Full Press Release Details
Analyst and Investor Research Day
OCTOBER 7, 2019 BOSTON, MASSACHUSETTS Exhibit 99.1
Welcome Paul Bolno, MD, MBA President
and CEO Wave Life Sciences
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, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking
statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of Wave Life Sciences Ltd. (the "Company") to be materially different
from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should,"
"expect," "plan," "aim," "anticipate," "could," "intend," "target," "project," "contemplate," "believe," "estimate,"
"predict," "potential" or "continue" or the negative of these terms or other similar expressions. The forward-looking statements in this presentation are only predictions. The Company has based these
forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company's business, financial condition and results of operations. These forward-looking
statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company's Form 10-K and other filings with the SEC, some of which
cannot be predicted or quantified and some of which are beyond the Company's control. The events and circumstances reflected in the Company's forward-looking statements may not be achieved or occur, and actual results could differ
materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict
all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information,
future events, changed circumstances or otherwise.
Our purpose at Wave Genetic medicines
company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox I II III
Our purpose at Wave Genetic medicines
company committed to delivering life-changing treatments for people battling devastating diseases I One tool appears suitable from a distance Building a genetic toolbox for a lifetime of treatment
Our purpose at Wave Genetic medicines
company committed to delivering life-changing treatments for people battling devastating diseases Target variability requires a comprehensive toolkit I Building a genetic toolbox for a lifetime of treatment
Our purpose at Wave Genetic medicines
company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox I II III Splicing, silencing, editing Non-viral delivery to nucleus Optimized, stereopure oligonucleotides
Our purpose at Wave Genetic medicines
company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox Designing precision medicines for complex diseases I II III Restoring functional protein Selectively reducing toxic protein
Pursuing broad distribution Splicing, silencing, editing Non-viral delivery to nucleus Optimized, stereopure oligonucleotides
Our purpose at Wave Genetic medicines
company committed to delivering life-changing treatments for people battling devastating diseases Building a genetic toolbox Designing precision medicines for complex diseases Committed to patients in need I II III Restoring functional protein
Selectively reducing toxic protein Pursuing broad distribution Advancing innovative drug development approaches Scaling manufacturing expertise and capacity Building commercial infrastructure Developing novel payor strategies Splicing, silencing,
editing Non-viral delivery to nucleus Optimized, stereopure oligonucleotides
Today's Agenda Gregory
Verdine, Ph.D. Co-founder / Board Member | Wave Life Sciences Chandra Vargeese, Ph.D. SVP, Head of Drug Discovery | Wave Life Sciences Elena Cattaneo, Ph.D. University of Milano Fr d ric Saudou, M.Sc., Ph.D. Grenoble Institute of
Neurosciences (GIN) Chandra Vargeese, Ph.D. SVP, Head of Drug Discovery | Wave Life Sciences Michael Byrne, Ph.D. Director In Vivo Biology & Ophthalmology | Wave Paul Bolno, MD, MBA President & CEO | Wave Life Sciences Chirality Matters in
Biology PRISM Biology of Huntingtin (HTT) Biology of Huntingtin (HTT) Advancing HD Portfolio with mHTT SNP3 Lead Inherited Retinal Disease Program: USH2A Closing Remarks PRISM Huntington's disease Ophthalmology Paul Bolno, MD, MBA President
& CEO | Wave Life Sciences Opening Remarks
Chirality Matters in Biology Gregory
Verdine, Ph.D. Co-founder and Board Member Wave Life Sciences
Chirality in biology carvone
R-carvone S-carvone H Chirality Matters
Stereochemistry Matters in Drugs
- Case of Thalidomide Vargesson et al., 2015. Thalomide-induced teratogenesis: History and mechanisms. Birth Defects Res C Embryo Today 105:140-156. ACS Molecule of the week archive: Sept. 1, 2014. Thalidomide was prescribed for the treatment
of morning sickness in pregnant women. Between 1957 and 1962, thalidomide caused severe birth defects in >10,000 children. Thalidomide is a mixture of two stereoisomers. One stereoisomer (R) is responsible for the therapeutically beneficial
effects. The other (S) isomer causes birth defects. Drugs should be stereochemically pure. (R) (S) Teratogen Anti-emetic Chirality Matters
Oligonucleotides Phosphorothioate
(PS) modifications introduce chiral centers Nucleoside Enormous number of permutations exist (2n) Resulting in thousands of different molecules in every dose Stereopure ASO 1 diastereoisomer 215 = 32,768 diastereoisomers Stereorandom ASO
Phosphodiester Stereorandom Rp Sp Phosphorothioate (PS) Chirality Matters
Stereochemical diversity No. PS
linkages Antisense, exon skipping, ssRNAi CRISPR guide ADAR oligonucleotide No. diastereomers Exponential diversity arises from uncontrolled stereochemistry (Rp) (Sp) Top view Side view
Mipomersen Iwamoto et al., 2017.
Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat. Biotechnol. 35:845-851. 524,288 diastereomers Stereopure diastereomers of mipomersen (WV-1-WV-6) Mipomersen Chirality
Overall ASO/RNA/RNase H complex
structure Yellow spheres represent S' atoms + Target RNA + ASO drug ASO/RNA duplex RNase H Phosphate Binding Pocket RNA Cleavage site Chirality Matters
Phosphate binding pocket 1.3
resolution RNase H1 Phosphate Binding Pocket 5' 3' Rp Sp Sp Scissile Phosphate R179 W225 I239 N240 ASO RNA T181 S223 Chirality Matters
Precision RNase H-mediated RNA
degradation In RNase H1 assay, ASOs were pre-annealed to surrogate MALAT1 mRNA (1:1, Cf=5 mM). RNase H (250:1, E:S) was added and quenched with EDTA at the indicated times. Products were quantified, and V0 was calculated from the best-fit line (n=3
per time point). In iCell neurons, 10, 30, 100, 300, 1,000 or 3,000 nM ASO was added to iCell neurons under free-uptake conditions. 4-days post-treatment, RNA was harvested and processed. MALAT1 mRNA expression was determined by qPCR (n=2 per
concentration). Control is non-targeting oligonucleotide. In two separate experiments, mice received a single IVT injection of 1 L in both eyes. One-week post-injection, eyes were enucleated, flash frozen, bisected into anterior and posterior
and processed for RNA. MALAT1 mRNA expression was determined by qPCR (each dot represents one eye). Improved rate and amount of cleavage Increased potency in vitro Translatable potency shift in vivo (eye) V0=18 nM/sec V0=8.9 nM/sec Stereorandom
Stereopure Control IC50 Stereorandom 2,864 nM Stereopure 120 nM 24- fold 2- fold Stereorandom Stereopure % mRNA Remaining (Malat1/Sfrs9) ~50- fold ( g) Chirality Matters Control
PRISM Chandra Vargeese, Ph.D. SVP,
Head of Drug Discovery Wave Life Sciences
PRISM: Wave's proprietary
discovery and drug development platform PRISM Platform progress Applied learnings New modality: ADAR-mediated RNA editing
PRISM Continuous Learning PRISM
platform enables rationale drug design
PRISM platform advancing Stereopure
Stereorandom ~5-fold improvement in primary screen hit rates Advancement of PRISM platform PRISM All screens used iPSC-derived neurons; Data pipeline for improved standardization
PRISM: Wave's proprietary
discovery and drug development platform PRISM Platform progress Applied learnings New modality: ADAR-mediated RNA editing
Broad tissue distribution and
durable target engagement Single IV injection of Wave compounds targeting MALAT1 (human equivalent of 1.6 mg/kg) PBS Compound-1 Compound-3 Gastrocnemius Quadriceps Diaphragm Sciatic nerve Lung Heart PRISM Mice were dosed with a single IV injection
(25 mg/kg) of MALAT1-targeting compound, and tissues were assessed for RNA expression 1-, 2-. 4-, and 8-weeks post-dose. Relative percentage of MALAT1 RNA to PBS-treated mice (n=5 per group). MALAT1 RNA levels are normalized to Hprt1.
CNS: Potent and durable targeting
with PRISM designed oligonucleotides MALAT1 knockdown in mouse CNS 10-weeks post-dose Compound-2 Broad distribution >80% knockdown of MALAT1 in multiple regions and cell types Knockdown observed 10-weeks after single 100 g dose PRISM Mice
received a single 100 mg ICV injection (n=3 per group). Relative fold-change in MALAT1 expression is shown for the indicated tissues 10-weeks post-dose. MALAT1 expression levels are normalized to Hprt1. PBS, phosphate buffered saline; Ctx, cortex;
Str, striatum; Cb, cerebellum; Hp, hippocampus; SC, spinal cord. In vivo durability
CNS: Allele-selective silencing of
expanded C9orf72 repeat containing transcripts C9orf72 genetic mutations are the strongest genetic risk factor found to date for the more common, non-inherited (sporadic) forms of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia
(FTD); GGGGCC repeat drives the formation and accumulation of dipeptide repeat proteins that accumulate in brain tissue Wave's approach: Selectively silence the GGGGCC repeat containing transcript while minimizing the impact on normal C9orf72
protein Repeat containing transcripts in spinal cord **** ns PBS Lead Candidate PBS Lead Candidate PRISM Experimental description: 2 x 50 ug on day 1 and day 8; mRNA Samples were analyzed using quantitative PCR (Taqman assay), Protein samples were
measured by Western Blot. Selective silencing of C9orf72 in vivo (transgenic mouse) Clinical development expected to initiate in 2H 2020 C9orf72 protein in spinal cord Reduction of repeat containing transcripts Protein preservation
PRISM enables resolution of
different stereoisomer toxicity profiles Single Rp to Sp shift increases biomarkers for hepatotoxicity Compound-4 and Compound-5 have identical: Sequence Chemical modifications Backbone modifications In vitro potency In vivo potency GalNAc GalNAc
Wave Compound-4 Wave Compound-5 Wave Compound-4 Wave Compound-5 PRISM CD1 mice dosed four by 5 mg/kg on days 1, 4, 8, 11; necropsy done day 14
Bright field view Nucleus:
Hematoxylin; Light Blue Wave oligo: ViewRNA, Fast Red Nucleus: Hoechst33342; Blue Wave oligo: Fast Red/Cy3; Pink Red 63x oil Fluorescence channel view Z Stack view Stereopure 51, n=82 Stereorandom 5, n=132 # of oligo foci/nuclei 0 50 100 150 200 250
P < 0.001 Stereopure Stereorandom Red Oligonucleotide Blue Nucleus PRISM stereopure oligonucleotides designed to enter the nuclei of cells under free-uptake conditions Free uptake of stereorandom and stereopure oligonucleotides Rapid distribution
of stereopure oligonucleotide to muscle in vivo PRISM Experimental conditions: Free uptake of ASOs in 18 hour differentiating human DMD myoblasts ( 48-50). Data derived from in vivo preclinical research. Experimental conditions: A single dose
of stereopure oligonucleotide 30 mg/kg IV was administered to mdx 23 mice. Tissues collected 24 hours post dose and ASO was detected in muscles using ViewRNA. Stereopure oligonucleotides more readily enter the nuclei of cells under free-uptake
conditions, which approximates natural delivery in the body
PRISM exon-skipping programs restore
significant dystrophin in vitro Analogs dystrophin (400-427 kDa) vinculin (120 kDa) Marker Mock drisapersen eteplirsen* suvodirsen WV-isomer 2 WV-isomer 3 Skeletal Muscle Tissue lysates Dystrophin protein restoration of up to 71% in vitro Western
Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of ~52% in vitro 4Q 2019: Interim clinical dystrophin data readout from OLE expected 2H 2020: Topline clinical data expected PRISM Experimental conditions: DMD
protein restoration by western blot in patient-derived myotubes with no transfection reagents. Free uptake at 10 M concentration (left panel) of each compound. Clear dose effect for WVE-N531 (right panel). Suvodirsen (Exon 51) WVE-N531
PRISM: Wave's proprietary
discovery and drug development platform PRISM Platform progress Applied learnings New modality: ADAR-mediated RNA editing
RNA-editing can be used for several