Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — TIDES: Oligonucleotides and Peptide Therapeutics 2020
29 slides from Wave Life Sciences's conference presentation, Sep 18, 2020
Slide 1: Stereopure oligonucleotides produce potent and durable activity in the eye
Stereopure oligonucleotides produce potent and durable activity in the eye supporting their development for inherited retinal diseases TIDES: Oligonucleotides and Peptide Therapeutics Michael Byrne, PhD Sept 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 Sugar modifications Backbone PN backbone stereochemistry chemistry Drug approvals (FDA) • Mixtures of 2n molecules1 • ~500,000 different molecules per dose Phosphorothioate (PS) Phosphorodiamidate Morp
Slide 4: Foundational value
Foundational value • PRISM has the capability to address a wide variety of genetic diseases • Each oligo is optimized based on our ability to control: – Sequence – Chemistry – Stereochemistry • Manufacturing • We continue to innovate with each new program, and these innovations have resulted in exci
Slide 5: 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 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 220 = 1,048,576 diastereoisome
Slide 6: PRISM platform advancements
PRISM platform advancements Primary screen hit rates in neurons far above industry standard hit rates 100 Chemistry & stereochemistry + Machine learning optimization 80 80.0% (2020) % Hit Rate 60 55.4% (2019) 40 32.9% Stereopure 20 Stereorandom 12.2% 0 Evolution of primary screen hit rates with chem
Slide 7: PRISM enables optimal placement of backbone stereochemistry
PRISM enables optimal placement of backbone stereochemistry Crystal structure confirms phosphate-binding pocket of RNase H binds 3’-SSR-5’ motif in stereopure oligonucleotide – supports design strategy for Wave oligonucleotides RNA Target RNA Stereopure Oligonucleotide cleavage site (C9orf72 compoun
Slide 8: Stereopure oligonucleotide is more potent in vitro
Precision RNase H-mediated RNA degradation Stereopure oligonucleotide is more potent in vitro In vitro dose-response RNase H cell-free assay iCell neurons IC50: Total cleavage product (nM) 2,864 nM Percentage MALAT1 RNA 120 nM remaining Time (seconds) Concentration (nM) (Left) Time-dependent activit
Slide 9: Oligonucleotides in Ophthalmology
Oligonucleotides in Ophthalmology Stereopure oligonucleotides can: • be administered by intravitreal (IVT) injection during an office visit; targeting twice-per-year dosing • open novel strategies in both dominant and recessive IRDs; potential for potent and durable effect with low immune response •
Slide 10: Potency benefits translate in vivo in mouse eye 1-week post injection
Potency benefits translate in vivo in mouse eye 1-week post injection PK-PD relationship of 50 µg dose levels In vivo activity Percentage MALAT1 RNA Percentage MALAT1 RNA Improved remaining efficacy remaining Dose (µg) Tissue exposure (µg/g) 10-fold potency shift Stereorandom Stereopure (Left) In vi
Slide 11: Stereopure oligonucleotide is more durable in vivo in mouse eye
Stereopure oligonucleotide is more durable in vivo in mouse eye In vivo durability (days) • 50 µg stereorandom: Malat1 recovered to ~50% levels by 29 days • 50 µg stereopure: Malat1 recovered by day 85 • 5 µg stereopure: Malat1 recovered by day 56 in the anterior and day 85 in the posterior • 5 µg a
Slide 12: Stereopure oligonucleotide yields greater knockdown in vivo in mouse eye
Stereopure oligonucleotide yields greater knockdown in vivo in mouse eye, with better tissue exposure Knockdown Exposure • 50 µg stereorandom rises above 50% Malat1 knockdown threshold at day 59 • 50 µg stereopure reaches 50% threshold at day 119 • Stereopure has greater tissue exposure than stereor
Slide 13: Stereopure oligonucleotide induces potent and durable activity in the NHP eye
Stereopure oligonucleotide induces potent and durable activity in the NHP eye Dose response (single dose) Duration (single dose) • Stereopure oligonucleotide was detected throughout the retina (GCL, INL, ONL, and RPE) 4 months after 450 µg injection • MALAT1 was detected at very low levels in the IN
Slide 14: Efficacy and potency benefit in human retinal tissue ex vivo
Stereopure oligonucleotide shows efficacy and potency benefit in human retinal tissue ex vivo • Stereopure oligonucleotide was more active than stereorandom at 0.3 and 1 µM, with larger decrease MALAT1 RNA expression (P<0.05) • 0.3 µM stereopure was more active than 1 µM stereorandom (P<0.05) Percen
Slide 15: Oligonucleotides durably deplete Malat1 for months in vivo in mice
Stereopure oligonucleotides durably deplete Malat1 for 9 months in vivo in mice ~50% MALAT1 knockdown at 9 months in the posterior of the eye **** for investor day 2019Posterior OD/OS PD Oligonucleotide (ug) per tissue (g) *** Minimal exposure 0.15 Percentage Malat1 expression 250 required for inves
Slide 16: Autosomal dominant retinitis pigmentosa associated with Rhodopsin P23H mutation
Autosomal dominant retinitis pigmentosa (adRP) associated with Rhodopsin P23H mutation • Retinitis pigmentosa (RP) is a group of rare, genetic disorders of the eye resulting in progressive photoreceptor cell death and gradual functional loss • Currently no cure for RP • Rhodopsin accounts for >25% o
Slide 17: Allele-selective reduction of SNP-containing RNA in RNase H assay
adRP associated with Rhodopsin P23H mutation Stereopure oligonucleotides achieve allele-selective reduction of SNP-containing RNA in RNase H biochemical assay Stereorandom Stereopure 23415 20847 Mutant RNA + oligo + RNase H enzyme 120 Mutant RNA + oligo + RNase H enzyme 120 Wild-type RNA + oligo + R
Slide 18: Stereopure oligonucleotide achieves selective knockdown of mutant allele
adRP associated with Rhodopsin P23H mutation Stereopure oligonucleotide achieves selective knockdown of mutant allele Stereorandom Stereopure W V -2 0 8 7 0 W V -2 0 8 6 5 1 2 5 R h o -W t R h o P 2 3 H 125 R h o -W t R hoP23H 200 PBS 5 µg 50 µg Relative RNA expression 1 0 0 100 150 R e la tiv e R h
Slide 19: Stereopure treatment retains rod outer segments and cone pedicles
adRP associated with Rhodopsin P23H mutation Stereopure oligonucleotide treatment retain rod outer segments and cone pedicles 16 weeks post single treatment Treated Untreated McCall Lab Single IVT injection of 25 µL of human P23H targeting oligo in human P23H pig model. Eyes collected 16-weeks post
Slide 20: Usher Syndrome Type 2A: a progressive vision loss disorder
Usher Syndrome Type 2A: a progressive vision loss disorder • Autosomal recessive disease characterized by hearing loss at birth and progressive vision loss beginning in adolescence or adulthood • Caused by mutations in USH2A gene (72 exons) that disrupt production of usherin protein in retina, leadi
Slide 21: Stereopure oligonucleotide is more potent in vitro: exon skipping
Stereopure oligonucleotide is more potent in vitro Exon skipping: EC50 shift in Y79 cells 100 WV-30205 Stereopure Percentage skipped transcript WV-20781 Stereorandom reference • Stereorandom reference from van (Normalized to SRFS9) 80 Diepen et al., 2018 EC50: 4.11 µM 60 EC50: 8.73 µM • Dose-respons
Slide 22: Stereopure oligonucleotide yields greater knockdown in vivo
Stereopure oligonucleotide yields greater knockdown in vivo 2-fold efficacy improvement in mouse eye 125 Percentage exon skipping (Normalized to SRFS9) 100 • Oligonucleotides tested in new mouse 75 model with human USH2A exon 13 50 • Evaluated 1-week post-single 50 µg 38 IVT injection 25 • Efficacy
Slide 23: RNA-seq confirms integrity of RNA transcript in vivo
RNA-seq confirms integrity of RNA transcript in vivo Human Exon 13 Exon Junction PBS Stereopure Significant difference between PBS and treated Human exon 13 • RNA-seq performed • Confirms specific human exon-13 skipping in vivo (in mouse model) • Validates generation of correct full USH2A-skipped tr
Slide 24: Stereopure oligonucleotide yields greater knockdown ex vivo
Stereopure oligonucleotide yields greater knockdown ex vivo ~ 3-fold efficacy improvement ex vivo in NHP retinal cultures stereopure stereorandom 0.3 1 3 10 20 uM Whole NHP were enucleated (n=4) and compounds (1–20 µM) were added to extracted retinas under free-uptake conditions. Exon skipping was e
Slide 25: Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP in vivo
Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP in vivo Dose-dependent and specific exon skipping in NHP eye USH2A-02 (NHP TE Study); PrimerSet 3 100 • Oligonucleotide is complementary to NHP Percentage USH2A Skipping USH2A exon 12* (Normalized to SRFS9) 75 • Evaluated 1-week
Slide 26: Visualization of oligonucleotide, skipped USH2A transcript and safety in NHP retina
Visualization of oligonucleotide, skipped USH2A transcript and safety in vivo in NHP retina Stereopure oligonucleotide USH2A-skipped transcript Safety 150 µg 150 µg 150 µg Baseline post-IVT 1-week NTC Stereopure nuclei nuclei Optical coherence oligonucleotide USH2A transcript Electroretinography tom
Slide 27: Using PRISM to unlock ADAR-mediated RNA editing
RNA editing Using PRISM to unlock ADAR-mediated RNA editing • ADAR is an endogenously expressed class Structure of ADAR deaminase domain bound to dsRNA substrate of enzymes that catalyzes conversion of adenosine (A) to inosine (I) on dsRNA substrates • Inosine (I) is recognized as guanosine (G) by c
Slide 28: Oligonucleotides direct sequence-specific RNA editing in vitro and ex vivo
Stereopure oligonucleotides direct sequence-specific RNA editing in vitro and ex vivo Dose-dependent ACTB editing ACTB editing in NHP retina iCell neurons Ex vivo 100 Percentage A-to-I(G) editing Percentage A-to-I(G) editing 80 80 80 % A→G Editing 3.3 uM % A->G Editing % A->G Editing 60 60 60 0.3 uM
Slide 29: Summary
Summary • Using MALAT1 for Proof of concept, we show that stereopure RNase H-active oligonucleotides: – Are more potent in vitro and in vivo in mice and NHP – Are more durable in vivo in mice and NHP – Have superior tissue exposure profile in the eye compared with stereorandom – Have improved durabi
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