Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — 26th Annual ASGCT Meeting 2023
15 slides from Wave Life Sciences's conference presentation, May 17, 2023
Slide 1: PN-containing oligonucleotides support exon skipping in skeletal muscle in mice and boys with DMD
Phosphoryl guanidine (PN)-containing oligonucleotides support exon skipping in skeletal muscle in mice and boys with DMD Pachamuthu Kandasamy Vice President, Medicinal Chemistry May 17, 2023 26th Annual ASGCT meeting, May 16-20, 2023
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 Pachamuthu Kandasamy1, Graham McClorey, Laurent Servais, Craig Campbell, Xiao Shelley Hu 1, Andrew Hart1, Joseph Haegele1, Kuldeep Singh1, Jeanette Rheinhardt1, Anamitra Ghosh1, Mamoru Shimizu1, Nayantara Kothari1, Naoki Iwamoto1, Michael Byrne1, Fangjun Liu1, Chikdu Shivalila1, Carlo Ri
Slide 4: PRISM platform enables rational drug design
PRISMTM platform enables rational drug design 5’ B 3’ 2’ X R B Base 5’ B R 2’-ribose modification 3’ 2’ X Stereochemistry & R X: backbone modification O: Phosphodiester S: Phosphorothioate N: Phosphoryl guanidine Phosphoryl guanidine 4
Slide 5: Duchenne muscular dystrophy and WVE-N531
Duchenne muscular dystrophy and WVE-N531 Duchenne Muscular Dystrophy Disease State Restored State A rapidly progressive, rare disease characterized Dysfunctional Splicing Exon Skipping Oligo by irreversible muscle degeneration and Mutant pre-mRNA Mutant pre-mRNA weakness, loss of ambulation and uppe
Slide 6: PN chemistry improves pharmacological properties in multiple preclinical model systems
PN chemistry improves pharmacological properties in multiple preclinical model systems mdx23 mouse Double knockout mouse Nonhuman primate (dKO) (NHP) Protein Pathology Protein Pathology Protein Pathology ✓ Utrophin Mild Utrophin Severe muscular ✓ Utrophin Healthy No decrease in survival dystrophy
Slide 7: WVE-N531 surrogate yields excellent muscle exposure, exon skipping and dystrophin expression in dKO mouse
WVE-N531 surrogate yields excellent muscle exposure, exon skipping and dystrophin protein expression in dKO mouse model Skeletal muscle Diaphragm Heart Muscle concentration 100 100 100 PBS ** 75 ** 75 75 (ug/g) *** WVE-N531 surrogate 50 50 50 for mouse Dmd exon 23 25 25 25 0 0 0 %Exon skipping 60 60
Slide 8: Biweekly WVE-N531 surrogate improves survival and muscle function in dKO mouse model
Biweekly administration of WVE-N531 surrogate improves survival and muscle function in dKO mouse model Median survival Respiratory function comparable PBS 49 days to age-matched healthy controls dKO P=2 x 10-11 (6 x weekly doses, dKO mouse) WVE-N531 280 days biweekly surrogate Healthy controls Treat
Slide 9: WVE-N531 reached high concentrations in heart and diaphragm in NHP
WVE-N531 reached high concentrations in heart and diaphragm in NHP Dosing at 15 mg/kg biweekly 2-days post-final dose Weeks 0 2 4 6 Muscle 15 mg/kg 15 mg/kg 15 mg/kg 15 mg/kg biopsies NHP Mean Tissue Concentration Skeletal Diaphragm Heart 15 mg/kg* muscle IV dose 2.17 ug/g 10.8 ug/g 57.2 ug/g *appro
Slide 10: WVE-N531 restores dystrophin expression in patient-derived myoblasts
WVE-N531 restores dystrophin expression in patient- derived myoblasts Dystrophin protein restoration up to 71% in vitro western blot normalized to primary healthy human myoblast lysate 10
Slide 11: WVE-N531: First-in-human study design
WVE-N531: First-in-human study design WVE-N531-001: First-in-human study Single-ascending intra-patient doses Multidosing at 10 mg/kg every other week 10 Weeks 0 2 4 6 mg/kg Muscle 10 mg/kg 10 mg/kg 10 mg/kg 6 Biopsy mg/kg Period before initiating multidosing 3 (~1–2 months) mg/kg 1 mg/kg Endpoints:
Slide 12: Muscle concentrations and exon skipping indicate WVE-N531 is engaging target
Muscle concentrations and exon skipping indicate WVE-N531 is engaging target Plasma t1/2: 25 days (10 mg/kg single dose) Tissue Tissue concentration % Exon skipping Dystrophin by western blot Patient Source (µg/g) by RT-PCR (% of normal) 1 Deltoid 85.5 61.5 0.24 2 Deltoid 33.5 49.8 0.23 3 Bicep 8.3
Slide 13: Intracellular WVE-N531 enabling exon skipping
Intracellular WVE-N531 enabling exon 53 skipping Myofibers WVE-N531 (in red) in myofiber cytoplasm (stars) and nuclei (black arrows) UBC Control DapB Control Probe Probe RNAscope (ISH – in situ hybridization). Mag: 40x for WVE-N531; Mag: 20x for control probes 13 Control Probes: Ubiquitin (UBC) – Po
Slide 14: Summary
Summary • WVE-N531 surrogate increased muscle concentration, percentage of exon skipping and dystrophin expression in mdx23 and dKO mouse models compared with control • In dKO model, WVE-N531 surrogate substantially extended survival and rescued respiratory function • In NHPs, WVE-N531 reached high
Slide 15: Acknowledgements
Wave publications on PN chemistry Acknowledgements Silencing - antisense Silencing - siRNA Study participants & families Investigators • Laurent Servais • Craig Campbell Splicing RNA Editing Thanks to all colleagues and contributors from Wave Life Sciences and our collaborators For additional inform