Arvinas Inc (ARVN) 2024 Q3 法說會逐字稿

Thank you for standing by. At this time, I would like to welcome everyone to Arvinas' third-quarter 2024 earnings call. (Operator Instructions)

感謝您的支持。現在，我歡迎大家參加 Arvinas 2024 年第三季財報電話會議。（操作員指令）

I will now turn the conference over to Jeff Boyle. Please go ahead.

現在我將會議交給傑夫·博伊爾。請繼續。

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our third-quarter 2024 financial results and a corporate update, which can be accessed in the Investor section of our website at arvinas.com. Joining the call today are John Houston, Arvinas' Chief Executive Officer, President, and Chairperson; Noah Berkowitz, Chief Medical Officer; and Andrew Saik, Chief Financial Officer. Angela Cacace, our Chief Scientific Officer, will join for the Q&A portion of the call.

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 2024 年第三季的財務業績和公司最新消息，您可以在我們網站 arvinas.com 的投資者部分訪問。今天參加電話會議的有 Arvinas 執行長、總裁兼董事長 John Houston； Noah Berkowitz，首席醫療官；以及財務長 Andrew Saik。我們的首席科學官 Angela Cacace 將參加此次電話會議的問答部分。

Before we begin, I want to remind you that today's discussion will contain forward-looking statements that involve risks, uncertainties, and assumptions. These factors 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.

在我們開始之前，我想提醒您，今天的討論將包含涉及風險、不確定性和假設的前瞻性陳述。這些因素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都有概述，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。

I'll now 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 for our inaugural earnings conference call. So why are we starting earnings calls now, some six years after our IPO? Well, we have a truly exciting year ahead of us, and we are on the cusp of a huge transition for the company as we await our first pivotal data readout coming by the end of 2024 or the first quarter of 2025. In addition, we continue to make significant progress with a novel approach to discover, develop, and commercialize a new class of medicines for the treatment of cancers and neurodegenerative diseases.

謝謝，傑夫。大家早安，感謝大家參加我們的首次收益電話會議。那麼，為什麼我們在首次公開募股六年後的現在才開始召開收益電話會議呢？好吧，我們迎來了真正令人興奮的一年，我們正處於公司巨大轉型的邊緣，我們期待在 2024 年底或 2025 年第一季獲得第一個關鍵數據。此外，我們繼續以新方法發現、開發和商業化用於治療癌症和神經退化性疾病的新型藥物，並取得重大進展。

Actually, we look now forward to providing updates each quarter as we move closer to our goal of becoming a multi-product commercial-stage organization with a robust pipeline across several indications. We have a lot to discuss this morning, so I would like to provide an overview of the topics we'll be covering. 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 expectations for the VERITAC-2 trial and discuss our confidence in the combined ability of vepdegestrant or vepdeg with other metastatic breast cancer treatments.

實際上，我們現在期待每個季度提供更新，因為我們正越來越接近我們的目標，即成為一個多產品商業階段的組織，擁有涵蓋多種適應症的強大產品線。今天早上我們有很多內容要討論，因此我想概述我們將要討論的主題。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。然後，Noah 將概述我們對 VERITAC-2 試驗的期望，並討論我們對 vepdegestrant 或 vepdeg 與其他轉移性乳癌治療的綜合能力的信心。

And finally, Andrew will provide an overview of our third-quarter financial highlights. I will add some closing remarks, including what we believe is the opportunity for vepdeg, both as a combination and monotherapy, before opening the call for Q&A when, as Jeff mentioned, we will be joined by our Chief Scientific Officer, Angela Cacace.

最後，安德魯將概述我們第三季的財務亮點。在開始問答環節之前，我將做一些結束語，包括我們認為 vepdeg 作為聯合療法和單一療法的機會，正如 Jeff 提到的，我們的首席科學官 Angela Cacace 將加入我們的問答環節。

In the 11 years since our founding, we have taken major strides towards our mission to improve the lives of patients with serious 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.

自成立以來的11年裡，我們朝著改善嚴重疾病患者生活的使命邁出了重要的一步。我們的蛋白水解靶向嵌合體或 PROTAC 蛋白降解劑管道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。

This groundbreaking protein degradation platform has enabled us to create an exciting pipeline, driving some of the most significant breakthroughs in targeted protein degradation in the industry. These breakthroughs include designing degraders with drug-like properties that are orally bioavailable, and when needed, able to cross the blood-brain barrier. Very soon, we'll have in hand the first-ever Phase 3 data readout for our PROTAC.

這個突破性的蛋白質降解平台使我們能夠創建令人興奮的管道，推動產業在標靶蛋白質降解方面取得一些最重大的突破。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，並且在需要時能夠穿過血腦屏障。很快，我們將獲得 PROTAC 的首個第 3 階段資料讀數。

While the majority of our call this morning will be focused on our progress with vepdeg, we will also briefly cover the advancements we've made with our other clinical programs. In future calls, we will provide a deeper dive into our exciting pipeline that spans oncology and neuroscience. Our most advanced program, vepdeg, is an orally bioavailable PROTAC protein degrader specifically designed to target and degrade the estrogen receptor for the treatment of patients with ER positive/HER2 negative breast cancer.

雖然我們今天早上的主要會議內容將集中在 vepdeg 方面的進展上，但我們也將簡要介紹我們在其他臨床項目方面取得的進展。在未來的電話會議中，我們將更深入地探討涵蓋腫瘤學和神經科學的令人興奮的管道。我們最先進的項目 vepdeg 是一種口服生物可利用的 PROTAC 蛋白質降解劑，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。

Vepdeg works by degrading the estrogen receptor to block signaling through the ER pathway. By degrading the estrogen receptor, we believe vepdeg could potentially benefit patients with breast cancer who have ER positive/HER2 negative disease. As a reminder, in 2021, we entered a global 50/50 collaboration agreement with Pfizer, developed and commercialized vepdeg as a potential next-generation ER-targeting backbone therapy of choice in breast cancer as both monotherapy and in combination with other therapies.

Vepdeg 透過降解雌激素受體來阻斷 ER 路徑的訊號傳導。透過降解雌激素受體，我們相信 vepdeg 可能使 ER 陽性/HER2 陰性乳癌患者受益。提醒一下，2021 年，我們與輝瑞達成了全球 50/50 合作協議，開發並商業化了 vepdeg，作為乳腺癌的潛在下一代 ER 靶向骨幹療法，既可單獨治療，也可與其他療法聯合使用。

Together with Pfizer, we initiated the first-ever Phase 3 trial with the PROTAC, the VERITAC-2 trial. This is a randomized open-label multi-center trial of vepdeg versus fulvestrant in patients with ER positive/HER2 negative advanced breast cancer whose disease progressed after prior endocrine-based treatment for advanced disease. The readout of data from this pivotal Phase 3 clinical trial will be a landmark event for Arvinas.

我們與輝瑞合作，啟動了 PROTAC 的首個 3 期試驗，即 VERITAC-2 試驗。這是一項隨機開放標籤多中心試驗，比較了 vepdeg 與氟維司群對 ER 陽性/HER2 陰性晚期乳癌患者的療效，這些患者在先前接受內分泌治療後病情出現進展。這個關鍵性 3 期臨床試驗的資料讀取對於 Arvinas 來說將是一個里程碑事件。

We are on track to share top-line data by the end of 2024 or the first quarter of 2025 based on timing of events. If positive, these results will support our first new drug application and our potential transition to a commercial-stage company. If proven effective, vepdeg can offer an oral monotherapy treatment in the second-line setting, which could be a promising option for appropriate patients progressing on a CDK4/6 inhibitor-based regimen.

根據事件發生的時間，我們將在 2024 年底或 2025 年第一季分享營收資料。如果結果呈陽性，這些結果將支持我們的第一個新藥申請以及我們向商業階段公司的潛在轉型。如果證明有效，vepdeg 可以在二線環境中提供口服單藥治療，這對於在基於 CDK4/6 抑制劑的方案中取得進展的合適患者來說可能是一個有希望的選擇。

For context, approved ER targeting treatments provide a few months of progression-free survival in this setting, a once-daily oral monotherapy that offers a clinically meaningful improvement in PFS and if well tolerated could be an important advance for patients and commercially very attractive in a highly fragmented second-line treatment landscape.

就背景而言，已獲批准的 ER 標靶治療在這種情況下可以提供數月的無進展生存期，每日一次的口服單一療法可以為 PFS 帶來臨床上有意義的改善，如果耐受性良好，可能對患者來說是一個重要的進步，並且在高度分散的二線治療領域具有商業吸引力。

Additionally, we continue evaluating vepdeg in combination with other agents, including the approved CDK4/6 inhibitors, ribociclib and abemaciclib in the ongoing Phase 1b/2 TACTIVE-U umbrella trial. We look forward to presenting initial Phase 1b data from the abemaciclib substudy of TACTIVE-U in a poster at the San Antonio Breast Cancer Symposium later this year. The TACTIVE-K trial, which is evaluating vepdeg in combination with Pfizer's CDK4 selective inhibitor atirmociclib, continues to enroll patients.

此外，我們將繼續評估 vepdeg 與其他藥物的聯合作用，包括正在進行的 1b/2 期 TACTIVE-U 綜合試驗中已批准的 CDK4/6 抑制劑 ribociclib 和 abemaciclib。我們期待在今年稍後的聖安東尼奧乳癌研討會上以海報形式展示 TACTIVE-U abemaciclib 子研究的 1b 期初步數據。TACTIVE-K 試驗正在評估 vepdeg 與輝瑞 CDK4 選擇性抑制劑 atirmociclib 的聯合治療效果，目前試驗仍在繼續招募患者。

I will now turn to our earlier-stage programs where we see exciting potential opportunities for PROTAC across oncology and neuroscience targets. First, neuroscience is an area where the unique properties of PROTAC degraders are particularly well suited, especially given the potential drawbacks of other drug modalities like antibodies and antisense oligonucleotides.

現在我將轉向我們早期的項目，我們在其中看到了 PROTAC 在腫瘤學和神經科學領域令人興奮的潛在機會。首先，PROTAC 降解劑的獨特特性特別適合神經科學領域，尤其是考慮到抗體和反義寡核苷酸等其他藥物形式的潛在缺點。

Our most advanced neuroscience program, ARV-102, is a novel oral PROTAC designed to cross the blood-brain barrier and target leucine-rich repeat kinase 2 or LRRK2, which is a large multi-domain scaffolding kinase. We have shown that ARV-102 achieves deep brain region 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.

我們最先進的神經科學計畫 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，這是一種大型多結構域支架激酶。我們已經證明 ARV-102 能夠穿透非人類靈長類動物的深部腦區域並降解 LRRK2。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。

We intend to explore the potential of ARV-102 in two severe neurodegenerative disorders that are linked to LRRK2 dysregulation. Progressive supranuclear palsy, a disease with a strong genetic link implicating LRRK2 with faster progressing disease; and Parkinson's disease, where LRRK2 has been shown to contribute to the pathology of the disease. Earlier this year, we initiated dosing in a first-in-human Phase 1 clinical trial of ARV-102 in healthy volunteers.

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。進行性核上性麻痺是一種具有強烈遺傳關聯的疾病，顯示 LRRK2 與疾病進展速度更快有關；以及帕金森氏症，其中 LRRK2 已被證明是導致該疾病病理的原因之一。今年早些時候，我們開始在健康志願者中進行 ARV-102 的首次人體 I 期臨床試驗。

This ongoing Phase 1 trial is primarily designed to establish the safety of ARV-102 but will also measure LRRK2 degradation in the periphery and cerebrospinal fluid or CSF to establish the ability of ARV-102 to cross the blood-brain barrier and degrade LRRK2 in humans. The learnings from this Phase 1 trial will be valuable as we strive to address the incredibly high unmet need in neurodegenerative diseases. We look forward to sharing initial data for ARV-102 in 2025.

正在進行的 1 期試驗主要是為了確定 ARV-102 的安全性，但也將測量週邊和腦脊髓液或 CSF 中的 LRRK2 降解，以確定 ARV-102 穿過血腦屏障並在人體內降解 LRRK2 的能力。當我們努力解決神經退化性疾病領域中大量未滿足的需求時，從這個第一階段試驗中獲得的經驗將非常寶貴。我們期待在 2025 年分享 ARV-102 的初始數據。

We are also working with the Michael J. Fox Foundation's Parkinson's Progression Markers Initiative to identify novel LRRK2-dependent proteins that are altered in non-human primate CSF following administration of ARV-102. We recently presented at the Michael J. Fox Foundation's Annual Parkinson's Disease Therapeutics Conference, where we disclosed new pre-clinical biomarker data for ARV-102.

我們也與邁克爾·J·福克斯基金會的帕金森氏症進展標記計劃合作，以識別非人類靈長類動物腦脊髓液中註射 ARV-102 後發生改變的新型 LRRK2 依賴性蛋白質。我們最近在邁克爾·J·福克斯基金會的年度帕金森氏症治療會議上發表了報告，披露了 ARV-102 的新臨床前生物標記數據。

To our knowledge, this is the first data set to demonstrate that the degradation of LRRK2 induces changes in pathway biomarkers of lysosomal function and inflammation in the CSF of non-human primates, an exciting discovery suggesting that the PROTAC mechanism may lead to differential outcomes versus LRRK2 inhibitors. The presentation is posted in the Scientific Publications section of our website.

據我們所知，這是第一組證明 LRRK2 的降解會誘導非人類靈長類動物腦脊髓液中溶酶體功能和發炎途徑生物標記發生變化的數據集，這一令人興奮的發現表明 PROTAC 機制可能導致與 LRRK2 抑制劑不同的結果。該簡報已發佈在我們網站的科學出版物部分。

Turning now to our third clinical program, we are also pleased with the pre-clinical profile of ARV-393, our PROTAC designed to degrade B-cell lymphoma 6 protein or BCL6, a transcriptional repressor and a major driver of B-cell lymphomas. The BCL6 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 become dysregulated in several types of non-Hodgkin lymphomas.

現在談到我們的第三個臨床項目，我們對 ARV-393 的臨床前概況也感到滿意，ARV-393 是我們的 PROTAC，旨在降解 B 細胞淋巴瘤 6 蛋白或 BCL6，BCL6 是一種轉錄阻遏物和 B 細胞淋巴瘤的主要驅動因素。BCL6 蛋白透過抑制細胞週期檢查點、終末分化、細胞凋亡和 DNA 損傷反應來促進 B 細胞對快速增殖和體細胞基因重組的耐受，而這些在幾種類型的非何杰金氏淋巴瘤中會出現失調。

PROTAC-mediated degradation has the potential to overcome the traditional undruggable nature of BCL6. We are recruiting patients with non-Hodgkin lymphoma in a Phase 1 clinical trial of ARV-393 and look forward to updating you on our progress next year.

PROTAC 介導的降解有可能克服 BCL6 傳統上無法用藥的性質。我們正在招募 ARV-393 第 1 期臨床試驗中的非何杰金氏淋巴瘤患者，並期待明年向您通報我們的進展。

Finally, we are preparing to file an investigational new drug application in 2025 for our KRAS G12D program. KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. We are also developing a novel pan-KRAS degrader and look forward to sharing more about this as we progress this promising program.

最後，我們準備在 2025 年為我們的 KRAS G12D 計畫提交新藥試驗申請。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。我們也正在開發一種新型泛 KRAS 降解劑，並期待在這個有前景的專案進展過程中分享更多相關資訊。

With that, I'll turn the call over to Noah for a more detailed overview of the vepdeg program. Noah?

說完這些，我將把電話轉給 Noah，以便他對 vepdeg 計劃進行更詳細的概述。諾亞？

Thanks, John. And good morning, everyone. I'm happy to provide an update on the progress we and our partner, Pfizer, have made with our vepdeg program. Let me first note that even with the recent advances in treatment options, there is still a high unmet medical need in ER positive/HER2 negative metastatic breast cancer. Despite the availability of multiple therapies, as patients move into the late-line setting, most will experience disease progression within a few months of initiating treatment.

謝謝，約翰。大家早安。我很高興向大家介紹我們和我們的合作夥伴輝瑞公司在 vepdeg 專案上的進展。首先我要指出的是，即使最近治療方案取得了進展，但 ER 陽性/HER2 陰性轉移性乳癌仍然存在很大的未滿足的醫療需求。儘管有多種治療方法，但隨著患者進入後期治療，大多數患者在開始治療後的幾個月內就會出現病情進展。

Also the tolerability and the route of administration of available therapies may adversely affect patient's quality of life. We believe vepdeg has the potential to become a best-in-class backbone ER-targeting therapy with superior efficacy and tolerability, which could support it becoming a preferred and valuable treatment option for physicians and their patients. This is why I'm excited to discuss the VERITAC-2 trial, our second-line plus Phase 3 trial with vepdeg, which is on track for a top-line data readout by the end of 2024 or in the first quarter of 2025 with timing driven by accumulation of PFS events.

此外，現有療法的耐受性和給藥途徑可能會對患者的生活品質產生不利影響。我們相信，vepdeg 有潛力成為一流的骨幹 ER 標靶治療方法，具有卓越的療效和耐受性，這可以支持它成為醫生及其患者的首選和有價值的治療選擇。這就是為什麼我很高興討論 VERITAC-2 試驗，這是我們與 vepdeg 進行的二線加三期試驗，該試驗預計將在 2024 年底或 2025 年第一季讀取頂線數據，時間安排由 PFS 事件的累積決定。

The trial is evaluating the efficacy and safety of vepdeg compared with fulvestrant in patients with ER positive/HER2 negative advanced breast cancer. The patients enrolled in VERITAC-2 have previously received and progressed on a combination of CDK4/6 inhibitors and endocrine therapy. VERITAC-2 has two co-primary endpoints, progression-free survival or PFS and the ITT or intention-to-treat population, and PFS in the ESR1 mutations subpopulation.

該試驗正在評估 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。參與 VERITAC-2 試驗的患者之前曾接受過 CDK4/6 抑制劑和內分泌療法聯合治療，並取得進展。VERITAC-2 有兩個共同主要終點，無惡化存活期或 PFS 和 ITT 或意圖治療族群，以及 ESR1 突變亞群中的 PFS。

PFS will be assessed by blinded independent central review. Secondary outcome measures include overall survival; anti-tumor activity, including objective response, duration of response, and clinical benefit rate; and safety and quality of life assessments. Although important progress has been made in treatment of metastatic breast cancer for patients who have received prior treatment with CDK4/6 inhibitors, the most recently approved oral agent has an approval limited to patients with ESR1 mutations and has shown a median PFS of 3.8 months.

PFS 將透過盲法獨立中央審查進行評估。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；以及安全和生活品質評估。儘管對於接受 CDK4/6 抑制劑治療的轉移性乳癌患者的治療已經取得了重要進展，但最近批准的口服藥物僅限於 ESR1 突變患者，且中位 PFS 為 3.8 個月。

The VERITAC-2 study of vepdeg is in CDK4/6-inhibitor-experienced patients and was designed to demonstrate a benefit over fulvestrant in both the ITT and ESR1 mutant subpopulations. Now let's discuss our expectations for the VERITAC-2 trial. Based on our study design, we expect to show a meaningful improvement over fulvestrant. We look forward to sharing top-line data in the coming months and submitting this for review to health authorities.

VERITAC-2 對 vepdeg 的研究針對接受過 CDK4/6 抑制劑治療的患者，旨在證明其在 ITT 和 ESR1 突變亞群中均優於氟維司群。現在讓我們討論一下我們對 VERITAC-2 試驗的期望。根據我們的研究設計，我們期望顯示出比氟維司群更有意義的改進。我們期待在未來幾個月內分享主要數據並將其提交給衛生當局審查。

If successful, this may result in the first-ever regulatory approval of a PROTAC degrader and act as the first step in establishing vepdeg as a backbone ER therapy of choice. In addition to the Phase 3 VERITAC-2 trial, as John mentioned, we and Pfizer continue to evaluate data from several additional studies to inform the design of the potential Phase 3 combination trials that we anticipate will start in 2025, pending regulatory feedback.

如果成功，這可能導致 PROTAC 降解劑首次獲得監管部門批准，並成為將 vepdeg 確立為首選 ER 骨幹療法的第一步。除了第三階段 VERITAC-2 試驗之外，正如約翰所提到的，我們和輝瑞公司還將繼續評估幾項其他研究的數據，以便為我們預計將於 2025 年開始的潛在第三階段聯合試驗的設計提供信息，等待監管部門的反饋。

One is the second-line plus setting, and the other is in the first-line setting. We will evaluate data from TACTIVE-U, TACTIVE-K, and the study lead-in portion of VERITAC-3 to inform our decision about which agents can be combined with vepdeg. Preliminary data from the combination of vepdeg and abemaciclib will be presented at the San Antonio Breast Cancer Symposium in December.

一種是二線加設置，一種是一線設置。我們將評估 TACTIVE-U、TACTIVE-K 和 VERITAC-3 的研究導入部分的數據，以便我們決定哪些藥物可以與 vepdeg 聯合使用。vepdeg 和 abemaciclib 聯合治療的初步數據將於 12 月在聖安東尼奧乳癌研討會上公佈。

We believe these data will show a manageable safety profile at the full doses of both agents and that the preliminary PK safety and early efficacy will reinforce the potential of vepdeg to be used in combination with standard-of-care breast cancer agents. With respect to other sub-studies within TACTIVE-U, enrollment is ongoing, and we anticipate that initial data from the ribociclib combination will be available next year.

我們相信這些數據將顯示兩種藥物全劑量下的可控安全性，初步的 PK 安全性和早期療效將增強 vepdeg 與標準乳癌藥物聯合使用的潛力。對於 TACTIVE-U 內的其他子研究，招募工作正在進行中，我們預計明年將獲得 ribociclib 組合的初步數據。

We expect these data will further show vepdeg's potential as an ER backbone therapy of choice. We are also making progress in the Phase 1/2 TACTIVE-K trial, which is evaluating vepdeg's plus Pfizer's novel CDK4 inhibitor, atirmociclib. We and Pfizer look forward to evaluating data from this trial later this year, which we will use to inform the design of our Phase 3 trial in the first-line setting. Overall, we believe vepdeg has the potential to provide superior efficacy and tolerability, both as a monotherapy and in combination for patients with breast cancer who are in need of new treatment options.

我們預計這些數據將進一步顯示 vepdeg 作為首選 ER 骨幹療法的潛力。我們也在 1/2 期 TACTIVE-K 試驗中取得進展，該試驗正在評估 vepdeg 與輝瑞新型 CDK4 抑制劑 atirmociclib 的聯合作用。我們和輝瑞期待在今年稍後評估該試驗的數據，我們將利用這些數據來指導我們在第一個試驗環境中的 3 期試驗的設計。總的來說，我們相信，對於需要新治療方案的乳癌患者來說，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。

With that, I'll now turn the call over to Andrew for a review of our financials. Andrew?

說完這些，我現在將電話轉給安德魯，讓他審查我們的財務狀況。安德魯？

Thanks, Noah. I'm pleased to share financial highlights for the third quarter ended September 30, 2024. As a reminder, detailed financial results for the third quarter are included in the press release we issued this morning. As we near our first Phase 3 trial readout, we are in a strong financial position with cash on hand sufficient to support our operations into 2027.

謝謝，諾亞。我很高興分享截至 2024 年 9 月 30 日第三季的財務亮點。提醒一下，我們今天早上發布的新聞稿中包含了第三季的詳細財務結果。隨著我們接近第一階段 3 試驗的結果，我們的財務狀況強勁，手頭上的現金足以支持我們到 2027 年的營運。

At the end of Q3, we had $1.1 billion in cash, cash equivalents, and marketable securities on the balance sheet. This allows us to progress all of our key strategic objectives, which include progressing the vepdeg clinical program, including two expected Phase 3 programs starting later next year; preparing for our first launch of a commercial product; and advancing our promising portfolio of PROTAC degraders. Let me now turn to financial highlights from the third quarter.

截至第三季末，我們的資產負債表上有 11 億美元現金、現金等價物和有價證券。這使我們能夠推進所有關鍵戰略目標，包括推進 vepdeg 臨床計劃，其中包括預計於明年稍後啟動的兩個第 3 階段計劃；為我們首次推出的商業產品做準備；並推進我們有前景的 PROTAC 降解劑產品組合。現在我來介紹一下第三季的財務亮點。

During the quarter, we recorded $102.4 million in revenue. That was compared to $34.6 million in revenue for the same period in 2023. The increase of $67.8 million was primarily due to revenue from the Novartis license agreement of $76.7 million, offset by a decrease in revenue from the Vepdeg Collaboration Agreement with Pfizer of $7.6 million and a decrease in revenue from Bayer of $1.1 million.

本季度，我們的營收為 1.024 億美元。相較之下，2023 年同期的營收為 3,460 萬美元。6,780 萬美元的增幅主要由於來自諾華許可協議的收入 7,670 萬美元，但與輝瑞簽訂的 Vepdeg 合作協議的收入減少 760 萬美元以及來自拜耳的收入減少 110 萬美元抵消了這一增長。

General and administrative expenses were $75.8 million in the third quarter compared to $22.6 million for the same period in 2023. The increase of $53.2 million was primarily due to the termination of our laboratory and office space lease with 101 College Street of $43.4 million as well as increases in personnel and infrastructure-related costs of $5 million.

第三季的一般及行政費用為 7,580 萬美元，而 2023 年同期為 2,260 萬美元。5,320 萬美元的增加主要是由於我們終止與 101 College Street 的實驗室和辦公空間租約（價值 4,340 萬美元）以及人員和基礎設施相關成本增加 500 萬美元。

Research and development expenses were $86.9 million in the third quarter compared to $85.9 million for the same period in 2023. The increase of $1 million is primarily due to an increase in personnel-related expenses of $2.8 million, partially offset by a decrease in program-related expenses of $2.2 million. As we embark on a pivotal year for Arvinas, we are focused on making strategic investments in programs that are meaningful to patients and truly differentiated. And I'm confident that our strong balance sheet will enable us to accomplish our objectives.

第三季研發費用為 8,690 萬美元，而 2023 年同期為 8,590 萬美元。100萬美元的增加主要是因為人員相關費用增加280萬美元，但部分被項目相關費用減少220萬美元所抵銷。隨著我們進入 Arvinas 的關鍵一年，我們專注於對患者有意義且真正差異化的專案進行策略性投資。我相信，我們強勁的資產負債表將使我們能夠實現我們的目標。

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. This is clearly an exciting time for Arvinas. We are well on our way to becoming a commercial-stage organization with strong leadership and a rich pipeline across multiple therapeutic areas. In partnership with our colleagues in breast cancer at Pfizer, we have an exceptional team of experienced leaders who stand ready to bring vepdeg to breast cancer patients in need of new treatments.

謝謝，安德魯。對阿爾維納斯來說，這顯然是一個激動人心的時刻。我們正順利成為一個商業階段的組織，擁有強大的領導力和跨多個治療領域的豐富產品線。我們與輝瑞公司的乳癌同事合作，擁有一支經驗豐富的領導團隊，他們隨時準備為需要新療法的乳癌患者提供 vepdeg。

We believe that the upcoming top-line data from the Phase 3 VERITAC-2 trial will be the first step in establishing vepdeg as an ER backbone therapy, first as a monotherapy, and over the next few years, in combination with other treatments. Every year, nearly 40,000 patients with metastatic breast cancer are treated in the second-line-plus setting with approximately one-third receiving monotherapy treatment.

我們相信，即將發布的 3 期 VERITAC-2 試驗的頂線數據將是確立 vepdeg 作為 ER 骨幹療法的第一步，首先作為單一療法，並在未來幾年與其他治療方法相結合。每年有近 4 萬名轉移性乳癌患者接受二線加治療，其中約三分之一接受單一療法治療。

In the first-line setting, another 40,000 patients are treated every year, and most of these patients will receive an ER therapy as part of their treatment. By establishing vepdeg as a monotherapy into the second-line-plus setting, we have an opportunity to lay the foundation to potentially change the treatment paradigm for many thousands of patients with advanced ER positive/HER2 negative breast cancer. In addition to vepdeg, we are advancing a broad pipeline of product candidates across several therapeutic areas, including hematology and neurology with our PROTAC discovery engine.

在第一線治療中，每年還有另外 40,000 名患者接受治療，其中大多數患者將接受 ER 治療作為治療的一部分。透過將 vepdeg 作為單一療法納入二線加用方案，我們有機會為數千名晚期 ER 陽性/HER2 陰性乳癌患者的治療模式奠定基礎。除了vepdeg之外，我們還利用PROTAC發現引擎，在多個治療領域（包括血液學和神經病學）推進廣泛的候選產品線。

Before opening the call to your questions, I would like to thank the patients and physicians who are participating in our clinical trials. I'd also like to thank our talented and dedicated Arvinas team and our partners in breast cancer at Pfizer for the hard work and passion they bring every day. Our progress would not be possible without their commitment. And lastly, I'd like to thank our shareholders for their continued support.

在開始回答你們的問題之前，我想感謝參與我們臨床試驗的病人和醫生。我還要感謝我們才華橫溢、敬業的 Arvinas 團隊以及輝瑞乳癌領域的合作夥伴，感謝他們每天的辛勤工作和熱情。如果沒有他們的承諾，我們的進步就不可能實現。最後，我要感謝股東們的持續支持。

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 ask that you limit yourself to one question per cycle to make sure we are able to give appropriate time to everyone. Feel free to rejoin the queue for any follow-up questions. And with that, operator, can you please open up the queue?

謝謝，約翰。在我將電話轉給接線員之前，我會要求您在每個週期內將自己限制為一個問題，以確保我們能夠為每個人提供適當的時間。如果還有任何後續問題，歡迎隨時重新加入隊列。接線員，您能打開排隊嗎？

(Operator Instructions) Akash Tewari, Jefferies.

(操作員指示) Akash Tewari，Jefferies。

Hi. This is Manoj in for Akash. Thanks for taking our question. So just one, should investors' base case be that Pfizer moves with their CDK4 combo with the vepdeg, not only for the first line, but also for the second line, why would IBRANCE or any other CDK4/6 combination be used at all in your pivotal studies if CDK4 inhibition shows meaningfully better hematotoxicity?

你好。這是 Manoj，代替 Akash。感謝您回答我們的問題。因此，首先，投資者的基本情況是否應該是輝瑞將其 CDK4 組合與 vepdeg 一起用於第一線治療，也用於第二線治療，如果 CDK4 抑制顯示出明顯更好的血液毒性，那麼為什麼在您的關鍵研究中要使用 IBRANCE 或任何其他 CDK4/6 組合呢？

Thanks for the question. Could you just repeat the beginning of the question?

謝謝你的提問。您能重複問題的開頭嗎？

Should the base case be like Pfizer moves with the CDK4 inhibitor combo with vepdeg in the first line and second line?

基本情況是否應該像輝瑞公司在第一線和第二線採用 CDK4 抑制劑與 vepdeg 的組合？

I see, so you're asking whether or not our base case should be -- in the first line should be CDK4 plus vepdegestrant.

我明白，所以你問的是我們的基準情況是否應該是——第一行應該是 CDK4 加 vepdegestrant。

Yes.

是的。

That's a great question. And clearly, first of all, we're very excited about the fact that our data is right on our doorstep. So by the end of this year, beginning of next year, we'll have our pivotal data. We're also excited by the fact that we have a combination ongoing with atirmociclib.

這是一個很好的問題。顯然，首先，我們對我們的數據就在我們家門口這一事實感到非常興奮。所以到今年年底或明年年初，我們就會獲得關鍵數據。我們也很高興能夠與 atirmociclib 進行聯合治療。

Clearly, that's a very exciting asset. I think if we end up choosing that with Pfizer, that is the combination partner, I think that will be a great step forward. But obviously, we've got data ongoing with our palbociclib combination. We'll have that data this year and allow us to make decisions next year with Pfizer and the combination. But yes, I think we would be very excited if the data tells us that the CDK4/vepdegestrant combination is the right one. We would be very excited.

顯然，這是一項非常令人興奮的資產。我認為，如果我們最終選擇輝瑞作為聯合合作夥伴，那將是向前邁出的一大步。但顯然，我們已經獲得了有關 palbociclib 組合的持續數據。我們今年將獲得這些數據，以便我們明年與輝瑞和該組合做出決策。但是的，我認為如果數據告訴我們 CDK4/vepdegestrant 組合是正確的，我們會非常興奮。我們會非常興奮。

Yes, thank you.

是的，謝謝。

Brad Canino, Stifel.

布拉德‧卡尼諾 (Brad Canino)，Stifel。

Good morning and thank you for the updates. Question for me on the upcoming abemaciclib combo data. Could you help frame that expectation relative to the palbo combo data you presented last year where you had the 11-month PFS, strong response rates, activity in both ESR1 mutant and wild type? Is that the bar as we think about additional CDK combos that you will be unveiling over the next several quarters in these pre-treated Phase 1b populations? Thank you.

早上好，感謝您的更新。向我詢問有關即將推出的 abemaciclib 組合資料的問題。您能否幫助根據您去年提供的 Palbo 組合數據來構建該預期，其中您擁有 11 個月的 PFS、強大的反應率、ESR1 突變體和野生型的活性？當我們考慮在接下來的幾個季度中在這些經過預先治療的 1b 期人群中推出額外的 CDK 組合時，這就是標準嗎？謝謝。

Yes. Thanks. Great question. Clearly, we were very, very excited about our data set with the palbo combination. I'm going to hand this over to Noah in a second. The thing to remember is that data set, that was not 100% patients that were CDK4/6 experienced. 86% of patients had CDK4/6 and then 14% didn't. In this trial with abemaciclib, when you see this data, it is 100% post CDK4/6. So just with that caveat, I'll ask Noah to make some comments.

是的。謝謝。好問題。顯然，我們對包含 Palbo 組合的資料集感到非常興奮。我馬上就把這個交給諾亞。要記住的是，該資料集並不是 100% 的患者都有 CDK4/6 經驗。 86% 的患者有 CDK4/6，14% 的患者沒有。在本次 abemaciclib 試驗中，當您看到這些數據時，它是 100% 後 CDK4/6。因此，出於這個警告，我會請諾亞發表一些評論。

Sure. So we had the benefit when we reported the results of the palbo/vepdeg combination last year to have long follow-up of patients. And so that's why I think you referenced the median PFS we observed there. But in addition, as you suggested, we were able to look at response rate and safety in that population.

當然。因此，當我們去年報告 palbo/vepdeg 組合治療的結果時，我們就受益於對患者的長期追蹤。所以我認為這就是您引用我們在那裡觀察到的中位 PFS 的原因。但此外，正如您所建議的，我們還能夠觀察該族群的回應率和安全性。

So I would view this smaller data set that we're going to be presenting from abemaciclib with shorter follow up as a data set that can inform about the efficacy of the drug, but looking at things like the response rate, which can mature further and similar for CBR. And then on top of it, the safety profile, which will include actually even more recently treated patients and will be a larger data set and then you can make that type of comparison.

因此，我認為我們將從 abemaciclib 中展示的這個較小的數據集，加上較短的追蹤時間，可以作為了解藥物療效的數據集，但同時會考慮諸如響應率之類的因素，這些因素可以進一步成熟，與 CBR 類似。在此基礎上，安全性概況實際上將包括更多最近接受治療的患者，並且將是一個更大的數據集，然後您就可以進行這種類型的比較。

Got it. Thank you.

知道了。謝謝。

Etzer Darout, BMO Capital Markets.

Etzer Darout，BMO資本市場。

Great. Thanks for taking the question. Thank you for the updates today. Just a question around the fulvestrant control arm for VERITAC-2. We've gotten questions on that, sort of, if you could maybe frame your expectations? And do you think if there's anything we can read through to the Lilly upcoming data sets around where that control arm lands and where -- how it actually could perform for VERITAC-2? Anything incremental on your expectations around that? Thank you.

偉大的。感謝您回答這個問題。感謝您今天的更新。我只想問一下有關 VERITAC-2 的氟維司群控制臂。我們已經收到了一些關於這方面的疑問，您能否闡述一下您的期望？您是否認為，我們可以透過禮來公司即將發布的資料集來了解控制臂的位置以及它在 VERITAC-2 中的具體表現？您對此有什麼新的期望嗎？謝謝。

Yes. Great question. And again, I'll be handing over to Noah just to give you some detail in terms of the answer there. Clearly, the design of our VERITAC-2 trial was based on standard of care, which was fulvestrant. It still is. And our design is to show that we can be superior to fulvestrant.

是的。好問題。再次，我將把問題交給諾亞 (Noah)，以便他能為您提供一些詳細的答案。顯然，我們的 VERITAC-2 試驗設計是基於標準治療，即氟維司群。現在依然如此。我們的設計是為了證明我們可以優於氟維司群。

We're also very excited to see what the EMBER-3 data will show when it comes out. And now clearly, we want to be able to look at the different patient populations there. Again, VERITAC-2 will be 100% CDK4/6 experienced patients. And when we look at EMBER-3 data, you want to be able to look at that data and be able to do the kind of like-for-like comparison.

我們也非常興奮地看到 EMBER-3 數據發布後將會顯示什麼。現在顯然，我們希望能夠觀察那裡不同的患者群體。再次強調，VERITAC-2 將 100% 針對 CDK4/6 經驗豐富的患者。當我們查看 EMBER-3 數據時，您希望能夠查看這些數據並進行同類比較。

Noah, do you want to say anything more about the fulvestrant control arm and how that may be compared to what Lilly might do?

諾亞，您是否想再談談氟維司群對照組以及它與禮來可能採取的措施有何不同？

Sure. Thanks, John, and thanks for the question. So overall, we -- it's difficult, obviously, to predict exactly what we're going to see from the fulvestrant arm. We expect that given the prior treatment that patients have experienced, it will be somewhere in between what was observed in the EMERALD study and what was observed in the post-MONARCH study. So we would expect it to be somewhere in the three- to four-month range.

當然。謝謝，約翰，謝謝你的提問。所以總的來說，我們——顯然很難準確預測氟維司群組會產生什麼結果。我們預計，考慮到患者先前接受的治療，其結果將介於 EMERALD 研究和 MONARCH 後研究中觀察到的結果之間。因此我們預計它將介於三到四個月的範圍內。

And by comparison, we would hope to see a few months better for the vepdeg arm. And in terms of your -- that second part of your question about EMBER-3, we don't know exactly what to expect from that. What we'll be looking at is what is the safety and tolerability of that combination and also in what patient population. There is some -- when you look at the inclusion criteria for EMBER-3, it looks like patients who were not CDK4/6 exposed could be enrolled in the study. So we'd have to understand the results in the context of prior CDK4/6 exposure to draw any comparison to our study.

相比之下，我們希望看到 vepdeg 團隊的表現能好幾個月。關於您關於 EMBER-3 的問題的第二部分，我們不知道它到底會帶來什麼結果。我們將關注的是這種組合的安全性和耐受性，以及適用於哪些患者群體。當您查看 EMBER-3 的納入標準時，似乎未接觸 CDK4/6 的患者也可以參加研究。因此，我們必須在先前 CDK4/6 暴露的背景下理解結果，才能與我們的研究進行比較。

Great, thank you.

太好了，謝謝。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）

Hey, guys, thanks for taking the question. So I guess into VERITAC-2, how are you thinking about the potential for success in the non-ESR1 population? And if you could sort of review the reasons you think that this could be successful? And then what do you think is the minimum threshold for success here on PFS to be able to get this broader label across ESR1 and non-ESR1 patients? Thanks.

嘿夥計們，感謝你們回答這個問題。所以我猜測，對於 VERITAC-2，您如何看待其在非 ESR1 人群中取得成功的可能性？您能否回顧一下您認為這可能成功的原因？那麼您認為 PFS 成功的最低門檻是什麼，才能在 ESR1 和非 ESR1 患者中獲得更廣泛的標籤？謝謝。

Thanks, Ellie, that's great question. And again, I'll be handing over to Noah for the specific answer. Clearly, in this second-line-plus patient population, we are fighting against the biology of the disease. Obviously, a significant part of the disease is driven by ESR1 mutation. We think around 40% of the patients who have tumors that are still endocrine sensitive.

謝謝，艾莉，這個問題問得真好。再次，我將把具體答案交給 Noah。顯然，在這個二線以上患者群體中，我們正在與疾病的生物學作鬥爭。顯然，很大一部分的疾病是由 ESR1 突變引起。我們認為大約 40% 的腫瘤患者仍然對內分泌敏感。

And then there's a large group of patients with tumors that have got wild-type and other driving mutations. And we think a slice of that patient population will also be able to react well to vepdegestrant. So just remember that there's that biology there of the disease that we're fighting against. But yes, Noah, do you want to be specific about it?

還有一大群腫瘤患者存在野生型和其他驅動突變。我們認為，其中一部分患者也能夠對 vepdegestrant 產生良好的反應。所以請記住，我們正在對抗的這種疾病存在著生物學特性。但是的，諾亞，你想具體說明一下嗎？

Sure. Not a lot to add there because I think you addressed it, but I would say that our expectation is, as you know, we have co-primary endpoints in the study. We're looking at the ESR1 mutant and ITT population. So our expectation is that we're going to be successful with those primary endpoints. Our base case for what will be approved is the ESR1 mutant subpopulation more than anything else because that's the precedent that's been set at regulatory bodies.

當然。沒有太多需要補充的，因為我認為你已經解決了這個問題，但我想說的是，我們的期望是，如你所知，我們在研究中有共同的主要終點。我們正在觀察 ESR1 突變體和 ITT 族群。因此，我們的期望是能夠成功實現這些主要終點。我們對獲得批准的基本情況是 ESR1 突變亞群，因為這是監管機構已經樹立的先例。

What we have to see, though, in the non-mutated patients would be some type of -- I would assume regulatory bodies will want to do some post hoc analysis, and we'll be looking at that with them. And we would want to see some benefit, though I'd remind you that the study is not powered for that population.

然而，我們必須在未發生突變的患者身上看到某種類型——我認為監管機構將希望進行一些事後分析，我們將與他們一起研究這一點。我們希望看到一些好處，但我要提醒你，這項研究並不是針對該族群。

We believe that it would be successful, as John outlined, because the underlying biology of the wild-type population is that many of those patients are still endocrine sensitive and don't have alternative driver mutations that might limit their responsiveness to vepdegestrant. So we remain pretty confident that we can see a positive result for ESR1 mutant and for the ITT population. Thanks, Ellie.

正如約翰所概述的，我們相信它會成功，因為野生型群體的潛在生物學特性是，許多患者仍然對內分泌敏感，並且沒有可能限制其對 vepdegestrant 的反應性的替代驅動突變。因此，我們仍然非常有信心看到 ESR1 突變體和 ITT 群體的正面結果。謝謝，艾莉。

Great, thanks.

非常好，謝謝。

Derek Archila, Wells Fargo.

富國銀行的德里克‧阿奇拉 (Derek Archila)。

Good morning. This is [Elane] for Derek. Thanks for taking our question. One from us. Can you help frame a little bit the market for vepdeg, assuming you hit stat/sig in both ESR1 mutant patients and wild type? And what if you only hit in the ESR1 mutant patients? Are there any good analogs there? Thanks.

早安.我是 [Elane]，代表 Derek。感謝您回答我們的問題。其中一個是我們的。假設您在 ESR1 突變患者和野生型中都達到了 stat/sig，您能否幫助建立一些 vepdeg 的市場？那麼如果你只擊中了 ESR1 突變患者會怎麼樣呢？那裡有沒有什麼好的類似物？謝謝。

Yes. Thanks for the question. And clearly, we think there's a significant opportunity here, specifically for monotherapy, then even bigger opportunity as we move into second-line combination and first-line combination. I think as I said earlier, nearly 40,000 patients with metastatic breast cancer are treated in the second-line setting. And right now, about a third of them are getting monotherapy treatment.

是的。謝謝你的提問。顯然，我們認為這是一個重大機遇，特別是對於單一療法而言，而隨著我們進入二線聯合治療和一線聯合治療，機會甚至更大。我想正如我之前所說，近 40,000 名轉移性乳癌患者接受第二線治療。目前，約有三分之一的患者正在接受單一療法治療。

And then in the first-line setting, it's another 40,000 patients are diagnosed every year. And the majority of those patients will receive an ER therapy as part of their treatment. So we believe the game plan of establishing vepdegestrant and its potential as a monotherapy in that second-line plus setting will give us the opportunity to lay that foundation to potentially change the treatment paradigm for those many thousands of patients that have got ER positive/HER2 negative breast cancer. And of course, if we can show a PFS in line with combination therapies, we believe we can grow the monotherapy opportunity significantly.

在第一線治療中，每年又有 40,000 名患者被診斷出患有此疾病。大多數患者將接受急診室治療作為治療的一部分。因此，我們相信，建立 vepdegestrant 的計劃及其作為二線以上單一療法的潛力將使我們有機會奠定基礎，從而有可能改變數千名 ER 陽性/HER2 陰性乳癌患者的治療模式。當然，如果我們能夠展示與聯合療法一致的 PFS，我們相信我們可以顯著增加單一療法的機會。

I just wanted to offer one comment, not addressing the underlying market question, but you had mentioned stat/sig for wild-type and for ESR1 mutant. So again, I wanted to remind that the study design is to look at and we'll be doing our statistics on the ESR1 mutant and for the ITT population. We're not doing stats for the wild-type subset of the ITT population. I just wanted to make sure that was clear.

我只是想提供一條評論，不解決潛在的市場問題，但您提到了野生型和 ESR1 突變體的 stat/sig。所以，我再次提醒，研究設計是為了觀察，我們將對 ESR1 突變體和 ITT 族群進行統計。我們沒有對 ITT 族群的野生型子集進行統計。我只是想確保這一點清楚。

Li Watsek, Cantor.

李·瓦特塞克，領唱。

Hey. Good morning, guys, and thanks for taking our questions. I guess for the Phase 3 combo trials in front line and second line, wondering if you can elaborate a little bit on the key regulatory inputs that you still need before you nail down the final design? And how much of that is still dependent on the data that you need to generate?

嘿。大家早安，謝謝你們回答我們的問題。我想，對於一線和二線的第三階段組合試驗，想知道您是否可以詳細說明一下在確定最終設計之前仍然需要的關鍵監管輸入？其中有多少仍然依賴您需要產生的數據？

Thank you for the question. Yes, the question is about the key regulatory thinking in terms of the path forward for our first-line and second-line combos. Noah, do you want to talk to that?

感謝您的提問。是的，問題是關於我們的一線和二線組合未來發展的關鍵監管思路。諾亞，你想談談這個嗎？

So again, these are ahead of us. So after the VERITAC-2 results, which we're expecting in Q4, Q1, we head into the planning for next year that I think you're alluding to, which is combinations for first and second line. Each of those requires a health authority discussion. You've seen in our guidance that we -- and heard in our conversation a moment ago that we're looking to combine in the second line with palbo and/or a CDK4, another CDK4/6 inhibitor.

所以，這些都還在我們前面。因此，在獲得我們預計在第四季度和第一季度公佈的 VERITAC-2 結果之後，我們將開始製定明年的規劃，我想您提到了這一點，即第一線和第二線的組合。每一個問題都需要衛生當局的討論。您在我們的指導中看到，並且在剛才的談話中聽說，我們正在尋求將 Palbo 和/或 CDK4（另一種 CDK4/6 抑製劑）結合到第二線治療中。

And in first line, we'd be combining with atirmo or palbo. And we've also shared that we're very excited about that opportunity if we can combine with atirmo. So those -- there are different considerations for each. It will be -- it depends on what is the comparator arm for -- in each of these studies. We haven't announced that. So that would be a discussion point with regulators, the exact patient population that's being chosen.

在第一行，我們將與 atirmo 或 palbo 結合使用。我們也表示，如果能夠與 atirmo 結合，我們會對這個機會感到非常興奮。所以 — — 每個人都有不同的考量。這取決於每項研究中比較組的目的。我們還沒有宣布這個消息。因此，這將成為與監管機構討論的要點，即所選的確切患者群體。

And particularly in first line, there's no doubt we would get into a deeper conversation about contribution of components if we're using two novel agents. But we believe that there are a lot of supportive data that will allow us to navigate that discussion. But at this point, that's probably the most guidance we can offer about what the regulatory discussion might look like for combinations in those settings.

特別是在第一線，如果我們使用兩種新型藥劑，毫無疑問我們會對成分的貢獻進行更深入的討論。但我們相信，有大量的支持數據可以幫助我們進行這項討論。但目前，這可能是我們能夠提供的有關這些環境下的組合監管討論的最多指導。

Ted Tenthoff, Piper Sandler.

泰德·坦托夫，派珀·桑德勒。

Great. Thank you very much. And thanks, guys, for hosting this call today. It's nice to get to hear from you and get the update. I know there's a lot going on. I know most of the questions have been on vepdeg, but just to ask with Novartis and 766, what's the latest there? And how do you and they anticipate advancing that in prostate cancer? Thank you.

偉大的。非常感謝。感謝大家今天主持這次電話會議。很高興收到您的來信並獲悉最新消息。我知道發生了很多事。我知道大多數問題都與 vepdeg 有關，但我只想問一下 Novartis 和 766 的最新情況是什麼？您和他們如何預期前列腺癌治療的進展？謝謝。

Thanks, Ted. Great question. Yes, as you know, we did the out-licensing of 766 earlier this year, and we spent the last several months in the process of handing over data materials, all the information that's needed to get Novartis up and running to progress ARV-766. Clearly, the excitement for us in terms of doing that out-licensing was Novartis' commitment to go into early prostate cancer. And that is the game plan that they still have.

謝謝，泰德。好問題。是的，如您所知，我們在今年早些時候完成了 766 的授權，並且在過去的幾個月中我們一直在移交數據材料，以及讓諾華公司開始推進 ARV-766 所需的所有資訊。顯然，對我們來說，進行這項對外授權令人興奮之處在於諾華致力於研究早期前列腺癌。這就是他們依然保留的比賽計畫。

So they'll be looking at early and late-stage prostate cancer using ARV-766. And we think based on the interactions we've had, they're well on track for that. Obviously, now with it being out-licensed, all of the kind of significant updates will come from Novartis themselves, but we are really pleased with how the transfer of information material went and the game plan that Novartis has actually shared with us on 766. And of course, we will be able to share in the future scenarios for 766 as it progresses. And we're looking forward to getting updates from Novartis as it does.

因此他們將使用 ARV-766 研究早期和晚期前列腺癌。我們認為，根據我們之間的互動，他們已經很好地實現了這一目標。顯然，現在它已經獲得了授權，所有重要的更新都將來自諾華自己，但我們對資訊材料的轉移情況以及諾華在 766 上與我們分享的計劃感到非常滿意。當然，隨著 766 的進展，我們將能夠分享其未來場景。我們期待獲得諾華公司的最新消息。

Thanks, John.

謝謝，約翰。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Thanks. Good morning. Maybe to switch topics to ARV-102, can you talk about the size of the PD population that you're specifically examining that have this elevated LRRK2? And how are you going to use the biomarker to determine segmentation of the population?

謝謝。早安.也許可以把話題轉到 ARV-102 上，您能談談您正在研究的 LRRK2 升高的 PD 患者規模嗎？那麼您打算如何使用生物標記來確定人群細分呢？

Thanks, Tazeen. Great question. We have in the room here with us, Angela Cacace, our Chief Scientific Officer, and I'll hand directly over to her to talk about the answers for those questions.

謝謝，Tazeen。好問題。我們的首席科學官安吉拉‧卡塞斯也在我們這間會議室裡，我將直接交給她來討論這些問題的答案。

It's a great question. So the estimated size of the population that's believed to have elevation of LRRK2 is about a third of the idiopathic Parkinson's disease population, pretty sizable. And so it is still under active investigation how you would actually employ the biomarkers that we've recently described at the Michael J. Fox Foundation Therapeutics Conference.

這是一個很好的問題。因此，估計 LRRK2 升高的人口規模約為特發性帕金森氏症人口的三分之一，相當可觀。因此，如何實際運用我們最近在邁克爾·J·福克斯基金會治療學會議上描述的生物標誌物仍然在積極研究中。

And so we're partnering with that group. So both the Parkinson's Progression Marker Initiative as well as their LRRK2 initiative to really understand how do you stratify patients. But we're really encouraged by the data that we have that suggests that we can study both inflammatory markers as well as lysosomal markers to stratify the patients appropriately to conduct a reasonable clinical trial.

因此我們正在與該組織合作。因此，帕金森氏症進展標記計劃及其 LRRK2 計劃都旨在真正了解如何對患者進行分層。但我們所掌握的數據確實讓我們感到鼓舞，這些數據表明我們可以研究發炎標記和溶酶體標誌物，以適當地對患者進行分層，進行合理的臨床試驗。

Yes. And I might build on what Angela said, just reminding you that we are currently running a study with ARV-102. We completed the single ascending dose portion of the healthy volunteer study. We're currently in the multiple ascending dose portion. And the -- but the take-home message is that in this study, we're looking at all comers, and these are healthy volunteers. They don't necessarily have elevated LRRK2.

是的。我可能要根據安吉拉所說的話來提醒你，我們目前正在對 ARV-102 進行研究。我們完成了健康志願者研究的單次遞增劑量部分。我們目前正處於多次遞增劑量階段。但最重要的一點是，在這項研究中，我們關注的是所有人，這些都是健康的志願者。他們的 LRRK2 水準不一定升高。

We're going to move next and look in patients who have Parkinson's disease. You heard from Angela that we expect one-third of patients will have elevations. There's going to be no selection at the start of that study. But we're going to learn from doing these -- from looking at our degradation of LRRK2 at various doses of the drug and looking at those downstream biomarkers what our overall approach. And I think at this point, there's a wide-open field. We can end up being not selective of patients at all or we could end up choosing to look at patients with elevations. It will all depend on the data that we generate and how we interpret it.

接下來我們將研究患有帕金森氏症的患者。您從安吉拉那裡聽說了，我們預計三分之一的患者會出現升高。在這項研究開始時，不會有任何選擇。但我們將從這些研究中學習——透過觀察不同劑量藥物下 LRRK2 的降解情況，並觀察下游生物標記物，了解我們的整體方法。我認為就這一點而言，這是一個廣泛的領域。我們最終可能會完全不選擇患者，或者我們最終可能會選擇觀察患有升高的患者。這一切都取決於我們產生的數據以及我們如何解釋它。

Michael Schmidt, Guggenheim.

古根漢的邁克爾施密特。

Hey, thanks for taking my question. I just had a follow up on ARV-102 and the Phase 1 study. How should investors interpret the Phase 1 data in healthy volunteers next year? Are there specific PD markers perhaps other than LRRK2 degradation that you're assessing? And how predictive are those for potentially improving outcomes longer term?

嘿，謝謝你回答我的問題。我剛剛跟進了 ARV-102 和第一階段研究。投資人明年該如何解讀健康志工的第一階段數據？除了您正在評估的 LRRK2 降解之外，是否還有其他特定的 PD 標記？那麼這些對於長期潛在改善結果的預測能力有多強呢？

Right. So the healthy volunteer portion of the study is really designed to understand the PK/PD relationship of the drug and track what we're doing peripherally and more importantly, in the central nervous system is monitoring the drug and the LRRK2 expression in the CSF. We don't expect that healthy volunteers will have elevated downstream biomarkers that are associated with the neurodegeneration that's seen with this disease. That's something that we'll be looking at more confidently, obviously, when we move to patients as opposed to healthy volunteers.

正確的。因此，研究中健康志願者部分實際上是為了了解藥物的 PK/PD 關係，並追蹤我們在周邊所做的事情，更重要的是，在中樞神經系統中監測藥物和腦脊髓液中的 LRRK2 表達。我們並不認為健康志願者的體內會出現與疾病所見的神經退化性疾病相關的下游生物標記升高。顯然，當我們轉向患者而不是健康志願者時，我們會更加自信地看待這一點。

But I think that what we can walk out of this confident about, if things move or are successful, is that the modeling that we did to predict dosing of the drug and its impact in the CNS compartment, the modeling we did in the cynos that is so promising that that can be recapitulated in human beings, that this can drive the right dose selection, and then that sets us up for success when we move to -- when we're looking for this on-target activity at the right dose in patients with PD. And I think that's helped quite a lot right there.

但我認為，如果事情進展順利或取得成功，我們可以充滿信心地走出困境，因為我們為預測藥物劑量及其對中樞神經系統的影響而建立的模型，以及我們在食蟹猴中建立的模型非常有希望，可以在人類身上重現，這可以推動正確的劑量選擇，然後當我們在 PD 患者中尋找正確劑量的靶向活性時，這將為我們取得成功奠定基礎。我認為這有很大幫助。

Tyler Van Buren, TD Cowen.

泰勒·範布倫（Tyler Van Buren），TD Cowen。

Hey, guys. Thanks for hosting the call. I just want to follow up on your response to an earlier question for the VERITAC-2 trial readout. So if the control fulvestrant arm does three to four months on median PFS and you hope to see a few months better per your earlier comment or a three-month plus delta in the ITT population or a near doubling, how do you expect median PFS to improve for both arms for the ESR1 population analysis?

嘿，大家好。感謝您主持此次電話會議。我只是想跟進一下您對 VERITAC-2 試驗讀數的先前問題的回答。因此，如果對照氟維司群組的中位 PFS 為三至四個月，並且您希望按照您先前的評論看到幾個月的改善，或者 ITT 人群的增量為三個月以上或接近翻倍，那麼您預期 ESR1 人群分析中兩個組的中位 PFS 會如何改善？

Thanks, Tyler. Noah, do you want to take that?

謝謝，泰勒。諾亞，你想拿著那個嗎？

Sure. Well, I just want to -- going back to the earlier comments, I think what we said -- I said part of that, but I'm not sure all of it. Our expectation is three or four months in the fulvestrant arm, a few months better on the treatment arms. We haven't differentiated what we're going to see for the ESR1 mutant or for the total population.

當然。好吧，我只是想——回到之前的評論，我想我們所說的——我說了一部分，但我不確定全部。我們預期氟維司群組的效果會持續三到四個月，而治療組的效果會好幾個月。我們還沒有區分 ESR1 突變體或整體群體將會看到什麼。

We would expect that ESR1 mutant patients will do a little better because they have this dependency on the ligand-independent estrogen-receptor-driven binding -- estrogen-receptor-driven proliferation for their tumors. So we're not -- we just haven't gotten into those specifics or gone through the operating characteristics of the statistical plan. But suffice it to say, a few months better, as I outlined.

我們預期 ESR1 突變患者的情況會好一些，因為他們對配體獨立的雌激素受體驅動的結合有依賴性——雌激素受體驅動的腫瘤增殖。所以我們還沒有——我們只是還沒有了解這些細節，也沒有經歷過統計計劃的運作特點。但正如我所概述的，可以說，情況會好幾個月。

Jonathan Miller, Evercore ISI.

喬納森·米勒（Jonathan Miller），Evercore ISI。

Hi, guys. Thanks for taking the question. I'd like to talk more about the vepdeg combo Phase 3s that you're talking about getting started next year. Can you contrast VERITAC-3 Phase 3 portion with these new Phase 3s that you're talking about? And it seems like the PR suggests you're focused on palbo and CDK4.

嗨，大家好。感謝您回答這個問題。我想多談談您所說的明年開始的 vepdeg 組合第 3 階段。您能將 VERITAC-3 第 3 階段部分與您正在談論的這些新的第 3 階段進行比較嗎？而且 PR 似乎表明你專注於 palbo 和 CDK4。

It seems like you're not pursuing ribo or abema combos in first-line, at least it wasn't called out. So can you talk a little bit about how the data from -- what you're still waiting for from the TACTIVE trials to make the decisions about ultimate combo partner, a?

看起來你並沒有在第一線追求 ribo 或 abema 組合，至少它沒有被叫出來。那麼，您能否稍微談談您還在等待 TACTIVE 試驗的數據來決定最終的組合夥伴？

And b, given the CDK4 combo data you mentioned will be available internally this year for use in deciding about those combination Phase 3, is it fair to expect that you would give some key details on the CDK4/vepdeg combo data when you decide on a Phase 3 course? Because I noticed you don't -- you haven't given guidance on when we could see that TACTIVE-K update.

並且 b，鑑於您提到的 CDK4 組合數據將在今年內部提供，以用於決定第 3 階段的組合，當您決定第 3 階段課程時，是否可以公平地期望您提供有關 CDK4/vepdeg 組合數據的一些關鍵細節？因為我注意到您沒有——您沒有就何時我們可以看到 TACTIVE-K 更新提供指導。

Yes. Thanks. Yes, great question. And I think clearly, there's a number of different trials we have ongoing that are going to generate data that's going to really influence our decision making. We have VERITAC-2. We have abema combo. We have the atirmo combo. We have the palbo SLI. We also have the ribo combo ongoing as well.

是的。謝謝。是的，很好的問題。我認為，我們正在進行許多不同的試驗，這些試驗將產生真正影響我們決策的數據。我們有 VERITAC-2。我們有 abema 組合。我們有 atirmo 組合。我們有 palbo SLI。我們還有正在進行的 ribo 組合。

So a whole bunch of data that's coming out now and then through into the early part of next year that sitting down with our colleagues, with Pfizer, we'll be able to decide what is the right combination. Obviously, there's preferences there, but we'll wait for the data to actually drive that decision. But Noah, do you want to go into any more of the specifics?

因此，透過現在公佈的大量數據，直到明年年初，我們將與輝瑞的同事一起坐下來討論，以確定正確的組合。顯然，這其中存在偏好，但我們會等待數據來真正推動這一決定。但是諾亞，你想進一步了解具體情況嗎？

Yes. Maybe we could dive in a little more. And thanks for the question, Jonathan. So let's look at first line and then we can look at second line. So first line, I think the original intent some years ago was to go with the vepdeg/palbo in first line, and that was an obvious choice. Palbo was the most prescribed drug in that CDK4/6 in that setting. Pfizer is our partner, and so they could supply it.

是的。也許我們可以進一步深入探討。謝謝你的提問，喬納森。因此，我們先看第一行，然後再看第二行。所以第一行，我認為幾年前的初衷是在第一行使用 vepdeg/palbo，這是一個顯而易見的選擇。在這種環境下，Palbo 是 CDK4/6 中最常用的處方藥。輝瑞是我們的合作夥伴，因此他們可以提供。

And unfortunately, we weren't able to roll straight into that because we were challenged to find a lower dose of palbo that would satisfy benefit risk from the perspective of health authorities. And so we started the VERITAC-3, which is -- the SLI portion of it is reading out, as John mentioned. But in the meantime, we have -- we will have the fullness of that data set, but also have now done the work for atirmo.

不幸的是，我們無法直接進入這個領域，因為我們面臨的挑戰是找到一種較低劑量的 Palbo 藥物，以滿足衛生當局對效益風險的要求。因此我們啟動了 VERITAC-3，正如 John 所提到的，它的 SLI 部分正在讀取。但同時，我們將擁有完整的資料集，現在也已經為 atirmo 完成了工作。

And we're very excited about an atirmo combination into the first-line because it would be a very differentiating combination, possibly best-in-class CDK4 or CDK4/6 drug combined with what we believe would be a best-in-class PROTAC in this setting, which would be superior to the SERD alternatives. And it would fit perfectly in this partnership as well. So we're waiting for that study, but we weren't considering things like ribo and abema because I think they don't really solve for those problems, right? Atirmo gives us that differentiation and palbo was ease of use.

我們對 atirmo 組合進入一線治療感到非常興奮，因為這將是一個非常差異化的組合，可能是同類最佳的 CDK4 或 CDK4/6 藥物，與我們認為在這種情況下同類最佳的 PROTAC 相結合，這將優於 SERD 替代品。它也非常適合這種合作關係。所以我們正在等待這項研究，但我們沒有考慮核醣體和阿貝瑪之類的東西，因為我認為它們並不能真正解決這些問題，對嗎？Atirmo 為我們提供了差異化，而 palbo 則易於使用。

In the second-line setting, we've guided to either using a palbo combination because we have great results in this setting that we've already shared or -- and maybe offering some choice to prescribers or to investigators in this case by allowing another CDK4/6, which could be presumably something like abema. We're not guiding specifically to this.

在二線治療中，我們指導要么使用哌柏索組合，因為我們已經分享了這種情況下很好的結果，或者——也許通過允許另一種 CDK4/6（可能類似於 abema）為處方人員或研究人員提供一些選擇。我們並不是專門針對這一點進行指導。

But the idea is that we may end up doing it, and you should just look forward to the San Antonio Breast Cancer data to make your evaluation of this abema/vepdeg combination and the viability of that in the second plus setting. What we really like, of course, about all of these opportunities is that vepdeg is a very combinable drug.

但我們的想法是，我們最終可能會這樣做，而您應該只期待聖安東尼奧乳癌的數據，以便對這種 abema/vepdeg 組合及其在第二個加設置中的可行性進行評估。當然，我們真正喜歡這些機會的原因是，vepdeg 是一種非常適合結合的藥物。

While we did see that there was more neutropenia for the -- with full-dose palbo and vepdeg in the original data set we performed, we will now be sharing more data about the broad combinability of this drug. You'll see the abema data set. You'll see some work about better understanding of metabolism with the midazolam study. And then as we've said, next year, we'll provide some updates as the data mature for the ribociclib portion of the TACTIVE-U as well as atirmociclib combination seen in TACTIVE-K.

雖然我們確實看到，在我們進行的原始數據集中使用全劑量 Palbo 和 Vepdeg 時，中性粒細胞減少症的發生率更高，但我們現在將分享更多有關該藥物廣泛結合性的數據。您將看到 abema 資料集。您會看到一些關於透過咪達唑侖研究更好地理解代謝的工作。正如我們所說的，明年，隨著 TACTIVE-U 中 ribociclib 部分以及 TACTIVE-K 中 atirmociclib 組合的數據成熟，我們將提供一些更新。

Paul Choi, Goldman Sachs.

高盛的保羅·崔（Paul Choi）。

Hi, everyone. This is Khalil calling in for Paul. Thank you so much for taking our question, and congratulations on the first earnings call. I guess a quick modeling question from us is, one, I guess, real quick is, as you have a lot of these earlier-stage assets entering the clinic or IND filings, how should we think about the cost ramp for next year, maybe the year after?

大家好。這是 Khalil 代替 Paul 打來的。非常感謝您回答我們的問題，並祝賀您舉行了第一次財報電話會議。我想我們要提出的一個快速建模問題是，首先，我想，非常快速的問題是，由於您有很多這些早期資產進入臨床或 IND 申請，我們應該如何考慮明年甚至後年的成本上漲？

And then just on the Novartis agreement, given the revenue recognition that you had this quarter, are we correct in thinking there's about $930 million in additional payments? Or is that -- how do you -- how should we think about like the cadence of that going forward? Thank you so much.

然後僅就諾華協議而言，考慮到本季的收入確認，我們是否正確地認為有大約 9.3 億美元的額外付款？還是那是 — — 您如何 — — 我們應該如何思考未來發展的節奏？太感謝了。

Yes. Thanks for your question, and I'll hand over to our CFO, Andrew, to answer these questions.

是的。感謝您的提問，我將把這個問題交給我們的財務長安德魯來回答。

Yes. Thanks for the question. Yes, look, we haven't given specific guidance on our expense structure, and we're not planning on doing that in the near term. Obviously, the mix of projects that we have, programs going out is changing, right? So previously, the company had the two Phase 3s. We've out-licensed the one to Novartis. That was done consciously by the company to manage expenses and manage our burn.

是的。謝謝你的提問。是的，我們還沒有對我們的費用結構給予具體的指導，而且我們短期內也不打算這樣做。顯然，我們現有的專案組合和正在進行的專案正在發生變化，對嗎？此前，該公司已有兩個第三階段。我們已將這個專利授權給了諾華公司。這是公司有意識地採取的措施，目的是為了管理費用和控制我們的資金消耗。

As we have these other programs coming through the clinic, clearly, they're going to start costing a little bit of money. We're well aware of what we're going to be spending on them, and we're very confident in the guidance that we've given in terms of cash into 2027 with our current balance sheet. I think you had another question on Novartis. Can you just repeat that? I'm not sure if I heard that.

隨著我們診所開展其他項目，顯然它們會開始花費一點錢。我們非常清楚我們將在它們上面花多少錢，而且我們對根據我們目前的資產負債表給出的 2027 年現金指導非常有信心。我想您還有關於諾華的另一個問題。你能重複一遍嗎？我不確定我是否聽說過。

Yes, of course. So just given that we assume that the $120 million upfront payment has already occurred and then you reported today like $67 million or so in revenue from that agreement, our understanding is that there's a total of about $1 billion-ish in payments that are contingent on certain milestones. Obviously, those I don't think have been disclosed, but we were just wondering if you could share any color on how we should think about the cadence of revenue from that agreement in 2025?

是的當然。因此，假設我們假設 1.2 億美元的預付款已經支付，而您今天報告的該協議收入約為 6,700 萬美元，我們的理解是，總計約有 10 億美元的付款取決於某些里程碑。顯然，我認為這些尚未披露，但我們只是想知道您是否可以分享一些關於我們應該如何看待 2025 年該協議的收入節奏的信息？

Yes, so the revenue that you're seeing on our P&L right now is all deferred revenue from the upfront. So that doesn't have anything to do with future milestones, et cetera. We amortized the upfront from the Novartis agreement over this year because that's the period during which we were handing over responsibilities for the trials, and so we still have responsibilities.

是的，所以您現在在我們的損益表上看到的收入都是預付款的遞延收入。所以這與未來的里程碑等等沒有任何關係。我們今年攤銷了諾華協議中的預付款，因為這是我們移交試驗責任的期間，所以我們仍然有責任。

With Pfizer, it's much longer. So we obviously had the large upfront from them, and that's a deal that's a 50-50. So we're actively engaged in that. So we're amortizing those revenues over a longer period of time. So you'll actually see the Novartis drop off this year. The Pfizer will continue on for some years.

對輝瑞公司來說，這個時間要長得多。因此，我們顯然從他們那裡獲得了一大筆預付款，這是一筆 50-50 的交易。因此我們積極參與其中。因此我們會在更長的時間內攤提這些收入。因此你實際上會看到諾華今年的業績下滑。輝瑞公司也將繼續經營幾年。

Got it. That's really helpful. Thank you so much.

知道了。這真的很有幫助。太感謝了。

Yigal Nochomovitz, Citigroup.

花旗集團的 Yigal Nochomovitz。

Hi, thank you for taking the questions. I just wanted to follow up on some of the questions regarding the front-line strategy and the comments Noah was making on contribution of components. So if it turns out that you pick -- you and Pfizer pick atirmo plus vepdeg, are you going to be able to do a trial where it's atirmo/vepdeg versus palbo/fulvestrant?

您好，感謝您回答這些問題。我只是想跟進一些有關前線戰略的問題以及諾亞對組件貢獻的評論。所以如果結果是你和輝瑞選擇了 atirmo 加 vepdeg，你是否能夠進行 atirmo/vepdeg 與 palbo/fulvestrant 對比的試驗？

Or given the consideration of contribution of components, is it going to potentially be more complicated with including a palbo/vepdeg arm as well as an atirmo/fulvestrant arm? I'm not sure how that would work, if you could comment. And then I'm just also curious if you've generated data today to support the fact that you won't have a DDI with atirmo and vepdeg. Thanks.

或者考慮到組件的貢獻，包括 palbo/vepdeg 組以及 atirmo/fulvestrant 組是否會變得更加複雜？我不確定這會如何起作用，如果你能發表評論的話。然後我也很好奇您今天是否已經產生了數據來支持您不會與 atirmo 和 vepdeg 建立 DDI 的事實。謝謝。

Thanks, Yigal. Great, great questions. Noah?

謝謝，伊加爾。非常好、非常好的問題。諾亞？

Okay. I'll try and tackle this. Let's jump in with a follow up if I missed part of that. So first of all, so in first line, we're not guiding to the exact design of the study, but I think we're going to be -- I think you can be confident that we would be focusing more on an AI combination in that setting rather than fulvestrant. So that's the initial thing. Whether it's palbo alone or CDK4/6 choice on the part of physicians, these things are not defined, haven't been resolved with regulatory authorities yet. In terms of -- but I think that kind of addresses what you asked. Is there something else?

好的。我會盡力解決這個問題。如果我遺漏了部分內容，讓我們繼續跟進。首先，在第一線，我們並沒有指導研究的確切設計，但我認為我們會——我認為你可以相信，我們會在這種環境下更多地關注 AI 組合，而不是氟維司群。這是最初的事。無論是單獨使用帕博利珠單抗還是醫生選擇 CDK4/6，這些事情都尚未定義，也尚未與監管機構解決。就……而言，但我認為這已經回答了你所問的問題。還有什麼嗎？

That's related to the design part. I think Yigal had a secondary question related to do we have any idea we have a DDI with atirmociclib. I mean, Yigal, what I would say about that is we believe that the data, which you'll start to see from the San Antonio Breast Cancer Symposium and onward, will show that vepdegestrant is a compound that is going to be very broadly combinable with any of the kind of medications in the breast cancer space that would include atirmociclib. Clearly, in all of our studies, we're tracking this now. And as I say, the data will come out and show that this is a non-issue from a clinical perspective.

這與設計部分有關。我認為 Yigal 還有一個次要問題，即我們是否知道 atirmociclib 是否存在 DDI。伊加爾，我想說的是，我們相信從聖安東尼奧乳癌研討會及以後開始看到的數據將顯示，vepdegestrant 是一種可以與乳癌領域中的任何藥物（包括 atirmociclib）廣泛結合的化合物。顯然，在我們所有的研究中，我們現在都在追蹤這一點。正如我所說，數據將會表明，從臨床角度來看這不是什麼問題。

Okay, appreciate it. Thank you very much.

好的，謝謝。非常感謝。

Thanks, Yigal.

謝謝，伊加爾。

Billal Jahangiri, Truist Securities.

Truist Securities 的 Billal Jahangiri。

Hi, thanks for the call. This is Bill on for Kripa. We were wondering what's going to be the final deciding factor or maybe factors on choosing which combo to take forward? Is it strictly on efficacy? Or is there some sort of strategic IP factor involved too that you're thinking of as well? Thanks.

您好，謝謝您的來電。這是代表克里帕 (Kripa) 的 Bill。我們想知道什麼將成為最終的決定因素，或決定選擇哪種組合繼續前進的因素？是否嚴格遵循功效？或者您是否也考慮過某種策略性 IP 因素？謝謝。

Well, obviously, it's going to be based on all the data that we're going to be generating and are generating. As I mentioned earlier, we have ongoing combination trials with abemaciclib, with atirmociclib, with ribociclib, that type of -- and the SLI data in palbociclib. All of that data will be in our hands tail end of this year, first half of next year. And that will really drive the data-driven aspect of our decision making.

嗯，顯然，它將基於我們將要生成和正在生成的所有數據。正如我之前提到的，我們正在進行 abemaciclib、atirmociclib 和 ribociclib 的聯合試驗，以及 palbociclib 的 SLI 數據。所有這些數據將在今年年底或明年上半年掌握在我們手中。這將真正推動我們決策的數據驅動方面。

It won't all just be looking at the efficacy or we're looking at safety tolerability. So we'll get a true gestalt view of our overall data set. So I think we'll actually be in an incredibly good position to make a really smart decision about the combinations. As I said, there's clearly, we have some biases, but the biases will be influenced completely by the data set.

我們不會只專注於功效或關注安全耐受性。這樣我們就能獲得整個資料集的真實格式塔視圖。因此我認為我們實際上處於一個非常有利的位置，可以對組合做出非常明智的決定。正如我所說，顯然我們存在一些偏見，但這些偏見完全受到資料集的影響。

Yes. And I would just add a small point, John, that when it comes to efficacy, look, we're sharing data about what we see in the second-line setting. And I think the efficacy there is characterized by things like ORR and CBR. In first line, the efficacy that would be at our disposal is probably -- are probably those type of data points. We're not going to wait for median PFS. Obviously, in first line, where you have median PFSs that can exceed two years, one wouldn't wait for that. We would use other signals when looking at efficacy and obviously, then safety, to make a decision.

是的。約翰，我只想補充一點，當談到療效時，看，我們正在分享我們在二線環境中看到的數據。我認為其療效可以用 ORR 和 CBR 等來表徵。首先，我們可以利用的功效可能是──可能是那些類型的資料點。我們不會等待中位 PFS。顯然，在第一線，如果你的中位 PFS 可以超過兩年，那麼人們不會等待那麼久。在考慮功效以及安全性時，我們會使用其他訊號來做出決定。

Great, thanks.

非常好，謝謝。

Matt Biegler, Oppenheimer.

奧本海默的馬特比格勒 (Matt Biegler)。

Hey, guys, thanks for squeezing me in. I realize we're at the top of the hour. It's like covering a large cap with a number of analysts here. I just wanted to ask about the statistical plan for VERITAC-2 to the extent you can tell us. Is it hierarchical testing? Or are the co-primary endpoints effectively the alpha split between them, between the ESR1 and the ITT population? And secondly, do you think a 0.7 hazard ratio would be good enough for an all-comers label? Thanks.

嘿，夥計們，感謝你們擠進我。我意識到我們已經到了正午。這就像在這裡用多位分析師來覆蓋一隻大盤股。我只是想問一下您能否告訴我們有關 VERITAC-2 的統計計劃。它是分層測試嗎？或者共同主要終點實際上是 ESR1 和 ITT 族群之間的 alpha 分割？其次，您認為 0.7 的風險比對於「萬能」標籤來說足夠好嗎？謝謝。

Okay, so thanks for the question, Matt. The -- in terms of the hierarchy, we have two co-primary endpoints, and we can win on either one of them. We're going to -- but for all purposes, we think that the ESR1 mutant is obviously going to be even more likely than the ITT. That's just the nature of the disease we're treating in. There is some hierarchical testing that goes on from there, the specifics of which we haven't defined yet. In terms of -- what was the second part of your question, remind me?

好的，謝謝你的提問，馬特。從層次結構方面來看，我們有兩個共同的主要端點，我們可以在任何一個端點上獲勝。我們會 — — 但就所有目的而言，我們認為 ESR1 突變體顯然比 ITT 更有可能。這正是我們所治療的疾病的本質。從那裡開始進行一些分層測試，我們尚未定義其具體細節。就——請提醒我一下，你的問題的第二部分是什麼？

The hazard ratio?

風險比？

Yes, so we haven't gone to the specifics of the hazard ratio. I will say that we would expect a better hazard ratio or are expecting to achieve a better hazard ratio in the ESR1 mutant than in the ITT population. And -- but more specific than that, I won't go into.

是的，所以我們還沒有討論風險比的具體細節。我想說的是，我們期望 ESR1 突變體的風險比或有望實現比 ITT 族群更好的風險比。而且——但比這更具體的，我不會深入討論。

Appreciate it. Thank you.

非常感謝。謝謝。

Michael Schmidt, Guggenheim.

古根漢的邁克爾施密特。

Hi, guys. Thanks for taking the follow up. I just had a clarification question regarding your earlier comments on VERITAC-2. I think you said you expect about three to four months PFS for fulvestrant in the control arm. And yes, I was just wondering what are -- or are there any major differences in enrollment criteria relative to the post-MONARCH trial where fulvestrant obviously did much better than that?

嗨，大家好。感謝您的跟進。我只是想澄清一下您之前對 VERITAC-2 的評論。我記得您說過，您預期對照組中氟維司群的 PFS 約為三至四個月。是的，我只是想知道，與 MONARCH 試驗後相比，入組標準是否存在重大差異，其中氟維司群的效果顯然要好得多？

Yes. Well, the fulvestrant didn't do much better than it, a little better. There was four months in the interim analysis, and I think 5.3 months in the final analysis. People are hard-pressed to understand why the median PFS improved and was there a change in the patient population between those two analyses, which were both presented at the same time at ASCO.

是的。嗯，氟維司群的效果並不比它好多少，只是好一點而已。中期分析花了四個月的時間，而最終分析則花了 5.3 個月的時間。人們很難理解為什麼中位 PFS 會改善，以及在 ASCO 上同時提出的這兩項分析之間患者群體是否發生了變化。

But the differences are that we have the ability to have patients that were treated with an endocrine therapy twice. They may have had an exemestane, let's say, after an initial treatment with the CDK4/6 and an AI. So we will have some patients that are third line, technically. Not all our patients will be second line, but I think the large majority will be, and they were a pure second-line study.

但不同之處在於，我們有能力讓患者接受兩次內分泌治療。他們可能在接受 CDK4/6 和 AI 的初步治療後，服用了依西美坦。因此，從技術上講，我們將會有一些屬於三線的患者。並非所有患者都會接受二線治療，但我認為絕大多數都會，而且這是一項純粹的二線研究。

Great. Yes, it makes a lot of sense. I really appreciate that clarification.

偉大的。是的，這很有道理。我非常感謝您的澄清。

Thank you.

謝謝。

Jonathan Miller, Evercore ISI.

喬納森·米勒（Jonathan Miller），Evercore ISI。

Hi, guys. Thanks so much squeezing in my follow up here. I figured since nobody has asked about it, I'd love to ask one question about the upcoming KRAS PROTAC programs that you're working on, the G12D and the pan-KRAS that you discussed during your prepared remarks.

嗨，大家好。非常感謝您抽出時間在這裡跟進。我想既然沒有人問過這個問題，我很想問一個問題，關於您正在開展的即將開展的 KRAS PROTAC 計劃、G12D 以及您在準備好的發言中討論過的泛 KRAS。

Can you compare these programs to other G12D or pan-KRAS approaches? And how do you think a degrader is going to be better suited than some of the other approaches, notably the inhibitors? How will a degrader compare to a RevMed-like molecular glue pan-KRAS approach?

您能將這些程式與其他 G12D 或泛 KRAS 方法進行比較嗎？您認為降解劑比其他方法（尤其是抑制劑）更適合嗎？降解劑與類似 RevMed 的分子膠泛 KRAS 方法相比如何？

Yes, great question, and thanks. And yes, we're very excited about our KRAS programs, G12D, and the pan-KRAS -- and Angela and Noah can discuss the answers to the question you're posing in terms of the profile and what it looks like in terms of the competition.

是的，這個問題問得很好，謝謝。是的，我們對我們的 KRAS 計劃、G12D 和泛 KRAS 感到非常興奮——Angela 和 Noah 可以從概況和競爭角度討論您提出的問題的答案。

Sure. We've been actively comparing our -- both our G12D PROTAC lead degrader to the inhibitors that have been described and have shown superiority, and we've disclosed some of those data. But we've been also actively comparing both our G12D and our pan-PROTAC degraders in a range of non-clinical models to examine the known inhibitors that are out there. And so generally, we're looking really very favorable with respect to our non-clinical profile, and we're very encouraged to pursue these molecules in clinical studies. So I'm going to hand it over to Noah for further commentary.

當然。我們一直在積極地將我們的 G12D PROTAC 鉛降解劑與已描述並顯示優越性的抑制劑進行比較，並且我們已經揭露了其中一些數據。但是我們也一直在積極地在一系列非臨床模型中比較我們的 G12D 和泛 PROTAC 降解劑，以檢查已知的抑制劑。因此總體而言，我們的非臨床概況看起來非常有利，我們非常鼓勵在臨床研究中探索這些分子。因此我將把它交給 Noah 進行進一步評論。

Thanks, Angela. So I guess I can address just the comparative part. But look, we haven't entered the clinic yet. That's forward looking and something we're excited about for next year. But I think what we've seen from the competition suggests that there still is opportunity.

謝謝，安吉拉。所以我想我可以只討論比較部分。但是你看，我們還沒有進入診所。這是具有前瞻性的，我們對明年的事情感到興奮。但我認為，我們從競爭中看到的情況表明，仍然存在機會。

So when we look at the first data for example, I won't address the revolution, but you look at Astellas' KRAS G12D degrader and we see that there is modest ORR and there are some liver toxicities at higher doses. These are opportunities for us to catch up, differentiate, and demonstrate first in class, which would be needed in this space. And I think we could go through those types of specifics for other agents, but probably a little premature for us right now.

因此，當我們查看第一個數據時，我不會討論革命，但您可以查看安斯泰來 (Astellas) 的 KRAS G12D 降解劑，我們會發現 ORR 適中，較高劑量時會出現一些肝毒性。這些都是我們在這個領域迎頭趕上、脫穎而出、並展現一流水準的機會。我認為我們可以為其他代理商討論這些具體細節，但現在對我們來說可能還為時過早。

And this concludes our question-and-answer session. I will turn the call back over to John Houston.

我們的問答環節到此結束。我會將電話轉回給約翰休斯頓。

Thank you, and thanks, everybody, for calling into our first-ever earnings call. And hopefully, we'll be able to give you updates over the coming months of the very rich data sets that we'll be getting from the various clinical trials. But thank you for your time this morning. Appreciate it.

謝謝大家參加我們的首次財報電話會議。希望我們能夠在未來幾個月內為您提供從各種臨床試驗中獲得的非常豐富的數據集的更新。但感謝您今天上午抽出時間。非常感謝。

This concludes today's conference call. You may now disconnect.

今天的電話會議到此結束。您現在可以斷開連線。