu, Principal Scientist, Biology May 10, 2024 Presented at the American Society for Gene & Cell Therapy 27th Annual Meeting
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: Disclosures
Disclosures Wei Liu, Naoki Iwamoto, Subramanian Marappan, Himali Shah, Snehlata Tripathi, Erin Purcell-Estabrook, Khoa Luu, Anthony Lamattina, Qianli Pan, Fangjun Liu, Frank Favaloro, Arindom Chatterjee, Tomomi Kawamoto, Genliang Lu, Jake Metterville, Priyanka Shiva Prakasha, Hailin Yang, Yuan Yin,
Slide 4: Oligonucleotide-directed gene silencing by RNA interference
Oligonucleotide-directed gene silencing by RNA interference siRNA induce mRNA degradation GalNAc conjugation mediates hepatocyte delivery of siRNA1 Endogenous AGO2 mRNA (liver) RISC siRNA Extrahepatic tissue targeting remains a major challenge for the field 4 1Zhang L, Liang Y, Liang G, Tian Z, Zhan
Slide 5: 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 O 5’ B B O B Base - 3’ 2’ XX O R P R R 2’-Ribose O O 5’ B B O Stereochemistry and X backbone modification 3’ R 2’ O R Phosphoryl guanidine (PN-1) Phosphorothioate (PS) Phosphodiester (PO) 5
Slide 6: Incorporation of PN chemistry improves GalNAc-siRNA potency and durability in mice
Incorporation of PN chemistry improves GalNAc-siRNA potency and durability in mice Ago2 loading in liver Ttr mRNA in liver Ago2 loading in liver (C57BL/6J mice) (C57BL/6J mice) Serum Ttrprotein Serum Ttr protein (C57BL/6J mice) 25 (C57BL/6J mice) (C57BL/6J mice) * 150 125 20 Relative fold change (Tt
Slide 7: Wave's new design for GalNAc-siRNA demonstrates improved durability in mice
Wave’s new design for GalNAc-siRNA demonstrates improved durability in mice 125 PBS 100 Reference siRNA1 Serum Ttr ±SEM Liu et al. NAR 2023 design siRNA2 (rel to PBS) 75 * New design siRNA 50 * 25 * 0 0 5 10 15 20 25 30 35 40 45 50 Day 0.5 mpk SubQ Serum collection 7 1Foster, DJ. et.al. Mol Ther. 20
Slide 8: Wave's platform chemistry enables siRNA extrahepatic delivery
Wave’s platform chemistry enables siRNA extrahepatic delivery • Chemical impact of PN - Introduction of neutral pKa backbone linkages - Unique structural feature of PN, specifically guanidine, allows conjugation on oligonucleotide outside of 5’ and 3’ ends - Increased lipophilicity - Stereochemistry
Slide 9: Single dose of siRNA with PN variant (PN-2) linkages delivers broad, potent and durable CNS target engagement in mice
Single dose of siRNA with PN variant 2 (PN-2) linkages delivers broad, potent and durable CNS target engagement in mice D0 W8 W16 ICV 100 ug Necropsy Necropsy App siRNA Week 8 Week 16 125 %mRNA remaining (SEM) 100 PBS App silencing (App/Hprt) **** **** **** **** **** **** 75 **** **** **** **** ****
Slide 10: Single dose of siRNA incorporating PN-2 supports durable protein knockdown across the mouse CNS
Single dose of siRNA incorporating PN-2 supports durable protein knockdown across the mouse CNS D0 W8 W16 Frontal Cortex Striatum Hippocampus Cerebellum Brain Stem ICV 100 ug Necropsy Necropsy App siRNA PBS 8 weeks post-dose App siRNA PBS 16 weeks post-dose App siRNA Brown: App Blue: Nuclei 10 C57BL
Slide 11: Tunable PN variants enhance single-dose potency and alter extra-hepatic delivery of non-GalNAc siRNA in mice
Tunable PN variants enhance single-dose potency and alter extra- hepatic delivery of non-GalNAc siRNA in mice 200 (Sod1/Hprt) relative to PBS Liver White adipose Brown adipose %Sod1 mRNA remaining ns ns ns ns ns 150 **** * PN-1 siRNA 100 PBS PN-2 siRNA **** 50 **** **** D0 D14 D28 **** **** 5 mpk So
Slide 12: Tunable PN variants alter tissue delivery and target engagement of non-GalNAc siRNA after a single dose in mice
Tunable PN variants alter tissue delivery and target engagement of non- GalNAc siRNA after a single dose in mice 150 Liver Kidney ns %mRNA remaining relative to PBS * PBS (Sod1/Hprt) 100 PN-1 siRNA **** ** **** **** PN-3 siRNA 50 *** *** D0 D14 D28 0 5 mpk Sod1 Necropsy Necropsy 14 28 14 28 siRNA Su
Slide 13: Tunable PN variants enhance single-dose siRNA potency in mouse heart and muscle
Tunable PN variants enhance single-dose siRNA potency in mouse heart and muscle Quad Heart Diaphragm ns 150 % mRNA remaining ns relative to PBS ns ns ns ns (Sod1/Hprt) 100 PBS PN-1 siRNA **** **** PN-2 siRNA 50 **** **** **** **** D0 D14 D28 0 14 28 14 28 14 28 5 mpk Sod1 Necropsy Necropsy Day siRNA
Slide 14: Summary
Summary • PRISMTM, our discovery and drug development platform, enables the development of a new siRNA chemistry design that improves durability and leverages the chemical flexibility of PN linkages to improve potency and enhance extra-hepatic delivery in mice. • Applying the new stereopure design t
Slide 15: Acknowledgements
Acknowledgements • Thanks to all colleagues and contributors from Wave Life Sciences and our collaborators. • Nicole Neuman, Wave Life Sciences, assisted in preparing this presentation. Silencing (RNase H and Ago2) Splicing Editing 15 Selected Wave publications: PMC10201370, PMC9092894, PMID 3525681
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