Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — 28th International Symposium on ALS/MND 2017
15 slides from Wave Life Sciences's conference presentation, Dec 11, 2017
Slide 1: Preclinical Data for WVE-3972-01 Supporting ALS and FTD Programs
Preclinical Data for WVE-3972-01 Supporting ALS and FTD Programs Robert Brown, Jr., DPhil, MD Chair and Professor of Neurology at the University of Massachusetts Medical School 28th International Symposium on ALS/MND December 10, 2017
Slide 2: Disclosures
Disclosures Robert Brown, Jr., DPhil, MD is Chair and Professor of Neurology at the University of Massachusetts Medical School. In January 2017, Wave Life Sciences and the University of Massachusetts Medical School established a collaboration to further understand neurodegenerative and neuromuscular
Slide 3: Forward-looking statements
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical fact contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, re
Slide 4: Targeting C9orf72 in ALS
Lessons from SOD1 Gene Silencing Recent Data for SOD1 Novel Reagents for Silencing C9orf72 Targeting C9orf72 in ALS
Slide 5: Targeting C9orf72 in ALS (contributors)
Lessons from SOD1 Gene Silencing Recent Data for SOD1 Novel Reagents for Silencing C9orf72 Targeting C9orf72 in ALS H. Tran J. C. Dodart M. Moazami Z. Zhong C. Pinto Y. Liu J. Watts
Slide 6: Stereopure Nucleic Acids Therapeutics: Wave Chemistry
Stereopure Nucleic Acids Therapeutics: Wave Chemistry Traditional method • Chemically modified oligonucleotides are typically 20 nucleotides long and held together by a backbone of phosphorothioate linkages with uncontrolled chirality • The orientation of atoms at each linkage occurs randomly, adopt
Slide 7: Preferential knockdown of repeat-containing transcripts by targeting intron 1
Preferential knockdown of repeat-containing transcripts by targeting intron 1 (with the toxic hexanucleotide expansion) All transcripts Pre-mRNA mRNA V3 transcripts Healthy allele Intron1 Pathological by-products Mis-spliced V1/V3 Stabilized intron1 Antisense RNA ASO targeting intron 1
Slide 8: Screening and lead optimization funnel
Screening and lead optimization funnel Sequence search BioInformatics CANDIDATE SELECTION ~200 sequences Screening Reporter assay ~10 sequences Profiling PHARMACOLOGY C9-ALS fibroblasts Sequence selection C9-ALS neurons C9-BAC mouse C9 mouse 1ary neurons Lead Optimization 5-10 leads Chemistry & Ster
Slide 9: Stereorandom ASOs targeting intron 1 reduce repeat-containing C9orf72 transcripts
STEREORANDOM ASOs Targeting intron1 leads to preferential reduction in repeat-containing C9orf72 transcripts (vs. exon 2 targeting) Patients fibroblast (transfection) – 100 nM C9-BAC mouse primary neurons n 1 . 5 (gymnosis) – 10 mM 1 . 5 V3 Transcripts All Transcripts V3 Transcripts All Transcripts
Slide 10: Chemical and stereochemical optimization improve selectivity and potency in C9-ALS neurons
Chemical and stereochemical optimization greatly improve selectivity and potency in C9-ALS neurons V3 Transcripts V3 Transcripts Transcripts Knockdown (% of Control, means * SEM) Lead OP SP-3 WVE-3972-01 IC 50 = 0.5 uM All Transcripts SP-3 WVE-3972-01 Same sequence Stereorandom stereopure SR= stereo
Slide 11: Stereochemical optimization dramatically improves ASO in vitro potency
Stereochemical optimization dramatically improves ASO in vitro potency Stereochemistry improves RNAse H cleavage efficiency Percentage of substrate remaining 120 100 80 60 40 20 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 SR-1 SR-2 SP-3 WVE-3972-01 SR-3 NTC time (mins) SR= stereorandom ASO; SP = stere
Slide 12: WVE-3972-01 produces sustained reduction in repeat-containing transcripts in C9-BAC mice
WVE-3972-01 produces a sustained reduction in repeat- containing transcripts in C9-BAC transgenic mice V3 Transcripts Intron 1 Transcripts All Transcripts Spinal Cord Cortex PBS WVE-3972-01 2 wks 4 wks 8 wks 2 wks 4 wks 8 wks 2 wks 4 wks 8 wks 2 wks 4 wks 8 wks 2 wks 4 wks 8 wks V3 Transcripts V3 Tr
Slide 13: WVE-3972-01 decreases polyGPs and RNA foci in C9-BAC mice
WVE-3972-01 shows significant and sustained decreases in polyGPs and RNA foci in C9-BAC transgenic mice Cortex Spinal Cord RNA Foci in MNs (8 weeks) PBS WVE-3972-01 PBS WVE-3972-01 PolyGP’s ASO concentration PBS WVE-3972-01 RNA Foci / 100 MNs 0 200 400 600 PBS WVE-3972-01 No effects on C9orf72 Prote
Slide 14: Widespread and sustained distribution of ASOs in nuclei of motor neurons
Widespread and sustained distribution of ASOs in the nuclei of motor neurons of the spinal cord up (8 weeks after treatment) Light View Fluorescence Bright/Flour 40X Oil 40X Zoom
Slide 15: Conclusions: C9 Program
Conclusions: C9 Program • In vitro, stereopure ASOs showed greater selectivity and potency in knockdown of repeat-containing transcripts vs. stererandom ASOs • In vivo studies in C9-BAC transgenic mice: – Confirmed selectivity and potency, and showed sustained reduction of repeat-containing transcri
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