Slide 1: Stereopure Oligonucleotides in Development for the Treatment of Genetically Defined Diseases
Stereopure Oligonucleotides in Development for the Treatment of Genetically Defined Diseases Michael A. Panzara, MD, MPH Chief Medical Officer Head of Therapeutics Discovery and Development Wave Life Sciences TIDES Boston Virtual Conference September 15-18, 2020
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: PRISM has unlocked novel and proprietary advances in oligonucleotide design
PRISM has unlocked novel and proprietary advances in oligonucleotide design Backbone modifications Backbone PN backbone stereochemistry chemistry Sugar modifications Drug approvals (FDA) • Mixtures of 2n molecules1 • ~500,000 different molecules per dose Phosphorothioate (PS) Phosphorodiamidate Morp
Slide 4: Stereopure oligonucleotides
Stereopure oligonucleotides Phosphorothioate (PS) modifications introduce chiral centers An enormous number of permutations exist (2n), often resulting in over 500,000 different molecules in every dose Stereorandom ASO Stereopure ASO Nucleotide Rp Stereorandom Sp 4
Slide 5: New backbone chemistry: PN modification
New backbone chemistry: PN modification Extending backbone pharmacology Backbone linkage PO PS PN Phosphodiester Phosphorothioate Phosphoramidate diester Charge Negative Negative Neutral Phosphoryl guanidine x-ray structure PRISM stereopure PS/PO chemistry backbones PS/PO/PN chemistry Wave continues
Slide 6: Innovative pipeline led by neurology programs
Innovative pipeline led by neurology programs THERAPEUTIC AREA / TARGET DISCOVERY PRECLINICAL CLINICAL PARTNER NEUROLOGY Huntington’s disease mHTT SNP1 WVE-120101 Huntington’s disease mHTT SNP2 WVE-120102 Huntington’s disease Takeda mHTT SNP3 WVE-003 50:50 option ALS and FTD C9orf72 WVE-004 SCA3 ATX
Slide 7: Our Approach to HD: Selective Targeting of Mutant Huntingtin (mHTT) Protein
Our Approach to HD: Selective Targeting of Mutant Huntingtin (mHTT) Protein
Slide 8: Huntington's Disease: a hereditary, fatal disorder
Huntington’s Disease: a hereditary, fatal disorder DNA CAG Repeat • Autosomal dominant disease, characterized by cognitive decline, psychiatric illness and chorea; fatal • No approved disease-modifying therapies RNA RNA wildtype (healthy) allele mutant allele Normal CAG Repeat Expanded CAG Repeat •
Slide 9: Wave approach: allele-selective silencing
Wave approach: allele-selective silencing Aims to lower mHTT transcript while leaving healthy wild-type HTT relatively intact SNP SNP2 SNP3 SNP1 RNase H and ASO:RNA Allele-selectivity possible by targeting SNPs associated with expanded long CAG repeat in HTT gene 9
Slide 10: SNP detection in HTT gene opens door to allele-selective treatment for Huntington's disease
SNP detection in HTT gene opens door to allele-selective treatment for Huntington’s disease Prospective Observational Study The most frequently occurring genotype in the study: wtHTT with 18 CAG repeats and mHTT with 43 CAG repeats 202 patients with HD Long-range CAG repeats • Number and Heterozygos
Slide 11: PRECISION-HD trial endpoints
& Primary endpoint • Safety and tolerability of treatment, compared with placebo, as assessed by – Number (%) of patients with AEs – Severity of AEs – Number (%) of patients with SAEs – Number (%) of patients who withdrew due to AEs Secondary endpoints • Pharmacokinetics, pharmacodynamics, Total Fun
Slide 12: Broadening reach in Huntington's disease with SNP3
Broadening reach in Huntington’s disease with SNP3 % Huntington’s Disease Patient SNP3 Population with SNP • Due to overlap, ~80% of the SNP1 ~50% total HD patient population carry SNP1 and/or SNP2 SNP2 ~50% and/or SNP3 • In vivo models for SNP3 SNP3 ~40% available for preclinical development SNP1 +
Slide 13: SNP3: Selective reduction of mHTT mRNA in vitro
SNP3: Selective reduction of mHTT mRNA in vitro Patient-derived iPSC neurons 0.8 mHTT wtHTT Normalized allelic HTT expression (mean + SEM) 0.6 0.4 0.2 0.0 M M M M M M M M M 20 01 03 08 25 74 22 67 0 0. 0. 0. 0. 0. 2. 6. iPSC = induced pluripotent stem cell The neurons were treated with WVE-
Slide 14: SNP3: Dose-dependent reduction of mHTT mRNA in vivo
SNP3: Dose-dependent reduction of mHTT mRNA in vivo BACHD mice homozygous for mHTT with SNP3 mHTT = mutant huntingtin; PBS = phosphate-buffered saline; TUBB3 = Tubulin Beta 3 Class III BACHD mice received 3 injections through an ICV cannula of PBS and WVE-003 (12.5 μg, 25 μg, 50 μg, or 100 μg) on Da
Slide 15: C9orf72 program
C9orf72 program Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 16: C9orf72 repeat expansions: A critical genetic driver of ALS and FTD
C9orf72 repeat expansions: A critical genetic driver of ALS and FTD Normal (non-expanded) Allele Expanded Allele Typically 100’s- < 25 1000’s of GGGGCC GGGGCC repeats repeats • C9orf72 hexanucleotide repeat expansions (GGGGCC) are the strongest known risk factor for sporadic and inherited forms of A
Slide 17: C9orf72 repeat expansions: Mechanisms of cellular toxicity
C9orf72 repeat expansions: Mechanisms of cellular toxicity • C9-ALS and C9-FTD may be caused by multiple factors: – Insufficient levels of C9orf72 protein – Accumulation of repeat-containing RNA transcripts – Accumulation of aberrantly translated DPR proteins • Recent evidence suggests lowering C9or
Slide 18: 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 19: WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro
WVE-004: Potent and selective knockdown of repeat- containing transcripts in vitro In vitro activity in C9 patient-derived neurons In vitro selectivity in C9 patient-derived neurons 1.5 V3 1.5 All V 1.5 1.5 1.5 1.5 Relative fold change fold change IC50:201.7nM C9orf72 V3/HPRT1 Relative fold change R
Slide 20: WVE-004 shows dose dependent knockdown of V3 mRNA and DPRs in C9 transgenic mouse model
WVE-004 shows dose dependent knockdown of V3 mRNA and DPRs in C9 transgenic mouse model Spinal Cord V3 mRNA DPRs PK 1.5 PBS PBS PBS 1.5 WVE-004 WVE-004 WVE-004 10 Relative Poly-GP levels ug of oligo/g of tissue Relative fold change (normalized to PBS) C9orf72 V3/mHPRT 1.0 1.0 **** ** 5 0.5 0.5 ****
Slide 21: WVE-004: Potent and selective knockdown of repeat transcripts and DPRs in spinal cord of mice
WVE-004: Potent and selective knockdown of repeat transcripts and DPRs in spinal cord of mice Repeat-containing Dipeptide repeat proteins Total C9orf72 protein transcripts (DPRs) 1.5 1.5 1.5 1.5 1.5 1.5 Protein preservation C9orf72/mHPRT/PBS Relative Poly-GP levels NS Relative fold change (normalize
Slide 22: WVE-004 reaches target brain regions and cell types in vivo
WVE-004 reaches target brain regions and cell types in vivo In situ hybridization of WVE-004 in spinal cord and cortex at 8 weeks Spinal cord Cortex PBS Control WVE-004 PBS Control WVE-004 In situ hybridization: Red - ViewRNA for WVE-004; Blue – Hematoxylin. 40X magnification. C9 BAC transgenic mice
Slide 23: Durable knockdown of repeat transcripts in vivo after months in spinal cord and cortex of mice
Durable knockdown of repeat transcripts in vivo after 6 months in spinal cord and cortex of mice Spinal cord Cortex C9orf72 V3/mHPRT1 C9orf72 V3/mHPRT1 Relative fold change Relative fold change 1.0 1.0 1.0 1.0 p≤0.0001 p≤0.0001 0.5 0.5 0.5 0.5 0.0 0.0 0.0 0.0 week 4 12 18 24 4 12 18 24 week 4 12 18
Slide 24: Durable knockdown of DPRs in vivo after months in spinal cord and cortex of mice
Durable knockdown of DPRs in vivo after 6 months in spinal cord and cortex of mice Spinal cord Cortex 1.5 1.5 1.5 1.5 Relative Poly-GP levels Relative Poly-GP levels (normalized to PBS) (normalized to PBS) 1.0 1.0 1.0 1.0 0.5 0.5 * ** 0.5 0.5 p≤0.0001 *** 0.0 0.0 0.0 0.0 week 4 12 18 24 4 12 18 24 w
Slide 25: WVE-004 proof-of-concept clinical trial to include both ALS and FTD patients
WVE-004 proof-of-concept clinical trial to include both ALS and FTD patients • Patients with documented C9orf72 expansion and confirmed ALS or FTD diagnosis • Single and multiple ascending doses to be explored • Safety and tolerability • Pharmacodynamic effects on key biomarkers while on treatment –
Slide 26: RNA editing: Application of PRISM to ADAR editing
RNA editing: Application of PRISM to ADAR editing Oligonucleotide Target ADAR Edited RNA RNA A I(G) Modification Delivery Oligonucleotide establishes double-stranded RNA complex • A-to-I editing is one of most common post-transcriptional modifications • ADAR is ubiquitously expressed across tissues,
Slide 27: RNA editing: A promising new therapeutic modality for treatment of genetic diseases
RNA editing: A promising new therapeutic modality for treatment of genetic diseases Disease associated mutations are frequently ADAR amenable • Nearly half of known human genetic pathogenic SNPs are G-to-A mutations • Tens of thousands of potential disease variants A-to-I(G) editing could target Pat
Slide 28: Wave's Mission: Apply innovative nucleic acid chemistry and deep biological insights
Wave’s Mission: Apply innovative nucleic acid chemistry and deep biological insights to develop transformative medicines for people living with devastating conditions Wave is developing investigational stereopure oligonucleotides designed to selectively target the mutant allele of the huntingtin (mH