Arvinas Inc (ARVN) 2025 Q3 法說會逐字稿

Thank you for standing by, and welcome to Arvinas third-quarter 2025 earnings call. I'd like to remind everyone that this call is being recorded. (Operator Instructions) Thank you.

感謝您的耐心等待，歡迎參加 Arvinas 2025 年第三季財報電話會議。我想提醒大家，本次通話正在錄音。（操作說明）謝謝。

I would now like to turn the call over to Mr. Jeff Boyle. You may begin.

現在我將把電話交給傑夫·博伊爾先生。你可以開始了。

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our third quarter 2025 financial results, which is available in the Investor and Media section of our website at arvinas.com.

各位早安，感謝各位的參與。今天早些時候，我們發布了一份新聞稿，公佈了我們 2025 年第三季的財務業績，該新聞稿可在我們網站 arvinas.com 的投資者和媒體版塊中找到。

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

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

Before we begin the call, I'll remind you that today's discussions contain forward-looking statements that involve risks, uncertainties and assumptions, which are outlined in today's press release and in the company's recent filings with the US Securities and Exchange Commission, which I urge you to read. Our actual results may differ materially from what is discussed on today's call. A replay of today's call as well as an updated corporate deck will be available on the Investor and Media section of our website.

在電話會議開始之前，我要提醒各位，今天的討論包含前瞻性陳述，涉及風險、不確定性和假設，這些內容已在今天的新聞稿和公司最近向美國證券交易委員會提交的文件中進行了概述，我敦促各位閱讀這些文件。我們的實際結果可能與今天電話會議上討論的內容有重大差異。今天電話會議的錄音回放以及更新後的公司介紹文件將在我們網站的投資者和媒體版塊提供。

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

現在我把電話交給約翰。約翰？

Thanks, Jeff. Good morning, everyone, and thank you for joining us today. As highlighted in our third quarter earnings release issued earlier this morning, this has been a dynamic and productive period for Arvinas marked by meaningful progress across both our corporate initiatives and clinical development programs.

謝謝你，傑夫。各位早安，感謝大家今天收看我們的節目。正如我們今天早上發布的第三季財報中所強調的那樣，對於 Arvinas 而言，這是一個充滿活力和成果豐碩的時期，我們在公司各項舉措和臨床開發項目方面都取得了實質進展。

During the quarter, we announced significant developments, both in our pipeline and enhancing efficiency across our organization, all geared at driving value from our portfolio to deliver benefit to patients and value to shareholders. Our deep pipeline provides multiple opportunities for value creation, as we work to address the largest areas of significant unmet need in oncology and neurology.

本季度，我們宣布了多項重大進展，包括研發管線的推進和提升公司整體效率的舉措，所有這些都旨在從我們的產品組合中創造價值，從而為患者帶來益處，為股東創造價值。我們擁有豐富的研發管線，為創造價值提供了多種機會，因為我們致力於解決腫瘤學和神經病學領域最大的未滿足需求。

We have entered the beginning of a data-rich period with multiple readouts from our early-stage clinical programs, including recent clinical data from ARV-102, our LRRK2 degrader and preclinical data from ARV-806, our KRAS G12D degrader. We also presented the first preclinical data from ARV-027, our promising new clinical candidate that targets polyglutamine-expanded androgen receptor or polyQ-AR, the root cause of spinal bulbar muscular atrophy or SBMA.

我們已經進入了一個數據豐富的時期，我們早期臨床項目獲得了多項讀數，包括來自我們的 LRRK2 降解劑 ARV-102 的最新臨床數據和來自我們的 KRAS G12D 降解劑 ARV-806 的臨床前數據。我們也展示了 ARV-027 的首個臨床前數據，ARV-027 是我們很有前途的新臨床候選藥物，它靶向多聚谷氨酰胺擴展的雄激素受體或 polyQ-AR，這是脊髓延髓肌萎縮症或 SBMA 的根本原因。

In addition, we also anticipate sharing preclinical data from our BCL6 degrader, ARV-393, at the ASH Conference in December and preclinical data from our new HPK1 degrader, ARV-6723 later this week at the SITC Conference.

此外，我們也預計將在 12 月的 ASH 會議上分享我們 BCL6 降解劑 ARV-393 的臨床前數據，並在本週稍後的 SITC 會議上分享我們新的 HPK1 降解劑 ARV-6723 的臨床前數據。

Noah will also share a promising update from our ongoing Phase I monotherapy trial with ARV-393 later in the call today. We have a strong track record of translating promising preclinical results into important successes in the clinic with a platform that has consistently shown its versatility and promise.

諾亞今天稍晚也將在電話會議上分享我們正在進行的 ARV-393 I 期單藥治療試驗的最新進展。我們擁有將有前景的臨床前研究結果轉化為臨床重要成功的良好記錄，我們的平台也展現出其多功能性和發展前景。

We continue to build on that record with multiple ongoing and planned clinical trials in areas of high unmet need, a pipeline of high-value assets, a strong research engine and cash on hand into the second half of 2028 that gives us financial and strategic flexibility.

我們將繼續鞏固這一成績，在高度未滿足的需求領域開展多項正在進行和計劃中的臨床試驗，擁有高價值資產儲備、強大的研發引擎以及到 2028 年下半年的充足現金，這為我們提供了財務和戰略上的靈活性。

In September, we announced that we and Pfizer will jointly select a third party for the commercialization and potential further development of vepdegestrant with the goal of rapidly bringing it to patients, if approved. Vepdeg's new drug application is currently under review by the FDA, and the agency has issued a PDUFA action date of June 5, 2026.

9 月，我們宣布，我們將與輝瑞共同選擇一家第三方公司，負責維普地孕烷的商業化和潛在的進一步開發，目標是在獲得批准後儘快將其帶給患者。Vepdeg 的新藥申請目前正在接受 FDA 的審查，該機構已發布 PDUFA 行動日期為 2026 年 6 月 5 日。

Our goal is to have a partner in place before this date to make sure that Vepdeg, if approved, is launch-ready as a potentially best-in-class therapeutic option for ER-positive/HER2-negative advanced breast cancer in the second-line ESR1 mutant setting of ARV-393. Noah?

我們的目標是在此日期之前找到合作夥伴，以確保 Vepdeg 如果獲得批准，能夠作為二線 ESR1 突變治療方案中 ER 陽性/HER2 陰性晚期乳腺癌的潛在最佳治療選擇，在 ARV-393 的基礎上進行推廣。諾亞？

Thanks, John, and good morning, everyone. I'll begin with ARV-102, our oral PROTAC LRRK2 degrader, specifically designed to be brain penetrant. Enthusiasm from key opinion leaders and investigators, most recently about the biomarker data we presented at MDS, has further strengthened our belief that this is a truly differentiated program.

謝謝你，約翰，大家早安。我先從 ARV-102 開始，這是我們專門設計的口服 PROTAC LRRK2 降解劑，能夠穿透大腦。關鍵意見領袖和研究人員的熱情，尤其是最近我們在 MDS 會議上展示的生物標記數據，進一步增強了我們對這是一個真正與眾不同的項目的信念。

Let me begin with some background about ARV-102's target and what has come into focus as potential diseases of interest. LRRK2 is a multi-domain protein with three key functions of kinase, GTPase and scaffolding activities.

首先，讓我介紹一下 ARV-102 的目標以及目前已知的潛在疾病。LRRK2 是一種多結構域蛋白，具有激酶、GTP酶和支架蛋白三種主要功能。

These activities help it regulate endolysosomal trafficking. When LRRK2 expression or activity is elevated, it disrupts lysosomal function, impairing the clearance of aggregated pathologic proteins that would normally be degraded through the pathway. Degrading LRRK2 may restore endolysosomal homeostasis and provide therapeutic benefit in disorders characterized by lysosomal dysfunction.

這些活動有助於調節內溶小體運輸。當 LRRK2 表現或活性升高時，會破壞溶小體功能，損害通常經由此途徑降解的聚集病理蛋白的清除。降解 LRRK2 可能恢復內溶小體穩態，並為以溶小體功能障礙為特徵的疾病提供治療益處。

Unlike inhibitors that only inhibit LRRK2's kinase activity intermittently, ARV-102 eliminates the entire LRRK2 protein. This is important because the three key functions, not just kinase activity, may be linked to neuroinflammation and lysosome dysfunction.

與只能間歇性抑制 LRRK2 激酶活性的抑制劑不同，ARV-102 可以消除整個 LRRK2 蛋白。這很重要，因為這三個關鍵功能（而不僅僅是激酶活性）可能與神經發炎和溶酶體功能障礙有關。

Increased activity, scaffolding and expression of LRRK2 have been implicated in the pathogenesis of neurological diseases, including idiopathic Parkinson's disease, a prevalent neurodegenerative disease, and progressive supranuclear palsy or PSP, a rapidly progressing neurodegenerative disease that is typically fatal within five to seven years of diagnosis. We believe that eliminating all three functions of LRRK2 through PROTAC-mediated degradation offers the potential for deeper and more durable therapeutic benefit versus traditional inhibitors.

LRRK2 的活性、支架作用和表達增強與神經系統疾病的發病機制有關，包括特發性帕金森氏症（一種常見的神經退化性疾病）和進行性核上性麻痺（PSP，一種快速進展的神經退化性疾病，通常在確診後五到七年內致命）。我們相信，透過 PROTAC 介導的降解消除 LRRK2 的所有三種功能，與傳統抑制劑相比，具有更深層、更持久的治療益處的潛力。

At the MDS Conference last month, we were pleased to share data from two ongoing Phase 1 clinical trials with ARV-102, one in healthy volunteers and one in patients with Parkinson's disease. Both trials included single ascending and multiple dose portions. ARV-102 is generally well tolerated in both trials.

在上個月的 MDS 會議上，我們很高興地分享了 ARV-102 的兩項正在進行的 1 期臨床試驗的數據，一項針對健康志願者，另一項針對帕金森氏症患者。兩項試驗均包括單次遞增劑量和多次劑量部分。在兩項試驗中，ARV-102 的耐受性整體良好。

In the healthy volunteer study, ARV-102 was well tolerated at single doses up to 200 milligrams and multiple daily doses up to 80 milligrams with no discontinuations due to adverse events or serious adverse events observed in the study population. In the Parkinson's disease study, single doses of ARV-102 at 50 milligrams or 200 milligrams, were well tolerated with only mild treatment-related adverse events, which were generally lumbar puncture procedure related and with no serious adverse events.

在健康志願者研究中，ARV-102 單次劑量高達 200 毫克和每日多次劑量高達 80 毫克均耐受良好，研究人群中未觀察到因不良事件或嚴重不良事件而中止治療的情況。在帕金森氏症研究中，單次服用 50 毫克或 200 毫克 ARV-102 耐受性良好，僅出現輕微的治療相關不良事件，這些不良事件通常與腰椎穿刺手術有關，沒有出現嚴重不良事件。

Pharmacokinetic data were also excellent across both trials. ARV-102 demonstrated dose-dependent PK in both periphery and the CSF, the latter indicating brain penetration. In terms of pharmacodynamic effects in healthy volunteers, repeated daily dosing of ARV-102 led to LRRK2 reductions of up to 90% in peripheral blood mononuclear cells or PBMCs and more than 50% in the CSF.

兩項試驗的藥物動力學數據也都非常出色。ARV-102 在周邊血液和腦脊髓液中均表現出劑量依賴性的藥物動力學特徵，後者顯示其能穿透血腦屏障。就健康志願者的藥效學效應而言，每日重複服用 ARV-102 可使周邊血單核細胞 (PBMC) 中的 LRRK2 減少高達 90%，腦脊髓液中的 LRRK2 減少超過 50%。

Repeated daily doses of ARV-102 resulted in reduced concentrations of phospho-Rab10T73 in PBMCs and urine concentrations of BMP. Both of these are important biomarkers for modulation of the lysosomal pathway downstream of LRRK2. In patients with Parkinson's, we showed that single doses of ARV-102 resulted in median PBMC LRRK2 protein reductions of 86% with the 50-milligram dose and 97% with the 200-milligram dose.

每日重複服用 ARV-102 可降低 PBMC 中磷酸化 Rab10T73 的濃度和尿液中 BMP 的濃度。這兩種都是 LRRK2 下游溶小體路徑調節的重要生物標記。在帕金森氏症患者中，我們發現單次服用 ARV-102 可使 PBMC LRRK2 蛋白中位數減少 86%（50 毫克劑量）和 97%（200 毫克劑量）。

Perhaps most interestingly of all, in healthy volunteers treated with 80 milligrams of ARV-102 once daily for 14 days, unbiased proteomic analysis of CSF showed decreases in many lysosomal pathway markers such as GPNMB and neuroinflammatory microglial markers like CD68. A recently published proteomics analysis showed the same panel of biomarkers was elevated in patients with LRRK2-related Parkinson's disease.

最有趣的是，在接受 80 毫克 ARV-102 每日一次治療 14 天的健康志願者中，對腦脊髓液進行無偏蛋白質組學分析顯示，許多溶酶體通路標誌物（如 GPNMB）和神經炎症小膠質細胞標記（如 CD68）均有所下降。最近發表的蛋白質體學分析顯示，LRRK2 相關帕金森氏症患者體內同一組生物標記水平升高。

We are aware of inhibitor data showing the movement of some of these biomarkers, but only in patients with Parkinson's disease and only after at least a month of treatment to engage the intended disease pathway even in healthy volunteers where the biomarkers would not be expected to be elevated and after only 14 days of treatment is direct evidence that our approach is working as designed.

我們注意到抑制劑數據顯示，某些生物標記發生了變化，但這僅限於帕金森氏症患者，並且至少需要治療一個月才能啟動預期的疾病路徑。即使在健康志願者中，這些生物標記預計也不會升高，而僅僅治療 14 天後就出現了變化，這直接證明我們的方法正在按設計發揮作用。

This rapid pathway biomarker response suggests that our total protein degradation approach may have best-in-class impact on underlying disease processes compared to kinase-only targeting inhibitors. We believe that in totality, our data to date set a very high bar and further strengthen our belief in the promise of ARV-102.

這種快速路徑生物標記反應表明，與僅靶向激酶的抑制劑相比，我們的總蛋白質降解方法可能對潛在的疾病過程產生一流的影響。我們相信，總體而言，我們迄今為止的數據設定了一個非常高的標準，並進一步增強了我們對 ARV-102 前景的信心。

The multiple dose cohort of our trial in Parkinson's patients is ongoing, and we look forward to sharing data, including CSF LRRK2 degradation data, at a medical conference in 2026. We also intend to initiate a Phase 1b trial in patients with PSP in the first half of 2026.

我們正在對帕金森氏症患者進行多劑量隊列試驗，並期待在 2026 年的醫學會議上分享數據，包括腦脊髓液 LRRK2 降解數據。我們也計劃在 2026 年上半年啟動針對 PSP 患者的 1b 期試驗。

I'll now turn to ARV-393, our investigational oral PROTAC designed to degrade B-cell lymphoma 6 protein or BCL6. BCL6 is a previously undrugged transcription factor, a master regulator of multiple cellular processes during B-cell development, including proliferation, survival and apoptosis. Altered BCL6 activity has been implicated as an oncogenic driver in several subtypes of non-Hodgkin lymphoma, making it an exciting therapeutic target with initial clinical validation emerging.

現在我將介紹 ARV-393，這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 BCL6。BCL6 是一種先前未被藥物靶向的轉錄因子，是 B 細胞發育過程中多種細胞過程（包括增殖、存活和凋亡）的主要調節因子。BCL6 活性改變已被證實是多種非何杰金氏淋巴瘤亞型的致癌驅動因素，使其成為一個令人興奮的治療標靶，初步的臨床驗證正在出現。

With its iterative activity, ARV-393 potently and rapidly degrades the BCL6 protein, which is critical to overcoming its rapid resynthesis rate and sustaining antitumor activity. Preclinically, ARV-393 has shown robust in-vitro potency and in-vivo efficacy as a monotherapy.

ARV-393 具有迭代活性，能夠有效且快速地降解 BCL6 蛋白，這對於克服其快速的再合成速率和維持抗腫瘤活性至關重要。臨床前研究表明，ARV-393 作為單一療法具有強大的體外效力和體內療效。

And earlier this year, we presented preclinical data showing enhanced antitumor activity with ARV-393 in combination with five classes of small molecule inhibitors in models of aggressive diffuse large B-cell lymphoma or DLBCL. Our development plan for ARV-393 includes combination strategies in DLBCL. And at next month's American Society of Hematology Annual Meeting, we will present new preclinical data showing the combinability of ARV-393 with glofitamab, a CD20xCD3 bispecific antibody, and an emerging standard of care for DLBCL.

今年早些時候，我們公佈了臨床前數據，顯示 ARV-393 與五類小分子抑制劑聯合使用，在侵襲性瀰漫性大 B 細胞淋巴瘤 (DLBCL) 模型中，可增強抗腫瘤活性。我們針對 ARV-393 的開發計畫包括針對 DLBCL 的合併治療策略。在下個月的美國血液學會年會上，我們將展示新的臨床前數據，證明 ARV-393 與 CD20xCD3 雙特異性抗體 glofitamab 聯合使用，而 glofitamab 是 DLBCL 的新興標準療法。

BCL6 degradation has the potential to increase CD20 expression, which provides rationale for the exploration of ARV-393 with CD20-targeted agents and in the context of low or loss of CD20 expression. We intend to initiate a combination trial with glofitamab next year and look forward to updating you on our progress.

BCL6 降解有可能增加 CD20 表達，這為探索 ARV-393 與 CD20 標靶藥物聯合使用以及在 CD20 表達低或缺失的情況下提供理論依據。我們計劃明年啟動與 glofitamab 的聯合試驗，並期待向您報告我們的進展。

Turning to our clinical progress to date, enrollments in our Phase 1 monotherapy trial is ongoing. This is a first-in-human dose escalation trial, and we have not yet achieved the predicted efficacious exposure level. However, this morning, I'm pleased to report that even in exposure levels below those predicted to be efficacious, we have already seen responses in early cohorts in both B- and T-cell lymphomas.

就我們目前的臨床進展而言，我們的 1 期單藥治療試驗的受試者招募工作正在進行中。這是首次人體劑量遞增試驗，我們尚未達到預期的有效暴露水準。不過，今天早上我很高興地報告，即使在低於預期有效水平的暴露水平下，我們也已經在早期隊列中觀察到了 B 細胞和 T 細胞淋巴瘤的療效。

We also see evidence of robust BCL6 degradation and the safety profile of ARV-393 has supported continued dose escalation. We are very pleased with these early data, which we believe support an emerging and differentiated therapeutic benefit of ARV-393. We look forward to sharing additional data from the Phase 1 trial at a medical congress in 2026.

我們也觀察到 BCL6 降解的顯著證據，而 ARV-393 的安全性也支持繼續增加劑量。我們對這些早期數據感到非常滿意，我們相信這些數據支持了 ARV-393 正在顯現的、差異化的治療優勢。我們期待在 2026 年的醫學大會上分享 1 期試驗的更多數據。

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

接下來，我將把電話交給安琪拉。安吉拉？

Thanks, Noah, and good morning, everyone. I'm pleased to share compelling preclinical data we recently presented that reinforces our confidence in our ability to deliver differentiated treatments across our oncology and neuroscience pipeline.

謝謝諾亞，大家早安。我很高興與大家分享我們最近公佈的令人信服的臨床前數據，這些數據增強了我們對自身能力的信心，使我們能夠在腫瘤學和神經科學產品線中提供差異化治療。

I'll begin with ARV-806, our novel PROTAC degrader targeting KRAS G12D. KRAS G12D is a well-characterized oncogenic driver associated with poor prognosis and recalcitrant to standard treatments across several major tumor types, including pancreatic, colorectal and non-small cell lung cancers. There are currently no approved targeted therapies for KRAS G12D.

我將首先介紹 ARV-806，我們新型的 PROTAC 降解劑，靶向 KRAS G12D。KRAS G12D 是一種特徵明確的致癌驅動基因，與多種主要腫瘤類型（包括胰腺癌、結直腸癌和非小細胞肺癌）的不良預後和對標準治療的抗藥性有關。目前尚無核准的針對 KRAS G12D 的標靶療法。

At the Triple Meeting in October, we shared preclinical data highlighting the high potency of ARV-806 and its clear differentiation from both KRAS inhibitors and degraders currently in the clinic. These preclinical data showed dose-dependent robust antitumor activity with regressions across preclinical models of KRAS G12D mutant cancers.

在 10 月的三方會議上，我們分享了臨床前數據，重點介紹了 ARV-806 的高效性及其與目前臨床中使用的 KRAS 抑制劑和降解劑的明顯區別。這些臨床前數據表明，在 KRAS G12D 突變癌症的臨床前模型中，該藥物具有劑量依賴性的強效抗腫瘤活性，並能抑制腫瘤生長。

ARV-806 forms productive ternary complexes with the on and off states of KRAS G12D, demonstrated in vitro picomolar potency with near complete degradation and high selectivity. ARV-806 demonstrates antiproliferative activity approximately 25 times greater than KRAS inhibitors and the leading clinical stage degrader. Importantly, ARV-806 induces durable degradation greater than 90% for seven days after a single dose with efficacy across pancreatic, colorectal and lung cancer models.

ARV-806 與 KRAS G12D 的開啟和關閉狀態形成有效的三元複合物，體外實驗證明其具有皮摩爾級的效力，且降解幾乎完全，選擇性很高。ARV-806 的抗增殖活性比 KRAS 抑制劑高約 25 倍，是領先的臨床階段降解劑。重要的是，ARV-806 單次給藥後可在 7 天內誘導 90% 以上的持久降解，並且在胰腺癌、結直腸癌和肺癌模型中均有效。

We also presented early and very promising preclinical data from our oral pan-KRAS degrader and look forward to sharing more as this program advances. We are rapidly enrolling a Phase 1 clinical trial of ARV-806, reflecting strong interest from clinical investigators and underscoring the high unmet need for effective KRAS-targeted therapies. We look forward to sharing initial clinical data from this trial next year.

我們也展示了我們口服泛KRAS降解劑的早期且非常有前景的臨床前數據，並期待隨著該計畫的進展分享更多資訊。我們正在快速開展 ARV-806 的 1 期臨床試驗，這反映了臨床研究人員的濃厚興趣，並凸顯了對有效的 KRAS 標靶療法的巨大未滿足需求。我們期待明年分享這項試驗的初步臨床數據。

Finally, I'd like to briefly mention updates from two other promising programs that you'll hear more about in 2026. First, at World Muscle in October, we shared exciting preclinical data for ARV-027, a PROTAC degrader designed to target polyglutamine-expanded androgen receptor or polyQ-AR in skeletal muscle.

最後，我想簡要提及另外兩個有前景的項目的最新進展，你們將在 2026 年聽到更多關於它們的消息。首先，在 10 月的世界肌肉展上，我們分享了 ARV-027 的令人興奮的臨床前數據，ARV-027 是一種 PROTAC 降解劑，旨在靶向骨骼肌中的多聚谷氨酰胺擴展雄激素受體或 polyQ-AR。

This degrader will be developed for patients with spinal and bulbar muscular atrophy or SBMA, a rare genetically defined neuromuscular disease with no approved treatments and significant unmet need. Second, this week at SITC, we will introduce our first immuno-oncology focused PROTAC degrader, ARV-6723. ARV-6723 targets HPK1, which functions as a negative regulator of T-cell signaling causing tumor microenvironment immune suppression and could be relevant for numerous solid tumors.

該降解劑將用於治療脊髓延髓肌萎縮症（SBMA）患者，這是一種罕見的、由基因定義的神經肌肉疾病，目前尚無核准的治療方法，存在巨大的未滿足需求。其次，本週在 SITC，我們將推出我們首個專注於免疫腫瘤學的 PROTAC 降解劑 ARV-6723。ARV-6723 針對 HPK1，HPK1 是 T 細胞訊號的負調控因子，可導致腫瘤微環境免疫抑制，可能與多種實體瘤相關。

Our preclinical work to date suggests that degrading HPK1 leads to differentiated biology versus HPK1 inhibitors and anti-PD-1 therapies. We anticipate beginning first-in-human studies for ARV-027 and ARV-6723 in 2026.

我們迄今為止的臨床前研究表明，HPK1 的降解會導致與 HPK1 抑制劑和抗 PD-1 療法不同的生物學特性。我們預計將於 2026 年開始 ARV-027 和 ARV-6723 的首次人體試驗。

As we begin those studies, we look forward to providing full updates on the unmet need for each disease, the rationale for each high-impact target and why we believe that our PROTAC degraders will represent highly differentiated therapies for patients.

隨著這些研究的開始，我們期待著全面更新每種疾病的未滿足需求、每個高影響力靶點的理由，以及我們為什麼相信我們的 PROTAC 降解劑將為患者提供高度差異化的療法。

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

接下來，我將把電話交給安德魯，讓他來回顧我們的季度財務資訊。

Thanks, Angela, and good morning, everyone. I'm pleased to provide financial highlights for the third quarter ended September 30, 2025, and expand on our approach to capital allocation, capital returns and development strategy.

謝謝安琪拉，大家早安。我很高興向大家介紹截至 2025 年 9 月 30 日的第三季財務亮點，並詳細介紹我們的資本配置、資本回報和發展策略。

As a reminder, detailed financial results for the third quarter are included in the press release we shared this morning. I'll begin by briefly touching on some key financial highlights for the third quarter of 2025. At the end of the third quarter, we had approximately $787.6 million in cash, cash equivalents and marketable securities on the balance sheet compared with $1.04 billion as of December 31, 2024.

再次提醒，第三季的詳細財務業績已包含在我們今天早上發布的新聞稿中。首先，我將簡要介紹2025年第三季的一些主要財務亮點。截至第三季末，我們的資產負債表上約有 7.876 億美元的現金、現金等價物和有價證券，而截至 2024 年 12 月 31 日，這一數字為 10.4 億美元。

Revenue for the three months ended September 30, 2025, totaled $41.9 million compared to $102.4 million for the three months ended September 30, 2024. The decrease of $60.5 million was driven by the Novartis License Agreement, which was entered into during the second quarter of 2024 with revenue recognized through the end of 2024, offset by the recognition of a milestone payment from Novartis of $20 million this quarter as part of the same agreement.

截至 2025 年 9 月 30 日止三個月的收入總計為 4,190 萬美元，而截至 2024 年 9 月 30 日止三個月的收入為 1.024 億美元。6050萬美元的減少是由於諾華許可協議造成的，該協議於2024年第二季度簽訂，收入確認至2024年底，但本季度確認的諾華里程碑付款2000萬美元作為同一協議的一部分，抵消了這一減少。

General and administrative expenses were $21 million in the third quarter, compared to $75.8 million for the same period of 2024. The decrease of $54.8 million was primarily due to a decrease of $43.4 million from the termination of our lease of 101 College Street in August 2024, a decrease in personnel and infrastructure-related costs of $7.3 million and professional fees of $3.6 million. Total non-GAAP G&A for the quarter was $14.6 million, compared with $64.8 million in the prior year.

第三季一般及行政費用為 2,100 萬美元，而 2024 年同期為 7,580 萬美元。減少 5,480 萬美元主要是由於 2024 年 8 月終止了 101 College Street 的租賃合同，導致支出減少 4,340 萬美元，人員和基礎設施相關成本減少 730 萬美元，以及專業費用減少 360 萬美元。本季非GAAP一般及行政費用總額為1,460萬美元，而上年同期為6,480萬美元。

Research and development expenses were $64.7 million in the third quarter compared to $86.9 million for the same period of 2024. The decrease of $22.2 million was primarily driven by a decrease in the vepdeg program of $5.4 million, a decrease in the luxdeg program of $4.7 million and a decrease in personnel expenses and non-program-specific expenses of $15.1 million, offset by an increase in the KRAS program of $4.3 million.

第三季研發費用為 6,470 萬美元，而 2024 年同期為 8,690 萬美元。減少 2,220 萬美元主要是由於 vepdeg 項目減少 540 萬美元、luxdeg 項目減少 470 萬美元以及人員費用和非項目特定費用減少 1510 萬美元，但被 KRAS 項目增加 430 萬美元所抵消。

Total non-GAAP R&D for the quarter was $56.9 million compared to $73.2 million in the prior quarter. Total non-GAAP expenses were $71.5 million in the quarter. We expect expenses to continue to decline as we work with Pfizer to ramp down our spend on vepdeg and as our cost reduction programs take full effect.

本季非GAAP研發總支出為5,690萬美元，上一季為7,320萬美元。本季非GAAP總支出為7,150萬美元。我們預計，隨著我們與輝瑞合作逐步減少在維普地格上的支出，以及我們的成本削減計劃全面生效，支出將繼續下降。

Our goal is to continue with a quarterly run rate spend below $75 million, which will allow us to manage non-GAAP expenses below $300 million in fiscal year 2026. In September, we announced that our Board had authorized the repurchase of up to $100 million of our outstanding common stock. This authorization underscores the Board's confidence in our long-term strategy and its belief that our current share price is undervalued relative to our long-term opportunity.

我們的目標是繼續保持季度支出低於 7,500 萬美元，這將使我們能夠在 2026 財年將非 GAAP 支出控制在 3 億美元以下。9 月，我們宣布董事會已授權回購最多 1 億美元的流通普通股。這項授權凸顯了董事會對我們長期策略的信心，以及認為我們目前的股價相對於我們的長期發展機會被低估的觀點。

As of the end of September, we have bought back approximately 2.56 million shares at an average share price of $7.91 per share. Details of our stock repurchase program can be found in our 10-Q. At the same time, we announced further cost reductions that allowed us to maintain our prior cash runway guidance into the second half of 2028. We remain committed to investing in areas that will maximize shareholder value as we move towards important catalysts in the coming months. In addition, we will continue to look at ways to reduce costs and increase efficiency while continuing to focus on our goal of progressing our very promising early pipeline. With that, I'll turn the call over to John for closing remarks. John?

截至 9 月底，我們已回購約 256 萬股股票，平均每股價格為 7.91 美元。有關我們股票回購計劃的詳細信息，請參閱我們的 10-Q 表格。同時，我們宣布了進一步的成本削減措施，使我們能夠將先前的現金流量預期維持到 2028 年下半年。我們將繼續致力於投資能夠最大限度提升股東價值的領域，並在未來幾個月迎來重要的催化劑。此外，我們將繼續尋找降低成本和提高效率的方法，同時繼續專注於推進我們非常有前景的早期研發管線的目標。接下來，我會把電話交給約翰，請他作總結發言。約翰？

Thanks, Andrew. We are focused on continuing to deliver innovative and differentiated assets in areas of high unmet need. We are operating with scientific rigor and building on our proven track record of success from discovery to clinical to collaborations.

謝謝你，安德魯。我們致力於在高度未滿足需求的領域繼續提供創新和差異化的資產。我們秉持科學嚴謹的態度，並依賴我們從發現、臨床到合作等各方面所取得的成功經驗。

We have a deep pipeline with multiple clinical candidates for near-, mid- and long-term value creation and the potential to be differentiated with critically important therapies for patients. Arvinas is entering a pivotal phase in its growth trajectory.

我們擁有豐富的研發管線，包含多個臨床候選藥物，可在近期、中期和長期創造價值，並有可能透過對患者至關重要的療法實現差異化。Arvinas正進入其發展軌跡的關鍵階段。

Our clinical pipeline offers a rich set of catalysts throughout the balance of the year and into 2026 with multiple study initiations and data readouts anticipated across our neuroscience and oncology franchises. With our PDUFA date now confirmed for next year, we are approaching an historic moment with the potential for the first ever approval of our PROTAC therapy. We are well positioned to deliver significant value for our shareholders, our partners and for the patients we serve.

在今年剩餘時間和 2026 年，我們的臨床研發管線將提供豐富的催化劑，預計在我們的神經科學和腫瘤學領域將啟動多項研究並公佈數據。隨著我們的 PDUFA 日期確定在明年，我們即將迎來一個歷史性的時刻，我們的 PROTAC 療法有可能獲得首次批准。我們有能力為我們的股東、合作夥伴以及我們服務的患者創造巨大價值。

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

接下來，我會把電話交給傑夫，讓他開始問答環節。傑夫？

Before I turn the call over to the operator, I'm going to ask that you limit yourself to one question per cycle to make sure we're able to give everyone the appropriate time. You can feel free to join the queue afterwards for a follow-up question. So with that, operator, can you please open up the queue?

在將電話轉接給接線員之前，我希望您每次只提出一個問題，以確保我們能夠給每個人足夠的時間。之後您可以隨時排隊提出後續問題。那麼，操作員，請您開啟隊列好嗎？

(Operator Instructions)

（操作說明）

Etzer Darout, Barclays.

埃策爾·達魯特，巴克萊銀行。

Great. Thanks for taking the question. Just a quick question on the BCL6 degrader program. Just we're going to see some updated data from (inaudible) at ASH. I just wanted to -- if you could comment on points of differentiation there that they're doing (technical difficulty) and if you could just talk a little bit about the dosing profile that you envision for the molecule and any areas you could potentially differentiate longer term of that molecule? Thank you.

偉大的。感謝您回答這個問題。關於BCL6降解程序，我有個小問題。我們將看到來自 ASH 的一些更新數據（聽不清楚）。我只是想問一下——您能否就他們正在做的差異化工作（技術難題）發表一下看法？您能否簡單談談您所設想的該分子的給藥方案，以及您認為該分子在長期發展中可能有哪些差異化優勢？謝謝。

Great. Thank you so much for the question. And yes, we're very excited about our BCL6 program, and we do believe that we have a profile that will differentiate itself as the compound continues to be developed.

偉大的。非常感謝您的提問。是的，我們對 BCL6 專案感到非常興奮，我們相信隨著化合物的不斷開發，我們的產品將具有獨特的優勢。

Noah, do you want to add some comments?

諾亞，你想補充些什麼嗎？

Sure. Thanks, John, and thanks for the question. Yes. So indeed, we -- and by the way, you broke up a little bit, but if it had to do with dosing -- yes and differentiation. So the drug is being dosed once daily in oral drug. Differentiation has to do there on a couple of different levels.

當然。謝謝你，約翰，也謝謝你的提問。是的。所以，我們——順便說一句，你們之間有點小摩擦，但如果這與劑量有關——是的，還有差異化。所以這種藥物是每天口服一次。這裡需要在幾個不同層面上區分。

Number one is that we've already demonstrated and will continue to demonstrate upcoming at ASH some kind of, I guess, a differentiated profile for combinations of a drug and even for monotherapy preclinically. So we noticed that we can achieve complete responses in various models versus tumor growth inhibitions that are seen with some competitor -- or yes, some competitor drugs.

第一點是，我們已經證明，並將在即將到來的 ASH 會議上繼續證明，藥物組合甚至單藥治療在臨床前方面具有某種差異化特徵。因此我們注意到，與某些競爭對手（或某些競爭藥物）只能抑制腫瘤生長不同，我們在各種模型中都能實現完全緩解。

In terms of our program, we're focused in -- we've said pretty explicitly that we're focused in monotherapy for AITL, and we're interested in developing the combination with the bispecific for DLBCL. So there's, at this point, several competitors that have entered the market. One little -- one of them that has already reported data, the others seem to have just filed their IND.

就我們的計畫而言，我們專注於——我們已經非常明確地表示，我們專注於 AITL 的單藥治療，並且我們有興趣開發與雙特異性藥物聯合治療 DLBCL 的方案。所以目前已經有幾家競爭對手進入市場了。其中一家小型公司——已經公佈了數據，其他公司似乎剛剛提交了IND申請。

We believe that -- and we've shared data here that we have monotherapy activity in T-cell and B-cells. That has not been reported by the competitor that's already reported out some B-cell malignancy responses. And so that's a point of potential differentiation in the future.

我們相信——並且我們在這裡分享了數據——我們的單藥療法對 T 細胞和 B 細胞具有活性。競爭對手尚未報告此類情況，但他們已經公佈了一些 B 細胞惡性腫瘤的治療反應。因此，這可能是未來一個潛在的差異化優勢。

Great thank you.

非常感謝。

Yigal Nochomovitz, Citi.

Yigal Nochomovitz，花旗集團。

This is Caroline on for Yigal. Thanks for taking our question. On your LRRK2 program, can you tell us about the first types of signals you'd be looking for in the Parkinson's disease MAD Phase 1? And how long do you hypothesize you'll need to dose for the PK effects that you've already observed in healthy volunteers in Parkinson's patients to translate to clinical benefit? Thanks.

這裡是卡洛琳，為您報道伊加爾。感謝您回答我們的問題。在您的 LRRK2 專案中，您能否告訴我們，在帕金森氏症 MAD 第一階段中，您會尋找哪些類型的訊號？您認為需要多長時間的給藥才能使帕金森氏症患者從健康志願者身上觀察到的藥物動力學效應轉化為臨床效益？謝謝。

Yes. No, thank you, Caroline. Great question, and I'll hand back to Noah.

是的。不，謝謝你，卡洛琳。問得好，我把問題交給諾亞。

Thanks, John and Caroline. Thank you for the question. So yeah, we're pretty excited about what we've seen so far with our LRRK2 degrader and the reception that we received at a recent conference at MDS. So as you state, we are currently moving pretty aggressively through a Parkinson's disease Phase 1 study that has 28 days of dosing. We expect that this will generate data that's principally biomarker related.

謝謝約翰和卡洛琳。謝謝你的提問。是的，我們對目前為止 LRRK2 降解器所取得的成果以及在最近 MDS 會議上獲得的回饋感到非常興奮。正如您所說，我們目前正在積極推進一項帕金森氏症 1 期研究，該研究的給藥週期為 28 天。我們預計這將產生主要與生物標記相關的數據。

And -- but we may also start to collect a little clinical efficacy data that's not expected with 28 days dosing. Now what we've shared is that we've already been able to demonstrate pathway engagement in ways that competitor LRRK2 inhibitors have been -- at least have not reported to date. So we know in healthy volunteers, we can impact endolysosomal trafficking and also neuroinflammation, at least through microglial pathways -- mediated pathways.

而且—但我們也可能開始收集一些臨床療效數據，這是 28 天給藥方案所無法預期的。現在我們已經分享的是，我們已經能夠證明，我們的 LRRK2 抑制劑能夠以競爭對手尚未報導的方式參與通路——至少到目前為止還沒有。因此我們知道，在健康志願者中，我們可以透過小膠質細胞途徑（介導的途徑）影響內溶小體運輸和神經發炎。

And so now when we look at our Parkinson's disease patients, the idea would be we have patients at baseline who have more than 2, maybe even 3 times the baseline level of LRRK2 in their CSF. There's much more activation of these pathways.

因此，現在當我們觀察帕金森氏症患者時，我們的想法是，在基線水平上，患者的腦脊髓液中 LRRK2 的含量可能超過基線水平的 2 倍，甚至 3 倍。這些通路被活化的程度大大增加。

And it will be important to see how much the degradation that we've already reported out in healthy volunteers, we can recapitulate now in this Parkinson's disease population and look at that pathway engagement. So we've guided to an update on those pathway markers next year, relatively early next year.

重要的是要觀察我們在健康志願者中已經報告的退化情況，現在我們能否在帕金森氏症患者群體中重現這些退化情況​​，並研究該通路參與情況。因此，我們建議在明年，也就是明年年初，對這些通路標記進行更新。

And -- but I think that the next step for clinical data will be when we can have more than 28 days of treatment. So for that, we're working our way through the chronic tox study. And so you'll see as we file our IND next year that allows us to move into PSP that we're prepared to continue with chronic treatment of patients, and that will be an opportunity for us to demonstrate the clinical benefits in diseases like PSP and potentially Parkinson's.

但我認為，臨床數據的下一步將是當我們能夠進行超過 28 天的治療時。因此，我們正在著手進行慢性毒性研究。因此，明年我們將提交 IND 申請，允許我們進入 PSP 領域，屆時您將會看到我們已準備好繼續對患者進行慢性治療，這將是我們證明 PSP 等疾病以及潛在的帕金森氏症具有臨床益處的機會。

Michael Schmidt, Guggenheim.

麥可·施密特，古根漢美術館。

Hi, this is Sarah on for Michael. Thanks for taking my question. I just wanted to ask on your KRAS G12D. So you've mentioned before and we've seen evidence for KRAS amplification as a mechanism of resistance to inhibitors. So -- and the fact that potentially with the iterative activity of a PROTAC might be able to overcome that. So I just wanted to ask if you have any plans to potentially test ARV-806 or maybe even eventually a pan-KRAS in the clinic in a KRAS amplified population

大家好，我是莎拉，替麥可為您報道。謝謝您回答我的問題。我只是想問一下關於您的 KRAS G12D 的問題。正如你之前提到的，我們也看到了KRAS擴增作為對抑制劑產生抗藥性的機制的證據。所以——而且，PROTAC 的迭代活動或許能夠克服這一點。所以我想問一下，您是否有任何計劃在KRAS擴增人群中，在臨床上測試ARV-806，或者最終測試泛KRAS靶向藥物？

Yeah. Great questions, Sarah. I'm going to ask both Angela Cacace, our CSO, and Noah to give you two parts to that answer.

是的。莎拉，問得好。我將請我們的首席策略長安吉拉·卡卡斯和諾亞分別從兩個方面回答這個問題。

Great. Thank you for the question. We have been studying certainly our G12D degrader ARV-806 in resistant setting. And we look after -- we see amplification of KRAS G12D, and we see that we durably repress KRAS in all conditions. And then for our pan-KRAS degrader, we've also been studying the amplified setting, the wild-type amplified setting.

偉大的。謝謝你的提問。我們一直在研究我們的 G12D 降解劑 ARV-806 在抗藥性環境下的表現。我們觀察發現－KRAS G12D 擴增，我們發現，在所有情況下，KRAS 都能持久抑制。此外，對於我們的泛 KRAS 降解劑，我們也一直在研究擴增設置，即野生型擴增設置。

And in the wild-type amplified setting, we're gratified to see some early data that shows that we see very nice tumor growth inhibition. And in cases of PDX models, we've also seen regression. So we're advancing very quickly with our pan-KRAS degrader program, and I'll turn over to Noah for the clinical perspective.

在野生型擴增環境中，我們很高興看到一些早期數據顯示，腫瘤生長抑制效果非常好。對於PDX模型，我們也觀察到了回歸現象。所以，我們的泛KRAS降解劑計畫進展非常迅速，接下來我將把麥克風交給諾亞，讓他從臨床角度談談。

Thanks, Angela. And so Sarah, to your question about amplification and what we've seen. So we specifically, right, in the ongoing Phase 1 study, we exclude patients that have been treated previously with KRAS inhibitors. So that's not something we're going to see in the dose escalation portion of our study, and you would understand why we would want the cleanest signal. We've made that choice as really anyone would.

謝謝你，安吉拉。那麼，莎拉，關於你提出的放大問題以及我們所看到的現象。因此，在正在進行的 1 期研究中，我們刻意排除了先前接受過 KRAS 抑制劑治療的患者。所以，在研究的劑量遞增部分，我們不會遇到這種情況，您也會明白為什麼我們想要最清晰的訊號。我們做出這個選擇，其實任何人都會這麼做。

But we have learned over the past year, and this is really data that's generated outside of our company, right, that as data -- we see many reports of amplification being a principal mechanism of resistance after patients have been exposed to KRAS inhibitors.

但在過去一年中，我們了解到，這些數據實際上是由我們公司以外的機構產生的，對吧？數據顯示，許多報告顯示，在患者接觸 KRAS 抑制劑後，基因擴增是主要的抗藥性機制。

So we've obviously -- as Angela has pointed to, we've done work in our models to show that this creates a great opportunity for us moving forward. (technical difficulty) expect some updates over the course of the next year in terms of if we want to expand our targeting or thinking in this regard. It certainly is compelling science.

所以很明顯——正如安吉拉所指出的那樣——我們已經在模型中進行了研究，表明這為我們未來的發展創造了巨大的機會。 （技術難題）預計在未來一年內，我們會就是否要擴大目標群體或在這方面的思考進行一些更新。這的確是引人入勝的科學。

Thanks.

謝謝。

Derek Archila, Wells Fargo.

Derek Archila，富國銀行。

Good morning. This is Hal calling in for Derek from Wells Fargo. Thank you so much for the question. So I guess we have a question on the ARV-102. For the SAD data, do you see any CSF degradation for LRRK2? And then for the MAD data next year in 2026, just wanted to see do you have any expectations? Is more than 50% in healthy volunteer you wanted to repeat or just some expectation for us to set up? Thank you so much.

早安.這裡是哈爾，替富國銀行的德瑞克打電話。非常感謝您的提問。所以我想我們這裡有一個關於ARV-102的問題。對於 SAD 數據，您是否觀察到 LRRK2 的 CSF 降解？那麼對於明年（2026 年）的 MAD 數據，我想了解您有什麼預期？你是想讓超過 50% 的健康志願者重複實驗，還是只是希望我們設定一些預期目標？太感謝了。

So thanks for the question. Absolutely. So Noah, do you want to take that?

謝謝你的提問。絕對地。諾亞，你想拿嗎？

Yes. So -- but I think we've guided to this. Essentially, we will provide our LRRK2 degradation data when we've completed the MAD in the Parkinson's disease patients. And that's basically what we're going to guide to for next year.

是的。所以——但我認為我們已經引導到了這一點。基本上，我們將在完成帕金森氏症患者的 MAD 後提供 LRRK2 降解數據。這就是我們明年要努力的方向。

Thank you.

謝謝。

Jeet Mukherjee, BTIG.

Jeet Mukherjee，BTIG。

Great, thanks for taking my question. Just coming back to ARV-806. Based on your learnings from other G12D inhibitors and degraders in development, are there any molecular features or attributes that may be correlated to or linked to the GI tolerability and elevated liver enzymes we've seen with some of these molecules? And if yes, does ARV-806 avoid those features? Thanks.

太好了，謝謝你回答我的問題。剛回到ARV-806。根據您從其他正在研發的 G12D 抑制劑和降解劑中獲得的經驗，是否存在一些分子特徵或屬性可能與我們觀察到的某些分子的胃腸道耐受性和肝酶升高有關？如果答案是肯定的，那麼ARV-806是否避免了這些特性？謝謝。

Yeah. Thanks for the question. I mean I think certainly, the -- our G12D compound has a very exciting profile. Obviously, the molecule is different from other G12D inhibitors. Maybe, Angela, do you want to talk to what you think might be some of the kind of the features that give the profile that we see?

是的。謝謝你的提問。我的意思是，我認為當然，我們的 G12D 化合物具有非常令人興奮的特性。顯然，該分子與其他 G12D 抑制劑不同。安琪拉，或許你想談談你認為構成我們所看到的這種形象的一些特徵？

Sure. So as we described, our ARV-806 G12D PROTAC really does have some very nice features from a molecular perspective. It binds to both the on- and the off-state and is 25 times more potent than all mechanisms that are currently in the clinic that we've tested to date. But given what we've seen with the clinical degrader, we're also several orders of magnitude more potent at engaging the target and degrading the target durably. So with that in mind, we expect to have greater potency which should translate clinically.

當然。正如我們所描述的，從分子角度來看，我們的 ARV-806 G12D PROTAC 確實具有一些非常好的特性。它與開啟和關閉狀態均有結合，其效力比我們迄今為止在臨床上測試的所有機制高 25 倍。但根據我們從臨床降解劑中看到的情況來看，我們在與目標結合併持久降解目標方面也比以前強幾個數量級。因此，考慮到這一點，我們期望它能具有更強的效力，這應該會在臨床上得到體現。

And I'll let Noah go ahead and take the liver and other questions.

我會讓諾亞繼續回答肝臟檢查和其他問題。

Yeah. So I think our strategy there right now based on the science that's available is to win on that potency issue, meaning we already know from a competitor's degrader that they were limited in their ability to escalate their dose because of transaminitis that was seen. So the fact that we can engage our target at much lower concentrations suggests that we have the potential not to run into those types of toxicities and still get the significant degradation we're shooting for. So we're looking for more than 80% degradation of our target. We could probably do significantly better than that. And we'll provide updates as we go through our dose escalation cohorts.

是的。所以我認為，根據現有的科學依據，我們目前的策略是贏得效力問題，這意味著我們已經從競爭對手的降解劑中了解到，由於出現了轉氨酶升高，他們提高劑量的能力受到了限制。因此，我們能夠在更低的濃度下與目標物發生反應這一事實表明，我們有可能不會遇到這類毒性，並且仍然可以獲得我們所追求的顯著降解效果。所以我們希望目標效能下降超過 80%。我們或許可以做得更好。我們將隨著劑量遞增試驗的進行，提供最新進展。

Sudan Loganathan, Stephens Inc.

蘇丹洛加納森史蒂芬斯公司

Hey, good morning. This is [Keith Alve] on behalf of Sudan. I got a quick one on ARV-806. Are you all evaluating how PROTAC medicated KRAS G12D degradation might complement or differ from combination strategies like the cetuximab pairing seen with Verastem's KRAS12 G12D inhibitor? Thanks.

嘿，早安。我是基斯·阿爾維，代表蘇丹發言。我很快就搞定了ARV-806。你們都在評估 PROTAC 藥物治療的 KRAS G12D 降解與西妥昔單抗聯合治療等聯合策略（例如 Verastem 的 KRAS12 G12D 抑制劑）相比，可能會有哪些補充或差異？謝謝。

Yeah. So preclinically, we have evaluated combination with anti-EGFR inhibitors like cetuximab. And so we think this is a big advantage because we have a selective approach to degrading G12D KRAS. We combine very well in that case, and we'll be sharing the preclinical data that we've generated in those combinations within the year.

是的。因此，在臨床前研究中，我們已經評估了與抗 EGFR 抑制劑（如西妥昔單抗）合併用藥的情況。因此，我們認為這是一個很大的優勢，因為我們選擇性地降解 G12D KRAS。在這種情況下，我們合作得非常好，我們將在年內分享我們針對這些組合產生的臨床前數據。

And yeah, I would just add that there certainly are accumulating evidence that combinations of inhibitors with chemotherapy, but also, as you mentioned, with an EGFR inhibitor can lead to cumulative tox which may be limiting for this drug, but creates the -- for this set of inhibitors, but that creates an opportunity for us, especially, right? Because going back to this potency argument, if we can get our drug on board, which right now requires weekly -- once-a-week dosing and may allow us eventually to also get to once every two-week dosing, and we can do this with lower dosing -- lower doses, and we might not achieve the same type of cut tox from combinations, that opens up a whole set of opportunities to generate the better benefit risk profile. So, again, we have to get through our monotherapy dosing. It's moving very fast. And we're hoping that we can get into our combinations next year already, but more to follow on that.

是的，我還要補充一點，越來越多的證據表明，抑制劑與化療聯合使用，而且正如您所提到的，與 EGFR 抑制劑聯合使用，可能會導致累積毒性，這可能會限制這種藥物的應用，但同時也為我們創造了機會，特別是對於這類抑制劑而言，對吧？回到效力論證，如果我們能夠讓我們的藥物上市，目前需要每週一次給藥，最終可能還可以實現每兩週一次給藥，而且我們可以用更低的劑量做到這一點，雖然我們可能無法像聯合用藥那樣減少毒性，但這卻為我們創造了一系列機會，從而產生更好的獲益風險比。所以，我們又得完成單藥治療的劑量階段了。它移動得非常快。我們希望明年就能開始進行組合訓練，但更多細節稍後再公佈。

And just to briefly add that tackling the pan-KRAS mechanism is a challenge in that combination setting largely because they're also hitting and in HRAS. And that becomes a big challenge for adding on an EGFR-based mechanism. So our KRAS G12D degrader would avoid that.

另外，簡單補充一下，在這種組合環境下，解決泛 KRAS 機制是一個挑戰，主要是因為它們也受到 HRAS 的影響。這就為添加基於 EGFR 的機制帶來了很大的挑戰。因此，我們的 KRAS G12D 降解器可以避免這種情況。

Tyler Van Buren, TD Securities.

泰勒·範·布倫，TD證券。

Good morning. This is Francis on for Tyler. Thanks for taking my question. So for the BCL6 asset, what combination partners do you believe are most exciting? And where do you think it's most likely to exist in the lymphoma treatment paradigm if successfully developed?

早安.這是弗朗西斯替泰勒上場。謝謝您回答我的問題。那麼對於 BCL6 資產，您認為哪些合併合作夥伴最令人興奮呢？如果研發成功，您認為它最有可能在淋巴瘤治療模式中扮演什麼角色？

Thanks for the question. Yeah, there's a lot of potentially exciting combinations that we can carry out with BCL6. I'll ask Noah to maybe give an overview of where we're thinking

謝謝你的提問。是的，我們可以利用 BCL6 來實現許多令人興奮的潛在組合。我會請諾亞概述一下我們的想法。

Sure. So we've shared data about the ability to combine this drug, which uses an orthogonal approach to many of the agents that are currently approved in the B-cell malignancy setting. And we see just beautiful synergies and combinability with -- preclinically with EZH2 inhibitors, BTK inhibitors, BCL2 inhibitors, and also anti-CD20 agents.

當然。因此，我們分享了有關這種藥物聯合應用能力的數據，它採用了一種與目前在 B 細胞惡性腫瘤治療中獲批的許多藥物正交的方法。我們看到它在臨床前與 EZH2 抑制劑、BTK 抑制劑、BCL2 抑制劑以及抗 CD20 藥物之間存在著非常漂亮的協同作用和組合性。

So those -- that's a whole set of opportunities for combination. We recognize that the way the field is evolving, there's going to be a significant outsized role for bispecifics targeting CD20 in the -- eventually the first-line setting, but in the second- and third-line setting as well for large B-cell lymphoma.

所以，這些——這提供了一系列組合的機會。我們認識到，隨著該領域的發展，靶向 CD20 的雙特異性抗體將在大 B 細胞淋巴瘤的一線治療中發揮非常重要的作用，但在二線和三線治療中也將發揮作用。

We think that's our -- we want to be laser-focused as a company, and we recognize that's a significant opportunity where we can combine these therapies that have non-overlapping toxicities. Ours -- we first have to identify a toxicity. But obviously, there is CRS with the bispecifics, and we should be able to combine favorably with those. And that would be our plan. That's why we've announced that next year, we expect to be moving ahead in our Phase 1 study with combinations with bispecifics.

我們認為這是我們——我們希望公司能夠精準聚焦，我們也意識到這是一個重要的機遇，我們可以將這些毒性不重疊的療法結合在一起。我們的方法－首先要確定毒性。但顯然，雙特異性抗體存在 CRS，我們應該能夠與它們進行有利的結合。這就是我們的計劃。因此，我們宣布，明年我們預計將推進雙特異性抗體聯合療法的 1 期研究。

Li Watsek, Cantor Fitzgerald.

李·瓦特塞克，康托·菲茨傑拉德。

Hey, good morning guys. A strategy question for me. It looks like you're moving more programs into the preclinical clinical settings and then maybe deepening your footprint in neuromuscular space and expanding into I-O. So just curious, number one, your BD strategy here, given that you got five programs. And then two, your approach to resource allocation.

嘿，各位早安。我有策略方面的問題。看起來你們正在將更多項目轉移到臨床前臨床環境，然後可能會加深在神經肌肉領域的影響力，並擴展到工業與骨科領域。所以，我很好奇，第一，鑑於你獲得了五個項目，你的業務拓展策略是什麼？其次，還有你對資源分配的態度。

Yeah. So thanks for the question. Clearly, the last several months, the company has done a significant reset, obviously, with the decision along with Pfizer to find a new partner or out-license vepdegestrant allowed us to focus on the rest of our pipeline. And obviously, KRAS G12D, LRRK2, BCL6 are next in line assets that are in Phase 1 heading fairly rapidly to Phase 2. And then we have two programs behind that that should be in the clinic relatively soon, one in SDMA, which we can talk to and the other HPK1, which is an I-O.

是的。謝謝你的提問。顯然，在過去的幾個月裡，公司進行了重大調整，顯然，與輝瑞公司共同決定尋找新的合作夥伴或對外授權維普地孕烷，使我們能夠專注於我們研發管線的其他部分。顯然，KRAS G12D、LRRK2、BCL6 是接下來處於第一階段並很快進入第二階段的資產。然後我們還有兩個項目正在研發中，應該很快就能進入臨床階段。一個是 SDMA，我們可以和他們談談；另一個是 HPK1，它是一種 I-O 藥物。

And we believe that gives us an array of different programs across oncology and neuro. And yes, HPK1 has a huge amount of potential in immuno-oncology. So we're excited about that. It gives us a lot of flexibility. It gives us a lot of choices.

我們相信，這將使我們在腫瘤學和神經學領域擁有一系列不同的項目。是的，HPK1 在免疫腫瘤學領域具有巨大的潛力。我們對此感到很興奮。這給了我們很大的靈活性。它給了我們很多選擇。

And as ever in the history of -- the whole history of Arvinas, those choices have also included appropriate and well-placed BD opportunities. So we'll always be open for that. We think that some of our targets that really lend themselves to BD opportunities.

就像 Arvinas 的整個發展歷程一樣，這些選擇也包括適當且位置適當的業務拓展機會。所以我們會一直持開放態度。我們認為，我們的一些目標公司確實很適合進行業務拓展。

And right now, as we stand today, all of our portfolio is fully owned by our vepdegestrant, and we did do a great deal with Novartis on luxdegalutamide. So yes, we move forward with a lot of confidence, and we have some really great exciting data that should be coming out over the next several months and year, and we'll be able to position our portfolio the best way we can. And that could include selective partnering.

就目前而言，我們所有的產品組合都完全由我們的維普地孕烷組成，而且我們與諾華公司就盧地加魯胺達成了一項非常好的交易。所以，是的，我們充滿信心地向前邁進，未來幾個月和一年內我們將公佈一些非常令人興奮的數據，我們將能夠以最佳方式調整我們的投資組合。這可能包括選擇性合作。

Srikripa Devarakonda, Truist.

Srikripa Devarakonda，Truist。

Thank you so much for taking my question guys. Maybe a follow-up question to the previous one. With nearly $800 million in cash and runway to second half of '28, not just in terms of the time line -- the run rate time line, but in terms of what studies you can get through with this cash would be helpful. And also, as you are advancing your pipeline, do you continue to -- do you expect to continue PROTACs in both oncology and CNS? Or at this point of time, do you think there is a need to prioritize from a therapeutic area perspective? Thank you.

非常感謝各位回答我的問題。或許這是對上一個問題的後續問題。擁有近 8 億美元的現金，並且資金可以維持到 2028 年下半年，這不僅體現在時間表上——也就是運行速度的時間安排上，還體現在可以用這筆現金完成哪些研究上。另外，隨著你們推進產品線，你們是否繼續——是否期望繼續在腫瘤學和中樞神經系統領域開展 PROTAC 試驗？或者，在目前這個階段，您認為從治療領域的角度來看，是否有必要確定優先事項？謝謝。

Thanks for the question. I'll certainly hand over to our CFO, Andrew, to talk about the first half of that question. But in terms of the balance, yeah, the company right from its beginning has been an oncology company and the very -- I think it was the third target we worked on was a neuroscience target.

謝謝你的提問。我一定會把麥克風交給我們的財務長安德魯，讓他來談談這個問題的前半部。但就平衡而言，是的，公司從一開始就是一家腫瘤公司，而我們研究的第三個目標——我想是神經科學目標。

So we've been in neuroscience right from the beginning of the company's inception. And we think PROTACs and the ability to get brain penetrant PROTACs gives us a huge potential advantage in neurodegenerative diseases.

從公司成立之初，我們就一直從事神經科學領域的研究。我們認為，PROTAC 以及獲得可穿透大腦的 PROTAC 的能力，為我們在神經退化性疾病方面提供了巨大的潛在優勢。

So we want to explore that as we go forward with our programs like LRRK2. We'll also be -- now we're very excited to be looking at neuromuscular target like SBMA. And we do still think we've got a lot of differentiation in the oncology space. So although it may sound like two very radically different therapeutic areas, the insights and the ability to use PROTACs in those areas really does allow us to, I think, unlock a lot of differentiated opportunity.

所以，我們希望在推進 LRRK2 等專案的過程中探索這一點。我們現在也非常興奮地開始研究像脊髓延髓肌萎縮症 (SBMA) 這樣的神經肌肉標靶。我們仍然認為我們在腫瘤學領域擁有很大的差異化優勢。因此，儘管這聽起來像是兩個截然不同的治療領域，但我認為，在這些領域中運用 PROTAC 的洞察力和能力確實能夠讓我們獲得許多差異化的機會。

So we're going to continue with that for now. We are open and always looking for other opportunities as well. But right now, and I'll hand over to Andrew, we're well placed to fund the programs that we have, certainly after we did the reset that we did. Andrew?

所以，我們暫時會繼續這樣做。我們也一直持開放態度，尋找其他機會。但現在，我把麥克風交給安德魯，我們完全有能力為我們現有的項目提供資金，尤其是在我們進行了調整之後。安德魯？

Yeah. Thanks, John. So the way I think about capital allocation for at least the next year or two, the company has had significant spend on the vepdegestrant Phase 3s the last several years. You're going to see those costs start to ramp down. And what's going to happen is that those costs are going to be replaced by a series of Phase I early phase studies, right?

是的。謝謝你，約翰。因此，就我目前對未來至少一兩年的資本配置情況來看，該公司在過去幾年中對維普地孕酮三期臨床試驗投入了大量資金。你會看到這些成本開始逐步下降。接下來，這些成本將被一系列 I 期早期研究所取代，對吧？

So we're making a bet on the early-stage programs. We love them. We can't obviously right now tell you which ones we're going to take through on our own and which ones we're going to license. We're going to push on all of them. We think that many of them are highly, highly promising.

所以我們把賭注押在了早期項目上。我們喜歡他們。我們現在顯然無法告訴你們哪些項目我們將自行推進，哪些項目我們將獲得授權。我們將全力推進所有這些工作。我們認為其中許多都非常有前途。

And we'll be making decisions on those as we go through the development pipeline. So we look at these programs all the way out. Obviously, we've known our programs for a long time. So they've been incorporated into our spend even before we announced that they were coming into the clinic. So this is not a surprise to us.

我們將在開發過程中對這些問題做出決定。所以我們對這些項目進行了全面考察。顯然，我們對我們的程序已經很熟悉了。所以，甚至在我們宣布他們要進入診所之前，他們就已經被納入了我們的支出範圍。所以這對我們來說並不意外。

And we're just delighted. So we're going to continue pushing on our Phase 1 programs, and we'll make decisions as we go through based on which ones we think make the most sense for us to keep and which ones make the most sense for us to partner potentially.

我們真是太高興了。因此，我們將繼續推進第一階段項目，並根據我們認為哪些項目最值得保留以及哪些項目最值得潛在合作，在推進過程中做出決定。

Thank you so much.

太感謝了。

Tazeen Ahmad, Bank of America.

塔津·艾哈邁德，美國銀行。

Hi, good morning. Thanks for taking my questions. Just as it relates to 102, just given the current data that you have in biomarkers, how do we think about the translatability of those into clinical endpoints as it relates to PD? And then I just wanted to know about once you show the PD data in 2026, what do you think is going to be your area of focus that will allow you to support the advancement into a Phase 1b study into PSP? Thanks.

您好，早安。謝謝您回答我的問題。就像 102 一樣，鑑於您目前擁有的生物標記數據，我們如何看待這些生物標記在與 PD 相關的臨床終點中的轉化性？然後，我想知道，一旦您在 2026 年公佈了 PD 數據，您認為您的重點領域將是什麼，才能支持推進 PSP 的 1b 期研究？謝謝。

Thank you. Great question. Noah.

謝謝。問得好。諾亞。

Sure. Thanks, John, and good to hear from you, Tazeen. So yeah, 102, it's just such an exciting story for us because just to review and build off of what John and Andrew just said, if you think back, we've been working in oncology, but also developing neuroscience. And here, we are on the heels of a positive registration study for [VEP-2], out-licensing of luxdegalutamide, an AR degrader to Novartis, and we're advancing two oncology drugs. And here now, we have ARV-102 that -- where we've shared some incredible results recently that drive us in this direction for PSP and possibly for Parkinson's disease.

當然。謝謝你，約翰，很高興收到你的來信，塔津。所以，是的，102，這對我們來說是一個非常令人興奮的故事，因為回顧約翰和安德魯剛才所說的，如果你回想一下，我們一直在腫瘤學領域工作，同時也在發展神經科學。現在，我們剛完成了一項針對 [VEP-2] 的積極註冊研究，將 AR 降解劑 luxdegalutamide 授權給了諾華公司，並且我們正在推進兩種腫瘤藥物的研發。現在，我們有了 ARV-102，我們最近分享了一些令人難以置信的結果，這些結果推動我們朝著治療進行性核上性麻痺症 (PSP) 和可能治療帕金森氏症的方向發展。

So for years -- over the past many years, there's been tremendous investment in the Parkinson's disease community and the PSP community to understand what are the pathways that drive this neurodegenerative disease. And so there's a large biomarker study called PPMI, and this looks at the natural progression of Parkinson's disease.

因此，在過去的許多年裡，帕金森氏症患者群體和進行性核上性麻痺症患者群體都投入了大量資金，以了解導致這種神經退化性疾病的途徑。因此，有一項名為 PPMI 的大型生物標記研究，該研究著眼於帕金森氏症的自然進展。

And it has demonstrated that there are markers such as GPNMB, IAB1 -- IBA1 and also CD68, a series of cathepsin. So markers that are predictive of progression of disease because they are driving neuroinflammation and also driving neurodegeneration because of mistrafficking of proteins. And so that's because of endolysosomal function.

研究表明，存在 GPNMB、IAB1、IBA1 以及 CD68 等一系列組織蛋白酶標記物。因此，這些標記可以預測疾病的進展，因為它們會引發神經炎症，並且由於蛋白質轉運錯誤而引發神經退化。這是由於內溶小體的功能所致。

So these markers are all elevated in the disease. And we just reported out a study at MDS that drew tremendous excitement from investigators or scientists more broadly because we showed that in healthy volunteers, we were able to reduce these biomarkers, right? And now we're running the Parkinson's disease study that is looking at all of these biomarkers and we expect that if we degrade LRRK2 as much as we saw in healthy volunteers where we achieved 75% reduction, more than enough to advance this into PSP and PD studies that we should be able to drive down these biomarkers that cause the neuroinflammation and the mistrafficking of proteins such as tau.

因此，這些指標在這種疾病中都會升高。我們剛剛在 MDS 會議上發表了一項研究，引起了研究人員或更廣泛意義上的科學家們的極大興奮，因為我們表明，在健康志願者中，我們能夠降低這些生物標誌物，對吧？現在我們正在進行帕金森氏症研究，研究所有這些生物標記。我們預計，如果我們能像在健康志願者中一樣降低 LRRK2 的水平（我們實現了 75% 的降低），這足以推進 PSP 和 PD 的研究，我們應該能夠降低導致神經發炎和 tau 蛋白等蛋白質錯誤轉運的這些生物標記。

So building on that, we have the healthy volunteer data. We're going to report out our Parkinson's disease, LRRK2 degradation and biomarker data. And then next year, things go right, start a PSP study. PSP is a neurodegenerative disease that relies also on this mistrafficking of tau and we know that our drug can correct this mistrafficking.

在此基礎上，我們獲得了健康志願者的數據。我們將公佈我們的帕金森氏症、LRRK2降解和生物標記數據。然後，如果明年一切順利，就啟動PSP研究。PSP 是一種神經退化性疾病，它也依賴 tau 蛋白的錯誤轉運，而我們知道我們的藥物可以糾正這種錯誤轉運。

It can improve the -- decrease the neuroinflammation that is also at a root cause of PSP. And we'll be treating patients for continuously, meaning no longer just limited to 28 days, continue to accumulate biomarker data and correlate that with clinical measures like PSPRS and others. And we will hope to report out in short order the results of that Phase 1b study.

它可以改善——減少神經炎症，而神經炎症也是 PSP 的根本原因之一。我們將持續治療患者，不再局限於 28 天，繼續累積生物標記數據，並將其與 PSPRS 等臨床指標相關聯。我們希望盡快公佈該 1b 期研究的結果。

And if things go right, we may be able to start a Phase 2 study even before we have the Phase 1b study has completed. So a registration quality Phase 2 study. But exactly guiding on when that can start that we have to await clearing our IND and starting the Phase 1b study.

如果一切順利，我們甚至可能在 1b 期研究完成之前就開始 2 期研究。因此，這是一項註冊級別的二期研究。但具體何時可以開始，我們還要等到獲得 IND 批准並開始 1b 期研究。

And just to add to that, we do know that human genetics point to LRRK2 and LRRK2 is elevated in the brain of patients in idiopathic Parkinson's disease in microglia as Noah stated. And then also in progressive supranuclear palsy, these same SNPs that elevate LRRK2 also drive increased progression in a clinically meaningful way and time to death. And so by going in with a clear way to modulate the LRRK2 pathway, we feel that we stand the best chance of proving the LRRK2 hypothesis in disease in both progressive supranuclear palsy and potentially Parkinson's disease.

補充一點，我們知道人類遺傳學指向 LRRK2，正如 Noah 所說，LRRK2 在特發性帕金森氏症患者的大腦小膠質細胞中含量升高。此外，在進行性核上性麻痺症中，這些導致 LRRK2 升高的 SNP 也會以具有臨床意義的方式加速病情進展並延長死亡時間。因此，透過明確調節 LRRK2 路徑的方法，我們認為我們最有機會在進行性核上性麻痺症和潛在的帕金森氏症中證明 LRRK2 假說。

Paul Choi, Goldman Sachs.

Paul Choi，高盛。

Hi, good morning and thank you for taking the question. I wanted to check if you might have any additional dosing cohorts for ARV-393 at the upcoming ASH Meeting, including ones that might potentially be in the target therapeutic range where that you're aiming for. And then on ARV-027, I'm just curious if you thought of other CAG repeat related diseases as being potential areas to explore, including Huntington's or other neuromuscular diseases beyond spinal cerebellar that you focused on initially. Thanks for taking the question.

您好，早安，感謝您回答這個問題。我想確認一下，在即將舉行的 ASH 會議上，您是否會有 ARV-393 的其他劑量組，包括那些可能達到您所追求的目標治療範圍的劑量組。關於 ARV-027，我很好奇您是否考慮過其他與 CAG 重複相關的疾病作為潛在的探索領域，包括亨廷頓舞蹈症或其他神經肌肉疾病，而不僅僅是您最初關注的脊髓小腦疾病。感謝您回答這個問題。

Yes. Thank you. Noah and Angela can probably cover those.

是的。謝謝。諾亞和安琪拉或許可以勝任這些工作。

Sure. So to the first question of ARV-393, we've given particular guidance here. I think we would have liked to be able to give a full update at ASH this year on our dose escalation in ARV-393. But in fact, we are not yet in what we had anticipated to be the -- or predicted to be the efficacious range, although fascinatingly to us and very promisingly in our data, we are seeing responses, significant responses, CRs even in T-cell and B-cell malignancies. So we don't think it's prudent just to report what we're seeing at low dose levels.

當然。所以對於 ARV-393 的第一個問題，我們在這裡給了具體的指導。我認為我們原本希望能夠在今年的 ASH 會議上全面介紹我們在 ARV-393 劑量遞增方面的最新進展。但事實上，我們還沒有達到我們預期的——或者說預測的有效範圍，儘管令我們著迷，並且在我們的數據中非常有希望的是，我們看到了反應，顯著的反應，甚至在 T 細胞和 B 細胞惡性腫瘤中也出現了完全緩解。因此，我們認為僅僅報告我們在低劑量水平下觀察到的情況是不明智的。

Usually, studies would want to report out when you know that you're hitting your target fully and you could see the full robustness of the drug. That would be an appropriate time. But certainly, we didn't want to leave you -- people hanging. So we wanted to share that we're making progress, and we're seeing efficacy and tolerability of the drug.

通常情況下，研究人員會在確定完全達到目標並能夠看到藥物的全部效力時，才希望發布報告。那將是一個合適的時機。當然，我們不想讓你們──大家──失望。因此，我們想與大家分享，我們取得了進展，我們看到了該藥物的療效和耐受性。

Regarding the 027 question, I'll turn it back to Angela.

關於 027 的問題，我把它轉回給 Angela 回答。

Sure. Great. 027, we selected based on its unique profile for degrading the polyglutamine repeat androgen receptor in the nucleus and the cytoplasm, which is really important for a disease driver for spinal and bulbar muscular atrophy. And we reported out some very exciting data showing that we rescue muscle function, including grip strength and endurance to end of phenotypes that are really important for patients with that disease. So that's a very exciting opportunity.

當然。太好了。我們選擇 027 是基於它獨特的降解細胞核和細胞質中多聚谷氨酰胺重複雄激素受體的特性，這對於脊髓延髓肌萎縮症的致病因素來說非常重要。我們公佈了一些非常令人興奮的數據，顯示我們能夠恢復肌肉功能，包括握力和耐力，達到對該疾病患者來說非常重要的表型。所以這是一個非常令人興奮的機會。

With respect to polyglutamine repeat expansion disorders, we have a robust approach. We're taking to those repeat disorders. We're taking a two-pronged approach also for Huntington's disease. For Huntington's disease, we have identified selective ligands for mutant Huntington and sparing wild type. So we're continuing our efforts.

針對多聚谷氨酰胺重複序列擴增疾病，我們擁有穩健的方法。我們正在研究這些重複的疾病。我們對亨廷頓舞蹈症也採取了雙管齊下的方法。針對亨廷頓舞蹈症，我們已經確定了對突變型亨廷頓蛋白具有選擇性的配體，而對野生型亨廷頓蛋白沒有影響。所以我們會繼續努力。

We're early, but we're making good progress there. And then also the idea of tackling repeat expansion disorders is something we're taking very seriously, and we have a very unique opportunity there as well. So that's early, but very exciting space for Arvinas.

雖然時間尚早，但我們在這方面取得了良好進展。此外，我們也非常認真地處理解決重複序列擴增疾病的問題，而且我們在這方面也擁有一個非常獨特的機會。所以現在說這些還為時過早，但對於 Arvinas 來說，這是一個非常令人興奮的領域。

Just one more comment, if I could build on that. So look, when we go into the SBMA, we're starting in healthy volunteers. That's the appropriate thing to do. The great opportunity here is this disease is -- it's basically a monogenic disease. We know exactly what the target is, the polyQ-AR.

我還有一點要補充。所以你看，當我們進入SBMA時，我們首先招募的是健康的志工。這樣做才是正確的。這裡最大的機會在於，這種疾病基本上是一種單一基因疾病。我們確切地知道目標是什麼，即 polyQ-AR。

And we know from -- we know that we can degrade it. So in healthy volunteers, we're going to be able to also do muscle biopsies if permitted, and it's going to be very validating very quickly for this technology. So it's the perfect setup for us to enter a rare disease space because we can get to results and have conviction about our pathway engagement in healthy volunteer studies, which is an unusual opportunity.

我們知道——我們知道我們可以破壞它。因此，如果條件允許，我們還可以在健康志願者身上進行肌肉活檢，這將很快驗證這項技術的有效性。因此，這為我們進入罕見疾病領域創造了完美的條件，因為我們可以在健康志願者研究中獲得結果並對我們的研究路徑參與充滿信心，這是一個難得的機會。

Thanks, Noah.

謝謝你，諾亞。

Jonathan Miller, Evercore ISI.

Jonathan Miller，Evercore ISI。

Hi guys, thanks for taking my question and congrats on all the progress in the early pipeline. I'd like to start with KRAS combos, if I might. You mentioned a couple of interesting potential combo partners for the KRAS program, things that other players in the space maybe had trouble combining with given tolerability profile. How early could we get into combo cohorts? Is this the sort of thing that we could expect to see even in expansion cohorts starting next year? Or should we think about rituximab combos and beyond maybe being a little bit more delayed from that?

大家好，感謝你們回答我的問題，也恭喜你們在早期研發階段所取得的所有進展。如果可以的話，我想先從KRAS連招開始講解。您提到了一些 KRAS 計劃中有趣的潛在組合夥伴，而其他參與者可能難以將它們與給定的耐受性特徵結合。我們最早可以多久開始進行聯合隊列研究？這種情況是否也會出現在明年開始的擴招批次？還是我們應該考慮將利妥昔單抗合併療法及其他療法的研發時間再延後一段時間？

And then secondly, just on the HPK1 program, that seems like it's obviously very early still, but potentially pretty interesting. I noticed not much on the deck. When would you expect to show us more of that preclinical data and give us a sense for what indications maybe are the most fruitful for early looking there?

其次，就 HPK1 計畫而言，雖然目前看來還處於非常早期的階段，但可能非常有趣。我注意到甲板上沒什麼東西。您預計何時會向我們展示更多臨床前數據，並讓我們了解哪些適應症可能最值得早期研究？

Great questions, and I'll use my usual double act here of Noah and Angela to answer that.

問得好，我會像往常一樣，由諾亞和安琪拉這對搭檔來回答這個問題。

Thanks, John, and thanks for the question. Yes, so to field the 806 question, we're not guiding yet to the timing of combination. So it'd be speculative on my part, but I love speculating. So the bottom line is we're really tearing through our dose escalation right now because there's tremendous interest in this and tolerability, it seems for patients.

謝謝你，約翰，也謝謝你的提問。是的，所以對於 806 的問題，我們目前還不會給出合併時間的指導。所以這只是我的推測，但我喜歡推測。所以，關鍵在於，我們現在正在全力推進劑量遞增，因為人們對這種療法非常感興趣，而且患者的耐受性似乎也很好。

And so the idea is we are planning to go into that combination immediately after we do some -- we don't even have to wait until we have our expansions read out completely. We could start that earlier. So we're hopeful if things go very fast, it might be something we could start next year, but I can't offer guidance. It's all going to be clinical data dependent on, right? That's certainly possible.

因此，我們的想法是，在完成一些工作後，我們計劃立即進行這種組合——我們甚至不必等到我們的擴張計劃完全公佈出來。我們可以更早開始。所以我們希望，如果進展非常迅速，明年我們就能開始，但我無法提供具體指導。這一切都將取決於臨床數據，對吧？這當然有可能。

Great. And then your next question was about ARV-6723, our HPK1 degrader. And so we're very excited about the opportunity for that degrader. It has a very differential profile with respect to both PD-1, and also the kinase inhibitor, the HPK kinase inhibitor that's in the clinic. So what we've been able to show and what you'll hear about at SITC is the impact to T-cell exhaustion and importantly, the impact to the T-cell microenvironment.

偉大的。然後你的下一個問題是關於我們的 HPK1 降解劑 ARV-6723。因此，我們對這種降解劑的出現感到非常興奮。它對 PD-1 和激酶抑制劑（即臨床上使用的 HPK 激酶抑制劑）都具有非常不同的特性。因此，我們已經能夠展示，並且你們將在 SITC 上聽到的是，對 T 細胞耗竭的影響，更重要的是，對 T 細胞微環境的影響。

We are seeing dramatic changes there and outperforming anti-PD-1 and HPK1 inhibitors in both low and high immunogenic tumor models preclinically. So stay tuned. You'll hear a lot more about our oral immunotherapy that we think will outperform, and also be very useful in the setting that is resistant to checkpoint blockade. So we have a lot of enthusiasm around that asset.

我們看到這方面發生了巨大的變化，在臨床前低免疫原性和高免疫原性腫瘤模型中，其療效均優於抗 PD-1 和 HPK1 抑制劑。敬請期待。您將會聽到更多關於我們口服免疫療法的消息，我們認為這種療法將優於其他療法，並且在對檢查點阻斷療法無效的情況下也非常有用。所以我們對這項資產充滿熱情。

Andrew Berens, Leering Partners.

安德魯貝倫斯，Leering Partners。

Hi, good morning, everyone. This is Amanda on for Andy. Thanks for taking our question. We wanted to know what you've learned about drug-drug interactions with vepdeg that gives you confidence you won't be seeing similar interactions with the new degraders. I mean, there's something (inaudible) holds or how they're metabolized in different or similar ways.T hanks so much.

大家早安。這裡是阿曼達替安迪報道。感謝您回答我們的問題。我們想知道您在使用 vepdeg 治療藥物時，對藥物交互作用有哪些了解，從而確信不會在使用新的降解劑時出現類似的相互作用。我的意思是，它們之間肯定存在某種（聽不清楚）聯繫，或者說它們的代謝方式可能不同或相似。非常感謝。

Yes. Thanks for the questions. I mean, in general, PROTACs are no different from small molecules in terms of how you'd analyze them for DDIs. Every single molecule is different. They get metabolized differently. They interact with other molecules differently. So there's not a generic answer on PROTACs because every single PROTAC is going to be unique and different.

是的。謝謝大家的提問。我的意思是，總的來說，PROTAC 在藥物交互作用分析方面與小分子藥物並無不同。每個分子都各不相同。它們代謝方式不同。它們與其他分子的相互作用方式不同。因此，PROTAC 沒有通用的答案，因為每個 PROTAC 都是獨一無二的。

So yes, some compounds like many drugs, you look at to see how they're metabolized to see if they have a drug-drug interaction, you might see some of that, you might not. That's exactly what we're seeing with PROTAC. So there's no difference between a PROTAC and its DDI potential versus any small molecule.

所以，是的，有些化合物，例如很多藥物，你需要觀察它們的代謝情況，看看它們是否會發生藥物相互作用，你可能會看到一些，也可能不會。這正是我們在 PROTAC 中看到的情況。因此，PROTAC 與其 DDI 潛力與任何小分子之間沒有區別。

Got it. Thank you.

知道了。謝謝。

There are no further questions. I will now turn the call back over to Mr. John Houston for closing remarks.

沒有其他問題了。現在我將把電話交還給約翰·休斯頓先生，請他作總結發言。

Well, thank you very much, and thanks for everybody's great questions. As you can tell, we're very excited about this next wave of programs coming through our early development pipeline, and we're going to be excited to tell you more about them in the coming months. We've got a lot of interesting data coming out. So again, thank you for your time.

非常感謝，也感謝大家提出的精彩問題。正如你所看到的，我們對即將進入早期開發階段的下一批專案感到非常興奮，我們將在接下來的幾個月裡很高興地向你詳細介紹這些專案。我們有很多有趣的數據即將發布。再次感謝您抽出時間。

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

女士們、先生們，今天的電話會議到此結束。感謝各位的參與。您現在可以斷開連線了。