Luxdegalutamide

– Submitted New Drug Application for vepdegestrant for the treatment of ESR1m, ER+/HER2- advanced or metastatic breast cancer – – Presented ARV-102 SAD and MAD data from the Phase 1 clinical trial in healthy volunteers; initiated dosing in patients with Parkinson’s disease – – Presented preclinical data from ARV-393 program demonstrating single-agent activity and favorable combinability profile – – Initiated Phase 1 clinical trial evaluating ARV-806 in patients with solid tumors harboring KRAS G12D mutations – – Company to host conference call today at 8:00 a.m. ET – NEW HAVEN, Conn., Aug. 06, 2025 (GLOBE NEWSWIRE) -- Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company working to develop a new class of drugs based on targeted protein degradation, today reported financial results for the second quarter ended June 30, 2025, and provided a corporate update. “It was an eventful and exciting quarter at Arvinas, with significant clinical and regulatory progress across our pipeline of PROTAC degraders,” said John Houston, Ph.D., Chairperson, Chief Executive Officer and President at Arvinas. “The recent submission of a New Drug Application to the U.S. Food and Drug Administration for vepdegestrant represents a truly significant first for Arvinas – the first PROTAC degrader to enter clinical trials and have a positive readout in a Phase 3 clinical trial, and the first ever new drug application submitted for a PROTAC. We also continued to advance our early-stage programs, presenting compelling first in human data from ARV-102, our LRRK2 degrader, and preclinical data for our BCL6 degrader, ARV-393, as well as initiating a Phase 1 clinical trial with our KRAS G12D degrader, ARV-806. We have multiple near-term clinical and regulatory milestones, and our programs offer a rich set of catalysts over the next 12 months.” 2Q 2025 Business Highlights and Recent Developments Vepdegestrant: Oral PROTAC ER degraderAs part of Arvinas’ global collaboration with Pfizer, the companies: Submitted a New Drug Application to the U.S. Food and Drug Administration for vepdegestrant.Presented results from the VERITAC-2 Phase 3 clinical trial in a late-breaker oral presentation at the American Society of Clinical Oncology, with simultaneous publication of results in the New England Journal of Medicine. Pivotal Phase 3 VERITAC-2 clinical trial results demonstrated 2.9-month improvement in median progression-free survival (PFS) when compared to fulvestrant in previously treated patients with an estrogen receptor 1 mutation; the trial did not reach statistical significance in improvement in PFS in the intent-to-treat population.Vepdegestrant was generally well tolerated, with few discontinuations and low rates of gastrointestinal-related adverse events Added a combination cohort of vepdegestrant plus Pfizer’s KAT6 inhibitor (PF-07248144) to Pfizer’s ongoing Phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT04606446). The trial is currently evaluating Pfizer’s KAT6 inhibitor in combination with endocrine therapies following CDK4/6 inhibitor treatments; the trial is being operationalized and funded by Pfizer. ARV-102: Oral PROTAC LRRK2 degrader Presented single ascending dose (SAD) and multiple ascending dose (MAD) 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 and at the International Association of Parkinsonism and Related Disorders demonstrating blood-brain barrier penetration, central and peripheral LRRK2 degradation, and reduction of pathway biomarkers: At a single oral dose of at least 60 mg, and once daily repeated oral doses of at least 20 mg, ARV-102 achieved greater than 50% LRRK2 reduction in the cerebral spinal fluid (CSF) and greater than 90% LRRK2 reduction in the peripheral blood mononuclear cells (PBMCs), indicating substantial central and peripheral LRRK2 protein degradation.Inhibition of Rab10 phosphorylation in PBMCs and reduction of bis(monoacylglycerol)phosphate (BMP) in urine following single doses of ARV-102, signifying downstream LRRK2 pathway engagement.Bioavailable and brain penetrant with dose dependent exposure in the CSF.ARV-102 was generally safe and well tolerated with no serious adverse events reported after single or multiple doses. Completed enrollment in the SAD cohort of the ongoing Phase 1 clinical trial in patients with Parkinson’s disease.Activated site in preparation for multiple dose cohort initiation in patients with Parkinson’s disease. ARV-393: Oral PROTAC BCL6 degrader Continued recruiting patients in the first-in-human Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) (ClinicalTrials.gov Identifier: NCT06393738).Presented new preclinical data at the 2025 American Association for Cancer Research (AACR) annual meeting and the European Hematology Association (EHA) 2025 Congress: Data presented at AACR demonstrated that ARV-393 had broad and significant combinability with standard of care chemotherapy, standard of care biologics and investigational small molecule inhibitors targeting clinically validated oncogenic drivers of lymphoma.Data presented at EHA demonstrated: Significant single-agent activity of ARV-393 in models of nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (also known as AITL) and transformed follicular lymphoma.Enhanced tumor growth inhibition, including tumor regressions, with ARV-393 in combination with small molecule inhibitors in models of aggressive diffuse large B-cell lymphoma (DLBCL). Overall, current preclinical data suggest that ARV-393 has the potential to be an attractive combination partner for development of novel therapies for lymphoma, including chemo-free combination regimens and/or “all oral” treatment options. ARV-806: Novel PROTAC KRAS G12D degrader Initiated enrollment in the Phase 1 clinical trial evaluating ARV-806 in patients with solid tumors harboring KRAS G12D mutations (ClinicalTrials.gov Identifier: NCT07023731). Corporate updates: Announced that John Houston, Ph.D., Chairperson, Chief Executive Officer (CEO) and President at Arvinas, informed the Board of Directors of his plans to retire from his role as CEO and President following a search for, and the appointment of, a new CEO. The Arvinas Board of Directors has begun a search for a new CEO, and Dr. Houston will remain Chairperson of Arvinas’ Board of Directors upon retiring as CEO and President. Anticipated Upcoming Milestones and Expectations Vepdegestrant: Oral PROTAC ER degraderAs part of Arvinas’ global collaboration with Pfizer, the companies plan to: Continue market preparations for vepdegestrant in advance of the PDUFA action date.Revise our vepdegestrant collaboration with Pfizer with the goal of maximizing the value of vepdegestrant.Present patient reported outcomes data from the VERITAC-2 clinical trial evaluating vepdegestrant versus fulvestrant for previously treated patients with ESR1 mutated- ER+/HER2- advanced or metastatic breast cancer at the European Society for Medical Oncology 2025 Congress (October 2025).Present results of the TACTIVE-N trial, a Phase 2 clinical trial of neoadjuvant vepdegestrant, in a mini oral session at European Society for Medical Oncology 2025 Congress (ClinicalTrials.gov Identifier: NCT05549505) (October 2025). ARV-102: Oral PROTAC LRRK2 degrader Share final data from the SAD/MAD cohorts of the Phase 1 clinical trial in healthy volunteers (2H 2025).Share initial data from the SAD cohort of the ongoing Phase 1 clinical trial in patients with Parkinson’s disease (2H 2025).Initiate enrollment in the multiple dose cohort of the Phase 1 clinical trial in patients with Parkinson’s disease (2H 2025); present initial data from multiple dose cohort (2026).Initiate Phase 1b clinical trial in patients with progressive supranuclear palsy (1H 2026). ARV-393: Oral PROTAC BCL6 degrader Share preclinical data in combination with glofitamab in models of aggressive high grade DLBCL (2H 2025).Share preliminary clinical data from the ongoing Phase 1 clinical trial in patients with NHL (ClinicalTrials.gov Identifier: NCT06393738) (2H 2025). ARV-806: Novel PROTAC KRAS G12D degrader Continue enrollment in the Phase 1 clinical trial of ARV-806 in patients with solid tumors harboring KRAS G12D mutations (ClinicalTrials.gov Identifier: NCT07023731).Share preclinical data from the clinical stage ARV-806 program (2H 2025). Financial GuidanceBased on its current operating plan, Arvinas believes its cash, cash equivalents, and marketable securities as of June 30, 2025, is sufficient to fund planned operating expenses and capital expenditure requirements into the second half of 2028. Second Quarter Financial ResultsCash, Cash Equivalents, and Marketable Securities Position: As of June 30, 2025, cash, cash equivalents and marketable securities were $861.2 million, as compared with $1,039.4 million as of December 31, 2024. The decrease in cash, cash equivalents and marketable securities of $178.2 million for the six months ended June 30, 2025 was primarily related to cash used in operations of $177.0 million, the purchase of lab equipment and leasehold improvements of $1.6 million and $0.1 million of long-term debt repayments, partially offset by proceeds from the issuance of shares under the ESPP of $0.5 million. Research and Development Expenses: Generally Accepted Accounting Principles (GAAP) Research and development (R&D) expenses were $68.6 million for the quarter ended June 30, 2025, as compared with $93.7 million for the quarter ended June 30, 2024. The decrease in research and development expenses of $25.1 million for the quarter was primarily due to a decrease in external expenses of $18.3 million and a decrease in compensation and related personnel expenses of $7.9 million, which are not allocated by program. External expenses include (i) program-specific expenses, which decreased by $15.9 million, primarily driven by decreases in our vepdegestrant (ARV-471) and luxdegalutamide (ARV-766) programs of $10.0 million and $9.5 million, respectively, partially offset by increases in our ARV-102 and ARV-806 programs of $2.1 million and $1.5 million, respectively, and (ii) our non-program specific expenses, which decreased by $2.4 million. Non-GAAP R&D expenses were $59.5 million for the quarter ended June 30, 2025, as compared with $83.0 million for the quarter ended June 30, 2024, excluding $0.6 million of restructuring expense for the three months ended June 30, 2025, and $8.5 million and $10.7 million of non-cash stock-based compensation expense for the three months ended June 30, 2025 and 2024, respectively. A reconciliation of GAAP to non-GAAP financial measures used in this press release can be found at the end of this press release. General and Administrative Expenses: GAAP General and administrative (G&A) expenses were $25.3 million for the quarter ended June 30, 2025, as compared with $31.3 million for the quarter ended June 30, 2024. The decrease in general and administrative expenses of $6.0 million for the quarter was primarily due to a decrease in personnel and infrastructure-related costs of $4.8 million and professional fees of $2.2 million, partially offset by an increase in costs related to developing our commercial operations of $1.1 million. Non-GAAP G&A expenses were $20.2 million for the quarter ended June 30, 2025, as compared with $20.4 million for the quarter ended June 30, 2024, excluding $0.4 million of restructuring expense for the quarter ended June 30, 2025, and $4.7 million and $10.9 million of non-cash stock-based compensation expense for the quarter ended June 30, 2025 and 2024, respectively. A reconciliation of GAAP to non-GAAP financial measures used in this press release can be found at the end of this press release. Revenue: Revenue was $22.4 million for the quarter ended June 30, 2025 as compared with $76.5 million for the quarter ended June 30, 2024. Revenue for the quarter is related to the Vepdegestrant (ARV-471) Collaboration Agreement with Pfizer and the collaboration and license agreement with Pfizer. The decrease of $54.1 million was primarily due to $45.6 million of decreased revenue from the Novartis License Agreement and the Novartis Asset Agreement, both of which were entered into during the three months ended June 30, 2024 and were completed by December 31, 2024 as the technology transfer of our ongoing and planned clinical trials of luxdegalutamide (ARV-766) were transitioned to Novartis. Revenue from the Vepdegestrant (ARV-471) Collaboration Agreement with Pfizer decreased by $6.8 million related to the removal of the first-line Phase 3 combination trial with Pfizer’s novel investigational CDK4 inhibitor, atirmociclib, and the removal of the second-line Phase 3 combination trial with a CDK4/6 inhibitor from the development plan during the first quarter of 2025 and revenue from the Bayer Collaboration Agreement decreased by $1.6 million as a result of the termination of the Bayer Collaboration Agreement in August 2024. Investor Call & Webcast DetailsArvinas will host a conference call and webcast today, August 6, 2025, at 8:00 a.m. ET to review its second quarter 2025 financial results and discuss recent corporate updates. Participants are invited to listen by going to the Events and Presentation section under the Investors page on the Arvinas website at www.arvinas.com. A replay of the webcast will be available on the Arvinas website following the completion of the event and will be archived for up to 30 days. About ArvinasArvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROTAC (PROteolysis TArgeting Chimera) protein degrader platform, Arvinas is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; ARV-102, targeting LRRK2 for neurodegenerative disorders; and ARV-806, targeting KRAS G12D for mutated cancers, including pancreatic and colorectal cancers. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X. About VepdegestrantVepdegestrant is an investigational, orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER positive (ER+)/human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-) breast cancer. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits. About ARV-102ARV-102 is an investigational, orally bioavailable and brain-penetrant PROTAC protein degrader designed to specifically target and degrade leucine-rich repeat kinase 2 (LRRK2), which is a large, multidomain scaffolding kinase. Increased activity and expression of LRRK2 have been implicated in the pathogenesis of neurological diseases, including LRRK2 genetic and idiopathic Parkinson’s disease and progressive supranuclear palsy. About ARV-393ARV-393 is an investigational, orally bioavailable PROTAC designed to specifically target and degrade B-cell lymphoma 6 protein (BCL6), a transcriptional repressor and major driver of B-cell lymphomas. During B-cell development, tightly controlled BCL6 protein expression regulates >600 genes to facilitate rapid B-cell proliferation and tolerance of somatic hypermutation and gene recombination for antibody generation. Deregulated BCL6 expression is common in B-cell lymphoma and promotes cancer cell survival, proliferation, and genomic instability. PROTAC-mediated degradation has the potential to address the historically undruggable nature of BCL6. ARV-393 is currently in a Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin lymphoma. About ARV-806 ARV‑806 is a novel, investigational PROTAC degrader designed to selectively target and degrade mutant Kirsten rat sarcoma (KRAS) G12D — a highly prevalent oncogenic driver in solid tumors such as pancreatic, colorectal, and lung cancers. Engineered using Arvinas’ proprietary protein degradation platform, ARV‑806 has demonstrated potent, selective degradation of KRAS G12D in preclinical models, resulting in sustained MAPK pathway suppression and robust anti-tumor activity. ARV‑806 is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors harboring KRAS G12D mutations, following FDA clearance of an Investigational New Drug (IND) application in 2025. Non-GAAP Financial InformationThe results presented in this press release include both Generally Accepted Accounting Principles (GAAP) information and non-GAAP information. As used in this release, non-GAAP research and development (“R&D”) expense is defined by Arvinas as GAAP R&D expense excluding restructuring and stock-based compensation expense, and non-GAAP general and administrative (“G&A”) expense is defined by Arvinas as GAAP G&A expense excluding restructuring and stock-based compensation expense. Arvinas uses these non-GAAP financial measures to evaluate Arvinas’ ongoing operations and for internal planning and forecasting purposes. Arvinas believes that non-GAAP financial information, when taken collectively, may be helpful to investors because it provides consistency and comparability with past financial performance. However, non-GAAP financial information is presented for supplemental informational purposes only, has limitations as an analytical tool, and should not be considered in isolation or as a substitute for financial information presented in accordance with GAAP. Other companies, including companies in Arvinas’ industry, may calculate similarly titled non-GAAP measures differently or may use other measures to evaluate their performance, all of which could reduce the usefulness of Arvinas’ non-GAAP financial measures as tools for comparison. Investors are encouraged to review the related GAAP financial measures and the reconciliation of these non-GAAP financial measures to their most directly comparable GAAP financial measures and not rely on any single financial measure to evaluate Arvinas’ business Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding: current preclinical data suggesting that ARV-393 has the potential to be an attractive combination partner for development of novel therapies for lymphoma, including chemo-free combination regimens and/or “all oral” treatment options; Arvinas’ plans, along with Pfizer, with respect to vepdegestrant and the timing related to such plans, including: plans to continue market preparations for vepdegestrant in preparation for PDUFA action date, to revise the vepdegestrant collaboration with Pfizer with the goal of maximizing the value of vepdegestrant, to present patient reported outcomes data from the VERITAC-2 clinical trial evaluating vepdegestrant versus fulvestrant for previously treated patients with ESR1 mutated- ER+/HER2- advanced or metastatic breast cancer, and to present results of the TACTIVE-N clinical trial; Arvinas’ plans with respect to ARV-102 and the timing of such plans, including: plans to share final data from the SAD/MAD cohorts of the Phase 1 clinical trial of ARV-102 in healthy volunteers, to share initial enrollment from the SAD cohort of the ongoing Phase 1 clinical trial of ARV-102 in patients with Parkinson’s disease, to initiate enrollment in the multiple dose cohort of the Phase 1 clinical trial of ARV-102 in patients with Parkinson’s disease, and to initiate a Phase 1b clinical trial of ARV-102 in patients with progressive supranuclear palsy; Arvinas’ plans with respect to ARV-393 and the timing of such plans, including: plans to share preclinical data of ARV-393 in combination with glofitamab in models of aggressive high grade DLBCL and to share preliminary clinical data from the ongoing Phase 1 clinical trial of ARV-393 in patients with NHL; Arvinas’ plans with respect to ARV-806 and the timing of such plans, including: plans to continue enrollment in the Phase 1 clinical trial of ARV-806 in patients with solid tumors harboring KRAS G12D mutations, and to share preclinical data from the clinical stage ARV-806; the potential benefits of Arvinas’ product candidates, including vepdegestrant, ARV-102, ARV-393 and ARV-806; John Houston, Ph.D.’s retirement from his role as CEO and President and his continuing role as chairperson of the Arvinas Board of Directors, and statements regarding Arvinas’ search for and succession plan for the CEO position of Arvinas; and statements regarding Arvinas’ cash, cash equivalents and marketable securities, including their sufficiency to fund planned operating expenses and capital expenditure requirements into the second half of 2028. All statements, other than statements of historical fact, contained in this press release, including statements regarding Arvinas’ 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,” “goal,” “potential,” “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. Arvinas may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on such forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Arvinas makes as a result of various risks and uncertainties, including but not limited to: whether Arvinas and Pfizer will be able to successfully conduct and complete clinical development for vepdegestrant; whether Arvinas and Pfizer will successfully perform their respective obligations under the current or any revised collaboration between Arvinas and Pfizer; whether Arvinas will be able to successfully conduct and complete development for its other product candidates, including ARV-393, ARV-102, ARV-806, and including whether Arvinas initiates and completes clinical trials for its product candidates and receives results from its clinical trials and preclinical studies on its expected timelines or at all; whether Arvinas and Pfizer, as appropriate, will be able to obtain marketing approval for and commercialize vepdegestrant and other product candidates on current timelines or at all; risks related to the ability to identify and attract a qualified candidate to serve as Arvinas’ next CEO; Arvinas’ ability to protect its intellectual property portfolio; Arvinas’ reliance on third parties; the impact of the workforce reduction on the Company’s business and reputation; whether Arvinas will be able to raise capital when needed; whether Arvinas’ cash and cash equivalent resources will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other important factors discussed in the “Risk Factors” section of Arvinas’ Annual Report on Form 10-K for the year ended December 31, 2024 and subsequent other reports on file with the U.S. Securities and Exchange Commission. The forward-looking statements contained in this press release reflect Arvinas’ current views with respect to future events, and Arvinas assumes no obligation to update any forward-looking statements, except as required by applicable law. These forward-looking statements should not be relied upon as representing Arvinas’ views as of any date subsequent to the date of this release. ContactsInvestors:Jeff Boyle+1 (347) 247-5089Jeff.Boyle@arvinas.com Media:Kirsten Owens+1 (203) 584-0307Kirsten.Owens@arvinas.com Arvinas, Inc.Condensed Consolidated Balance Sheets (Unaudited) (dollars and shares in millions, except per share amounts)June 30, 2025December 31, 2024Assets Current assets: Cash and cash equivalents$114.9 $100.5 Marketable securities 746.3 938.9 Accounts receivable 0.5 5.7 Other receivables 10.6 8.0 Prepaid expenses and other current assets 17.2 14.2 Total current assets 889.5 1,067.3 Property, equipment and leasehold improvements, net 6.1 7.0 Operating lease right-of-use assets 9.3 9.0 Collaboration contract asset and other assets 4.4 8.1 Total assets$909.3 $1,091.4 Liabilities and stockholders' equity Current liabilities: Accounts payable and accrued liabilities$53.1 $71.8 Deferred revenue 102.9 156.2 Current portion of operating lease liabilities 1.8 1.8 Total current liabilities 157.8 229.8 Deferred revenue 134.1 292.0 Long-term debt 0.5 0.6 Operating lease liabilities 7.6 7.3 Total liabilities 300.0 529.7 Stockholders’ equity: Preferred stock, $0.001 par value, zero shares issued and outstanding as of June 30, 2025 and December 31, 2024, respectively — — Common stock, $0.001 par value; 73.2 and 68.8 shares issued and outstanding as of June 30, 2025 and December 31, 2024, respectively 0.1 0.1 Accumulated deficit (1,509.9) (1,531.6)Additional paid-in capital 2,118.1 2,092.2 Accumulated other comprehensive income 1.0 1.0 Total stockholders’ equity 609.3 561.7 Total liabilities and stockholders’ equity$909.3 $1,091.4 Arvinas, Inc.Condensed Consolidated Statements of Operations (Unaudited) For the Three Months Ended June 30,For the Six Months Ended June 30,(dollars and shares in millions, except per share amounts) 2025 2024 2025 2024 Revenue$22.4 $76.5 $211.2 $101.8 Operating expenses: Research and development 68.6 93.7 159.4 178.0 General and administrative 25.3 31.3 51.9 55.6 Total operating expenses 93.9 125.0 211.3 233.6 Loss from operations (71.5) (48.5) (0.1) (131.8)Interest and other income 10.0 13.5 21.6 27.5 Net (loss) income before income taxes (61.5) (35.0) 21.5 (104.3)Income tax benefit (expense) 0.3 (0.2) 0.2 (0.3)Net (loss) income$(61.2)$(35.2)$21.7 $(104.6) (Loss) earnings per common share Basic$(0.84)$(0.49)$0.30 $(1.46)Diluted$(0.84)$(0.49)$0.30 $(1.46)Weighted average common shares outstanding Basic 73.0 71.9 72.8 71.7 Diluted 73.0 71.9 73.0 71.7 Arvinas, Inc.Reconciliation of GAAP to Non-GAAP Information For the Three Months Ended June 30,For the Six Months Ended June 30,(dollars and shares in millions, except per share amounts)2025202420252024Research and development reconciliation GAAP research and development expenses 68.6 93.7 159.4 178.0Less: restructuring expense 0.6 — 0.6 —Less: stock-based compensation expense (*) 8.5 10.7 20.0 23.0Non-GAAP research and development expenses$59.5$83.0$138.8$155.0General and administrative reconciliation GAAP general and administrative expenses 25.3 31.3 51.9 55.6Less: restructuring expense 0.4 — 0.4 —Less: stock-based compensation expense (*) 4.7 10.9 10.2 17.2Non-GAAP general and administrative expenses$20.2$20.4$41.3$38.4 (*) Excludes restructuring related stock-based compensation.

编者按：今日，Arvinas和辉瑞（Pfizer）公司宣布已为其联合开发的明星PROTAC分子vepdegestrant向美国FDA提交新药申请（NDA），用于治疗既往接受过内分泌治疗的雌激素受体阳性（ER+）/人表皮生长因子受体2阴性（HER2-）、ESR1突变的晚期或转移性乳腺癌患者。根据新闻稿，若获批，vepdegestrant将成为首个获美国FDA批准的PROTAC雌激素受体降解剂。值得一提的是，近10年前，在此类技术刚刚起步之时，药明康德就开始布局相关的能力和技术，并积累了大量成功经验。随着近年来对PROTAC了解的逐步深入，公司针对这类创新分子已搭建了完善的一体化赋能平台，集发现、合成、分析纯化和测试等能力于一体，目前已成功支持超过100款PROTAC分子的开发，其中超过20个分子顺利推进至临床阶段。今天这篇文章里，药明康德内容团队将从vepdegestrant的最新监管进展出发，与读者分享PROTAC药物的研发历史与未来的潜在进展。上市申请的主要依据Vepdegestrant是一款潜在“first-in-class”的口服PROTAC降解剂，利用人体天然的蛋白质降解系统特异性地靶向并降解雌激素受体。它已经获得美国FDA授予的突破性疗法认定，用于治疗经治ER阳性、HER2阴性乳腺癌。这次vepdegestrant上市申请的递交，主要基于VERITAC-2临床3期试验的积极结果。试验分析显示，在携带ESR1突变的激素受体（HR）阳性、HER2阴性乳腺癌患者群体中，vepdegestrant与活性对照相比，为患者的无进展生存期（PFS）带来统计显著并具有临床意义的改善。这些患者在此前接受CDK4/6抑制剂和内分泌治疗后疾病出现进展。在携带ESR1突变的患者群体中，患者的疾病进展或死亡风险降低43%（HR=0.57；95% CI：0.42–0.77，P<0.001），vepdegestrant组患者的PFS达5.0个月，对照组患者则仅有2.1个月。在携带ESR1突变的所有患者亚群当中，vepdegestrant的获益情形一致。次要终点总生存期（OS）数据尚不成熟，仍需要研究继续评估。Arvinas董事长、首席执行官兼总裁John Houston博士表示：“我们期待新药申请的审评结果，也期待这个潜在首个获FDA批准的PROTAC ER降解剂有望为有需要的患者带来一种新治疗选择。”PROTAC演化史说到PROTAC分子的历史，还要追溯到Arvinas公司的联合创始人，耶鲁大学的Craig Crews教授与其合作伙伴，在2001年发表的一篇具有里程碑意义的论文。研究人员设计了一种人造双功能性分子，它的一端能够结合目标蛋白，另一端则是能结合E3连接酶的多肽。研究发现，这种分子能将目标蛋白拉到E3连接酶附近，让E3连接酶给目标蛋白打上泛素标签，标记它们送入细胞的蛋白酶体系统进行降解。 “未来，这一方法有望用于让蛋白出现有条件失活，以及降解导致疾病的蛋白。”该论文的摘要里写道。这一分子也被命名为蛋白靶向嵌合分子-1（protein-targeting chimeric molecule 1），缩写为Protac-1。在2008年，Crews教授团队的科学家更近一步，开发出一种双功能小分子药物。这款小分子的一端可选择性结合雄激素受体，另一端结合叫做MDM2的E3连接酶。这种能够靶向蛋白进行降解的双功能分子也被命名为PROTAC（PROteolysis TArgeting Chimera）。我们如今常用来指代靶向蛋白降解疗法的“PROTAC”正是由此而来。2013年，Crews教授联合创办了Arvinas公司，加速推进这一技术的科学转化。为了测试此类分子的成药可行性，该公司优先选择雄激素受体和雌激素受体这两个比较成熟的靶点。其中靶向雌激素受体的PROTAC分子，就是这次递交上市申请的vepdegestrant（曾名为ARV-471）。由于它在前期临床试验中表现出选择性降解野生型和突变型雌激素受体的出色能力，辉瑞公司在2021年与Arvinas达成超20亿美元的研发合作，共同打造这款PROTAC分子成为治疗ER阳性乳腺癌患者的支柱性内分泌疗法。除了vepdegestrant之外，Arvinas公司的其他PROTAC降解剂也取得了显著进展。去年，Arvinas与诺华（Novartis）就其针对雄激素受体的第二代PROTAC降解剂ARV-766达成了超过10亿美元的研发合作协议。此外，Arvinas针对LRRK2的蛋白降解剂ARV-102已进入1期临床试验，旨在治疗帕金森病。初步分析显示，单次口服剂量≥60 mg，或每日重复口服剂量≥20 mg时，患者脑脊液中LRRK2降解率超过50%，外周单核细胞中LRRK2降解率超过90%，表明ARV-102可实现中枢神经系统及外周LRRK2蛋白的显著降解。新靶点、新模式，靶向蛋白降解走向多元化Arvinas之外，还有多家公司正在开发与PROTAC分子具有类似作用机制的新药。例如，Kymera Therapeutics公司和赛诺菲（Sanofi）联合开发的IRAK4靶向蛋白降解剂KT-474（SAR444656）已处于2期临床开发阶段，用于治疗化脓性汗腺炎（HS）和特应性皮炎（AD）。该公司靶向STAT6的蛋白降解剂KT-621处于1期临床开发阶段，潜在治疗与2型炎症相关的多种免疫和炎症性疾病。日前公布的数据显示，KT-621在每日一次口服给药下，于所有高于1.5 mg剂量水平中实现了超过90%的平均血液STAT6降解；在所有≥50 mg的多剂量递增组中，更在血液与皮肤中均达成完全降解。Nurix Therapeutics公司可穿越血脑屏障的布鲁顿氏酪氨酸激酶（BTK）蛋白降解剂NX-5948目前处于1b/2期临床开发阶段，去年公布的早期临床试验数据显示，在治疗复发/难治性华氏巨球蛋白血症（WM）患者时，NX-5948达到77.8%的客观缓解率，其中两例患者已接受治疗超过1年。该公司的另一款蛋白降解剂NX-2127可同时降解BTK和IKZF蛋白，已进入治疗B细胞恶性肿瘤的首个人体临床试验。PROTAC分子之外，基于诱导接近（induced proximity）的创新蛋白降解模式也不断涌现。分子胶蛋白降解剂领域近两年来得到多家大型药企的关注。诺华（Novartis）、渤健（Biogen）、辉瑞、艾伯维（AbbVie）、武田（Takeda）、卫材（Eisai）与诺和诺德（Novo Nordisk）等公司纷纷达成分子胶相关的研发合作。专注于蛋白降解的新锐持续涌现，也进一步扩展了创新蛋白降解模式。例如，Pinetree Therapeutics开发多特异性靶向蛋白质降解剂，A轮融资1700万美元，且与阿斯利康（AstraZeneca）达成总额超5亿美元合作；Draupnir Bio和Booster Therapeutics基于溶酶体机制开发蛋白降解剂，种子轮融资逾千万美元；Firefly Bio由诺贝尔化学奖得主Carolyn Bertozzi教授联合创立，开发蛋白降解剂-抗体偶联药物（DAC）。Bertozzi教授联合创建的Lycia Therapeutics在去年也完成超1亿美元的C轮融资，推进其可降解细胞外和细胞膜蛋白的溶酶体靶向嵌合体（LYTAC）技术进入临床开发。此外，Automera公司则致力于开发自噬靶向嵌合小分子（AUTACs）。Expansion Therapeutics开发的核糖核酸酶靶向嵌合体（RIBOTAC）技术，可以实现对特定RNA的靶向降解。Vicinitas则是一家针对癌症与遗传疾病，以专有靶向蛋白稳定平台开发创新疗法的公司，其靶向去泛素化酶嵌合体（DUBTAC）平台生成的小分子可以促进蛋白质上的泛素链移除，进而避免蛋白质的降解。▲药明康德快速构建双功能性降解剂的平台能力作为业内靶向蛋白降解药物开发的重要赋能平台之一，药明康德早在此类药物的浪潮刚刚兴起之际，就快速搭建了综合性的赋能平台，能力涵盖PROTAC、分子胶、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS、以及DAC等主要分子类型。根据去年投资者开放日公布的信息，自2021年起，该平台已为靶向蛋白降解领域中66%的活跃公司提供了赋能合作。展望未来，靶向蛋白降解剂有着更为深远的意义。正如这一领域的权威，丹娜-法伯癌症研究所（Dana–Farber Cancer Institute）的Eric Fischer教授指出的那样，利用口服小分子去降解蛋白质，可以让科学家摆脱“可成药性”的束缚，真正思考哪些靶点能够最大程度地改变疾病进程。我们也期待看到更多蛋白降解药物能在临床上获得积极进展，造福广大患者。参考资料：[1] Arvinas Announces Submission of New Drug Application to U.S. FDA for Vepdegestrant for Patients with ESR1-Mutated ER+/HER2- Advanced or Metastatic Breast Cancer. Retrieved June 6, 2025 from https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-submission-new-drug-application-us-fda[2] Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. Retrieved March 11, 2025, from https://www.globenewswire.com/news-release/2025/03/11/3040386/0/en/Arvinas-and-Pfizer-Announce-Positive-Topline-Results-from-Phase-3-VERITAC-2-Clinical-Trial.html[3] 2024 WuXi AppTec Investor Day. Research Enabling Platforms Enhance CRDMO Model. Retrieved March 11, 2025, from https://static.wuxiapptec.com/6f/20240926/2024%20WuXi%20AppTec%20Investor%20Day%20-%20Research%20Enabling%20Platforms.pdf[4] PROTAC protein degraders to drug the undruggable enter phase 3 trials. Retrieved March 11, 2025, from https://www.nature.com/articles/d41591-024-00072-8[5] Nurix Corporate Presentation. Retrieved March 11, 2025, from https://ir.nurixtx.com/static-files/ee8cb2f8-e482-486e-a861-ececbd15f703[6] Arvinas and Pfizer's Vepdegestrant Significantly Improves Progression-Free Survival for Patients with ESR1-Mutant, ER+/HER2- Advanced Breast Cancer. Retrieved June 6, 2025 from https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-significantly-improves版权说明：本文欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。