UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):
(Exact name of registrant as specified in its charter)
| (State or other jurisdiction of incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
| (Address of principal executive offices) | (Zip Code) |
Registrant’s telephone number, including area code: +
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
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).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading |
Name of each exchange | ||
| Item 2.02 | Results of Operations and Financial Condition. |
On November 10, 2021, Wave Life Sciences Ltd. (the “Company”) announced its financial results for the quarter ended September 30, 2021. 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 November 10, 2021, 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 November 10, 2021 | |
| 99.2 | Corporate Presentation of Wave Life Sciences Ltd. dated November 10, 2021 | |
| 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: November 10, 2021
Exhibit 99.1
Wave Life Sciences Reports Third Quarter 2021 Financial Results and Provides Business Update
Strengthened balance sheet with approximately $52 million; focusing additional investment in RNA editing programs led by hepatic editing
Optimized AIMers for AATD program demonstrate potent, highly specific RNA editing and restoration of functional AAT protein substantially above therapeutic threshold; potential for best-in-class, potent and durable RNA editing in vivo in multiple preclinical models and tissues
Dosing ongoing in three clinical programs (WVE-004, WVE-003, WVE-N531); data being generated through 2022 to enable decision-making
Wave to host investor conference call and webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., November 10, 2021 (GLOBE NEWSWIRE) — Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced financial results for the third quarter ended September 30, 2021 and provided a business update.
“In the third quarter, we achieved several important milestones including providing a comprehensive update on our potentially best-in-class ADAR editing capability and the initiation of dosing in three clinical trials evaluating our next-generation stereopure PN-modified oligonucleotides,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “RNA editing is a novel therapeutic modality that greatly expands our landscape of addressable genetically defined diseases. We are leading the way in this new field and quickly working toward announcing our first ADAR editing development candidate for our alpha-1 antitrypsin deficiency program next year. With this program, we are on a path to generate proof of principle that we can harness human biological machinery to edit RNA for the treatment of genetic diseases of the liver, CNS, and beyond.”
“Our robust and diversified pipeline is driven by our PRISM platform, which enables a unique ability to design and optimize oligonucleotides with novel, stereopure backbone modifications, including PN chemistry. We expect data being generated from our three ongoing clinical trials will enable us to make decisions on next steps for the programs next year. Finally, we recently strengthened our balance sheet via our at-the-market facility and funds received from Takeda under the terms of the amendment, leaving us well-capitalized to deliver on our portfolio, including advancing our first ADAR editing program toward the clinic and expanding our AIMer pipeline to include additional indications.”
ADAR editing capability recent events and upcoming milestones
Leading RNA editing capability using AIMers to harness endogenous ADAR enzymes
| • | Wave’s RNA editing capability leverages widely expressed endogenous ADAR enzymes to achieve highly specific A-to-I (G) RNA editing using stereopure oligonucleotides, called “AIMers,” with and without GalNAc conjugation, to edit RNA in the liver, central nervous system (CNS), and other tissues. |
| • | In September 2021, during its Analyst and Investor Research Webcast, Wave presented new preclinical data that demonstrated potent and durable editing of UGP2 mRNA out to at least four months post-dose in multiple regions of mouse CNS. Wave is applying ADAR editing to multiple therapeutic targets in the CNS, including restoring functional MECP2 protein for the treatment of Rett Syndrome. |
| • | Wave also presented preclinical data demonstrating up to 50% editing of UGP2 mRNA in the posterior of the eye of mice at one-month post-single intravitreal injection and ACTB RNA editing in non-human primates (NHPs) using systemic administration, including in the kidneys, liver, lungs, and heart, as well as editing of ACTB in multiple immune cell types in vitro. |
| • | Wave expects to share additional ADAR editing data using AIMers in scientific publications and presentations in 2022. |
Alpha-1 antitrypsin deficiency (AATD) program with ADAR editing:
| • | Wave’s AATD program, its first therapeutic ADAR editing program, uses stereopure oligonucleotides to correct the single base mutation in mRNA coded by the SERPINA1 Z allele. Restoring circulating levels of healthy alpha-1 antitrypsin (M-AAT) protein and reducing aggregation in the liver of mutant protein (Z-AAT) with RNA editing could potentially address both the lung and liver manifestations of the disease simultaneously. |
| • | In September 2021, during its Analyst and Investor Research Webcast, Wave shared new in vivo data demonstrating durable restoration of M-AAT protein in the liver of transgenic mice with human SERPINA1 and human ADAR following initial doses of a GalNAc-conjugated SERPINA1 AIMer. Using PRISM chemistry optimization, Wave AIMers can achieve highly specific editing of up to 50% of SERPINA1 mRNA in vivo and restore AAT protein in serum to a level four-fold higher than phosphate-buffered saline (PBS) control (or more than 15 micromolar). |
| • | Ongoing and planned preclinical studies are assessing durability, dose response, pharmacokinetics, and pharmacodynamics. Wave also plans to assess reduction of Z-AAT aggregates in the liver and changes in liver pathology in its transgenic mouse model, with data expected in 2022. |
| • | Wave expects to announce its AATD AIMer development candidate in 2022. |
Clinical silencing and exon skipping programs and upcoming milestones
WVE-004 for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD):
| • | WVE-004 is an investigational stereopure antisense oligonucleotide designed to selectively target transcript variants containing a hexanucleotide repeat expansion (G4C2) associated with the C9orf72 gene, which is one of the most common genetic causes of the sporadic and inherited forms of ALS and FTD. WVE-004 uses Wave’s novel PN backbone chemistry modifications (PN chemistry). |
| • | In July 2021, Wave announced the initiation of dosing in the Phase 1b/2a FOCUS-C9 clinical trial, which is adaptive, with an independent committee to guide dose level and dosing frequency. |
WVE-003 targeting SNP3 for Huntington’s disease (HD):
| • | WVE-003, Wave’s first HD candidate to use PN chemistry and leverage transgenic models to assess target engagement in vivo, is designed to selectively target the mutant allele of the huntingtin (mHTT) gene, while leaving the wild-type (healthy) HTT (wtHTT) protein relatively intact. Wave’s approach to HD is guided by the recognition that people with HD have less wtHTT protein compared to unaffected individuals and a growing body of scientific evidence suggests that preserving as much of this essential protein as possible, when in the setting of stress from toxic mHTT protein, may be important for favorable clinical outcomes. |
| • | In September 2021, Wave announced the initiation of dosing in the Phase 1b/2a SELECT-HD clinical trial of WVE-003 in patients with early manifest HD. The SELECT-HD trial is adaptive, with an independent committee to guide dose level and dosing frequency. |
WVE-N531 for Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping:
| • | WVE-N531 is Wave’s first stereopure splicing candidate and first systemically administered candidate to incorporate PN chemistry. |
| • | In September 2021, Wave announced the initiation of dosing in an open-label clinical trial of WVE-N531 dosed intravenously bi-weekly in patients with DMD amenable to exon 53 skipping. Dose level and dosing frequency will be guided by tolerability and plasma PK, with possible cohort expansion driven by an assessment of drug distribution in muscle and biomarkers, including dystrophin. |
Upcoming clinical milestones:
| • | Wave expects to generate clinical data through 2022 from WVE-004, WVE-003, and WVE-N531 to provide insight into the clinical effects of PN chemistry and enable decision-making regarding next steps for each program. |
Corporate developments
| • | In October 2021, Wave issued and sold an aggregate block of approximately $30 million in ordinary shares through its at-the-market (ATM) equity program, based on interest received from new and existing shareholders following its Analyst and Investor Research Webcast in September 2021. Wave intends to use the additional capital to accelerate its RNA editing capability, led by its AATD program. |
| • | In October 2021, Wave announced an amendment to its ongoing collaboration with Takeda, which streamlined the collaboration and allows Wave to advance or partner early-stage CNS programs, including those using ADAR editing. Wave received $22.5 million from Takeda under the terms of the amendment. The amendment did not impact the late-stage component of the collaboration, including Takeda’s option to co-develop and co-commercialize WVE-004 and WVE-003. Should Takeda opt in on any of these programs, Wave would receive an opt-in payment, global costs and potential profits would be shared 50:50, and Wave would be eligible to receive development and commercial milestone payments. |
Third quarter 2021 financial results and financial guidance
Wave reported a net loss of $6.2 million in the third quarter of 2021 as compared to $33.1 million in the same period in 2020.
Revenue earned during the three months ended September 30, 2021 was $36.4 million, as compared to $3.4 million for the three months ended September 30, 2020. The increase in revenue year-over-year is primarily driven by the $22.5 million paid as part of the amendment to Wave’s collaboration agreement with Takeda, which was recognized as revenue in the three months ended September 30, 2021, as well as the recognition of the remaining revenue related to Category 2 research support payments previously paid by Takeda.
Research and development expenses were $31.1 million in the third quarter of 2021 as compared to $28.3 million in the same period in 2020. The increase in research and development expenses in the third quarter was primarily due to increased external expenses related to preclinical programs and compensation-related expenses, partially offset by decreased external expenses related to our discontinued programs.
General and administrative expenses were $12.9 million in the third quarter of 2021 as compared to $9.6 million in the same period in 2020. The increase in general and administrative expenses in the third quarter of 2021 was driven by increases in compensation-related and other external general and administrative expenses.
As of September 30, 2021, Wave had $123.9 million in cash and cash equivalents as compared to $184.5 million as of December 31, 2020. The decrease in cash and cash equivalents was mainly due to Wave’s year-to-date net loss of $87.5 million, partially offset by the receipt of $21.2 million in proceeds under Wave’s ATM equity program through September 30, 2021.
Subsequently, in October 2021 Wave received an additional $52.1 million in cash, including $22.5 million from Takeda under the terms of the amendment to Wave’s collaboration agreement with Takeda, and $29.6 million in proceeds under its ATM equity program from a block sale of ordinary shares based on interest received from new and existing shareholders following its Analyst and Investor Research Webcast in September 2021.
Wave expects that its existing cash and cash equivalents will enable the company to fund its operating and capital expenditure requirements into the second quarter of 2023.
Investor Conference Call and Webcast
Wave management will host an investor conference call today at 8:30 a.m. ET to discuss the company’s third quarter and 2021 financial results and provide a business update. The conference call may be accessed by dialing (866) 220-8068 (domestic) or (470) 495-9153 (international) and entering conference ID: 6995569. The live webcast may be accessed from the Investor Relations section of the Wave Life Sciences corporate website at ir.wavelifesciences.com. Following the webcast, a replay will be available on the website.
About PRISM™
PRISM is Wave Life Sciences’ proprietary discovery and drug development platform that enables genetically defined diseases to be targeted with stereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing and editing. PRISM combines the company’s unique ability to construct stereopure oligonucleotides with a deep understanding of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacological properties. By exploring these interactions through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, the company continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles.
About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a clinical-stage genetic 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 for decision-making and completion of our adaptive clinical trials, and the announcement of such events; the protocol, design and endpoints of our ongoing and planned 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 with partners; the potential of our in vitro and in vivo 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 therapeutic benefits of our potential therapies compared to others; our ability to design compounds using multiple modalities and the anticipated benefits of that model; the potential benefits of PRISM, including our novel PN backbone chemistry modifications, and our stereopure oligonucleotides compared with stereorandom oligonucleotides; the potential benefits of our novel ADAR-mediated RNA editing platform capabilities, including our AIMers, compared to others; the benefit of nucleic acid therapeutics generally; the strength of our intellectual property; our assumptions based on our balance sheet and the anticipated duration of our cash runway; our intended uses of capital; and our expectations regarding the impact of the COVID-19 pandemic 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; our ability to maintain the company infrastructure and personnel needed to achieve our goals; the clinical results of our programs, which may not support further development of product candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, including their receptiveness to our adaptive trial designs; our effectiveness in managing future clinical trials and regulatory interactions; the effectiveness of PRISM, including our novel PN backbone chemistry modifications; the effectiveness of our novel ADAR-mediated RNA editing platform capability and our AIMers; the continued development and acceptance of oligonucleotides as a class of medicines; 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 similar indications; the severity and duration of the COVID-19 pandemic and its negative impact on the conduct of, and the timing of enrollment, completion and reporting with respect to our clinical trials; and any other impacts on our business as a result of or related to the COVID-19 pandemic, as well as 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)
| September 30, 2021 | December 31, 2020 | |||||||
| Assets |
||||||||
| Current assets: |
||||||||
| Cash and cash equivalents |
$ | 123,896 | $ | 184,497 | ||||
| Accounts receivable |
22,500 | 30,000 | ||||||
| Prepaid expenses |
7,627 | 10,434 | ||||||
| Other current assets |
3,964 | 5,111 | ||||||
|
|
|
|
|
|||||
| Total current assets |
157,987 | 230,042 | ||||||
|
|
|
|
|
|||||
| Long-term assets: |
||||||||
| Property and equipment, net |
24,020 | 29,198 | ||||||
| Operating lease right-of-use assets |
14,639 | 16,232 | ||||||
| Restricted cash |
3,651 | 3,651 | ||||||
| Other assets |
215 | 115 | ||||||
|
|
|
|
|
|||||
| Total long-term assets |
42,525 | 49,196 | ||||||
|
|
|
|
|
|||||
| Total assets |
$ | 200,512 | $ | 279,238 | ||||
|
|
|
|
|
|||||
| Liabilities, Series A preferred shares and shareholders’ equity |
||||||||
| Current liabilities: |
||||||||
| Accounts payable |
$ | 7,443 | $ | 13,795 | ||||
| Accrued expenses and other current liabilities |
11,364 | 11,971 | ||||||
| Current portion of deferred revenue |
8,736 | 91,560 | ||||||
| Current portion of operating lease liability |
4,097 | 3,714 | ||||||
|
|
|
|
|
|||||
| Total current liabilities |
31,640 | 121,040 | ||||||
|
|
|
|
|
|||||
| Long-term liabilities: |
||||||||
| Deferred revenue, net of current portion |
107,606 | 41,481 | ||||||
| Operating lease liability, net of current portion |
22,477 | 25,591 | ||||||
| Other liabilities |
1,014 | 474 | ||||||
|
|
|
|
|
|||||
| Total long-term liabilities |
$ | 131,097 | $ | 67,546 | ||||
|
|
|
|
|
|||||
| Total liabilities |
$ | 162,737 | $ | 188,586 | ||||
|
|
|
|
|
|||||
| Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at September 30, 2021 and December 31, 2020 |
$ | 7,874 | $ | 7,874 | ||||
|
|
|
|
|
|||||
| Shareholders’ equity: |
||||||||
| Ordinary shares, no par value; 51,998,032 and 48,778,678 shares issued and outstanding at September 30, 2021 and December 31, 2020, respectively |
$ | 716,118 | $ | 694,085 | ||||
| Additional paid-in capital |
84,254 | 71,573 | ||||||
| Accumulated other comprehensive income |
258 | 389 | ||||||
| Accumulated deficit |
(770,729 | ) | (683,269 | ) | ||||
|
|
|
|
|
|||||
| Total shareholders’ equity |
$ | 29,901 | $ | 82,778 | ||||
|
|
|
|
|
|||||
| Total liabilities, Series A preferred shares and shareholders’ equity |
$ | 200,512 | $ | 279,238 | ||||
|
|
|
|
|
|||||
WAVE LIFE SCIENCES LTD.
UNAUDITED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(In thousands, except share and per share amounts)
| Three Months Ended September 30, |
Nine Months Ended September 30, |
|||||||||||||||
| 2021 | 2020 | 2021 | 2020 | |||||||||||||
| Revenue |
$ | 36,423 | $ | 3,450 | $ | 39,199 | $ | 10,638 | ||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Operating expenses: |
||||||||||||||||
| Research and development |
31,086 | 28,275 | 96,114 | 100,911 | ||||||||||||
| General and administrative |
12,944 | 9,590 | 33,991 | 32,791 | ||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Total operating expenses |
44,030 | 37,865 | 130,105 | 133,702 | ||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Loss from operations |
(7,607 | ) | (34,415 | ) | (90,906 | ) | (123,064 | ) | ||||||||
| Other income, net: |
||||||||||||||||
| Dividend income and interest income, net |
6 | 23 | 25 | 544 | ||||||||||||
| Other income, net |
1,371 | 1,292 | 3,421 | 1,399 | ||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Total other income, net |
1,377 | 1,315 | 3,446 | 1,943 | ||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Loss before income taxes |
(6,230 | ) | (33,100 | ) | (87,460 | ) | (121,121 | ) | ||||||||
| Income tax provision |
— | — | — | — | ||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Net loss |
$ | (6,230 | ) | $ | (33,100 | ) | $ | (87,460 | ) | $ | (121,121 | ) | ||||
|
|
|
|
|
|
|
|
|
|||||||||
| Net loss per share attributable to ordinary shareholders—basic and diluted |
$ | (0.12 | ) | $ | (0.86 | ) | $ | (1.75 | ) | $ | (3.36 | ) | ||||
|
|
|
|
|
|
|
|
|
|||||||||
| Weighted-average ordinary shares used in computing net loss per share attributable to ordinary shareholders—basic and diluted |
50,709,877 | 38,364,224 | 50,017,521 | 36,021,256 | ||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Other comprehensive income (loss): |
||||||||||||||||
| Net loss |
$ | (6,230 | ) | $ | (33,100 | ) | $ | (87,460 | ) | $ | (121,121 | ) | ||||
| Foreign currency translation |
(11 | ) | 23 | (131 | ) | 34 | ||||||||||
|
|
|
|
|
|
|
|
|
|||||||||
| Comprehensive loss |
$ | (6,241 | ) | $ | (33,077 | ) | $ | (87,591 | ) | $ | (121,087 | ) | ||||
|
|
|
|
|
|
|
|
|
|||||||||
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 November 10, 2021 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.
UNLOCKING THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE realizing a brighter future for patients and families
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; HD: Huntington’s disease; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency 1stereopure oligonucleotides and novel backbone chemistry modifications Diversified Pipeline CNS: ALS, FTD, HD Muscle: DMD Hepatic diseases: AATD Ophthalmology Clinical Expertise Multiple global clinical trials Innovative trial designs Innovative Platform Stereopure oligonucleotides Novel backbone modifications (PN chemistry) Silencing, splicing, and editing modalities Strong and broad IP position1 GMP Manufacturing Internal manufacturing capable of producing oligonucleotides at scale LEVERAGING THE ONGOING genetic revolution DRUGGING THE TRANSCRIPTOME TO UNLOCK THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE >6,000 monogenic diseases; vastly more polygenic diseases Increase in genetic testing Biomarkers to assess target engagement early in clinical development Greater understanding of genetic disease and cellular biology Many diseases out of reach for traditional medicines Innovations for precise modification of transcriptome, proteome and interactome
Established regulatory, manufacturing, access and reimbursement pathways Continued progress towards longer dosing intervals while still being reversible and titratable Freely taken up by cells in multiple tissues or compatible with simple ligands – no need for complex delivery vehicles Changes erroneous messages, not erroneous code Strategic focus on intervening at RNA level RNA-targeting therapeutics offer ideal balance of precision, durability, potency, and safety Address underlying genetic drivers of disease Durable effects to enable infrequent dosing Defined path to commercialization Simplified delivery
Biological machinery in our cells can be harnessed to treat genetic diseases Silencing Splicing Editing Oligonucleotide-directed delivery of RNA to regulate enzymes Leverages exon skipping machinery to restore a working transcript Efficient editing of RNA bases using endogenous ADAR Endogenous ADAR enzyme Restored Reading Frame Endogenous RNase H Endogenous AGO2 RISC
Built-for-Purpose Candidates to Optimally Address Disease Biology Silencing | Splicing | RNA Editing DESIGN Unique ability to construct single isomers and control three structural features of oligonucleotides to efficiently engage biological machinery OPTIMIZE Provides the resolution to observe this structural interplay and understand how it impacts key pharmacological properties Sequence Stereochemistry Chemistry Unlocking the body’s own ability to treat genetic disease
Seminal 2017 publication from Wave, increasingly recognized by leaders in nucleic acid therapeutics1 Current therapeutics with chiral backbone modifications: Enables design and optimization of fully-characterized, single-isomer RNA therapeutics Wave is the leader in rationally designed stereopure oligonucleotides Stereochemistry is a reality of chemically-modified nucleic acid therapeutics Strong and broad IP portfolio and unique ability to manufacture and screen stereopure oligonucleotides siRNA RNA guide strands mRNA therapeutics Antisense oligonucleotides Exon-skipping oligonucleotides PRISM controls stereochemistry throughout drug discovery and development process Chirality matters: affects pharmacology of oligonucleotides in vitro and in vivo 1Jahns et al., NAR, 2021; Hansen, et al. 2021; Funder, Albaek et al. 2020
… … Innovating stereopure backbone chemistry modifications Chirality None PN backbone Sp PN backbone Rp Chirality … … PS backbone Rp PS backbone Sp Chirality … … PRISM backbone linkages PO: phosphodiester PS: phosphorothioate -O -S N (Rp) (Sp) PO PS PN Negative charge Neutral charge Negative charge Phosphoryl guanidine x-ray structure example
Silencing Potency is enhanced with addition of PN modifications across modalities Improved knockdown Splicing Editing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) Concentration (mM) % Editing 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
Choose modality to best address genetic target Rapidly develop clinical candidates in reproducible way Scalable, cost-effective manufacturing Genetic code carried by RNA to predict sequence PRISM platform is continuously improving Continuous definition of design principles deployed across programs Design & optimize PN chemistry Stereochemistry Machine learning Predictive modeling In vivo models Iterative analysis of in vitro and in vivo outcomes Platform improves as learnings from each program are applied Silencing Splicing Editing
Improvements in PRISM primary screen hit rates accelerate drug discovery Primary screen hit rates with silencing far above industry standard hit rates Stereorandom Chemistry, PN stereochemistry & machine learning optimization Stereopure Chemistry improvements and PRISM advancement All screens used iPSC-derived neurons; Data pipeline for improved standardization. Hit rate = % of oligonucleotides with target knockdown greater than 50%. Each screen contains >100 oligonucleotides. ML: machine learning (2019) (2020 - current)
THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NEUROLOGY Takeda 50:50 option ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple 100% global DMD Exon 53 100% global HEPATIC AATD SERPINA1 100% global OPHTHALMOLOGY Retinal diseases USH2A and RhoP23H 100% global Robust portfolio of stereopure, PN-modified oligonucleotides ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; SCA3: Spinocerebellar ataxia 3; CNS: Central nervous system; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency Modality Silencing Splicing ADAR editing (AIMers) WVE-004 (FOCUS-C9) WVE-003 (SELECT-HD) WVE-N531 NEUROLOGY HEPATIC OPHTHALMOLOGY
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 disease across phenotypes 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 Neuro C9orf72
C9orf72 repeat expansions: Mechanisms of cellular toxicity in ALS and FTD C9-ALS and C9-FTD may be caused by multiple factors: Insufficient levels of C9orf72 protein Accumulation of repeat-containing RNA transcripts Accumulation of aberrantly translated DPR proteins Recent evidence suggests lowering C9orf72 protein exacerbates DPR-dependent toxicity Sources: Gitler et al, Brain Research, September 2016. Zhu et al, Nature Neuroscience, May 2020 Targeted by Wave ASOs Variant-selective targeting could address multiple potential drivers of toxicity Neuro C9orf72
C9orf72 protein is important for normal regulation of neuronal function and the immune system WVE-004 targets hexanucleotide repeat containing transcript variants that lead to loss of normal C9orf72 function and production of pathological mRNA products and toxic dipeptide repeat (DPR) proteins Poly-GP is an important DPR transcribed from sense and antisense toxic mRNA transcripts Poly-GP is a sensitive biomarker of target engagement and reductions of mRNA transcripts and other toxic proteins by WVE-004 Neurofilament Light-Chain (NfL) measurements will provide important insight into potential for neuroprotection WVE-004 selectively targets repeat-containing transcripts to address multiple drivers of toxicity Liu et al, Nature Communications, 2021 pre-mRNA variants Pathological mRNA products V1 V2 Mis-spliced V1/V3 Stabilized intron1 V3 Disease-contributing factors RNA foci DPRs GGGGCC expansion Accessible target for variant selectivity Reduced by WVE-004 Repeat-containing transcripts Neuro C9orf72
Adding PN chemistry modifications to C9orf72-targeting oligonucleotides improved potency in vivo Exposure (µg/g) Exposure (µg/g) Cortex %C9orf72 V3 transcript remaining Target knockdown: Liu, TIDES poster 2021; Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% confidence intervals (shading) for PK-PD analysis. Manuscript submitted. Spinal Cord C9orf72-targeting oligonucleotides PS/PO backbone chemistry PS/PO/PN backbone chemistry Improved knockdown Improved tissue exposure Neuro C9orf72
WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro V3 Dose (μM) All V WVE-004 NTC Dose (μM) In vitro activity in C9 patient-derived neurons WVE-004 NTC Dose (μM) IC50:201.7nM In vitro selectivity in C9 patient-derived neurons C9 patient-derived motor neurons were treated with C9orf72 candidate and NTC under gymnotic conditions up to 10uM. Taqman qPCR assays were used to evaluating V3 and all V transcripts. NTC- non-targeting control. Relative fold change C9orf72 V3/HPRT1 1.5 1.0 0.5 0.0 0.001 0.01 0.1 1 10 Relative fold change C9orf72 V3/HPRT1 0.016 0.08 0.4 2 10 0.016 0.08 0.4 2 10 0.016 0.08 0.4 2 10 0.016 0.08 0.4 2 10 1.5 1.0 0.5 0.0 1.5 1.0 0.5 0.0 Relative fold change C9orf72/HPRT1 Neuro C9orf72
* *** ** *** Spinal cord Relative Poly-GP levels (normalized to PBS) Cortex >90% knockdown of Poly-GP DPR protein Two doses of WVE-004 Six months >80% knockdown of Poly-GP DPR protein Relative Poly-GP levels (normalized to PBS) p≤0.0001 Full results presented at the 31st International Symposium on ALS/ MND (December 2020); 2 x 50 ug (day 0, day 7) dosed ICV; DPRs measured by Poly-GP MSD assay. *: p≤ 0.05 **: P ≤ 0.01, ***: P ≤ 0.001. DPR: Dipeptide repeat protein Weeks Weeks PBS Poly-GP DPR Oligonucleotide concentration WVE-004: WVE-004: C9orf72 protein unchanged at 6 months ns ug of oligo / g of tissue ug of oligo / g of tissue ns Relative fold change C9orf72/HPRT1 1.5 0.5 0.0 1.0 Relative fold change C9orf72/HPRT1 1.5 0.5 0.0 1.0 WVE-004 PBS WVE-004 PBS Durable reduction in vivo of Poly-GP in spinal cord and cortex after 6 months Preclinical in vivo results: Neuro C9orf72
Day 1-3 15 29 57 85 Dose q PK / Biomarker Samples l l l l l Clinical Evaluations l l l l FOCUS-C9 clinical trial: Dose level and dosing frequency guided by independent committee Dose level and dosing frequency guided by independent committee Single ascending dose Dose Level Cohort 1 Cohort 1 Additional cohorts Proceed to MAD Monthly or less frequent dosing PK / Biomarker samples Clinical evaluations Additional cohorts l l q Safety and tolerability ALSFRS-R CDR-FTDLD FVC HHD Clinical evaluations PolyGP DPR in CSF p75NTRECD in urine NfL in CSF Key biomarkers: PK: pharmacokinetic Multi-ascending dose Adaptive cohorts Neuro C9orf72
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 Wild-type HTT is critical for normal neuronal function Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein Huntington’s disease affects entire brain Monogenic autosomal dominant genetic disease; fully penetrant Characterized by cognitive decline, psychiatric illness, and chorea; fatal disease Stresses wtHTT Stresses wtHTT mHTT + ~50% decrease in wtHTT Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration Loss of wtHTT functions Neuro HD
Plays an essential role in the transport of synaptic proteins—including neurotransmitters and receptors—to their correct location at synapses9-12 Promotes neuronal survival by protecting against stress (e.g., excitotoxicity, oxidative stress, toxic mHTT aggregates)1-8 BRAIN CIRCUITS SYNAPSE NEURON CSF circulation Supplies BDNF to the striatum to ensure neuronal survival13-16 Regulates synaptic plasticity, which underlies learning and memory17-22 Plays a critical role in formation and function of cilia—sensory organelles that control the flow of CSF—which are needed to clear catabolites and maintain homeostasis23 HD: Wild-type HTT is a critical protein for important functions in the central nervous system BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; mHTT, mutant huntingtin protein. Sources: 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 Neuro HD
Cerebral cortex Striatum BDNF- containing vesicle To the striatum Microtubule HTT HTT provides BDNF, a growth factor critical for survival of striatal neurons BDNF, brain-derived neurotrophic factor; HD, Huntington’s disease; HTT, huntingtin protein. 1. Altar CA, Cai N, Bliven T, et al. Nature. 1997;389(6653):856-860. 2. Zuccato C, Ciammola A, Rigamonti D, et al. Science. 2001;293(5529):493-498. 3. Gauthier LR, Charrin BC, Borrell-Pagès M, et al. Cell. 2004;118(1):127-138. 4. Ferrer I, Goutan E, Marín C, et al. Brain Res. 2000;866(1-2):257-261. 5. Baquet ZC, Gorski JA, Jones KR. J Neurosci. 2004;24(17):4250-4258. 6. Cattaneo E, et al. Nat Rev Neurosci. 2005;6(12):919-930. From the cerebral cortex Striatal neurons do not produce BDNF, but they need it to survive1 HTT promotes the production of BDNF and transports BDNF from the cortex to the striatum2,3 In HD, decreased levels of BDNF contribute to degeneration of corticostriatal circuits2,4,5 Reduction of wtHTT may decrease the availability of BDNF and accelerate corticostriatal degeneration6 Corticostriatal circuits Neuro HD
Target mutant mRNA HTT transcript to reduce mutant HTT protein Preserve wild-type HTT protein reservoir in brain Allele-selective approach to treating HD Wave has only allele-selective clinical program in Huntington’s disease Only an allele-selective approach is designed to address both toxic gain of function and toxic loss of function drivers of HD Stresses wtHTT mHTT + Reduce Preserve Neuro HD
Allele-selective approach to treating HD Neuro HD 1 Claassen et al. Neurol Genet Jun 2020; Carroll et al. Mol Ther. 2011 Dec; HDSA.org : 2000 patients ~30,000 people with manifest HD in US ~40% of HD Patients Carry SNP3 Allele-selective Treatments Have Potential to Benefit Many of Those At-risk of HD ~200,000 people at-risk of developing HD in US SNP3 C A G C A G C A G C A G C A G expanded CAG repeat mHTT Personalized approach to wtHTT sparing opens possibility of early treatment
Nature publication contributes to weight of evidence on importance of wild-type huntingtin Source: Poplawski et al., Nature, April 2019 Htt: Huntingtin protein Conditional knock-out of Htt in 4-month old mice (post-neuronal development) Results suggest that: Htt plays a central role in the regenerating transcriptome (potentially influencing genes such as NFKB, STAT3, BDNF) Htt is essential for regeneration Indeed, conditional gene deletion showed that Htt is required for neuronal repair. Throughout life, neuronal maintenance and repair are essential to support adequate cellular functioning Neuro HD
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in HD iPSC neurons in vitro 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 a cannula on days 1, 3, and 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 Similar results in cortex Pan-silencing reference compound WVE-003 PBS Weeks *** **** **** **** **** **** Pan-silencing reference compound WVE-003 Percentage HTT mRNA Remaining Durable striatal mHTT knockdown for 12 weeks in BACHD mouse model Neuro HD Incorporates PN backbone chemistry modifications
WVE-003: In vivo studies support distribution to cortex and striatum in BACHD and NHPs PK: pharmacokinetic PD: pharmacodynamic IC50: the concentration of observed half of the maximal effect mHTT: mutant huntingtin protein Achieved sufficient concentrations of WVE-003 in cortex and striatum for target engagement NHP Anticipated mHTT knockdown in cortex and striatum based on PK-PD modeling Human BACHD model Achieved maximum mHTT knockdown of 70-75% in cortex and striatum with ~50% knockdown persisting for at least 3 months with WVE-003 Clinical starting dose of WVE-003 informed by PK-PD modeling Neuro HD
Day 1-3 15 29 57 85 Dose q PK / Biomarker Samples l l l l l Clinical Evaluations l l l l SELECT-HD clinical trial: Dose level and dosing frequency guided by independent committee Dose level and dosing frequency guided by independent committee Single ascending dose Dose Level Cohort 1 Cohort 1 Additional cohorts Proceed to MAD Monthly or less frequent dosing PK / Biomarker samples Clinical evaluations Additional cohorts l l q Safety and tolerability UHDRS Clinical evaluations mHTT wtHTT NfL Key biomarkers: PK: pharmacokinetic Multi-ascending dose Adaptive cohorts Neuro HD
Neuro HD Assessment of wild-type protein in CSF Ab: antibodyCSF: cerebrospinal fluidHTT: huntingtin proteinMW1: Wild et al. JCI 2015 CSF sample Total HTT mt wt wt wt mt mt mt mt mt wt wt wt Wild-type HTT wt wt wt wt wt wt wt wt Deplete mutant HTT Add polyQ Ab magnetic beads to CSF sample mt mt mt mt mt mt polyQ Ab magnetic beads Biotin polyQ Ab (MW1) Magnetic streptavidin beads Wild-type huntingtin protein Mutant huntingtin protein wt mt Depletion of mutant HTT key to ability to measure wild-type HTT protein
WVE-N531 Duchenne muscular dystrophy
100 75 50 25 0 Survival probability (%) 0 4 8 12 16 20 24 28 32 36 40 Time (weeks) Dramatic increase in effect with PN-modified splicing oligonucleotide in dKO mouse model dKO; double knockout mice lack dystrophin and utrophin protein. mdx mice lack dystrophin. dKO: PS/PO/PN 150 mg/kg n= 8 (p=0.0018); PS/PO/PN 75 mg/kg n=9 (p=0.00005); PS/PO n=9 (p=0.0024), PBS n=12 Stats: Chi square analysis with pairwise comparisons to PBS using log-rank test PS/PO/PN, 75 mg/kg bi-weekly PBS PS/PO, 150 mg/kg weekly PS/PO/PN, 150 mg/kg weekly Note: Untreated, age-matched mdx mice had 100% survival at study termination [not shown] Treatment with PN-modified molecules led to 100% survival of dKO mice at time of study termination Neuro DMD
WVE-N531: First splicing candidate to use PN chemistry Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function. Current disease modifying treatments have demonstrated minimal dystrophin expression and clinical benefit has not been established. Impacts 1 in every 5,000 newborn boys each year; 20,000 new cases annually worldwide. Western Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of up to 71% in vitro Neuro DMD
Clinical trial of WVE-N531 underway Unmet need in DMD remains high Open-label clinical trial of up to 15 boys with DMD amenable to exon 53 skipping Powered to evaluate change in dystrophin production Includes assessment of drug concentration in muscle and initial safety Study planned for every-other-week administration Potential to apply PN chemistry to other exons if successful Dose level and dosing frequency guided by independent committee DMD: Duchenne muscular dystrophy Neuro DMD
ADAR editing RNA editing capability
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides ADAR enzymes Catalyze conversion of A-to-I (G) in double-stranded RNA substrates A-to-I (G) edits are one of the most common post-transcriptional modifications ADAR1 is ubiquitously expressed across tissues, including liver and CNS Endogenous enzymes Free-uptake of chemically modified oligonucleotides First publication (1995) using oligonucleotide to edit RNA with endogenous ADAR1 Wave goal: Expand toolkit to include editing by unlocking ADAR with PRISM oligonucleotides AIMer: Wave’s A-to-I editing oligonucleotides ADAR RNase H AGO2 Spliceosome Learnings from biological concepts Applied to ASO structural concepts Applied PRISM chemistry 1Woolf et al., PNAS Vol. 92, pp. 8298-8302, 1995 ADAR editing
AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Efficient ADAR recruitment AIMer design principles SAR developed to design AIMers for different targets Systematized AIMer design enables rapid advancement of new targets Strong and broad IP in chemical and backbone modifications, stereochemistry patterns, novel and proprietary nucleosides Potent and specific editing in vivo Efficient ADAR recruitment Stability Delivery and intracellular trafficking Beyond liver Decade of investment and learnings to improve stability of single-stranded RNAs GalNAc compatible for targeted liver delivery Endosomal escape and nuclear uptake AIMer design also works for delivery to CNS and other tissue types Potential for infrequent dosing Subcutaneous dosing IT, IVT, systemic dosing ADAR editing
Opportunity for novel and innovative AIMer therapeutics SNP: single nucleotide polymorphism A: Adenosine I: Inosine G: Guanosine 1ClinVar database 2Gaudeli NM et al. Nature (2017) 3Keeling KM et al., Madame Curie Bioscience Database 2000-2013 4Luck, K et al. Nature (2020) 5Prasad, TSK et al. Nucleic Acids Research (2009) 6Huang, K et al. Nucleic Acids Research (2016) Correct driver mutations with AIMers AATD Rett syndrome Recessive or dominant genetically defined diseases Examples >32,000 pathogenic human SNPs2 – ~50% ADAR amenable Tens of thousands of potential amenable disease variants1 ~12% of all reported disease-causing mutations are single point mutations that result in a premature stop codon3 Upregulate expression Modify function Modulate protein- protein interaction Post-translational modification Alter folding or processing Restore or correct protein function Haploinsufficient diseases Loss of function Neuromuscular Dementias Familial epilepsies Neuropathic pain Examples Modulate protein interactions with AIMers Large patient populations Human Reference Interactome documents >50K protein-protein interactions involving >8K proteins4 >90K Post-translational modifications across ~30K proteins mapped,5 thousands associated with disease6 ADAR editing
Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR and quantified by Sanger sequencing Stereochemistry and PN chemistry enhance potency and editing efficiency of AIMers ACTB editing in primary human hepatocytes using GalNAc-mediated uptake AIMer chemistry ADAR editing
Levels of endogenous ADAR enzyme are not rate limiting for editing Percentage A-to-I editing detected on the indicated transcripts in presence of 20 nM each of a single (Isolated) or multiple (Multiplex) AIMers after transfection of primary human hepatocytes (left). Data are presented as mean ± SEM, n=3. P values as determine by two-tailed Welch’s t-test are indicated. NTC non-targeting control. Manuscript submitted. Endogenous ADAR enzyme supports editing on multiple independent targets Editing efficiency comparable even when additional AIMers targeting different sequences are added, suggesting there is a more than sufficient reservoir of ADAR enzyme Single AIMer Multiple AIMers targeting different sequences “multiplex” ns ns ADAR editing
XAX NNN AIMer mRNA target Sequence space is defined >300 unique AIMers tested containing different base pair combinations Identified base modification combinations with high editing efficiency to optimize sequence Optimization of every dimension to inform future rational design of AIMers Motif on target Motif on AIMer Learnings inform design principles deployed across future targets Example: Sequence is one of multiple dimensions for optimization Heat map for sequence impact on SAR ADAR editing
ADAR interacts with double-stranded RNA duplex in a sequence independent way RNA-editing design applicable across targets in vitro in primary human hepatocytes Editing achieved across several distinct RNA transcripts Supports potential for technology to be applied across variety of disease targets The intrinsic function of ADAR is to recognize dsRNA independent of sequence Data presented at 1st International Conference on Base Editing – Enzymes and Applications (Deaminet 2020). Manuscript submitted. I(G) A AIMer ADAR editing
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs Left: AIMer PK C: 5mg/kg SC: Day 1,2,3,4,5; Liver biopsy; Right: Dosed 1um AIMer, 48 hrs later RNA collected, RNAseq conducted using strand-specific libraries to quantify on / off-target editing; plotted circles represent sites with LOD>3. Manuscript submitted. NHP: non-human primate; ACTB: Beta-actin 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 ADAR editing
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues Transgenic huADAR mice administered 100 mg AIMer or PBS on day 0 and evaluated for UGP2 editing across CNS tissues at 1, 4, 8, 12, and 16-weeks post dose. Percentage UGP2 editing determined by Sanger sequencing. Stats: 2-way ANOVA compared to PBS (n=5 per time point per treatment) *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. ICV intracerebroventricular; PBS phosphate buffered saline ADAR editing
RNA editing of nonsense mutation found in MECP2 (Rett Syndrome) restores functional protein 293T cells transfected with both nonsense mutation on MECP2 (GFP-fusion construct) and ADAR plasmids. AIMers transfected for 48h prior to RNA extraction and sequencing. Percentage editing determined by Sanger sequencing. Left: Single dose (25nM) treatment Middle: Full dose response curve (25nM, 5-fold dilution, 48h treatment) in presence or absence of hADAR Right: Western blot for MECP2 protein. Three biological replicates, NTC AIMer, mock and naïve 293T cells probed for fusion protein. in vitro ADAR editing of over 60% targeting MECP2 disease transcript Full length MECP2 protein is expressed following ADAR editing Loading Control Endogenous MECP2 ADAR Edited MECP2 Mock Naive NTC Ladder Dose-dependent RNA editing of MECP2 mutation with PS/PN AIMer Control (no hADAR) PS/PN AIMer … CGA… wild type protein … TGA… premature stop codon … TGG… restored protein Normal: Rett Syndrome: ADAR editing: Variant base ADAR editing site Nonsense mutations found in Rett Syndrome can occur in multiple locations on RNA transcript: PN chemistry improved editing efficiency in vitro Dosed with hADAR ADAR editing
Achieving productive editing in multiple NHP tissues with unconjugated systemic AIMer delivery NHP study demonstrated productive editing in kidney, liver, lung and heart with single subcutaneous dose PBS ACTB AIMer GalNAc-conjugated (Targeted - subcutaneous) Unconjugated (Local – IVT, IT) Unconjugated (Systemic) Editing in NHP 1-week post-single dose SC administration Kidney Liver Lung Heart NHP: non-human primate; ACTB: Beta-actin Dose: 50 mg/kg SC on Day 1 Necropsy for mRNA (ACTB Editing) Day 8 ADAR editing
Achieving productive editing in multiple immune cell types with AIMers in vitro Human peripheral blood mononuclear cell (PBMC) CD4+ T-cell CD19 B-cell CD14 Monocytes Tregs T-cell CD8+ T-cell NK NK-cell Human PBMCs dosed with 10 uM ACTB AIMers, under activating conditions (PHA). After 4 days, different cell types isolated, quantitated for editing %. ACTB: Beta-actin; Two-way ANOVA followed by post hoc comparison per cell line. P values were Bonferroni-corrected for multiple hypotheses ACTB AIMer Mock Activate (PHA) à Dose à Sort ***** ***** ***** ***** ***** ***** ADAR editing
Expanding addressable disease target space using ADAR editing to modulate proteins Correction Protein- protein interaction Upregulation Processing Folding (stability) Post-translational modification ADAR editing of mRNA Restore or modify protein function Impact diseases Examples: Familial epilepsies Neuropathic pain Neuromuscular disorders Dementias Haploinsufficient diseases Loss of function I(G) ADAR editing
Alpha-1 antitrypsin deficiency
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver RNA editing is uniquely suited to address the therapeutic goals for AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin; Sources: Strnad 2020; Blanco 2017; Remih 2021 Wave ADAR editing approach addresses all goals of treatment: PI*MM Normal PI*MZ Low PI*SZ PI*ZZ High (lung + liver) Null (no AAT) Highest risk (lung) Risk of disease Wild-type M-AAT protein replaces Z-AAT with RNA correction Z-AAT 1) Restore circulating, functional wild-type M-AAT ~200K people in US and EU with mutation in SERPINA1 Z allele (PI*ZZ) Current protein augmentation addresses only lung manifestations siRNA approaches only address the liver disease Alternative approaches address only a subset of treatment goals: Small molecule approaches may address the lung and liver but do not generate wildtype M-AAT AATD
AAT Protein ng/ml SA1-1 NT SA1-2 % Z allele mRNA editing SA1-1 NT SA1-2 Focused on restoring wild-type M-AAT in vivo In vivo proof of concept In vitro proof of concept SERPINA1 Z allele mRNA editing AAT protein concentration in media 3-Fold increase Liver AAT aggregation observed in AATD is recapitulated in mouse model AATD: Alpha-1 antitrypsin deficiency, Z-AAT: mutated protein, M-AAT: wild-type human AAT protein (Left) Hematoxylin and PAS stain and (Right) immunohistochemistry for AAT protein with hematoxylin counterstain in the huADAR/AATD mouse liver AATD
Achieving 40% editing of Z allele mRNA at single time point SERPINA1 Z allele mRNA editing levels nearing correction to heterozygote (MZ) AAT protein increase Wild-type M-AAT functional Z allele mRNA editing in vivo GalNAc-conjugated compounds Up to 40% editing of Z allele mRNA in liver of transgenic human ADAR mice at day 7 huADAR/SERPINA1 mice administered PBS or 3 x 10 mg/kg AIMer (days 0, 2, and 4) SC. Samples collected day 7. Stats: One-way ANOVA; NTC: non-targeting control SERPINA1 editing huADAR mouse SA1 - 3 SA1 - 4 UGP2 NTC PBS AIMers % Editing **** **** SERPINA1 editing huADAR hepatocytes % Editing SA1-3 SA1-4 Concentration (mM) AATD
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing within transcriptome (mouse liver) ADAR editing is highly specific; no bystander editing observed on SERPINA1 transcript SERPINA1 (PiZ mutation site) % Editing Dose 3 x 10mg/kg days (0, 2, 4) SC. Liver biopsies day 7. RNAseq, To quantify on-target SERPINA1 editing reads mapped to human SERPINA1, to quantify off-target editing reads mapped to entire mouse genome; plotted circles represent sites with LOD>3 (N=4); Analyst and Investor Research Webcast September 28, 2021 Coverage Coverage Editing site (PiZ mutation) PBS SA1-4 AIMer C 0% T 100% C 48.2% T 51.8% AATD
Statistics (ELISA): Matched 2-way ANOVA with correction for multiple comparisons (Bonferroni) was used to test for differences in AAT abundance in treated samples compared to PBS Statistics; de Serres et al., J Intern Med. 2014; NTC: non-targeting control Achieving therapeutically meaningful increases in circulating human AAT protein AAT protein increase Wild-type M-AAT functional Z allele mRNA editing in vivo Human AAT concentration in serum 3-fold increase in circulating human AAT as compared to PBS at initial timepoint PI*SZ ~2-fold increase ~3 to 5-fold increase PI*MZ PI*ZZ ~3 – 7 uM AAT serum levels by genotype 3-fold increase at day 7 11µM AATD
ADAR editing restores circulating, functional M-AAT Human wild-type M-AAT AAT protein increase Wild-type M-AAT functional Z allele mRNA editing in vivo Wild-type M-AAT detected with ADAR editing ~2.5-fold increase Significant increase in neutrophil elastase inhibition with ADAR editing 3-fold increase in total AAT Left: Mass spectrometry and ELISA Right: (Elastase inhibition): Matched 2-way ANOVA with correction for multiple comparisons (Bonferroni) was used to test for differences in elastase inhibition activity in serum collected at day 7 vs pre-dose for each treatment group; NTC: non-targeting control AATD
Serum AAT mg/mL PBS PBS SA1-4 SA1-4 Dose Days ns *** *** ** *** 11 mM ** Increase in circulating human AAT is durable, with restored M-AAT detected one month post last dose SA1-4: GalNAc AIMer (Left) huADAR/SERPINA1 mice administered PBS or 3 x 10 mg/kg AIMer (days 0, 2, and 4) SC. AAT levels quantified by ELISA. Data presented as mean ± sem. Stats: Matched 2-way ANOVA ns nonsignificant, ** P<0.01, *** P<0.001. (Right) Proportion of AAT in serum, Z type (mutant) or M type (wild type), measured by mass spectrometry, total AAT levels quantified by ELISA Serum AAT mg/mL Days M-AAT production Elevated Z-AAT at Day 35 suggests clearance of intracellular Z-AAT aggregates with AIMers Human AAT serum concentration ≥3-fold higher over 30 days post-last dose Restored wild-type M-AAT detected over 30 days post-last dose Z-AAT (mutant) M-AAT (wild type) AATD
Optimized AIMers achieve ~50% mRNA editing and restore AAT protein well above therapeutic threshold Left: AIMers administered huADAR/SERPINA1 mice (3x5 mg/kg) on days 0, 2, and 4. Livers collected on day 7, and SERPINA1 editing was quantified by Sanger sequencing (shown as mean ±. sem) Stats: One-way ANOVA was used to test for differences in editing between SA1-4 and other oligos * P<0.05 Right: huADAR/SERPINA1 mice administered PBS or 3 x 10 mg/kg AIMer (days 0, 2, and 4) SC. Proportion of AAT protein in serum, Z type or M type, measured by mass spectrometry, total AAT protein levels quantified by ELISA. SERPINA1 RNA editing huADAR mouse (3x5 mg/kg, SC) % Editing PBS SA1-4 SA1-5 Optimized * 85% M-AAT 11 mM Z-AAT (mutant) M-AAT (wild-type) 4-fold increase in total AAT 3-fold increase in total AAT SA1-4 PBS SA1-5 PBS AAT protein concentration in serum (3x10 mg/kg, SC) Serum AAT protein (ug/ml) (Mean, s.e.m) Optimized Additional preclinical data expected in 2022, including reduction in Z-AAT aggregates and changes in liver pathology AATD AIMer development candidate expected in 2022 AATD
Demonstrate restoration of functional M-AAT Chemistry optimization to improve potency Path to development candidate ADAR editing is highly specific Restored, circulating wild-type M-AAT in serum at 1-month post-last dose Chemistry optimization of AIMers further increases potency Optimized AIMers restore AAT in serum by 4-fold (>15uM) at Day 7 Restored wild-type M-AAT at 85% of total AAT Assess specificity and duration of effect AATD development candidate expected in 2022 GalNAc-conjugated AIMers restore therapeutically meaningful levels of functional, wild-type M-AAT Ongoing and planned preclinical studies assessing durability, dose response and PK/PD Assessment of reduction in Z-AAT aggregates and changes in liver pathology AATD
Ophthalmology
Stereopure oligonucleotides for inherited retinal diseases (IRDs) Wave ophthalmology opportunity Oligonucleotides can be administered by intravitreal (IVT) injection; targeting twice per year dosing Stereopure oligonucleotides open novel strategies in both dominant and recessive IRDs; potential for potent and durable effect with low immune response Successful targeting of MALAT1 is a surrogate for an ASO mechanism of action Widely expressed in many different cell types Only expressed in the nucleus Intravitreal injection Sources: Daiger S, et al. Clin Genet. 2013;84:132-141. Wong CH, et al. Biostatistics. 2018; DOI: 10.1093/biostatistics/kxx069. Athanasiou D, et al. Prog Retin Eye Res. 2018;62:1–23. Daiger S, et al. Cold Spring Harb Perspect Med. 2015;5:a017129. Verbakel S, et al. Prog Retin Eye Res. 2018:66:157-186.; Short, B.G.; Toxicology Pathology, Jan 2008. Ophthalmology
Durable Malat1 knockdown through 9 months with PN backbone chemistry modifications Compound or PBS (1 x 50 ug IVT) was delivered to C57BL6 mice. Relative percentage of Malat1 RNA in the posterior of the eye (retina, choroid, sclera) to PBS-treated mice is shown at 12, 20 and 36 weeks post-single injection. PBS = phosphate buffered saline; NTC= chemistry matched non-targeting control ~50% Malat1 knockdown at 36 weeks in the posterior of the eye PBS NTC PS/PO PS/PN % Malat1 expression Time (weeks) p≤0.01 Ophthalmology
Usher Syndrome Type 2A: a progressive vision loss disorder Autosomal recessive disease characterized by hearing loss at birth and progressive vision loss beginning in adolescence or adulthood Caused by mutations in USH2A gene (72 exons) that disrupt production of usherin protein in retina, leading to degeneration of the photoreceptors No approved disease-modifying therapies ~5,000 addressable patients in US Sources: Boughman et al., 1983. J Chron Dis. 36:595-603; Seyedahmadi et al., 2004. Exp Eye Res. 79:167-173; Liu et al., 2007. Proc Natl Acad Sci USA 104:4413-4418. Oligonucleotides that promote USH2A exon 13 skipping may restore production of functional usherin protein Ophthalmology
Potent USH2A exon 13 skipping with stereopure compound in vitro and ex vivo Oligonucleotides were added to Y79 cells under free-uptake conditions. Exon skipping was evaluated by Taqman assays. USH2A transcripts were normalized to SRSF9. Data are mean±s.d., n=2. Stereorandom: Compound identified in van Diepen et al. 2018. Antisense oligonucleotides for the treatment of eye disease. W02018055134A1. Stereopure: is a stereopure antisense oligonucleotide. Right: Whole NHP were enucleated (n=4) and compounds (1–20 mM) were added to extracted retinas under free-uptake conditions. Exon skipping was evaluated by Taqman assays on RNA. USH2A transcript levels were normalized to SRSF9. Data presented are mean± s.e.m. stereorandom compound is from van Diepen et al. 2018. Antisense oligonucleotides for the treatment of eye disease. W02018055134A1. Compound-1 is a stereopure antisense oligonucleotide. Enhanced potency over a stereorandom reference compound (in vitro) Ophthalmology Target engagement in NHP retinas
Stereopure oligonucleotide elicits dose-dependent exon skipping in NHP eye in vivo Oligonucleotide is complementary to NHP USH2A exon 12* Evaluated 1-week post-single IVT injection Dose-dependent activity of stereopure oligonucleotides Substantial exposure in retina Exon-skipping integrity confirmed by RNA-seq at both doses NTC 150 mg 75 mg 150 mg PBS Stereopure Stereopure USH2A skipping oligonucleotide, PBS or NTC antisense oligonucleotide was delivered to NHP by single IVT injection. One-week post-injection, retina was isolated and exon skipping was evaluated by Taqman assays. USH2A skipped transcript levels were normalized to SRSF9. Data are mean± s.e.m. Stereopure is an USH2A exon-13 skipping stereopure antisense oligonucleotide. PBS, phosphate buffered saline; NTC, non-targeting control; IVT, intravitreal Dose-dependent and specific exon skipping in NHP eye *NHP exon 12 = human exon 13 Ophthalmology
Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation Left: Reporter assays on a sequence described in WO2016138353A1. Oligonucleotide and luciferase reporter plasmids (wild-type and mutant RHO) are transfected into Cos7 cells. Cells are harvested after 48 hrs, and relative luminescence is measured. Right: Single IVT injection (1 mL) in mouse Rho P23H mouse model or (150 mL) in human P23H pig model. Eyes collected 1-week post injection for mouse or 2-weeks post injection for pig; RNA isolated; Rho, Hprt1, and Gapdh levels determined by qPCR. Ophthalmology Retinitis pigmentosa (RP): group of rare, genetic eye disorders resulting in progressive photoreceptor cell death and gradual functional loss; currently no cure ~10% of US autosomal dominant RP cases are caused by the P23H mutation in the rhodopsin gene (RHO) Mutant P23H rhodopsin protein is thought to misfold and co-aggregate with wild-type rhodopsin, resulting in a gain-of-function or dominant negative effect in rod photoreceptor cells
AIMers in retina at 4 weeks ADAR editing: Up to 50% editing in vivo in posterior of eye one month post-single IVT dose Mice received a single IVT injection (10 or 50 ug AIMer), and eyes were collected for RNA analysis and histology 1 or 4 weeks later. Left: editing evaluated by Sanger sequencing, and % RNA editing calculated with EditR. Right: FFPE and RNA scope assay specific for AIMer, red = oligo, blue = nuclei. Posterior region: retina, choroid, sclera. PBS 10 ug 50 ug Ophthalmology
Wave’s discovery and drug development platform
OMe, MOE, F, other modifications PO, PS, PN 5’ modifications, backbone modifications A, T, C, mC, G, U, other modified bases PRISM enables precision modulation of RNA therapeutic properties using unique chemistry toolkit 2’ modifications Backbone chemistry Bases Chiral control of any stereocenter Potency Tissue exposure Duration of activity
Keys to delivering therapeutic success in CNS Current and future unmet need Right target for disease Right patient population Selection of relevant biomarkers, clinical endpoints, study duration, dosing regimen PRISM platform PN backbone modifications in the setting of chiral control and other PRISM advancements improve potency, tissue distribution, and duration of effect Increased emphasis on translational pharmacology PRISM platform Rational design Innovative development plans Safety Target engagement Tissue distribution
PN chemistry improves distribution to CNS *Isomer 3; NHPs administered 1x12 mg oligonucleotide or PBS by intrathecal injection/lumbar puncture (IT). CNS tissue evaluated 11 or 29 days after injection (n=6 per group). Oligonucleotide was visualized by ViewRNA (red), and nuclei are counterstained with hematoxylin. Images from day 29. Cerebral Cortex Cerebellum Striatum Hippocampus Spinal cord PS/PO PS/PO/PN* Backbone chemistry Midbrain Distribution of oligonucleotides in NHP CNS 1-month post single IT dose Oligonucleotide (red staining)
Rational design to achieve target engagement and preclinical tolerability Isomer 1 Isomer 2 ns Stereoisomers have similar pharmacodynamic effects in vivo Changing backbone stereochemistry leads to different tolerability profiles in vivo Same sequence, but different backbone stereochemistry Unconjugated oligonucleotide administered ICV Isomer 2 Left: In a target engagement study, 7 mice administered 2 x 50 ug oligonucleotide or PBS by ICV on days 0 and 7. Tissue collected on day 14. Target mRNA normalized to Tubb3 and plotted relative to PBS. Data presented as mean ± SD (n=7). Stats: One-way ANOVA ns not significant, PBS phosphate buffered saline. Right: wt mouse tolerability study, n=4 administered 100 ug oligonucleotide or PBS by ICV on day 0 and monitored for 8 weeks. Percentage Body Weight Change CNS target knockdown in vivo Isomer 1 PBS PBS Isomer 1 Isomer 2 Isomer 3 Isomer 3 Isomer 3
Single intrathecal dose in NHP leads to substantial and widespread target mRNA reduction throughout the CNS Target mRNA knockdown 28 days post-dose (WVE-005) Striatum Control NHPs: Non-human primates NHPs were administered 12 mg on day 1 via IT bolus injection; tissue samples were collected from 3 NHPs at 28 days post-dose. Target mRNA knockdown 28 days post-dose (WVE-005) Potential for infrequent IT administration, widespread CNS distribution of PN modified oligonucleotides, and availability of disease biomarkers facilitates development of differentiated CNS portfolio
PRISM enables optimal placement of backbone stereochemistry Crystal structure confirms phosphate-binding pocket of RNase H binds 3’-SSR-5’ motif in stereopure oligonucleotide – supports design strategy for Wave oligonucleotides ASO/RNA duplex Yellow spheres represent ‘S’ atoms Phosphate binding pocket RNA cleavage site Target RNA Stereopure Oligonucleotide (C9orf72 compound) RNase H + +
Importance of controlling stereochemistry (Rp) (Sp) Top view Side view Yellow spheres represent ‘S’ atomsPS: Phosphorothioate Number of PS linkages in oligonucleotide backbone No. diastereomers 80T 60T 40T 20T 30B 22M 12M 2M 1M 500K 0 0 10 20 30 40 50 Antisense, exon skipping, ssRNAi ADAR oligonucleotide CRISPR guide Stereochemical diversity Exponential diversity arises from uncontrolled stereochemistry
Upcoming milestones
Upcoming milestones throughout 2022 will unlock opportunities Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Liver (Subcutaneous GalNAc) WVE-004 C9orf72 ALS & FTD Clinical data being generated to enable decision making WVE-003 HD SNP3 Clinical data being generated to enable decision making WVE-N531 DMD Exon 53 Clinical data being generated to enable decision making AIMer AATD SERPINA1 Additional preclinical data, including reduction in Z-AAT aggregates and changes in liver pathology AATD AIMer development candidate expected Success with any current program validates platform and unlocks modalities and tissues
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations krausch@wavelifesci.com 617.949.4827