Slide 1: Enhancing the pharmacologic profiles of CNS targeting therapeutic oligonucleotides
Enhancing the pharmacologic profiles of CNS targeting therapeutic oligonucleotides Elena Dale, PhD Senior Director, CNS Biology TIDES USA Sept 23, 2021
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: Overview
Overview • PRISMTM Platform • Wave Neurology Pipeline • WVE-004 in ALS and FTD • WVE-003 in Huntington’s disease • RNA Editing as a New Therapeutic Modality 3
Slide 4: PRISM
PRISM
Slide 5: 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 Sequence Chemistry P O O X: backbone chemistry 5’ B Stereochemistry Phosphodiester (PO), O Stereochemistry ph
Slide 6: Expanding repertoire of backbone modifications with novel PN backbone chemistry
Expanding repertoire of backbone modifications with novel PN backbone chemistry Backbone linkages PO PS PN Backbone Phosphodiester Phosphorothioate Phosphoramidate diester modification (X) Stereorandom PN backbone Stereorandom Stereochemistry Not chiral Chiral PS backbone Rp Chiral PN backbone Rp PS
Slide 7: PN chemistry increases durability across CNS tissues
PN chemistry increases durability across CNS tissues Malat1 knockdown at 10 weeks in mouse CNS (100 µg) Hippocampus Cerebellum Cortex Striatum Spinal cord 150 ** ** Relative fold change ** 150 *** Malat1/HPRT1 100 100 50 50 0 0 S PO N S O N S O N PB /P PB PB /P /P /P /P / PS PS PS PS PS PS PS/PO PS/
Slide 8: Robust portfolio of stereopure, investigational PN-modified oligonucleotides
Robust portfolio of stereopure, investigational PN- modified oligonucleotides THERAPEUTIC AREA / TARGET DISCOVERY PRECLINICAL CLINICAL PARTNER NEUROLOGY ALS and FTD C9orf72 WVE-004 (FOCUS-C9) Huntington’s disease Takeda mHTT SNP3 WVE-003 (SELECT-HD) 50:50 option SCA3 ATXN3 CNS diseases Takeda milest
Slide 9: WVE-004
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 10: C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Hexanucleotide (G4C2)- repeat expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Typically 100’s- 1000’s of GGGGCC repeats Different manifestations across a clinical spectrum Amyotrophic Later
Slide 11: C9orf72 targeting strategy spares C9orf72 protein
C9orf72 targeting strategy spares C9orf72 protein • Normal C9orf72 allele produces three mRNA transcripts (~80% are V2, ~20% are V1 and V3) • Pathological allele with expanded repeat leads to healthy V2 and pathological V1 and V3 transcript by-products pre-mRNA variants Pathological mRNA products Di
Slide 12: WVE-004: Durable reduction in vivo of poly-GP in spinal cord and cortex
WVE-004: Durable reduction in vivo of poly-GP in spinal cord and cortex; Preservation of C9orf72 protein Preclinical in vivo results (transgenic mouse): C9orf72 protein Six months unchanged at 6 months Spinal 150 8 cord 1.5 1.5 change ug of oligo / g of tissue 6 ns Relative Poly-GP levels C9orf72/HP
Slide 13: FOCUS-C9: Adaptive trial designed to enable rapid assessment of target engagement
FOCUS-C9: Adaptive trial designed to enable rapid assessment of target engagement Phase 1b/2a global, multicenter, randomized, double-blind, placebo-controlled trial Primary objectives ~50 patients with C9-ALS, C9-FTD or mixed phenotype • Safety and tolerability Cohort 4 Proceed to MAD Cohort 4 Seco
Slide 14: WVE-003
WVE-003 Huntington’s Disease
Slide 15: Huntington's disease: a hereditary, fatal disorder
Neuro HD Huntington’s disease: a hereditary, fatal disorder DNA • Autosomal dominant disease, characterized by CAG Repeat cognitive decline, psychiatric illness and chorea; fatal • No approved disease-modifying therapies • Expanded CAG triplet repeat in HTT gene results in production of mutant hunti
Slide 16: Allele-selective approach to treating HD
Allele-selective approach to treating HD Preserve neuroprotective effects of wildtype HTT and reduce toxic mutant HTT Preserve Reduce wtHTT Stresses + mHTT wtHTT supports healthy brain function, especially in the context of stress Promotes neuronal Essential role in Supplies BDNF to Critical role in
Slide 17: Allele-selectivity achieved by targeting downstream SNPs
Allele-selectivity achieved by targeting downstream SNPs Target mHTT transcript to selectively reduce mHTT protein with antisense oligonucleotides Wildtype huntingtin RNA SNP3 Mutant huntingtin RNA C AG C AGC AGC AGC AG expanded CAG repeat Next Generation Chemistry Investigational WVE-003 targets mH
Slide 18: WVE-003 is potent and allele selective in vitro
WVE-003 is potent and allele selective in vitro Potently decreases HTT in Selectively reduces mHTT in HD motor neurons HD motor neurons Percentage HTT RNA remaining Percentage HTT RNA Remaining % wtHTT mRNA 125 % mtHTT mRNA 100 75 50 25 WVE-003: EC50: 0.5 µM Pan-silencing control 0 0.001 0.01 0.1 1
Slide 19: Mouse models
Mouse models Evaluation of potency Evaluation of selectivity BACHD Mouse1 Hu97/18 Mouse2 HTT Key characteristics HTT Key characteristics mHTT 97 CAA-CAG repeats mHTT 97 CAA-CAG repeats (human) (human) Multiple copies Multiple copies Subset of copies contain SNP3 Subset of copies contain
Slide 20: WVE-003 has potent and durable effects in cortex and striatum of BACHD mice
WVE-003 has potent and durable effects in cortex and striatum of BACHD mice Maximum knockdown of 75% with ~50% knockdown persisting for at least 3 months Cortex Striatum Relative mHTT RNA expression Relative mHTT RNA expression 1.5 1.5 *** (mHTT/Tubb – PBS) (mHTT/Tubb – PBS) * 1.0 **** 1.0 **** ***
Slide 21: Allele-selective activity in CNS of Hu97/18 mice
Allele-selective activity in CNS of Hu97/18 mice mHTT wtHTT Cortex Striatum Hippocampus Percentage HTT RNA expression wtHTT & mHTT 150 150 *** ns ns ns ns ns 150 **** **** ns *** ns ns (mHTT/Tubb - PBS) **** *** ns ** ns ns wtHTT **** * ns **** **** **** **** **** **** mHTT 100 100 100 50 50 50 0 0
Slide 22: SELECT-HD: Adaptive first-in-human study for investigational WVE-003
SELECT-HD: Adaptive first-in-human study for investigational WVE-003 Ph 1b/2a global, multicenter, randomized, double-blind placebo-controlled trial Eligible PRECISION-HD participants can transition to this study after wash out Patients • Targeting 36 patients • ≥18 and ≤60 years of age Cohort 4 (P1
Slide 23: ADAR Editing
ADAR Editing
Slide 24: RNA editing opens many new therapeutic applications
RNA editing opens many new therapeutic applications AIMers direct RNA editing with endogenous ADAR enzymes Nearly half of known human genetic pathogenic SNPs are G-to-A mutations Delivery Editing Restore protein function – Recessive or dominant genetically defined A I(G) diseases Modify protein func
Slide 25: AIMers direct editing throughout CNS of hADAR mouse
AIMers direct editing throughout CNS of hADAR mouse PN-containing AIMers direct editing of UGP2 in vivo In vitro dose-response curves In vivo CNS editing in proprietary hADAR transgenic mouse (1 week) ACTB UGP2 100 100 80 Percentage ACTB editing AIMer (single, 100 µg ICV dose) Percentage UGP2 editin
Slide 26: Summary
Summary • PRISM creates new therapeutic opportunities across a range of CNS diseases • New backbone modifications, including PN chemistry, improve potency and durability for oligonucleotides in the CNS • WVE-004, a variant-selective oligonucleotide targeting C9orf72, is the first molecule in clinica