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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Name of each exchange on which registered | ||
| Item 2.02 | Results of Operations and Financial Condition. |
On May 9, 2024, Wave Life Sciences Ltd. (the “Company”) announced its financial results for the quarter ended March 31, 2024. 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 May 9, 2024, the Company updated its corporate presentation, which is available on the “Investors” 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 May 9, 2024 | |
| 99.2 | Corporate Presentation of Wave Life Sciences Ltd. dated May 9, 2024 | |
| 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/ Kyle Moran | |
| Kyle Moran | ||
| Chief Financial Officer | ||
Date: May 9, 2024
Exhibit 99.1
Wave Life Sciences Reports First Quarter 2024 Financial Results and Provides Business Update
RestorAATion-2 clinical trial of WVE-006 in AATD patients underway; expected proof-of-mechanism data in patients with AATD remains on track for 2024
INHBE program for obesity expected clinical trial initiation in 1Q 2025; preclinical data demonstrate weight loss similar to semaglutide, fat loss with no loss of muscle mass, and curtailed rebound weight gain upon cessation of semaglutide, with potential for dosing 1 – 2 times per year
Continued momentum in GSK collaboration; advancing first two GSK collaboration programs following successful target validation; both programs utilize Wave’s GalNAc-siRNA format and discovery collaboration continues to span all Wave modalities, including RNA editing
Clinical data on track for first-in-class, allele-selective HD program (expected 2Q 2024) and potentially registrational FORWARD-53 trial in DMD (expected 3Q 2024)
Cash and cash equivalents of $181 million as of March 31, 2024; with an additional $12 million aggregate initiation payment earned under GSK collaboration subsequent to quarter-end for advancement of programs; runway expected into 4Q 2025
Investor conference call and webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., May 9, 2024 – Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced financial results for the first quarter ended March 31, 2024, and provided a business update.
“Since our last update, we have made excellent progress across our multimodal pipeline of novel RNA medicines and continued to advance our collaboration with GSK. We are on-track to deliver key data sets this year, which enable opportunities to unlock the broad potential of our RNA editing, silencing and splicing capabilities,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “In RNA editing, we are advancing WVE-006, having used data from healthy volunteers in RestorAATion-1 to identify a starting dose in our RestorAATion-2 study that is expected to engage target in patients. With RestorAATion-2 now underway, we remain on track to deliver expected proof of mechanism data in patients with AATD this year, which would represent the first-ever clinical demonstration of RNA editing and be an important milestone for the alpha-1 community, as well as serve to validate our wholly owned RNA editing pipeline.”
Dr. Bolno continued, “In addition to pioneering the field of RNA editing, we are working expeditiously to advance our GalNAc-siRNA INHBE program in obesity and expect to initiate a clinical trial in the first quarter of next year. In DMD and HD, we are approaching clinical data readouts as we plan to deliver multidose data for our allele-selective HD program in the second quarter and potentially registrational data from our FORWARD-53 trial in DMD in the third quarter. Our efforts to accelerate development of our INHBE program and advance our pipeline and collaborations have laid a strong foundation for Wave’s future and we look forward to demonstrating our leadership in RNA medicines as we reimagine what’s possible for science, for medicine, and for human health.”
Recent Business Highlights
AATD and AIMer pipeline (RNA editing)
| • | RestorAATion-2 underway; clinical program investigating WVE-006 as a first- and best-in-class treatment for alpha-1 antitrypsin deficiency (AATD) |
| • | WVE-006 is Wave’s GalNAc-conjugated, subcutaneously delivered, RNA editing oligonucleotide that is uniquely designed to address AATD-related lung disease, liver disease, or both. WVE-006 does not use a lipid-nanoparticle (LNP) delivery system. |
| • | The RestorAATion-2 clinical trial is now underway. RestorAATion-2 is a Phase 1b/2a open label study designed to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of WVE-006 in patients with AATD who have the homozygous Pi*ZZ mutation. The trial includes both single ascending dose (SAD) and multiple ascending dose (MAD) portions. It is designed to provide an efficient path to proof-of-mechanism as measured by restoration of wild-type alpha-1 antitrypsin (M-AAT) protein in serum. |
| • | Wave’s progress in dose-escalating healthy volunteers in RestorAAtion-1 enabled the quick identification of a starting dose level in RestorAATion-2 that, based on preclinical data, is expected to engage target in patients. |
| • | In addition to WVE-006, Wave continues to advance its pipeline of wholly owned RNA editing therapeutics across a range of high-impact GalNAc-hepatic and extra-hepatic targets. Powered by genetic datasets and deep learning models, Wave is utilizing its proprietary “edit-verse” to identify new RNA editing targets that leverage easily accessible biomarkers, offer efficient paths to proof-of-concept in humans, address diseases of high unmet need, and represent meaningful commercial opportunities. Wave plans to share new preclinical data from its wholly owned RNA editing pipeline in 2024. |
| • | Expected upcoming milestone: Wave expects to deliver proof-of-mechanism data from RestorAATion-2 in patients with AATD in 2024 |
Obesity (siRNA)
| • | Advancing lead clinical candidate for INHBE program with a potentially best-in-class profile for obesity toward anticipated clinical trial initiation in 1Q 2025 |
| • | Wave’s wholly owned INHBE clinical candidate is a GalNAc-small interfering RNA (siRNA) that utilizes Wave’s next generation siRNA format and is designed to silence the INHBE (Inhibin bE) gene, with a goal of inducing lipolysis (fat-burning) while preserving muscle mass to restore and maintain a healthy metabolic profile. |
| • | INHBE loss-of-function (LoF) heterozygous human carriers have a favorable cardiometabolic profile, including reduced abdominal obesity and reduced odds of type 2 diabetes and coronary artery disease. Silencing INHBE is expected to recapitulate the cardiometabolic profile of these LoF carriers and may also address limitations of GLP-1s. |
| • | Wave’s INHBE GalNAc-siRNA has demonstrated highly potent (ED50 < 1mg/kg) and durable silencing following one, low-single-digit dose supporting every-six-month or annual subcutaneous dosing in preclinical mouse models. Data also demonstrated weight loss with no loss of muscle mass and a reduction in fat mass with preferential effects on visceral fat, consistent with the profile of INHBE LoF carriers in human genetics. |
| • | In an ongoing, head-to-head study in diet-induced obesity mice, Wave has observed a weight loss effect from a single dose of its INHBE GalNAc-siRNA similar to semaglutide. In addition, treatment with Wave’s INHBE GalNAc-siRNA upon cessation of semaglutide treatment curtailed expected rebound weight gain. The company plans to share additional preclinical data later this year. |
| • | Expected upcoming milestone: Wave expects to initiate a clinical trial for its INHBE candidate in the first quarter of 2025. |
GSK Collaboration
| • | Advancing first two collaboration programs recently selected by GSK following target validation; programs utilize Wave’s next generation GalNAc siRNA format |
| • | In April 2024, GSK selected its first two Collaboration Programs, which are in hepatology, to advance to development candidates following achievement of target validation. GSK will provide an aggregate initiation payment of $12 million to Wave. |
| • | The first two GSK Collaboration Programs utilize Wave’s GalNAc-siRNA formats. Under the agreement, GSK can advance up to eight programs leveraging Wave’s PRISM platform and multiple RNA-targeting modalities, including RNA editing, with target validation ongoing in multiple therapy areas. |
| • | In total, Wave is eligible for up to $3.3 billion in potential milestone payments, as well as tiered royalties on net sales, for GSK’s eight Collaboration Programs and WVE-006, for which GSK has an exclusive global license. |
DMD (exon skipping)
| • | Advancing FORWARD-53 clinical trial toward potentially registrational 24-week dystrophin data in the third quarter of 2024 |
| • | Wave’s WVE-N531 program for boys with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping is designed to induce production of endogenous, functional dystrophin protein. |
| • | In Part A of Wave’s WVE-N531 trial, WVE-N531 demonstrated industry-leading exon skipping levels of 53%, muscle tissue concentrations of 42 µg/g (~42,000 ng/g), and myogenic stem cell distribution in all study participants. |
| • | WVE-N531 is currently being evaluated in the ongoing FORWARD-53 clinical trial of 11 boys with DMD, which is powered to evaluate endogenous, functional dystrophin expression following 24 and 48 weeks of 10 mg/kg dosing administered every-other-week. The primary endpoint is dystrophin protein levels, and the trial will also evaluate pharmacokinetics, digital and functional endpoints, and safety and tolerability. |
| • | Pending positive results from the FORWARD-53 trial, the company is planning to advance a broader DMD pipeline of PN-modified oligonucleotides for skipping other exons, with the goal of providing new treatment options for a larger population of boys with DMD. |
| • | Expected upcoming milestone: Wave expects to deliver data, including dystrophin protein expression from muscle biopsies at 24 weeks, in the third quarter of 2024. |
HD (antisense silencing)
| • | WVE-003 SELECT-HD multi-dose data with extended follow-up remains on track for 2Q 2024; first-in-class program designed to lower mutant HTT while sparing wild-type HTT |
| • | WVE-003 is a first-in-class investigational allele-selective Huntington’s disease (HD) therapeutic designed to reduce mutant huntingtin (mHTT) protein while also sparing healthy wild-type huntingtin (wtHTT) protein. Due to the significance of wtHTT function for the health of the central nervous system and the potential for mHTT to disrupt wtHTT function, selectively lowering mHTT while preserving wtHTT protein expression and function may offer advantages over nonselective HTT-lowering approaches for the treatment of HD. |
| • | WVE-003 has demonstrated single-dose reductions in mean mHTT in cerebrospinal fluid of 35% compared to placebo, with preservation of wtHTT, as previously shared in September 2022. |
| • | The ongoing multi-dose portion of the SELECT-HD clinical trial is evaluating a cohort of 24 patients with HD receiving 30 mg doses of WVE-003 administered every eight weeks. |
| • | Data from the ongoing SELECT-HD clinical trial will form the basis for decision making for Wave’s advancement of this program, including supporting an opt-in package for Takeda. |
| • | Expected upcoming milestone: Wave expects to report data from the 30 mg multi-dose cohort with extended follow-up, along with all single-dose data, in the second quarter of 2024. |
Corporate
| • | Dr. Erik Ingelsson appointed CSO; builds on Wave’s recent progress advancing innovative genetic targets and adds experience to accelerate rapid identification and translation of unique genetic insights |
| • | Today, Wave announced the appointment of Erik Ingelsson, MD, PhD, as Chief Scientific Officer (CSO). Dr. Ingelsson joins Wave to drive the emerging therapeutic portfolio strategy, including growing its genetics and genomics capabilities for identifying new, high impact targets and leveraging Wave’s multimodal platform to advance transformative RNA medicines. Dr. Ingelsson brings deep expertise in genetics and drug discovery, as well as substantial experience in metabolic diseases, such as obesity, MASH and cardiovascular disease. |
| • | Most recently, Dr. Ingelsson served as Senior Vice President, Head of Target Discovery, at GSK, and prior to that, was SVP of Genomic Sciences at GSK. Previously, he was a Professor of Medicine at Stanford University. (See May 9, 2024 press release here) |
Financial Highlights
| • | Cash and cash equivalents were $180.9 million as of March 31, 2024, compared to $200.4 million as of December 31, 2023. Subsequent to March 31, 2024, GSK advanced two programs to candidate development, triggering a $12.0 million aggregate initiation payment to Wave. Wave expects that its current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025. Potential future milestone and other payments to Wave under its GSK and Takeda collaborations are not included in its cash runway. |
| • | Revenue was $12.5 million for the first quarter of 2024, as compared to $12.9 million in the first quarter of 2023. The slight decrease in revenue was due to decreased revenue from the Takeda collaboration. Revenue from the GSK collaboration was consistent for the first quarter of 2024 and 2023. |
| • | Research and development expenses were $33.4 million in the first quarter of 2024, as compared to $31.0 million in the first quarter of 2023. General and administrative expenses were $13.5 million in the first quarter of 2024, as compared to $12.2 million in the first quarter of 2023. |
| • | Net loss was $31.6 million for the first quarter of 2024, as compared to $27.4 million for the first quarter of 2023. |
Investor Conference Call and Webcast
Wave will host an investor conference call today at 8:30 a.m. ET to review the first quarter 2024 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-publications/events. 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 biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s RNA medicines platform, PRISM®, combines multiple modalities, chemistry innovation and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. Its toolkit of RNA-targeting modalities includes editing, splicing, RNA interference and antisense silencing, providing Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s diversified pipeline includes clinical programs in Duchenne muscular dystrophy, Alpha-1 antitrypsin deficiency and Huntington’s disease, as well as a preclinical program in obesity. Driven by the calling to “Reimagine Possible”, Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit www.wavelifesciences.com and follow Wave on X (formerly Twitter) and LinkedIn.
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 and reporting of data and completion of our clinical trials, including interactions with regulators and any potential registration based on these data, 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; ongoing and 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 and pipeline compared to our competitors; our ability to design compounds using various modalities and the anticipated benefits of that approach; the breadth and versatility of our PRISM drug discovery and development platform; 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 potential for certain of our programs to be best-in-class or first-in-class; the potential benefits of our GalNAc-conjugated siRNA program targeting INHBE; the potential benefits that our “edit-verse” may provide us, including identifying new RNA editing targets; the status and progress of our programs relative to potential competitors; anticipated benefits of our proprietary manufacturing processes and our internal manufacturing capabilities; the benefits of RNA medicines generally; the strength of our intellectual property and the data that support our IP; the anticipated duration of our cash runway and our ability to fund future operations; our intended uses of capital; and our expectations regarding the impact of any potential global macro events 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)
| March 31, 2024 | December 31, 2023 | |||||||
| Assets |
||||||||
| Current assets: |
||||||||
| Cash and cash equivalents |
$ | 180,922 | $ | 200,351 | ||||
| Accounts receivable |
— | 21,086 | ||||||
| Prepaid expenses |
11,139 | 9,912 | ||||||
| Other current assets |
4,706 | 4,024 | ||||||
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|||||
| Total current assets |
196,767 | 235,373 | ||||||
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| Long-term assets: |
||||||||
| Property and equipment, net of accumulated depreciation of $43,687 and $42,709 as of March 31, 2024 and December 31, 2023, respectively |
12,418 | 13,084 | ||||||
| Operating lease right-of-use assets |
21,502 | 22,637 | ||||||
| Restricted cash |
3,715 | 3,699 | ||||||
| Other assets |
868 | 156 | ||||||
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| Total long-term assets |
38,503 | 39,576 | ||||||
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| Total assets |
$ | 235,270 | $ | 274,949 | ||||
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| Liabilities, Series A preferred shares, and shareholders’ equity |
||||||||
| Current liabilities: |
||||||||
| Accounts payable |
$ | 11,730 | $ | 12,839 | ||||
| Accrued expenses and other current liabilities |
6,621 | 16,828 | ||||||
| Current portion of deferred revenue |
140,586 | 150,059 | ||||||
| Current portion of operating lease liability |
6,936 | 6,714 | ||||||
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| Total current liabilities |
165,873 | 186,440 | ||||||
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| Long-term liabilities: |
||||||||
| Deferred revenue, net of current portion |
12,536 | 15,601 | ||||||
| Operating lease liability, net of current portion |
23,598 | 25,404 | ||||||
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| Total long-term liabilities |
36,134 | 41,005 | ||||||
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| Total liabilities |
$ | 202,007 | $ | 227,445 | ||||
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| Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at March 31, 2024 and December 31, 2023 |
$ | 7,874 | $ | 7,874 | ||||
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| Shareholders’ equity: |
||||||||
| Ordinary shares, no par value; 122,321,384 and 119,162,234 shares issued and outstanding at March 31, 2024 and December 31, 2023, respectively |
$ | 949,877 | $ | 935,367 | ||||
| Additional paid-in capital |
132,118 | 129,237 | ||||||
| Accumulated other comprehensive loss |
(198 | ) | (124 | ) | ||||
| Accumulated deficit |
(1,056,408 | ) | (1,024,850 | ) | ||||
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| Total shareholders’ equity |
$ | 25,389 | $ | 39,630 | ||||
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| Total liabilities, Series A preferred shares, and shareholders’ equity |
$ | 235,270 | $ | 274,949 | ||||
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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 March 31, | ||||||||
| 2024 | 2023 | |||||||
| Revenue |
$ | 12,538 | $ | 12,929 | ||||
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| Operating expenses: |
||||||||
| Research and development |
33,447 | 30,979 | ||||||
| General and administrative |
13,549 | 12,235 | ||||||
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|
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| Total operating expenses |
46,996 | 43,214 | ||||||
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| Loss from operations |
(34,458 | ) | (30,285 | ) | ||||
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| Other income, net: |
||||||||
| Dividend income and interest income |
2,535 | 1,873 | ||||||
| Other income, net |
365 | 1,007 | ||||||
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|
|
|
|||||
| Total other income, net |
2,900 | 2,880 | ||||||
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| Loss before income taxes |
(31,558 | ) | (27,405 | ) | ||||
| Income tax benefit (provision) |
— | — | ||||||
|
|
|
|
|
|||||
| Net loss |
$ | (31,558 | ) | $ | (27,405 | ) | ||
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| Net loss per share attributable to ordinary shareholders—basic and diluted |
$ | (0.24 | ) | $ | (0.27 | ) | ||
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| Weighted-average ordinary shares used in computing net loss per share attributable to ordinary shareholders—basic and diluted |
129,271,678 | 102,056,712 | ||||||
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| Other comprehensive loss: |
||||||||
| Net loss |
$ | (31,558 | ) | $ | (27,405 | ) | ||
| Foreign currency translation |
(74 | ) | (21 | ) | ||||
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| Comprehensive loss |
$ | (31,632 | ) | $ | (27,426 | ) | ||
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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 May 9, 2024
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
Building a leading RNA medicines company Multi-modal drug discovery and Differentiated RNA medicines pipeline development platform • Therapeutic candidates that optimally • Clinical data updates expected in 2024 from AATD, address disease biology DMD, HD clinical programs • RNA editing, siRNA, splicing, antisense • INHBE clinical trial initiation for obesity expected 1Q 2025 • Best-in-class oligonucleotide chemistry • Initiated first-ever clinical trial in RNA editing Strategic collaborations In-house GMP manufacturing Strong and broad IP (GSK and Takeda) Well capitalized with cash runway into 4Q 2025* 3 *Cash runway does not include potential future milestones or opt-in payments under GSK and Takeda collaborations AATD: Alpha-1 antitrypsin deficiency, DMD: Duchenne muscular dystrophy, HD: Huntington’s disease
Wave has driven foundational advances in nucleic acid chemistry to expand platform technologies and develop next generation of RNA therapeutics Further information can be found in recent platform publications Silencing (RNase H and Ago2) Splicing Editing 4 Selected Wave publications: PMC10201370, PMC9092894, PMID 35256816, PMC9177980, PMC9178015, PMC7870851, PMC7804567, PMID 28829437
Wave's versatile multimodal RNA medicines platform ideal for capitalizing on new genetic insights in rare and common diseases Accessing UK Biobank and building proprietary machine learning models to generate unique genetic insights 5 Claussnitzer, et al. Nature (2020) 577, 179; King et al. PLoS Genet (2019) 15, e1008489
Robust, diversified RNA medicines pipeline including first-in-class RNA editing programs IND / CTA Enabling Patient population Program Discovery / Preclinical Clinical Rights Studies (US & Europe) RNA EDITING GSK exclusive WVE-006 RestorAATion Clinical Program 200K SERPINA1 (AATD) global license Multiple undisclosed 100% global >20K (multiple) Correction Multiple undisclosed 100% global >3M (multiple) Upregulation SILENCING: siRNA INHBE lead clinical candidate (Obesity and 100% global 47M other metabolic disorders) SPLICING WVE-N531 FORWARD-53 Trial (Phase 2) 100% global 2.3K Exon 53 (DMD) Other exons (DMD) 100% global Up to 18K SILENCING: ANTISENSE WVE-003 25K Manifest (SNP3) SELECT-HD Trial (Phase 1b/2a) Takeda 50:50 Option mHTT (HD) 60K Pre-Manifest (SNP3) Editing for correction Editing for upregulation 6 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease
Strategic collaboration with GSK to develop transformative RNA medicines Maximize global Advance up to eight Collaboration Expand Wave’s potential for GSK collaboration Highlights pipeline WVE-006 for AATD programs 1 • $170 million upfront Wave to advance up to Up to $525 million in Up to $2.8 billion in three wholly owned • Additional research total milestones and total milestones and collaboration programs funding tiered royalties on net tiered royalties on (or more with GSK’s sales net sales 3 consent) • Potential for up to $3.3 billion in 2 milestones ü ü ü $20 million milestone INHBE is Wave’s first $12 million aggregate with first individual dosing wholly owned program initiation payment for • Leverage GSK’s GSK’s selection of two emerging from GSK expertise in genetics RestorAATion-2 trial programs to advance collaboration and genomics underway (AATD patients) 7 1. $120 million in cash and $50 million equity investment 2. Initiation, development, launch, and commercialization milestones for WVE-006 and programs progressed during initial 4-year research term (8 GSK collaboration programs), 3. GSK eligible to receive tiered royalty payments and commercial milestones from Wave Recent Highlights
WVE-006 (RNA editing) AATD 8
WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD WVE-006 for AATD WVE-006 ADAR editing approach to address key goals of AATD treatment: 1) Restore circulating, 2) Reduce Z-AAT protein 3) Retain M-AAT A functional wild-type M-AAT aggregation in liver physiological regulation 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 secretion into M-AAT reaches lungs to mutant Z-AAT protein with bloodstream protect from proteases wild-type M-AAT protein Edited SERPINA1 mRNA enables wild-type M-AAT protein production 200,000 Pi*ZZ patients in US and Europe 9 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 et al., 2021 Curr Opin Pharmacol 59:149-56.
WVE-006 in AATD: First-in-class RNA editing clinical candidate 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 of up to 30 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 ≥50% editing supports restoration of MZ phenotype 10 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 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 1 5 0 0 0 Week 0 Week 13 11 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 ± 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 RNA editing only detected at PiZ mutation RNA editing across transcriptome site in SERPINA1 transcript PBS SERPINA1 C 0% (PiZ mutation site) T 100% AATD AIMer C 48.2% T 51.8% Editing site % Editing (PiZ mutation) No bystander editing observed on SERPINA1 transcript 12 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 Coverage Coverage
RestorAATion-2 underway, proof-of-mechanism data expected in 2024 Informs dose & dose frequency R Rest estor orA AA ATion Tion--1: 1: H Healt ealthy hy V Volunt olunteer eers s RestorAATion-2: AATD Patients SAD à MAD cohorts Dose E Up to 7 doses Dose D Cohort 3 Dose C Cohort 2 Dose B Cohort 1 Multiple assessments of serum AAT throughout cohort Dose A Study key objectives Safety and tolerability Pharmacokinetics Serum M-AAT levels 13 HV: healthy volunteer; SAD: single-ascending dose; MAD: multi-ascending dose
AIMers RNA editing capability 14
The AIMer-targetable ‘Edit-Verse’ is substantial Gene-Disease Network • The Edit-verse is the editable gene-disease universe, including upregulation 1 • >13,000 genes with a high-probability of being amenable to transcriptional regulation with A-to-G editing • Model development ongoing to expand access to more protein-coding genes and expand the Edit-verse • AIMers are expected to be able to target ~50% of the transcriptome 15 1 (score >95th p-tile)
Proprietary and unique chemistry supports efficient editing in vivo with GalNAc-AIMers Orphan site base, sugar 5’ 3’ RNA editing in primary mouse RNA editing in vivo liver (GalNAc hepatocytes (GalNAc mediated delivery) mediated delivery) 100 100 ✱ ✱✱✱ N3U, Sugar 2’-OMe N3U, Sugar 2’-H 80 ✱ ✱✱✱ 80 60 60 40 40 C, Sugar 2’-H 20 20 C, Sugar 2’-OMe 0 0 0.001 0.01 0.1 1 10 C C N3U N3U Base PBS NTC -20 2’-H 2’-OMe 2’-H 2’-OMe Sugar Concentration (uM) GalNAc-AIMers 16 Left: GalNAc-conjugated AIMers targeting Ugp2 dosed in primary hepatocytes isolated from hADAR1-p110 hemizygous knock-in mice. Data: mean ± SEM. Dashed lines: 95% CI. Right: 8-week-old transgenic hADAR-p110 knock-in mice dosed with PBS (black) or GalNAc-conjugated AIMer subcutaneously (day 0, 2, 4) and evaluated for UGP2 editing on day 7. NTC: Non-targeting control, targeting ACTB. **** p<0.0001 %Ugp2 mRNA editing %Ugp2 mRNA editing
Innovating on applications of ADAR beyond restoring protein function Restore or correct Upregulate expression to increase endogenous protein activity protein function Attenuated gene expression mRNA mRNA Decay Cascade Unique RNA motifs “Dialed up” Gene Expression • Correct G-to-A driver mutations with AIMers WVE-006 (GalNAc-AIMer) Edited mRNA AATD A single edited base on mRNA permanently disrupts the motif Stable mRNA yields increased protein production 17
Multiple RNA editing opportunities to build high-value pipeline beyond WVE-006 Potential to advance any combination of targets into preclinical development Hepatic (GalNAc-AIMers) Extra-Hepatic (AIMers) Target A Target B Target X Target E Target F Target G Approach Upregulation Upregulation Upregulation Correction Upregulation Correction Tissue Liver Liver Liver Liver Kidney Lung Therapeutic Area Metabolic Metabolic Renal Rare Renal Rare Estimated Patients (US and ~90M ~3M ~170K ~17K ~85K ~5K Europe) • The Edit-verse is substantial and still expanding • Advancing work for a diverse set of undisclosed targets addressing areas of high unmet need, including both rare and prevalent diseases 18
INHBE program (siRNA silencing) Obesity and other metabolic disorders 19
Potential for best-in-class siRNA enabled by Wave’s PRISM® platform • Unprecedented Ago2 loading increases potency and durability of silencing following administration of single subcutaneous dose Ago2 loading Antisense strand Ago2 loading HSD17B13 mRNA (liver, transgenic mice) (Liver, transgenic mice) 25 (liver, transgenic mice) (liver, transgenic mice) 5 125 Wk 2 Wk 7 Wk 14 Wk 2 Wk 7 Wk 14 4 20 100 3 2 15 75 1 11 .0 1 50 10 25 * 0.5 * 5 0 0 2 4 6 8 10 12 14 16 0.0 0 Time (weeks) PBS Reference Wave first gen Reference Wave first gen siRNA siRNA siRNA silencing is one of multiple Wave modalities being advanced in strategic research collaboration with GSK 20 Left, Middle, and right: Mice expressing human HSD17B13 transgene treated with siRNA (3 mg/kg) 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; % mRNA remaining (HSD17B13/Hprt) ug of oligo/g of tissue (mean± sem) Fold change relative to Reference 2
Driven by clinical genetics, Wave’s first RNAi program addresses high unmet need in obesity INHBE program (GalNAc-siRNA) is Wave’s first wholly owned program to emerge from GSK collaboration GLP-1 receptor agonists have several INHBE silencing expected to induce fat reported limitations loss, while maintaining muscle mass • siRNA to silence INHBE gene is expected to recapitulate 1 × Lead to weight loss at the expense of muscle mass the healthy metabolic profile of INHBE loss of function 1,2,3 (LoF) heterozygous human carriers, including: 4 × Associated with poor tolerability profile with 68% drop- 3 off after 1 year ü Reduced waist-to-hip ratio ü Reduced serum ü Reduced odds ratio of type 2 triglycerides × Discontinuation of therapy leads to rapid weight regain diabetes and coronary artery ü Elevated HDL-c 4 × Suppress general reward system disease by >25% • INHBE (Inhibin βE) expressed primarily in liver and gene 4 product (activin E) acts on its receptor in adipose tissue Wave’s INHBE siRNA program may address these • Lowering of INHBE mRNA promotes fat burning limitations and / or work complementarily with GLP-1s 5,6 (lipolysis) and decreases fat accumulation (adiposity) ≥50% reduction of INHBE in patients expected to restore and maintain a healthy metabolic profile 21 1. Sargeant, et al. 2019 Endocrinol Metab (Seoul) 34(3):247-262; 2. Prime Therapeutics Claims 1. Nat Commun 2022. https://doi.org/10.1038/s41467-022-32398-7; 2. Nat Commun 2022. Analysis, July 2023; 3. Müller, et al. 2019 Molecular Metabolism 30: 72-130. https://doi.org/10.1038/s41467-022-31757-8; 3. PLOS ONE 2018. https://doi.org/10.1371/journal.pone.0194798; 4. Adam, RC. et.al. Proc Natl Acad Sci USA. 2023, 120(32): e2309967120. 5. Yogosawa et al. 2013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526038/ 6. Zhao et al. 2023 https://pubmed.ncbi.nlm.nih.gov/36626233/
First generation INHBE GalNAc-siRNA led to lower body weight and significant decrease in visceral fat in DIO mouse model Lower body weight as Reduction in fat mass across multiple types of white adipose ✓✓ compared to control tissue, with preferential effect on visceral fat reduction Subcutaneous fat (inguinal) Visceral fat (mesenteric) Control First generation (HFD, PBS) INHBE siRNA *** ~56% reduction 5 1.5 1.5 *** ~38% reduction 0 1.0 1.0 -5 -10 0.5 0.5 -15 0.0 0.0 -20 Chow HFD HFD 1 2 3 4 5 Chow HFD HFD PBS PBS First generation PBS PBS First generation Weeks INHBE siRNA INHBE siRNA Results of in vivo preclinical study are consistent with UK Biobank human data on loss-of-function carriers 22 Right: Reduction in fat mass at Week 5; DIO: Diet-induced obesity Body weight relative to PBS (%) mesWAT weight (g) ingWAT weight (g)
INHBE lead clinical candidate has Wave’s next generation siRNA format and best-in-class profile Next generation siRNA results in more INHBE program: Data from DIO mouse potent and durable target knockdown model supports best-in-class profile ü Highly potent silencing (ED50 < 1mg/kg) 125 PBS ü Durable silencing following one, low-single-digit 100 Benchmark dose, supporting every-six-month or annual dosing First gen siRNA 75 ü Weight loss similar to semaglutide with no loss of Next gen siRNA * muscle mass 50 * ü Reduction in fat mass, with preferential effect to the Next generation 25 * * visceral fat siRNA 0 ü Curtailed rebound weight gain upon cessation of 0 5 10 15 20 25 30 35 40 45 50 semaglutide Day Expect to initiate clinical trial for INHBE candidate in 1Q 2025 23 Left: Benchmark: Foster, DJ. et.al. Mol Ther. 2018, 26(3), 708. B6 mice administered PBS or 0.5 mg/kg of siRNA (subcutaneous). Stats: Mixed Two-way ANOVA followed by post hoc test comparing siRNA vs. Next gen siRNA per day derived from linear mixed effects model * P < 0.0001; DIO: diet-induced obesity Serum Ttr±SEM (rel to PBS)
Wave’s platform chemistry enables siRNA extra-hepatic delivery • Chemical impact - Introduction of neutral backbone - Unique structural feature of PN, specifically guanidine - Increased lipophilicity - Stereochemistry • Extra-hepatic delivery PN - Titrating siRNA lipophilicity tunable PNs (PN variants) - Maintaining high Ago2 loading and intracellular trafficking - Titrating plasma protein binding - Altered delivery, enhanced potency and durability in various tissues PN variants can tune extra-hepatic siRNA delivery 24
Single dose of Wave’s next generation siRNA delivers broad, potent and durable CNS target engagement Robust target engagement translates to substantial App protein reduction across brain Next gen siRNA wk8 Next gen siRNA wk16 regions 8-weeks post single dose 125 100 PBS 75 50 25 Next gen siRNA 0 Sustained APP knockdown of at least 75% throughout the 16-week study in vivo in mice 25 PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly lower than PBS at both time points for all tissues at P < 0.0001 level; Immunohistochemical nd analysis of FFPE Mouse Brain tissue labeling App protein (Color Brown) with CS#19389 followed by a ready to use Polymer-HRP 2 Detection antibody. Nuclei were counterstained with Hematoxylin (Color Blue). Single 100 ug ICV injection Cortex Striatum Cerebellum Hippocampus Brainstem Spinal cord APP silencing %mRNA remaining (SEM) (App/Hprt)
Wave siRNA demonstrates more potent and durable silencing as compared to published state-of-the-art Wave (APP – Cortex) Alnylam (APP – Cortex) Nat Biotechnol 40, 1500–1508 (2022) Single dose 100 μg Single dose by ICV 120 μg by ICV 1 25 Knockdown < 90 days 1 00 post-dose Knockdown 75 > 112 days post-dose 50 25 0 C o r te x Wave Wave next generation siRNA next generation siRNA Next gen siRNA wk16 Next gen siRNA wk8 Week 8 (Day 56) Week 16 (Day 112) 26 PBS (dotted line) or 100 μg of App siRNA administered ICV (n=7). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: Three-way ANOVA followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly lower than PBS at both time points for all tissues at P < 0.0001 level. Source: Brown, K.M., Nair, J.K., Janas, M.M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat Biotechnol 40, 1500–1508 (2022). %mRNA remaining (SEM) %mRNA remaining (SEM) (App/Hprt) (App/Hprt) % message remaining (relative to aCSF)
WVE-N531 (splicing) Duchenne muscular dystrophy 27
Duchenne muscular dystrophy • Genetic mutation in dystrophin gene prevents Disease State Restored State the production of dystrophin protein, a critical Dysfunctional Splicing Exon Skipping Oligo component of healthy muscle function Mutant pre-mRNA Mutant pre-mRNA • Impacts approx. 1 in every 5,000 newborn boys 50 51 53 54 55 50 51 53 54 55 each year; approx. 20,000 new cases annually Skip worldwide – Approx. 8-10% are amenable to exon 53 50 51 53 54 55 50 51 54 55 skipping mRNA with disrupted reading frame Restored mRNA • Dystrophin protein established by FDA as surrogate endpoint reasonably likely to predict 1 Translation halted Translation continues 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 in greater benefit for boys with DMD Functional No dystrophin protein dystrophin produced produced 28 1 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 Wave’s PN-modified exon-skipping therapeutics for DMD 100% survival at time of study termination Restored muscle and respiratory function to wild-type levels 300 dKO: PBS 200 Wild-type dKO: PS/PO/PN 100 0 20 40 60 80 100 120 Tidal volume Stimulation Frequency (Hz) Wild-type dKO: PBS dKO (PS/PO/PN Time (weeks) oligonucleotide) PS/PO/PN 150 mg/kg weekly PS/PO/PN 75 mg/kg bi-weekly PS/PO 150 mg/kg weekly PBS Age (days) Note: Untreated, age-matched mdx mice had 100% survival at study termination [not shown] PN chemistry improved function and survival in dKO mice 29 Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 dKO: double knock-out Survival probability (%) TVb (ml) 2 Specific Force (Nm )
Wave’s PN chemistry yields excellent muscle exposure, exon skipping and dystrophin protein expression in dKO mouse model Skeletal muscle Diaphragm Heart 100 *** 100 60 ** PBS ** 75 75 40 PS/PO modified oligonucleotides 50 50 for mouse exon 23 20 25 25 PS/PO/PN modified oligonucleotides 0 0 0 for mouse exon 23 60 60 40 *** 30 40 40 **** 20 **** dKO* 20 20 mouse 10 0 0 0 D37 30 30 *** 30 dose 20 ** ** 20 20 10 10 10 0 0 0 30 Kandasamy et al., 2022 Nuc Acids Res doi: 10.1093/nar/gkac018 Muscle concentration %Dystrophin %Exon skipping (ug/g)
Preclinical data supported advancing WVE-N531 to clinical development WVE-N531: Dystrophin restoration of up to WVE-N531 reached high concentrations in 71% in vitro in patient-derived myoblasts heart and diaphragm in NHP 31 th 26 Annual ASGCT meeting, May 16-20, 2023
Clinical data from WVE-N531 Part A: High exon-skipping & muscle concentrations after three doses every other week WVE-N531 uptake in myocyte stem cells suvodirsen WVE-N531 Mean muscle 1 0.7 µg/g (~700 ng/g) 42 µg/g (~42,000 ng/g) concentration Mean exon Not detectable 53% skipping Half-life in WVE-N531 18 hours 25 days plasma uptake in myogenic stem cells 3 doses of 10 mg/kg 22 weekly doses of 5 mg/kg Dose every other week Important for potential muscle regeneration 32 1: 42 µg/g = 6.1 µM (6,100 nM), WVE-N531 data presented March 22, 2023 at Muscular Dystrophy Association Clinical and Scientific Conference; WVE-N531 biopsies collected ~2 weeks post-last dose (3 biweekly doses of 10 mg/kg); Suvodirsen biopsies collected post-last dose (weekly doses of 5 mg/kg) on week 22; Half-life as indicated by PK analysis; suvodirsen: discontinued first-generation non-PN chemistry compound; Right: Dual staining utilizing in-situ hybridization for WVE-N531 and PAX7 immunohistochemistry for stem cells. Suvodirsen N= 8; WVE-N531 N=3 boys
Advancing FORWARD-53, a potentially registrational Phase 2 clinical trial of WVE-N531 in DMD (Exon 53) Screening Every other week IV dosing Safety Follow-up • Biopsy after 24 weeks of • Functional • Biopsy after 48 weeks of assessment treatment treatment • Functional assessment • Functional assessment • Design of FORWARD-53: Phase 2, open-label, 10 mg/kg every other week • Endpoints: Dystrophin (powered for >5% of normal), safety/tolerability, pharmacokinetics, digital and functional assessments (incl. NSAA and others) • Muscle biopsies to assess dystrophin expression • Fully enrolled (n=11) and dosing underway Potentially registrational 24-week dystrophin expression data are expected in 3Q 2024 33 IV: intravenous; NSAA: North star ambulatory assessment
Potential for Wave to address up to 40% of DMD population Exon skipping and dystrophin restoration demonstrated in vitro Exon Skipping DMD Population 1.1 µM 2.5 µM 2.5 µM 3.3 µM 5 µM 5 µM 100 100 100 10 µM 10 µM 10 µM WVE-N531 Exon 53 Not Amenable to Skipping 50 50 50 8-10% Exon 51 17% 11-13% 0 0 0 Ex51 Ex51 mock Ex52 Ex52 mock Ex44 Ex44 mock SSO-1 SSO-2 SSO-1 SSO-2 SSO-1 SSO-2 6% Exon 44 Protein Restoration 1.1 µM 2.5 µM 2.5 µM 150 150 4% 3.3 µM 5 µM 5 µM Exon 52 100 10 µM 10 µM 10 µM 8% 100 100 Exon 45 44% 50 Other Exons 50 50 0 0 0 Ex51 Ex51 mock Ex52 Ex52 mock Ex44 Ex44 mock SSO-1 SSO-2 SSO-1 SSO-2 SSO-1 SSO-2 Exon 51 Exon 52 Exon 44 34 Left: Aartsma-Rus, et al. 2009 Hum Mutat 30, 293. % Dystrophin Relative to WT % Exon 51 Skipping Rel to Total DMD % Dystrophin Relative to WT % Exon 52 Skipping Rel to Total DMD % Dystrophin Relative to WT % Exon 44 Skipping Rel to Total DMD
WVE-003 (antisense silencing) Huntington’s Disease 35
mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD Healthy individual Huntington’s disease (HD) • Wild-type HTT (wtHTT) is critical for normal 1 neuronal function • Expanded CAG triplet repeat in HTT gene wtHTT Stresses results in production of mutant huntingtin protein (mHTT) • HD is a monogenic autosomal dominant Huntington’s disease genetic disease; fully penetrant and affects entire brain • Fatal disease characterized by cognitive decline, psychiatric illness, and chorea ~50% decrease in wtHTT Stresses mHTT + wtHTT • 30,000 people with HD in the US and more Loss of wtHTT functions than 200,000 at risk of developing HD Synaptic dysfunction | Healthy CNS function Cell death | Neurodegeneration 36 1 – Sources on wtHTT: 1. Leavitt 2006 2. Cattaneo 2005 3. Kumar 2016 4. Franco-Iborra 2020 5. Hamilton 2015 6. Ochaba 2014 7. Wong 2014 8. Rui 2015 9. Caviston 2007 10. Twelvetrees 2010 11. Strehlow 2007 12. Milnerwood 2010 13. Smith-Dijak 2019 14. Tousley 2019 15. Zhang 2018 16. McAdam 2020 17. Altar 1997 18. Zuccato 2001 19. Gauthier 2004 20. Ferrer 2000 21. Baquet 2004 22. Liu 2011 23. Karam 2015
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in Durable striatal mHTT knockdown for 12 HD iPSC neurons in vitro weeks in BACHD mouse model Striatum Similar results in cortex *** **** **** **** **** **** Weeks Pan-silencing WVE-003 Pan-silencing WVE-003 PBS reference compound reference compound NHP study demonstrating significant tissue exposure levels of WVE-003 in deep brain regions resulted in $7 million milestone payment from Takeda in 4Q 2023 37 Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1. Oligonucleotide or PBS [100 μg ICV injections through cannula on days 1, 3, 5] delivered to BACHD transgenic. Mean ± SD (n=8, *P<0.0332, ***P<0.0002, ****P<0.0001 versus PBS unless otherwise noted). HPRT1, hypoxanthine-guanine phosphoribosyl transferase; iPSC, induced pluripotent stem cell; ICV, intracerebroventricular; PBS, phosphate-buffered saline
WVE-003: First-in-class allele-selective candidate for HD Reductions in mean CSF mHTT and preservation of wtHTT observed in pooled analysis of single-dose cohorts in SELECT-HD clinical study wtHTT protein levels mHTT protein levels Placebo WVE-003 (30 and 60 mg Reduction in mHTT protein: pooled*) 22% from baseline 35% vs. placebo Preservation of wtHTT Single dose of WVE-003 Single dose of WVE-003 Data from 30 mg multi-dose cohort with extended follow-up, along with all single-dose data, expected 2Q 2024 38 mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein *Pooled considering no apparent dose response between 2 single-dose cohorts; Data cut-off: August 29, 2022 Reductions in mHTT
Anticipated upcoming milestones 39
Wave is poised for significant and sustained growth AATD WVE-006 Obesity INHBE Lead HD Clinical Candidate WVE-003 SNP3 Clinical trial initiation expected 1Q 2025 DMD Add’l AIMer Programs WVE-N531 Add’l SNPs Exon 53 Add’l Exons Clinical data in 2024 and advancement of INHBE candidate unlock potential to address > 50M patients in US and Europe alone 40 Note: Bubble size illustrative of size of total addressable US market (assuming 100% share of addressable patients)
Anticipated milestones in 2024 and beyond WVE-006 (AATD) 2024: Deliver proof-of-mechanism data from RestorAATion clinical Most advanced clinical RNA editing candidate & program potential best-in-class approach for AATD INHBE lead clinical candidate (Obesity) 1Q 2025: Initiate clinical trial for INHBE candidate Driven by protective LoF variants in human genetics, potential next-gen therapeutic for obesity WVE-N531 (DMD) 3Q 2024: Deliver potentially registrational 24-week dystrophin Potential best-in-class approach with highest expression data from FORWARD-53 exon skipping reported WVE-003 (HD) 2Q 2024: Deliver data from 30 mg multi-dose cohort with extended First-in-class mHTT lowering, wtHTT-sparing follow up, along with all single-dose data approach Potential for significant cash inflows in 2024 from collaboration milestones from GSK and Takeda 41 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; mHTT: Mutant huntingtin; wtHTT: Wild-type huntingtin
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