UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form
CURRENT REPORT
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
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| Item 2.02 | Results of Operations and Financial Condition. |
On August 3, 2023, Wave Life Sciences Ltd. (the “Company”) announced its financial results for the quarter ended June 30, 2023. The full text of the press release issued in connection with the announcement is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated by reference herein.
| Item 7.01 | Regulation FD Disclosure. |
From time to time, the Company presents and/or distributes slides and presentations to the investment community to provide updates and summaries of its business. On August 3, 2023, the Company updated its corporate presentation, which is available on the “For Investors & Media” section of the Company’s website at http://ir.wavelifesciences.com/. This presentation is also furnished as Exhibit 99.2 to this Current Report on Form 8-K
The information in these Items 2.02 and 7.01 are being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that Section, nor shall they be deemed incorporated by reference into any registration statement or other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
| Item 9.01 | Financial Statements and Exhibits. |
| (d) | Exhibits |
The following exhibits relating to Items 2.02 and 7.01 are furnished and not filed:
| Exhibit No. | Description | |
| 99.1 | Press Release issued by Wave Life Sciences Ltd. dated August 3, 2023 | |
| 99.2 | Corporate Presentation of Wave Life Sciences Ltd. dated August 3, 2023 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| WAVE LIFE SCIENCES LTD. | ||
| By: | /s/ Paul B. Bolno, M.D. | |
| Paul B. Bolno, M.D. | ||
| President and Chief Executive Officer | ||
Date: August 3, 2023
Exhibit 99.1
Wave Life Sciences Reports Second Quarter 2023 Financial Results and Provides Business Update
Preparing for imminent submission of clinical trial applications (CTAs) for GalNAc-conjugated AATD candidate (WVE-006), the industry’s first RNA editing clinical candidate
Novel DMD therapeutic candidate (WVE-N531) with best-in-class exon skipping clinical data is on track to enter a potentially registrational Phase 2 clinical study in 2H 2023, with dystrophin data expected in 2024
“R&D Day” virtual event planned for September 28, 2023; will focus on Wave’s leading RNA editing capability and highlight its current and future pipeline of transformative RNA medicines
Cash and cash equivalents of $173.0 million as of June 30, 2023, with runway expected into 2025, plus additional potential milestone payments from GSK collaboration in 2023 and beyond
Investor conference call and webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., August 3, 2023 — Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced financial results for the second quarter ended June 30, 2023, and provided a business update.
“In the second quarter, we continued to rapidly advance our pipeline of RNA medicines towards meaningful inflection points. We are on the cusp of moving the industry’s first RNA editing therapeutic candidate, WVE-006 for alpha-1 antitrypsin deficiency or AATD, into the clinic, which will mark an important milestone not only for Wave, but also for individuals living with AATD and the entire RNA medicines field. WVE-006 has the potential to transform the standard of care for people living with AATD, and the goal of our initial clinical trial will be delivering early clinical proof-of-concept via measurement of validated serum surrogate markers,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “While we were disappointed to discontinue WVE-004 for C9-ALS and FTD in the second quarter, we did see successful translation of our preclinical pharmacodynamic effects to clinical biomarker effects, including robust, sustained reductions of up to 50% in poly(GP) with multiple doses. These results are also important validation of our PN chemistry, which is encouraging for our current and upcoming clinical programs, including in DMD, HD, and AATD.”
Dr. Bolno continued: “Momentum is building rapidly in our collaboration with GSK, which kicked off at the start of this year, and we are actively working on multiple targets while leveraging proprietary genetic insights through the collaboration. We are excited to share new data on RNA editing disease targets at our annual ‘R&D Day’ virtual event in September. Wave is well-capitalized to leverage our unique, multimodal platform to develop novel RNA medicines and deliver on a steady cadence of clinical data through 2024 and beyond.”
Recent Business Highlights
| • | Presented new preclinical data for WVE-006 supporting its potential to be a first-and best-in-class treatment for alpha-1 antitrypsin deficiency (AATD). In May 2023, at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, Wave presented data demonstrating that treatment with WVE-006 improved several markers of liver disease in mice, including a decrease in liver inflammation and hepatocyte turnover and reduction in the size of PAS-D positive globules. WVE-006 is uniquely designed to address both liver and lung disease related to AATD and is poised to be the industry’s first RNA editing candidate to reach the clinic. The company expects to submit clinical trial applications (CTAs) for WVE-006 imminently. |
| • | Highlighted clinical data for WVE-N531 to DMD community at Parent Project Muscular Dystrophy (PPMD) Annual Conference. In June 2023, in an oral presentation at the PPMD Conference, Wave highlighted its clinical data from the proof-of-concept study of WVE-N531, including the highest level of exon skipping seen in any DMD trial, high muscle concentrations, and a safe and tolerable profile. Wave is on track to initiate dosing in Part B, a potentially registrational Phase 2 trial of WVE-N531, in 2023, which will be powered to evaluate functional dystrophin expression following 24 and 48 weeks of biweekly dosing. The primary endpoint will be dystrophin protein levels, and the study will also evaluate safety and tolerability, pharmacokinetics, and functional endpoints. Data are expected in 2024. If successful, WVE-N531 has potential to become a near-term wholly owned commercial opportunity for Wave and would enable accelerated development of additional exon skipping candidates for other mutations. |
| • | Multi-dose portion of SELECT-HD study of WVE-003 for HD underway. In the second quarter, Wave initiated the multi-dose portion of its ongoing Phase 1b/2a SELECT-HD clinical trial of WVE-003 (allele-selective silencing oligonucleotide) for Huntington’s disease, and dosing is currently underway. |
| • | Emerging best-in-class siRNA designs highlighted at ASGCT. Also at the May 2023 ASGCT Annual Meeting, Wave highlighted its novel siRNA formats in a poster presentation titled “PN modification of stereopure GalNAc-siRNAs enhances durability of human HSD17B13 silencing in transgenic mouse model.” Wave’s GalNAc-siRNAs were more potent and had better durability of effect in mice compared with reference GalNAc-siRNA designs, which were driven by improved Ago2 loading. These data were also included in Wave’s Nucleic Acids Research publication from April 2023, which can be accessed here. |
| • | Wave Life Sciences added to Russell Indexes. In June 2023, the company joined the Russell 2000® and Russell 3000® Indexes as part of the annual reconstitution. |
Anticipated Upcoming Milestones and Events
WVE-N531 for DMD:
| • | Initiate dosing in Part B of potentially registrational Phase 2 clinical trial in 2023 |
| • | Deliver data from Part B in 2024 |
WVE-006 for AATD:
| • | Submit CTAs for first-in-human study in 2H 2023 |
WVE-003 for HD:
| • | Deliver additional single-dose and available multi-dose biomarker and safety clinical data in 2H 2023 |
Platform and Pipeline:
| • | “R&D Day” virtual event to be held on September 28, 2023, during which Wave will demonstrate how it is continuing to extend its leadership in RNA editing and share preclinical data on new wholly owned programs |
| • | Advance collaboration activities with GSK, with potential for additional cash inflows in 2023 and beyond |
Second Quarter 2023 Financial Results
Wave reported a net loss of $21.1 million in the second quarter of 2023, as compared to $41.3 million in the same period in 2022. The decrease in net loss year-over-year was primarily driven by revenue recognized under the company’s collaboration with GSK, which became effective January 27, 2023. Revenue recognized under the GSK and Takeda collaborations in the second quarter of 2023 was $22.1 million. During the second quarter of 2022, revenue of $0.4 million was recognized under the Takeda collaboration.
Research and development expenses were $33.3 million in the second quarter of 2023, as compared to $29.7 million in the same period in 2022. The increase in research and development expenses was primarily due to increased external expenses related to Wave’s clinical programs.
General and administrative expenses were $12.3 million in the second quarter of 2023, as compared to $12.8 million in the same period in 2022, primarily due to a decrease in share-based compensation.
As of June 30, 2023, Wave had $173.0 million in cash and cash equivalents, as compared to $88.5 million as of December 31, 2022. The company expects that its current cash and cash equivalents will be sufficient to fund operations into 2025.
Investor Conference Call and Webcast
Wave will host an investor conference call today at 8:30 a.m. ET to review second quarter 2023 financial results and pipeline updates. A webcast of the conference call can be accessed by visiting “Investor Events” on the investor relations section of the Wave Life Sciences website: https://ir.wavelifesciences.com/events-and-presentations. Analysts planning to participate during the Q&A portion of the live call can join the conference call at the following audio-conferencing link: available here. Once registered, participants will receive the dial-in information. Following the live event, an archived version of the webcast will be available on the Wave Life Sciences website.
About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a clinical-stage RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization, and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on Twitter @WaveLifeSci.
Forward-Looking Statements
This press release contains forward-looking statements concerning our goals, beliefs, expectations, strategies, objectives and plans, and other statements that are not necessarily based on historical facts, including statements regarding the following, among others: the anticipated initiation, site activation, patient recruitment, patient enrollment, dosing, generation of data and completion of our clinical trials, and the announcement of such events; the protocol, design and endpoints of our clinical trials; the future performance and results of our programs in clinical trials; future preclinical activities and programs; regulatory submissions; the progress and potential benefits of our collaborations; the potential achievement of milestones under our collaborations and receipt of cash payments therefor; the potential of our preclinical data to predict the behavior of our compounds in humans; our identification and expected timing of future product candidates and their therapeutic potential; the anticipated benefits of our therapeutic candidates compared to others; our ability to design compounds using multiple modalities and the anticipated benefits of that approach; the breadth and versatility of PRISM; the expected benefits of our stereopure oligonucleotides compared with stereorandom oligonucleotides; the potential benefits of our RNA editing capability, including our AIMers, compared to others; the status and progress of our programs relative to potential competitors; anticipated benefits of our proprietary manufacturing processes and our internal manufacturing capabilities; the benefit of nucleic acid therapeutics generally; the strength of our intellectual property and the data that support our IP; the anticipated duration of our cash runway; our intended uses of capital; and our expectations regarding any potential global macro events beyond our control on our business. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the following: our ability to finance our drug discovery and development efforts and to raise additional capital when needed; the ability of our preclinical programs to produce data sufficient to support our clinical trial applications and the timing thereof; the clinical results of our programs and the timing thereof, which may not support further development of our product candidates; actions of regulatory authorities and their receptiveness to our adaptive trial designs, which may affect the initiation, timing and progress of clinical trials; our effectiveness in managing regulatory interactions and future clinical trials; the effectiveness of PRISM; the effectiveness of our RNA editing capability and our AIMers; our ability to demonstrate the therapeutic benefits of our candidates in clinical trials, including our ability to develop candidates across multiple therapeutic modalities; our dependence on third parties, including contract research organizations, contract manufacturing organizations, collaborators and partners; our ability to manufacture or contract with third parties to manufacture drug material to support our programs and growth; our ability to obtain, maintain and protect our intellectual property; our ability to enforce our patents against infringers and defend our patent portfolio against challenges from third parties; competition from others developing therapies for the indications we are pursuing; our ability to maintain the company infrastructure and personnel needed to achieve our goals; and the information under the caption “Risk Factors” contained in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings we make with the SEC from time to time. We undertake no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances.
WAVE LIFE SCIENCES LTD.
UNAUDITED CONSOLIDATED BALANCE SHEETS
(In thousands, except share amounts)
| June 30, 2023 | December 31, 2022 | |||||||
| Assets |
||||||||
| Current assets: |
||||||||
| Cash and cash equivalents |
$ | 172,974 | $ | 88,497 | ||||
| Prepaid expenses |
9,012 | 7,932 | ||||||
| Other current assets |
2,722 | 2,108 | ||||||
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|
|
|
|
|||||
| Total current assets |
184,708 | 98,537 | ||||||
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|
|
|||||
| Long-term assets: |
||||||||
| Property and equipment, net of accumulated depreciation of $40,423 and $37,846 as of June 30, 2023, and December 31, 2022, respectively |
14,983 | 17,284 | ||||||
| Operating lease right-of-use assets |
24,805 | 26,843 | ||||||
| Restricted cash |
3,668 | 3,660 | ||||||
| Other assets |
1,821 | 62 | ||||||
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|
|
|
|||||
| Total long-term assets |
45,277 | 47,849 | ||||||
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|
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|||||
| Total assets |
$ | 229,985 | $ | 146,386 | ||||
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| Liabilities, Series A preferred shares and shareholders’ equity (deficit) |
||||||||
| Current liabilities: |
||||||||
| Accounts payable |
$ | 12,379 | $ | 16,915 | ||||
| Accrued expenses and other current liabilities |
10,429 | 17,552 | ||||||
| Current portion of deferred revenue |
111,133 | 31,558 | ||||||
| Current portion of operating lease liability |
6,285 | 5,496 | ||||||
|
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|
|||||
| Total current liabilities |
140,226 | 71,521 | ||||||
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| Long-term liabilities: |
||||||||
| Deferred revenue, net of current portion |
104,540 | 79,774 | ||||||
| Operating lease liability, net of current portion |
28,875 | 32,118 | ||||||
| Other liabilities |
190 | 190 | ||||||
|
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|
|
|||||
| Total long-term liabilities |
133,605 | 112,082 | ||||||
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|
|
|
|||||
| Total liabilities |
$ | 273,831 | $ | 183,603 | ||||
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| Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at June 30, 2023, and December 31, 2022 |
$ | 7,874 | $ | 7,874 | ||||
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|
|
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| Shareholders’ equity (deficit): |
||||||||
| Ordinary shares, no par value; 98,566,816 and 86,924,643 shares issued and outstanding at June 30, 2023, and December 31, 2022, respectively |
$ | 839,675 | $ | 802,833 | ||||
| Additional paid-in capital |
124,601 | 119,442 | ||||||
| Accumulated other comprehensive income (loss) |
(150 | ) | (29 | ) | ||||
| Accumulated deficit |
(1,015,846 | ) | (967,337 | ) | ||||
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|||||
| Total shareholders’ equity (deficit) |
$ | (51,720 | ) | $ | (45,091 | ) | ||
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| Total liabilities, Series A preferred shares and shareholders’ equity (deficit) |
$ | 229,985 | $ | 146,386 | ||||
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WAVE LIFE SCIENCES LTD.
UNAUDITED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(In thousands, except share and per share amounts)
| Three Months Ended June 30, | Six Months Ended June 30, | |||||||||||||||
| 2023 | 2022 | 2023 | 2022 | |||||||||||||
| Revenue |
$ | 22,106 | $ | 375 | $ | 35,035 | $ | 2,125 | ||||||||
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| Operating expenses: |
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| Research and development |
33,314 | 29,733 | 64,293 | 57,203 | ||||||||||||
| General and administrative |
12,265 | 12,806 | 24,500 | 25,180 | ||||||||||||
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| Total operating expenses |
45,579 | 42,539 | 88,793 | 82,383 | ||||||||||||
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| Loss from operations |
(23,473 | ) | (42,164 | ) | (53,758 | ) | (80,258 | ) | ||||||||
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| Other income, net: |
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| Dividend income and interest income, net |
2,251 | 124 | 4,124 | 150 | ||||||||||||
| Other income, net |
118 | 744 | 1,125 | 998 | ||||||||||||
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| Total other income, net |
2,369 | 868 | 5,249 | 1,148 | ||||||||||||
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| Loss before income taxes |
(21,104 | ) | (41,296 | ) | (48,509 | ) | (79,110 | ) | ||||||||
| Income tax provision |
— | — | — | — | ||||||||||||
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| Net loss |
$ | (21,104 | ) | $ | (41,296 | ) | $ | (48,509 | ) | $ | (79,110 | ) | ||||
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| Net loss per share attributable to ordinary shareholders—basic and diluted |
$ | (0.20 | ) | $ | (0.62 | ) | $ | (0.47 | ) | $ | (1.25 | ) | ||||
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| Weighted-average ordinary shares used in computing net loss per share attributable to ordinary shareholders—basic and diluted |
105,462,414 | 66,479,293 | 103,768,971 | 63,514,426 | ||||||||||||
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| Other comprehensive loss: |
||||||||||||||||
| Net loss |
$ | (21,104 | ) | $ | (41,296 | ) | $ | (48,509 | ) | $ | (79,110 | ) | ||||
| Foreign currency translation |
(100 | ) | (142 | ) | (121 | ) | (228 | ) | ||||||||
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| Comprehensive loss |
$ | (21,204 | ) | $ | (41,438 | ) | $ | (48,630 | ) | $ | (79,338 | ) | ||||
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Investor Contact:
Kate Rausch
+1 617-949-4827
krausch@wavelifesci.com
Media Contact:
Alicia Suter
+1 617-949-4817
asuter@wavelifesci.com
Exhibit 99.2 Wave Life Sciences Corporate Presentation August 3, 2023
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. 2
Emerging leader in RNA medicines Multi-modal drug Differentiated, clinical- Strategic collaborations to discovery and stage RNA medicines expand and advance development platform to pipeline with first-in- pipeline (GSK and Takeda) address new areas of class RNA editing disease biology programs RNA editing, splicing and silencing Multiple pipeline and Well-capitalized with GMP manufacturing platform catalysts expected cash runway Strong and broad IP expected in 2023 and into 2025 beyond position Wave Life Sciences is an RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases 3 3 3
RNA medicines allow matching disease target to therapeutic modality RNA Base Editing Splicing Silencing • Efficient editing of RNA bases • Restore RNA transcripts and • Degradation of RNA transcripts to restore or modulate turn on protein production to turn off protein production protein production Endogenous Skip RNase H Restored Reading Frame Endogenous AGO2 Endogenous RISC ADAR enzyme Functional Protein 4
Potential for best-in-class RNAi enabled by Wave’s PRISM platform • First in vivo study of unconjugated siRNAs • Unprecedented Ago2 loading following demonstrated 70-90% APP silencing across administration of single subcutaneous dose six brain regions in mouse CNS at 8 weeks Ago2 Ago2 l l ooa adindi g ng HSD17B13 mRNA (liver, transgenic mice) (liver, transgenic mice) 25 (liver, transgenic mice) 125 Wk 2 Wk 7 Wk 14 20 100 15 75 50 10 **** * 25 * 5 0 0 2 4 6 8 10 12 14 16 0 Time (weeks) PBS Reference Wave siRNA Reference Wave siRNA RNAi is one of multiple Wave modalities being advanced in strategic research collaboration with GSK Left, Middle: Mice expressing human HSD17B13 transgene treated (3 mg/kg)siRNA or PBS, liver mRNA, guide strand concentration, Ago2 loading quantified. Stats: Two-way ANOVA with post-hoc test * P<0.05, ****P<0.0001. Liu et al., 2023 Nuc Acids Res doi: 10.1093/nar/gkad268; Right: ICV: Intracerebroventricular; APP: Amyloid precursor protein ; CNS: 5 central nervous system; B6 mice were administered PBS or 100 μg of APP siRNA by ICV injection on day 0 (n=7). Mice euthanized 8 weeks after administration. Taqman qPCR assays used for RNA PD, relative fold changes of App to Sfrs9 mRNA normalized to percentage of PBS group. All treated group show P≤0.0001 compared to PBS group in 2way ANOVA. % mRNA remaining (HSD17B13/Hprt) Fold change relative to Reference 2
Proprietary PN chemistry enhances potency across modalities RNA Editing Splicing Silencing % Editing % Skipping Target knockdown (% remaining) 100 80 60 40 20 0 -8 -6 -4 -2 0 2 10 10 10 10 10 10 Concentration (µM) Concentration (µM) Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) PS/PO reference compound PS/PN modified compound Left: Experiment was performed in iPSC-derived neurons in vitro; target mRNA levels were monitored using qPCR against a control gene (HPRT1) using a 6 linear model equivalent of the ∆∆Ct method; Middle: DMD patient-derived myoblasts treated with PS/PO or PS/PO/PN stereopure oligonucleotide under free-uptake conditions. Exon-skipping efficiency evaluated by qPCR. Right: Data from independent experiments % Editing Improved editing Improved skipping Improved knockdown
Robust RNA medicines pipeline including first-in- class RNA editing programs Patient population Program Discovery Preclinical Clinical Rights (US & Europe) RNA EDITING WVE-006 GSK exclusive 200K SERPINA1 (AATD) global license Multiple undisclosed 100% global - SPLICING WVE-N531 100% global 2.3K Phase 1/2 Exon 53 (DMD) Other exons (DMD) 100% global Up to 18K SILENCING: ANTISENSE 25K Manifest (SNP3) Takeda 50:50 WVE-003 Phase 1/2 60K Pre-Manifest mHTT (HD) Option (SNP3) Takeda 50:50 SCA3 (ATXN3) 8K Option SILENCING: RNAi Undisclosed 100% global - Through GSK collaboration, Wave can advance up to three collaboration programs and GSK can advance up to eight collaboration programs 7 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; SCA3: Spinocerebellar ataxia 3
WVE-N531 Duchenne muscular dystrophy
Duchenne muscular dystrophy • Genetic mutation in dystrophin gene Disease State Restored State prevents the production of dystrophin Dysfunctional Splicing Exon Skipping Oligo protein, a critical component of healthy Mutant pre-mRNA Mutant pre-mRNA muscle function 50 51 53 54 55 50 51 53 54 55 • Impacts approx. 1 in every 5,000 Skip newborn boys each year; approx. 20,000 new cases annually worldwide 50 51 53 54 55 50 51 54 55 – Approx. 8-10% are amenable to exon 53 skipping mRNA with disrupted reading frame Restored mRNA • Dystrophin protein established by FDA as Translation halted Translation continues surrogate endpoint reasonably likely to 1 predict benefit in boys for accelerated approval in DMD • Increasing amount of functional dystrophin expression over minimal amount shown with approved therapies is expected to result No dystrophin Functional in greater benefit for boys with DMD protein produced dystrophin produced 1 9 Vyondys: www.fda.gov; viltepso; www.fda.gov; Exondys; www.fda.gov; Amondys: www.fda.gov
Extended survival in dKO preclinical model supports potential of exon-skipping therapeutics for DMD PN chemistry improved function and survival in dKO mice dKO survival studies in literature Restored muscle and respiratory 100% survival at time of study termination function to wild-type levels 300 200 100 0 20 40 60 80 100 120 Stimulation Frequency (Hz) Wild-type dKO: PBS dKO: PS/PO/PN Tidal volume Time (weeks) PS/PO/PN 150 mg/kg weekly PS/PO/PN 75 mg/kg bi-weekly PS/PO 150 mg/kg weekly PBS Age (days) Wild-type dKO: PBS dKO (PS/PO/PN Note: Untreated, age-matched mdx mice had 100% survival at oligonucleotide) study termination [not shown] 10 Left: Kandasamy et al., 2022; doi: 10.1093/nar/gkac018; Right: Forand et al., 2020; doi: https://doi.org/10.1016/j.omtm.2020.03.011. Survival probability (%) 2 TVb (ml) Specific Force (Nm )
Preclinical data supported advancing WVE-N531 to clinical development WVE-N531 reached high concentrations in heart and WVE-N531: Dystrophin diaphragm in NHP restoration of up to 71% in vitro Western Blot normalized to primary healthy human myoblast lysate Conc (uM) % Dystrophin Dystrophin Vinculin 11 th 26 Annual ASGCT meeting, May 16-20, 2023
In multidose portion of study, patients received three biweekly 10 mg/kg doses Single ascending intra-patient doses Multidosing at 10 mg/kg every other week Weeks 0 2 4 6 Muscle 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg Biopsy Initial cohort Period before initiating 6 mg/kg multidosing (~1 – 2 months) •Boys with DMD 3 mg/kg amenable to exon 53 skipping 1 mg/kg Data include: • WVE-N531 muscle • Exon skipping concentrations • Dystrophin protein • WVE-N531 localization Dose WVE-N531 12
WVE-N531 in DMD: Delivered positive proof-of-concept data in 4Q 2022 Tissue % Exon Dystrophin • High exon skipping and Tissue Patient concentration skipping by Western blot muscle concentrations Source (µg/g) by RT-PCR (% of normal) after three biweekly 10 mg/kg doses 1 Deltoid 85.5 61.5 0.24 • Similar exon skipping 2 Deltoid 33.5 49.8 0.23 regardless of mutation – Patient 1: del48-52 3 Bicep 8.3 47.9 0.34 – Patient 2: del45-52 – Patient 3: del51-52 Mean Mean muscle Mean exon dystrophin: • PK analysis indicated concentration: s k ipping: 0.27% of 42 µg/g 53% 25-day half-life in normal (BLQ) plasma • WVE-N531 appeared safe and well-tolerated Data presented March 22, 2023 at Muscular Dystrophy Association Clinical and Scientific Conference Biopsies collected ~2 weeks post-last dose (3 biweekly doses of 10 mg/kg) 42 µg/g = 6.1 µM BLQ: Below level of quantification (1%) Data cut-off: December 6, 2022 13
Initiating Part B, a potentially registrational Phase 2 clinical trial of WVE-N531 Screening Biweekly Dosing (10 mg/kg IV) Safety Follow-up • Functional • Biopsy after 24 weeks of • Biopsy after 48 weeks of assessment treatment treatment • Functional assessment • Functional assessment • Design of Part B: Phase 2, open-label, 10 mg/kg every other week, up to 10 patients • Endpoints: Dystrophin (powered for >5% of normal), safety/tolerability, pharmacokinetics, functional assessments (incl. NSAA and others) • Biopsies: – After 24 weeks of treatment – After 48 weeks of treatment • Data from Part B expected in 2024 14 IV: intravenous; NSAA: North star ambulatory assessment
GSK Collaboration and WVE-006 for Alpha-1 antitrypsin deficiency (AATD)
Strategic collaboration with GSK to develop transformative RNA medicines for genetically defined diseases Multiple value drivers to Wave ü $170 million upfront to 1 Milestone / royalties Milestone / royalties Genetic targets Wave (cash and equity ) Wave to leverage GSK granted exclusive global GSK to advance up to eight ü Additional research support GSK’s genetic license to WVE-006 for AATD collaboration programs insights funding Up to $1.2 billion in aggregate in ü Potential for up to $3.3 Up to $225 million in development initiation, development and launch 2 and launch milestones billion in milestones milestones ü Expands Wave’s pipeline Up to $300 million in sales-related Up to $1.6 billion in aggregate in Wave to advance up milestones sales-related milestones to three wholly owned collaboration programs (or more Double-digit tiered royalties as a pending agreement Tiered royalties as a percentage of Extends cash runway percentage of net sales up to high- 3 with GSK) net sales up to low-teens teens into 2025 Development and commercialization Development and commercialization responsibilities transfer to GSK after responsibilities transfer to GSK at completion of first-in-patient study development candidate First-in-class RNA Collaboration leverages Wave’s unique stereopure, TM editing program PN-chemistry containing PRISM platform, including editing, splicing, silencing (RNAi and antisense) 1 2 $120 million in cash and $50 million equity investment received in January 2023, Initiation, development, launch, and commercialization milestones for WVE-006 16 3 and programs progressed during initial 4-year research term (8 GSK collaboration programs) GSK eligible to receive tiered royalty payments and commercial milestones from Wave
WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD WVE-006 designed to correct WVE-006 ADAR editing approach to address key goals of AATD treatment: Z allele mRNA to enable M-AAT protein to be produced 2) Reduce Z-AAT 1) Restore circulating, 3) Retain M-AAT protein aggregation in A functional wild-type M-AAT physiological regulation liver SERPINA1 Z allele mRNA encodes Z-AAT protein with E342K mutation Z-AAT WVE-006 (GalNAc- conjugated AIMer) I(G) RNA correction replaces M-AAT reaches lungs to M-AAT secretion into mutant Z-AAT protein protect from proteases bloodstream with wild-type M-AAT protein Edited SERPINA1 mRNA enables wild- type M-AAT protein production AAT: Alpha-1 antitrypsin Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al., 2017 Int J Chron Obstruct Pulmon Dis 12:561-69; Remih 17 et al., 2021 Curr Opin Pharmacol 59:149-56.
WVE-006 in AATD: First-in-class RNA editing candidate approaching the clinic Potentially comprehensive approach to address both lung and liver manifestations of AATD Increased AAT protein Confirmed restored Demonstrated functionality in NSG-PiZ mice wild-type M-AAT protein of M-AAT protein WVE-006 treatment results in serum AAT Overall percentages of serum AAT Serum neutrophil elastase protein levels >11 uM in NSG-PiZ mice protein isoforms in NSG-PiZ mice inhibition activity in NSG-PiZ mice (Week 13) 2000 PBS 1800 WVE-006 1600 WVE-006 (NO LOADING DOSE) 1400 1200 ~7-fold 1000 increase 800 600 11μM 400 200 0 Week CTA submissions for first-in-human study expected in 2H 2023 AATD: Alpha-1 antitrypsin deficiency; M-AAT protein: wild-type AAT protein; WVE-006 administered subcutaneously (10 mg/kg bi-weekly) in 7-week old NSG-PiZ mice (n=5 per group); Loading dose: 3 x 10 mg/kg at Day 0. Left: Liver biopsies collected at wk 13 (1 wk after last dose) and SERPINA1 editing quantified by Sanger sequencing; Right: Total 18 serum AAT protein quantified by ELISA; Stats: Two-Way ANOVA with adjustment for multiple comparisons (Tukey) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Serum AAT protein (ug/ml) (Mean, s.e.m)
WVE-006 decreases lobular inflammation and PAS-D globule size, prevents increase in hepatocyte turnover Fibrosis à Cirrhosis à Hepatocellular Carcinoma Correction of gain-of-function liver phenotypes Lobular inflammation Mitoses PAS-D-positive globule size (NSG PiZ mice, week 13) (NSG PiZ mice, week 13) (NSG PiZ mice, week 13) ns ✱✱✱ ✱ ns ✱✱✱ ✱ 5 40 ✱ ns ✱✱ 25 ✱✱✱ ✱ ✱ 4 20 30 3 15 20 2 10 10 5 1 0 0 0 Week 0 Week 13 Week 0 Week 13 Week 0 Week 13 Left (Lobular inflammation) and Middle (Mitoses): Scatter plot showing inflammation grade or mitoses score. Each circle represents an individual mouse, (Mean ± SEM); Right (PAS-D Globule Size): 40 largest globules in each of 5 mice were measured. Each circle represents a single PAS-D globule, (Mean ± 19 SEM). Baseline: week 0 (7 weeks old); Treated week 13 (20 weeks old); Stats: Kruskal-Wallis followed by Dunn’s test Baseline PBS WVE-006 Baseline PBS WVE-006 Baseline PBS WVE-006 Score (0-4) Number of mitotic figures/10 MPF + Mean PAS-D globule diameter (μm)
AIMer-directed editing is highly specific in mice No bystander editing observed on SERPINA1 transcript RNA editing only detected at PiZ mutation site in SERPINA1 transcript RNA editing across transcriptome (mouse liver) (mouse liver) C 0% SERPINA1 PBS (PiZ mutation site) T 100% C 48.2% AATD AIMer T 51.8% % Editing Editing site (PiZ mutation) Dose 3x10 mg/kg (days 0, 2, 4) SC with AATD AIMer (SA1 – 4). Liver biopsies day 7. RNA-seq to quantify on-target SERPINA1 editing, to quantify off-target editing reads mapped to entire mouse genome; plotted circles represent sites with LOD>3 (N=4), SERPINA1 edit site is indicated 20 Coverage Coverage
WVE-003 Huntington’s Disease
mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD Huntington’s disease (HD) Healthy individual • Wild-type HTT (wtHTT) is critical for normal neuronal function • Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT) wtHTT Stresses • HD is a monogenic autosomal dominant genetic disease; fully Huntington’s disease penetrant and affects entire brain • Fatal disease characterized by cognitive decline, psychiatric illness, and chorea ~50% decrease wtHTT Stresses mHTT + • 30,000 people with HD in the US in wtHTT and more than 200,000 at risk of Loss of wtHTT functions developing HD Synaptic dysfunction | Healthy CNS function Cell death | Neurodegeneration 22
WVE-003: First-in-class allele-selective candidate for HD Reductions in mean CSF mHTT and preservation of wtHTT • mHTT protein reductions observed in pooled analysis of single dose cohorts in observed in single dose cohorts SELECT-HD clinical study (Sep. 2022) wtHTT protein levels mHTT protein levels • wtHTT protein levels appear consistent with allele-selectivity • Generally safe and Reduction in mHTT protein: well-tolerated Placebo 22% from baseline 35% vs. placebo WVE-003 • Additional single-dose and (30 and 60 mg pooled*) available multi-dose biomarker and safety clinical data expected in 2H 2023 Single dose Single dose of WVE-003 of WVE-003 mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein 23 *Pooled considering no apparent dose response between 2 cohorts; Data cut-off: August 29, 2022
AIMers RNA base editing capability
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022) • Specificity in vitro & in vivo (NHPs) • GalNAc conjugation • In vitro-in vivo translation (NHPs) • Foundational AIMer SAR AIMers detected in liver of NHP at Day 50 Substantial and durable editing in NHP ADAR editing with ACTB AIMer is (PK) liver in vivo highly specific (PD) RNA editing within full transcriptome (primary human hepatocytes) GalNAc AIMers Day 50 RNA editing ACTB in NHP GalNAc AIMers % Editing 25 RNA editing only detected at editing Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 site in ACTB transcript SAR structure-activity relationship Confidence (LOD score)
Expanding addressable disease target space using AIMers to activate pathways and upregulate expression Correct G-to-A driver mutations with AIMers Modulate protein interactions with AIMers Modulate protein- Restore or correct Achieved protein interaction protein function POC Upregulate expression WVE-006 Modify function (GalNAc AIMer) AATD Post-translational modification Alter folding or processing AIMers provide dexterity, with applications beyond precise correction of genetic mutations, including upregulation of expression, modification of protein function, or alter protein stability 26 POC: proof of concept
Modulation of protein-protein interactions: AIMers enable activation of gene pathway in vivo with single edit 27 n=2; Primary hepatocytes 48h of treatment with the indicated dose concentration of AIMers
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression RNA binding proteins recognize sequence motifs to regulate various mRNA properties Stability Transport Processing Protein production • Enhance or inhibit • Intracellular localization • Splicing • Translational efficiency • PolyA usage mRNA decay • Capping AIMer edits mRNA à “dials up” gene expression No binding RNA binding protein I(G) Edited mRNA A mRNA Decay 28
AIMers upregulate mRNA and downstream serum protein in vivo above anticipated threshold Target A mRNA editing mRNA upregulation Protein upregulation (undisclosed liver 7 days post-initial dose 7 days post-initial dose 7 days post-initial dose target) GalNAc AIMer GalNAc AIMer GalNAc AIMer 20 • High unmet need ** * with potential for 20 * ** 80 multiple large 15 indications 15 60 • Preserves endogenous protein 10 10 function 40 • Serum protein with 5 5 biomarkers of 20 pathway activation 0 • Potential benefit 3- 0 0 PBS AIMER-1 AIMER-2 PBS AIMER-1 AIMER-2 PBS AIMER-1 AIMER-2 fold+ upregulation in mouse Potential threshold for benefit ü In vitro to in vivo translation of mouse Target A mRNA upregulation ü In vivo mRNA upregulation corresponds to an upregulation of Target A protein in serum at Day 7 demonstrating proof-of-concept 29 hADAR mouse dosed subcutaneously 3 x 10 mg/kg GalNAc-conjugated AIMer or PBS days (0, 2, 4), taken down at day 7 RNA editing Percent Editing Upregulation Target A mRNA fold change Fold increase pre-post dose Serum Target A (pg/mL)
Anticipated upcoming milestones
Delivering on pipeline and platform catalysts RNA ANTISENSE SPLICING RNAi EDITING SILENCING WVE-006 for AATD WVE-N531 for DMD WVE-003 for HD Newest modality in Wave Most advanced RNA Potential best-in-class First-in-class platform editing candidate & approach with highest exon wild-type huntingtin protein Preclinical data suggest potential best-in-class skipping reported (wtHTT)-sparing best-in-class potential for approach for AATD approach Wave RNAi capability Dosing in potentially WVE-006 CTA registrational clinical Data expected 2H 2023 Hepatic, CNS, and submissions expected trial expected in 2023; beyond in 2H 2023 data expected in 2024 Enables discussion on next steps with Takeda Expansion Expansion opportunities opportunities in liver, in other exons, as well CNS, and kidney as other muscle and CNS diseases DISCOVERY PIPELINE & COLLABORATIONS Anticipate “R&D Day” virtual event on September 28, 2023 during which Wave will demonstrate how it is continuing to extend its leadership in RNA editing and share preclinical data on new wholly-owned programs Advance collaboration activities with GSK, with potential for additional cash inflows in 2023 and beyond 31
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations InvestorRelations@wavelifesci.com 617.949.4827 32