EX-99.2 3 d857761dex992.htm EX-99.2 EX-99.2

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PRECISION-HD2 Topline Results December 30, 2019 Exhibit 99.2

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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.

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Agenda Paul Bolno, MD, MBA President & CEO | Wave Life Sciences Opening Remarks Michael Panzara, MD, MPH Chief Medical Officer| Wave Life Sciences PRECISION-HD2 topline results and clinical trial expansion Q&A Paul Bolno, MD, MBA President & CEO | Wave Life Sciences SNP3 and closing remarks

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Huntington’s disease: a hereditary, fatal disorder Sources: Auerbach W, et al. Hum Mol Genet. 2001;10:2515-2523. Dragatsis I, et al. Nat Genet. 2000;26:300-306. Leavitt BR, et al. J Neurochem. 2006;96:1121-1129. Nasir J, et al. Cell. 1995;81:811-823. Reiner A, et al. J Neurosci. 2001;21:7608-7619. White JK, et al. Nat Genet. 1997;17:404-410. Zeitlin S, et al. Nat Genet. 1995;11:155-163. Carroll JB, et al. Mol Ther. 2011;19:2178-2185. Huntington Disease Society of America (HDSA). What is Huntington’s disease? Available at: https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/ Accessed: November 2, 2018. DNA CAG Repeat RNA wild-type (healthy) allele RNA mutant allele Normal CAG Repeat Expanded CAG Repeat Healthy protein (HTT) Mutant protein (mHTT) Autosomal dominant disease, characterized by cognitive decline, psychiatric illness and chorea; fatal No approved disease-modifying therapies Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT); accumulation of mHTT causes progressive loss of neurons in the brain Wild-type (healthy) HTT protein critical for neuronal function; suppression may have detrimental long-term consequences 30,000 people with Huntington’s disease in the US; another 200,000 at risk of developing the condition

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Utilize association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including Huntington’s disease (HD) Potential to provide treatment for up to 80% of HD population Wave approach: novel, allele-selective silencing Source: Kay, et al. Personalized gene silencing therapeutics for Huntington disease. Clin Genet. 2014;86:29–36. Aims to lower mHTT transcript while leaving healthy wild-type HTT relatively intact Allele-selectivity possible by targeting SNPs associated with expanded long CAG repeat in HTT gene RNase H and ASO:RNA RNA mutant allele

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Michael Panzara, MD, MPH Chief Medical Officer

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PRECISION-HD2 clinical trial design Phase 1b/2a trial Single Dose (3:1) Multidose Randomization 3:1 196 1 At least 8 week washout CSF sample Dose 28 56 84 112 Study Day* 140 OLE Initiated October 2019 2 mg 4 mg 8 mg 16 mg 32 mg Multidose Cohorts Expected to initiate in January 2020 N = 12 per cohort As of data cut-off: 44 patients participated in multidose portion 39 had data available for mHTT assessment 10 patients had not reached Day 140 OLE: Open label extension; CSF: cerebrospinal fluid *Study day may be longer depending on patient washout period

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WVE-120102 generally safe and well tolerated A total of 72% of those who received WVE-120102 experienced an adverse event (AE) as compared with 83% on placebo, mostly mild to moderate in intensity Most common AEs (those occurring in at least 10% of patients on WVE-120102) were headache, procedural pain, falls, and viral upper respiratory infection No serious adverse events related to treatment and no stopping rules met No notable changes in laboratory tests including liver or renal function tests, platelets, or markers of immune activation Supports the addition of higher dose cohorts

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Significant reduction in CSF mHTT WVE-120102 compared to placebo   Pooled Placebo (N=12) Pooled WVE-120102 (N=27) Median (% Change from Baseline) 9.5 -6.0 95% CI (%) 1.77, 20.38 -9.57, 4.85 Difference (%)*   -12.4 95% CI (%)   -24.58, -0.40 p-value†   <0.05 *Hodges-Lehmann non-parametric shift estimates of the difference between treatment and placebo †Wilcoxon-Mann-Whitney non-parametric significance test Pooled analysis performed for all WVE-120102 treated patients compared to placebo demonstrated 12.4% statistically significant reduction in mHTT Statistical analysis across treatment groups using all available data from each cohort suggests dose response at the highest doses tested (p=0.03)

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Healthy or wild-type HTT transcript is required to produce healthy HTT protein which is important for neuronal function There is currently no assay available to directly measure wtHTT in the CSF Total HTT assay, developed by CHDI Foundation, measures total HTT protein to indirectly assess effects on wtHTT With this assay, a non-allele selective, pan-silencing approach would be expected to lead to a commensurate reduction in tHTT relative to mHTT While there was a statistically significant reduction in mHTT compared to placebo in the topline analysis, there was no difference in tHTT compared to placebo, suggesting WVE-120102 may have a potentially differential effect on HTT Wave plans to explore this with higher doses, where larger reductions of mHTT are expected and where a more discernible impact on tHTT may be observed wtHTT: wild-type HTTtHTT: total HTTCSF: cerebrospinal fluid Total HTT WVE-120102 compared to placebo

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Neurofilament light chain Neurofilament light chain (NfL) is an indicator of axonal damage and is elevated in many neurological disorders, including Huntington’s disease No change in CSF neurofilament light chain (NfL) between WVE-120102 and placebo-treated groups Byrne LM, Rodrigues FB, Johnson EB, et al. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease. Science translational medicine 2018;10. CSF: cerebrospinal fluid

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Advancing PRECISION-HD programs PRECISION-HD2 (WVE-120102) WVE-120102 demonstrated statistically significant reduction in mutant HTT compared to placebo Topline data support advancing to higher doses No difference in total HTT or neurofilament light chain in treated patients compared to placebo Data from 32 mg cohort expected in 2H 2020 PRECISION-HD1 (WVE-120101) PRECISION-HD1 trial will remain blinded Additional 32 mg dosing cohort planned Topline results (including 32 mg cohort) now expected in 2H 2020

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Paul Bolno President and CEO

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SNP3: Broadening reach in Huntington’s disease Due to overlap, ~80% of the total HD patient population carry SNP1 and/or SNP2 and/or SNP3 In vivo models for SNP3 available for preclinical development SNP3 % Huntington’s Disease Patient Population with SNP SNP1 SNP2 SNP3 SNP1 SNP2 SNP1 SNP2 SNP3 ~50% ~50% ~40% ~70% ~80% +10% of HD patients vs. SNP1 + SNP2 Predicted patient coverage calculated from published phasing data from Canadian HD patients (Carroll et al., 2011)​​

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SNP3: Potent mutant HTT knockdown activity and demonstration of allele-selective silencing Stereopure compounds selectively deplete mutant HTT mRNA in preclinical study involving heterozygous patient-derived neurons [Left] HTT mRNA remaining in iCell neurons (homozygous for SNP) incubated with the indicated ASO under free-uptake conditions. Data show mean ± sem (n=4). [Right] Neurons were derived from GM21756 patient-derived fibroblasts (heterozygous for SNP) and treated with 20 mM of the indicated ASO under gymnotic conditions for 7 days. RNA was quantified and normalized to TUBB3. Data are mean ± sem (n=3). Percentage of remaining wtHTT and mHTT mRNA is indicated. PBS Pan-silencing RG6042 analog Wave SNP3 Compound-1 Wave SNP3 Compound-2 ~7-fold shift Pan-silencing RG6042 analog Wave SNP3 Compound-1 Wave SNP3 Compound-2 Wave allele-selective compounds are more potent than pan-silencing RG6042 analog in preclinical study involving homozygous patient-derived neurons

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SNP3: Durable in vivo mutant HTT knockdown with stereopure compounds Knockdown persists for 12 weeks Oligonucleotide or PBS (3 x 100 mg ICV) was delivered to BACHD mice. Relative percentage of HTT/TUBB3 mRNA in cortex with respect to levels in PBS-treated mice is shown at 2-12 weeks post-injection. Statistics: All oligo treatment groups are statistically significantly different from PBS; One-way ANOVA ****, P≤0.0001. Wave SNP3 Compound-1 and Compound-2 are also significantly different from RG6042 analog at 8 and 12 weeks ***, P<0.005; **P=0.001. Relative percentage mHTT expression Relative percentage mHTT expression BACHD model only has mutant HTT (no wild-type HTT) PBS Pan-silencing RG6042 analog Wave SNP3 Compound-1 Wave SNP3 Compound-2 PBS Pan-silencing RG6042 analog Wave SNP3 Compound-1 Wave SNP3 Compound-2 BACHD Cortex BACHD Striatum ** **** *** **** **** ****

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Anticipated upcoming Wave milestones CNS 2H 2020: PRECISION-HD2 data from 32 mg cohort in Huntington’s disease 2H 2020: PRECISION-HD1 topline data, including 32 mg cohort, in Huntington’s disease 2H 2020: Initiate clinical development of SNP3 program in Huntington’s disease 2H 2020: Initiate clinical development of C9orf72 program in ALS and FTD Ophthalmology 2020: Advance USH2A exon-skipping program RNA-editing 2020: In vivo ADAR editing data

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PRECISION-HD2 Topline Results December 30, 2019