arvn-20241231

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

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FORM 10-K

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(Mark One)

For the fiscal year ended December 31, 2024

Commission File Number: 001-38672

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ARVINAS, INC.

(Exact name of registrant as specified in its Charter)

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5 Science Park395 Winchester Ave.New Haven, Connecticut 06511

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (203) 535-1456

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Securities registered pursuant to Section 12(b) of the Act:

Securities registered pursuant to Section 12(g) of the Act:

None

(Title of class)

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yesx No o

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act.YesoNox

Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yesx No o

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yesx No o

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large Accelerated Filer x Accelerated filer o

Non-accelerated filer o Smaller reporting company o

Emerging growth company o

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. o

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report.☒

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. □

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to § 240.10D-1(b). □

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No x

As of June 28, 2024, the last business day of the registrant’s most recently completed second fiscal quarter, the aggregate market value of the Common Stock held by non-affiliates of the registrant was approximately $1,796.6 million, based on the closing price of the registrant’s Common Stock on such date. The number of shares of registrant’s Common Stock, $0.001 par value per share, outstanding as of February 5, 2025 was 68,771,867.

DOCUMENTS INCORPORATED BY REFERENCE

Part III of this Annual Report incorporates by reference information from the definitive Proxy Statement for the registrant’s 2025 Annual Meeting of Stockholders, which is expected to be filed with the Securities and Exchange Commission not later than 120 days after the registrant’s fiscal year ended December 31, 2024.

Table of Contents

Page

PART I

Item 1. Business 6

Item 1A. Risk Factors 78

Item 1B. Unresolved Staff Comments 127

Item 1C Cybersecurity 127

Item 2. Properties 128

Item 3. Legal Proceedings 129

Item 4. Mine Safety Disclosures 129

PART II

Item 6. [Reserved] 131

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 149

Item 8. Financial Statements and Supplementary Data 149

Item 9A. Controls and Procedures 149

Item 9B. Other Information 152

Item 9C. Disclosure Regarding Foreign Jurisdictions That Prevent Inspection 152

PART III

Item 10. Directors, Executive Officers and Corporate Governance 153

Item 11. Executive Compensation 153

Item 14. Principal Accountant Fees and Services 153

PART IV

Item 15. Exhibits, Financial Statement Schedules 154

CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS AND RISK FACTOR SUMMARY

Forward-Looking Statements

This Annual Report on Form 10-K contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this Annual Report on Form 10-K, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “goals,” “will,” “would,” “could,” “should,” “continue” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

The forward-looking statements in this Annual Report on Form 10-K include, among other things, statements about:

•the initiation, timing, progress and results of our current and future clinical trials of vepdegestrant, ARV-393 and ARV-102, and current clinical trials of bavdegalutamide, including statements regarding the period during which the results of the clinical trials will become available or the forum in which we will present such results;

•the timing of, and our ability to obtain, marketing approval of our product candidates, including vepdegestrant, and the ability of our product candidates, including vepdegestrant, to meet existing or future regulatory standards;

•the potential achievement of milestones and receipt of payments under our collaborations, including our collaboration with Pfizer Inc. entered into in July 2021;

•potential receipt of payments based on the achievement of milestones related to luxdegalutamide (ARV-766) and future royalties under our license agreement with Novartis Pharma AG;

•our plans to pursue research and development of other product candidates;

•our expectation to wind down our bavdegalutamide program after completion of current ongoing clinical trials (ARV-110-101 and ARV-110-103);

•the filing of an investigational new drug application for our kirsten rat sarcoma GD12 program;

•the potential advantages of our platform technology and potential advantages and therapeutic benefits of our product candidates;

•the extent to which our scientific approach and platform technology may potentially address a broad range of diseases and disease targets;

•favorable clinical trial results in our ongoing oncology and neurodegenerative programs providing further validation of our platform as a new therapeutic modality for the potential treatment of diseases caused by dysregulated intracellular proteins regardless of therapeutic area;

•the potential receipt of revenue from future sales of our product candidates;

•the rate and degree of market acceptance and clinical utility of our product candidates;

•our estimates regarding the potential market opportunity for our product candidates;

•our commercialization plans, and sales, marketing and distribution capabilities and strategy;

•our ability to establish and maintain arrangements for manufacture and testing of our product candidates;

•our ability to enter into additional collaborations with third parties;

•our intellectual property position;

•our estimates regarding expenses, future revenues, capital requirements and needs for additional financing and statements regarding Arvinas’ cash, cash equivalents and marketable securities, including their sufficiency to fund planned operating expenses and capital expenditure requirements into 2027;

•our belief that there are not currently any risks from known cybersecurity threats that have materially affected or are reasonably likely to materially affect us;

•our belief that our facilities are sufficient to meet our current needs and that suitable additional or alternative space will be available as and when needed on commercially reasonable terms for our future growth;

•the impact of government laws and regulations; and

•our competitive position.

We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. We have included important factors in the cautionary statements included in this Annual Report on Form 10-K, particularly in the “Risk Factors” section, that we believe could cause actual results or events to differ materially from the forward-looking statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make.

You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to this Annual Report on Form 10-K completely and with the understanding that our future results may differ materially from what we expect. We do not assume any obligation to update any forward-looking statements except as required by applicable law.

This Annual Report on Form 10-K also contains estimates and other statistical data made by independent parties and by us relating to market size and other data about our industry. This data

involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data and estimates. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Cross-trial comparisons are not based on head-to-head studies and no direct comparisons can be made.

Throughout this Annual Report on Form 10-K, the “Company,” “Arvinas,” “we,” “us,” and “our,” except where the context requires otherwise, refer to Arvinas, Inc. and its consolidated subsidiaries, or any one or more of them as the context may require, and “our board of directors” refers to the board of directors of Arvinas, Inc.

The Arvinas name and logo are our trademarks. This Annual Report on Form 10-K contains references to our trademarks and service marks and to those belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report on Form 10-K, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entity.

Risk Factor Summary

Our business is subject to a number of risks that if realized could materially affect our business, prospects, operating results and financial condition. These risks are discussed more fully in the “Risk Factors” section of this Annual Report on Form 10-K. These risks include the following:

•We have incurred significant losses since our inception. We expect to incur losses over at least the next several years and may never achieve or maintain profitability. Our net losses totaled $198.9 million, $367.3 million and $282.5 million for the years ended December 31, 2024, 2023, and 2022, respectively.

•We have never generated revenue from product sales and may never be profitable.

•We will need substantial additional funding to continue our operations. If we are unable to raise capital when needed, we may be required to delay, limit, reduce or terminate our research, product development programs or future commercialization efforts.

•Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

•Our approach to the discovery and development of product candidates based on our PROTAC technology platform is unproven, which makes it difficult to predict the time, cost of development and likelihood of successfully developing any products.

•We are early in our development efforts. If we are unable to commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.

•Drug development involves a lengthy and expensive process, with an uncertain outcome. We may incur unexpected costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of our product candidates. We cannot be certain of the timely completion or outcome of our preclinical testing and studies and cannot predict if the U.S. Food and Drug Administration, or FDA, or similar regulatory authorities outside the United States will accept our proposed clinical programs or if the outcome of our preclinical testing and studies will ultimately support the further development of our programs.

•Positive data from preclinical or early clinical studies of our product candidates are not necessarily predictive of the results of later clinical studies and any future clinical trials of our product candidates. If we cannot replicate the positive data from our preclinical or early clinical studies of our product candidates in our future clinical trials, we will be unable to successfully develop, obtain regulatory approval for and commercialize our product candidates.

•We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

•We are developing and plan to continue to develop our product candidates in combination with other drugs. If the FDA or similar regulatory authorities outside of the United States do not approve these other drugs, or revoke their approval of such drugs, or if safety, efficacy, manufacturing or supply issues arise with the drugs we choose to evaluate in combination with our product candidates, we may be unable to obtain approval of or market our products.

•We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.

•We currently depend, and expect to continue to depend, on collaborations, license arrangements, and other strategic alliances with third parties for the research, development, and the potential future commercialization of certain of the product candidates we may develop. If any such collaborations are not successful, we may not be able to capitalize on the market potential of those product candidates.

•We may seek to establish additional collaborations or out-license the development of our product candidates. If we are not able to establish collaborations or enter into these out-licenses on commercially reasonable terms, we may have to alter our business development plans or product development and commercialization plans.

•We rely and expect to continue to rely on third parties to conduct our clinical trials, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials.

•We rely on third-party CMOs for the manufacture and testing of both drug substance and finished drug product for our product candidates for preclinical testing and clinical trials and expect to continue to do so for commercialization. This reliance on third parties may increase the risk that we will not have sufficient quantities of our product candidates or products or such quantities at an acceptable cost or quality, which could delay, prevent or impair our development or commercialization efforts.

•Changes in U.S. and international trade policies, particularly with respect to China, may adversely impact our business and operating results.

•Even if any of our product candidates receives marketing approval, it may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success.

•Even if we are able to commercialize any product candidates, the products may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, which would harm our business.

•If we are unable to obtain and maintain patent protection for our technology and products or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize technology and products similar or identical to ours, and our ability to successfully commercialize our technology and products may be impaired, and we may not be able to compete effectively in our market.

•Even if we complete the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain and may prevent us from obtaining approvals for the commercialization of any or all of our product candidates. If we are not able to obtain, or if there are delays in obtaining, required regulatory approvals, we will not be able to commercialize our product candidates, and our ability to generate revenue will be materially impaired.

•Compliance with global privacy and data security requirements could result in additional costs and liabilities to us or inhibit our ability to collect and process data globally, and the failure to comply with such requirements could subject us to significant fines and penalties, which may have a material adverse effect on our business, financial condition or results of operations.

•Our future success depends on our ability to retain key employees, consultants and advisors and to attract, train, retain and motivate qualified personnel.

•Our internal computer systems and those of our collaborators, contractors, consultants and other third parties are vulnerable to cyber attacks, cyber intrusions and security breaches, which could not only materially disrupt our business operations and result in the loss of confidential information, but also damage the integrity of our clinical trials, impact our regulatory filings, compromise our ability to protect our intellectual property, and subject us to regulatory actions that could result in significant fines or other penalties.

•The price of our common stock is volatile and may fluctuate substantially, which could result in the loss of all or part of our stockholders’ investment.

PART I

Item 1. Business.

Overview, Programs and Pipeline

We are a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through our PROteolysis TArgeting Chimera, or PROTAC, Discovery Engine, our technology platform to engineer proteolysis-targeting chimeras, or PROTAC protein degraders, we are pioneering the development of protein degradation therapies designed to harness the body’s own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. We believe that our targeted protein degradation approach is a therapeutic modality that may provide distinct advantages over existing modalities, including traditional small molecule therapies and gene-based medicines. We have a robust preclinical pipeline of PROTAC protein degraders targeting a broad range of intracellular disease targets, including those representing proteins that currently cannot be addressed by existing small molecule therapies, commonly referred to as “undruggable” targets. We are using our PROTAC Discovery Engine to build an extensive pipeline of protein degradation product candidates to target diseases in areas of unmet need, including oncology (including hematology and immuno-oncology), neuroscience, and other therapeutic areas. We and our collaborators have initiated programs across multiple therapeutic areas with the goal of developing and delivering life-changing therapies to patients in need. We are currently progressing multiple product candidates through clinical development programs, including vepdegestrant, targeting the estrogen receptor, or ER, for the treatment of locally advanced or metastatic ER positive / human epidermal growth factor receptor 2, or HER2, negative, or ER+/HER2-, breast cancer; ARV-393, targeting the B-cell lymphoma 6, or BCL6, protein for the treatment of relapsed/refractory non-Hodgkin Lymphoma, or NHL; and ARV-102, targeting the leucine-rich repeat kinase 2, or LRRK2, protein for the treatment of neurodegenerative disorders. We also have programs in preclinical development, including our Kirsten rat sarcoma, or KRAS, G12D program.

Our pipeline, which includes an overview of our ongoing and planned pivotal trials for vepdegestrant, as well as our clinical and preclinical programs, is summarized below.

a. A list of the prioritized vepdegestrant development program pipeline is included on page 7 of this Annual Report on Form 10-K.

b. Pending emerging data and health authority feedback

ER, estrogen receptor; 1L, first-line; 2L, second-line; CDK, cyclin-dependent kinase; BCL6, B-cell lymphoma 6; LRRK2, leucine-rich repeat kinase 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; IND, investigational new drug; AR, androgen receptor

In addition to the programs above and our early-stage collaborations, including with Pfizer, Inc., or Pfizer, and Genentech, Inc. and F. Hoffman-La Roche Ltd., or Genentech, we are conducting exploratory research and development work on multiple other undisclosed targets.

Further, in 2024, we had two programs designed to target the androgen receptor, or AR, luxdegalutamide (ARV-766) and bavdegalutamide (ARV-110). In the second quarter of 2024, we entered into and closed a transaction with Novartis Pharma AG, or Novartis, pursuant to which we granted Novartis an exclusive worldwide license for the development, manufacture and commercialization of luxdegalutamide (ARV-766). As of December 31, 2024, we completed the transition of our ongoing and planned clinical trials of luxdegalutamide (ARV-766) to Novartis. Based on a decision early in the fourth quarter of 2023, to prioritize clinical development of luxdegalutamide (ARV-766), we will not be enrolling new patients in our ongoing trial activities with bavdegalutamide (ARV-110-101 and ARV-110-103) and we expect to wind down our bavdegalutamide programs after completion of these clinical trials.

Introduction to the Company

We have been a leader in the field of directed protein degradation using chimeric small molecules since our founding in 2013. We have assembled a scientific team with extensive know-how and translational medicine expertise to develop PROTAC targeted protein degraders with features not previously disclosed in published third-party studies. Our management team draws on extensive experience in all phases of drug discovery and development gained at large pharmaceutical and biotechnology companies to continue to advance our product pipeline and expand the capabilities of our platform.

We have designed and optimized our proprietary PROTAC Discovery Engine for the discovery of PROTAC therapeutics to address diseases caused by abnormal proteins or aberrant protein expression. We engineer our PROTAC targeted protein degraders to tag a target protein for degradation through the ubiquitin proteasome system, one of the cell’s natural protein disposal systems, and then to iteratively degrade additional target protein molecules. The PROTAC Discovery Engine includes advanced screening capabilities, including in-house high-throughput and deoxyribonucleic acid, or DNA, -encoded library screening abilities that are tailored to the needs of incorporation into PROTAC protein degraders and to optimize their drug-like properties. Following selection and identification, we use tools including predictive computational modeling and privileged linkers that allow the potential for increased potency and selectivity. Finally, we have utilized our own proprietary PROTAC-specific optimization strategies, which we refer to as the Arvinas Rules, to create PROTAC degraders that, for example, are capable of being delivered through multiple routes of administration, including oral delivery, as well as PROTAC targeted protein degraders that are able to penetrate the blood brain barrier.

Each of our programs has demonstrated potent and selective protein degradation in our preclinical studies. We believe favorable clinical trial results in our ongoing oncology and neurodegenerative programs could provide further validation of our platform as a new therapeutic modality for the potential treatment of diseases caused by dysregulated intracellular proteins regardless of therapeutic area.

Additional information regarding each of our programs and pipeline is summarized below and later described in additional detail.

Oncology Programs: Vepdegestrant and ARV-393

Estrogen Receptor Program: Vepdegestrant

Vepdegestrant is an investigational orally bioavailable PROTAC protein degrader designed to target and degrade the ER for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer. We are co-developing vepdegestrant with Pfizer pursuant to a collaboration agreement that we and Pfizer entered into in July 2021. We granted Pfizer worldwide co-exclusive rights to develop and commercialize vepdegestrant.

In preclinical studies, vepdegestrant demonstrated near-complete ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models and showed superior anti-tumor activity when compared to a standard of care agent, fulvestrant, both as a single agent and in combination with a cyclin-dependent kinase, or CDK, 4/6 inhibitor.

We, along with Pfizer, have several ongoing clinical trials of vepdegestrant, designed to potentially position vepdegestrant as a backbone ER-targeting therapy treating the ER+/HER2- metastatic breast cancer, as outlined below:

a. Pending emerging data and health authority feedback

ER, estrogen receptor; HER, human epidermal growth factor receptor; mBC, metastatic breast cancer; 1L, first-line; 2L second-line

As part of our global collaboration with Pfizer, we expect to announce topline data for the VERITAC-2 Phase 3 monotherapy clinical trial in a topline press release in the first quarter of 2025 and present the full results of the VERITAC-2 clinical trial at a medical conference in 2025. We completed enrollment for this clinical trial in the fourth quarter of 2024.

In the first quarter of 2025, we announced that we, as part of our global collaboration with Pfizer, plan to initiate two new Phase 3 combination trials of vepdegestrant in patients with ER+/HER2- metastatic breast cancer in 2025, pending emerging data and regulatory feedback:

•A first-line Phase 3 combination trial with Pfizer’s CDK4 inhibitor, atirmociclib; and

•A second-line Phase 3 combination trial with a CDK/6 inhibitor.

Additional information regarding our progress with respect to each of the vepdegestrant clinical trials is included below in "Item 1. Business—Our Clinical Stage Programs—Oncology Programs—Estrogen Receptor Program: Vepdegestrant for the Treatment of Patients with Locally Advanced or Metastatic ER+/HER2- Breast Cancer".

Hematology Program: ARV-393

ARV-393 is an investigational, orally bioavailable PROTAC designed to degrade BCL6, a transcriptional repressor and a key regulator of normal B-cell maturation and differentiation processes. Deregulation of BCL6 function (e.g., via chromosomal translocation, mutations) may lead to malignant transformation and development of NHL. Prior to the advent of PROTAC technology, the BCL6 protein was considered "undruggable." We believe that ARV-393 PROTAC-mediated degradation of BCL6 may provide an important novel therapeutic option for patients with NHL.

We are currently enrolling a Phase 1 first-in-human clinical trial of ARV-393 in patients with relapsed/refractory NHL. This is an open-label, multicenter, Phase 1 dose escalation study to evaluate the safety, tolerability and preliminary anti-tumor activity of ARV-393 as a single agent in adult patients with relapsed/refractory NHL. We plan to disclose preliminary data from this ongoing Phase 1 clinical trial in patients with NHL in 2025.

We plan to present preclinical data of ARV-393 in combination with standard of care biologic agents and small molecule inhibitors in high grade and aggressive diffuse large B-cell lymphoma in vivo models at the American Association for Cancer Research, or AACR, Annual Meeting in the second quarter of 2025.

Additional information regarding our preclinical and clinical progress with ARV-393 is included below in "Item 1. Business—Our Clinical Stage Programs—Oncology Programs—Hematology Program: ARV-393".

Neuroscience Program: ARV-102

ARV-102 is our first oral PROTAC protein degrader in development to treat neurodegenerative diseases. In preclinical studies, ARV-102 has been shown to cross the blood-brain barrier and degrade LRRK2, which is a large multidomain scaffolding kinase. In human genetics, increased activity and expression of LRRK2 are genetically involved in the pathogenesis of neurological diseases including progressive supranuclear palsy, or PSP, and Parkinson’s Disease, or PD. We are currently conducting two ongoing clinical trials with ARV-102, a Phase 1 clinical trial in healthy volunteers and a Phase 1 clinical trial in patients with PD.

In the second quarter of 2024, we received health authority approval to initiate the multiple ascending dose, or MAD, portion of the ongoing Phase 1 clinical trial of ARV-102 in healthy volunteers, and we initiated the MAD portion of this clinical trial in the third quarter of 2024. We completed enrollment of this MAD cohort in the first quarter of 2025.

We completed enrollment in the single ascending dose, or SAD, portion of the Phase 1 clinical trial of ARV-102 in healthy volunteers in the third quarter of 2024.We plan to present SAD data from the ongoing Phase 1 clinical trial in healthy volunteers in an oral session at the Alzheimer’s Disease/Parkinson’s Disease (AD/PD) conference in Vienna, Austria in the second quarter of 2025.

In the fourth quarter of 2024, we initiated dosing in the SAD portion of the Phase 1 clinical trial with ARV-102 in patients with PD. We expect to complete enrollment and present initial data from the ongoing SAD portion of the Phase 1 clinical trial in patients with PD, and initiate the MAD cohort of the Phase 1 clinical trial in patients with PD, in 2025.

Additional information regarding our preclinical and clinical progress with ARV-102 is included below in "Item 1. Business—Our Clinical Stage Programs—Neuroscience Program: ARV-102".

Pipeline

In addition to our clinical product candidates, we are expanding our pipeline by utilizing our platform to potentially address historically undruggable targets. Unlike existing small molecule inhibitor therapies, our PROTAC targeted protein degraders can degrade proteins using any available binding site, including low-affinity active binding sites or non-functional binding sites, bringing biological utility to ligands that would otherwise be ineffective. While some gene-based medicines are also seeking to address undruggable targets, we believe that our PROTAC targeted protein degraders confer the advantages of traditional small molecule therapies, such as broad tissue distribution, multiple routes of administration, including oral delivery, a well-established development pathway and relative ease of manufacturing.

We are further diversifying our pipeline by developing new PROTAC targeted protein degraders against targets for which we believe protein degradation offers advantages to existing therapeutic modalities, including PROTAC degraders that are designed to reach targets in deep brain regions and are capable of being delivered through multiple routes of administration, including oral delivery. We have engineered PROTAC targeted protein degraders that, in preclinical studies, have successfully achieved blood-brain barrier penetration, a key step in developing drugs with the potential to treat neurodegenerative diseases. We believe there are many other indications for which our PROTAC technology may be advantageous.

In the second quarter of 2023, we presented in vivo and in vitro data at the AACR Annual Meeting - Targeting RAS Special Conference that demonstrated that our PROTAC KRAS G12D degraders were potent, selective, and led to tumor stasis in a mouse xenograft model with intermittent dosing and that degradation of KRAS G12D provides an advantage versus inhibition in vitro and in vivo. Our KRAS G12D program is currently in preclinical development and we anticipate filing an IND application for our PROTAC KRAS G12D degrader in 2025.

Other Programs: Luxdegalutamide (ARV-766) and Bavdegalutamide (ARV-110)

Luxdegalutamide (ARV-766) is an investigational orally bioavailable PROTAC protein degrader designed to target AR as a potential treatment for men with metastatic castration resistant prostate cancer, or mCRPC, and metastatic castration-sensitive prostate cancer. Bavdegalutamide is an investigational orally bioavailable PROTAC protein degrader designed to target and degrade the AR for the treatment of men with mCRPC. Early in the fourth quarter of 2023, based on signs of superior tolerability and efficacy of luxdegalutamide (ARV-766) in clinical settings to date as compared to bavdegalutamide (ARV-110), we prioritized the initiation of a Phase 3 clinical trial with luxdegalutamide (ARV-766) in mCRPC instead of the previously planned Phase 3 clinical trial for bavdegalutamide. We will not be enrolling new patients into our ongoing trial activities with bavdegalutamide (ARV-110-101 and ARV-110-103) and we expect to wind down our bavdegalutamide program after completion of these clinical trials.

In the second quarter of 2024, we entered into and closed a transaction, or the Novartis Transaction, including both a license agreement, or the Novartis License Agreement, and an asset purchase agreement, or the Novartis Asset Agreement, with Novartis. Pursuant to the Novartis License Agreement, we granted Novartis an exclusive worldwide license for the development, manufacture and commercialization of luxdegalutamide (ARV-766), and, as of December 31, 2024, we completed the transition of our ongoing and planned clinical trials of luxdegalutamide (ARV-766) to Novartis. Pursuant to the Novartis Asset Agreement, we sold Novartis all of our rights, title and interest in our PROTAC protein degrader targeting AR-V7, a splice variant of the AR.

Our Strategy

Our mission is to improve the lives of patients suffering from debilitating and life-threatening diseases through the discovery, development, and commercialization of therapies that degrade disease-causing proteins. We use our PROTAC protein degrader platform to pioneer the development of protein degradation therapies that are designed to harness the body’s own natural protein disposal system to selectively and efficiently remove disease-causing proteins. We believe that our proprietary PROTAC technology is a therapeutic modality with the potential to provide distinct advantages over existing therapies and to address a broad range of targets, including historically undruggable proteins. We are currently developing PROTAC degraders to address targets within oncology, hematology, and neuroscience, and we see applicability in other therapeutic areas as well. The key elements of our strategy are to:

•Focus on near-term patient impact and advance clinical development of our lead PROTAC program, vepdegestrant, which is designed to degrade the ER, that is well-understood to be a biological pathway driving breast cancer. Vepdegestrant is the first PROTAC ER degrader to enter Phase 3 clinical trials and we have characterized its degradation and potent anti-tumor effects alone and in combination with CDK inhibitors across preclinical disease models. In addition, ER degradation is being evaluated in clinical samples from our ongoing clinical trials, including VERITAC AND TACTIVE-N. Vepdegestrant is our one product candidate in Phase 3 clinical development, and we are planning for multiple potential launches with vepdegestrant as both a monotherapy and in combination.

•Progress our therapeutic footprint beyond ER by furthering the programs in our oncology (including hematology) and neuroscience portfolios. We are focused on creating potential therapies for patients with hematological and neurological diseases, including our product candidates, ARV-393 and ARV-102, which are currently in Phase 1 clinical development. We believe that favorable clinical trial results with these initial hematology and neuroscience programs will validate the broader therapeutic potential of our PROTAC technology. In addition, ARV-393 degrades the historically "undruggable" BCL6 with potential to impact and provide oral therapeutic alternatives to patients with NHL, while ARV-102 degrades LRRK2 with potential to impact patients with PSP or PD.

•Utilize our PROTAC Discovery Engine platform to address historically undruggable and difficult-to-drug targets. We are applying our platform to develop treatments for patients with diseases associated with historically undruggable targets. Our platform enables us to build PROTAC targeted protein degraders with the potential to degrade these proteins through the cell’s natural protein degradation process using any available binding site, including low-affinity active binding sites or non-functional binding sites, bringing biological utility to ligands that would

otherwise be inactive. We also believe that many “difficult-to-drug” targets, where prior approaches are inadequate, will also provide opportunities to apply our PROTAC technology.

•Develop new therapeutics with distinct advantages over existing modalities, including gene-based medicines. We intend to address targets for which we believe protein degradation and the tunable features of our PROTAC targeted protein degraders are designed to offer advantages compared to existing therapeutic modalities. Our PROTAC protein degraders have been shown preclinically to eliminate, rather than inhibit, disease-causing proteins, disrupt scaffolding functions of target proteins, bind and degrade classically "undruggable" proteins, and can act iteratively. Unlike gene-based medicines, our PROTAC targeted protein degraders have been shown preclinically to confer the advantages of traditional small molecule therapies, such as multiple routes of administration, including oral delivery, a well-established development pathway and relative ease of manufacturing. In addition, we have engineered PROTAC targeted protein degraders that, in preclinical studies, have successfully achieved broad tissue distribution, including across the blood-brain barrier, creating potential opportunities for our PROTAC technology in neurological diseases. We also believe there are many other debilitating and progressive disease indications for which our technology may be advantageous, including autoimmune, anti-infective and inflammatory conditions.

•Selectively collaborate to realize the full potential of our platform. We are using our PROTAC Discovery Engine to build an extensive pipeline of product candidates. Our co-development/co-commercialization collaboration with Pfizer has the potential to accelerate and broaden global development and commercialization of vepdegestrant. The outlicensing of luxdegalutamide (ARV-766) to Novartis was intended to maximize the patient impact and commercial opportunity of that program. In an effort to realize the full potential of our PROTAC technology, our ongoing strategic collaborations with Pfizer and Genentech address targets across multiple therapeutic areas. In addition to these collaborations in human therapeutics, in 2019 we established a joint venture, with Bayer, called Oerth Bio LLC, or Oerth Bio, which was converted to a corporation in 2023, to pursue our PROTAC technology in agricultural applications. We have and plan to continue to selectively pursue collaborations with leading biopharmaceutical companies with specialized capabilities or know-how, including global development and commercial expertise and capabilities for those products for which we retain full development and commercialization rights. We believe this selective approach to collaboration will further broaden the therapeutic reach of our PROTAC technology, as well as complement and expand our internal development expertise.

•Continue to expand the capabilities of our PROTAC Discovery Engine and the breadth of our intellectual property portfolio. We are investing in our research and development activities to expand the capabilities of our PROTAC Discovery Engine and the breadth of our intellectual property portfolio. This includes: research into ligands for novel E3 ligases, key proteins in the ubiquitin proteasome system, that may have tissue-specific, differentiating pharmacokinetic opportunities or disease-specific features; the discovery of novel binding ligands for targets; the discovery of orally bioavailable and blood brain barrier penetrant PROTAC protein degraders; and improvement of our PROTAC targeted protein degrader design and optimization processes. We have exclusive worldwide rights to our platform technology. Detailed information regarding our intellectual property portfolio is described below in "Item 1. Business—Intellectual Property".

Our Focus

The Role of Proteins in Disease

Human cells produce tens of thousands of different proteins, the entirety of which is referred to as the proteome. Proteins are responsible for many structural, functional and regulatory processes in cells.

Proteins are large, complex biomolecules made through a series of steps based on instructions carried from DNA, the genetic “blueprint” within the cell. Generally, sequences of DNA are converted into messenger ribonucleic acid, or mRNA, during a process called transcription. mRNA provides the template that specifies the assembly of a particular sequence of amino acids into proteins during a process known as translation. The amino acid sequence dictates, among other things, the conformation, or 3-D shape, of the resulting protein. Proteins can have complex shapes, with multiple chains of amino acids folding together in some cases to reach a final form. The final form of the protein, as well as the timing, location and concentration of its expression within the cell, is essential to the protein’s intended function.

In healthy cells, the transcription and translation processes contribute to producing properly folded proteins in the right amounts and at the correct times to ensure normal cell health and function. This balance can be disrupted by a variety of events and factors, such as cellular stress, genetic mutations and transcriptional or translational errors, which can then lead to cellular overexpression, abnormal production rates, misfolding or mutations of proteins. When proteins are overexpressed or mutated, homeostatic pathway biology can be disrupted and a wide variety of diseases can result. For example, overexpression of estrogen receptor is known to be associated with breast cancer. In neurodegenerative diseases, abnormal deposition of misfolded or aggregated proteins in the brain, including the intraneuronal aggregation of the microtubule-associated protein tau, are associated with Alzheimer’s disease, PD, PSP and other neurological disorders. Recent genomic advances continue to implicate the role of specific proteins in many disease states.

There are multiple therapeutic approaches, both approved and in development, to treat diseases caused by abnormal proteins or aberrant protein expression. Each operates at a different point in the lifecycle of the protein, as illustrated in the following graphic:

Small Molecule Inhibitors, Gene Therapy and Gene Editing

Traditional small molecules seek to block or inhibit the expression or function of an errant protein. While there are numerous examples of safe and effective small molecule therapies, their efficacy can be limited by weak or incomplete binding of the therapeutic molecule to the relevant binding site on the protein, the cell’s ability to counteract the inhibitory effect of the drug by producing more of the protein, mutation of the target, or evolution of the cell to rely on alternate pathways. These cellular responses often result in a need for higher dosing levels, which can in turn introduce safety challenges from off-target and toxic effects, or drug resistance.

Gene therapy approaches act by augmenting the errant protein with normal protein by using viral vectors to introduce DNA from an exogenous source that codes for a functional protein. While there have been

promising advances in this field, the fundamental approach is limited by delivery, expression efficacy, pre-treatment conditioning, durability and manufacturing challenges that curtail the practical utility of gene therapy.

Gene editing or gene silencing approaches such as CRISPR/Cas9, RNA interference and antisense act by either correcting or inactivating, or knocking out, the gene that would otherwise be transcribed and translated to express the errant protein. By correcting or knocking out the gene, the errant protein is never made, preventing its downstream negative effects. In the case of CRISPR/Cas9, the resulting modification of the gene occurs at the DNA level and is believed to be irreversible. While there are examples of approved therapies in this field that have the potential to correct specific genetic defects, gene editing and gene silencing approaches generally face delivery, stability, biodistribution, specificity and selectivity challenges, in addition to significant manufacturing hurdles.

Protein Degradation

When proteins become old, mutated, misfolded or simply have served their purpose, they are naturally degraded by the body through the ubiquitin proteasome system in which cells mark or tag a particular protein for disposal by attaching several molecules of the small regulatory protein ubiquitin to the protein to be disposed. This process generally proceeds along the following steps in rapid sequence:

•The E1 enzyme activates ubiquitin, which is then transferred to an E2 enzyme.

•An E3 ubiquitin ligase, or E3 ligase, transfers the ubiquitin from the E2 enzyme to a specific target protein.

•Once a chain of at least four ubiquitins are attached to the target protein, the proteasome recognizes the polyubiquinated protein.

•The proteasome breaks down or degrades the protein into its amino acid components.

Several therapeutic approaches work at the protein level by modulating the ubiquitin proteasome system to harness the cell’s natural protein disposal system to degrade and remove a protein. Degradation can be induced by inhibiting chaperone molecules such as HSP90, which are known to facilitate correct protein folding, resulting in tagging misfolded proteins for degradation. HSP90 inhibitors, however, have shown limited efficacy in the clinic to date.

Some degraders use an approach that causes a conformational change in a specifically targeted protein, resulting in a misfolded protein, which triggers the cell’s innate protein degradation system to dispose of the misfolded protein. Although these compounds have shown efficacy, they only induce the degradation of those proteins able to adopt a non-native state, leaving a wide array of protein targets unaddressed.

Chimeric small molecules, such as our PROTAC protein degraders, use a different protein degradation approach. Instead of causing improper folding or inhibiting molecules that facilitate proper folding of the target protein, chimeric small molecules directly recruit an E3 ligase to tag specifically targeted proteins with ubiquitin, signaling the proteasome to degrade the targeted protein. Our PROTAC targeted protein degraders take this approach to protein degradation.

PROTAC Targeted Protein Degraders — Our Approach to Protein Degradation

We have engineered our PROTAC targeted protein degraders to utilize the cell’s naturally occurring protein disposal system, directing the proteasome to recognize and degrade specific proteins associated with disease. Our PROTAC targeted protein degraders are chimeric small molecules with two operative ends—one, a ligand that binds to the protein targeted for degradation, and the other, a ligand that binds to an E3 ligase. These two ligands are connected by a chemical chain linker. Our PROTAC targeted protein degraders bring the targeted protein and the E3 ligase together into a three-component grouping known as a ternary complex to facilitate the transfer of ubiquitin to the target protein. Once four ubiquitins are attached in a chain to the target protein, the proteasome recognizes and degrades the protein. The entire cycle from the formation of the trimer complex, which can occur in a period of nanoseconds, to degradation of the target protein by the proteasome happens over a period of minutes. After our PROTAC targeted protein degrader facilitates the tagging of a target protein molecule with ubiquitin through formation of the ternary complex, it can move on to another target protein molecule to conduct the degradation process again, potentially completing this cycle hundreds of times

before eventually being metabolized or eliminated from the cell. We refer to this recycling as our PROTAC targeted protein degraders’ iterative mechanism of action.

The figure below depicts our PROTAC-induced cycle from E3 ligase binding and target protein recruitment, to ternary formation and ubiquitin transfer, to degradation of the target protein by the proteasome, to the release of ubiquitin and PROTAC targeted protein degrader for further degradation cycles.

Our Discovery Platform — PROTAC Discovery Engine

We have designed and optimized our PROTAC Discovery Engine for the discovery of PROTAC targeted protein degrader therapeutics to address diseases caused by abnormal proteins or aberrant protein expression. The PROTAC Discovery Engine includes advanced screening capabilities, including in-house high-throughput DNA-encoded library screening, computational and machine learning abilities that are tailored to the needs of incorporation into PROTAC protein degraders and to optimize their drug-like properties. Following selection and identification, we use tools including predictive computational modeling and privileged linkers that allow the potential for increased potency and selectivity. Finally, we have utilized our own proprietary Arvinas Rules and machine learning tools to create and accelerate the design of PROTAC degraders that, for example, are capable of being delivered through multiple routes of administration, including oral delivery, as well as PROTAC targeted protein degraders that are able to penetrate the blood brain barrier.

Design and Optimization of our PROTAC Targeted Protein Degraders

As genomic knowledge and advances in genome mapping have increased, the understanding of proteins implicated in diseases has similarly increased. We undertake a rigorous evaluation process to prioritize protein targets for which we believe our PROTAC approach can achieve differentiated clinical outcomes for patients over existing modalities. Our PROTAC Discovery Engine is built from over 20 years of experience, know-how, and intellectual property and comprises three stages:

Ligase Selection and Ligand Identification

•E3 KnowledgeBase- The human body has more than 600 E3 ligases, and we select ligands for E3 ligases from our proprietary library for incorporation into our PROTAC targeted protein degraders. We continue to research additional E3 ligases that are expressed in specific tissues or diseases, and identify or discover associated binding ligands, to create novel PROTAC protein degraders that recruit E3 ligases with targeted expression patterns, such as tumor or central nervous system-localized E3 ligases, that may be beneficial for the development of targeted oncologic and neurologic therapies. To enable targeted protein degradation via alternative E3 ligases, we have discovered and characterized novel small molecule ligands targeting the E3 ligase KLHDC2. We have functionalized these novel KLHDC2-targeting small molecules into robust and potent PROTAC KLHDC2-degraders and demonstrate KLHDC2-dependent degradation of target proteins across cell lines. Furthermore, we have leveraged biochemical studies to understand mechanistic assembly of the KLHDC2 holo-E3 complex together with its cognate adapter proteins in addition to structural studies to show the dynamic tetramer formation of KLHDC2 E3 assemblies induced by small molecule engagement. In doing so, we have expanded the arsenal of E3 ligases that can be targeted by small molecules and may be hijacked for targeted protein degradation. We believe our success with the diverse set of E3 ligases that we are currently employing and the binders of other E3 ligases that we are researching provide us with a competitive advantage as we develop a range of products with different technical characteristics.

•Advanced Screening Capabilities - We select ligands for incorporation into our PROTAC targeted protein degraders from a variety of sources. The ligands we select, which target the desired protein for degradation or E3 ligase for incorporation into our PROTAC targeted protein degraders, may include (1) de novo ligands discovered through high-throughput screening, biophysical directed binding approaches, virtual or in silico computer-based screening, and affinity-based hit identification through our in-house DNA-encoded libraries that that are tailored to the needs of incorporation into PROTAC protein degraders and to optimize their drug-like properties or (2) ligands that are known to bind protein targets but may have faced therapeutic limitations that we believe our PROTAC technology can overcome, such as lack of potency or function, metabolic instability or off-target effects.

Rapid PROTAC Design

•Deep understanding of the "Zone of Ubiquitination" - Bringing the targeted protein and the E3 ligase together into a ternary complex is necessary but not sufficient for degradation. We use structural and biochemical information to predict precisely which lysine residues on the target protein can be “tagged” with ubiquitin, and we design PROTAC degraders to exploit this knowledge.

•ANGLE: Arvinas Next Generation Linker Evolution - We connect the selected protein-targeting ligands and E3 ligase ligands with our privileged chemical linkers. Linker selection is critical for rapid identification of protein degraders and can introduce function and selectivity to a nonfunctional or nonselective binding ligand upon incorporation into a PROTAC targeted protein degrader molecule. Linker composition can also be used to modulate properties of our PROTAC targeted protein degraders, such as membrane permeability, aqueous solubility, metabolic stability and biodistribution. We select from a proprietary library of conformationally privileged linkers to enable the efficient formation of the ternary complex essential to ubiquitin transfer and protein degradation.

•Predictive Computational Modeling - We use ternary structure-based and dynamic computational modeling, many times aided by structural biology-generated insights, and design algorithms to rapidly identify potent degraders.

•Proteomics Capabilities - A PROTAC degrader is often more selective than the targeting warhead. We have proteomics capabilities that enable us to understand that specificity in precise detail and iterate quickly to optimize the selectivity of our PROTAC degraders for the protein target. These proteomic capabilities also enable novel ligand characterization and ultra-sensitive protein biomarker detection to enable translation and quantitative protein degradation in the clinic.

Turning Degraders into Drugs

•Arvinas Rules - Optimization of traditional small molecule agents tends to focus on guidelines that increase the chances of such molecules having sufficient permeability and solubility to make them orally bioavailable. Chimeric small molecules, including our PROTAC targeted protein degraders, are larger than traditional small molecule therapeutics, such that the conventional optimization parameters prevalent in traditional drug discovery do not readily apply. As such we have developed and apply our own proprietary Arvinas Rules and machine learning algorithms to accelerate design of our PROTAC targeted protein degraders. Through our Arvinas Rules, we have made PROTAC targeted protein degraders that are orally bioavailable and that cross the blood brain barrier.

•Deep Knowledge of in vivo PK/PD and Efficacy Relationships - Our understanding of molecular features that impact PROTAC biodistribution and target degradation, in the body, enables us to create PROTAC degraders with drug-like properties and activities. We can use this understanding to rapidly progress from target identification to PROTAC optimization and development.

Key Features of Our PROTAC Targeted Protein Degraders

In the design, optimization and development of our PROTAC targeted protein degraders, we focus on the following key features that we believe are critical to successfully engineering PROTAC targeted protein degrader therapeutics with potentially robust application across multiple indications and therapeutic areas: potency, selectivity, deliverability, differential biology and versatility. We have harnessed these features to successfully target and degrade a wide range of protein classes, including nuclear proteins, transcription factors, epigenetic modulators, membrane proteins, cytosolic proteins and high molecular weight neuropathologic protein oligomers.

Potency

The potency of our PROTAC technology is driven by two key characteristics: the iterative mechanism of our PROTAC targeted protein degraders and the ability to turn weak binders into potent degraders.

Iterative Mechanism

Our PROTAC targeted protein degraders behave iteratively to repeatedly induce the ubiquitination and subsequent degradation of proteins. As a result, protein degradation may be observed with PROTAC targeted protein degrader concentrations much lower than those required for typical small molecule inhibition, even operating at picomolar concentrations. We expect that the high cellular potency of PROTAC targeted protein degrader could provide the possibility of removal of proteins at levels equivalent to the knock out effect intended by gene-based medicines currently being explored. Our PROTAC targeted protein degraders offer potentially significant therapeutic advantages, including low doses, low drug exposures and practical dosing intervals, potentially mitigating toxicity and tolerability risks.

The iterative mechanism of our PROTAC targeted protein degraders potentially leads to more complete and lasting inactivation of downstream signaling in cells. In oncology, this translates into improved inhibition of tumor cell growth and reduces the likelihood of cell compensation through activation of alternative proteins, a common risk associated with small molecule inhibitors. In neurological diseases, our PROTACs have been shown preclinically to deliver low concentrations of drug to deep brain regions and remove disease proteins that impact disease pathobiology in ways that inhibitors, antibodies, genetic approaches, and inhibitors cannot. This mechanism enables PROTAC targeted protein degraders to operate in a broad therapeutic space between desired degradation-induced pharmacology and unwanted inhibition-induced effects.

Once the pre-existing reservoir of the targeted protein is depleted, our PROTAC targeted protein degraders only need to degrade newly resynthesized protein to maintain their effect. Depending on the resynthesis rate of the protein, this may be achievable with low tissue concentrations of PROTAC targeted protein degrader, which could lead to safety benefits and opportunities for flexible dosing regimens.

Weak Binders Become Potent Degraders

Using our platform and know-how, we are able to engineer potent PROTAC targeted protein degraders that do not require a high degree of binding strength to their targets. This contrasts with small molecule inhibitors, which require strong binding to a target protein and function by continually occupying the protein’s active site. The potency of our PROTAC targeted protein degraders is determined by a number of kinetic factors: formation of the ternary complex, rapid ubiquitination, trafficking of the ubiquitinated target to the proteasome and release of the PROTAC targeted protein degrader to enter another iterative cycle of degradation. As a result, a PROTAC targeted protein degrader with a low level of target protein occupancy can maintain a deep and prolonged suppression of protein levels, leading to the desired pharmacological effect. This provides opportunities to use our PROTAC technology to repurpose small molecules that only weakly bind to their target to create potent degraders as PROTAC targeted protein degraders.

Selectivity

When a ligand is incorporated into a PROTAC targeted protein degrader, the ternary complex initiated by the PROTAC targeted protein degrader often causes the ligand’s selectivity to increase, meaning that the degradation profile of a PROTAC targeted protein degrader can be even more selective than the binding profile of the ligand alone. By minimizing the binding of a ligand to off-target proteins and maximizing selectivity for a target protein, our PROTAC targeted protein degraders may reduce the potential for incidental degradation of normal, healthy proteins and unwanted drug effects and toxicity.

We published experiments in which a ligand binding to 133 kinases degraded fewer than ten proteins when incorporated into a PROTAC targeted protein degrader with limited additional modification. With further modification, and based on our experience, we believe it is possible to engineer promiscuous binders into more selective protein degraders, and when starting with less promiscuous, yet still unselective, binders, identify very selective PROTAC target protein degraders.

This selectivity allows for engineering of PROTAC targeted protein degraders that degrade only the mutated and unwanted protein, while sparing the normal, or wild-type, protein that may be necessary for healthy function. For example, we have demonstrated degradation of abnormal, but not wild-type, forms of the BRAF protein using a PROTAC targeted protein degrader. Wild-type BRAF helps transmit chemical signals from outside the cell to the cell’s nucleus and is part of a pathway that regulates cell proliferation, differentiation, migration and apoptosis. Mutations of BRAF, however, have been associated with a number of different cancers. As shown in the figure below, our PROTAC targeted protein degrader degraded BRAF mutants, as depicted by a lighter shade in the columns labeled 300 nM, representative of each of the three classes of BRAF mutations, while not degrading the wild-type BRAF, as depicted by an unchanging shade in each of the columns shown on the western blot.

1hMito is a protein this particular PROTAC targeted protein degrader is not targeted to degrade, and is included as a control to ensure total protein is equivalent in each lane.

An additional example of the selectivity achievable with a PROTAC degrader is seen in the figure below, showing that a KRAS G12D PROTAC only degrades the mutant G12D protein and not any other mutant forms of KRAS nor any of the wild type RAS isoforms. This selective reduction in the KRAS G12D protein is depicted by the loss of the red band in the row labeled AsPC-1, the name of a pancreatic cancer cell line that harbors the KRAS G12D mutation. The red band showing the KRAS G12D protein is lightest in the column with 30 nM

PROTAC and returns at 3000 nM PROTAC due to a common phenomenon observed with heterobifunctional molecules called the hook effect.

Deliverability and Versatility

Our PROTAC targeted protein degraders have the potential for delivery through multiple routes of administration to reach target proteins, and certain of our PROTAC targeted protein degraders are capable of penetrating the blood brain barrier. In addition, the broad expression of the E3 ligases we target and the potential to turn weak binding ligands into potent degraders allows the application of our PROTAC technology to develop treatments for diseases associated with proteins that cannot be addressed by existing small molecule therapies.

Deliverability

We have developed PROTAC targeted protein degraders that are capable of being delivered orally, intravenously, subcutaneously and intrathecally, among other routes of administration, as well as PROTAC targeted protein degraders that are able to penetrate the blood brain barrier after oral administration. The multiple routes of delivery for our PROTAC targeted protein degraders potentially provide many attractive clinical dosing options. For example, oral delivery can offer a differentiating, competitive and commercial advantage over other therapeutic approaches such as gene-based medicines which require parenteral administration. Further, oral administration avoids risks of adverse events associated with intravenous or intramuscular administration, such as the potential for infection and blood clots at the infusion site.

Versatility

We believe our PROTAC targeted protein degraders may have potential application in a wide range of therapeutic areas because the E3 ligases we currently target are expressed widely across tissue types. Ligands that bind to some proteins may be of only weak affinity. However, we believe that our PROTAC technology will allow the degradation of proteins through such low affinity active binding sites or non-functional binding sites. Our ability to design weak binding PROTAC targeted protein degraders that nonetheless initiate rapid ubiquitination and subsequent degradation of targeted proteins has the potential to expand the number of disease-causing proteins targeted for drug development to include undruggable targets. We believe that rendering these targets druggable for the first time represents the true breadth and potential of our PROTAC Discovery Engine.

We have demonstrated that non-functional binding sites, analogous to those that may be present on proteins considered undruggable, can be used to target proteins for degradation by PROTAC targeted protein degraders. The figure below depicts a structural model of the Abl tyrosine kinase. This protein kinase possesses an enzymatic active site that is inhibited by the marketed small molecule, imatinib. The Abl kinase also has a second, non-functional active site, called an allosteric site, in its structure that can bind a different small molecule, named GNF-2, which despite binding allosterically (with a relatively weak KD of 500 nM), inhibits only the wild type protein (C-Abl), but not BCR-Abl-a mutated form of Abl implicated in chronic myelogenous leukemia.

When GNF-2 is converted into a PROTAC targeted protein degrader and used to treat cells, both BCR-Abl and C-Abl are effectively degraded. The figure below shows western blots of cells treated by increasing concentrations of our PROTAC targeted protein degrader and shows decreasing presence of each of BCR-Abl and C-Abl protein (depicted by a lighter shade of the BCR/Abl and C-Abl band in the western blot). Downstream signaling, as denoted by reduction of phosphorylated Stat5 (pStat5), is subsequently inhibited.

1Tubulin is a protein the GNF-2 PROTAC targeted protein degrader is not targeted to degrade, and is included as a control to ensure total protein is equivalent in each lane.

PROTAC-induced degradation may offer a solution for historically undruggable proteins because only binders, not functional inhibitors, are needed to facilitate E3 ligase recruitment and initiation of the degradation process. The probability of finding a suitable ligand using binding-site-agnostic screening is increased because the function of the ligand itself is not required. As a result, there is the potential for PROTAC targeted protein degraders to generate therapeutics from poorly selective ligands, weak-affinity ligands, or ligands that may not be intrinsically biologically active.

Our Clinical Stage Programs

Oncology Programs

Estrogen Receptor Program: Vepdegestrant for the Treatment of Patients with Locally Advanced or Metastatic ER+/HER2- Breast Cancer

We are developing vepdegestrant, an investigational orally bioavailable PROTAC ER degrader designed to specifically target and degrade the ER for the treatment of patients with ER+/HER2- breast cancer. Vepdegestrant is being developed as a potential monotherapy and as part of a combination therapy across multiple treatment settings for ER+/HER2- metastatic breast cancer, as an alternative to, and potentially more potent degrader than, the intramuscular injection fulvestrant and other selective ER degraders, or SERDs, currently approved or in development for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer. We chose ER degradation as a therapeutic focus given the well-documented biology of ER signaling as a principal driver in a high percentage of breast cancers. In July 2021, we announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant.

Vepdegestrant has demonstrated activity in ER+ breast cancer preclinical models and is being evaluated across clinical trials, including clinical trials in breast cancer patients and clinical pharmacology trials in healthy volunteers. In addition to monotherapy clinical trials, vepdegestrant is being evaluated in multiple clinical trials in combination other agents including Pfizer's novel investigational CDK4 inhibitor atirmociclib, CDK4/6 inhibitors such as abemaciclib, ribociclib, palbociclib, the CDK7 inhibitor samuraciclib, everolimus, and other targeted therapies. Vepdegestrant is the first PROTAC ER degrader to enter Phase 3 pivotal trials. We believe vepdegestrant has the potential to become a first-in-class ER-degrading PROTAC in advanced breast cancer and an oral, best-in-class targeted therapy, and the potential to improve clinical outcomes over current standards of care for patients with locally advanced or metastatic ER+/HER2- breast cancer as well as in earlier treatment settings.

Breast Cancer - Patient Population and Market Opportunity

Breast cancer is the most common cancer diagnosed among women in the United States, other than skin cancers, and the second leading cause of cancer death in women. Approximately one in eight women in the United States will develop invasive breast cancer in their lifetime. The American Cancer Society estimates that in 2025 there will be approximately 316,950 new cases of invasive breast cancer diagnosed in women in the United States. Approximately 70% of all breast cancer cases, including males, are ER+.

Treatment options for breast cancer depend on many different factors, including the stage of the cancer and whether the cancer cells contain hormone receptors. Patients with locally advanced or metastatic breast cancer are treated with systemic therapy, including hormone therapy, chemotherapy and targeted therapy, either as single-agents or in combination. Patients with locally advanced or metastatic ER+/HER2- breast cancer are often treated with hormone therapy, such as an aromatase inhibitor, typically in combination with targeted drugs such as CDK4/6 inhibitors. In patients with aggressive disease or whose disease continues to progress with a hormonal treatment regimen, chemotherapy may be prescribed. Treatment with chemotherapy is generally postponed for as long as possible due to the potential for severe side effects including neuropathies, nausea, diarrhea, decreased mental capacity and increased risk of infections.

A current standard of care for patients with ER+/HER2- locally advanced or metastatic breast cancer who experience progression on first-line therapy is fulvestrant, a SERD, administered as a monthly intramuscular injection, either as a single-agent or in combination with another targeted therapy. While fulvestrant has validated the importance of ER degradation as a therapeutic intervention, up to 50% of ER can remain when compared to baseline levels after six months of treatment with fulvestrant, providing an opportunity for more potent ER degraders. In January 2023, the FDA approved the SERD elacestrant for postmenopausal women or adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Preclinical Development

We have conducted a comprehensive preclinical program to study vepdegestrant as a potential treatment for patients with locally advanced or metastatic ER+ / HER2- breast cancer. In our preclinical studies, vepdegestrant demonstrated superior ER degradation compared to fulvestrant. Vepdegestrant has also demonstrated superior tumor regression when combined with a CDK4/6 inhibitor compared to fulvestrant and the same combination partner.

In in vitro models, vepdegestrant has induced ER degradation in multiple cell lines typically used in breast cancer research. In in vivo experiments vepdegestrant has achieved superior tumor growth inhibition and degradation compared to fulvestrant. We have tested vepdegestrant for tumor growth inhibitory activity using an industry-standard MCF-7 xenograft mouse model. MCF-7 is a well-characterized estradiol-dependent ER+ / HER2- cell line that forms tumors when implanted in the mammary fat pad of female mice. Vepdegestrant resulted in very high tumor growth inhibition when dosed daily orally at 10 mpk and more than 80% tumor shrinkage when dosed daily orally at 30 mpk for 28 days. At both doses, vepdegestrant demonstrated superior activity compared to a clinically relevant dose of fulvestrant, which is 200 mpk twice per week for two weeks and then once per week for two weeks. After 28 days of dosing in this efficacy study, the MCF-7 tumors were removed from the mice and processed for western blots to observe the level of ER degradation induced by oral dosing of vepdegestrant. Vepdegestrant reduced ER by 85%, on average, at 10 mpk as compared to the control tumors and by 89%, on average, at 30 mpk as compared to the control tumors.

We have also conducted preclinical studies to test vepdegestrant in a tumor line derived directly from a patient, referred to as a patient derived xenograft, or PDX, model. This model is derived from a tumor with an ESR1 mutation (Y537S), which is a mutation in the ER that occurs in patients who have been treated with standard-of-care agents such as tamoxifen or an aromatase inhibitor, such as letrozole, and has been cited as a mechanism of resistance to those drugs. These studies included a comparison with fulvestrant. In this 28-day dosing study, oral vepdegestrant inhibited tumor growth by 99% at the 10 mpk dosing level and by 106% at the 30 mpk dosing level which was observed to be superior at both dosing levels to a clinically relevant dose of 200 mpk of fulvestrant. Further, vepdegestrant was shown to reduce ER by 79% and 88% at the 10 mpk and 30 mpk dosing levels, respectively, compared with 63% at the 200 mpk of fulvestrant dosing level.

We have also conducted preclinical studies of vepdegestrant in combination with abemaciclib, a CDK4/6 inhibitor that is standard of care when used together with endocrine therapy. In these studies, we have achieved significant tumor shrinkage with vepdegestrant in ER+/HER2- MCF-7 xenograft models. As shown in the figure below, in a 28-day dosing study in MCF-7 xenografts, vepdegestrant at 30 mpk daily in combination with abemaciclib was superior in shrinking tumors, as compared to either abemaciclib as a single agent at 50

mpk daily, or the standard-of-care combination of abemaciclib at 50 mpk daily plus fulvestrant at 200 mpk twice per week for two weeks and then once per week for two weeks.

We conducted similar studies for vepdegestrant in combination with palbociclib or ribociclib in the MCF-7 xenograft model, which demonstrated similar results for improved tumor growth inhibition for vepdegestrant in combination with palbociclib or vepdegestrant in combination with ribociclib relative to single agents or relative to fulvestrant in combination palbociclib or fulvestrant in combination with ribociclib, respectively, as shown in the figures below.

We believe that vepdegestrant also has the potential to show compelling activity in combination with other targeted agents currently used or in clinical trials for locally advanced or metastatic breast cancer including PI3K and mammalian target of rapamycin inhibitors and have tested and plan to continue to test these combinations in preclinical models.

In the second quarter of 2023, we presented vepdegestrant preclinical data at the American Association for Cancer Research annual meeting that demonstrated the potential utility of vepdegestrant as an endocrine therapy backbone for combination with other targeted agents in early and late-stage ER+/HER2- breast cancer and the potential mechanisms of acquired resistance to vepdegestrant that may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery.

In the fourth quarter of 2024, we presented vepdegestrant preclinical data at the San Antonio Breast Cancer Symposium, or SABCS, including vepdegestrant plus CDK4/6 inhibitor combinations in palbociclib-resistant patient derived xenograft, or PDX, models. In one PDX model harboring an ESR1 mutation (Y537S), vepdegestrant demonstrated anti-tumor activity as a single agent as well as enhanced activity in combination with abemaciclib, ribociclib or palbociclib compared to single agents, respectively. In a second PDX model harboring wild-type ESR1, vepdegestrant also demonstrated anti-tumor activity as a single agent as well as enhanced activity in combination with palbociclib. In this second model, both single agent vepdegestrant as well as vepdegestrant plus palbociclib treatment arms demonstrated superior anti-tumor activity relative to fulvestrant treatment alone or fulvestrant treatment plus palbociclib.

Our Clinical Trials

Overview

We, along with Pfizer, have several ongoing clinical trials of vepdegestrant, designed to potentially position vepdegestrant as a backbone ER-targeting therapy in breast cancer, including:

•VERITAC-2, a Phase 3 second/third-line clinical trial evaluating vepdegestrant as a monotherapy, in advanced/metastatic breast cancer patients, for which we completed enrollment of patients in the fourth quarter of 2024;

•VERITAC, a Phase 2 dose expansion trial to evaluate two doses (200 mg and 500 mg) of vepdegestrant monotherapy in metastatic breast cancer patients, for which enrollment of patients is complete;

•TACTIVE-K, a Phase 1b/2 clinical trial of vepdegestrant in combination with Pfizer's CDK4 inhibitor, atirmociclib (PF-07220060), for which we are currently enrolling patients globally;

•TACTIVE-N, a Phase 2 clinical trial of vepdegestrant as a monotherapy in the neoadjuvant breast cancer setting, for which we completed enrollment of patients in the first quarter of 2024;

•TACTIVE-U, Phase 1b/2 clinical trials of vepdegestrant in combination with multiple targeted therapies including abemaciclib, ribociclib or Carrick Therapeutics, Inc.'s, or Carrick, cyclin-dependent kinase 7, or CDK7 inhibitor, samuraciclib, for which we have completed enrollment for the abemaciclib trial and are currently enrolling patients globally for the ribociclib and samuraciclib trials; and

•TACTIVE-E, a Phase 1b clinical trial evaluating vepdegestrant in combination with everolimus in metastatic breast cancer patients, for which enrollment of patients is complete.

•A first-line Phase 3 combination trial with Pfizer’s CDK4 inhibitor, atirmociclib; and

•A second-line Phase 3 combination trial with a CDK/6 inhibitor.

With the prioritization of the vepdegestrant plus atirmociclib combination for the first-line setting, VERITAC-3, a Phase 3 clinical trial evaluating vepdegestrant plus IBRANCE® (palbociclib) in the first-line setting, will not proceed beyond the study lead-in. We and Pfizer had previously gained alignment with the FDA on an approach for VERITAC-3 in the first quarter of 2023, and in the second quarter of 2023, we, along with Pfizer, initiated the study-lead in of the VERITAC-3 Phase 3 clinical trial in combination with palbociclib as a first-line treatment in patients with ER+/HER2- locally advanced or metastatic breast cancer. We completed enrollment of patients in the study lead-in of VERITAC-3 in the second quarter of 2024. The decision to prioritize vepdegestrant in combination with atirmociclib in the first-line setting was based on the totality of evidence from the ongoing Phase 1b/2 TACTIVE-K combination clinical trial evaluating vepdegestrant in combination with atirmociclib in the late-line setting and our trials evaluating vepdegestrant in combination with palbociclib.

VERITAC-2

In the fourth quarter of 2022, we and Pfizer initiated the VERITAC-2 Phase 3 clinical trial with vepdegestrant as a second-line or third line treatment in patients with ER+/HER2- advanced/metastatic breast cancer. VERITAC-2 has two primary endpoints: progression-free survival, or PFS, in the intention-to-treat, or ITT, population, and PFS in the ESR1 mutation sub-population. PFS will be assessed by blinded independent central review. Secondary outcome measures include overall survival; antitumor activity including objective response, duration of response, and clinical benefit rate; and safety and quality of life assessments.

In the third quarter of 2023, we were awarded Innovation Passport Designation for vepdegestrant by the U.K. Innovative Licensing and Access Pathway Steering Group. In the first quarter

of 2024, the FDA granted Fast Track designation for the investigation of vepdegestrant as a monotherapy in the treatment of adults with ER+/HER- locally advanced or metastatic breast cancer previously treated with endocrine based therapy.

We completed enrollment for this clinical trial in the fourth quarter of 2024. We, along with Pfizer, expect to announce topline data from the VERITAC-2 clinical trial in a topline press release in the first quarter of 2025 and present the full results of the VERITAC-2 clinical trial at a medical conference in 2025.

ARV-471-mBC-101, including Part B (VERITAC)

Part A: In 2019, we initiated dosing in a Phase 1 clinical trial for vepdegestrant. The trial is an open-label dose-escalation study in which we treated patients with locally advanced or metastatic ER+/HER2- breast cancer who had progressed on at least two prior endocrine therapy regimens and a CDK4/6 inhibitor. Eligible patients may have also received up to three prior regimens of cytotoxic chemotherapy. Part A was the dose escalation portion of our Phase 1/2 clinical trial of vepdegestrant and was designed to assess the dose-limiting toxicities, safety, tolerability and pharmacokinetics, or PK, of vepdegestrant monotherapy in patients with locally advanced or metastatic ER+/HER2- breast cancer, as well as measures of anti-tumor activity as secondary endpoints. Enrollment in this cohort is complete. Initial data from Part A of this clinical trial were presented at SABCS 2021 and updated results were presented at the European Society for Medical Oncology, or ESMO, in the fourth quarter of 2023.

Part B (VERITAC): In 2021, we initiated VERITAC, the Phase 2 cohort expansion portion of the vepdegestrant clinical trial. The enrollment of patients is complete. We announced initial results from VERITAC in the fourth quarter of 2022 at 2022 SABCS. In VERITAC, patients were treated with either 200 mg or 500 mg vepdegestrant with a primary endpoint of clinical benefit rate, or CBR. Secondary endpoints included overall response rate, or ORR, duration of response, or DOR, progression free survival, or PFS, and overall survival, as well as safety and pharmacokinetics. As of the data cut-off date of June 6, 2022, 71 patients with locally advanced or metastatic ER+/HER2- breast cancer in the VERITAC expansion cohort were treated once-daily with oral doses of vepdegestrant at 200 mg (n=35) or 500 mg (n=36). All patients were previously treated with CDK 4/6 inhibitors; 79% of patients were previously treated with fulvestrant; 73% of patients were previously treated with chemotherapy; and 45% received chemotherapy in the metastatic setting. Patients in VERITAC had a median of four lines of prior therapies.

At the time of data cutoff (June 6, 2022), vepdegestrant administered at 200 mg (n=35) and 500 mg (n=36) demonstrated:

•Antitumor activity in 100% CDK4/6 inhibitor-pretreated patients, as measured by a CBR of 38% (total n=71) in all patients and 51.2% in patients with mutant ESR1 tumors (n=41).

•Preliminary median progression-free survival, or mPFS, of 3.7 months, a key secondary endpoint, in all evaluable patients and 5.7 months in patients with mutant ESR1 tumors (n=41).

•A favorable tolerability profile, with the majority of treatment-related adverse events, or TRAEs, reported as Grade 1 or 2.

In the fourth quarter of 2022, we also announced that in post-hoc analysis from the Phase 2 cohort expansion portion of the VERITAC Phase 1/2 study, a patient subgroup (n=8) with no prior treatment with fulvestrant or chemotherapy in the metastatic setting, which approximated the expected VERITAC-2 Phase 3 trial population, achieved a CBR (rate of confirmed complete response, confirmed partial response, or stable disease ≥ 24 weeks) of 62.5%. All patients were previously treated with CDK 4/6 inhibitors and while the subgroup in the post-hoc analysis was not actively selected by ESR1 status, all 8 patients harbored ESR1 mutations by circulating tumor DNA analysis. mPFS for patients in the post-hoc analysis had not been reached as of the fourth quarter data analysis. Three of the 8 patients discontinued as of November 2022; the 5 continuing on therapy had treatment durations of 8-14 months.

In the fourth quarter of 2023, we and Pfizer presented a VERITAC Phase 2 dose expansion update at 2023 SABCS. The Phase 2 monotherapy dose expansion of the ARV-471-mBC-101 study analyzed the safety, efficacy, and tolerability of vepdegestrant among 35 heavily pre-treated patients

with locally advanced or metastatic ER+/HER2- breast cancer. The update included 12 months of additional follow-up data, and the tolerability and efficacy profile remained largely consistent with previous data disclosures. In addition, in post-hoc analysis, of the eight patients in the VERITAC Phase 2 trial who would meet eligibility criteria for Phase 3 VERITAC-2 trial (no prior fulvestrant, no prior chemotherapy for locally advanced or metastatic disease), CBR was 62.5% or 5 of 8 patients, PFS was 19 months or four of eight events and the ORR was 29% or two confirmed responses in seven evaluable patients.

Part C: In 2021 we initiated a Phase 1b cohort to evaluate vepdegestrant in combination with palbociclib.

In the second quarter of 2023, we evaluated and announced preliminary results from the Part C dose escalation portion of the Phase 1b/2 clinical trial. Preliminary results from the Part C dose escalation trial, announced in the first quarter of 2023, (November 2022 data cut-off from the Phase 1b combination of vepdegestrant with palbociclib at 125 mg) demonstrated an observed CBR (rate of confirmed complete response, confirmed partial response, or stable disease ≥24 weeks) of 60.7% (95% CI, 40.6 – 78.5) across all dose cohorts (17 of 28 CBR-evaluable patients; patients are CBR-evaluable if they received their first dose >24 weeks prior to the cut-off). In particular, as announced in the second quarter of 2023, 85.7% of the 28 CBR-evaluable patients had received CDK4/6 inhibitor therapy prior to study entry. These data showed an increase in palbociclib exposure relative to historical palbociclib pharmacokinetic data. A similar overall safety profile was observed compared with that reported in our previous palbociclib and endocrine therapy combination studies, except for a higher incidence of grade 3/4 neutropenia, which was managed by monitoring and dose modification per the palbociclib label. Patients were started on palbociclib 125 mg irrespective of dose reduction during prior CDK4/6 inhibitor therapy.

In the fourth quarter of 2023, at the 2023 SABCS, we, along with Pfizer, presented preliminary data from the Phase 1b cohort of the first-in-human ARV-471-mBC-101 trial evaluating vepdegestrant in combination with palbociclib. Data from this clinical trial (data cut-off of June 6, 2023) assessed the safety, tolerability and anti-tumor activity of the combination among 46 patients with heavily pre-treated locally advanced or metastatic ER+/HER2- breast cancer. A similar overall safety profile was observed compared with that reported in previous palbociclib and endocrine therapy combination studies, except for a higher incidence of grade 3/4 neutropenia, which was managed by monitoring and dose modification per the palbociclib label. Patients were started on palbociclib 125 mg irrespective of dose reduction during prior CDK4/6 inhibitor therapy.

In the second quarter of 2024, we, along with Pfizer, presented updated clinical data from this clinical trial at the 2024 ESMO Breast Cancer Annual Congress. After six months of additional follow-up (data cutoff of December 18, 2023), these data were consistent with data presented at the 2023 SABCS in the fourth quarter of 2023, and showed that vepdegestrant in combination with palbociclib continued to demonstrate encouraging clinical activity in heavily pre-treated patients with a median of four lines of prior therapy with locally advanced or metastatic ER+/HER2- breast cancer.

Specifically, after six months of additional follow-up, updated data from the trial continued to demonstrate an encouraging CBR (63% across all dose levels (n=46)), ORR (42% in evaluable patients with measurable disease at baseline (n=31)) and median PFS (11.2 months (95% CI; 8.2 - 16.5) based on 27 (59%) events across all dose levels), and consistent safety profile of vepdegestrant in combination with palbociclib as previously reported at SABCS in December 2023. In addition, at the recommended Phase 3 dose, or RP3D, of 200 mg vepdegestrant in combination with 125 mg palbociclib, patients (n=21) achieved a median PFS of 13.9 months (95% CI: 8.1-NR). Further, across all vepdegestrant dose groups, circulating tumor DNA analyses showed marked reduction in tumor fraction after one treatment cycle, regardless of ESR1 gene mutation status, and at the 200 mg vepdegestrant dose, robust on-treatment decreases in mutant ESR1 circulating tumor DNA were sustained through multiple treatment cycles.

At the time of cut-off, patients in the study received a median of four prior therapies (median of three in the metastatic setting); 87% were previously treated with a CDK 4 and 6, or CDK4/6, inhibitor; 80% were previously treated with fulvestrant; and 78% were previously treated with chemotherapy,

including 48% in the metastatic setting. Patients were treated once daily with oral doses of vepdegestrant at 180 mg (n=2), the RP3D of 200 mg (n=21), 400 mg (n=3) or 500 mg (n=20), plus 125 mg of palbociclib given orally once daily for 21 days, followed by seven days off treatment in 28-day cycles. Detailed data presented at the 2024 ESMO Breast Cancer Annual Congress included:

Clinical Benefit Rate:

•CBR, defined as the rate of confirmed complete response, partial response, or stable disease ≥24 weeks across all dose levels (n = 46) was 63% (95% CI: 47.5 - 76.8), with a CBR of 72% in patients with mutant ESR1 (n=29; 95% CI: 52.8 - 87.3) and a CBR of 53% in patients with wild-type ESR1 (n=15; 95% CI: 26.6 – 78.7).

•CBR in patients dosed at the RP3D of 200 mg (n=21) was 67% (95% CI: 43.0 - 85.4) with a CBR of 79% in patients with mutant ESR1 (n=14; 95% CI: 49.2 - 95.3) and a CBR of 43% in patients with wild-type ESR1 (n=7; 95% CI: 9.9 - 81.6).

Objective Response Rate and Duration of Response:

•The ORR in evaluable patients with measurable disease at baseline (n=31) was 42% (95% CI: 24.5 - 60.9) with a median DOR in 13 responders of 14.6 months (95% CI: 9.5 – not reached). At the RP3D of 200 mg (n=15), the ORR was 53% (95% CI: 25.6 – 78.7).

•ORR in patients with mutant ESR1 (n=17): 47% (95% CI: 23.0 - 72.2).

▪ORR at the RP3D of 200 mg (n=10): 60% (95% CI: 26.2 - 87.8).

•ORR in patients with wild-type ESR1 (n=12): 42% (95% CI: 15.2 - 72.3).

▪ORR at the RP3D of 200 mg (n=5): 40% (95% CI: 5.3 - 85.3).

Progression-free Survival:

•Median PFS, or mPFS, based on 27 (59%) events across all dose levels was 11.2 months (95% CI: 8.2 – 16.5) with a mPFS of 13.7 months (95% CI: 8.2 - NR) in patients with ESR1 mutation (n=29) and mPFS of 11.1 months (95% CI: 2.8 - 19.3) in patients with wild-type ESR1 (n=15).

•mPFS in patients dosed at the RP3D of 200 mg (n=21) based on 12 events (57%) was 13.9 months (95% CI: 8.1 - NR) with a mPFS of 13.9 months (95% CI: 8.1 - NR) in patients with ESR1 mutation (n=14) and mPFS of 11.2 months (95% CI: 1.8 - NR) in patients with wild-type ESR1 (n=7).

Circulating Tumor DNA:

•Exploratory ctDNA analyses found marked reduction (median change, −98.9%) in tumor fraction after one treatment cycle (all dose groups) regardless of ESR1 mutant status and robust on-treatment decreases in mutant ESR1 ctDNA levels sustained through cycle 7 (evaluated in patients in 200 mg dose cohort), as presented in the poster session.

Safety Profile:

•The safety profile of vepdegestrant in combination with palbociclib was consistent with what was previously reported with Grade 3/4 treatment-related adverse events, or TRAEs, ≥10% of neutropenia (91%) and decreased white blood cell count (15%); no grade 5 TRAEs or febrile neutropenia were reported.

•The majority of Grade 4 neutropenia events occurred in the first cycle of treatment and occurrences of Grade 3/4 neutropenia decreased following palbociclib dose reductions as described in the prescribing label.

•The safety profile of vepdegestrant in combination with palbociclib was otherwise consistent with the profile of palbociclib and what has been observed in other clinical trials for vepdegestrant. Three of 46 patients discontinued palbociclib due to neutropenia including one out of 21 patients treated with the RP3D of vepdegestrant (200 mg) plus palbociclib 125 mg.

TACTIVE-K

In the third quarter of 2023, we received a Study May Proceed letter from the FDA for the planned Phase 1b/2 clinical trial evaluating vepdegestrant in combination with Pfizer's CDK4 inhibitor, atirmociclib, and we initiated this trial in the fourth quarter of 2023. In the first quarter of 2024, we initiated dosing for TACTIVE-K. We expect to continue to enroll patients to the TACTIVE-K Phase 2 clinical trial in 2025 and evaluate preliminary data from this clinical trial. We expect to submit initial Phase 1b data for presentation at medical conference.

TACTIVE-N

In the fourth quarter of 2022, we initiated sites for TACTIVE-N, a Phase 2 clinical trial with vepdegestrant as a monotherapy in patients with early breast cancer in the neoadjuvant setting. We completed enrollment of patients in this clinical trial in the first quarter of 2024.

TACTIVE-U

The TACTIVE-U umbrella clinical trial is divided into separate sub-studies focused on learning about the safety and efficacy of the investigational medicine vepdegestrant when given together with other medicines for potential treatment of advanced or metastatic breast cancer that has worsened after prior treatment. Sub-Study A is a clinical trial evaluating vepdegestrant in combination with abemaciclib, a CDK4/6 inhibitor; Sub-Study B is a clinical trial evaluating vepdegestrant in combination with ribociclib, a CDK4/6 inhibitor; and Stub-study C is a clinical trial evaluating vepdegestrant in combination with samuraciclib, a CDK7 inhibitor.

We and Pfizer initiated the clinical trial of vepdegestrant in combination with abemaciclib in the fourth quarter of 2022 and the clinical trial of vepdegestrant in combination with ribociclib in the first quarter of 2023. We entered into a collaboration agreement with Pfizer and Carrick to evaluate samuraciclib in combination with vepdegestrant in the second quarter of 2023, and initiated the Phase 1b combination clinical trial with Carrick's CDK7 inhibitor in the first quarter of 2024. Enrollment for the abemaciclib study is complete. The TACTIVE-U studies with ribociclib and samuraciclib remain open for enrollment.

In the fourth quarter of 2024, we and Pfizer announced initial safety and pharmacokinetic data (data cut-off: August 30, 2024) from the TACTIVE-U sub-study of abemaciclib at the 2024 SABCS. Preliminary results from 16 patients in the Phase 1b sub-study demonstrated a tolerable safety profile for the combination of abemaciclib 150 mg twice daily with the recommended 200mg once daily Phase 3 monotherapy dose of vepdegestrant. Pharmacokinetic data demonstrated no significant drug-drug interaction between vepdegestrant and abemaciclib and no clinically meaningful effect on abemaciclib exposure was observed. Below are the key findings included in the poster:

•100% of patients had prior treatment with a CDK4/6 inhibitor.

•Tolerability is generally consistent with the profile of abemaciclib and with results previously observed in other clinical trials of vepdegestrant. The most common any grade treatment-related adverse events, or TRAE, were diarrhea, nausea and fatigue. There were no dose-limiting toxicities and no grade 4 or 5 TRAEs.

•There was no significant drug-drug interaction, and data reflected vepdegestrant had no clinically meaningful effect on abemaciclib exposure.

•The CBR (CBR, defined as the rate of confirmed complete response, partial response, or stable disease ≥ 24 weeks) was 62.5% in all CBR-eligible patients (10/16), 62.5% in patients with mutant ESR1 (5/8), and 62.5% in patients with wild-type ESR1 (5/8).

•The ORR in evaluable patients was 26.7% overall (4/15), 37.5% in patients with mutant ESR1 (3/8), and 14% in patients with wild-type ESR1 (1/7).

•Five patients remained on study treatment as of the August 30, 2024 data cut-off.

These data support the ongoing Phase 2 portion of the TACTIVE-U clinical trial, which is evaluating full dose abemaciclib (150mg twice daily) in combination with vepdegestrant (200 mg once daily) in post-CDK4/6 inhibitor treated advanced breast cancer.

We expect to continue to collect safety and efficacy data from ongoing TACTIVE-U clinical trial sub-studies evaluating combinations of vepdegestrant with abemaciclib, ribociclib, or samuraciclib in 2025 and submit key data for presentation at a medical conference.

TACTIVE-E

In the third quarter of 2022, we initiated TACTIVE-E, a Phase 1b clinical trial with vepdegestrant in combination with everolimus, a mammalian target of rapamycin protein inhibitor, in patients with metastatic breast cancer. Enrollment of patients for this clinical trial is complete.

I-SPY-2

In the second quarter of 2023, we announced the inclusion of vepdegestrant in the I-SPY-2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) Endocrine Optimization Platform (EOP) trial sponsored by Quantum Leap. The I-SPY-2 EOP trial includes three arms containing vepdegestrant; a monotherapy arm, a vepdegestrant plus letrozole arm, and a vepdegestrant plus abemaciclib arm. We announced inclusion of the abemaciclib arm in the third quarter of 2023.

Other Clinical Trials

In the third quarter of 2022, we initiated, with Pfizer, a Phase 1b trial of vepdegestrant as a monotherapy in Japanese patients.

Also, in the fourth quarter of 2024, we presented data from the Phase 1 clinical pharmacology study of vepdegestrant in combination with midazolam to access potential for drug-to-drug interaction at the 2024 SABCS.

Hematology Program: ARV-393

Patient Population and Market Opportunity

There are approximately 80,000 new cases and 20,000 deaths in the U.S. related to NHL annually. NHL is a heterogeneous group of diseases, with large B-cell lymphoma, or LBCL, and follicular lymphoma, or FL, being the most common subtypes. Each subtype has a distinct biologic and clinical characteristics and requires different approaches to treatment. Unmet medical needs include managing aggressive subtypes, treatment resistance, and improving outcomes for older patients.

In particular, we believe our PROTAC BCL6 degrader could be a potential therapy for diffuse large B-cell lymphoma, or DLBCL, a sub-set of NHL, often associated with deregulated BCL6 expression and/or functions. More than 25,000 patients are diagnosed with DLBCL each year in the U.S. Treatment for DLBCL is largely devoid of oral options and there are currently no approved BCL6-targeted therapies on the market or in the clinic. NHL originates from B cells, T cells, and/or natural killer cells, with those of B-cell origin constituting approximately 80%–85% of all NHL cases. We believe additional opportunities for a BCL6 degrader exist in FL

and Angioimmunoblastic T-cell lymphoma. BCL6 may also be a clinically relevant therapeutic target in other hematologic malignancies, some solid tumors and B-cell driven autoimmune diseases.

Preclinical and Clinical Development

Based on our preclinical models, complete tumor stasis, which correlates with 95%-100% degradation of measurable BCL6, was achieved when our oral, BCL6-targeting PROTAC clinical candidate was taken at low, oral daily doses. We saw similar activity in multiple DLBCL models, including for activated B-cell and germinal center B-cell lymphoma.

In the second quarter of 2024, we presented preclinical data for ARV-393 at the European Hematology Association 2024 Annual Congress, which showed anti-tumor activity in preclinical models of B-cell lymphoma. In these preclinical models, ARV-393 potently and rapidly degraded the BCL6 protein and inhibited cell growth in DLBCL and Burkitt cell lines. ARV-393 showed tumor growth inhibition, including tumor regression, in various DLBCL cell line-derived xenograft models and in multiple patient-derived xenograft models of NHL including germinal center B-cell-like, or GCB, activated B-cell, or ABC, GCB/ABC, and BCL not otherwise specified subtypes of DLBCL, and Burkitt lymphoma. We plan to present preclinical data of ARV-393 in combination with standard of care biologic agents and small molecule inhibitors in high grade and aggressive diffuse large B-cell lymphoma in vivo models at the AACR Annual Meeting in the second quarter of 2025.

In the first quarter of 2024, we announced that the FDA cleared our IND for ARV-393. We initiated our first-in-human Phase 1 clinical trial of ARV-393 in patients with relapsed or refractory NHL in the second quarter of 2024 and are currently recruiting patients for this clinical trial. This is an open-label, multicenter, Phase 1 dose escalation study to evaluate the safety, tolerability and preliminary anti-tumor activity of ARV-393 as a single agent in adult patients with relapsed/refractory NHL. Going forward, we expect to continue recruiting patients for this clinical trial and plan to disclose preliminary data from the ongoing Phase 1 clinical trial in patients with NHL in 2025.

Neuroscience Program: ARV-102

ARV-102 is our first oral PROTAC protein degrader in development to treat neurodegenerative diseases. In preclinical studies, ARV-102 has been shown to cross the blood-brain barrier and degrade LRRK2, which is a large multidomain scaffolding kinase. In human genetics, single cell ribonucleic acid sequencing from post-mortem PD brain samples and protein data from PD patient derived induced pluripotent stem cell microglia suggest that increased activity and expression of LRRK2 are genetically involved in the pathogenesis of neurological diseases including PSP and PD.

Patient Population and Market Opportunity

PD is the second most common neurodegenerative disease after Alzheimer's disease, affecting approximately 1 million people in the U.S. and more than 10 million people world-wide. Nearly 90,000 people in the U.S. are diagnosed with PD each year. It is commonly thought of as a movement disorder because patients can experience tremors, slowness of movement, stiffness and difficulty with walking and balance. In addition, PD patients can have other non-motor type problems such as constipation, depression and memory loss. PD results from the loss of dopamine-producing cells in the brain and is likely caused by a combination of genetic and environmental risk factors. No disease-modifying therapies have been approved for patients with PD.

Mutations in the LRRK2 gene are one of the most common genetic risk factors for PD. LRRK2 is a multidomain GTPase/kinase that acts, in part, as a scaffolding protein to interact with components of downstream signaling pathways regulating lysosomal function, mitochondrial processes, neuroinflammation and alpha-synuclein accumulation to negatively impact neuronal survival. Human genetics in the form of a protective PD variant (N551K/R1398H) and preclinical animal model data suggest that a reduction of 50% of LRRK2 protein, but not kinase inhibition, may impact pathology and dysfunction in PD. Therefore, reduction of LRRK2 in the brain may be beneficial for the treatment of PD. We have identified potent, selective, orally bioavailable LRRK2 PROTAC protein degraders that cross the blood-brain barrier in preclinical species and are biodistributed to deep brain regions impacted in PD.

PSP is a rare progressive neurological disorder that affects movement, balance and cognitive function. Emerging research suggests that LRRK2 plays a role in PSP by contributing to disease mechanisms such as neuroinflammation and cellular dysfunction. LRRK2 is involved in immune system regulation and may influence tau protein accumulation, a hallmark of PSP. It also plays a role in autophagy and inflammation, which could contribute to neurodegeneration seen in PSP. Additionally, variants in the LRRK2 gene have been associated with PSP progression and survival. Approximately 30,000 to 40,000 people in the U.S. are diagnosed with PSP each year. It is currently estimated that 10 to 12 people per 100,000 are living with PSP. There are currently no approved disease-modifying therapies that halt or delay PSP progression and which often leads to patients progressing with time to death within 5 to 7 years.

Preclinical and Clinical Development

ARV-102, our oral PROTAC LRRK2-targeting protein degrader clinical candidate, has been shown preclinically to broadly bio-distribute to deep brain regions and degrade LRRK2 more than 85% in non-human primates, or NHPs.

In the second quarter of 2024, we presented preclinical data at the Biennial International LRRK2 Meeting, which further supported PROTAC-induced LRRK2 degradation as a potential treatment for neurodegenerative diseases. The preclinical data presented highlighted, with our PROTAC LRRK2 degrader, near complete LRRK2 target engagement, as well as LRRK2 degradation, in mouse and NHP lung and brain. The preclinical data also showed differing effects of the PROTAC LRRK2 degraders in the lungs compared to kinase inhibitors, suggesting reduced pulmonary function risk, including:

•substantially less Type II pneumocyte enlargement compared to MLi-2, an experimental LRRK2 kinase inhibitor;

•surfactant protein accumulation in mouse lung was observed after treatment with the LRRK2 kinase inhibitor MLi-2, but not after treatment with the PROTAC LRRK2 degrader; and

•no evidence of collagen deposition in lung to date with PROTAC LRRK2 degraders in NHPs.

In October 2024, we presented preclinical data at the 2024 Michael J. Fox Foundation Parkinson’s Disease Conference further supporting the potential of PROTAC-induced LRRK2 degradation as a potential treatment for patients with neurodegenerative diseases. New findings presented included data demonstrating:

•orally delivered ARV-102 crossed the blood-brain barriers and degraded LRRK2 in the cerebrospinal fluid, or CSF, of NHPs;

•degradation of LRRK2 by ARV-102 induced changes in pathway (lysosomal and inflammation) biomarkers in the CSF of NHPs, which has not previously been demonstrated by kinase inhibitors of LRRK2; and

•in murine tauopathy models, oral PROTAC LRRK2 degrader treatment led to ~50% pathologic tau reduction.

The European Medicines Agency cleared our clinical trial application for ARV-102 in the fourth quarter of 2023. We currently are conducting two clinical trials with ARV-102, a Phase 1 clinical trial in healthy volunteers and a Phase 1 clinical trial in patients with PD.

We initiated the first-in-human Phase 1 clinical trial for ARV-102 in the first quarter of 2024. The trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARV-102, including the evaluation of LRRK2 degradation and exploratory LRRK2 pathway biomarkers. In the second quarter of 2024, we received health authority approval to initiate the multiple ascending dose, or MAD, portion of the ongoing Phase 1 clinical trial of ARV-102 in healthy volunteers, and we initiated the MAD portion of this clinical trial in the third quarter of 2024. We completed enrollment of this MAD cohort in the first quarter of 2025.

We completed enrollment in the SAD portion of the Phase 1 clinical trial of ARV-102 in healthy volunteers at the Centre for Human Drug Research in Leiden, the Netherlands in the third quarter of 2024. We plan to present SAD data from the ongoing Phase 1 clinical trial of ARV-102 in healthy volunteers in an oral session at the Alzheimer’s Disease/Parkinson’s Disease (AD/PD) conference in Vienna, Austria in the second

quarter of 2025, demonstrating bioavailability and brain penetration with dose dependent exposure in cerebral spinal fluid, or CSF, and degradation of LRRK2 in the periphery and CSF of healthy volunteers.

In the fourth quarter of 2024, we initiated dosing of the first patients with PD in the SAD portion of the Phase 1 clinical trial of ARV-102. We plan to complete enrollment and present initial data from the ongoing SAD Phase 1 clinical trial of ARV-102 in patients with PD and initiate the MAD portion of the Phase 1 clinical trial in patients with PD in 2025.

Our Preclinical Programs

We have active preclinical programs and in line with our therapeutic strategies in oncology and neurologic disorders, we assess potential exploratory programs on a target-by-target basis to decide whether our PROTAC targeted protein degraders provide a compelling differentiated approach over standard-of-care or other, existing or potential competing mechanisms of action directed against a specific target. In the case of currently or historically undruggable targets, we assess whether the features of our PROTAC targeted protein degraders, including their potential to degrade proteins via sites other than enzymatic active sites and the ability to initiate the degradation process using only weak binders, offer us opportunities to degrade those targets.

Oncology

KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. Preclinically, our degrader is a highly selective and potent molecule that demonstrates dose-responsive degradation of KRAS G12D, leading to robust antitumor activity in KRAS G12D mutated cancers including pancreatic and colorectal cancers. In the second quarter of 2023, we presented in vivo and in vitro data at the AACR - Targeting RAS Special Conference that demonstrated that our PROTAC KRAS G12D degraders were potent, selective and led to tumor stasis in a mouse xenograft model with intermittent dosing and degradation of KRAS G12D that provides an advantage versus inhibition in vitro and in vivo. Our degrader is designed to eliminate, rather than inhibit, KRAS G12D and, in preclinical studies, it was 30-fold more potent than an inhibitor in vitro and provides additional aspects of differential biology contributing to its potent and broad antitumor effect in vivo. Our KRAS G12D program is currently in preclinical development and we anticipate filing an IND application for our PROTAC KRAS G12D degrader in 2025.

Our exploratory and research activities in oncology include programs directed to degrade KRAS, as noted above; Myc, an oncogenic transcription factor driving tumor cell proliferation; and hematopoietic progenitor kinase 1, a suppressor of T cell activation.

Neurologic Diseases

Neurologic diseases, in particular, neurodegenerative diseases, are generally progressive in nature and result in the degeneration and often death of neurons in the brain, leading to cognitive decline, functional impairment and eventually death. These diseases affect a rapidly growing patient population and represent one of the largest unmet medical needs of our time. Alzheimer’s and PD encompass the largest patient populations among the neurodegenerative diseases. The Alzheimer’s Association estimated that 6.9 million Americans aged 65 and older, about one in nine individuals, were living with Alzheimer’s dementia in 2024, with 73% aged 75 or older, and the Parkinson’s Foundation estimated that nearly one million Americans are living with PD. Alzheimer’s disease is marked by the progressive accumulation of aggregated tau protein, while aggregation of alpha-synuclein is thought to cause PD.

Antibody or aggregation inhibitor-based therapies targeting these proteins thought to be the cause of these neurodegenerative diseases have failed to show clinically meaningful benefit to date. While some existing products provide symptomatic relief to Alzheimer’s and PD patients, they have significant side effect risks and over time gradually lose their effectiveness in treating the symptoms of the disease. Further, while there are now amyloid-directed antibody therapies that modestly impact extracellular A-beta with vascular side effects that can be severe, there are no approved disease-modifying treatments targeting intracellular tau or alpha-synuclein for Alzheimer’s or PD.

Developing PROTAC Targeted Protein Degraders that Cross the Blood Brain Barrier

Engineering PROTAC degraders that cross the blood-brain barrier is necessary to achieve targeted elimination of disease-causing intracellular proteins from within the CNS. The ability of a targeted therapy to cross the blood-brain barrier is a highly desirable characteristic in developing effective therapeutics for patients with neurodegenerative diseases as compared with therapies delivered directly into the CNS via invasive intrathecal delivery. Any product candidates for neurodegenerative disease must reach their intended intracellular targets in the brain at exposure levels that will provide a therapeutic effect, while having an acceptable safety profile.

Importantly, we have achieved brain penetration in preclinical models following parenteral administration of PROTAC degrader molecules. These PROTAC degrader molecules achieved concentrations in the brain sufficient to induce degradation of the aggregated proteins, widespread penetration into different parts of the brain, and brain/plasma ratios of 0.5 to 5.0, comparable to approved therapeutics with CNS activity. Our research efforts are aimed at designing PROTAC degraders to either specifically target pathologic oligomers or monomers of mutant huntingtin, tau, and α-synuclein, for the treatment of Huntington's disease, Alzheimer’s disease (tauopathies) and PD (synucleinopathies), respectively, or to impact pathway proteins contributing to their pathology in these diseases.

Developing PROTAC Targeted Protein Degraders that Degrade Proteins Associated with Neurodegenerative Diseases

We have conducted preclinical studies to establish the potential of our PROTAC Discovery Engine in the CNS for the treatment of neurodegenerative diseases, including tauopathies, the largest of which is Alzheimer’s disease. We have demonstrated that tau PROTAC protein degrader molecules could be dosed peripherally and degrade pathogenic tau in the brain of mouse tauopathy models.

In preclinical studies, we have demonstrated that alpha-synuclein PROTAC degraders can specifically degrade aggregated forms of the protein. We have conducted in vitro experiments in cells expressing the A53T mutant form of alpha-synuclein, a mutation that causes aggregation of alpha-synuclein and early-onset PD in patients. We treated these cells with alpha-synuclein targeting PROTAC degraders at 1 μM for 48 hours.

In addition to our tau and alpha-synuclein programs, our neuroscience pipeline includes a program directed to mutant huntingtin, or mHTT, a key protein target for Huntington’s disease. We have identified ligands that bind to mutant mHTT protein without binding to wild-type HTT protein in preclinical studies. This selectivity differentiates these ligands from other small molecule splice modulators that reduce both mHTT and wild-type HTT protein. We believe that our discovery of selective mHTT PROTAC degraders has the potential to eliminate the toxic mHTT protein that causes this devastating disease. In our preclinical neurology research efforts, we have expanded our focus into additional mechanisms that contribute to the pathologic dysfunction in the brain including those that contribute to neuroinflammation and aging.

Other Programs: Luxdegalutamide (ARV-766) and bavdegalutamide (ARV-110)

We had been developing luxdegalutamide (ARV-766) and bavdegalutamide (ARV-110), each an investigational, orally bioavailable, AR degrading PROTAC targeted protein degrader, for the treatment of men with mCRPC. Both luxdegalutamide (ARV-766) and bavdegalutamide (ARV-110) demonstrated activity in preclinical models of AR overexpression and AR mutations, both common mechanisms of resistance to current standard-of-care agents in men with prostate cancer. We believe that the differentiated PROTAC pharmacology of luxdegalutamtide (ARV-766) and bavdegalutamide (ARV-110), including their iterative activity, has the potential to translate into significantly improved clinical outcomes over current standard-of-care agents. However, our clinical data showed signals of improved tolerability and efficacy with luxdegalutamide (ARV-766) as compared to bavdegalutamide. In addition, luxdegalutamide (ARV-766) activity in late-line settings suggested additional potential benefit in earlier-line, less pretreated patients. As such, early in the fourth quarter of 2023, we determined to prioritize the initiation of a Phase 3 clinical trial with luxdegalutamide (ARV-766) in mCRPC instead of the previously planned Phase 3 clinical trial for bavdegalutamide. While we expect to continue ongoing trial activities with bavdegalutamide (ARV-110-101 and ARV-110-103), we will not be enrolling new patients in these clinical trials and expect to wind down our bavdegalutamide program after completion of these clinical trials.

In the second quarter of 2024, we entered into and closed the Novartis Transaction, including both the Novartis License Agreement and the Novartis Asset Agreement with Novartis. Pursuant to the Novartis License Agreement, we granted Novartis an exclusive worldwide license for the development, manufacture and commercialization of ARV-766, our second generation PROTAC AR degrader for patients with prostate cancer and, as of December 31, 2024, we have completed the transition of our ongoing and planned clinical trials of luxdegalutamide (ARV-766) to Novartis. Pursuant to the Novartis Asset Agreement, we sold Novartis all of our rights, title and interest in our PROTAC protein degrader targeting AR-V7, a splice variant of the AR.

Prostate Cancer - Patient Population and Market Opportunity

In the United States, prostate cancer is the second leading cause of cancer death in men. Current estimates predict that one in eight men will be diagnosed with prostate cancer in their lifetime. The American Cancer Society estimates that in 2025 in the United States there will be approximately 313,780 new cases of prostate cancer and approximately 35,770 deaths from the disease. Prostate cancer is the second-leading cause of cancer death in American men, behind only lung cancer. The American Cancer Society estimates that about one in 44 men will die of prostate cancer. Men with mCRPC have a poor prognosis and a predicted survival rate of just over two years from the initial time of progression.

Treatment options for prostate cancer depend on many different factors, including the stage of the cancer. Castration-resistant prostate cancer is defined by disease progression despite androgen deprivation therapy, or ADT, and is often indicated by rising levels of PSA. In making treatment evaluations, physicians monitor disease burdens in several ways, including changes in PSA levels. Increased PSA blood levels are considered by many physicians as indicative of cancer progression, and alternative treatment options may be considered. Current standard of care for men with castration-resistant prostate cancer provides that patients should initially receive a combination of ADT and either abiraterone, which works by decreasing androgen levels, or enzalutamide, which works by blocking androgen binding to AR. If the disease progresses despite these second-generation hormonal therapies, chemotherapy is considered the next treatment option. Treatment with chemotherapy is generally postponed for as long as possible due to the potential for severe side effects including neuropathies, nausea, diarrhea, decreased mental capacity and increased risk of infections.

AR remains the principal driver of castration-resistant prostate cancer progression during the transition from localized to metastatic disease, with AR gene amplification occurring in 40% to 60% of patients, amplification of a transcription regulatory region upstream of the AR gene occurring in 70% to 87% of patients, and AR point mutations occurring in approximately 15% of patients. Between 15% to 25% of patients do not respond to either abiraterone or enzalutamide and the vast majority of the responsive patients will ultimately become resistant, resulting in limited survival. There remains meaningful unmet medical need in the treatment paradigm of mCRPC, including a significant underserved set of patients who are or become resistant to current therapies. Based on our preclinical data, we believe our AR-targeting PROTAC protein degraders may overcome these known resistance mechanisms and create meaningful clinical benefit for patients.

Bavdegalutamide Preclinical and Clinical Development

We have conducted a comprehensive preclinical program to study bavdegalutamide as a potential treatment for men with mCRPC. In in vitro models, bavdegalutamide degraded 95% to 98% of AR in multiple cell lines typically used in prostate cancer research. Bavdegalutamide is also highly selective for AR. A proteomic analysis of VCaP cells treated in vitro with bavdegalutamide at a 10 nM concentration for eight hours demonstrated that only AR was degraded from the nearly 4,000 measured proteins.

Importantly, in addition to AR degradation and selectivity, we have observed in preclinical studies the ability of bavdegalutamide to potently inhibit prostate cancer cell growth and reduce PSA levels. In addition to guiding treatment decisions, reduction in PSA is often an indicator of the effectiveness of treatment in clinical trials, however, it is not recognized as a surrogate endpoint for purposes of regulatory approval. For example, bavdegalutamide demonstrated equivalent reduction in PSA to enzalutamide at ten-fold lower concentration levels in an in vitro inhibition study of PSA synthesis in Lymph Node Cancer of the prostate cells, which are androgen-sensitive human prostate adenocarcinoma cells, that have been engineered to overexpress AR.

In in vivo mouse models, bavdegalutamide has inhibited AR-dependent tumor growth in a statistically significant manner. Bavdegalutamide exhibited superior tumor growth inhibition compared to enzalutamide in both castrated and intact (non-castrated) xenograft models derived from VCaP cell lines.

To assess the ability of bavdegalutamide to treat enzalutamide-resistant cancers, we conducted in vivo studies of bavdegalutamide in an enzalutamide-resistant VCaP xenograft model. These VCaP tumors acquired resistance to enzalutamide after being continuously propagated in castrated, enzalutamide treated mice for approximately three years. We observed that tumors in mice dosed with enzalutamide grew at nearly the same rate as tumors in mice dosed only with the drug vehicle - a control similar to dosing a placebo. Orally delivered bavdegalutamide significantly inhibited tumor growth, described as tumor growth inhibition, or TGI, in these enzalutamide-resistant VCaP tumors.

We have also conducted preclinical studies of bavdegalutamide for enzalutamide-insensitive tumors. We conducted an in vivo study in a PDX model that is derived from a tumor from a patient not treated with enzalutamide but that is insensitive to enzalutamide and showed that tumors in mice dosed with enzalutamide grew at only a slightly slower rate than tumors in mice dosed only with the drug vehicle. In contrast, orally delivered bavdegalutamide significantly inhibited tumor growth in these enzalutamide-insensitive tumors, achieving a TGI value of 100%. Further, PSA levels in the plasma of mice following 20 days of bavdegalutamide dosing significantly decreased in comparison to those dosed with only the drug vehicle or enzalutamide. We believe the activity of bavdegalutamide in the VCaP and PDX models may closely reflect enzalutamide resistance or insensitivity in the clinic and shows the potential for treatment of patients whose tumors have become resistant to, or demonstrate intrinsic resistance to, a current standard-of-care agent. Bavdegalutamide was shown to reduce the levels of PSA in plasma comparable to levels achieved with enzalutamide in a different VCaP xenograft mouse model but at a lower dosing level.

In 2019, we initiated dosing in a Phase 1 clinical trial of bavdegalutamide. Our Phase 1 trial was designed as an open label, dose-escalation study of bavdegalutamide in men with mCRPC whose disease had progressed on at least two prior systemic therapies, one of which must have been enzalutamide or abiraterone. The Phase 1 trial was designed to primarily investigate the safety and tolerability of bavdegalutamide. Secondary endpoints included characterization of bavdegalutamide’s pharmacokinetic profile and preliminary assessment of biochemical and clinical activity based on evaluation of PSA levels, and radiographic measurement of evaluable lesions. The anti-tumor effects of bavdegalutamide in measurable lesions were assessed using RECIST, a standardized set of rules for response assessment based on tumor shrinkage which is widely used in oncology clinical trials. We also evaluated exploratory markers of disease burden, such as circulating tumor cell enumeration, as exploratory endpoints of the trial.

A potential drug-drug interaction between bavdegalutamide and rosuvastatin, or ROS, was identified during the trial. One patient receiving 280 mg bavdegalutamide experienced a Grade 4 dose-limiting toxicity of elevated aspartate transaminase/alanine transaminase, or AST/ALT, liver enzymes followed by acute renal failure. A second patient, receiving 70 mg bavdegalutamide, experienced a Grade 3 AST/ALT elevation, which resolved after the removal of ROS, and the patient was retreated with bavdegalutamide. Follow-up exploratory findings indicate that ROS concentrations, but not bavdegalutamide concentrations, were elevated in both patients who had liver function test increases. Subsequent in vitro transport pump studies indicated that bavdegalutamide inhibited breast cancer resistant pump transporter, of which ROS is a substrate. Following the initial data that supported a potential interaction with ROS, concomitant use of ROS was precluded.

In 2020, we amended the protocol for our Phase 1 clinical trial for bavdegalutamide to include the addition of a Phase 2 expansion cohort. Based on our observations of a molecularly defined, late-line population with a particularly strong response to bavdegalutamide in the Phase 1 portion of the trial, we designed our Phase 2 dose expansion to assess bavdegalutamide in four specific subgroups: patients with tumors with AR T878X (T878X = T878A or T878S) and/or H875Y mutations but excluding other AR variants; patients with tumors with wild-type AR or AR alterations other than T878X, H875Y, L702H, and AR-V7; patients with tumors with AR-V7 or L702H, which are variants of AR that, preclinically, bavdegalutamide did not degrade, or did not degrade potently, respectively; and patients with biomarker agnostic tumors treated with no more than one prior NHA, such as enzalutamide or abiraterone, and had no prior chemotherapy.

In the fourth quarter of 2020, we initiated the ARDENT Phase 2 expansion portion of the trial at a dose of 420 mg once-daily, the recommended Phase 2 dose, or RP2D.

In February 2022, we announced completed Phase 1 and interim ARDENT data for bavdegalutamide with a data cut-off date of December 20, 2021 at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium. We reported that bavdegalutamide showed reduced PSA50 in 46% of the 28 patients with tumors harboring AR T878X/H875Y mutations. These results also demonstrated PSA declines and tumor regressions in patients without tumors harboring AR T878X/H875Y mutations, suggesting an opportunity to develop bavdegalutamide more broadly in prostate cancer.

As of the data cut-off date, 195 patients were enrolled across the Phase 1/2 clinical trial (71 in Phase 1; 124 in Phase 2). The Phase 1 dose escalation trial evaluated bavdegalutamide at doses ranging from 35–700 mg, once-daily, or 210–420 mg twice-daily, in patients with mCRPC and two or more prior therapies (including abiraterone and/or enzalutamide).

Patients in the ARDENT trial received a median of four prior lines of therapy with 100% receiving at least one NHA (64% abiraterone, 75% enzalutamide or other AR inhibitor, 39% both abiraterone and an AR inhibitor) and 31% receiving at least one chemotherapy regimen.

Efficacy Measures

We presented efficacy measures on a combined basis for patients in both the completed Phase 1 dose escalation trial and the interim analysis from the ongoing ARDENT Phase 2 dose expansion trial. In the biomarker defined (“more pretreated”) subgroups, we observed the following:

•In eight patients with tumors with AR T878X and/or H875Y mutations but excluding other AR variants, PSA50=75%; PSA decline of more than 30%, or PSA30, =75%

•In 44 patients with tumors with wild-type AR or AR alterations other than T878X, H875Y, L702H, or AR-V7, PSA50=11%; PSA30=20%

•In 25 patients with tumors with AR L702H or AR-V7, PSA50=4%; PSA30=20%

In the biomarker agnostic (“less pretreated”) subgroup comprising 27 patients with no more than one prior NHA and no prior chemotherapy, the PSA50 response rate was 22% and the PSA30 response rate was 26%.

In biomarker-evaluable patients treated at or above the RP2D and with tumors harboring AR T878X/H875Y mutations (across all subgroups and thus regardless of prior therapy regimens or other mutations; n=28), the PSA50 response rate was 46% and the PSA30 response rate was 57%.

Of seven RECIST-evaluable patients across the Phase 1 and Phase 2 trials with tumors harboring AR T878X/H875Y mutations, two had confirmed durable partial responses. These patients were on treatment for approximately nine months (ongoing as of the data cut-off) and ten months; the duration of treatment ranged from eight weeks to 44 weeks, with three of the seven patients continuing on treatment as of the data cutoff of December 20, 2021.

Twelve (43%) of the 28 patients with AR T878X/H875Y-positive mutations received bavdegalutamide for 24 weeks or more, with nine patients ongoing as of the data cutoff.

PSA reductions and evidence of anti-tumor activity as measured by RECIST were observed across all subgroups regardless of mutation status, including tumors not harboring AR T878X/875Y mutations.

RECIST responses were seen in patients with tumors lacking AR T878X/H875Y mutations (one confirmed and three unconfirmed RECIST responses).

The “less pretreated” subgroup (n=27) had a similar molecular profile—as assessed by circulating tumor DNA analysis—to the more pretreated, biomarker-defined subgroups in the ARDENT trial. These similarities included both AR variations (point mutations and AR-V7 splice variants) and non-AR mutations frequently associated with poor outcomes (e.g., TP53, BRCA1). Six of the 27 patients (22%) had PSA50 reductions, and this PSA50 rate was similar to that observed collectively in the “more pretreated” subgroups (16%; n=77). Four of the six “less pretreated” patients with PSA50 declines had tumors with AR T878X/H875Y mutations.

Safety and Tolerability

Bavdegalutamide had a manageable tolerability profile at the RP2D. The majority of treatment-related adverse events, or TRAEs, were Grade 1/2 and there were no Grade 4 or greater TRAEs in the 138 patients treated at the RP2D.

TRAEs that occurred in 10% or more of patients treated at the RP2D were nausea (Gr 1: 30%; Gr 2: 16%; Gr 3: 1%), fatigue (Gr 1: 23%; Gr 2: 12%; Gr 3: 1%), vomiting (Gr 1: 20%; Gr 2: 5%; Gr 3: 1%), decreased appetite (Gr 1: 14%; Gr 2: 11%; Gr 3: 1%), diarrhea (Gr 1: 14%; Gr 2: 4%; Gr 3: 2%), alopecia (Gr 1: 13%; Gr 2: 1%; Gr 3: N/A) AST increased (Gr 1: 9%; Gr 2: 3%; Gr 3: 1%), weight decreased (Gr 1: 7%; Gr 2: 5%; Gr 3: 0%), and anemia (Gr 1: 4%; Gr 2: 1%; Gr 3: 5%).

TRAEs at the RP2D led to dose reduction in 11 (8%) patients and discontinuation in 12 (9%) patients.

In the third quarter of 2023 we completed enrollment in the Phase 1b combination trial of bavdegalutamide and abiraterone. In the fourth quarter 2023, we presented interim data at ESMO from the Phase 1/2 trial with bavdegalutamide (data cut-off date August 11, 2023). In a post-NHA (median prior therapies = 4) mCRPC population, bavdegalutamide at the recommend Phase 2 dose (420 mg, oral, once daily) demonstrated:

•Median rPFS of 11.1 months in patients harboring AR 878/875 mutations (n=26) and median rPFS of 8.2 months in patients with tumors harboring any AR LBD mutation except L702H alone (n=45)

•PSA50 rates of 54% in patients with tumors harboring AR 878/875 mutations and 36% in patients with tumors harboring any AR LBD mutation except L702H alone

•The presence of AR L702H mutations greatly diminished the efficacy of bavdegalutamide

•PSA50rate of 8% in patients with any tumor harboring an AR L702H mutation

•A manageable tolerability profile with no grade > 4 treatment-related adverse events (TRAEs). The most common TRAEs were nausea (56%), fatigue (35%), vomiting (33%), decreased appetite (25%) and diarrhea (24%). The discontinuation rate due to TRAEs was 12%.

As discussed above, while we expect to continue ongoing trial activities with bavdegalutamide (ARV-110-101 and ARV-110-103), we will not be enrolling new patients in these clinical trials and expect to wind down our bavdegalutamide program after completion of these clinical trials.

Intellectual Property

Our commercial success depends in part upon our ability to secure and maintain patent and other proprietary protection for our platform protein degradation technologies, including our PROTAC targeted protein degrader programs, product candidates, and know-how related to our business, defend and enforce our intellectual property rights, in particular our patent rights, preserve the confidentiality of our trade secrets, and operate without infringing valid and enforceable intellectual property rights of others.

The patent positions for biotechnology companies like us are generally uncertain and can involve complex legal, scientific and factual issues. In addition, the coverage claimed in a patent application can be significantly reduced before a patent is issued, and its scope can be reinterpreted and even challenged after issuance. As a result, we cannot guarantee that any of our product candidates will be protected or remain protectable by enforceable patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or invalidated by third parties.

As of December 31, 2024, our patent estate that we own, co-own and in-license includes 57 issued U.S. patents, 278 granted foreign patents, and 589 pending patent applications (178 domestic and 511 foreign).

Vepdegestrant

Vepdegestrant is a PROTAC ER targeting protein degrader for the potential treatment of metastatic and locally advanced breast cancer. As of December 31, 2024, our vepdegestrant patent portfolio includes a family with issued composition of matter patents in the U.S. and in foreign jurisdictions, including China, Japan and Europe, as well as pending applications in U.S. and certain foreign jurisdictions. Any granted patents in this family will expire in 2037, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. This patent portfolio also includes patent families with pending applications directed to methods of treatment with a combination of vepdegestrant and palbociclib; methods of treating breast cancer with ER mutations; crystalline forms; formulations; manufacturing methods; dosage regimens; drug treatment combinations; and drug-drug interactions in the U.S. and certain foreign jurisdictions. Patents from these additional families, if issued, will expire between 2040 and 2045, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid.

ARV-393

We are developing ARV-393, a PROTAC BCL6 degrader, for the potential treatment of B-cell malignancies. As of December 31, 2024, our ARV-393 patent portfolio includes a composition of matter patent family, which includes an issued U.S. patent and an issued foreign patent, as well as pending applications in the U.S. and certain foreign jurisdictions including Europe, China, and Japan, and a method of treatment patent family with pending U.S. and PCT applications, as well as one pending foreign application. Any granted patents in these families will expire between 2042 and 2044, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. In addition, the ARV-393 BCL6 portfolio includes pending U.S. applications directed to drug treatment combinations, and drug formulation. These additional families, if issued, will expire in 2045, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid.

ARV-102

We are developing PROTAC LRRK2 degraders, including ARV-102, for the potential treatment of PSP, PD and other neurodegenerative disorders. As of December 31, 2024, we have one family in our LRRK2 patent portfolio directed, in part, to the composition of matter of ARV-102 that includes a granted U.S. patent as well as pending U.S. and foreign applications. Any granted patent in this family will expire in 2042, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. In addition, the ARV-102 portfolio includes pending U.S. and PCT applications directed to manufacturing methods. These additional applications, if issued, will expire between 2044 and 2045, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid.

KRAS G12D

KRAS has historically been considered a “undruggable” target due to its lack of deep “pockets” and is associated with poor prognosis and resistance to standards of care in several tumor types. We are developing mutant-specific KRAS G12D degraders. As of December 31, 2024, our KRAS G12D patent portfolio includes a composition of matter patent family, which includes pending U.S. and PCT applications, as well as two pending foreign applications. In addition, the KRAS G12D portfolio includes a pending U.S. method of treatment application. Any granted patents in this family will expire between 2044 and 2045, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid.

PROTAC Platform

Our PROTAC platform patent estate that we own, and in-license, covers constructs that have ligands for the Von Hippel Lindau, or VHL, E3 ubiquitin ligase, the cereblon, or CRBN, E3 ubiquitin ligase, the inhibitor apoptosis protein, or IAP, E3 ubiquitin ligase, and the human mouse double minute homolog (MDM2) E3 ubiquitin ligase. As of December 31, 2024, the VHL patent portfolio, which we exclusively license from Yale University, includes composition-of-matter patents in the U.S., as well as certain foreign jurisdictions, as well as pending applications in the U.S. and foreign jurisdictions including Europe, China, and Japan. Any granted patents in this family will expire in 2033, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. As of December 31, 2024, the CRBN patent portfolio that we own includes issued composition of matter patents in in certain foreign jurisdictions including Europe China,

and Japan, as well as pending applications in the U.S. and certain foreign jurisdictions. Any patents in this family will expire in 2035, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. As of December 31, 2024, the IAP patent portfolio that we own has pending composition of matter applications in the U.S. and Europe. Any granted patents in this family will expire in 2036, excluding potential patent term extension and potential patent term adjustment, assuming all appropriate maintenance fees are paid.

As of December 31, 2024, the MDM2 patent portfolio that we own includes an issued composition of matter foreign patent, and pending composition of matter applications in the U.S. and Europe. Any granted patents in this family will expire in 2036, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid.

Bavdegalutamide (ARV-110)

Bavdegalutamide (ARV-110) is a PROTAC AR targeting protein degrader for the potential treatment of men with metastatic prostate cancer. As of December 31, 2024, our bavdegalutamide patent portfolio includes a family with issued composition of matter patents in the U.S. and in foreign jurisdictions including Europe, Japan, and China, as well as pending applications in the U.S. and certain foreign jurisdictions. Any granted patents in this family will expire in 2037, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. This patent portfolio also includes pending method of treatment applications in the U.S. and certain foreign jurisdictions, which if granted would expire in 2040, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. In addition, the bavdegalutamide portfolio includes patent families directed to drug treatment combinations, treatment of cancer having somatic AR tumor mutations, crystalline forms, drug formulation, and manufacturing, in the U.S. and certain foreign jurisdictions, as well as pending PCT applications. These additional families, if issued, will expire between 2041 and 2044, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid.

Luxdegalutamide (ARV-766)

Luxdegalutamide (ARV-766) is a PROTAC AR targeting protein degrader for the potential treatment of men with metastatic prostate cancer. Pursuant to the Novartis License Agreement, we granted Novartis an exclusive worldwide license for the development, manufacture and commercialization of luxdegalutamide (ARV-766). The intellectual property rights related to ownership of inventions, patent prosecution and maintained of licensed patents, as defined in the Novartis License Agreement, are outlined in the Novartis License Agreement, including that, we own the licensed patents and Novartis has first right to file, prosecute and maintain all licensed patents and joint patents specified in the Novartis License Agreement, throughout the world. The ARV-766 patent portfolio includes a patent family directed to the ARV-766 composition of matter, which includes an issued U.S. patent and two foreign patents, including China. In addition, there are pending composition of matter pending applications in the U.S. and certain foreign jurisdictions including Europe, Japan, and China. Any granted patent in this family will expire in 2040, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. This patent portfolio also includes pending method of treatment applications in the U.S. and one foreign country, as well as a pending PCT application. This additional family, if issued, will expire in 2043, excluding any potential patent term extensions or adjustments, assuming all appropriate maintenance fees are paid. In addition, this portfolio includes patent families directed to crystalline forms, drug formulation, manufacturing, and drug-drug interaction, in the U.S. and one foreign jurisdiction, as well as pending PCT applications.

Co-Owned Patent Portfolios

We co-own with Yale University six patent families describing composition of matter claims of PROTAC targeted protein degrader compounds addressing certain discovery and other potential protein targets, and associated methods of use. As of December 31, 2024, one or more U.S. patents have been issued in all of these families, and one or more patents have been issued in certain foreign jurisdictions for two of these families. There are also pending patent applications in the U.S. and/or certain foreign jurisdictions in four of these families.We also co-own with Yale University a composition of matter patent family that covers constructs that have ligands for the VHL E3 ubiquitin ligase. This family includes issued patents in the U.S and certain foreign jurisdictions including Japan, and pending patent applications in the U.S. and certain foreign

jurisdictions. Our rights to several of these patent applications are governed by the Amended Yale University License Agreement described below in "Item 1. Business—Licenses and Strategic Collaborations".

We co-own four patent families with Genentech directed to PROTAC targeted protein degrader compounds addressing a specific protein. Our rights to these patent applications are governed by the Genentech License Agreement described below in "Item 1. Business—Licenses and Strategic Collaborations".

ARVN US Equity

ARVN · 10-K · period ended 2024-12-31

Item 1. Business.

ARVN US Equity☆

ARVN · 10-K · period ended 2024-12-31

Item 1. Business.

ARVN US Equity