Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Technical Presentation (October 2018)
23 slides from Wave Life Sciences's technical presentation, Oct 3, 2018
Slide 1: Stereochemical Control of Antisense Oligonucleotides Enhances Target Efficacy
Stereochemical Control of Antisense Oligonucleotides Enhances Target Efficacy Chandra Vargeese, PhD SVP, Drug Discovery Wave Life Sciences October 3, 2018 Exhibit 99.1
Slide 2: Acknowledgements & Disclosures
Acknowledgements & Disclosures All Wave Life Sciences employees Prof. Gregory Verdine, co-founder & Director Wave Life Sciences Prof. Takeshi Wada, co-founder Wave Life Sciences Prof. Matthew Wood, Department of Physiology, Anatomy and Genetics, University of Oxford Chandra Vargeese is an employee o
Slide 3: 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 4: Architects of transformation
Architects of transformation Wave Life Sciences is a clinical-stage, genetic medicines company unlocking the potential of a proprietary chemistry platform that enables the precise design, optimization and production of stereopure nucleic acid therapies. Wave has reinvented the design, synthesis and
Slide 5: History of oligonucleotide therapeutics
History of oligonucleotide therapeutics Backbone modifications • Introduce chiral centers • Generate mixtures Sugar modifications Drug approvals (FDA) Chiral Phosphorothioate Chiral Phosphorodiamidite Morpholino (PMO) Mixtures of 2n molecules (n=No. of chiral centers) SEQUENCE STEREOCHEMISTRY CHEMIS
Slide 6: Advances in stereopure oligonucleotide synthesis and manufacturing
Advances in stereopure oligonucleotide synthesis and manufacturing Versatility in Chemistry Versatility in Scale High Crude Purity • Improved synthetic capabilities • Custom building blocks – Tunable ‘R’ groups – Various 2’-modifications Candidate Optimization and Selection GMP Quality High-throughp
Slide 7: Wave's chemistry platform
Wave’s chemistry platform INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY DESIGN & OPTIMIZE VALIDATE SEQUENCE STEREOCHEMISTRY CHEMISTRY Free uptake in cellular models Animal models POTENCY STABILITY SPECIFICITY IMMUNE POTENCY DURABILITY TOXICOLOGY Candidates
Slide 8: Wave's chemistry platform: Antisense
INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY DESIGN & OPTIMIZE VALIDATE SEQUENCE STEREOCHEMISTRY Free uptake in cellular models Animal models POTENCY STABILITY SPECIFICITY IMMUNE POTENCY DURABILITY TOXICOLOGY Candidates CHEMISTRY Wave’s chemistry platform: A
Slide 9: Precision RNase H-mediated RNA degradation
Precision RNase H-mediated RNA degradation Antisense In RNase H1 assay, ASOs were pre-annealed to surrogate MALAT1 mRNA (1:1, Cf=5 mM). RNase H (250:1, E:S) was added and quenched with EDTA at the indicated times. Products were quantified, and V0 was calculated from the best-fit line (n=3 per time p
Slide 10: Potency of stereopure oligonucleotides under in vitro free-uptake conditions translates in vivo
Potency of stereopure oligonucleotides under in vitro free-uptake conditions translates in vivo In vitro: In iCell neurons, 10, 30, 100, 300, 1,000 or 3,000 nM ASO was added to iCell neurons under free-uptake conditions. 4-days post-treatment, RNA was harvested and processed. MALAT1 mRNA expression
Slide 11: Stereopure oligonucleotides enhance potency across tissues in vivo
Stereopure oligonucleotides enhance potency across tissues in vivo Muscle Single SC injection in Mice (25 mg/kg) Eye Single IVT injection in Mice (50 µg) CNS Single ICV injection in Mice (50 µg) Antisense Tissues were harvested 1 week post-dose and processed for RNA. mRNAs were quantified by qPCR. P
Slide 12: Stereopure oligonucleotides induce potent and durable activity in the eye
Stereopure oligonucleotides induce potent and durable activity in the eye Tissues were harvested at the indicated time points, post-dose and processed for RNA. mRNAs were quantified by qPCR. Plots show percentage mRNA remaining with respect to control mRNA. Each symbol represents one animal. 9-fold
Slide 13: Stereopurity improves potency and durability of GalNAc-conjugated oligonucleotides
Stereopurity improves potency and durability of GalNAc-conjugated oligonucleotides Antisense Stereopure ASO yields potency comparable to state-of-the-art GalNAc-dsRNAi Stereopure ASO yields durable effect in transgenic mice
Slide 14: Wave's chemistry platform: Splicing
INDICATION, TARGET TRANSCRIPT, PRODUCT PROFILE SPLICING RNAi ANTISENSE DEFINE MODALITY DESIGN & OPTIMIZE VALIDATE Free uptake in cellular models Animal models POTENCY STABILITY SPECIFICITY IMMUNE POTENCY DURABILITY TOXICOLOGY SEQUENCE STEREOCHEMISTRY CHEMISTRY Candidates Wave’s chemistry platform: S
Slide 15: Stereopure oligonucleotides induce exon skipped transcript
Stereopure oligonucleotides induce exon 23 skipped transcript (OTS poster #119) Splicing Stereorandom (SR) Stereopure
Slide 16: Stereopure oligonucleotide induces dystrophin protein restoration and reduces elevated serum enzymes
Stereopure oligonucleotide induces dystrophin protein restoration and reduces elevated serum enzymes Splicing Multiple Doses (in vivo mdx23 mice) 70-90% of natural dystrophin restoration 87% reduction in creatine kinase levels ALT=alanine aminotransferase; AST=aspartate aminotransferase; CK=creatine
Slide 17: Stereopure surrogate restores dystrophin in muscle fibers after single dose
Stereopure surrogate restores dystrophin in muscle fibers after single dose Neuro DMD PBS DMD-1742 Immunohistochemistry of dystrophin in gastrocnemius in mdx23 mice at 4 weeks 10X Experimental conditions: mdx23 mice received a single IV injection of PBS or DMD-1742 (150 mg/kg). Immunohistochemistry:
Slide 18: Stereopure surrogate restores dystrophin in muscle fibers after multiple doses
Stereopure surrogate restores dystrophin in muscle fibers after multiple doses Experimental conditions: mdx23 mice received 4 weekly IV injections of PBS or DMD-1742 (150 mg/kg). Immunohistochemistry: Blue: Nuclei, Hoechest; Yellow: Rabbit anti-Dystrophin(#ab15277) 1:400 diluent, 555/Cy3, Yellow is
Slide 19: Stereopure oligonucleotide traffics to nuclei in myoblasts
Stereopure oligonucleotide traffics to nuclei in myoblasts Cultured myoblasts were treated with 10 mM of the indicated ASO under free-uptake conditions. ASO was detected with ViewRNA; nuclei are stained with DAPI. Exon skipping efficiency was quantified by Taqman assay. Nuclear ASO was quantified wi
Slide 20: Stereopure oligonucleotides access myofiber nuclei in mice
Mdx23 mice were treated with a single 30 mg/kg dose of optimized, stereopure ASO (IV). Tissues were collected 24-hours post-dose. ASO was detected using ViewRNA, and nuclei were stained with Hoechst33342 or hematoxylin. Nucleus: Hematoxylin (blue) ASO: ViewRNA (red) Nucleus: Hoechst33342 (blue) ASO:
Slide 21: We have developed a scalable process for generating stereopure ASOs
We have developed a scalable process for generating stereopure ASOs Compared with stereorandom, stereopure ASOs are: Taken up more readily by cells under gymnotic conditions in multiple cell lines More potent in multiple tissues More durable in vivo Optimized, stereopure ASOs exhibit improvements in
Slide 22: Future: Improving nucleic acid therapeutics through greater understanding of protein-nucleic acid interactions
Future: Improving nucleic acid therapeutics through greater understanding of protein-nucleic acid interactions Understanding innate immune receptor and broader DNA/RNA-protein interactions TLR9 bound to stereopure, CpG-containing oligonucleotide Stereochemistry of CpG-containing oligonucleotides imp
Slide 23: Future: More potent and durable CNS targeting with new chemistries
Future: More potent and durable CNS targeting with new chemistries PBS = phosphate buffered saline; Ctx = cortex; Str = striatum; Cb = cerebellum; Hp = hippocampus; SC = spinal cord. PBS Stereopure Cortex Spinal cord 15.9 nM 150 nM 2,900 nM Stereopure Stereopure Stereorandom IC50 MALAT1 Knockdown in
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