Arvinas Inc (ARVN) 2024 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Arvinas fourth-quarter 2024 earnings conference call. (Operator Instructions) Please be advised that today's conference is being recorded.

您好，感謝您的支持。歡迎參加 Arvinas 2024 年第四季財報電話會議。（操作員指示）請注意，今天的會議正在錄音。

I would now like to turn the conference over to your speaker for today, Jeff Boyle. Please go ahead.

現在我想將會議交給今天的發言人傑夫博伊爾 (Jeff Boyle)。請繼續。

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our fourth quarter and full year 2024 financial results, which is available in the Investors and Media section of the website at arvinas.com.

大家早安，感謝大家的收看。今天早些時候，我們發布了一份新聞稿，其中包含我們的第四季度和 2024 年全年財務業績，可在網站 arvinas.com 的「投資者和媒體」部分查閱。

Joining the call today are John Houston, Arvinas's Chief Executive Officer, President, and Chairperson; Noah Berkowitz, our Chief Medical Officer; Angela Cacace, our Chief Scientific Officer; and Andrew Saik, our Chief Financial Officer.

今天參加電話會議的有 Arvinas 執行長、總裁兼董事長 John Houston；我們的首席醫療官 Noah Berkowitz；我們的首席科學官 Angela Cacace；以及我們的財務長 Andrew Saik。

Before we begin the call, I'll remind you that today's discussion contains forward-looking statements that involve risks, uncertainties, and assumptions. These risks and uncertainties are outlined in today's press release and in the company's recent filings with the Securities and Exchange Commission, which I urge you to read. Our actual results may differ materially from what is discussed on today's call.

在我們開始通話之前，我要提醒您，今天的討論包含涉及風險、不確定性和假設的前瞻性陳述。這些風險和不確定性在今天的新聞稿和公司最近向美國證券交易委員會提交的文件中進行了概述，我建議您閱讀。我們的實際結果可能與今天電話會議上討論的結果有重大差異。

And now, I'll turn the call over to John Houston, our CEO, President, and Chairperson. John?

現在，我將把電話轉給我們的執行長、總裁兼主席約翰休斯頓。約翰？

Thanks, Jeff. Good morning, everyone, and thank you for joining us this morning. It's a very exciting time for us here at Arvinas as we're on the cusp of some major accomplishments that include our first Phase 3 top-line data results expected later this quarter and first in-human data from our first PROTAC targeting neurodegenerative disease.

謝謝，傑夫。大家早安，感謝大家今天早上加入我們。對於 Arvinas 來說，這是一個令人興奮的時刻，因為我們即將取得一些重大成就，包括預計在本季度稍後公佈的第一階段 3 頂線數據結果，以及我們第一個針對神經退化性疾病的 PROTAC 的第一份人體數據。

We continue progressing a robust portfolio of exciting development programs that have the potential to transform the treatment landscape across a broad range of cancers and neurodegenerative diseases. Our novel approach to discovering, developing, and commercializing a new class of medicines has always been the backbone of our company, and we're pleased to provide an update this morning at such an important time for the organization.

我們將繼續推動一系列令人興奮的開發項目，這些項目有可能改變多種癌症和神經退化性疾病的治療格局。我們發現、開發和商業化新類藥物的新穎方法一直是我們公司的支柱，我們很高興在今天早上對公司如此重要的時刻提供最新消息。

Today, I'll begin with a brief overview of Arvinas, our PROTAC discovery platform, and an update on our pipeline. Noah will then provide an overview of our vepdegestrant or vepdeg clinical program, including reviewing the Phase 3 VERITAC-2 trial, and also provide an update on our first neuro clinical program with ARV-102, our LRRK2 degrader.

今天，我將首先簡要介紹我們的 PROTAC 發現平台 Arvinas 以及我們的管道更新。隨後，Noah 將概述我們的 vepdegestrant 或 vepdeg 臨床項目，包括回顧第 3 階段 VERITAC-2 試驗，並提供我們的第一個神經臨床項目的最新進展，該項目採用了我們的 LRRK2 降解劑 ARV-102。

Angela will provide an update from our earlier stage programs, including our BCL6 degrader, ARV-393; and our KRAS G12D degrader. And finally, Andrew will provide an overview of our fourth quarter and full year 2024 financials before we open up the call for your questions.

Angela 將提供我們早期專案的最新進展，包括我們的 BCL6 降解劑 ARV-393；以及我們的 KRAS G12D 降解劑。最後，在我們開始回答您的問題之前，安德魯 (Andrew) 將概述我們第四季和 2024 年全年的財務狀況。

Over the course of the last year, we have made significant progress on our mission to improve the lives of patients with debilitating and life-threatening diseases. Our pipeline of proteolysis-targeting chimeras, or PROTAC protein degraders, have been designed to harness the body's natural protein disposal system to selectively and efficiently degrade and remove disease causing proteins.

在過去的一年裡，我們在改善患有衰弱性和危及生命的疾病的患者生活這一使命上取得了重大進展。我們的蛋白水解靶向嵌合體或 PROTAC 蛋白降解劑旨在利用人體的天然蛋白質處理系統來選擇性地和有效地降解和去除致病蛋白質。

Our innovative PROTAC platform has enabled us to create a deep pipeline while making significant breakthroughs in targeted protein degradation. These breakthroughs include designing degraders with drug-like properties that are orally bioavailable and, when needed, able to cross the blood-brain barrier.

我們創新的 PROTAC 平台使我們能夠創建深度管道，同時在靶向蛋白質降解方面取得重大突破。這些突破包括設計具有類藥物特性的降解劑，這些降解劑可以口服生物利用，並在需要時穿過血腦屏障。

Vepdeg is the most advanced program in our pipeline. And in addition to our ongoing Phase 3 monotherapy trial, our current development plan includes two additional Phase 3 combination trials across the first and second line settings in metastatic breast cancer. Vepdeg is an oral PROTAC protein degrader specifically designed to target and degrade the estrogen receptor for the treatment of patients with ER-positive, HER2 negative breast cancer.

Vepdeg 是我們流程中最先進的程式。除了我們正在進行的 3 期單一療法試驗外，我們目前的開發計畫還包括在轉移性乳癌的第一線和第二線環境中進行另外兩項 3 期聯合試驗。Vepdeg 是一種口服 PROTAC 蛋白降解劑，專門用於靶向和降解雌激素受體，用於治療 ER 陽性、HER2 陰性乳癌患者。

Together with Pfizer, we are developing vepdeg with a goal of becoming the best-in-class ER-targeting backbone therapy first as a monotherapy, then with multiple combination strategies. And soon, we expect to have data in hand from VERITAC-2, our first ever Phase 3 trial.

我們正與輝瑞公司合作開發 vepdeg，目標是首先作為單一療法成為一流的 ER 標靶骨幹療法，然後採用多種組合策略。而且很快，我們希望能夠獲得 VERITAC-2（我們的第一個第 3 階段試驗）的數據。

Data from this Phase 3 clinical trial will be an important milestone for Arvinas, and we look forward to sharing top-line results later this quarter. If positive, these results will support our first new drug application and mark our potential transition to a commercial stage company.

這項 3 期臨床試驗的數據將成為 Arvinas 的一個重要里程碑，我們期待在本季稍後分享頂線結果。如果結果呈陽性，這些結果將支持我們的第一個新藥申請，並標誌著我們可能過渡到商業階段的公司。

Noah will provide an overview of the trial later in the call. Now given how close we are to this disclosure, we will not be answering questions about trial progress or offering additional guidance on expectations for VERITAC-2 during the Q&A portion of our call.

諾亞將在稍後的電話會議中概述此次試驗的情況。現在，鑑於我們距離此揭露已經很近，我們將不會在電話會議的問答部分回答有關試驗進展的問題或對 VERITAC-2 的預期提供額外指導。

Last month, we announced updates to our clinical development plans for vepdeg combination trials in the first and second line settings, pending emerging data and health authority feedback. In the first line, we announced that in 2025, we intend to initiate a Phase 3 trial with vepdeg plus Pfizer's novel investigational CDK4 inhibitor, atirmociclib. In the second line, we announced that we plan to initiate a Phase 3 combination trial evaluating vepdeg with a CDK4/6 inhibitor, which we also expect to initiate in 2025.

上個月，我們宣布了在第一線和第二線環境中進行 vepdeg 聯合試驗的臨床開發計劃的更新，等待新出現的數據和衛生當局的反饋。在第一線，我們宣布，我們打算在 2025 年啟動 vepdeg 與輝瑞新型研究性 CDK4 抑制劑 atirmociclib 的 3 期試驗。在第二行，我們宣布計劃啟動一項 3 期聯合試驗，評估 vepdeg 與 CDK4/6 抑制劑的效果，我們也預計該試驗將於 2025 年啟動。

Beyond VEEG, we have a data-rich year ahead, and we believe there are exciting opportunities for PROTAC across oncology and neuroscience. In April, we plan to present the first in-human data from ARV-102, our LRRK2 degrader, which we believe will highlight the potential value our PROTAC degraders can offer to patients with neurodegenerative diseases.

除了VEEG之外，我們還有數據豐富的一年，我們相信PROTAC在腫瘤學和神經科學領域有令人興奮的機會。四月份，我們計劃展示我們的 LRRK2 降解劑 ARV-102 的首批人體數據，我們相信這將凸顯我們的 PROTAC 降解劑為神經退化性疾病患者提供的潛在價值。

Additionally, In 2025 we plan to share preliminary data from our Phase 1 trial with ARV- 393, our BCL-6 degrader, in patients with non-Hodgkin lymphomas. And finally, we are on track to file an investigational new drug application for our KRAS G12D degrader this year.

此外，我們計劃在 2025 年分享我們在非何杰金氏淋巴瘤患者中使用 BCL-6 降解劑 ARV-393 進行的第 1 階段試驗的初步數據。最後，我們將於今年為 KRAS G12D 降解劑提交新藥試驗申請。

I'll now turn the call over to Noah for an overview of the vepdeg and ARV-102 programs. Noah?

現在我會把電話轉給 Noah，請他概述 vepdeg 和 ARV-102 計畫。諾亞？

Thanks, John, and good morning, everyone. Last year, together with Pfizer, we made great progress with our vepdeg program.

謝謝，約翰，大家早安。去年，我們與輝瑞公司合作，在vepdeg專案上取得了巨大進展。

As John mentioned, in addition to sharing top-line results from VERITAC-2 later this quarter, we intend to initiate two new Phase 3 combination trials in the first and second line settings later this year. We continue to believe vepdeg has the potential to demonstrate superior efficacy and tolerability and become a best-in-class ER-targeting backbone therapy preferred by physicians and their patients.

正如約翰所提到的，除了本季稍後分享 VERITAC-2 的頂線結果外，我們還打算在今年稍後在一線和第二線環境中啟動兩項新的 3 期組合試驗。我們始終相信，vepdeg 有潛力展現出卓越的療效和耐受性，並成為醫生及其患者首選的一流 ER 標靶骨幹療法。

Given the proximity to the upcoming top-line data readout, I won't spend too much time discussing the VERITAC-2 trial, which, if successful, could result in a submission of a new drug application and the first-ever regulatory approval of a PROTAC degrader.

鑑於即將發布的頂線數據即將公佈，我不會花太多時間討論 VERITAC-2 試驗，如果成功，該試驗可能會導致提交新藥申請並獲得 PROTAC 降解劑的首個監管批准。

Recall, the VERITAC-2 clinical trial is evaluating the efficacy and safety of vepdeg compared with fulvestrant in patients with ER-positive HER2-negative advanced breast cancer who have previously received and progressed on a combination of CDK4/6 inhibitors and endocrine therapy.

回想一下，VERITAC-2 臨床試驗正在評估 vepdeg 與氟維司群相比對 ER 陽性 HER2 陰性晚期乳癌患者的療效和安全性，這些患者之前曾接受過 CDK4/6 抑制劑和內分泌療法聯合治療並出現進展。

Important progress has been made in the treatment of patients with metastatic breast cancer who have progressed after receiving prior treatment with the CDK4/6 inhibitor. Yet, there is an ongoing need for improvement in treatment.

在接受CDK4/6抑制劑治療後病情進展的轉移性乳癌患者的治療方面取得了重要進展。然而，治療方法仍需要不斷改進。

An oral agent approved a few years ago for patients with ESR1 mutations only managed to extend median PFS a few months to 3.8 months. This highlights the unmet medical need among patients with advanced metastatic breast cancer and the potential opportunity for vepdegestrant in the VERITAC-2 trial.

幾年前核准用於治療 ESR1 突變患者的口服藥物僅能將中位 PFS 延長數月至 3.8 個月。這凸顯了晚期轉移性乳癌患者尚未滿足的醫療需求以及 VERITAC-2 試驗中 vepdegestrant 的潛在機會。

VERITAC-2 has two primary endpoints, PFS in the ITT or intention to treat population and PFS in the ESR1 mutation subpopulation. The study also has secondary outcome measures that include overall survival; anti-tumor activity, including objective response, duration of response, and clinical benefit rate; and of course, there are safety and quality of life assessments.

VERITAC-2 有兩個主要終點，ITT 或意圖治療族群中的 PFS 和 ESR1 突變亞群中的 PFS。該研究還有次要結果測量，包括總體存活率；抗腫瘤活性，包括客觀反應、反應持續時間和臨床受益率；當然，還有安全和生活品質評估。

It is worth noting that events determining PFS will be assessed by blinded independent central review. We expect to announce the outcome of VERITAC-2 in a top-line press release in Q1 and to present full results at a medical congress in 2025 where we also intend to host an investor call.

值得注意的是，決定 PFS 的事件將透過盲法獨立中央審查進行評估。我們預計將在第一季的頭條新聞稿中宣布 VERITAC-2 的結果，並在 2025 年的醫學大會上展示完整結果，我們也打算在大會上召開投資者電話會議。

In addition to anticipating VERITAC-2 results, we are pleased to be progressing our plans to initiate registration trials evaluating vepdeg combinations. Later this year, we plan to initiate a first-line Phase 3 trial of vepdeg in combination with Pfizer's novel investigational CDK4 inhibitor, atirmociclib, pending emerging data and health authority feedback.

除了期待 VERITAC-2 的結果之外，我們還很高興能夠推進我們的計劃，啟動評估 vepdeg 組合的註冊試驗。今年晚些時候，我們計劃啟動 vepdeg 與輝瑞新型 CDK4 抑制劑 atirmociclib 聯合治療的一線 3 期試驗，目前正在等待新出現的數據和衛生當局的反饋。

The decision to prioritize vepdeg plus atirmociclib in the first-line setting is based on the totality of evidence from the ongoing Phase 1b/2 TACTIVE-K combination trial evaluating vepdeg plus atirmociclib in the late-line setting and our trials evaluating vepdeg plus palbociclib.

決定在一線治療中優先考慮 vepdeg 加 atirmociclib 是基於正在進行的 1b/2 期 TACTIVE-K 聯合試驗的全部證據，該試驗評估了 vepdeg 加 atirmociclib 在後線治療中的療效，以及我們評估 vepdeg 加 palbociclib 的試驗。

This evidence, in addition to shifting treatment paradigms for early and advanced breast cancer, gives us the confidence that vepdeg plus atirmociclib is the best combination to advance as a potential new treatment option in the first-line setting. We and Pfizer are excited by the potential this combination represents for a new treatment option in this setting.

這項證據除了改變早期和晚期乳癌的治療模式外，還讓我們相信，vepdeg 加 atirmociclib 是作為一線治療中潛在的新治療選擇的最佳組合。我們和輝瑞公司都對這一組合為這種情況下的一種新的治療選擇所帶來的潛力感到非常興奮。

Our plans also include initiating a second-line Phase 3 combination trial of vepdeg plus a CDK4/6 inhibitor in 2025, pending emerging data and health authority feedback. Compelling efficacy signals have been shared previously for vepdeg in combination with palbociclib or with abemaciclib in the second-line-plus setting.

我們的計畫還包括在 2025 年啟動 vepdeg 與 CDK4/6 抑制劑的二線 3 期聯合試驗，等待新出現的數據和衛生當局的回饋。先前已有研究分享了 vepdeg 與 palbociclib 聯合使用或與 abemaciclib 在二線加用療法中聯合使用具有令人信服的療效信號。

In December 2024, we presented preliminary data from 16 patients in the Phase 1b combination trial of vepdeg and abemaciclib at the San Antonio Breast Cancer Symposium. This combination demonstrated encouraging clinical activity with a clinical benefit rate of more than 60% and an overall response rate of nearly 30% in patients previously treated with the CDK4/6 inhibitor.

2024 年 12 月，我們在聖安東尼奧乳癌研討會上展示了 vepdeg 和 abemaciclib 1b 期聯合試驗中 16 名患者的初步數據。這種組合療法表現出了令人鼓舞的臨床活性，在先前接受過 CDK4/6 抑制劑治療的患者中，臨床受益率超過 60%，整體反應率接近 30%。

Safety and tolerability of the combination was generally consistent with the demonstrated profile of both agents. Importantly, no significant drug-drug interactions were observed, and vepdeg had no clinically meaningful effect on abemaciclib exposure.

此組合的安全性和耐受性與兩種藥物所顯示的特性大致一致。重要的是，沒有觀察到顯著的藥物交互作用，且 vepdeg 對 abemaciclib 暴露沒有臨床意義上的影響。

The combinability of vepdeg was also supported by a Phase 1 pharmacology trial of vepdeg which demonstrated that DDI potential is not a concern for the ongoing clinical development of vepdeg as a backbone neurotherapy. We look forward to initiating the second-line Phase 3 combination trial later this year, pending emerging data and regulatory feedback.

vepdeg 的 1 期藥理學試驗也支持了 vepdeg 的可組合性，該試驗表明，DDI 潛力對於 vepdeg 作為骨幹神經療法的持續臨床開發來說並不是一個問題。我們期待在今年稍後啟動二線 3 期聯合試驗，等待新數據和監管回饋。

In totality, the data we have generated continue to support our belief that vepdeg has the potential to provide superior efficacy and tolerability both as a monotherapy and in combination for patients with metastatic breast cancer who need new treatment options. I'm now going to turn to our neuroscience clinical program.

總的來說，我們產生的數據繼續支持我們的信念，即對於需要新治療選擇的轉移性乳癌患者，vepdeg 無論是作為單一療法還是聯合療法，都有可能提供卓越的療效和耐受性。我現在要談談我們的神經科學臨床計畫。

Our most advanced neuroscience PROTAC, ARV-102, is a novel oral PROTAC designed to cross the blood-brain barrier and target lucine-rich repeat kinase 2, or LRRK2. LRRK2 is a large multi-domain scaffolding kinase genetically implicated in progressive supranuclear palsy and Parkinson's disease.

我們最先進的神經科學 PROTAC ARV-102 是一種新型口服 PROTAC，旨在穿過血腦屏障並靶向富含亮氨酸重複激酶 2 或 LRRK2。LRRK2 是一種大型多結構域支架激酶，在遺傳上與進行性核上性麻痺和巴金森氏症有關。

Pre-clinically, we have shown that ARV-102 crosses the blood-brain barrier and achieves deep brain lesion penetration and degradation of LRRK2 in non-human primates. We've also observed differentiation from inhibitors by showing improved effects on lysosomal dysfunction and movement of disease-relevant biomarkers in the central nervous system in pre-clinical studies.

臨床前研究顯示，ARV-102 能夠穿過血腦屏障，實現非人靈長類動物深部腦部病變穿透和 LRRK2 降解。我們還觀察到與抑制劑的區別，在臨床前研究中顯示出對溶酶體功能障礙和中樞神經系統疾病相關生物標記運動的改善作用。

In 2024, we initiated dosing in a first in-human Phase 1 clinical trial of ARV-102 in healthy volunteers. This ongoing Phase 1 trial was primarily designed to establish the safety of ARV-102, but it will also measure LRRK2 degradation in the periphery and in the cerebrospinal fluid or CSF of patients to establish the ability of ARV-102 to cross the blood-brain barrier and degrade LRRK 2 in humans.

2024 年，我們開始在健康志願者中進行 ARV-102 首次人體第 1 期臨床試驗。這項正在進行的 1 期試驗主要是為了確定 ARV-102 的安全性，但它也將測量患者外周和腦脊髓液或 CSF 中的 LRRK2 降解情況，以確定 ARV-102 穿過血腦屏障並在人體中降解 LRRK 2 的能力。

And I'm pleased to share that initial data from the single ascending dose cohort of the trial will be presented in an oral session at the Alzheimer's Disease/Parkinson's Disease, or AD/PD, Conference in April. These data confirm that ARV-102 is orally bioavailable in brain penetrants with dose-dependent exposure in the CSF.

我很高興地告訴大家，該試驗的單次遞增劑量組的初步數據將於 4 月的阿茲海默症/帕金森氏症（AD/PD）會議的口頭會議上公佈。這些數據證實 ARV-102 口服後在腦滲透物中具有生物利用度，並且在腦脊髓液中的暴露具有劑量依賴性。

At the AD/PD conference, we will disclose degradation data from the peripheral blood and CSF of healthy volunteers, an exciting milestone that we look forward to sharing. The learnings from this Phase 1 trial will be valuable as we strive to address the incredibly high unmet medical need in neurodegenerative diseases.

在AD/PD會議上，我們將披露來自健康志願者外周血和腦脊髓液的降解數據，這是一個令人興奮的里程碑，我們期待分享。當我們努力解決神經退化性疾病領域中極為巨大的未滿足醫療需求時，從這個第一階段試驗中獲得的經驗將非常寶貴。

We intend to explore the potential of ARV-102 in two severe neurodegenerative disorders that are linked to LRRK2 dysregulation. The first is progressive supranuclear palsy, in which LRRK2 mutations are strongly linked with faster progressing disease. And the second is Parkinson's disease, in which LRRK2 has been shown to contribute to disease pathology.

我們打算探索 ARV-102 在治療與 LRRK2 失調相關的兩種嚴重神經退化性疾病的潛力。第一種是進行性核上性麻痺，其中 LRRK2 突變與疾病更快進展密切相關。第二種是帕金森氏症，已證明 LRRK2 與帕金森氏症的病理有關。

We recently initiated a Phase 1 ascending dose trial of ARV-102 in patients with Parkinson's disease and expect to complete enrollment and present the initial data from this study later this year. It should be noted that we also plan to initiate a multiple ascending dose cohort in patients with Parkinson's disease later this year.

我們最近啟動了針對帕金森氏症患者的 ARV-102 的 1 期遞增劑量試驗，預計將在今年稍後完成招募並提交該研究的初步數據。值得注意的是，我們也計劃今年稍後對帕金森氏症患者啟動多次遞增劑量試驗。

Now I'm going to turn it over to Angela, who'll talk about ARV-393, our BCL6 degrader, and our KRAS G12D degrader. Angela?

現在我將把主題交給 Angela，她將討論 ARV-393、我們的 BCL6 降解劑和我們的 KRAS G12D 降解劑。安吉拉？

Thanks, Noah, and good morning, everyone. The pre-clinical profile of ARV-393, our oral PROTAC designed to degrade B cell lymphoma 6 protein or BCL6, has been highly positive.

謝謝，諾亞，大家早安。ARV-393 是我們專為降解 B 細胞淋巴瘤 6 蛋白或 BCL6 而設計的口服 PROTAC，其臨床前概況非常正面。

For background, BCL6 is a transcriptional repressor and a major driver of B cell lymphomas. The BCL-6 protein facilitates B cell tolerance of rapid proliferation and somatic gene recombination through the repression of cell cycle checkpoints, terminal differentiation, apoptosis, and the DNA damage response which becomes disregulated in several types of non-Hodgkin's lymphomas.

背景是，BCL6 是一種轉錄抑制因子，也是 B 細胞淋巴瘤的主要驅動因素。BCL-6 蛋白透過抑制細胞週期檢查點、終末分化、細胞凋亡和 DNA 損傷反應促進 B 細胞對快速增殖和體細胞基因重組的耐受，而這種耐受性在幾種類型的非何杰金氏淋巴瘤中變得失調。

PROTAC-mediated degradation has the potential to overcome the historically undruggable nature of BCL6. ARV-393 has a differentiated pre-clinical profile. It potently and rapidly degrades BCL6 protein, which is critical to overcoming BCL6's rapid resynthesis rate and sustaining anti-tumor activity.

PROTAC 介導的降解有可能克服 BCL6 歷史上無法用藥的性質。ARV-393 具有差異化的臨床前特徵。它能強效、快速地降解 BCL6 蛋白，這對於克服 BCL6 的快速再合成率和維持抗腫瘤活性至關重要。

ARB-393 has demonstrated significant anti-tumor activity in numerous pre-clinical in vivo models of non-Hodgkin's lymphoma. We plan on presenting ARV-393 pre-clinical data at the American Association for Cancer Research conference in April. These data show the promise of ARV-393 as a monotherapy in angioimmunoblastic T cell lymphoma patient-derived in vivo models.

ARB-393 在多種非何杰金氏淋巴瘤臨床前體內模型中表現出顯著的抗腫瘤活性。我們計劃在四月的美國癌症研究協會會議上展示 ARV-393 臨床前數據。這些數據表明 ARV-393 作為血管免疫母細胞 T 細胞淋巴瘤患者體內模型的單一療法具有良好的前景。

Additionally, we will show ARV-393 in combination with standard-of-care biologic agents and small molecule inhibitors in high grade and aggressive DLBCL in vivo models. We have made significant progress in enrolling patients with non-Hodgkin's lymphoma in a Phase 1 clinical trial of ARV-393 and look forward to sharing initial data this year.

此外，我們將展示 ARV-393 與標準治療生物製劑和小分子抑制劑在高級別和侵襲性 DLBCL 體內模型中的聯合應用。我們在 ARV-393 的 1 期臨床試驗中招募非何杰金氏淋巴瘤患者方面取得了重大進展，並期待今年分享初步數據。

As a final note, we remain on track to file an investigational new drug application this year for our KRAS G12D degrader. KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care.

最後要說的是，我們仍計劃在今年為我們的 KRAS G12D 降解劑提交新藥試驗申請。KRAS 是幾種主要腫瘤類型的驅動致癌基因，與不良預後和對標準治療的抵抗有關。

Pre-clinically, our degrader is a highly selective and potent molecule that demonstrates dose responsive degradation of KRAS G12D, leading to robust anti-tumor activity in KRAS G12D-mutated cancers, including pancreatic and colorectal cancers. Our degrader forms a ternary complex with both the active and inactive states of KRAS G12D. This PROTAC-induced binding event results in the elimination, rather than the inhibition of KRAS G12D.

臨床前研究表明，我們的降解劑是一種高選擇性強效分子，可表現出對 KRAS G12D 的劑量響應性降解，從而對 KRAS G12D 突變癌症（包括胰腺癌和結直腸癌）產生強大的抗腫瘤活性。我們的降解劑與 KRAS G12D 的活性狀態和非活性狀態形成三元複合物。PROTAC 誘導的結合事件導致 KRAS G12D 的消除而不是抑制。

In addition, our KRAS degrader is at least 30-fold more potent in vitro than an inhibitor currently in the clinic. I look forward to updating you on our progress with KRAS G12D and other promising degraders that are in discovery at Arvinas in the coming months.

此外，我們的 KRAS 降解劑在體外的效力至少比目前臨床上的抑制劑高 30 倍。我期待在未來幾個月內向您通報我們在 KRAS G12D 以及 Arvinas 正在研究的其他有前景的降解劑方面的進展。

With that, I'll turn the call over to Andrew. Andrew?

說完這些，我會把電話轉給安德魯。安德魯？

Thanks, Angela, and good morning, everyone. I'm pleased to share financial highlights for the fourth quarter and full year end of December 31, 2024. As a reminder, detailed financial results for the fourth quarter and year end are included in the press release we issued this morning.

謝謝，安琪拉，大家早安。我很高興分享截至 2024 年 12 月 31 日第四季和全年的財務亮點。提醒一下，我們今天早上發布的新聞稿中包含了第四季度和年末的詳細財務結果。

As we move into 2025, we are in a strong financial position with cash on hand sufficient to support operations into 2027. At the end of the fourth quarter, we had just over $1 billion in cash, cash equivalents, and marketable securities on the balance sheet compared with $1.3 billion at the end of 2023.

隨著我們進入 2025 年，我們的財務狀況將非常強勁，手頭上的現金足以支持到 2027 年的營運。截至第四季末，我們的資產負債表上的現金、現金等價物和有價證券略高於 10 億美元，而 2023 年底為 13 億美元。

Our strong balance sheet will allow us to advance all of our key strategic objectives, which include progressing the vepdeg clinical program, preparing for our first commercial launch, and developing our promising portfolio of earlier stage PROTAC degraders. Let me now turn to the fourth quarter and full-year 2024 financial highlights.

我們強勁的資產負債表將使我們能夠推進所有關鍵戰略目標，包括推進 vepdeg 臨床計劃、為首次商業發布做準備以及開發我們有前景的早期 PROTAC 降解劑產品組合。現在，我來談談 2024 年第四季和全年的財務亮點。

During the quarter, we recorded $59.2 million in revenue compared to a negative $43.1 million in revenue for the same period of 2023. The increase of $102.3 million was primarily due to adjustments made in 2023 to revenue from changes in contract estimates which resulted in negative revenue in the fourth quarter of 2023. We recorded $263.4 million in revenue for the year compared to $78.5 million in the prior year.

本季度，我們的營收為 5,920 萬美元，而 2023 年同期的營收為負 4,310 萬美元。1.023 億美元的增加主要是由於 2023 年合約估算變化對收入進行的調整，導致 2023 年第四季的收入為負。我們今年的收入為 2.634 億美元，而前一年的收入為 7,850 萬美元。

General and administrative expenses were $34.1 million in the fourth quarter compared to $27 million for the same period of 2023. The increase of $7.1 million was primarily due to developing our commercial operations of $2.6 million, personnel and infrastructure-related costs of $2.2 million, and professional fees of $1.8 million. G&A expenses were $165.4 million for the year compared to $100.3 million in the prior year.

第四季一般及行政費用為 3,410 萬美元，而 2023 年同期為 2,700 萬美元。710 萬美元的增加主要歸因於開發我們的商業運營 260 萬美元、人員和基礎設施相關成本 220 萬美元以及專業費用 180 萬美元。本年度的一般及行政開支為 1.654 億美元，而上年度為 1.003 億美元。

Research and development expenses were $83.3 million in the fourth quarter compared to $95.2 million for the same period of 2023. The decrease of $11.9 million was driven by a net decrease of $9.9 million in external expenses primarily related to the outlicensing of ARV-766. For the year end of December 31, 2024, R&D expenses were $348.2 million compared to $379.7 million for the prior year.

第四季研發費用為 8,330 萬美元，而 2023 年同期為 9,520 萬美元。1,190 萬美元的減少是由於主要與 ARV-766 的授權許可相關的外部費用淨減少 990 萬美元。截至 2024 年 12 月 31 日的年度，研發費用為 3.482 億美元，而前一年為 3.797 億美元。

We are well capitalized as we move into 2025 with the potential for an exciting milestone-rich year, beginning with our first Phase 3 top-line results expected later this quarter for VERTIAC-2. For ARV-102, our first degrader targeting neurological disease, the presentation of first in-human data in April is another important milestone for the company.

隨著我們邁入 2025 年，我們已擁有充足的資本，有可能成為令人興奮的里程碑式的一年，首先是預計本季稍後公佈的 VERTIAC-2 第三階段第一階段頂線業績。對於我們首個針對神經系統疾病的降解劑 ARV-102，四月公佈的首批人體數據是該公司另一個重要里程碑。

Later this year, we expect to share data from the single ascending dose portion of our Phase 1 trial in patients with Parkinson's disease and initiate the multiple ascending dose cohort in the same study. We also look forward to sharing data from the Phase 1 study of our BCL6 degrader, ARV-393, in patients with non-Hodgkin's lymphoma and submitting an IND application for our KRAS G12D degrader.

今年晚些時候，我們預計將分享針對帕金森氏症患者進行的第 1 階段試驗的單次遞增劑量部分的數據，並在同一研究中啟動多次遞增劑量隊列。我們也期待分享我們的 BCL6 降解劑 ARV-393 在非何杰金氏淋巴瘤患者中的第 1 階段研究的數據，並為我們的 KRAS G12D 降解劑提交 IND 申請。

With that, I'll turn the call back over to John for closing remarks. John?

說完這些，我會把電話轉回給約翰，請他作最後發言。約翰？

Thanks, Andrew. We expect to have a data-rich year ahead of us as we prepare for a key clinical trial readout from our Phase 3 VERITAC-2 trial and advance our promising pipeline of protein degraders. As we prepare for our first Phase 3 data readout, the first ever for a PROTAC, the excitement here at Arvinas is palpable.

謝謝，安德魯。我們期待未來的一年擁有豐富的數據，因為我們正在為第三階段 VERITAC-2 試驗的關鍵臨床試驗讀數做準備，並推進我們有前景的蛋白質降解劑產品線。當我們為首次第 3 階段資料讀取（這是 PROTAC 的首次資料讀取）做準備時，Arvinas 的興奮之情溢於言表。

I want to thank our dedicated team for working tirelessly and enthusiastically to bring this potential new medicine to patients. But none of it would be possible without the patients and physicians who are participating in our clinical trials.

我要感謝我們敬業的團隊，他們孜孜不倦、充滿熱情地工作，為患者帶來這種潛在的新藥。但如果沒有參與臨床試驗的患者和醫生，這一切都不可能實現。

I want to express my sincere gratitude to them, as we could not have achieved our success to date without their collective efforts. I also want to thank our shareholders for your continued support and encouragement as we work together to bring the promise of protein degraders to benefit patients across multiple life-threatening diseases.

我要向他們表達最誠摯的感謝，因為如果沒有他們的共同努力，我們不可能取得迄今為止的成功。我還要感謝我們的股東一直以來的支持和鼓勵，我們共同努力，實現蛋白質降解劑的希望，使多種危及生命的疾病患者受益。

With that, I'll now turn the call over to Jeff to begin the Q&A portion of our call. Jeff?

說完這些，我現在將電話轉給傑夫，開始電話會議的問答部分。傑夫？

Thanks, John. Before I turn the call over to the operator, I'll remind you, we will not be answering questions related to the progress or status of the VERITAC-2 trial or providing additional guidance on our expectations for data at this time.

謝謝，約翰。在我將電話轉給接線員之前，我要提醒您，我們目前不會回答與 VERITAC-2 試驗的進度或狀態相關的問題，也不會就我們對數據的預期提供額外指導。

So with that, operator, will you please open up the queue?

那麼，接線員，您可以打開排隊嗎？

Thank you. (Operator Instructions) Derek Archila, Wells Fargo.

謝謝。（操作員指示）德里克·阿奇拉（Derek Archila），富國銀行。

Just one in terms of just the TACTIVE-U cohorts that you'll be reading out this year. You think about the cadence of that data across different medical meetings. And ultimately, are you waiting for that data to really decide on the second-line CDK4/6 combo?

就今年將要讀出的 TACTIVE-U 隊列而言，只有一個。你要考慮這些數據在不同的醫學會議上的節奏。最後，您是否正在等待這些數據來真正決定二線 CDK4/6 組合？

Thanks, Derek. I'll hand over directly to Noah, and he can answer that.

謝謝，德里克。我會直接交給諾亞，他可以回答這個問題。

So TACTIVE-U, as you know, is a -- for everyone's knowledge, is a study that is evaluating vepdeg in combination with some other agents. So those agents include a CDK7 inhibitor, ribociclib, and also abemaciclib.

因此，如您所知，TACTIVE-U 是一項評估 vepdeg 與其他一些藥物聯合使用效果的研究。這些藥物包括 CDK7 抑制劑、ribociclib 和 abemaciclib。

So we've shared data about the abemaciclib combination. Those data continue to mature. We haven't shared information for the other two yet. We haven't offered guidance about when we will share the specific updates of these, but the hope is that as data mature, we can be sharing more.

因此我們分享了有關 abemaciclib 組合的數據。這些數據正在不斷成熟。我們尚未分享另外兩個的資訊。我們尚未提供有關何時分享這些具體更新的指導，但希望隨著數據的成熟，我們可以分享更多資訊。

As to the question about whether or not this will determine the choice of the CDK4/6 inhibitor that's combined with vepdeg, we think at this point, we've established that vepdeg combines very nicely with palbo and combines with the abemaciclib. So overall, the likely determinant of what we combine with is what will be the best drug to combine in the second-line setting.

至於這是否會決定與 vepdeg 結合的 CDK4/6 抑制劑的選擇，我們認為目前我們已經確定 vepdeg 與 palbo 結合效果非常好，並且與 abemaciclib 結合效果很好。因此總的來說，我們合併使用哪一種藥物的可能決定因素是第二線治療中最佳合併用藥。

So I don't want to go into more detail on that right now, but we hope that we can give updates in the next few months.

所以我現在不想詳細談論這個問題，但我們希望能夠在接下來的幾個月內提供更新。

Understood. And if I can squeeze one more on LRRK2, just in terms of what you plan to share for the SAD. I guess, what level of degradation do you find to be therapeutic in the pre-clinical setting and how will that translate to the human setting? Thanks.

明白了。如果我可以在 LRRK2 上再擠出一點時間，那麼就您打算為 SAD 分享的內容而言。我想，您認為在臨床前環境中什麼程度的退化具有治療作用，以及這將如何轉化為人類環境？謝謝。

Yeah. Angela, do you want to answer that question?

是的。安琪拉，你想回答這個問題嗎？

Certainly. Thanks for the question, Derek. So based on pre-clinical data that's been published by many others, showing that 50% reduction of the protein is disease modifying in certain contexts, including In the context of alpha synucleonopathies as well as tauopathies. So those data are published.

當然。謝謝你的提問，德里克。因此，根據許多其他人發表的臨床前數據，顯示蛋白質減少 50% 在某些情況下可以改善病情，包括在 α 突觸核蛋白疾病和 tauopathies 的情況下。因此這些數據被公佈了。

In addition, human genetics guide us, more recently, OMIC studies that relate to single cell LRRK2 expression levels in the brain, in particular in microglia that show that there's twofold elevation in LRRK2 expression in microglia. And this has been confirmed in IPSC-derived cells from Parkinson's disease patients where there's overexpression of LRRK2 in idiopathic Parkinson's disease.

此外，人類遺傳學指導我們，最近，OMIC 研究涉及大腦中的單細胞 LRRK2 表達水平，特別是在小膠質細胞中，結果表明小膠質細胞中的 LRRK2 表達增加了兩倍。這已在帕金森氏症患者的 IPSC 衍生細胞中得到證實，其中特發性帕金森氏症中存在 LRRK2 過度表達。

So we believe that we stand the best chance of testing the LRRK2 hypothesis by reducing LRRK2 50% in the brain. And that's what we aim to show in the central compartment.

因此我們相信，透過減少大腦中的 LRRK2 50%，我們有最大的機會驗證 LRRK2 假設。這正是我們想要在中央隔間展示的。

Excellent. Thanks again. Congrats on the progress.

出色的。再次感謝。祝賀你取得進展。

Jonathan Miller, Evercore.

喬納森·米勒，Evercore。

I guess since we just had a question on the Phase 3 and the second-line getting factors, I'll ask on the first line. Obviously, you've already chosen the CDK combo here with the CDK4.

我想，既然我們剛剛對第三階段和第二線獲取因素有疑問，我將在第一行提問。顯然，您已經選擇了帶有 CDK4 的 CDK 組合。

What's the gating factor to getting that study started? How much data do you need in the atirmo combo at TACTIVE-K before you can make those trial design assumptions? Do you need six months' data to go to the FDA with a trial design for Phase 3?

開始這項研究的限制因素是什麼？在做出這些試驗設計假設之前，您需要 TACTIVE-K 的 atirmo 組合中的多少資料？您是否需要六個月的資料來向 FDA 提交第三階段的試驗設計？

Yeah, great question. Noah?

是的，很好的問題。諾亞？

So overall, as we've shared, we plan to combine vepdeg with atirmociclib in the first line. And this is based on the totality of evidence that we have in which we've assessed what we could do with atirmociclib from an earlier data set in which we were looking at two different doses of atirmo combined with vepdeg 200 and are now in the expansion part of that and also reflecting back on palbociclib, how we did in our combination there.

所以總的來說，正如我們所分享的，我們計劃在第一行將 vepdeg 與 atirmociclib 結合起來。這是基於我們掌握的全部證據，我們從早期的數據集中評估了 atirmociclib 的作用，在該數據中，我們研究了兩種不同劑量的 atirmo 與 vepdeg 200 的組合，現在正處於擴展部分，同時也回顧了 palbociclib，看看我們的組合效果如何。

These were where we're looking in later-line settings, but also in the first-line setting and, overall, recognizing how there's a shift in the use of CDK4/6s in first line. And palbocilcib is being used much less, and we see a great opportunity for atirmo in the future.

這些是我們在後線環境中所研究的內容，也是在一線環境中所研究的內容，整體而言，我們認識到 CDK4/6 在第一線的使用發生了怎樣的轉變。而且palbocilcib的使用越來越少，我們看到了atirmo在未來的巨大機會。

As for what's gating, there is a -- as we've shared, we need to have some health authority discussion. And we have to continue to look at data. The good news is that the data continue to mature nicely. It's not -- we do not feel that we need at least six months of data to have this conversation with the health authorities.

至於什麼是門控，正如我們所分享的，我們需要進行一些衛生當局的討論。我們必須繼續查看數據。好消息是數據正在不斷成熟。事實並非如此——我們不認為需要至少六個月的數據來與衛生當局進行對話。

Great. And maybe if I can squeeze one more, I know you're not answering questions about VERITAC-2. But could you talk to commercial preparations beyond what we assume is going to be a wonderful readout in a couple of weeks? How is your commercial prep going and what do you think ramp there needs to be ready for a launch?

偉大的。也許如果我可以再擠一個，我知道你沒有回答有關 VERITAC-2 的問題。但是您能否談談除了我們假設的幾週後將會有的精彩結果之外的商業準備工作？您的商業準備進行得怎樣？

Yeah. Clearly, we've been focused on building the initial runway for a commercial organization. We have that in place. All the other aspects of the different components for a launch are getting in place as well.

是的。顯然，我們一直專注於為商業組織建立初始跑道。我們已經實現了這一點。發射所需的各個不同組成部分的所有其他方面也都正在準備就緒。

As you know, we'll be launching with Pfizer, and we'll be the US lead, so a significant amount of planning related to that. So yeah, I'm very pleased with the progress getting made with the team and we're in good shape.

如您所知，我們將與輝瑞合作推出該產品，並且我們將在美國領先，因此大量的規劃與此相關。是的，我對團隊的進展感到非常高興，而且我們的狀態很好。

Li Watsek, Cantor.

李·瓦特塞克，領唱。

I wonder if you can maybe just comment on VERITAC-2, if it has any readthrough to the two Phase 3 trials that you plan to initiate this year. Any elements of the trial design might be impacted by the results?

我想知道您是否可以對 VERITAC-2 進行評論，看看它是否對您計劃今年啟動的兩項 3 期試驗有任何解釋。試驗設計的任何元素可能會受到結果的影響嗎？

Noah, do you want to at least talk about that part of the, yeah, potential influence?

諾亞，你至少想談談那部分潛在影響嗎？

I guess the readthrough, if anything, would be more in the second-line setting, understanding the scope of the activity we see for the monotherapy and second line. We don't see it having any readthrough to first line.

我想，如果有的話，通讀將更多地放在二線環境中，以了解單一療法和第二線治療的活動範圍。我們沒有看到它對第一行有任何讀讀。

I probably can't go into more details like that. We're in the process of going through our health authority preparation and discussion and also just continuing to evaluate maturity of data in the second-line setting.

我可能無法講得那麼詳細。我們正在進行衛生當局的準備和討論，同時也持續評估二線環境中資料的成熟度。

Understood. And I guess just from a pipeline perspective, you've got three additional programs that you're moving forward into the clinic. So I guess what level of investment that you guys are looking to make, especially for the larger indications like Parkinson's disease.

明白了。我想，僅從管道角度來看，您還有三個額外的項目正在推進到臨床階段。所以我想問你們想要進行多大程度的投資，尤其是針對帕金森氏症等較大的適應症。

Yeah, great question. Yeah, we're very pleased with the progress the portfolios made through the last year. Clearly, very excited about seeing our first neuroscience/neurogenative program moving forward. And PSP and Parkinson's disease are very interesting areas for us to move that compound into, and we are well placed to take the LRRK2 degrader to a significant stage of development.

是的，很好的問題。是的，我們對投資組合在去年的進展感到非常滿意。顯然，我們很高興看到我們的第一個神經科學/神經生成專案取得進展。PSP 和帕金森氏症是我們將該化合物應用到的非常有趣的領域，我們已做好準備，將 LRRK2 降解劑推向重要的開發階段。

And we'll see in the future how the progress of the compound is. Whether or not there's an ideal situation where we find a strategic partner, that's all ahead of us. Right now, we're very focused on moving that program forward internally and getting it to a significant milestone.

我們將在未來觀察該化合物的進展。無論我們是否能找到策略夥伴，這都是我們未來要面對的理想情況。現在，我們非常專注於在內部推進該計劃並使其成為一個重要的里程碑。

Akash Tewari, Jefferies.

傑富瑞 (Jefferies) 的 Akash Tewari。

So I just previously mentioned that the decision to progress the vepdeg-CK4 combo would be in part an efficacy-based decision. We know we're going to a first line right now.

所以我剛才提到，推進 vepdeg-CK4 組合的決定在某種程度上是基於功效的決定。我們知道我們現在要去第一線。

With that in mind, can you frame expectations on that upcoming combo data? Will we have enough follow-up to give an early take on CFS? And if not, what do you think response rate should be for both a first-line and second-line setting for your go-forward dose?

考慮到這一點，您能對即將到來的組合數據做出預期嗎？我們是否有足夠的後續行動來儘早對 CFS 做出了解？如果不是，您認為對於您的後續劑量，第一線和二線治療的反應率應該是多少？

And then on VERITAC-2, this isn't a timing question. But how concerned are you that a six-month prior ET requirement is not sufficient to remove ET fast progressors? And what percent of fast progressors do you expect in your study versus what we saw with Lily?

然後對於 VERITAC-2，這不是一個時間問題。但是，您是否擔心，六個月前的 ET 要求不足以排除 ET 快速進展者？與我們在 Lily 身上看到的情況相比，您預計您的研究中快速進步的患者比例是多少？

So for the second half of that question, again, as we said at the beginning, we won't be answering any questions related to VERITAC-2. First half of the question --

因此，對於該問題的後半部分，正如我們在開始時所說的那樣，我們不會回答任何與 VERITAC-2 相關的問題。問題的前半部分--

In terms of how much efficacy and safety data we'll be looking at, decisions about going into first line are mostly safety driven. We'll be looking at efficacy as well, but safety is the dominant deciding factor.

就我們將要研究的功效和安全性數據而言，進入第一線治療的決定主要是出於安全考量。我們也會關注功效，但安全性是主要的決定因素。

And you also just want to know the overall activity of your drug, which I think we've established already in the second-line-plus setting from the Phase 1 programs that we've run. So mostly now, it's just discussing whether or not the dose that we recommend is going to be acceptable with health authorities and continue, as we have those discussions, to just look at the maturity of the data to see if anything unfolds.

而且您只是想知道藥物的整體活性，我認為我們已經從我們運行的第一階段計劃中的二線加治療環境中確定了這一點。因此，現在主要是討論我們推薦的劑量是否可以被衛生當局接受，並且在討論的同時，繼續關注數據的成熟度，看看是否有任何進展。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Okay. I think that's me. So maybe I have a couple of questions. The first one is metastatic breast cancer. So what data do you think you'll need to show to give confidence to KOLs on the profile of that and atirmo, just considering that historically, they will have had a lot more experience with the other CDK inhibitors like ribo and palbo, for example? And then I have a follow-up.

好的。我想那就是我。我可能有幾個問題。第一個是轉移性乳癌。那麼，您認為需要展示哪些數據才能讓 KOL 對該藥物和 atirmo 的概況充滿信心，僅僅考慮到從歷史上看，他們對其他 CDK 抑製劑（例如 ribo 和 palbo）有更多的經驗？然後我有一個後續問題。

Noah?

諾亞？

Thanks. Yeah, thank you for the question. We have -- so I think if the question is focused on first line, what we expect to see, we're not prepared to go into the exact study design, the hazard ratio that's being targeted, the -- or other features of the statistical plan.

謝謝。是的，謝謝你的提問。所以我認為，如果問題集中在第一線，即我們期望看到什麼，我們還沒有準備好深入研究確切的研究設計、目標風險比或統計計劃的其他特徵。

But in general terms, all the feedback we get is that investigators would want to see more than the five months, six months of improvement in median PFS to know that they have something that's substantially different, even if we're up against a generic competition a few years from today when palbo is generic.

但一般而言，我們收到的所有回饋都是，研究人員希望看到中位 PFS 超過 5 個月、6 個月的改善，以便知道他們有實質性的不同，即使幾年後當 Palbo 成為仿製藥時我們面臨仿製藥的競爭。

And so if you view the first-line CDK4/6-plus AI combination as delivering somewhere between 24 and 28 months of median PFS, you'd want to see something in that range, five, six months, better to know that you have something special.

因此，如果您認為一線 CDK4/6 加 AI 組合可提供 24 至 28 個月的中位數 PFS，那麼您希望看到該範圍內的某個值，即五、六個月，最好知道您獲得了一些特別的東西。

Okay, got it. And then if I could ask a question on your KRAS degrader, can you talk about how you think it might be differentiated given that this G12 degrader space is pretty competitive? You've got other companies like Astellas in the clinic. And what would you want to see in order to move it forward?

好的，明白了。然後，如果我可以就您的 KRAS 降解劑問一個問題，您能否談談您認為它可能如何差異化，因為 G12 降解劑領域競爭相當激烈？您的診所裡還有其他公司，例如安斯泰來 (Astellas)。為了推動這項進程，您希望看到什麼？

Yeah, we're very excited about our KRAS program. And Angela, do you want to answer that?

是的，我們對我們的 KRAS 計劃感到非常興奮。安琪拉，你想回答這個問題嗎？

Yeah, sure. So based on the details that are public, we've compared to the Astellas molecule. We know we're 40-fold more potent than that Astellas degrader. It is encouraging that the Astellas degrader did show some efficacy at the higher doses but was, I think, discontinued for issues due to safety.

是的，當然。因此，根據公開的細節，我們與安斯泰來分子進行了比較。我們知道，我們的效力比阿斯特捷利康的降解劑強 40 倍。令人鼓舞的是，安斯泰來降解劑在較高劑量下確實表現出一定功效，但我認為由於安全問題該藥已停產。

We feel that we're very competitive with respect to the in vitro profile and in vivo profiles based on the data that we've generated. We do believe that in terms of the inhibitors in the G12D space that we're very competitive.

我們認為，根據我們產生的數據，我們在體外概況和體內概況方面非常具有競爭力。我們確實相信，就 G12D 領域的抑制劑而言，我們非常有競爭力。

We have a catalytic mechanism of action. We know that we bind to both the inactivated and activated states in terms of our ternary complex, so very different than an inhibitor. The degrader binds both. And we know that we're more potent in inhibiting cell proliferation and inducing cell death.

我們有一個催化作用機制。我們知道，就三元複合物而言，我們同時與失活狀態和活化狀態結合，因此與抑制劑非常不同。降解劑將兩者結合在一起。我們知道我們在抑制細胞增殖和誘導細胞死亡方面更有效。

We also disrupt the scaffolding functions that are known for G12D KRAS. And we have the potential for distinct and non-overlapping resistance mechanisms that we can impact with G12D. And beyond that, we have some very compelling data in terms of some of the neoantigen profiles that we're producing that we know inhibitors do not.

我們也破壞了已知的 G12D KRAS 支架功能。我們有可能利用 G12D 來影響獨特的、不重疊的抵抗機制。除此之外，就我們正在產生的一些新抗原譜而言，我們有一些非常令人信服的數據，而我們知道抑制劑沒有。

And just to add to that point, Angela, I think you touched on it. But this potency becomes an important issue because ultimately, the first line -- the first generation Astellas compound did demonstrate some (technical difficulty) abnormalities in patients that may have created some dose limitation. So we do have the opportunity with ours maybe to address efficacy before those come into play.

安琪拉，我再補充一點，我想你已經提到了這一點。但這種效力成為一個重要的問題，因為最終，第一線——第一代安斯泰來化合物確實在患者身上表現出一些（技術難度）異常，這可能造成了一些劑量限制。因此，我們確實有機會在這些問題發揮作用之前解決功效問題。

Devarakonda, Truist.

Devarakonda，Truist。

My first question is on ARV-393. Can you talk a little bit about enrollment status for this program and whether there's any focus on a particular subset of NHL patients? And given the profile of the target, where do you think this might fit into the landscape with other targets like BTKs or BCL2? Thank you. And I have a follow-up.

我的第一個問題是關於 ARV-393 的。您能否談談該計劃的招生情況以及是否重點關注特定群體的 NHL 患者？並且考慮到目標的概況，您認為這可能與 BTK 或 BCL2 等其他目標的情況相符嗎？謝謝。我還有一個後續問題。

That's a great question. Thanks, Kripa. Noah?

這是一個很好的問題。謝謝，克里帕。諾亞？

Yeah, Kripa, great question. We're pretty excited about this compound, and let's break it down into a few different areas.

是的，克里帕，這個問題問得很好。我們對這種化合物感到非常興奮，讓我們將其分解成幾個不同的區域。

In terms of enrollment so far, the study started its enrollment last year. It was a little later than we initially expected, but things are going very nicely, backlog of patients and making nice progress.

從目前的招募情況來看，研究去年就開始招募病患。這比我們最初預計的要晚一點，但事情進展得很順利，積壓的病人減少了，而且取得了很好的進展。

In terms of how this drug may differentiate itself, well, first of all, it's differentiated in the sense that there are no BCL6 inhibitors that are in the clinic really or approved. There is another degrader that's in development out there, and it's probably at a similar stage of development. Not much has been shared.

就這種藥物如何與眾不同而言，首先，它的獨特之處在於，目前還沒有真正在臨床上使用或獲得批准的 BCL6 抑制劑。目前還有另一種降解劑正在開發中，它可能處於類似的開發階段。分享的內容不多。

We are very satisfied with combination data, some of which we've shared, more of which is coming. And we want you to direct your attention to AACR, where there's going to be an opportunity for an update. What you would see there is a lot of potential combinations that can open up the door to this orthogonal approach towards anti-lymphoma activity.

我們對組合數據非常滿意，其中一些數據我們已經分享，未來還會有更多數據。我們希望您關注 AACR，那裡將有機會提供更新。您會發現有很多潛在的組合可以為這種正交方法打開抗淋巴瘤活性的大門。

One of the things that we're working out is to what degree do you need BCL6 expression or how much expression is necessary for this pathway to be targeted effectively with this agent?

我們正在研究的問題之一是，需要 BCL6 表達到什麼程度，或者需要多少表達才能使該途徑有效地被該藥物靶向？

The combinability, the fact that the drug hasn't really demonstrated pre-clinically and in our top studies evidence of real hematopoietic toxicity suggests that there are opportunities for us to combine nicely with any of these agents that we have, whether we're talking about BTKI inhibitor, anti-CD20 therapy; whether it's an antibody therapy or if it's bispecifics.

可組合性、該藥物在臨床前和我們的頂級研究中尚未真正證明真正的造血毒性證據這一事實表明，我們有機會與我們擁有的任何這些藥物很好地結合，無論我們談論的是 BTKI 抑製劑還是抗 CD20 療法；無論是抗體療法或是雙特異性療法。

So lots of paths we can follow. The first step, obviously, is generating data about a maximum tolerated dose and then moving on to combinability.

我們可以選擇的路徑有很多。顯然，第一步是產生有關最大耐受劑量的數據，然後進行可組合性研究。

Great. We'll keep an eye out for AACR. Just a follow-up question. We got some inbound around the Chief Commercial Officer leaving right before a key readout and potentially a year or so before potential commercial rollout. Can you talk a little bit about it and help alleviate investor concerns about this?

偉大的。我們將密切關注 AACR。這只是一個後續問題。我們得到了一些消息，首席商務官在一次關鍵的發布會之前離職，可能在商業推廣前一年左右離職。您能否稍微談論一下這個問題並幫助緩解投資者對此的擔憂？

Absolutely. Our Chief Commercial Officer, John Northcott, he had to leave, unfortunately, because of personal reasons which I can't get into. Luckily for us, and also through great planning, we had a second in line, highly experienced executive, Alex Santini, who has been able to step into the breach as our Interim Chief Commercial Officer; and he's absolutely superb.

絕對地。不幸的是，我們的首席商務官約翰·諾斯科特 (John Northcott) 因個人原因不得不離職，我無法透露。幸運的是，透過周密的計劃，我們有了一位經驗豐富的第二高階主管亞歷克斯·桑蒂尼 (Alex Santini)，他可以擔任我們的臨時首席商務官；他確實很出色。

So I can honestly say we haven't missed a beat. Alex has continued the game plan that was laid out by John, and the team is progressing really well. It was unfortunate. But because we had such a great depth in terms of the leadership team there, we've been able to move on really quite easily.

因此我可以誠實地說，我們沒有錯過任何一個節拍。亞歷克斯繼續執行約翰制定的比賽計劃，球隊的進展非常順利。這很不幸。但由於我們擁有實力雄厚的領導團隊，我們能夠非常輕鬆地繼續前進。

Jeet Mukherjee, BTIG.

Jeet Mukherjee，BTIG。

I was hoping you could elaborate a bit more on what we can expect from the Parkinson's patients update for ARV-102 later this year. And are there any biomarkers you'd be looking for that would translate to functional improvements in these patients? And I had a follow-up.

我希望您能更詳細地介紹一下今年稍後我們對帕金森氏症患者 ARV-102 的更新。您是否正在尋找任何可以改善這些患者功能的生物標記？我進行了後續行動。

Noah, let's start with you then we can go to Angela.

諾亞，我們先從你開始，然後我們再去找安琪拉。

Yeah. Thanks, Jeet. So just to put us on the same page, the immediate -- like the first step is to demonstrate or to share what we've demonstrated in healthy volunteers. And so this involves our understanding of PK/PD, so understanding how dosing leads to -- what dosing properties can be tracked in the periphery, but also in the central nervous system by virtue of what we see of drug in the CSF.

是的。謝謝，Jeet。因此，為了讓我們達成共識，最直接的——第一步就是展示或分享我們在健康志工身上所展示的內容。因此，這涉及到我們對 PK/PD 的理解，即了解劑量如何導致——哪些劑量特性可以在外周進行追踪，也可以透過我們在腦脊髓液中看到的藥物在中樞神經系統中進行追踪。

And then, of course, there's PD, so what's happening to LRRK, again, in the periphery and, more importantly, in the CSF. And so we expect the first glimpse of those data at the Alzheimer's Disease/Parkinson's Disease Conference in Vienna in early April.

當然，還有 PD，那麼 LRRK 又發生了什麼變化？因此，我們期待在四月初於維也納舉行的阿茲海默症/帕金森氏症會議上首次看到這些數據。

But as we've also shared, we have begun dosing on Parkinson's disease patients. Unfortunately, we can't offer guidance at this point about exactly when those data will be shared. But recognize that we started off, and this is for regulatory reasons, with SAD patients, so a single ascending dose, and then we would next move to MAD dosing, so multiple ascending dose in Parkinson's disease patients.

但正如我們所分享的，我們已經開始對帕金森氏症患者進行用藥。不幸的是，我們目前無法提供有關何時共享這些數據的具體指導。但要認識到，出於監管原因，我們一開始是針對 SAD 患者的，因此採用單次遞增劑量，然後我們接下來將轉向 MAD 劑量，因此對於帕金森氏症患者採用多次遞增劑量。

And depending on the progress of this, and it's going very nicely right now, we would hope we can -- and conference schedule, we hope we can share some update that would be at least SAD. But we'll have to see how much data we can accumulate by the appropriate conference later in the year.

根據這件事的進展情況，現在一切進展順利，我們希望能夠——以及會議日程，我們希望能夠分享一些至少是 SAD 的更新資訊。但我們必須看看我們能在今年稍後的適當會議上累積多少數據。

And just to continue with respect to what Noah was saying, at least in non-clinical primate studies, we've been able to conduct a discovery effort around biomarkers that we think are LRRK2-driven based on published Parkinson's Disease Progression Initiative from the Michael J. Fox Foundation.

繼續諾亞所說的內容，至少在非臨床靈長類動物研究中，我們已經能夠根據邁克爾·J·福克斯基金會發布的帕金森病進展計劃，圍繞我們認為由 LRRK2 驅動的生物標誌物開展發現工作。

So we're encouraged by our non-clinical data that suggests that we can move neuroinflammation endpoints, as well as lysosome function endpoints. So it's promising, and so we await getting toward the MAD portion of Parkinson's disease studies to assess this.

因此，我們的非臨床數據讓我們感到鼓舞，這些數據表明我們可以移動神經發炎終點以及溶酶體功能終點。所以它是有希望的，所以我們等待帕金森氏症研究的 MAD 部分來評估這一點。

Understood. That's helpful. And maybe a VERITAC-2 question if you just wouldn't mind. You said you'd present full results at a medical conference. Would any abstract embargo rules potentially limit what you could say as part of a top-line press release? Thanks.

明白了。這很有幫助。如果你不介意的話，也許還有一個 VERITAC-2 問題。您說過您會在醫學會議上展示完整的結果。任何抽象的禁運規則是否都會限制您在頭條新聞稿中可以說的內容？謝謝。

Yes, I think there would be. So we'll get more information as we get past that next stage.

是的，我認為會有。因此，當我們進入下一階段時，我們將獲得更多資訊。

Brad Canino, Stifel.

布拉德‧卡尼諾 (Brad Canino)，Stifel。

Listening to the large pharma earnings, we should expect front-line Phase 3 oral CERD trials in combination with the CDK4/6 inhibitors from Roche and AstraZeneca this year. That's right around the time you and Pfizer will be kicking off the front-line vep-CDK4. How will Arvinas think about these results of the studies as they pertain to your front-line plan?

聽聽大型製藥公司的獲利情況，我們應該期待今年羅氏和阿斯特捷利康的 CDK4/6 抑制劑聯合進行一線 3 期口服 CERD 試驗。那時您和輝瑞即將啟動一線 vep-CDK4 研發。阿維納斯將如何看待這些研究結果與您的第一線計畫的關係？

Thanks, Brad. Obviously, we're going to be very interested in the datasets coming from both of those companies. Noah, do you want to say anything about additional content?

謝謝，布拉德。顯然，我們對來自這兩家公司的數據集非常感興趣。諾亞，你還有什麼要說的關於附加內容嗎？

Sure. So thanks, Brad. I guess the question can be, will this impact standard of care? And the feeling is that with the study that's going to launch this year and take less than a couple of years to enroll, it's not going to have -- it's not likely to have impact on our -- on the operational feasibility of a study in any way.

當然。所以謝謝你，布拉德。我想問題是，這會影響護理標準嗎？我們的感覺是，這項研究將於今年啟動，並且只需要不到幾年的時間就能完成受試者招募，這不會對我們的研究的可行性產生任何影響，也不太可能產生任何影響。

So if anything, it just gets the -- creates some excitement in this area if there are some positive results. We also recognize at the end of the day that PROTACs are very different than CERDs because of our targeted degradation.

所以，如果有的話，它就會——如果有一些積極的結果，就會在這個領域創造一些興奮。我們最終也認識到，由於我們有針對性的降解，PROTAC 與 CERD 有很大不同。

So whatever we see, we can -- our hope and expectation would be that we can see something stronger from a PROTAC. So we're looking with anticipation, but recognize that it just creates opportunity.

所以無論我們看到什麼，我們都可以——我們的希望和期望是，我們可以從 PROTAC 中看到更強大的東西。因此我們滿懷期待，但也意識到這只是創造了機會。

Sudan Loganathan, Stephens.

蘇丹·洛加納坦，史蒂芬斯。

And my first one would be on atirmociclib. In regards to that first-line combination, you're playing with that, I think. I think atirmociclib is uniquely characterized by like a 20-fold and fourfold increase in productivity for CDK4 over CDK6, which -- I believe that probably helps with the neutropenia or any hematologic toxicities that may have showed up with like palbociclib, potentially.

我的第一個研究對像是 atirmociclib。關於第一線的組合，我認為你正在玩這個。我認為 atirmociclib 的獨特之處在於，CDK4 的生產力比 CDK6 的生產力高出 20 倍和 4 倍，我認為這可能有助於治療中性粒細胞減少症或 palbociclib 可能出現的任何血液學毒性。

But I'm curious to see how you view the glucose metabolism component for CDK4 involvement in that and how that may play out in the safety profile and just -- even just your very broad view on what makes atirmociclib, in your view, better than palbociclib, ribociclib, or any of the other CDK4/6 inhibitors out there. And then I have a follow-up.

但我很好奇，您如何看待 CDK4 參與的葡萄糖代謝成分，以及它在安全性方面可能發揮的作用，以及您對是什麼讓 atirmociclib 優於 palbociclib、ribociclib 或任何其他 CDK4/6 抑製劑的廣泛看法。然後我有一個後續問題。

Thanks, Sudan. Noah?

謝謝，蘇丹。諾亞？

So Sudan -- so you had mentioned specifically the neutropenia. So just as a general observation, we don't really view vepdeg as having a neutropenia liability. There was some neutropenia or increased neutropenia, which is really a palbo liability, that was observed in combination with palbo.

所以蘇丹——你特別提到了中性粒細胞減少症。因此，僅作為一般觀察，我們並不認為 vepdeg 具有導致中性粒細胞減少症的傾向。在與 Palbo 聯合使用時觀察到了一些中性粒細胞減少症或中性粒細胞減少症增多症，這實際上是 Palbo 的責任。

And since then, we've shared data, probably enough to give a very strong glimpse of safety for an abema combination. And there was no signal of anything like this. So when it comes to DDIs, that whole concept is fading away, and that may have been particular to palbo's toxicity.

從那時起，我們就分享了數據，這些數據可能足以讓我們非常清楚地了解 abema 組合的安全性。但沒有任何類似這樣的訊號。因此，當談到 DDI 時，整個概念正在消失，這可能與 Palbo 的毒性有關。

In terms of what to expect in first line, well, we should note that atirmo combined with AIs is already a Phase 3 study that Pfizer has announced. So you can see that listed on clinicaltrials.gov. That means that it's been -- presumably, that it's been reviewed by health authorities and there's a willingness to let that trial go forward. So the safety profile of that and tolerability profile of the dose that was chosen was acceptable to health authorities.

就第一線的預期而言，我們應該注意到，輝瑞公司已經宣布，atirmo 與 AI 的聯合治療已經是第三階段研究。您可以在 clinicaltrials.gov 上看到該清單。這意味著它——大概——已經通過了衛生當局的審查，並且願意讓試驗繼續進行。因此，所選劑量的安全性和耐受性是衛生當局可以接受的。

So in our case, we've now been dosing patients with vepdeg and atirmo in collaboration with Pfizer. We've been seeing a really attractive safety and early glimpse of efficacy look fine. So we're just planning to have those health authority discussions.

因此，在我們的案例中，我們現在已經與輝瑞公司合作，為患者使用 vepdeg 和 atirmo 治療。我們已經看到了真正有吸引力的安全性和早期的功效。所以我們只是計劃進行這些衛生當局的討論。

Hyperglycemia is not a significant concern of ours right now, and we'll keep you updated. But as we've shared, the hurdles for us are just to reach agreement with health authorities about dose and schedule, which we don't think is a high bar. And then, of course, we'll just update you on the trial design.

高血糖目前並不是我們關心的主要問題，我們會隨時向您通報最新情況。但正如我們所分享的，我們面臨的障礙只是與衛生當局就劑量和時間表達成一致，我們認為這並不是一個很高的標準。然後，當然，我們只會向您通報試驗設計的最新情況。

Great. No, I appreciate the insight there. And my second one is in regards to the BCL6 degrader, ARV-393. Could you share your perspective on the potential efficacy and utilization of the PROTAC technology in comparison to Bristol-Myers Squibb's BMS-986458, I believe, which employs the ligand-directed degradation for B cell malignancies, and if your strategy has evolved or changed in response to any preliminary data that BMS has provided up to this point with their degrader?

偉大的。不，我很欣賞你的見解。我的第二個問題與 BCL6 降解劑 ARV-393 有關。您能否與百時美施貴寶的 BMS-986458 相比，分享您對 PROTAC 技術的潛在功效和利用率的看法？ BMS-986458 採用配體導向降解技術治療 B 細胞惡性腫瘤。

Nice question. Yeah, we're obviously aware of the BMS degrader. We haven't seen much in the way of data from that company.

好問題。是的，我們顯然意識到了 BMS 降級因素。我們還沒有看到太多來自該公司的數據。

Our belief is our degrader is designed using our technology, our insights. So we have a belief that our technology and our program will be significantly better.

我們相信我們的降解器是利用我們的技術和我們的見解設計的。因此我們相信我們的技術和程序將會更好。

We have to see how that looks going forward, but it's difficult to mention anything about the BMS degrader because we haven't seen much in the way of data there. So we're very focused on our own program and moving that forward and taking that to the next stage.

我們必須觀察未來的發展情況，但很難提及有關 BMS 降解劑的任何信息，因為我們沒有看到太多相關數據。因此，我們非常專注於我們自己的計劃並推動其向前發展並進入下一階段。

Ted Tenthoff, Piper Sandler.

泰德·坦托夫，派珀·桑德勒。

I'm excited for all the data this year. Similar question to those asked earlier about how the front-line treatment paradigm is changing, but to the second line. How are you guys seeing -- like with the CERDs and the CDK4/6 up front in first line, how are you seeing the second-line treatment paradigm changing ahead of vepdeg monotherapy data and VERITAC-2 data?

我對今年的所有數據感到興奮。這個問題與先前詢問的關於第一線治療模式如何變化的問題類似，但涉及第二線。你們如何看待——例如，隨著 CERD 和 CDK4/6 成為一線治療藥物，在 vepdeg 單藥治療數據和 VERITAC-2 數據之前，您如何看待二線治療模式的變化？

Thanks, Ted. Great question. I'll pass you over to Noah.

謝謝，泰德。好問題。我會把你交給諾亞。

Hi, Ted. So thanks for the question. So certainly, there are changes in the treatment landscape. And the bigger trend is that ribo is being used more and more in the first-line setting and somewhat now in the adjuvant setting. And that's even more than abema. So -- and palbo's use is fading there.

你好，泰德。感謝您的提問。因此，治療領域肯定會改變。更大的趨勢是核醣體越來越多地被應用於第一線治療，現在也在一定程度上應用於輔助治療。這甚至比 abema 還要多。所以 —— Palbo 的使用在那裡正在逐漸減少。

So the question is, what happens? Is there use of CDK4/6 after CDK4/6? There's some; it's still limited. But in the second-line setting, you would think that there would be much less use of ribo. And the data outside of our experience with combining palbo and vepdeg, there aren't great data out there for palbo in the second-line setting. So there's probably some limit on the part of physicians about their interest in using that combination or using palbo after other CDK4/6 inhibitors.

那麼問題是，會發生什麼事？CDK4/6 之後還有用嗎？有一些；它仍然是有限的。但在二線環境中，您可能會認為核糖的使用會少很多。除了我們聯合使用 Palbo 和 Vepdeg 的經驗之外，目前還沒有關於 Palbo 在二線治療中的優質數據。因此，醫生對於使用該組合或在其他 CDK4/6 抑制劑後使用 Palbo 的興趣可能存在一些限制。

So where -- but what we do recognize, in addition to those general trends, is that there are accumulating data for the use of drugs targeting the PI3K pathway. And that's having some impact. You've obviously seen some exciting data. And we know there are Phase 3 program that's been kicked off for CAT6 in the second-line setting.

但是，除了這些總體趨勢之外，我們確實認識到，使用針對 PI3K 路徑的藥物的數據正在不斷累積。這確實產生了一些影響。您顯然已經看到了一些令人興奮的數據。我們知道，針對二線治療的 CAT6 的第三階段計劃已經啟動。

So this is -- and that's combined with fulvestrant. There's atirmo that's combined with fulvestrant. So there are a bunch of drugs that are being combined with fulvestrant. And we hope to do some practice informing work that will demonstrate how various drugs can be combined with vepdeg in this setting.

這是 — — 這是與氟維司群結合的。有一種與氟維司群結合的 atirmo。有很多藥物可以與氟維司群結合使用。我們希望做一些實踐指導工作，展示在這種情況下如何將各種藥物與 vepdeg 結合。

And it'll be up to physicians in the end, whether they want to be using fulvestrant or they'd be wanting to use an oral agent in those types of settings. And the data will probably support -- will just in the end have to support whatever decision they make.

最終還是由醫生決定，他們是否願意使用氟維司群或在這種環境下使用口服藥物。數據可能會支持——最終將支持他們所做的任何決定。

Okay, great. That's really helpful. I appreciate that color. I'm looking for data from the rest of the pipeline, too.

好的，太好了。這真的很有幫助。我很欣賞那個顏色。我也在尋找來自管道其餘部分的數據。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）

Just in terms of the front-line setting for vepdeg, how are you thinking about potential enrichment strategies for patients who might be more responsive to an oral CERD and your latest thinking on what the predictors are of which patients might develop an ESR1 mutation? And then I have a follow-up.

僅就 vepdeg 的第一線環境而言，您如何考慮口服 CERD 更敏感的患者的潛在富集策略，以及您對哪些患者可能發生 ESR1 突變的預測因子的最新想法？然後我有一個後續問題。

Thanks, Ellie. Oh, sorry --

謝謝，艾莉。噢，抱歉--

Yeah, please.

是的，請吧。

So yes. So Ellie, in the first line, we are not likely to be taking all comers in our study. So there are obviously some patients that have progressed rapidly in the adjuvant setting when they've been exposed to AIs. And standard of care now in these patients would be a CDK4/6 inhibitor plus fulvestrant. So those are not likely to be included in our study design.

所以是的。所以艾莉，首先，我們不太可能在我們的研究中接受所有人。因此，顯然有些患者在接觸 AI 後，在輔助治療中病情會迅速進展。目前這些患者的標準治療是 CDK4/6 抑制劑加氟維司群。所以這些不太可能被納入我們的研究設計中。

As for other enrichment strategies, we have a drug here that we believe degrades ESR1 wild type as well as ESR1 mutant and so therefore, should work very well in a broad population. 95% of patients in first line, something in that range, may have ESR1 wild type. So there's no thought of molecular enrichment there.

至於其他富集策略，我們有一種藥物，我們認為它可以降解 ESR1 野生型以及 ESR1 突變型，因此應該在廣泛人群中發揮良好作用。 95% 的第一線患者（大約在這個範圍內）可能具有 ESR1 野生型。因此，那裡沒有關於分子富集的想法。

One of the reasons that the first-line study may work even better is because maybe we can prevent the evolution of ESR1 mutant clones by effectively suppressing any clone that would develop because we degrade that as well. So I don't think ESR1 mutant selection anyway is going to play into the study design.

一線研究可能效果更好的原因之一是，也許我們可以透過有效抑制任何可能發展的克隆來阻止 ESR1 突變克隆的進化，因為我們也會降解它。所以我認為 ESR1 突變體選擇無論如何都不會影響研究設計。

Beyond that, not much to add clinically. We're happy to discuss that offline with you some more if you have some good ideas.

除此之外，臨床上沒有什麼好補充的。如果您有好的想法，我們很樂意與您進行進一步線下討論。

And then just a follow-up, maybe just a broader strategic question. There's been a lot of focus on STAT6 as a target for degraders. But obviously, there aren't so many companies that have expertise in making degraders. What's your perspective on whether you might expand your focus to targets or, say, a target in the immunology space?

然後只是一個後續問題，也許只是一個更廣泛的策略問題。STAT6 作為降解劑的目標受到廣泛關注。但顯然，擁有製造降解劑專業知識的公司並不多。您認為是否可以將焦點擴大到其他目標，或例如說免疫學領域的目標？

And just from a platform perspective, what's the latest on how long it would take from, say, selecting a target protein to making a PROTAC development candidate?

僅從平台角度來看，從選擇目標蛋白質到製作 PROTAC 開發候選物需要多長時間？

Yeah. Clearly, our focus over the last several years, Ellie, as you know, has been oncology and neuroscience. There's been elements of immuno-oncology that has brought in elements of immunology as well. So we're always aware of potential targets that we believe a degrader could drive differentiation.

是的。顯然，正如你所知，艾莉，過去幾年我們的重點一直是腫瘤學和神經科學。免疫腫瘤學的元素也引入了免疫學的元素。因此，我們始終意識到潛在的目標，我們認為降解劑可以推動差異化。

So we're not blind to that, and we do look at things like that. But our major focus has been neuro and oncology, and it will continue to be that for the foreseeable future.

所以我們對此並非視而不見，我們確實在關注這樣的事情。但我們的主要重點是神經學和腫瘤學，在可預見的未來仍將如此。

In terms of our approach to moving a target forward, it's very dependent on what the starting points are. Clearly, we have abilities to move the PROTAC design forward fairly rapidly. To get to that point, though, you need good starting points in terms of ligands against the target. So that is one of the big determinants of speed.

就我們推進目標的方法而言，這很大程度取決於起點是什麼。顯然，我們有能力相當迅速地推進 PROTAC 設計。然而，為了達到這一點，您需要在針對目標的配體方面有一個良好的起點。所以這是決定速度的重要因素之一。

Do you have a high-quality or a good-quality ligand that binds to the target of interest? And when you have that, we can move a program forward relatively fast because of our insight and know-how to apply the technology.

您是否有與目標結合的高品質或優質配體？當你擁有它時，我們就可以相對快速地推進一個項目，因為我們擁有洞察力和應用技術的專業知識。

So it's a fairly generic answer, but ligand discovery is an important piece to this early on. Angela, anything you want to add to that?

所以這是一個相當通用的答案，但配體的發現是早期的重要部分。安琪拉，您還有什麼要補充嗎？

Yeah. I just wanted to add -- that's great, John. I just wanted to add some of the learnings that we've had over the past 13 years that have been built into our platform technologies where we iteratively learn from some of the pharmacokinetic, pharmacodynamic properties that we have in our molecules that lead to more rapid designs and accelerated movement through our pipeline.

是的。我只是想補充一點——太好了，約翰。我只是想補充一些我們在過去 13 年中累積的經驗，這些經驗已融入我們的平台技術中，我們不斷學習分子中的一些藥物動力學、藥效學特性，從而實現更快速的設計和更快速的流程。

So with the constraints that John just defined, of course, building out our ligand capabilities is core to where we're focused now to tackle some of these under-drugged targets. And then just a point about the immunology indications.

因此，在約翰剛剛定義的限制條件下，當然，建立我們的配體能力是我們現在關注的核心，以解決一些藥物不足的目標。然後我再談一下免疫學指徵。

Of course, we are looking at some of our assets in some immune indications. So BCL6 may play a role in innate immune disorders like MS and other disorders. So preclinically, we're evaluating.

當然，我們正在研究一些免疫適應症的資產。因此，BCL6 可能在 MS 和其他疾病等先天免疫疾病中發揮作用。因此，在臨床前階段，我們正在進行評估。

And so we're keeping an eye open there as well as LRRK2 and its role in irritable bowel disease and Parkinson's disease that may be extended based on some of the biomarkers that we're seeing move, at least in preclinical studies. So I think there's a lot of opportunity and a lot of potential in our pipeline.

因此，我們將繼續關注 LRRK2 及其在腸躁症和帕金森氏症中的作用，根據我們看到的一些生物標記的變化，至少在臨床前研究中，這些作用可能會擴展。所以我認為我們的產品線中有很多機會和潛力。

Paul Choi, GS.

保羅·崔，GS。

I had just a couple quick ones on ARV-393. Can you maybe just comment on what you'd like to see from your initial clinical data in patients that's coming up later this year to think about potential expansion into the post-stem cell population or maybe other subpopulations such as the elderly who are traditionally too fragile for standard of care such as R-CHOP?

我對 ARV-393 只問了幾個問題。您能否評論一下，根據您即將在今年稍後公佈的患者初步臨床數據，您希望看到什麼，以考慮將其擴展到幹細胞治療後人群或其他亞群，例如傳統上因過於脆弱而無法接受 R-CHOP 等標準治療的老年人？

And second, can you just confirm if that initial Phase 1 data will either be at EHA or ASH? Any clarity there would be great.

其次，您能否確認初始第一階段的資料是否會在 EHA 或 ASH 上？任何澄清都是很好的。

Okay. Thanks, Paul. Noah here. So we -- well, we're not giving guidance as to when we're presenting this. It's a bit far off still. And obviously, we're also still enrolling patients in this Phase 1.

好的。謝謝，保羅。諾亞在這裡。所以我們—嗯，我們沒有給出關於何時提出這一問題的指導。還有點遠。顯然，我們仍在招募第一階段的患者。

In terms of trying to go back, did you say something about stem cell? Can you just repeat that?

在嘗試回歸方面，您是否談到了乾細胞？你能重複一遍嗎？

Post-stem cell.

後幹細胞。

Yeah. Post-transplant populations, yeah, or elderly populations who are traditionally too fragile for R-CHOP.

是的。是的，移植後族群，或傳統上身體過於虛弱而無法接受 R-CHOP 治療的老年族群。

Yeah. So these -- that gets into what's the -- that gets into study design issues and opportunities. So we recognize that there are some opportunities. There are limitations for R-CHOP in large B cell lymphoma. I'm sorry.

是的。所以這些 — — 這就牽涉到了研究設計問題和機會。因此我們認識到存在一些機會。R-CHOP 在治療大 B 細胞淋巴瘤方面有其限制。對不起。

We recognize that R-CHOP in large B cell lymphoma may cure 50% of patients up front. And so it's a preferred treatment. You also see [PoliV] being used with CHIP in this population increasingly. So that's become more of a standard of care.

我們認識到，大 B 細胞淋巴瘤的 R-CHOP 可能預先治癒 50% 的患者。因此，這是一種首選治療方法。您還會看到，[PoliV] 與 CHIP 在該人群中的使用日益增多。因此這已經成為一種護理標準。

Yet, there are patients that can't be addressed with those treatment options. And so your question, I guess, is, can we make inroads in that population? And we think of it. It's possible.

然而，有些患者無法透過這些治療方法得到治療。所以我想你的問題是，我們能否在該群體中取得進展？我們也想到了這一點。這是有可能的。

We're showing good pre-clinical data for a combination with anti-CD20 therapy. That would be a thought of how to bring this forward. But overall, we'd be looking at -- and then you referred to the post-transplant patients.

我們展示了與抗 CD20 療法聯合使用的良好臨床前數據。這就是關於如何實現這一目標的想法。但總的來說，我們會關注——然後您提到了移植後患者。

So I guess you're talking whether it's an autologous transplant or if it's with bispecifics or with CAR-T. And I think it's premature to comment on those populations. On one hand, that's -- no doubt, that's where there's the most significant medical need.

所以我猜你談論的是自體移植還是雙特異性移植或 CAR-T 移植。我認為現在對這些人群發表評論還為時過早。一方面，毫無疑問，那裡的醫療需求最大。

But those patients also have very severe disease or rapid progressors and are a challenging population to look at as your first indication. So it depends on the data that we continue to accumulate in our Phase 1 study.

但這些患者的病情也非常嚴重或進展迅速，因此作為首要適應症來觀察的困難族群。所以這取決於我們在第一階段研究中繼續累積的數據。

But I think there's some inevitability to combinability or to combining our 393 with other agents, whether it's an anti-CD20 therapy, a bispecific, or other agents, in these advanced late-line settings as a start and then obviously moving to combinations in second line and even hopefully, first line.

但我認為，在這些先進的後線治療環境中，將 393 與其他藥物（無論是抗 CD20 療法、雙特異性療法還是其他藥物）進行組合或組合是不可避免的，然後顯然會轉向二線甚至一線的組合。

And then if I could just add to that, there are key opinion leaders who have collected post-CAR-T refractory lines that we are taking a look at pre-clinically just to assess how ARV-393 performs in that setting specifically. So I think more to come.

然後我可以補充一點，有一些關鍵意見領袖已經收集了 CAR-T 後抗藥性系，我們正在進行臨床前研究，只是為了評估 ARV-393 在這種環境下的具體表現。因此我認為接下來還會有更多。

Michael Schmidt, Guggenheim.

古根漢的邁克爾施密特。

I'm sorry. A couple more on vepdegestrant. Are you planning to present any of the VERITAC-3 lead-in data with palbo this year? And are there any learnings in terms of efficacy from that experience that can perhaps be applied to the design of the planned Phase 3 study with atirmociclib?

對不起。再說一些關於 vepdegestrant 的內容。今年您打算向 Palbo 展示任何 VERITAC-3 匯入資料嗎？並且，從該經驗中是否可以學到一些療效方面的東西，可以應用到計劃中的 atirmociclib 第 3 階段研究的設計中？

And then for VERITAC-2, as we are trying to contextualize Lily's [EMBR3] data from last December, perhaps relative to the post-MONARCH data from ASCO, what is your base case assumption for PFS in the full vestibular control arm in ITT? And is there one mutant subset for that study?

然後對於 VERITAC-2，由於我們試圖將去年 12 月 Lily 的 [EMBR3] 數據情境化，可能相對於 ASCO 的 MONARCH 後數據，您對 ITT 中完全前庭對照組的 PFS 的基本假設是什麼？該研究中是否存在一個突變子集？

Thanks, Michael. Yeah, in relation to our SLI, at some point, we haven't guided. We'll be sharing that data. Clearly, we've moved to the point where atirmociclib is the combination partner of choice in our first-line setting.

謝謝，麥可。是的，就我們的 SLI 而言，在某些時候，我們還沒有提供指導。我們將會分享這些數據。顯然，我們已經發展到 atirmociclib 作為我們一線治療的首選聯合治療夥伴的地步。

So in terms of how we informed that decision, it was probably lower ranking in terms of the decision-making. Clearly, we made the decision in terms of the entirety of the data we got through the SLI plus the data we've seen with the atirmo-vepdeg combo.

因此，就我們如何告知該決定而言，它在決策方面的排名可能較低。顯然，我們根據透過 SLI 獲得的全部數據以及透過 atirmo-vepdeg 組合看到的數據做出了決定。

So we're very happy with that decision-making. But at some point, once we get past this next big data set, we'll be talking about when the next data sets will come out and potentially including that SLI.

因此我們對這個決定非常滿意。但是在某個時候，一旦我們獲得了下一個大數據集，我們就會討論下一個資料集何時會出現，並且可能包括該 SLI。

Again, the question related to VERITAC, we're really not answering any questions, as we said at the beginning, related to VERITAC. And I know that's a very frustrating scenario for people on this call. But you understand, we're so close to the data set. And once that data set comes out, all questions will be answered.

再一次，對於與 VERITAC 相關的問題，正如我們一開始所說的，我們實際上並沒有回答任何與 VERITAC 相關的問題。我知道這對通話中的人來說是一個非常令人沮喪的情況。但你明白，我們距離資料集非常接近了。一旦該資料集出來，所有問題都會得到答案。

Thank you. This does conclude the Q&A session for today. I would now like to turn the call back over to John Houston for closing remarks. Please go ahead.

謝謝。今天的問答環節到此結束。現在我想將電話轉回約翰休斯頓，請他作最後發言。請繼續。

Well, thank you, operator, and thanks to everyone for joining us and all the great questions. As you can expect, we're really pleased with our execution and progress in '24, and we look forward to a very exciting 2025. So thank you for your time this morning and have a great day.

好吧，謝謝接線員，也謝謝大家加入我們並提出所有精彩的問題。正如您所期望的，我們對 2024 年的執行情況和進展感到非常滿意，並且期待著非常令人興奮的 2025 年。感謝您今天上午抽出時間，祝您有個愉快的一天。

Thank you all for joining today's conference call. You may now disconnect.

感謝大家參加今天的電話會議。您現在可以斷開連線。