UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form
CURRENT REPORT
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| Item 2.02 | Results of Operations and Financial Condition. |
On May 3, 2023, Wave Life Sciences Ltd. (the “Company”) announced its financial results for the quarter ended March 31, 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 May 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 May 3, 2023 | |
| 99.2 | Corporate Presentation of Wave Life Sciences Ltd. dated May 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: May 3, 2023
Exhibit 99.1
Wave Life Sciences Reports First Quarter 2023 Financial Results and Provides Business Update
Emerging leader in RNA medicines with multi-modal discovery and development platform and first-in-class RNA editing
programs
Rapidly advancing toward 2023 CTA submissions and first-in-human study for WVE-006, the industry’s first RNA editing
clinical candidate
Planning for potentially registrational Phase 2 clinical study for WVE-N531 to assess functional dystrophin protein
restoration in DMD patients, following best-in-class exon-skipping data reported in December 2022
Preparing broad suite of first- and best-in-class medicines enabled by multi-modal RNA medicine platform and
proprietary genetic insights from GSK collaboration; investor event anticipated in 3Q 2023
Cash and cash equivalents of $207.6 million as of March 31, 2023, with runway expected into 2025, plus potential
milestone payments from GSK collaboration in 2023 and beyond
Investor conference call and webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., May 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 first quarter ended March 31, 2023 and provided a business update.
“The first quarter of 2023 was marked by the launch of our transformational collaboration with GSK, which we believe will allow us to build substantial patient and shareholder value by expanding and accelerating our pipeline with capital, clinical capability, and proprietary genetic insights. This collaboration, which provided $170 million in upfront cash and equity, has the potential to provide additional cash milestones in 2023 and beyond. We are expeditiously progressing the industry’s first RNA editing candidate, WVE-006, toward CTA submissions for alpha-1 antitrypsin deficiency, with the goal of early clinical proof-of-concept via measurement of validated serum surrogate markers in a clinical trial. In the first quarter, we also prepared for the launch of a potentially registrational Phase 2 study of WVE-N531 for boys with DMD, which is a program we believe may provide an important therapeutic option for them,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “We are well-capitalized through our existing cash and potential near-term milestones to deliver on a steady cadence of clinical data across 2023 and 2024. Additionally, using our clinically validated multi-modal RNA medicines platform, we are preparing the next set of development programs that leverage our unique RNA editing, splicing, and knockdown capabilities. In the third quarter of this year, we plan to hold an investor event, during which we will demonstrate how we are continuing to extend our leadership in RNA editing and share preclinical data on new programs.”
Recent Business Highlights
| • | Presented WVE-N531 clinical data at MDA Conference; progressing WVE-N531 to Phase 2 clinical trial to evaluate functional dystrophin protein production in boys with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. In March 2023, at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, Wave presented encouraging data from the initial cohort of the proof-of-concept open-label study of WVE-N531 to neuromuscular disease clinicians for the first time. Data for WVE-N531 included observation of best-in-class exon skipping and high muscle concentrations, while appearing safe and well-tolerated. A potentially registrational Phase 2 trial of WVE-N531 is planned, which will be powered to evaluate functional dystrophin expression following 24 and 48 weeks of biweekly dosing of WVE-N531. 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. |
| • | Collaboration activities with GSK underway. Wave’s strategic collaboration with GSK, to advance transformative RNA medicines using Wave’s multi-modal RNA platform, became effective in January 2023 and multiple target validation programs are already underway. The collaboration is designed to provide multiple value drivers to Wave, including maximizing the commercial opportunity for WVE-006 in alpha-1 antitrypsin deficiency (AATD), expanding Wave’s pipeline with new targets leveraging unique genetic insights from GSK, and continuing opportunities to strengthen Wave’s balance sheet. |
| • | Advancing WVE-006, a first-in-class RNA editing therapeutic for AATD, towards CTA submissions. At multiple scientific conferences in the first quarter of 2023, Wave highlighted the preclinical data supporting WVE-006, its GalNAc-conjugated candidate for AATD. WVE-006 is Wave’s first A-to-I(G) RNA base editing (“AIMer”) development candidate, which is also first-in-class in AATD, and is uniquely designed for restoration of both healthy hepatic and pulmonary function with the opportunity for reversibility and a favorable safety profile. IND enabling studies for WVE-006 continue to advance and Wave is on track to submit clinical trial applications (CTAs) in the second half of 2023. |
| • | Presented leading RNA editing capability at Gordon Research Conference. In March 2023, at the RNA Editing 2023 Gordon Research Conference, Wave presented an overview of its therapeutic base editing platform, including its novel base modifications and improvements in editing activity with optimized designs. |
Recent Scientific Publications
| • | In April 2023, preclinical data for the company’s novel siRNA formats were published in the journal of Nucleic Acids Research. The preclinical data demonstrated unprecedented, best-in-class Ago2 loading following administration of a single subcutaneous GalNAc-siRNA dose, leading to improved potency and durability in vivo versus comparator siRNA formats. Wave’s RNAi capability is one of multiple modalities being advanced through the strategic research collaboration with GSK. All of Wave’s publications can be viewed here. |
Anticipated Upcoming Milestones and Events
WVE-N531 for DMD:
| • | Initiate dosing in Part B of WVE-N531 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 multi-dose biomarker and safety clinical data in 2H 2023 |
| • | The update in expected timing for HD single-dose clinical data is due to a publicly announced cyber-attack that took place at Wave’s mHTT assay vendor in April 2023. No Wave data or patient samples were impacted by the attack and Wave remains in close contact with the vendor as they address this issue. |
WVE-004 for ALS/FTD:
| • | Deliver additional single- and multi-dose biomarker and safety clinical data in 1H 2023 |
Platform and Pipeline:
| • | Anticipate virtual investor event to be held in the third quarter of 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 |
First Quarter 2023 Financial Results
Wave reported a net loss of $27.4 million in the first quarter of 2023, as compared to $37.8 million in the same period in 2022. The decrease in net loss year-over-year was primarily driven by revenue earned under the company’s collaboration with GSK, which became effective January 27, 2023. Revenue earned under the GSK and Takeda collaborations in the first quarter of 2023 was $12.9 million. During the first quarter of 2022, revenue of $1.8 million was primarily earned under the Takeda collaboration.
Research and development expenses were $31.0 million in the first quarter of 2023, as compared to $27.5 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, as well as compensation-related expenses driven by growth to support the company’s programs.
General and administrative expenses were $12.2 million in the first quarter of 2023, as compared to $12.4 million in the same period in 2022, primarily due to a decrease in compensation-related expenses.
As of March 31, 2023, Wave had $207.6 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 first 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)
| March 31, 2023 | December 31, 2022 | |||||||
| Assets |
||||||||
| Current assets: |
||||||||
| Cash and cash equivalents |
$ | 207,562 | $ | 88,497 | ||||
| Prepaid expenses |
9,231 | 7,932 | ||||||
| Other current assets |
2,798 | 2,108 | ||||||
|
|
|
|
|
|||||
| Total current assets |
219,591 | 98,537 | ||||||
|
|
|
|
|
|||||
| Long-term assets: |
||||||||
| Property and equipment, net of accumulated depreciation of $39,197 and $37,846 as of March 31, 2023 and December 31, 2022, respectively |
16,005 | 17,284 | ||||||
| Operating lease right-of-use assets |
25,838 | 26,843 | ||||||
| Restricted cash |
4,660 | 3,660 | ||||||
| Other assets |
1,176 | 62 | ||||||
|
|
|
|
|
|||||
| Total long-term assets |
47,679 | 47,849 | ||||||
|
|
|
|
|
|||||
| Total assets |
$ | 267,270 | $ | 146,386 | ||||
|
|
|
|
|
|||||
| Liabilities, Series A preferred shares and shareholders’ equity (deficit) |
||||||||
| Current liabilities: |
||||||||
| Accounts payable |
$ | 11,906 | $ | 16,915 | ||||
| Accrued expenses and other current liabilities |
7,622 | 17,552 | ||||||
| Current portion of deferred revenue |
106,960 | 31,558 | ||||||
| Current portion of operating lease liability |
6,078 | 5,496 | ||||||
|
|
|
|
|
|||||
| Total current liabilities |
132,566 | 71,521 | ||||||
|
|
|
|
|
|||||
| Long-term liabilities: |
||||||||
| Deferred revenue, net of current portion |
130,820 | 79,774 | ||||||
| Operating lease liability, net of current portion |
30,534 | 32,118 | ||||||
| Other liabilities |
190 | 190 | ||||||
|
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|
|
|
|||||
| Total long-term liabilities |
161,544 | 112,082 | ||||||
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|
|
|||||
| Total liabilities |
$ | 294,110 | $ | 183,603 | ||||
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| Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at March 31, 2023 and December 31, 2022 |
$ | 7,874 | $ | 7,874 | ||||
|
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|
|
|
|||||
| Shareholders’ equity (deficit): |
||||||||
| Ordinary shares, no par value; 98,104,844 and 86,924,643 shares issued and outstanding at March 31, 2023 and December 31, 2022, respectively |
$ | 837,886 | $ | 802,833 | ||||
| Additional paid-in capital |
122,192 | 119,442 | ||||||
| Accumulated other comprehensive income (loss) |
(50 | ) | (29 | ) | ||||
| Accumulated deficit |
(994,742 | ) | (967,337 | ) | ||||
|
|
|
|
|
|||||
| Total shareholders’ equity (deficit) |
$ | (34,714 | ) | $ | (45,091 | ) | ||
|
|
|
|
|
|||||
| Total liabilities, Series A preferred shares and shareholders’ equity (deficit) |
$ | 267,270 | $ | 146,386 | ||||
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|
|
|
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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, | ||||||||
| 2023 | 2022 | |||||||
| Revenue |
$ | 12,929 | $ | 1,750 | ||||
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| Operating expenses: |
||||||||
| Research and development |
30,979 | 27,470 | ||||||
| General and administrative |
12,235 | 12,374 | ||||||
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| Total operating expenses |
43,214 | 39,844 | ||||||
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| Loss from operations |
(30,285 | ) | (38,094 | ) | ||||
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| Other income, net: |
||||||||
| Dividend income and interest income, net |
1,873 | 26 | ||||||
| Other income, net |
1,007 | 254 | ||||||
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| Total other income, net |
2,880 | 280 | ||||||
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|||||
| Loss before income taxes |
(27,405 | ) | (37,814 | ) | ||||
| Income tax provision |
— | — | ||||||
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|
|
|
|
|||||
| Net loss |
$ | (27,405 | ) | $ | (37,814 | ) | ||
|
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|
|||||
| Net loss per share attributable to ordinary shareholders—basic and diluted |
$ | (0.27 | ) | $ | (0.62 | ) | ||
|
|
|
|
|
|||||
| Weighted-average ordinary shares used in computing net loss per share attributable to
ordinary |
102,056,712 | 60,516,616 | ||||||
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|
|
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|||||
| Other comprehensive loss: |
||||||||
| Net loss |
$ | (27,405 | ) | $ | (37,814 | ) | ||
| Foreign currency translation |
(21 | ) | (86 | ) | ||||
|
|
|
|
|
|||||
| Comprehensive loss |
$ | (27,426 | ) | $ | (37,900 | ) | ||
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Investor Contact:
Kate Rausch
617-949-4827
krausch@wavelifesci.com
Media Contact:
Alicia Suter
617-949-4817
asuter@wavelifesci.com
Wave Life Sciences Corporate Presentation May 3, 2023 Exhibit 99.2
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.
Emerging leader in RNA medicines Multi-modal drug discovery and development platform to address new areas of disease biology RNA editing, splicing and silencing Differentiated, clinical-stage RNA medicines pipeline with first-in-class RNA editing programs Strategic collaborations to expand and advance pipeline (GSK and Takeda) Multiple pipeline and platform catalysts expected in 2023 and beyond Well-capitalized with expected cash runway into 2025 GMP manufacturing Strong and broad IP position1 Wave Life Sciences is an RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases 1stereopure oligonucleotides and novel backbone chemistry modifications 3
RNA medicines allow matching disease target to therapeutic modality Silencing Splicing RNA Base Editing Degradation of RNA transcripts to turn off protein production Restore RNA transcripts and turn on protein production Efficient editing of RNA bases to restore or modulate protein production Endogenous ADAR enzyme Restored Reading Frame Endogenous RNase H Endogenous AGO2 RISC Functional Protein Skip
Program Discovery Preclinical Clinical Rights Patient population (US & Europe) RNA EDITING WVE-006 SERPINA1 (AATD) GSK exclusive global license 200K Multiple undisclosed 100% global - SPLICING WVE-N531 Exon 53 (DMD) 100% global 2.3K Other exons (DMD) 100% global Up to 18K SILENCING: ANTISENSE WVE-003 mHTT (HD) Takeda 50:50 Option 25K Manifest (SNP3) 60K Pre-Manifest (SNP3) WVE-004 C9orf72 (ALS and FTD) Takeda 50:50 Option 4K (C9-ALS) 26K (C9-FTD) SCA3 (ATXN3) Takeda 50:50 Option 8K SILENCING: RNAi Undisclosed 100% global - Robust RNA medicines pipeline with first-in-class RNA editing programs Through GSK collaboration, Wave can advance up to three collaboration programs and GSK can advance up to eight collaboration programs Phase 1/2 Phase 1/2 Phase 1/2 AATD: Alpha-1 antitrypsin deficiency; DMD: Duchenne muscular dystrophy; HD: Huntington’s disease; ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; SCA3: Spinocerebellar ataxia 3
WVE-N531 Duchenne muscular dystrophy
Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function Impacts approx. 1 in every 5,000 newborn boys each year; approx. 20,000 new cases annually worldwide Approx. 8-10% are amenable to exon 53 skipping Dystrophin protein established by FDA as surrogate endpoint reasonably likely to predict benefit in boys1 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 1Vyondys: www.fda.gov; viltepso; www.fda.gov; Exondys; www.fda.gov; Amondys: www.fda.gov Dysfunctional Splicing Exon Skipping No dystrophin protein produced Functional dystrophin produced Translation halted Translation continues Mutant pre-mRNA Disease State Restored State mRNA with disrupted reading frame Restored mRNA Mutant pre-mRNA Skip Oligo 53 53 50 51 54 55 50 51 54 55 53 50 51 54 55 50 51 54 55
Preclinical data supported advancing WVE-N531 to clinical development Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN chemistry improved function and survival in dKO mice WVE-N531: Dystrophin restoration of up to 71% in vitro Western Blot normalized to primary healthy human myoblast lysate Conc (uM) % Dystrophin Dystrophin Vinculin 100% survival at time of study termination Restored muscle and respiratory function to wild-type levels Note: Untreated, age-matched mdx mice had 100% survival at study termination [not shown] Time (weeks) PS/PO/PN 150 mg/kg weekly PS/PO/PN 75 mg/kg bi-weekly PS/PO 150 mg/kg weekly PBS Survival probability (%) Tidal volume Age (days) TVb (ml) Wild-type dKO: PBS dKO: PS/PO/PN Wild-type dKO: PBS dKO (PS/PO/PN oligonucleotide)
In multidose portion of study, patients received three biweekly 10 mg/kg doses Initial cohort Boys with DMD amenable to exon 53 skipping 1 mg/kg 3 mg/kg 6 mg/kg 10 mg/kg Single ascending intra-patient doses Multidosing at 10 mg/kg every other week Weeks Dose WVE-N531 Period before initiating multidosing (~1 – 2 months) 10 mg/kg 10 mg/kg 10 mg/kg 0 2 4 6 Muscle Biopsy Data include: WVE-N531 muscle concentrations WVE-N531 localization Exon skipping Dystrophin protein
WVE-N531 in DMD: Delivered positive proof-of-concept data in 4Q 2022 Patient Tissue Source Tissue concentration (µg/g) % Exon skipping by RT-PCR Dystrophin by Western blot (% of normal) 1 Deltoid 85.5 61.5 0.24 2 Deltoid 33.5 49.8 0.23 3 Bicep 8.3 47.9 0.34 Mean exon skipping: 53% Mean muscle concentration: 42 µg/g Mean dystrophin: 0.27% of normal (BLQ) High exon skipping and muscle concentrations after three biweekly 10 mg/kg doses Similar exon skipping regardless of mutation Patient 1: del48-52 Patient 2: del45-52 Patient 3: del51-52 PK analysis indicated 25-day half-life in 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
Initiating Part B, a potentially registrational Phase 2 clinical trial of WVE-N531 Design: 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 Screening Safety Follow-up Biweekly Dosing (10 mg/kg IV) Functional assessment Biopsy after 24 weeks of treatment Functional assessment Biopsy after 48 weeks of treatment Functional assessment IV: intravenous; NSAA: North star ambulatory assessment
GSK Collaboration and WVE-006 for Alpha-1 antitrypsin deficiency (AATD)
Collaboration leverages Wave’s unique stereopure, PN-chemistry containing PRISMTM platform, including editing, splicing, silencing (RNAi and antisense) Strategic collaboration with GSK to develop transformative RNA medicines for genetically defined diseases 1$120 million in cash and $50 million equity investment received in January 2023, 2Initiation, development, launch, and commercialization milestones for WVE-006 and programs progressed during initial 4-year research term (8 GSK collaboration programs) 3GSK eligible to receive tiered royalty payments and commercial milestones from Wave First-in-class RNA editing program GSK granted exclusive global license to WVE-006 for AATD GSK to advance up to eight collaboration programs Up to $225 million in development and launch milestones Up to $1.2 billion in aggregate in initiation, development and launch milestones Up to $300 million in sales-related milestones Up to $1.6 billion in aggregate in sales-related milestones Double-digit tiered royalties as a percentage of net sales up to high-teens Tiered royalties as a percentage of net sales up to low-teens Development and commercialization responsibilities transfer to GSK after completion of first-in-patient study Development and commercialization responsibilities transfer to GSK at development candidate Wave to advance up to three wholly owned collaboration programs (or more pending agreement with GSK) 3 Wave to leverage GSK’s genetic insights Multiple value drivers to Wave Milestone / royalties Genetic targets Milestone / royalties $170 million upfront to Wave (cash and equity1) Additional research support funding Potential for up to $3.3 billion in milestones2 Expands Wave’s pipeline Extends cash runway into 2025
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver WVE-006: Designed to correct mutant SERPINA1 transcript to address both liver and lung manifestations of AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream 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 ADAR editing approach to address key goals of AATD treatment: RNA correction replaces mutant Z-AAT protein with wild-type M-AAT protein Z-AAT 1) Restore circulating, functional wild-type M-AAT I(G) A SERPINA1 Z allele mRNA encodes Z-AAT protein with E342K mutation Edited SERPINA1 mRNA enables wild-type M-AAT protein production WVE-006 (GalNAc-conjugated AIMer) WVE-006 designed to correct Z allele mRNA to enable M-AAT protein to be produced
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 in NSG-PiZ mice Demonstrated functionality of M-AAT protein Confirmed restored wild-type M-AAT protein WVE-006 treatment results in serum AAT protein levels >11 uM in NSG-PiZ mice Overall percentages of serum AAT protein isoforms in NSG-PiZ mice (Week 13) Serum neutrophil elastase inhibition activity in NSG-PiZ mice 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) CTA submissions for first-in-human study expected in 2H 2023
Early lead pre-optimization AATD AIMer (SA1-5) administered in huADAR/SERPINA1 mice (8–10 wKs old); lower left: 20x liver images PAS-D stained, 19 weeks; Quantification of PAS-D positive staining, Stats 2-way ANOVA; Right: Quantification lobular inflammation grade (Grade based on # of inflammatory foci in lobules: Grade 0: 0; G1 1-5; G2 6-10; G3 11-15; G4 ≥16) and mean globular diameter (40 largest globules/ animal) with HALO. Stats Wilcox rank-sum tests Early lead (pre-optimization) AATD AIMer reduces aggregation of Z-AAT and inflammation in mouse liver Lobular inflammation (19 weeks) * p=0.03 Inflammation grade PBS AIMer p<0.01 Mean diameter (mm) PBS AIMer **** p<0.0001 Weeks following first dose ** %PAS-D positive area (mean±sem) PBS Early lead AATD AIMer
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing across transcriptome (mouse liver) AIMer-directed editing is highly specific in mice SERPINA1 (PiZ mutation site) % Editing 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 No bystander editing observed on SERPINA1 transcript Coverage Coverage Editing site (PiZ mutation) PBS AATD AIMer C 0% T 100% C 48.2% T 51.8%
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Typically 100’s-1000’s of GGGGCC repeats Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD) Hexanucleotide (G4C2)- repeat expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Different manifestations across a clinical spectrum Fatal neurodegenerative disease Progressive degeneration of motor neurons in brain and spinal cord C9-specific ALS: ~2,000 patients in US Progressive neuronal degeneration in frontal / temporal cortices Personality and behavioral changes, gradual impairment of language skills C9-specific FTD: ~10,000 patients in US Including patients with C9-associated ALS, FTD or both Sources: Balendra et al, EMBO Mol Med, 2017; Brown et al, NEJM, 2017, DeJesus-Hernandez et al, Neuron, 2011. Renton et al, Neuron, 2011. Zhu et al, Nature Neuroscience, May 2020, Stevens et al, Neurology 1998
Target engagement in patients supported advancing FOCUS-C9 clinical study WVE-004 in C9-ALS/FTD: Successful translation of preclinical data to clinic PK/PD modeling using preclinical in vivo models predicted pharmacodynamically active starting dose Additional single- and multi-dose biomarker and safety clinical data expected in 1H 2023 from following cohorts: 20 mg single dose 30 mg single dose 60 mg single dose 10 mg monthly dosing 10 mg quarterly dosing PK: pharmacokinetic PD: pharmacodynamic; Right: Mixed model for repeated measures used to estimate geometric mean ratio to baseline via least squares mean and to calculate p-values. P-values represented by asterisks are for within-dose group geometric mean ratios. *p≤0.05, **p≤0.01, ***p≤0.001. Poly(GP) assay: Wilson et al., 2022 J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2021-328710. Data cut-off: March 24, 2022
WVE-003 Huntington’s Disease
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration; loss of wtHTT functions may also contribute to HD Stresses wtHTT Stresses wtHTT mHTT + ~50% decrease in wtHTT Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration Loss of wtHTT functions Huntington’s disease (HD) 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) HD is a monogenic autosomal dominant genetic disease; fully penetrant and affects entire brain Fatal disease characterized by cognitive decline, psychiatric illness, and chorea 30,000 people with HD in the US and more than 200,000 at risk of developing HD
WVE-003: First-in-class allele-selective candidate for HD mHTT protein levels Placebo WVE-003 (30 and 60 mg pooled*) wtHTT protein levels Reductions in mean CSF mHTT and preservation of wtHTT observed in pooled analysis of single dose cohorts in SELECT-HD clinical study Single dose of WVE-003 Single dose of WVE-003 mHTT protein reductions observed in single dose cohorts (Sep. 2022) wtHTT protein levels appear consistent with allele-selectivity Generally safe and well-tolerated Additional single-dose and multi-dose biomarker and safety clinical data expected in 2H 2023 Reduction in mHTT protein: 22% from baseline 35% vs. placebo mHTT: mutant huntingtin protein; wtHTT: wild-type huntingtin protein *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) Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 SAR structure-activity relationship Specificity in vitro & in vivo (NHPs) In vitro-in vivo translation (NHPs) GalNAc conjugation Foundational AIMer SAR AIMers detected in liver of NHP at Day 50 (PK) ADAR editing with ACTB AIMer is highly specific ACTB Confidence (LOD score) % Editing RNA editing within full transcriptome (primary human hepatocytes) Substantial and durable editing in NHP liver in vivo (PD) Day 50 RNA editing in NHP RNA editing only detected at editing site in ACTB transcript GalNAc AIMers GalNAc AIMers
Expanding addressable disease target space using AIMers to activate pathways and upregulate expression Modulate protein-protein interaction Upregulate expression Modify function Post-translational modification Alter folding or processing Restore or correct protein function Achieved POC WVE-006 (GalNAc AIMer) AATD POC: proof of concept Correct G-to-A driver mutations with AIMers Modulate protein interactions with AIMers AIMers provide dexterity, with applications beyond precise correction of genetic mutations, including upregulation of expression, modification of protein function, or alter protein stability
n=2; Primary hepatocytes 48h of treatment with the indicated dose concentration of AIMers Modulation of protein-protein interactions: AIMers enable activation of gene pathway in vivo with single edit
Upregulation: AIMers can edit RNA motifs to restore or upregulate gene expression RNA binding proteins recognize sequence motifs to regulate various mRNA properties Enhance or inhibit mRNA decay Stability Intracellular localization Transport Splicing Capping Processing PolyA usage Translational efficiency Protein production mRNA AIMer edits mRNA à “dials up” gene expression A I(G) Decay No binding RNA binding protein Edited mRNA
AIMers upregulate mRNA and downstream serum protein in vivo above anticipated threshold In vitro to in vivo translation of mouse Target A mRNA upregulation In vivo mRNA upregulation corresponds to an upregulation of Target A protein in serum at Day 7 demonstrating proof-of-concept mRNA upregulation 7 days post-initial dose GalNAc AIMer Protein upregulation 7 days post-initial dose GalNAc AIMer Upregulation mRNA editing 7 days post-initial dose GalNAc AIMer Target A (undisclosed liver target) High unmet need with potential for multiple large indications Preserves endogenous protein function Serum protein with biomarkers of pathway activation Potential benefit 3-fold+ upregulation in mouse Potential threshold for benefit 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
Wave’s discovery and drug development platform
Silencing Proprietary PN chemistry enhances potency across modalities Improved knockdown Splicing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound PS/PO reference compound PS/PN modified compound % Skipping Target knockdown (% remaining) Left: Experiment was performed in iPSC-derived neurons in vitro; target mRNA levels were monitored using qPCR against a control gene (HPRT1) using a linear model equivalent of the DDCt 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 RNA Editing Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) Concentration (mM) % Editing
Potential for best-in-class RNAi enabled by Wave’s PRISM platform **** 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: 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. Wk 2 Wk 14 Wk 7 Reference Wave siRNA * * Ago2 loading (liver, transgenic mice) Wave siRNA Reference PBS Unprecedented Ago2 loading following administration of single subcutaneous dose RNAi is one of multiple Wave modalities being advanced in strategic research collaboration with GSK First in vivo study of unconjugated siRNAs demonstrated 70-90% APP silencing across six brain regions in mouse CNS at 8 weeks
WVE-006 for AATD Most advanced RNA editing candidate & potential best-in-class approach for AATD WVE-006 CTA submissions expected in 2H 2023 Expansion opportunities in liver, CNS and kidney Newest modality in Wave platform Preclinical data suggest best-in-class potential for Wave RNAi capability Hepatic, CNS and beyond Delivering on pipeline and platform catalysts RNA EDITING RNAi DISCOVERY PIPELINE & COLLABORATIONS Anticipate investor event in 3Q 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 WVE-N531 for DMD Potential best-in-class approach with highest exon skipping reported Dosing in potentially registrational clinical trial expected in 2023; data expected in 2024 Expansion opportunities in other exons, as well as other muscle diseases and CNS SPLICING WVE-003 for HD First-in-class wtHTT-sparing approach Data expected 2H 2023 WVE-004 for ALS/FTD Variant-selective approach for C9orf72 Data expected 1H 2023 Enables discussion on next steps with Takeda ANTISENSE SILENCING
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations InvestorRelations@wavelifesci.com 617.949.4827