Arvinas Inc (ARVN) 2025 Q1 法說會逐字稿

Thank you for standing by. My name is Gayle and I will be the operator for today's call. At this time, I would like to welcome each and every one of you to the Arvinas's first quarter 2025 earnings call. (Operator Instructions)

感謝您的支持。我叫蓋爾，我將擔任今天電話的接線生。此時，我謹歡迎各位參加 Arvinas 2025 年第一季財報電話會議。（操作員指示）

It is now my pleasure to turn today's call over to our Arvinas's Vice President of Investor Relations, Jeff Boyle. Please go ahead.

現在我很高興將今天的電話轉給我們 Arvinas 的投資者關係副總裁 Jeff Boyle。請繼續。

Thank you and good morning everyone. Thanks for joining us. Earlier today we issued a press release with our first quarter of 2025 financial results, which is available on the investor and media section of our website at our arvinas.com.

謝謝大家，早安。感謝您的加入。今天早些時候，我們發布了一份新聞稿，其中包含我們 2025 年第一季的財務業績，您可以在我們網站 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; and Andrew Saik, our Chief Financial Officer. Our Chief Scientific Officer, Angela Cacace was scheduled to join us this morning, but at an unanticipated personal event and will not be able to.

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；以及我們的財務長 Andrew Saik。我們的首席科學官 Angela Cacace 原定於今天上午加入我們，但由於一次意外的個人活動而無法參加。

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。

And now I'll turn the call over to John.

現在我將把電話轉給約翰。

Thanks, Jeff. Good morning, everyone, and thank you for joining us today. As you saw on our earnings release this morning, we have reached an important moment in Arvinas's progress as a company. We recently shared the first ever positive pivotal data for a PROTAC degrader vepdegestrant, which we're moving towards filing and registration.

謝謝，傑夫。大家早安，感謝大家今天加入我們。正如您在我們今天早上發布的收益報告中看到的那樣，我們已經到達了 Arvinas 公司發展的重要時刻。我們最近分享了 PROTAC 降解劑維普德格斯特蘭 (vepdegestrant) 的首個積極關鍵數據，我們正在著手申請和註冊。

In addition, we continue making great progress with our pipeline and shared exciting first in human data for ARV-102 or LRRK2 degrader, and excellent preclinical combination data for ARV-393, our BCL-6 degrader in hematology. We also recently received a safety proceed from the FDA for ARV-806 or KRAS G12D degrader.

此外，我們在產品管線方面繼續取得巨大進展，並首次分享了 ARV-102 或 LRRK2 降解劑令人興奮的人體數據，以及 ARV-393（我們的血液學 BCL-6 降解劑）的出色臨床前組合數據。我們最近也從 FDA 獲得了 ARV-806 或 KRAS G12D 降解劑的安全批准。

We will discuss each of those items on the call today. Noah will review the clinical progress vepdegestrant, or Vepdeg, and for ARV-102. He will also then review our recent preclinical combination data for ARV-393 and provide an update on ARV-806. Finally, Andrew will provide a financial overview, including our capital allocation priorities and updated cash runway guidance.

我們將在今天的電話會議上討論上述每一項內容。諾亞將回顧 Vepdegestrant 或 Vepdeg 以及 ARV-102 的臨床進展。他還將回顧我們最近的 ARV-393 臨床前組合數據，並提供 ARV-806 的最新資訊。最後，安德魯將提供財務概覽，包括我們的資本配置優先事項和更新的現金流量指導。

However, before we get into our data updates, I'd like to cover three important topics up front. First, we are making excellent progress towards our filing and registrational plans for Vepdeg in the second line plus ESR1 mutant breast cancer. Based on the strong data from the VERITAC-2 study, we have a high conviction that Vepdeg has the potential to be a best-in-class monotherapy treatment for patients in a second line ESR1 mutant setting.

然而，在我們開始資料更新之前，我想先討論三個重要主題。首先，我們在二線及ESR1突變乳癌Vepdeg的備案和註冊計畫方面取得了巨大進展。根據 VERITAC-2 研究的強大數據，我們堅信 Vepdeg 有可能成為二線 ESR1 突變患者的最佳單一療法。

We are on track to submit a regulatory filing with health authorities in the coming months. We believe there is an attractive opportunity for Vepdeg as a second line plus ESR1 mutant treatment in metastatic breast cancer, and we will discuss this opportunity in greater detail after our ASCO presentation in June.

我們將在未來幾個月內向衛生部門提交監管文件。我們相信 Vepdeg 作為轉移性乳癌的二線加 ESR1 突變治療具有誘人的機會，我們將在 6 月的 ASCO 報告後更詳細地討論這一機會。

Secondly, we have aligned with Pfizer on the removal of the two phase 3 combination trials from our joint development plan that were planned for this year. The first of these trials was a combination with a CDK4/6 inhibitor in the second line setting and based on recent discussions with health authorities and our observations from other trials involving biomarker selected populations, we believe ER therapies will be restricted to patients with ESR1 mutations in the second line plus setting. With this in mind, we have removed the second line ITT combination trial which was planned to initiate in 2025 from our joint development plan.

其次，我們已與輝瑞公司達成一致，將原定於今年進行的兩項 3 期聯合試驗從我們的聯合開發計劃中刪除。這些試驗中的第一項是與 CDK4/6 抑制劑在二線治療中的聯合應用，根據最近與衛生當局的討論以及我們對涉及生物標誌物選定人群的其他試驗的觀察，我們認為 ER 療法將僅限於二線及以上治療中患有 ESR1 突變的患者。考慮到這一點，我們從聯合開發計劃中刪除了原定於 2025 年開始的二線 ITT 組合試驗。

The second trial was the first line combination trial with atirmociclib, Pfizer's CDK4 inhibitor, which was also planned to initiate in 2025. After reviewing the totality of emerging information, including external data results, the evolving treatment landscape in metastatic breast cancer, and long-term capital allocation, we have aligned with Pfizer to remove this first line combination study from our joint development plan as well.

第二項試驗是與輝瑞公司的 CDK4 抑制劑 atirmociclib 進行的第一線聯合試驗，也計劃於 2025 年啟動。在審查了所有新興資訊（包括外部數據結果、轉移性乳癌不斷發展的治療前景以及長期資本配置）後，我們已與輝瑞公司達成一致，將這項一線組合研究從我們的聯合開發計劃中刪除。

We and Pfizer will continue to evaluate our ongoing combination studies in the second line plus setting and generate valuable data in metastatic breast cancer to inform our path forward. In addition, Pfizer is adding a Vepdeg combo cohort to their ongoing Phase 1 clinical trial with their investigational KAT6 inhibitor. This trial will be operationalized and funded solely by Pfizer.

我們和輝瑞將繼續評估我們正在進行的二線聯合治療研究，並在轉移性乳癌中產生有價值的數據，為我們的前進方向提供參考。此外，輝瑞公司正在將 Vepdeg 組合隊列與其研究性 KAT6 抑制劑一起添加到他們正在進行的 1 期臨床試驗中。該試驗將由輝瑞公司獨自實施和資助。

As these trials complete, we'll make data-driven decisions about whether further investment in each of these combinations is warranted. I look forward to sharing additional details in the coming months as our trials continue.

隨著這些試驗的完成，我們將根據數據做出決策，確定是否有必要對每種組合進行進一步投資。隨著試驗的繼續，我期待在未來幾個月分享更多細節。

The third major topic is our company-wide cost reduction effort. The recent challenges in the capital markets are prompting us to extend our cash runway and ensure our programs reach data milestones before additional capital is needed. An important step in this process is maximizing our efficiency and reducing our operating expenses wherever possible. We have implemented a restructuring that includes a workforce reduction of approximately one third of the company. Portfolio reprioritization and overall cost reductions of approximately $80 million annually on a full year run rate basis.

第三個主要議題是我們全公司範圍內的成本削減工作。資本市場近期面臨的挑戰促使我們延長現金流，並確保我們的專案在需要額外資本之前達到資料里程碑。這一過程中的一個重要步驟是最大限度地提高我們的效率並盡可能降低我們的營運費用。我們已經實施了重組，其中包括裁減公司約三分之一的員工。以全年運行率計算，投資組合重新排序和總體成本削減每年約 8000 萬美元。

Although difficult, the workforce reduction, which will result in streamlined operations across the entire organization is a prudent decision that we believe will appropriately size the company for future success. We have also reprioritized our research portfolio to focus on assets that have the greatest potential to deliver the most value for patients, physicians, and shareholders.

儘管裁員很困難，但裁員將導致整個組織的運作精簡，這是一個審慎的決定，我們相信這將適當調整公司規模，以取得未來的成功。我們也重新調整了研究組合的優先順序，將重點放在最有可能為患者、醫生和股東帶來最大價值的資產。

Our clinical programs ARV-102 in neurodegeneration and ARV-393 in hematology remain on track to deliver important clinical data later this year. Overall, these steps will result in a combination of cost savings and cost avoidance of approximately $500 million over the next three years. The net results of these actions is a change in our guidance to extend our cash runway into the second half of 2028.

我們的神經退化性疾病臨床計畫 ARV-102 和血液學臨床計畫 ARV-393 仍將按計劃在今年稍後提供重要的臨床數據。總體而言，這些措施將在未來三年內節省和避免約 5 億美元的成本。這些行動的最終結果是我們改變了指導方針，將現金流延長至 2028 年下半年。

We believe these significant cost savings and a refined capital allocation strategy in addition to a strong balance sheet will allow us to advance our early development portfolio in a timely and efficient manner, as well as ensuring a financially disciplined approach to commercial readiness. Before I continue, I do want to thank all the talented employees who are directly impacted by this decision.

我們相信，這些顯著的成本節約和完善的資本配置策略以及強勁的資產負債表將使我們能夠及時有效地推進我們的早期開發組合，並確保以財務嚴謹的方式做好商業準備。在繼續之前，我確實想感謝所有直接受到這項決定影響的優秀員工。

I'm proud of the progress we have made together and want to acknowledge their contributions and commitment to discovering and developing new treatment options for patients with life altering diseases. We wish the best for these colleagues as they transition to new opportunities. I also want to thank the employees who are continuing the journey with Arvinas, as each of them will be instrumental in helping us achieve the ambitious goals we have laid out for the company.

我為我們共同取得的進步感到自豪，並想承認他們為發現和開發改變生活的疾病患者的新治療方案所做的貢獻和承諾。我們祝福這些同事在新的機會中一切順利。我還要感謝與 Arvinas 一起繼續前進的員工，因為他們每個人都將幫助我們實現為公司製定的雄心勃勃的目標。

I'll now turn the call over to the team to review our current -- our recent data and the details from the quarter. I'll return at the end of the call to review the milestones that we anticipate for the remainder of 2025. But for now, I'll turn the call over to Noah.

我現在將電話轉給團隊，以審查我們當前的最新數據和本季的詳細資訊。通話結束後，我將回來回顧我們預計 2025 年剩餘時間將實現的里程碑。但現在，我會把電話轉給諾亞。

Thanks, John, and good morning everyone. Together with Pfizer, we were pleased to announce positive Phase 3 results from the VERITAC-2 trial earlier in the first quarter. These data, the first from a pivotal trial with the PROTAC degrader, represents an exciting and validating step forward for our platform.

謝謝，約翰，大家早安。我們與輝瑞公司一起，很高興地宣布第一季早些時候 VERITAC-2 試驗的第三階段取得了積極的成果。這些數據是使用 PROTAC 降解劑進行關鍵試驗的首批數據，代表著我們的平台向前邁出了令人興奮且有效的一步。

As John mentioned, we are excited to announce that data from the VERITAC-2 trial were selected for a late breaking oral presentation at the American Society of Clinical Oncology, or ASCO meeting in late May and will also be featured in the ASCO press program. The VERITAC-2 abstract has also been selected for inclusion in the 2025 Best of ASCO program in July. This program is important, it's run by ASCO to increase access to clinically impactful research for those who are unable to attend the annual meeting.

正如約翰所提到的，我們很高興地宣布，VERITAC-2 試驗的數據被選為 5 月底美國臨床腫瘤學會 (ASCO) 會議的最新口頭報告，並將在 ASCO 新聞計劃中展示。VERITAC-2 摘要也被選入 7 月份的 2025 年 ASCO 最佳計劃。這個計畫很重要，它由 ASCO 運營，旨在為那些無法參加年會的人增加獲得具有臨床影響力的研究的機會。

Given our plans to present the full data set at ASCO, which imposes an embargo on the presentation, I will only be providing commentary on the information previously disclosed in the top line data release. In patients with the ESR1 mutant tumors, Vepdeg exceeded the pre-specified hazard ratio of 0.6 and demonstrated a clinically meaningful improvement in progression free survival over fulvestrant. Additionally, Vepdeg continued to demonstrate a safety and tolerability profile consistent with our previous studies.

鑑於我們計劃在 ASCO 上展示完整的資料集，而 ASCO 對該演示實施了禁令，因此我將僅對先前在頂線資料發布中披露的資訊提供評論。對於患有 ESR1 突變腫瘤的患者，Vepdeg 超過了預先指定的風險比 0.6，並且與氟維司群相比，無進展生存期表現出有臨床意義的改善。此外，Vepdeg 繼續表現出與我們先前的研究一致的安全性和耐受性。

We believe Vepdeg has a best in class profile, and our plans to seek global regulatory approvals remain on track. While we are no longer planning new registrational trials for Vepdeg, we will continue to generate valuable data in our ongoing combination trials, and we welcome Pfizer's addition of Vepdeg in combination with their KAT6 inhibitor to their ongoing Phase 1 trial.

我們相信 Vepdeg 擁有同類產品中最佳的產品特性，我們尋求全球監管部門批准的計劃仍在順利進行中。雖然我們不再計劃對 Vepdeg 進行新的註冊試驗，但我們將繼續在正​​在進行的組合試驗中產生有價值的數據，並且我們歡迎輝瑞將 Vepdeg 與其 KAT6 抑制劑組合添加到他們正在進行的 1 期試驗中。

I'll now turn to our most advanced neuroscience program. We have designed investigational oral PROTAC degraders to cross the blood-brain barrier and selectively degrade leucine-rich repeat kinase 2 or LRRK2. LRRK2 is a large multi-domain scaffolding kinase that plays a critical role in effective endolysosomal trafficking.

現在我將談談我們最先進的神經科學計畫。我們設計了研究性口服 PROTAC 降解劑，以穿過血腦屏障並選擇性降解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，在有效的內溶小體運輸中起著關鍵作用。

Unlike traditional small molecule inhibitors that only block LRRK2's kinase activity, LRRK2 degraders eliminate the pathological scaffolding function, the GTPA activity, and the kinase activity of LRRK2. ARV-102 is our lead LRRK2 degrader. We believe our LRRK2 degraders are particularly well positioned to be evaluated in two diseases; Parkinson's disease or PD and Progressive Supranuclear Palsy or PSP.

與傳統的僅阻斷 LRRK2 激酶活性的小分子抑制劑不同，LRRK2 降解劑消除了 LRRK2 的病理支架功能、GTPA 活性和激酶活性。ARV-102 是我們主要的 LRRK2 降解劑。我們相信我們的 LRRK2 降解劑特別適合在兩種疾病中進行評估；帕金森氏症或 PD 和進行性核上性麻痺或 PSP。

Familial and idiopathic Parkinson's disease have been associated with LRRK2 on the basis of genetics and models of lysosomal dysfunction. PSP disease severity is associated with LRRK2 genetic findings. Additionally, we have published data associating the tau pathology of PSP with LRRK2 mediated endolysosomal dysfunction.

根據遺傳學和溶小體功能障礙模型，家族性和特發性帕金森氏症與 LRRK2 有關。PSP 疾病的嚴重程度與 LRRK2 基因發現有關。此外，我們也發表了將 PSP 的 tau 病理與 LRRK2 介導的內溶小體功能障礙相關聯的數據。

Previously we have shared preclinical data demonstrating ARV-102's superior target engagement, enhanced potency, and lysosomal pathway engagement when compared to LRRK2 inhibitors. In nonhuman primates, ARV-102 crossed the blood brain barrier where it achieved LRRK2 targeted protein degradation in deep brain regions and reduced LRRK2 protein as well as neuroinflammatory biomarkers in cerebrospinal fluid or CSF.

先前，我們已經分享了臨床前數據，證明與 LRRK2 抑制劑相比，ARV-102 具有更優異的標靶參與度、增強的效力和溶小體途徑參與度。在非人類靈長類動物中，ARV-102 穿過血腦屏障，實現了深部腦部區域的 LRRK2 目標蛋白降解，並降低了腦脊髓液或 CSF 中的 LRRK2 蛋白以及神經發炎生物標記。

I am now pleased to share with you that we have observed a similar pattern of activity in our first in-human Phase 1 clinical trial in healthy volunteers. These data were presented last month at ADPD. Our trial evaluated single doses of ARV-102 ranging from 10 to 200 mg and multiple doses ranging from 10 to 80 mg. We met our objective of 50% LRRK2 reduction in CSF after a single oral dose of at least 60 mg and once daily repeated oral doses of at least 20 mg.

我現在很高興地與大家分享，我們在健康志願者中進行的首次人體 1 期臨床試驗中觀察到了類似的活動模式。這些數據是上個月在 ADPD 上展示的。我們的試驗評估了 ARV-102 的單劑量（10 至 200 毫克）和多劑量（10 至 80 毫克）。在單次口服至少 60 毫克以及每日重複口服至少 20 毫克後，我們達到了腦脊髓液中 LRRK2 減少 50% 的目標。

This indicates substantial central LRRK2 protein degradation. In the Phase 1 clinical trial, ARV-102 was safe and well tolerated, with no serious adverse events or discontinuations reported after single or multiple doses. ARV-102 also demonstrated dose dependent median reductions in LRRK2 protein levels compared to baseline in peripheral blood mononuclear cells, confirming target engagement in the peripheral compartment.

這顯示中心 LRRK2 蛋白質大量降解。在第 1 階段臨床試驗中，ARV-102 安全且耐受性良好，單次或多次服用後均未報告嚴重不良事件或停藥。ARV-102 也表現出與週邊血單核細胞基線相比 LRRK2 蛋白水平的劑量依賴性中位數降低，證實了周邊區室中的標靶參與。

Taken together, pharmacoid dynamic changes of LRRK2 reduction in the CSF, reduce biomarker levels in the periphery, and an acceptable safety and tolerability profile support further study of LRRK2 degraders in PD and PSP. That further work is ongoing. Dosing of the Phase 1 single ascending dose cohort in patients with Parkinson's has already begun, and the multiple ascending dose cohort will begin in the second half of the year. We anticipate providing an update on PKPD safety and tolerability from the Phase 1 SAD cohort in patients with PD later in the year.

綜上所述，腦脊髓液中 LRRK2 減少的藥物動態變化、週邊生物標記物水平的降低以及可接受的安全性和耐受性特徵支持進一步研究 PD 和 PSP 中的 LRRK2 降解劑。進一步的工作仍在進行中。帕金森氏症患者的 I 期單次遞增劑量隊列給藥已經開始，多次遞增劑量隊列給藥將於今年下半年開始。我們預計將在今年稍後提供 PD 患者第 1 期 SAD 隊列的 PKPD 安全性和耐受性的最新資訊。

The data I've shared demonstrate that we can make orally bioavailable PROTAC that are brain penetrant. While our lead program is focused on LRRK2 for PSP and PD, our discovery portfolio focuses on additional targets that may be relevant for Huntington's and Alzheimer's disease. We look forward to sharing updates on these in the coming months and years.

我分享的數據表明，我們可以製造出可口服並能滲透大腦的 PROTAC。雖然我們的主要項目專注於 PSP 和 PD 的 LRRK2，但我們的發現組合著重於可能與亨廷頓舞蹈症和阿茲海默症相關的其他目標。我們期待在未來的幾個月和幾年內分享這些更新資訊。

Turning back to oncology, ARV-393 is our investigational oral PROTAC designed to degrade B-cell lymphoma 6 protein or BCL-6. BCL-6 is a transcription factor, a master regulator of multiple cellular processes during B-cell development, including proliferation, survival, and apoptosis. Altered BCL-6 activity has been implicated as an oncogenic driver in several subtypes of non-Hodgkin lymphoma, making it a rational therapeutic target.

回到腫瘤學，ARV-393 是我們正在研究的口服 PROTAC，旨在降解 B 細胞淋巴瘤 6 蛋白或 BCL-6。BCL-6 是一種轉錄因子，是 B 細胞發育過程中多種細胞過程的主要調節器，包括增殖、存活和凋亡。改變的 BCL-6 活性被認為是幾種非何杰金氏淋巴瘤亞型的致癌驅動因素，使其成為合理的治療目標。

PRTAC mediated degradation has the potential to overcome the historically undruggable nature of BCL-6. ARV-393 potently and rapidly degrades BCL-6 protein with iterative activity, which is critical to overcoming BCL-6's rapid resynthesis rate and its sustaining anti-tumor activity. In 2024, we shared preclinical data demonstrating ARV-393 drives tumor regressions in multiple in-vivo models of B-cell-driven non-Hodgkin lymphoma, including large B-cell lymphoma. We are enrolling patients with non-Hodgkin lymphoma in a Phase 1 clinical trial and are on track to share initial data by the end of the year.

PRTAC 介導的降解有可能克服 BCL-6 歷史上無法用藥的性質。ARV-393 能夠強效、快速地降解 BCL-6 蛋白並具有迭代活性，這對於克服 BCL-6 的快速再合成速率及其持續的抗腫瘤活性至關重要。2024 年，我們分享了臨床前數據，證明 ARV-393 可在多種 B 細胞驅動的非何杰金氏淋巴瘤（包括大 B 細胞淋巴瘤）體內模型中推動腫瘤消退。我們正在招募非何杰金氏淋巴瘤患者參與第一階段臨床試驗，並有望在今年年底前分享初步數據。

At AACR this past week, we presented new preclinical in vivo data for ARV-393 in combination with standard of care biological and chemotherapy as well as oral investigational small molecule inhibitors. These new data highlight the potential of ARV-393 to drive synergistic anti-tumor activity across multiple aggressive large B-cell lymphoma, xenograph models. ARV-393 and has tumor regressions when combined with current standards of care including (inaudible) in various biologics. Notably ARV-393 monotherapy up regulated CD20 expression, providing mechanistic rationale for synergy with the anti-CD20 therapies such as rituximab.

上週在 AACR 上，我們展示了 ARV-393 與標準治療生物和化學療法以及口服研究小分子抑制劑相結合的新的臨床前體內數據。這些新數據凸顯了 ARV-393 在多種侵襲性大 B 細胞淋巴瘤異種移植模型中發揮協同抗腫瘤活性的潛力。ARV-393 與包括（聽不清楚）各種生物製劑在內的現行治療標準相結合時，腫瘤會消退。值得注意的是，ARV-393 單一療法上調了 CD20 表達，為與利妥昔單抗等抗 CD20 療法的協同作用提供了機制原理。

Additionally, ARV-393 demonstrated enhanced tumor regressions when paired with targeted small molecule inhibitors of BCL-2, ECH2, and BTK, key oncogenic partners of BCL-6. These results suggest that ARV-393 may enable highly effective chemotherapy free regimens whether in combination with biologics or as part of an all oral therapeutic strategy.

此外，ARV-393 與 BCL-2、ECH2 和 BTK（BCL-6 的關鍵致癌夥伴）的標靶小分子抑制劑配對使用時，表現出增強的腫瘤消退作用。這些結果表明，ARV-393 無論是與生物製劑合併使用還是作為全口服治療策略的一部分，都可能實現高效的無化療方案。

We will present new preclinical data in a patient derived model of angioimmunoblastic T-cell lymphoma, or AITL at the European Hematology Association conference in June of this year. This is an orphan indication with high unmet and limited treatment options. We believe this will be the first preclinical data to show human AITL dependency on BCL-6. We also plan to present preclinical combination data with an emerging standard of care by specific antibody and a model of aggressive large B-cell lymphoma in the second half of the year.

我們將在今年 6 月的歐洲血液學協會會議上展示血管免疫母細胞 T 細胞淋巴瘤（AITL）患者來源模型的新臨床前數據。這是一種孤兒適應症，未滿足的治療方案很多，且治療選擇有限。我們相信這將是第一個顯示人類 AITL 對 BCL-6 依賴性的臨床前數據。我們也計劃在今年下半年展示特定抗體的新興治療標準和侵襲性大 B 細胞淋巴瘤模型的臨床前組合數據。

And finally, we filed an IND for our KRAS G12D degrader, ARV-806 and recently received a Safe to Proceed letter from the FDA. We anticipate the beginning a Phase 1 trial in patients with solid tumors harboring KRAS G12D mutations in the second half of this year. KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. Our degrader has demonstrated high potency and differentiation from inhibitors and other degraders currently in the clinic.

最後，我們為 KRAS G12D 降解劑 ARV-806 提交了 IND，並且最近收到了 FDA 發出的安全性繼續進行函。我們預計今年下半年開始針對患有 KRAS G12D 突變的實體腫瘤患者進行第 1 期試驗。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。我們的降解劑已證明具有高效力，並且與目前臨床中的抑制劑和其他降解劑有區別。

In addition to selectivity in the preclinical setting, ARV-806 demonstrates robust anti-tumor activity through dose responsive degradation of KRAS G12D in mutated cancers, including pancreatic and colorectal cancers. In preclinical studies, our PROTAC degrader has demonstrated the ability to bind both the active and inactive states of KRAS G12D, ARV-10 -- KRAS G12D. ARV-806 will eliminate rather than inhibit KRAS G12D with in-vitro potency, and that potency can be 30-fold greater than inhibitors and degraders currently in the clinic.

除了臨床前環境中的選擇性之外，ARV-806 還透過突變癌症（包括胰腺癌和結直腸癌）中 KRAS G12D 的劑量反應性降解表現出強大的抗腫瘤活性。在臨床前研究中，我們的 PROTAC 降解劑已證明能夠結合 KRAS G12D、ARV-10——KRAS G12D 的活性和非活性狀態。ARV-806 將在體外消除而不是抑制 KRAS G12D，其效力可能比目前臨床上的抑制劑和降解劑高出 30 倍。

In totality, these preclinical data give us confidence, and we intend to show differential biology of our KRAS degraders at a conference later this year. I look forward to updating you on our progress in the coming months.

總的來說，這些臨床前數據給了我們信心，我們打算在今年稍後的會議上展示我們的 KRAS 降解劑的差異生物學。我期待在未來幾個月向您通報我們的進展。

With that, I'll turn the call over to Andrew to review our quarterly financial information.

說完這些，我將把電話轉給安德魯來審查我們的季度財務資訊。

Thanks, Noah, and good morning, everyone. I'm pleased to share financial highlights for the first quarter ended March 31, 2025. As a reminder, detailed financial results for the first quarter are included in the press release we issued this morning. Let me start with the financial implications of the corporate restructuring and the removal of the two Phase 3 combination trials from the Vepdeg development plan.

謝謝，諾亞，大家早安。我很高興分享截至 2025 年 3 月 31 日的第一季的財務亮點。提醒一下，第一季的詳細財務結果包含在我們今天早上發布的新聞稿中。首先，我想談談公司重組以及從 Vepdeg 開發計劃中刪除兩個 3 期組合試驗的財務影響。

The corporate restructuring and associated workforce reduction were difficult decisions to make and are impacting many talented employees. They were however, necessary to meet our goals of reducing our cost structure and extending our cash runway to support our promising pipeline. The reductions were focused on reducing internal costs without having an impact on clinical stage programs that will drive value over the next several years.

公司重組和相關的裁員是艱難的決定，並且影響了許多優秀員工。然而，為了實現我們降低成本結構和延長現金流以支持我們有前景的管道的目標，它們是必要的。削減的重點是降低內部成本，而不會對未來幾年推動價值的臨床階段項目產生影響。

We estimate the restructuring will result in a reduction of our ongoing infrastructure costs of approximately $80 million annually, with savings expected to begin to be fully realized in the fourth quarter of 2025.

我們估計，此次重組將使我們每年的持續基礎設施成本減少約 8,000 萬美元，預計節省的成本將在 2025 年第四季開始全面實現。

In addition, we anticipate cost avoidance of approximately $350 million to $400 million over the next three to five years as a result of the removal of the two Phase 3 combination trials from the Vepdeg development plan. These actions will allow us to continue progressing our promising pipeline without the need for a near-term cash infusion and maintain a strong financial position with a cash runway now into the second half of 2028.

此外，由於從 Vepdeg 開發計畫中刪除了兩項 3 期組合試驗，我們預計未來三到五年內可節省約 3.5 億至 4 億美元的成本。這些舉措將使我們能夠繼續推動我們有前景的產品線，而無需短期現金注入，並保持強勁的財務狀況，到 2028 年下半年仍有充足的現金流。

I'll now briefly touch on some key financial highlights for the first quarter of 2025. At the end of the first quarter, we had approximately $954 million in cash, cash equivalents, and marketable securities on the balance sheet compared with $1.04 billion for the year end 2024.

現在我將簡要介紹 2025 年第一季的一些主要財務亮點。截至第一季末，我們的資產負債表上擁有約 9.54 億美元的現金、現金等價物和有價證券，而 2024 年底則為 10.4 億美元。

Revenue for the three months ended March 31, 2025, total $188.8 million compared to $25.3 million for the three months ended March 31, 2024. The increase in revenue was primarily due to the accounting impact of the reduction in the Vepdeg collaboration agreement's program budget due to the removal of the first and second line Phase 3 trials from the development plan.

截至 2025 年 3 月 31 日的三個月的收入總計 1.888 億美元，而截至 2024 年 3 月 31 日的三個月的收入為 2530 萬美元。收入增加主要是由於從開發計劃中刪除第一和第二線 3 期試驗導致 Vepdeg 合作協議的項目預算減少的會計影響。

The revenue recognition accounting for this agreement uses the percentage of completion method. As the budgeted costs serve as a denominator in the percent complete calculation, a reduction in that budget compared to the same actual incurred costs resulted in a higher percent completion and therefore higher revenue recognized in the first quarter.

本協議的收入確認會計採用完工百分比法。由於預算成本是完成百分比計算的分母，因此與相同的實際發生成本相比，預算的減少會導致更高的完成百分比，因此第一季確認的收入也會更高。

General and Administrative expenses were $26.6 million for the first quarter compared to $24.3 million for the same period of 2024. Research and Development expenses were $90.8 million in the first quarter compared to $84.3 million for the same period of 2024. The increase of $6.5 million was primarily driven by a one-time inventory charge of $10 million for Vepdeg partially offset by lower than expected Vepdeg development costs and an increase in the LRRK2 program of $5.2 million offset by a reduction in non-specific research and personnel expenses of $3.6 million.

第一季的一般及行政費用為 2,660 萬美元，而 2024 年同期為 2,430 萬美元。第一季研發費用為 9,080 萬美元，而 2024 年同期為 8,430 萬美元。650 萬美元的增長主要是由於 Vepdeg 的 1000 萬美元的一次性庫存費用，但部分抵消了低於預期的 Vepdeg 開發成本和 LRRK2 計劃的 520 萬美元的增長，但非特定研究和人員費用的減少 360 萬美元抵消了這一增長。

As I mentioned earlier, taking into account the anticipated impact of the restructuring, the reprioritization of the research portfolio and Vepdeg development plan, and the anticipated launch of Vepdeg, our updated cash runway guidance is now into the second half of 2028. We believe our efforts are focused on areas that will maximize shareholder value as we move forward -- as we move towards important catalysts in the coming months.

正如我之前提到的，考慮到重組的預期影響、研究組合和 Vepdeg 發展計劃的重新排序以及 Vepdeg 的預期推出，我們更新後的現金流指引現已進入 2028 年下半年。我們相信，隨著我們在未來幾個月朝著重要的催化劑邁進，我們的努力將集中在能夠最大化股東價值的領域。

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

說完這些，我會把電話轉回給約翰，請他做最後發言。

Thanks, Andrew. These actions should offer significant clarity around our focus over the next few years and I will allow us to hit a number of key data inflection points from our early development programs, as well as the potential commercial launch of Vepdeg with our partner Pfizer.

謝謝，安德魯。這些行動應該會為我們未來幾年的重點提供重要的指導，我將使我們能夠從早期開發計劃中獲得一些關鍵的數據拐點，以及與我們的合作夥伴輝瑞一起實現 Vepdeg 的潛在商業發布。

As we progress through 2025, there will also be many opportunities to showcase why our belief in our portfolio is strong. These include data from the VERITAC-2 trial in the late breaking oral presentation at ASCO in June. The first Phase 1 data for a LRRK2 degrader ARV-102, in patients with Parkinson's disease and first in human Phase 1 data for our BCL-6 degrader ARV-393.

隨著我們邁入 2025 年，我們也將有很多機會展示我們對我們的投資組合的堅定信心。其中包括 6 月 ASCO 最新口頭報告中的 VERITAC-2 試驗數據。這是 LRRK2 降解劑 ARV-102 在帕金森氏症患者中的第一個 1 期數據，也是我們的 BCL-6 降解劑 ARV-393 在人體中的第一個 1 期數據。

We believe our progress will continue to demonstrate the potential of our PROTAC degraders to add meaningful value for patients, their caregivers, and our shareholders. As we embark on this new chapter, I want to thank you for your continued support.

我們相信，我們的進步將繼續證明我們的 PROTAC 降解劑的潛力，為患者、他們的照護者和我們的股東增加有意義的價值。當我們開啟新的篇章時，我要感謝你們一直以來的支持。

And with that, I'll turn the call over to Jeff to begin the Q&A portion of the call.

接下來，我將把電話交給傑夫，開始電話的問答部分。

Thanks John. Before I turn the call over to the operator, I do want to remind you that in order to comply with the ASCO embargoes policy, we aren't able to answer questions about the VERITAC-2 data beyond the top line results reported in our press release on March 11th.

謝謝約翰。在我將電話轉給接線員之前，我想提醒您，為了遵守 ASCO 的禁令政策，除了 3 月 11 日新聞稿中報告的頂線結果之外，我們無法回答有關 VERITAC-2 數據的問題。

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

那麼，請那位接線員打開隊列。

(Operator Instructions)

（操作員指示）

Michael Schmidt, Guggenheim.

古根漢美術館的麥可·施密特。

Hey guys, good morning. Thanks for taking our questions. I just had a few follow up questions on Vepdeg. Maybe just help us understand a little bit more on how much of the decision to not advance the CDK4/6 inhibitor combinations was driven by emerging data on the class overall versus specifically the VERITAC-2 results.

大家好，早安。感謝您回答我們的問題。我剛剛對 Vepdeg 有一些後續問題。也許只是幫助我們更多地了解不推進 CDK4/6 抑制劑組合的決定在多大程度上是由該類別的整體新興數據而不是具體的 VERITAC-2 結果驅動的。

And in the second line setting, how do you think Vepdeg will be positioned relative to other oral (inaudible) and help us understand how much you need to invest in a commercial infrastructure as you potentially maybe co-commercializing the product in the US next year. Thanks so much.

在第二行設定中，您認為 Vepdeg 相對於其他口服藥物的定位如何（聽不清楚），並幫助我們了解您需要在商業基礎設施上投資多少，因為您明年可能會在美國共同商業化該產品。非常感謝。

Thanks, great question. So, yeah, the first question in relation to -- is this a decision based on specific information related to Vegdeg or the class. I think we've had a general discussion with Pfizer as we -- as you see, or serve in the market as an ESR1 mutant only drug, we saw some of the data coming from [immunastrin], which also had a very strong ESR1 mutant only profile.

謝謝，好問題。所以，是的，第一個問題是——這是基於與 Vegdeg 或類別相關的具體資訊的決定嗎？我認為我們已經與輝瑞進行了一般性討論，正如您所見，或者作為市場上僅針對 ESR1 突變體的藥物，我們看到一些來自 [immunastrin] 的數據，它也具有非常強大的僅針對 ESR1 突變體的特性。

And clearly the data we had for VERITAC, which we can't discuss in detail, but we have already told you it has strong ESR1 mutant data, but we didn't hit ITT. So the general discussion we had with Pfizer was around whether or not in that second line setting, would the drugs really just be ESR1 mutant only. And we came to the conclusion that's likely to be the case and therefore the design of the study that we had was for an ITT combination with the CDK4/6, so we decided we would drop that.

顯然，我們擁有 VERITAC 的數據，我們無法詳細討論，但我們已經告訴您它具有強大的 ESR1 突變數據，但我們沒有觸及 ITT。因此，我們與輝瑞公司的一般討論是圍繞在第二線治療中，藥物是否真的只是 ESR1 突變體。我們得出的結論是，情況很可能如此，因此，我們先前的研究設計是針對 ITT 與 CDK4/6 的組合，所以我們決定放棄這一點。

So that I think that's -- I think a logical rationale for dropping that particular study based on the emerging data on in the second line setting of whether or not you're going to have just the ESR1 mutant only profile overall. In terms of positioning Vepdeg, I think, as Noah said, I think, again, you'll see the data at ASCO where we believe we've got the opportunity to be the best in class of the degraders in that second line plus setting. And with that, our positioning would be, I think, very strong in terms of our overall data set in terms of tolerability and, overall activity.

所以我認為——我認為放棄該特定研究的合理理由是基於第二行設定中出現的數據，即是否只總體擁有 ESR1 突變體概況。在定位 Vepdeg 方面，我認為，正如 Noah 所說，我認為，您會再次看到 ASCO 的數據，我們相信我們有機會成為第二線加環境中最好的降解劑。因此，我認為，就我們的整體數據集、耐受性和整體活動而言，我們的定位將非常強大。

So we have very great confidence of that actually be if we get approval and get to the point of launch, once we get through the regulatory hurdles, I think we'd be in a very strong position for positioning that in that marketplace.

因此，我們對此非常有信心，如果我們獲得批准並進入發布階段，一旦我們突破監管障礙，我認為我們將在該市場中佔據非常有利的地位。

And I think the third question was -- oh yeah, the commercial investment, clearly it's a 50/50 [coco] with Pfizer. We are the lead for that. What we've done is done a very kind of prudent approach to commercial build. It has been very small. It's all going to be data-driven and the point of approval. So yes, there will be a kind of significant backend recruitment to get a sale force in place, but right now our commercial footprint is really very small.

我認為第三個問題是──哦，是的，商業投資，顯然是與輝瑞各佔一半的份額。我們是這方面的領導者。我們採取了一種非常謹慎的商業建設方法。它已經非常小了。這一切都將由數據驅動，並以數據為準繩。所以是的，將會進行大量的後端招募來建立銷售隊伍，但目前我們的商業足跡確實非常小。

We also have the ability to have ongoing discussions with Pfizer about the best way to take the molecule forward in a commercial setting, both in the US and commercially, and we'll be able to update all of you on that as we complete those discussions.

我們也能夠與輝瑞公司持續討論在美國和商業環境中推動該分子發展的最佳方式，我們將在完成這些討論後向大家通報最新情況。

Andrew Berens, Leerink Partners.

安德魯貝倫斯，Leerink Partners。

Hi, thanks, and I'm sure you guys have had to make some difficult decisions over the last few weeks. So my question is about the future neuro efforts in LRRK2. You did give some color and prepared comments about the role of LRRK2 in neuro diseases, but wondering how much LRRK2 degradation you think is going to be clinically relevant and whether these would eventually be combination approaches.

嗨，謝謝，我相信你們在過去幾周里不得不做出一些艱難的決定。所以我的問題是關於 LRRK2 未來的神經研究。您確實對 LRRK2 在神經疾病中的作用給出了一些說明並準備好了評論，但想知道您認為 LRRK2 降解在多大程度上具有臨床相關性，以及這些最終是否會成為組合方法。

Yeah, I'll hand over to Noah for a specific answer to that, but we're very excited by the data we see so far with LRRK2. Our first neurodegeneration asset, the first PROTAC in this space, and the first to show brain penetrance as well. So the profile we're seeing initially is very exciting. But Noah, do you want to add some more color to that?

是的，我會將這個問題的具體答案交給諾亞，但我們對目前看到的 LRRK2 數據感到非常興奮。我們的第一個神經退化性疾病資產，該領域的第一個 PROTAC，也是第一個顯示出腦滲透性的資產。因此，我們最初看到的概況非常令人興奮。但是諾亞，你想添加一些顏色嗎？

Sure. So Andrew, thanks for the interest in what's a very exciting first neurodegeneration directed PROTAC for our company. So indeed we think that there are a few opportunities for us to develop this year and as I outlined earlier in the call, that's because there's both genetics that support it. And then also underlying biology in these two diseases that were highlighted PSP and Parkinson's disease.

當然。所以安德魯，感謝您對我們公司首個非常令人興奮的神經退化性疾病導向 PROTAC 的關注。因此，我們確實認為今年我們有一些發展機會，正如我在電話會議中早些時候概述的那樣，這是因為有兩個基因支持它。然後也研究了這兩種疾病（PSP 和帕金森氏症）的潛在生物學特性。

Your question around how much degradation we want to achieve. Well, the goal right now, what had been and remains to achieve more than 50% degradation. We don't want to completely eliminate it because there's obviously functional, there's purpose to this protein in terms of endolysosomal trafficking, but when there's over expression, when there's increased activity, you get mistrafficking, and that's tightly tied to the pathology of these diseases.

您的問題是關於我們想要實現多少降解。那麼，現在的目標是，實現 50% 以上的降解。我們不想完全消除它，因為這種蛋白質在溶酶體運輸方面顯然具有功能性和目的性，但當它過度表達、活性增加時，就會出現錯誤運輸，而這與這些疾病的病理密切相關。

We know that on average, Parkinson's disease patients have twice the level of LRRK2 in their CSF compared to age match controls, and so we think it's prudent therefore to target something in the 50% range. And so far we've seen in healthy volunteers that we can achieve that. And as well as achieve appropriate downstream signaling. So we know that it's on target, we think on mechanism, and the next thing is to really look at the data from the PD patients in the studies that are ongoing.

我們知道，帕金森氏症患者的腦脊髓液中 LRRK2 的含量平均是年齡匹配對照組的兩倍，因此我們認為將目標設定在 50% 左右是明智的。到目前為止，我們在健康志工身上看到我們可以實現這一目標。並實現適當的下游訊號傳輸。因此我們知道這是正確的，我們思考其機制，下一步是真正查看正在進行的研究中 PD 患者的數據。

Okay, and do you think it'll be a combination eventually?

好的，您認為最終會是兩種組合嗎？

Well, when you say combination -- right now, there really aren't disease altering drugs in the -- that are standard of care. So it's just a -- this may be on top of (inaudible) type of treatment for patients, but this is disease altering, so I'm not sure what you mean by combinations.

好吧，當你說組合療法時——目前，實際上並沒有可以改變病情的藥物——這是標準的治療方法。所以這只是 — — 這可能是對患者的（聽不清楚）治療類型，但這會改變病情，所以我不確定您所說的組合是什麼意思。

Right. I'm asking whether you think it'll be on top of standard of care currently.

正確的。我問的是您是否認為它會成為目前護理標準之上的治療。

Yeah, on top of standard of care, for sure.

是的，當然是在護理標準之上。

Yeah, okay. Thank you.

嗯，好的。謝謝。

Eliana Merle, UBS.

瑞銀的 Eliana Merle。

Hi, this is Joseph asking for Ellie. Thanks for taking our question. What is your view on the market size of that deck in the second line plus model therapy setting alone. And I have a follow up.

你好，我是約瑟夫，我找艾莉。感謝您回答我們的問題。您認為僅在第二線加模型治療設置中該甲板的市場規模是多少？我還有一個後續行動。

And you have a follow up. Do you want to ask it now or --

而你還有後續行動。你想現在問還是--

Sure. So, how do you think about the cadence of cost reductions from a modeling perspective and in terms of Vepdeg monotherapy after the VERITAC-2 data, can you help us think about what milestones you might be entitled from Pfizer on approval in this setting?

當然。那麼，從建模角度來看，您如何看待成本降低的節奏？就 VERITAC-2 數據之後的 Vepdeg 單藥療法而言，您能否幫助我們思考，在這種情況下，您可能有權從輝瑞獲得哪些里程碑批准？

Yeah. So the first question was related to the market size. Yeah, so we've been thinking there's a really significant opportunity in that second line plus setting. There's 40,000 new patients in the second line setting every year. Of that 40% are ESR1 mutants only, and that's our estimate. Some others estimate around 50%. So that's 25,000 new patients in the second line third space each year.

是的。所以第一個問題與市場規模有關。是的，所以我們一直認為第二行加設定中存在著一個非常重要的機會。每年有 40,000 名新患者進入二線治療。其中 40% 僅為 ESR1 突變體，這是我們的估計。另一些人估計約為50%。因此每年第二線第三空間將有 25,000 名新患者。

And, drugs, as like our (inaudible) are out in that space, they're probably capturing about a third of that. So there's a really significant opportunity there for a good profile of a degrader like the [degestrant] to hopefully capture quite a significant part of that market. So we're very excited about the opportunity in that space.

而且，像我們的（聽不清楚）這樣的藥物就存在於那個領域，它們可能佔據了其中的三分之一。因此，對於像 [degestrant] 這樣性能良好的降解劑來說，這是一個非常重要的機會，有望佔領相當大一部分市場。因此，我們對該領域的機會感到非常興奮。

The second question, Andre, I think it was more like a kind of a financial question.

第二個問題，安德烈，我認為這更像是財務問題。

Yeah, sure. So with regard to the restructuring, notifications to employees have gone out this week, so the restructuring has begun. As with all restructurings, there's a combination of employee reduction and cost control. I stated in my prepared remarks that we would have the full impact of the reductions by Q4. We'll obviously start seeing benefit prior to that, right?

是的，當然。關於重組，本週已經向員工發出通知，重組已經開始。與所有重組一樣，裁員和成本控制是結合的。我在準備好的發言中表示，到第四季度，我們將全面感受到減稅帶來的影響。我們顯然會在此之前開始看到好處，對嗎？

So we're offering our colleagues severance packages that will be paid out in Q2, so you won't see a charge in our Q1 financial statements that the notifications went out in Q2, so it was a subsequent event for the purposes of our financial statements in the first quarter. But for modeling purposes, you can assume that you'll start seeing savings relatively quickly. Q3 will have a significant amount of savings and full impact in the fourth quarter.

因此，我們將向同事提供遣散費，並將在第二季度支付，因此您不會在我們的第一季財務報表中看到第二季發出通知的費用，因此這是我們第一季財務報表的後續事件。但出於建模目的，您可以假設您將相對快速地開始看到節省。第三季將節省大量資金，並在第四季產生全面影響。

Derek Archila, Wells Fargo.

德里克·阿奇拉，富國銀行。

Good morning. This is Simone on for Derek. Thank you for taking our questions. I just have two, so I know you said that for the LRRK2 degrader you need to see 50% degradation, but how exactly do you risk is the target and what can we expect from the SAD cohort and PD patients in after '25?

早安.這是西蒙娜 (Simone) 代替德里克 (Derek)。感謝您回答我們的問題。我只有兩個，所以我知道您說對於 LRRK2 降解劑，您需要看到 50% 的降解，但您的目標風險究竟是多少，以及我們對 25 年後的 SAD 隊列和 PD 患者有何期待？

Noah, do you want to take?

諾亞，你想拿嗎？

Sure, I'll come -- I'm not sure I caught the second part, but for the first, (multiple speakers)

當然，我會來的——我不確定我是否看過第二部分，但對於第一部分，（多位發言者）

So in general, when you say de-risk, I guess that could be that could focus us on what are some of the liabilities associated with that target, right. So we do know that there are findings with type 2 pneumocyte enlargement or proliferation that could be associated with collagen deposition in the lung.

所以總的來說，當你說降低風險時，我想這可能是讓我們專注於與該目標相關的一些負債，對吧。因此，我們確實知道，2 型肺細胞增大或增生的發現可能與肺部膠原蛋白沉積有關。

We also know that there's some vacuolization seen with in -- and these are all inhibitors, right. So vacuolization seen in the proximal tubule in the kidney.

我們也知道，其中出現了一些空泡——這些都是抑制劑，對吧。因此在腎臟的近端小管可以看到空泡。

There's some typing going on in the background, so whoever's doing that, if you can pause, please. Thank you.

背景中正在進行一些打字操作，所以無論是誰在打字，請暫停一下。謝謝。

So that's known and that's been a challenge for inhibitors for reasons that we have our own hypothesis and it's probably too much to go into on the call right now, we have seen minimal evidence for the type 2 pneumocyte enlargement. We have associated much reduced pneumocyte proliferation that we observe with our degrader rather than what's observed with inhibitors. We associate that with different protein -- different profile of protein deposition in the alveoli.

這是眾所周知的，對於抑制劑來說這是一個挑戰，因為我們有自己的假設，而且現在在電話會議上討論的內容可能太多了，我們已經看到了關於 2 型肺細胞增大的證據很少。與抑制劑相比，我們在使用降解劑時觀察到的肺細胞增殖明顯減少。我們將其與不同的蛋白質——肺泡中不同的蛋白質沉積情況聯繫起來。

So we think that we have a differentiated profile when compared to inhibitors, and we're tracking patients in the meantime in our study, we look at diffusion capacity in the lung and we're measuring renal function on an ongoing basis and so far things have been safe to proceed.

因此，我們認為與抑制劑相比，我們具有差異化的特徵，同時我們在研究中追蹤患者，我們觀察肺的擴散能力，並持續測量腎功能，到目前為止，一切都是安全的。

In terms of your second question had to do with the SAD cohort expectation, but I'm not sure what you meant by the expectation there in terms of timing or results?

您的第二個問題與 SAD 群體期望有關，但我不確定您所說的時間或結果期望是什麼意思？

Results, like what type of results can we expect to see?

結果，例如我們可以期待看到什麼類型的結果？

Oh, what could we see? Well, so health -- so as I mentioned earlier, PD patients have twice the level of LRRK2 protein levels in the CSF and presumably in the deep brain regions compared to healthy volunteers. So, we would expect in our math studies, we can recapitulate what we saw in healthy volunteers. We could see now in higher baseline LRRK2 levels degradation that's achieving greater than 50% reduction, which is our target.

哦，我們能看到什麼？嗯，那麼健康——正如我之前提到的，與健康志願者相比，PD 患者的腦脊髓液中 LRRK2 蛋白質水平是健康志願者的兩倍，大概在深部大腦區域中也是如此。因此，我們希望在數學研究中能夠重現我們在健康志願者身上看到的情況。我們現在可以看到，在更高的基線 LRRK2 水平下，退化程度已達到 50% 以上的減少，這是我們的目標。

And then on top of that, because they also have neuroinflammation and other signs of neuronal fragility or that neuronal death that we can capture some signals of this with 28 days of treatment in the MAD study. So we are looking at biomarkers, and this should -- we would hope that we can see that signal in the MAD.

除此之外，由於他們還具有神經發炎和其他神經元脆弱性或神經元死亡的跡象，我們可以在 MAD 研究中透過 28 天的治療捕捉到一些這方面的訊號。因此，我們正在研究生物標誌物，我們希望能夠在 MAD 中看到該訊號。

Akash Tewari, Jefferies.

Akash Tewari，傑富瑞。

Hey, this is Manoj in for Akash. Just one question. Will you need any overall survival data trend for vepdeg regulatory submission or like what's the expected timeline for market entry there? Just one more on like, are you considering any partnership for like neuro programs there? Thanks.

嘿，我是 Manoj，代替 Akash。只有一個問題。您是否需要 vepdeg 監管提交的整體生存數據趨勢，或者預計進入市場的時間表是怎樣的？再問一個問題，您是否考慮在那裡建立神經計畫的合作關係？謝謝。

Going back to that -- I'm sorry, John, just going back to that first question, could you repeat that in terms of regulatory finding.

回到那個話題——對不起，約翰，回到第一個問題，你能否就監管結果重複一遍。

Any overall survival trend for regulatory submission? -- Overall survival data trend.

監管提交的整體生存趨勢如何？ ——整體生存數據趨勢。

Oh, overall survival data, I'm sorry.Yeah, so. So overall, we can't really talk about our data, beyond what has been shared in our topline results, and we recommend that you to join us at at ASCO to hear the presentation. Certainly, in answer to your question about how that impacts submissions ultimately, regulators generally want to see that there are no adverse, overall survival findings, when one looks at TFS, which is a [surrogate] for OS. But it's something that is there just isn't any companies don't power for OS when they submit.

哦，整體生存數據，對不起。是的，所以。因此總的來說，除了我們在頂線結果中分享的內容之外，我們無法真正談論我們的數據，我們建議您加入我們在 ASCO 的演講。當然，在回答您關於這最終如何影響提交的問題時，監管機構通常希望看到，當查看 TFS（OS 的替代指標）時，沒有不利的整體生存結果。但事實上，沒有任何一家公司在提交申請時不為作業系統提供支援。

And then the second question you asked about neuroscience and partnering, clearly as we move forward in the space, both in PSP and Parkinson's disease, we've always said that this would be an area that could lend itself to having a strategic partner. These would end up being set in the Parkinson's area, quite significant sized trials.

然後，您問到的第二個問題是關於神經科學和合作，顯然，隨著我們在 PSP 和帕金森氏症領域的發展，我們一直說這是一個可以尋求策略夥伴的領域。這些最終將在帕金森氏症領域進行相當大規模的試驗。

But, right now we're in a good position to be able to move our program forward to a significant data inflection points and, we'll review potential partners at that point.

但是，現在我們處於良好的位置，能夠將我們的計劃推進到重要的數據拐點，屆時我們將審查潛在的合作夥伴。

Jonathan Miller, Evercore ISI.

喬納森·米勒（Jonathan Miller），Evercore ISI。

Hi guys, thanks for taking my question.

大家好，感謝你們回答我的問題。

I'll do one more on vepdeg maybe since we haven't spoken about the first line potential there. You were a little more vague about the rationales for not proceeding with the [atirmociclib] Phase 3. Is your expectation that next gen estrogen receptor directed therapies are not going to be relevant in first line in general or is this more to do with vepdeg's profile or more to do with the (inaudible) profile or the data that you've seen in the combinations so far? So maybe I guess I'll start with that.

我可能會在 vepdeg 上再做一次，因為我們還沒有討論那裡的第一線潛力。您對不繼續進行 [atirmociclib] 第 3 階段的理由解釋得比較模糊。您是否預期下一代雌激素受體導向療法通常不會與一線治療相關，或者這更多地與 vepdeg 的概況有關，或者更多地與（聽不清）概況或您迄今為止在組合中看到的數據有關？所以我想我應該從那裡開始。

And then secondly. On the BCL-6 program, how much data in NHL patients can we expect to see in the next handful of releases, and would you expect to be able to show ORRs or at least meaningful efficacy data that will allow us to comp to other recent NHL data sets?

其次。在 BCL-6 計劃中，我們預計在接下來的幾次發布中看到多少 NHL 患者的數據，您是否希望能夠顯示 ORR 或至少有意義的療效數據，以便我們與其他最近的 NHL 數據集進行比較？

Yeah, great questions, and I'll take the first one and Noah I can take the second one.

是的，很好的問題，我回答第一個問題，Noah，我可以回答第二個問題。

Yes, certainly big decisions like this around going forward or not with a first line study, they don't happen overnight. So there's been lots of discussion with our colleagues at Pfizer. I suppose the genesis of the final decision was Pfizer looking at basically a press release from our VERITAC-2 data where we say that we've hit ESR1 mutant only, but we haven't hit ITT.

是的，像是否繼續進行一線研究這樣的重大決定當然不是一朝一夕就能做出的。因此，我們與輝瑞的同事進行了大量討論。我認為最終決定的起因是輝瑞公司基本上是根據我們的 VERITAC-2 數據發布的新聞稿，其中我們說我們只發現了 ESR1 突變體，但還沒有發現 ITT。

And without going into the data, if you just take that as the opening gambit. It probably started a conversation around, do degraders work against wild type either in the second line setting, which is a reasonable question, but then I think Pfizer then took it to the next level, which is do they work in the first line setting?

無需考慮數據，如果你只是將其作為開場白。它可能引發了一場討論，降解劑在第二線環境中是否對野生型起作用，這是一個合理的問題，但我認為輝瑞隨後將其提升到了一個新的水平，即它們在第一線環境中是否起作用？

So I'll give you the Venus view. We believe they do. We believe that degestrant will work very effectively in the frontline setting. For several years, we've talked about the difference between first line and second line disease. In the second line disease, probably around 40% of the patients have ESR1 mutations that basically give them an endocrine sensitivity, and around 60% of the patients have tumors that have wild type and other driving mutations that are largely endocrine and sensitive.

所以我會給你金星的景色。我們相信他們會的。我們相信，解毒劑在前線環境中將發揮非常有效的作用。多年來，我們一直在談論第一線疾病和二線疾病之間的差異。在二線疾病中，大約 40% 的患者俱有 ESR1 突變，這基本上使他們具有內分泌敏感性，大約 60% 的患者患有野生型腫瘤和其他驅動突變，這些突變主要是內分泌和敏感的。

Our hope with the second line trial was that we'd be able to capture whatever endocrine sensitive group of tumors that are in that broader ITT net. But in reality what you saw was that we missed the ITT, which is telling you that there's not as many endocrine sensitive tumors in that space. However, in the first line setting, we believe it's a very different story. We believe that maybe ESR1 mutations represent maybe only 5% of what you see in the first line setting.

我們希望透過二線試驗能夠捕捉更廣泛的 ITT 網路中的任何內分泌敏感腫瘤組。但實際上，您看到的是我們錯過了 ITT，這告訴您該空間中沒有那麼多內分泌敏感性腫瘤。然而，在第一行設定中，我們相信這是一個非常不同的故事。我們認為 ESR1 突變可能僅佔第一線治療中所見突變的 5%。

The vast majority of the tumors would be wild type, but most significantly, we believe that those would be endocrine sensitive, and therefore available to be tackled by a drug like degestrant. So that's our belief, it still is. But we're in a partnership with Pfizer and I think they want to have more mature data, not just from our internal programs and data sets, but also the external world. They want to see what's going to happen with (inaudible), the (inaudible) ER degrader, which is in the first line. So if that comes out and it's positive in the first line setting, that's going to be a great signal for all the therapies.

絕大多數腫瘤都是野生型，但最重要的是，我們認為這些腫瘤對內分泌敏感，因此可以用像消化劑這樣的藥物來治療。這就是我們的信念，現在依然如此。但我們與輝瑞公司有合作關係，我認為他們希望獲得更成熟的數據，不僅來自我們的內部程序和數據集，還來自外部世界。他們想看看（聽不清楚），（聽不清楚）ER 降解劑（位於第一行）會發生什麼事。因此，如果結果出來並且在第一線環境中呈陽性，那麼這對所有療法來說都是一個很好的信號。

Again, interesting data coming out from SERENA-6 more mature data there could also influence it. And of course, as our data matures overall. I think Pfizer also want to see our current [abemaciclib VEP] combo mature in terms of that data set also. So yeah, there's a number of different things that Pfizer would like to see in terms of maturity of data, both our internal data and the external data. And it's to say, we're in a partnership, good partners can look at two different data sets and two different scenarios and maybe come out with different options.

同樣，SERENA-6 產生的有趣數據以及更成熟的數據也可能對其產生影響。當然，隨著我們的數據整體日益成熟。我認為輝瑞也希望看到我們目前的 [abemaciclib VEP] 組合在該資料集方面成熟。是的，輝瑞希望看到資料成熟度方面的許多不同情況，包括我們的內部資料和外部資料。也就是說，我們處於合作關係中，好的合作夥伴可以查看兩個不同的資料集和兩種不同的場景，並可能提出不同的選擇。

But we're going along with this decision from the team to opt out of the first line study. And we move on, basically where we've taken the money that was targeted for that study that's now out of the budget. It allows us to plan to fund the rest of our portfolio, which is a very exciting portfolio in a more aggressive way. And as data matures, if Pfizer come back to us and say they actually do want to do a first time study, we could assess that at a later date. But right now that is not in our plan and we move on.

但我們同意團隊的決定，退出第一線研究。我們繼續前進，基本上我們已經拿走了原本用於這項研究的資金，而這些資金現在已經超出了預算。它使我們能夠以更積極的方式計劃為我們的投資組合的其餘部分提供資金，這是一個非常令人興奮的投資組合。隨著數據的成熟，如果輝瑞回覆我們並表示他們確實想進行首次研究，我們可以在以後進行評估。但目前這不在我們的計劃中，我們會繼續前進。

BCL-6?

BCL-6？

Regarding BCL-6, we're early in the dose escalation, but we've shared that we expect to share results later in the year. I don't think we can order or offer more guidance than that right now. Think of it as several cohorts.

關於 BCL-6，我們正處於劑量遞增的早期階段，但我們已經表示，預計將在今年稍後分享結果。我認為我們現在無法命令或提供比這更多的指導。可以將其視為幾個群體。

Do you expect to be --

你期望--

Sorry for that.

很抱歉。

Yeah, I was -- do we expect we would share, where we are in terms of, safety and efficacy with any data that we --

是的，我當時想——我們是否希望分享我們在安全性和有效性方面的數據？--

Do you expect to be in the active dosing range? Would you expect to be reaching dose levels that that are where you want them to be from the perspective of the level of degradation you're expecting to drive efficacy?

您預計會在有效劑量範圍內嗎？從您預期提高療效的降解程度的角度來看，您是否希望達到您想要的劑量水平？

We may be, yes.

是的，我們可能是。

Alright, thanks so much.

好的，非常感謝。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Okay, I have a few questions as well. I think a few minutes ago you had talked about the market op opportunity for these, VERITAC-2 patients that that were positive in the study. You mentioned that for (inaudible), one third of the 25,000 patients are on that drug. Does your market data give you any feedback about what the profile of those one third of patients are, and is there anything different about the other two third, that could makeeptech potentially more attractive, for patients.

好的，我也有幾個問題。我想幾分鐘前您已經談到了這些在研究中表現積極的 VERITAC-2 患者的市場運作機會。您提到（聽不清楚），25,000 名患者中有三分之一正在服用該藥物。您的市場數據是否能為您提供這三分之一患者概況的回饋？另外三分之二的患者有何不同之處？這些不同之處是否可能使 eptech 對患者更具吸引力？

And then, can you just provide any color on the remaining Pfizer milestones you expect to realize from here on out, and if there are any specifically related to the [KAT6] collaboration. And then the last one, I'm sorry if I missed this, but are you still planning on exploring Vepdeg in third line (inaudible)?

然後，您能否詳細介紹您期望從現在開始實現的剩餘輝瑞里程碑，以及是否有任何與 [KAT6] 合作具體相關的里程碑。然後最後一個，如果我錯過了，我很抱歉，但你還打算在第三行探索 Vepdeg 嗎？（聽不清楚）？

Yeah. So first of all, yeah, in terms of the patient population in the second line, yes, so we think based on our assessments and some of the other external data, 40,000 new patients in that second line setting, which we believe, as I said before, 40% are ESR1 mutant. So in that second line plus overall setting, the ESR1 mutant, that's probably, 16 to -- say 16,000 to 25,000 patients that are then available.

是的。首先，是的，就二線患者群體而言，是的，因此我們認為根據我們的評估和其他一些外部數據，二線環境中有 40,000 名新患者，正如我之前所說，我們相信其中 40％ 是 ESR1 突變體。因此，在第二線加上整體設定中，ESR1 突變，大概有 16 到 - 例如 16,000 到 25,000 名患者可用。

I think (inaudible) has done remarkably well, to capture a significant number of those patients, I think there's a growing opportunity in that market to have more effective drugs in there and it's a growing -- I think it's a growing space. So yeah, we think, as I said before, a really significant opportunity. And we also believe it's a very good opportunity to have very targeted launch into that space.

我認為（聽不清楚）做得非常好，吸引了大量患者，我認為這個市場有越來越大的機會獲得更有效的藥物，而且這是一個不斷增長的——我認為這是一個不斷增長的空間。是的，正如我之前所說，我們認為這是一個非常重要的機會。我們也相信，這是一個非常好的機會，可以有針對性地進軍該領域。

There's probably around 6,000 oncologists that drive 70% to 80% of the prescriptions in the space. So we can also target this prescribing population I think very effectively. So I think, yes, a really significant exciting opportunity.

大約有 6,000 名腫瘤學家，佔該領域處方量的 70% 至 80%。因此，我認為我們也可以非常有效地針對這個開處方的人群。所以我認為，是的，這是一個非常重要且令人興奮的機會。

As it relates to KAT6 and general milestones and Pfizer?

它與 KAT6 和一般里程碑以及輝瑞公司有關嗎？

Yeah, so, with regards to the to the Pfizer agreement, we are entitled to a milestone on first approval. I do not believe we've disclosed the exact amount of that, so I'll disclose it now, but we are entitled to something, and then there -- I think you asked a question specifically regarding KAT6. There's certainly nothing in the contract specifically regarding KAT6. So no, it would be related to the first approval which would be obviously Vepdeg.

是的，就輝瑞協議而言，我們有權在首次批准時取得里程碑。我認為我們還沒有披露確切的金額，所以我現在就披露，但我們有權獲得一些東西，然後——我認為你問了一個關於 KAT6 的具體問題。合約中確實沒有具體涉及 KAT6 的內容。所以不，這與第一個批准有關，顯然是 Vepdeg。

And then I think the final thing he asked was, I think do you see any opportunity to test out Vepdeg in the first time? Well, my answer, I mean, clearly the decision we've made right now with Pfizer is not to go forward in the first line setting. We've also said that from an awareness perspective we think Vepdeg would do well in that first line setting.

然後我認為他最後問的問題是，我認為您是否看到了第一次測試 Vepdeg 的機會？嗯，我的回答是，顯然我們現在與輝瑞公司做出的決定是不在第一線繼續前進。我們也說過，從意識的角度來看，我們認為 Vepdeg 在第一線設定中會表現良好。

So let's see how data matures over the whatever period of time the data is needed to mature. But as I said earlier, right now, we move on the money that we had sequestered for that first line study is now going to get moved to other parts of our portfolio, and we're very excited about those opportunities as well.

那麼讓我們看看資料在需要成熟期間是如何成熟的。但正如我之前所說，現在，我們將把為第一線研究預留的資金轉移到我們投資組合的其他部分，我們對這些機會也感到非常興奮。

Peter Lawson, Barclays.

巴克萊銀行的彼得·勞森。

Great. Thank you. Thanks for taking the questions. Just a couple of questions on the commercialization. So Vepdeg, have you kind of worked through the size of the sales force you need? And then your comments just around, Vepdeg in first line. Does the Pfizer partnership preclude you from going off and finding a different partner to run that first line study? Just if you could walk through kind of that process of potentially rekindling for a first line study.

偉大的。謝謝。感謝您回答這些問題。我只想問幾個關於商業化的問題。那麼 Vepdeg，您是否已經確定了所需的銷售隊伍規模？然後您的評論就在第一行，Vepdeg。與輝瑞的合作關係是否會妨礙您尋找其他合作夥伴來進行第一線研究？如果您能介紹一下可能重新點燃一線研究的那種過程就好了。

Yeah, so starting off with the size of the salesforce, as I mentioned, it's going to be a fairly targeted, I think financially prudent approach that we'll be taking, obviously in a 50, 50 setting. What we do, Pfizer will match in the US. 6,000 in colleges, where we can target, we should drive that [7% to 8%] of prescription. So, I think we're going to have an effective but appropriately sized sales force to hit there.

是的，正如我所提到的，從銷售團隊的規模開始，這將是一個相當有針對性的、我認為是財務上審慎的方法，顯然我們會採取 50、50 的比例。我們所做的，輝瑞公司將在美國進行配對。 6,000 所大學是我們的目標，我們應該推動 [7% 到 8%] 的處方。因此，我認為我們將擁有一支高效且規模適當的銷售團隊。

In terms of other partners, absolutely not, no, we're in a partnership with Pfizer, we're very pleased with the partnership we've had with Pfizer over the last year. They've been very supportive. And good partners can also have different views, and that's right now we've got a different view about the first line setting, but we agree overall with the decision and we'll see what happens as data matures for Pfizer.

就其他合作夥伴而言，絕對不是，不，我們與輝瑞公司有合作關係，我們對過去一年與輝瑞公司的合作感到非常滿意。他們一直都非常支持。好的合作夥伴也可能有不同的看法，現在我們對第一線的設定有不同的看法，但我們總體上同意這個決定，我們將看看隨著輝瑞數據的成熟會發生什麼。

But as I said, right now we take the money that we had sequestered for that and we move it into other things in our portfolio, and I think that's going to be a big value driver for Arvinas.

但正如我所說，現在我們將為此扣押的資金轉移到我們投資組合中的其他項目上，我認為這將成為 Arvinas 的一大價值驅動力。

Thank you. And then just on the KAT6 combination, is that under the same kind of profit share terms of agreement with Pfizer or is that a separate entity?

謝謝。那麼就 KAT6 組合而言，它是否與輝瑞公司簽訂了相同的利潤分享協議條款，還是說它是一個獨立的實體？

Well in one sense, yes, because Vepdegestrant is -- everything they do with Vepdegestrant, everything we do with Vepdegestrant is in that partnership. KAT6 is wholly owned by Pfizer. So in that scenario, as we've talked about before, we wanted to profile Vep against a whole series of different potential combinations. So we're actually excited to see Pfizer putting Vep into that KAT6 study. They're paying for it, and if it works out well, we'll get the benefit through the Vepdegestrant side of that.

從某種意義上說，是的，因為 Vepdegestrant 是——他們用 Vepdegestrant 所做的一切，我們用 Vepdegestrant 所做的一切都是建立在這種合作關係上的。KAT6 由輝瑞公司全資擁有。因此，在這種情況下，正如我們之前討論過的，我們希望根據一系列不同的潛在組合來分析 Vep。因此，我們非常高興看到輝瑞將 Vep 納入 KAT6 研究。他們為此付費，如果效果良好，我們將透過 Vepdegestrant 方面獲益。

Great. Thanks for taking the questions.

偉大的。感謝您回答這些問題。

Paul Choi, Goldman Sachs.

高盛的保羅·崔（Paul Choi）。

Hi, thank you, good morning everyone, and thanks for taking the question. I just want to ask if you have any sort of gating items or any remaining things to do prior to scheduling your pre-NDA meeting, and will that come presumably post-ASCO here or just some clarity on the color of when you plan to meet with FDA would be helpful as part of your second half of this year filing timeline.

嗨，謝謝大家，早安，謝謝你們回答這個問題。我只是想問一下，在安排您的 NDA 前會議之前，您是否有任何類型的門控項目或任何剩餘的事情要做，這些事情大概會在 ASCO 之後進行嗎？或者，只是明確您計劃何時與 FDA 會面，這將有助於您在今年下半年提交申請的時間表中。

And my, second question is just on the LRRK2 program in in Parkinson's just sort of when the next sort of data update could potentially be expected from that program. I think you know the early data that you presented looked interesting and promising. Just curious sort of what timelines for the next data set might be. Thanks for taking our questions.

我的第二個問題是關於帕金森氏症的 LRRK2 程序，該程序何時可能進行下一次數據更新。我想您知道您提供的早期數據看起來很有趣而且很有希望。只是好奇下一個資料集的時間表是什麼樣的。感謝您回答我們的問題。

Thank you. Noah, do you want to tackle?

謝謝。諾亞，你想挑戰嗎？

Sure. So we've met with the FDA for the free NDA meeting and we feel that we're cleared to move forward and that's why we've conveyed in the prepared remarks that we're moving ahead with our submission enthusiastically.

當然。因此，我們與 FDA 舉行了免費的 NDA 會議，我們覺得我們已獲準繼續前進，這就是為什麼我們在準備好的評論中表達了我們正在熱情地推進我們的提交。

Regarding LRRK2 next data sets, we've said that we'll share information later this year. It'll -- even though we said that we'll start the MAD in the second half, I'm not sure if we can squeeze in those data at any meaningful conference by the end of the year, so we expect that we'll be sharing data from the SAD portion Phase 1. (multiple speakers)

關於 LRRK2 的下一個資料集，我們已經表示將在今年稍後分享資訊。儘管我們說過將在下半年啟動 MAD，但我不確定我們是否能在年底前的任何有意義的會議上擠進這些數據，因此我們預計將分享 SAD 部分第 1 階段的數據。（多位發言者）

Okay, thank you very much.

好的，非常感謝。

Tyler Van Buren, TD Securities.

泰勒·範布倫（Tyler Van Buren），道明證券。

Hi, this is Francis on for Tyler. So first question, are you still confident in Pfizer's commitment to the partnership to commercialize Vepdeg in the second line ESR1 mutant setting? Are you in any discussions to re-evaluate the details of the partnership, such as selling the asset to Pfizer for royalties?

大家好，我是法蘭西斯，為泰勒服務。所以第一個問題，您是否仍相信輝瑞致力於在二線 ESR1 突變環境中將 Vepdeg 商業化的合作？你們是否正在討論重新評估合作關係的細節，例如將資產出售給輝瑞公司以獲取特許權使用費？

And then my next question is, where do you envision the KAT6 combo in the treatment paradigm, could potentially serve as a backbone treatment.

我的下一個問題是，您認為 KAT6 組合在治療模式中處於什麼位置，有可能成為一種骨幹治療方法。

Yeah, thanks for the question, and no one can take the second one. No, all of the interactions we have with Pfizer on Vep and the planning for regulatory filing, the NDA, getting ready for hopefully an approval and potential launch are all full blast. The team, the joint teams are laying out significant plans. As you'd expect for a launch that could be at some point next year, both from a global setting and from a US setting. So all that's going forward well. And as I said before, we think there's a significant opportunity.

是的，謝謝你的提問，沒有人可以回答第二個問題。不，我們與輝瑞在 Vep 方面的所有互動以及監管備案、NDA 的規劃，為獲得批准和可能的上市做好準備，一切都在全力進行。該團隊、聯合團隊正在製定重要計劃。正如您所期望的那樣，該應用程式可能會在明年某個時候推出，無論是從全球範圍還是從美國範圍。一切進展順利。正如我之前所說，我們認為這是一個重大機會。

In terms of the change, there's no ambiguity, there's a change there overall in terms of the broader scope of what we initially had as a collaboration with Pfizer and when we started off we were hoping for monotherapy first line adjuvant which is quite a significant opportunity. Right now, we're going to be very focused on making Vep the best ESR1 mutant degrader in that second line plus setting. And I think, as I said earlier, we wait to see how data matures for Pfizer over whatever period of time.

就變化而言，沒有任何歧義，就我們最初與輝瑞合作的更廣泛範圍而言，總體上發生了變化，當我們開始時，我們希望獲得單一療法的一線輔助治療，這是一個非常重要的機會。現在，我們將全力以赴，使 Vep 成為第二線加設定中最好的 ESR1 突變降解劑。我認為，正如我之前所說，我們等待著看輝瑞的數據在一段時間內如何成熟。

But as we move on in terms of making sure that we can get the best launch possible. And once we hopefully get an approval and we develop an ESR1 mutant only profile and that second line, third line opportunity. It's clear that physicians are looking for additional options in that space, and we Vep believe that will provide that and we look forward to moving it forward. So yeah, there's no change in the game plan with Pfizer.

但隨著我們不斷前進，我們會確保能夠獲得盡可能最好的發布。一旦我們希望獲得批准，我們就會開發出僅適用於 ESR1 突變體的配置檔案以及第二線、第三線機會。很明顯，醫生正在尋找該領域的其他選擇，我們 Vep 相信這將提供這些選擇，我們期待推動其向前發展。是的，輝瑞的比賽計畫沒有改變。

Regarding the KAT6, question. So in the prepared remarks, you've heard us mention that while there are no registration trials planned for Vepdeg, we continue to produce data from ongoing studies, and in fact there is a new study as it were that will start. We're adding Vepdeg to KAT6 and I think it's well premature to project what that can lead to because it's simply a Phase 1 study, but I think it just demonstrates that we're looking to combine Vepdeg, as we march into the second line space with other drugs to explore combinations that can bring more value to patients, so we'll have to wait to see those results.

關於KAT6，有疑問。因此，在準備好的發言中，您聽到我們提到，雖然沒有計劃對 Vepdeg 進行註冊試驗，但我們會繼續從正在進行的研究中獲取數據，事實上，一項新的研究即將開始。我們正在將 Vepdeg 添加到 KAT6 中，我認為現在預測這會帶來什麼結果還為時過早，因為這只是一項第一階段的研究，但我認為這表明我們正在尋求將 Vepdeg 與其他藥物結合起來，因為我們正進入二線領域，探索可以為患者帶來更多價值的組合，所以我們必須等待看到這些結果。

Srikripa Devarakonda, Truist Securities.

Sriripa Devarakonda，Truist 證券公司。

Hey guys, thank you so much for taking my question. I have a couple, first for ARV-393. I know you're currently enrolling Phase 1 trial, just wondering how easy it has been to enroll patients. You do seem to have a lot of centers open. And also based on the recent preclinical combo data that you presented at AACR, are you getting a better sense of where you think the drug and the combinations might fit in the landscape.

嘿夥計們，非常感謝你們回答我的問題。我有幾個，第一個是 ARV-393。我知道您目前正在進行第一階段試驗，只是想知道招募患者是否容易。你們確實似乎開設了很多中心。此外，根據您在 AACR 上展示的最新臨床前組合數據，您是否對這種藥物及其組合在未來的前景有了更好的了解。

And then just a question on your FDA communications with some of the changes happening at the FDA, is there any concern in terms of delayed timelines for meetings or review processes? Thank you.

然後我問一下關於您與 FDA 溝通時遇到的一些變化，是否有擔心會議或審查流程的時間表延遲的問題？謝謝。

Yeah, I'll take the second. First one, Noah can talk about 393. And clearly there's a lot of external changes that we're monitoring in the space and certainly with the FDA. From an adventist perspective, we have noticed no delay and no impact with our interactions with the FDA, which is great. But obviously we're going to continue to monitor that and as we've seen in the press, some other companies have had maybe a different experience. So far, so good with us, but like I say, we'll monitor that going forward.

是的，我會選擇第二個。第一個，Noah 可以談 393。顯然，我們正在監測該領域的許多外部變化，當然還有 FDA 的變化。從基督復臨安息日會的角度來看，我們注意到與 FDA 的互動沒有任何延遲或影響，這很好。但顯然我們將繼續監控這一點，正如我們在媒體上看到的那樣，其他一些公司可能有不同的經歷。到目前為止，我們一切順利，但就像我說的，我們會繼續監控。

Noah, 393.

諾亞，393。

Yeah, so 393. I think we could say that while the study began last year, enrollment was slow at the beginning. This is a Phase 1 study, so by nature it's slow. So it was I think, a slow last year. There's a lot of enthusiasm and we see that we can generate a backlog of patients now and it's enrolling steadily.

是的，所以是 393。我想我們可以說，雖然這項研究去年就開始了，但一開始的入學速度很慢。這是第一階段的研究，因此本質上進展緩慢。所以我認為去年的發展比較緩慢。大家的熱情很高，我們發現我們現在可以積壓大量患者，而且患者人數正在穩定增加。

In terms of where 393 can fit into the landscape. Well, certainly, depending on the data that we generate, there's the possibility of it being monotherapy. We'll have to see, what the overall benefit risk is as its monotherapy. But we're quite enthusiastic about from the pre-clinical models that we've shared recently is its ability to combine with many other drugs, but particularly with bispecific and particularly because it also seems to increase CD20 expression which could create a real synergistic opportunity.

就 393 可以融入景觀的位置而言。嗯，當然，根據我們產生的數據，它有可能是單一療法。我們必須看看其單一療法的整體利益風險是多少。但是，從我們最近分享的臨床前模型來看，我們對其與許多其他藥物結合的能力感到非常興奮，特別是與雙特異性藥物結合的能力，特別是因為它似乎還能增加 CD20 的表達，這可以創造真正的協同機會。

Yigal Nochomovitz, Citigroup.

花旗集團的 Yigal Nochomovitz。

Alright, great, thank you very much for taking the questions. I have 3 questions.

好的，太好了，非常感謝您回答這些問題。我有 3 個問題。

So the first one is, given the combo with the KAT6 and the Vepdeg, have you or Pfizer produced any preclinical work that would support that combo, or could you discuss the rationale for that combo on a scientific medical basis?

因此，第一個問題是，考慮到 KAT6 和 Vepdeg 的組合，您或輝瑞是否進行過任何支持該組合的臨床前研究，或者您能否從科學醫學角度討論一下該組合的原理？

Second question is. We haven't talked much about supply chain. Could you just review the structure and geographic location for the manufacturing supply chain for Vepdeg as well as where the IT is domiciled?

第二個問題是。我們還沒有談太多供應鏈。您能否回顧一下 Vepdeg 製造供應鏈的結構和地理位置以及 IT 所在地？

And then the last question, John, you gave a very comprehensive answer with respect to the rationale for Pfizer stopping the frontline study. I'm just wondering if the factors related to the novel combo with the turmo as well as the potential to do or need to do a forearm study perhaps to tease out contribution of components was a relevant factor in that decision or not. Thank you.

然後是最後一個問題，約翰，你對輝瑞停止一線研究的理由給了非常全面的答案。我只是想知道，與 Turmo 的新組合相關的因素以及進行或需要進行前臂研究以找出組件的貢獻的可能性是否是該決定的相關因素。謝謝。

Yigal, So yeah, the first one. Did we do any preclinical work with KAT6 and Vepdeg? I think the answer to that is no. I think the rationale is really related to the fact that Pfizer are very excited by the profile of KAT6. I do think they see the potential of the combination with Vepdeg enhancing potentially what they see with KAT6, and positioning Vepdeg and KAT6 as being a really strong combination.

Yigal，是的，第一個。我們是否對 KAT6 和 Vepdeg 做過任何臨床前工作？我認為答案是否定的。我認為原因其實與輝瑞對 KAT6 的概況感到非常興奮有關。我確實認為他們看到了與 Vepdeg 的組合的潛力，可以增強他們對 KAT6 的認識，並將 Vepdeg 和 KAT6 定位為真正強大的組合。

Noah, anything you'd add to that?

諾亞，您還有什麼要補充的嗎？

Yeah. Just some experience, with (inaudible) that looks attractive, so that would be other reasons.

是的。只是一些經驗，（聽不清楚）看起來很有吸引力，所以那將是其他原因。

In terms of supply chain, so Pfizer are accountable for the supply of Vep that's based in Ringaskiddy in Ireland. So we haven't had any supply chain issues. I think you asked a question about where does the IP reside? That resides here with us, US with (inaudible)

在供應鏈方面，輝瑞負責位於愛爾蘭 Ringaskiddy 的 Vep 的供應。所以我們沒有遇到任何供應鏈問題。我認為您問的是 IP 位於何處的問題？與我們同在，美國與（聽不清楚）

And then a really interesting question, Yigal, the novel-novel with a thermal composition of components. I'm sure that has factored into some of the thinking. The broader view I gave is maturation of data, the external environment. I'm sure that's part of the rationale that Pfizer want to see. Our current Vep data mature, that's in the second line setting, but they want to see what that looks like, overall.

然後是一個非常有趣的問題，Yigal，這部小說具有熱成分組成。我確信這已經影響了一些人的思考。我給出的更廣泛的觀點是數據的成熟度，外部環境。我確信這是輝瑞公司希望看到的部分原因。我們目前的 Vep 資料已經成熟，處於第二行設置，但他們想看看整體情況。

So I'm sure that has factored into the broader decision making around the data sets and changing landscape. But, yeah, great questions. Thank you.

所以我確信這已經成為圍繞數據集和不斷變化的情況的更廣泛的決策的因素。但是，是的，這些問題很棒。謝謝。

Okay, thank you very much.

好的，非常感謝。

Eiderman, BMO Capital Market.

艾德曼，BMO資本市場。

Hi, this is Malcolm Hoffman on for Evan. Thanks for taking our question. I was thinking about the LRRK2 degrader again. I know by just announced today that enrollment in their Phase 2 study is now complete with results in 2026. I just wanted to ask how you are starting to think of the competitive positioning for your degrader versus others and what your confidence is that yours could be differentiated versus slightly more advanced programs. Thank you.

大家好，我是馬爾科姆·霍夫曼，代替艾文。感謝您回答我們的問題。我又開始思考 LRRK2 降解劑了。我知道我們今天剛宣布，他們第二階段研究的招募工作已經完成，結果將於 2026 年公佈。我只是想問一下，您是如何開始考慮您的降級器相對於其他降級器的競爭定位的，以及您對您的降級器與稍微先進的程序相比有何不同有信心。謝謝。

Noah, do you want to take that?

諾亞，你想拿走那個嗎？

Sure, yeah, so thanks. We certainly look ahead at the Biogen Denali partnership enthusiastically we think it's validating to some degree but validating for an inhibitor that doesn't get brain penetration and does not even deliver significant inhibition in the brain. And so therefore with the degrader that gets significant brain penetration and can lead to more than 50% degradation, eliminating all functions of LRRK2, not just the kinase activity. We think that puts us in a very competitive spot.

當然，是的，謝謝。我們當然熱切地展望與 Biogen Denali 的合作，我們認為它在某種程度上是有效的，但對於一種無法滲透到大腦中甚至無法在大腦中產生顯著抑制的抑制劑來說，這種驗證是有效的。因此，當降解劑能夠顯著滲透到大腦中並導致超過 50% 的降解時，不僅會消除激酶活性，還會消除 LRRK2 的所有功能。我們認為這使我們處於非常有競爭力的地位。

So we're looking forward to those results. If they -- if it's successful, then I think there'll be a lot of enthusiasm for this program, if their study is -- the Phase 3 program failed, but it has some directional data that support it. There's also going to be quite significant enthusiasm, but overall, we just do not believe that inhibitors get you there. And the fact that, you'll see the our continuous updates from our studies to see the benefits from the degrader.

所以我們期待這些結果。如果他們——如果成功了，那麼我認為人們會對這個計畫產生很大的熱情，如果他們的研究——第三階段計畫失敗了，但它有一些方向性的數據來支持它。人們也會有相當大的熱情，但總的來說，我們只是不相信抑制劑能讓你達到目的。事實上，您會看到我們不斷更新研究以了解降解劑的好處。

Appreciate you guys, thank you.

感謝你們，謝謝。

Li Wang Watsek, Cantor Fitzgerald.

李旺·沃塞克，康托·菲茨杰拉德。

Hey guys, thanks for taking our questions. Maybe a BD strategic question. Are you open to bringing in the external assets just given your balance sheet, and then you got three earlier assets in the pipeline, maybe talk a little bit about your conviction and development strategy there. Sounds like you're going to have some data later this year where you'll be making some decisions then.

嘿夥計們，感謝你們回答我們的問題。也許是 BD 策略問題。鑑於您的資產負債表，您是否願意引入外部資產，然後您已經有三項早期資產正在籌備中，也許可以談談您的信念和發展策略。聽起來你今年稍後會獲得一些數據，然後做出一些決定。

And then secondly just for the KAT6 combo, when should we expect to see the data and then what would be the bar that you have to head, given it's early Phase 1 trial. And then, can you clarify, is it going to be in the ESR1 mutant patients or it's going to be in [all commerce]. Thank you.

其次，僅就 KAT6 組合而言，考慮到它處於第一階段的早期試驗階段，我們什麼時候可以看到數據，以及您必須達到的標準是什麼。然後，您能否澄清一下，它是在 ESR1 突變患者中，還是在[所有商業]。謝謝。

Yeah, Noah can tackle the KAT6 and that part of it. In terms of the BD strategy, I think overall, we've always been out there looking at opportunities to supplement certainly our technology. And as we go forward, if there was an asset out there that complemented our lead programs, I think we'd be open to that.

是的，諾亞可以解決 KAT6 及其部分問題。就 BD 策略而言，我認為總體而言，我們一直在尋找機會來補充我們的技術。隨著我們不斷前進，如果有資產可以補充我們的主要項目，我想我們會對此持開放態度。

Obviously we've been, our genesis as a company has been a platform-based company. We're very proud of that and our portfolio is replete with really exciting degraders. But yeah, if there was a significant opportunity to get an asset that complemented that, I don't think we'd have any issue with that.

顯然，我們公司從一開始就是一家以平台為基礎的公司。我們對此感到非常自豪，我們的產品組合充滿了真正令人興奮的降級劑。但是，是的，如果有重大機會獲得與之互補的資產，我認為我們不會對此有任何問題。

There was another subset in there, I can't remember what the subset of the question --

其中還有另一個子集，我不記得問題的子集是什麼--

Regarding KAT6 --

關於KAT6——

Again, just to frame this study, this is a Phase 1 study that's just very exploratory, so there are no timelines associated with it. We haven't even dosed the first patient yet. It's really shared in the spirit of that we'll continue to look for nice combinations that can be practiced in forming and continue to expand the attractiveness of our already potentially best in class Vepdeg in the second line setting.

再次強調，為了闡述這項研究，這是一項第一階段的研究，僅具有探索性，因此沒有相關的時間表。我們甚至還沒有給第一位病人注射藥物。我們確實本著這樣的精神：我們將繼續尋找可以在形成過程中練習的良好組合，並繼續擴大我們在第二線設置中已經具有潛力的最佳 Vepdeg 的吸引力。

And so that would be the case with this KAT6 combination also. It's Pfizer's wholly owned drug, we don't call the shots there in any way, and we're just looking to see what we can generate with that combo, and right now the thought is for all commerce.

KAT6 組合也是如此。這是輝瑞全資擁有的藥物，我們不會以任何方式對此發號施令，我們只是想看看我們能用這種組合產生什麼，現在我們的想法是針對所有商業。

Jeet Mukherjee, BTIG.

Jeet Mukherjee，BTIG。

Great, thank you for taking the question. Was wondering if you've thought about potential NCCN guideline inclusion for some of your Vepdeg CDK4/6 data to support combination use just given some of the notable PFS data you had shown at San Antonio 2023 and thereby allowed doctors to use a CDK4/6 off-label in combination with Vepdeg in the second line setting.

太好了，謝謝你回答這個問題。想知道您是否考慮過將部分 Vepdeg CDK4/6 數據納入 NCCN 指南以支持聯合使用，因為您在 2023 年聖安東尼奧會議上展示了一些值得注意的 PFS 數據，從而允許醫生在二線治療中將 CDK4/6 與 Vepdeg 聯合使用。

And My second question was just around your G12D degrader. Can you maybe talk about how that compares to [Stela's] degrader and some of the perhaps subpar efficacy and safety it had shown at last year at ESMO. Thanks.

我的第二個問題是關於您的 G12D 降解劑。您能否談談它與 [Stela] 降解劑相比如何，以及它在去年 ESMO 上表現出的一些可能低於標準的功效和安全性。謝謝。

Noah, do I take that?

諾亞，我可以接受嗎？

Sure, the first question -- the second one was about G12D. The first was --

當然，第一個問題——第二個問題是關於 G12D 的。第一個是--

NCCN.

NCCN。

Yeah, so look, we continue to generate, or we're going to be sharing the maturation of our combination data sets. We will -- this will be discussed with the commercial and medical affairs team about how to best share this information and be as practice informing as possible, so I don't want to get ahead of myself and speak about NCCN guidelines.

是的，所以看，我們將繼續生成，或者我們將分享我們的組合資料集的成熟度。我們將與商業和醫療事務團隊討論如何最好地分享這些資訊並儘可能地提供實踐信息，所以我不想超越自己並談論 NCCN 指南。

But overall, we would share whatever physicians need to make the best decisions, but obviously, we're seeking a monotherapy label, and that's the only way we will be marketing the drug for monotherapy use.

但總的來說，我們會分享醫生做出最佳決策所需的一切，但顯然，我們正在尋求單一療法標籤，這是我們行銷單一療法的藥物的唯一方法。

Regarding the G12D degrader, I think I had mentioned in the prepared remarks that we've seen that we have 30 times the potency of some other inhibitors and degraders in the space. One of the challenges for a leading degrader in the space is the (inaudible) toxicity, or I guess as evidence by [transaminitis] that has been seen that may be limiting in the dosing of that drug.

關於 G12D 降解劑，我想我在準備好的評論中提到過，我們已經看到我們的效力是該領域其他一些抑制劑和降解劑的 30 倍。對於該領域領先的降解劑來說，挑戰之一是（聽不清楚）毒性，或者我猜，正如已經看到的[轉氨炎]的證據那樣，這可能會限制該藥物的劑量。

In our case, we don't believe that this will be a limitation for our drug ARV-806, but of course, we're just starting our dosing of patients in the second half of this year. Thank you.

就我們而言，我們不認為這會成為我們藥物 ARV-806 的限制，但當然，我們在今年下半年才開始對患者進行給藥。謝謝。

Sudan Loganathan, Stephens.

蘇丹·洛加納坦，史蒂芬斯。

Hi, good morning, and thank you for taking my question this morning. I wanted to kind of dig deeper into the details for the ESR1 mutant patients again, that are naive to treatment. I believe you mentioned earlier on the call about approximately 5% are of ESR mutant is in the first line setting. Is Vepdeg with the monotherapy design actually going to be well positioned to be more of the standard of care even also in the first line that kind of demonstrate the ESR1 mutant as well, or will there be some additional trials or anything else that needs to be done there?

大家好，早安，感謝您今天早上回答我的問題。我想再次深入探討那些尚未接受治療的 ESR1 突變患者的細節。我相信您之前在電話中提到過，大約 5% 的 ESR 突變體處於第一線設定。以單一療法設計的 Vepdeg 是否真的能夠成為更標準的治療方法，甚至能夠成為一線治療 ESR1 突變的方法，或者是否需要進行一些額外的試驗或其他任何工作？

And then with the total of about 40% I guess of second line patients at ESR mutant, is that only specific to first line patients that were treated on CDK4/6 inhibitors or also other treatments as well? Thanks.

那麼，我猜 ESR 突變的二線患者總數約為 40%，這是否僅適用於接受 CDK4/6 抑制劑治療的第一線患者，還是也適用於其他治療？謝謝。

Yeah, so just for clarity, in the second line setting, we believe around 40% of the patients have tumors that have ESR1 mutant profiles, and that offers up a potential of 40,000 patients that could be amenable to a drug like vepdegestrant. So that's exciting. That's a great opportunity.

是的，為了清楚起見，在二線治療中，我們認為大約 40% 的患者患有具有 ESR1 突變特徵的腫瘤，這意味著可能有 40,000 名患者可以接受像 vepdegestrant 這樣的藥物治療。這很令人興奮。這是一個很好的機會。

In the first line setting, it's different. There's maybe only about 5% of the patients have tumors that have ESR1 mutation. The rest have wild type. And the biggest difference we believe is, wild type in the second line setting is probably endocrine insensitive, but wild type in the first line setting is endocrine sensitive, so there's a significant opportunity there.

在第一行的設定中，它是不同的。可能只有大約 5% 的患者患有具有 ESR1 突變的腫瘤。其餘均為野生型。我們認為最大的差異是，二線環境中的野生型可能對內分泌不敏感，但一線環境中的野生型對內分泌敏感，因此存在很大機會。

So our belief is that Vep within that setting, it would do well, but we've made this joint decision with Pfizer not to go there. And we move on to other things. And in the second line setting where we still see a significant opportunity, we'll be seeking approval for a drug in that setting and ideally then launching into that second life setting along with the partners Pfizer.

因此，我們相信 Vep 在這種環境下會表現良好，但我們與輝瑞公司共同決定不去那種環境。我們繼續討論其他事情。在第二線治療領域，我們仍然看到了巨大的機遇，我們將尋求該領域藥物的批准，然後理想情況下與合作夥伴輝瑞一起進入第二生命領域。

So significant opportunity there and, as I said before, we wait to see what the maturing information is in the first line setting, both from the point of view of our data but also the data coming from other companies.

這裡存在著重大機遇，正如我之前所說，我們等待著看第一線環境中成熟的資訊是什麼，既從我們的數據角度來看，也從來自其他公司的數據角度來看。

I appreciate it thanks for the clarity there.

我很感激，謝謝你的澄清。

Thank you.

謝謝。

And that concludes our Q&A session for today. I will now turn the call back over to John Houston. Please go ahead.

今天的問答環節到此結束。現在我將把電話轉回給約翰休斯頓。請繼續。

Well, thanks, operator, and thank you everyone. We gave you a lot of information today to digest. It remains for me just to say that we're incredibly confident about the future direction of the company and we'll be -- you'll be hearing more from us with additional updates through the year. So thank you very much for your time this morning.

好的，謝謝接線生，也謝謝大家。我們今天為您提供了大量資訊以供消化。我只想說，我們對公司的未來發展方向充滿信心，我們將在今年內為您提供更多更新。非常感謝您今天上午抽出時間。

Thank you everyone. That concludes today's call. You may not all disconnect. Have a nice day ahead.

謝謝大家。今天的電話會議到此結束。你們可能不會全部斷開連線。祝您有個愉快的一天。