Kura Oncology Inc (KURA) 2024 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen. Welcome to the Kura Oncology third-quarter 2024 financial results call. (Operator Instructions) Also, today's call is being recorded. Now at this time, I'll turn things over to Mr. Pete De Spain, Head of Investor Relations.

女士們、先生們，午安。歡迎參加 Kura Oncology 2024 年第三季財務業績電話會議。（操作員說明）此外，今天的通話正在錄音。現在這個時候，我會把事情交給投資人關係主管 Pete De Spain 先生。

Great. Thank you, Bo. Good afternoon, and welcome to Kura Oncology's Third Quarter 2024 Conference Call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer; and Tom Doyle, our Senior Vice President of Finance and Accounting. Dr. Mollie Leoni, our Executive Vice President of Clinical Development, is also with us and available to answer.

偉大的。謝謝你，博。下午好，歡迎參加 Kura Oncology 2024 年第三季電話會議。與我一起參加電話會議的還有我們的總裁兼執行長 Troy Wilson 博士；以及我們的財務和會計高級副總裁 Tom Doyle。我們的臨床開發執行副總裁 Mollie Leoni 博士也與我們在一起並可以回答問題。

Before I turn the call over to Dr. Wilson, I'd like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results.

在我將電話轉交給威爾遜博士之前，我想提醒您，今天的電話會議將包括基於當前預期的前瞻性陳述。此類陳述代表管理階層截至目前的判斷，可能涉及可能導致實際結果與預期結果有重大差異的風險和不確定性。

Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy.

請參閱 Kura 向 SEC 提交的文件，這些文件可從 SEC 或 Kura Oncology 網站上獲取，以了解有關可能影響該公司的風險因素的資訊。現在，我將把電話轉給特洛伊。

Thank you, Pete, and thank you all for joining us. We continue to generate what we believe is a robust clinical data package to support the broad development of our menin inhibitor program, beginning with ziftomenib.

謝謝你，皮特，也謝謝大家加入我們。我們將繼續產生我們認為可靠的臨床數據包，以支持我們的 menin 抑制劑項目（從 ziftomenib 開始）的廣泛發展。

We believe ziftomenib is well positioned to transform the treatment of menin-dependent AML so that patients with cancer may lead better, longer lives. Earlier this week, 2 abstracts reporting preliminary data from our KOMET-007 combination trial of ziftomenib were posted on the website of the American Society of Hematology.

我們相信 ziftomenib 能夠很好地改變 menin 依賴性 AML 的治療方法，使癌症患者可以過上更好、更長的生活。本週早些時候，美國血液學會網站上發布了 2 份摘要，報告了我們的 ziftomenib KOMET-007 聯合試驗的初步數據。

As of the June 21 data cutoff, the abstracts continue to support a potential best-in-class safety and tolerability profile for ziftomenib as well as robust and durable activity in combination with standards of care, including venetoclax plus azacitidine as well as cytarabine plus donorubicin, commonly known as 7+3.

截至6 月21 日數據截止，摘要繼續支持齊夫托美尼潛在的同類最佳安全性和耐受性概況，以及與護理標準相結合的穩健和持久的活性，包括維奈托克加阿扎胞苷以及阿糖胞苷加供體黴素，俗稱7+3。

In the Phase Ia dose escalation portion of the KOMET-007 study, ziftomenib combined with ven/aza was well tolerated and demonstrated promising activity in relapsed/refractory patients. No DLTs or ziftomenib-induced QTc prolongation were reported.

在 KOMET-007 研究的 Ia 期劑量遞增部分中，齊夫托美尼合併 ven/aza 具有良好的耐受性，並在復發/難治性患者中表現出有希望的活性。沒有 DLT 或齊托美尼誘導的 QTc 延長的報告。

On-target differentiation syndrome was observed in 12% of patients, including 3 of 20 KMT2A rearranged patients and all patients had resolution of DS with appropriate management. Encouraging clinical activity was observed at both 200- and 400-milligram dose levels, including activity in previously venetoclax-exposed NPM1 mutant and KMT2A rearranged patients.

在 12% 的患者中觀察到了靶向分化綜合徵，其中包括 20 名 KMT2A 重排患者中的 3 名，並且所有患者都通過適當的治療獲得了 DS 緩解。在 200 毫克和 400 毫克劑量水平下觀察到令人鼓舞的臨床活性，包括先前暴露於 Venetoclax 的 NPM1 突變體和 KMT2A 重排患者的活性。

Updated results, including data from the 600-milligram cohorts will be reported at ASH. In the AML frontline adverse risk population, we are very encouraged by the safety and tolerability profile, rates of complete response and rates of MRD negativity.

更新的結果，包括 600 毫克隊列的數據，將在 ASH 上報告。在 AML 一線不良風險族群中，我們對安全性和耐受性、完全緩解率和 MRD 陰性率感到非常鼓舞。

Notably, no events of differentiation syndrome were reported at 200 or 400 milligrams, including among KMT2A rearranged patients. suggesting ziftomenib can be safely combined with induction chemotherapy. We're particularly encouraged by the fact that in the context of the very challenging 7 3 adverse risk AML patient cohorts, 100% of the 15 NPM1 mutant AML patients and 84% of the 19 KMT2A rearranged patients remained on study as of the data cutoff, 1 year after study start.

值得注意的是，在 200 或 400 毫克劑量下，沒有報告分化症候群事件，包括 KMT2A 重排患者。顯示齊夫托美尼可以安全地與誘導化療合併使用。我們尤其感到鼓舞的是，在極具挑戰性的7-3 不良風險AML 患者群組中，截至資料截止時，15 名NPM1 突變AML 患者中的100% 和19 名KMT2A 重排患者中的84% 仍在研究中，學習開始後1年。

Here, again, updated results, including data from the 600-milligram cohorts will be presented at ASH. We look forward to sharing a more mature data set, including data from more than 100 patients with NPM1 mutant or KMT2A rearranged acute myeloid leukemia next month.

在此，更新的結果，包括來自 600 毫克隊列的數據，將在 ASH 上公佈。我們期待下個月分享更成熟的數據集，包括來自 100 多名 NPM1 突變或 KMT2A 重排急性髓系白血病患者的數據。

In the meantime, I'm pleased to report that all 4 cohorts in the Phase Ia dose escalation portion of KOMET-007 have cleared the highest dose and advanced into the Phase Ib expansion study at 600 milligrams.

同時，我很高興地報告，KOMET-007 Ia 期劑量遞增部分的所有 4 個隊列均已清除最高劑量，並進入 600 毫克的 Ib 期擴展研究。

The Phase Ib expansion study includes multiple combination cohorts, most notably, ziftomenib plus ven/aza in newly diagnosed NPM1 mutant or KMT2A rearranged AML, as well as ziftomenib plus 7+3 in newly diagnosed NPM1 mutant or KMT2A rearranged AML, removing the requirement for patients to have high-risk disease.

Ib 期擴展研究包括多個組合隊列，最值得注意的是，在新診斷的NPM1 突變或KMT2A 重排AML 中使用ziftomenib 加ven/aza，以及在新診斷的NPM1 突變或KMT2A 重排AML 中使用ziftomenib加7+3，從而消除了對新診斷NPM1 突變或KMT2A 重排AML 的要求。

Each combination cohort is enrolling independently, and we expect to enroll at least 20 patients per cohort. We believe the Phase Ib expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with NPM1 mutant or KMT2A rearranged AML in both the fit and unfit populations.

每個組合隊列都是獨立招募的，我們預計每個隊列至少招募 20 名患者。我們相信，Ib 期擴展研究將繼續奠定基礎，幫助我們重新定義針對健康和不健康人群中新診斷的 NPM1 突變或 KMT2A 重排 AML 患者的當前護理標準。

We anticipate sharing preliminary data from the Phase Ib expansion study at a medical meeting in 2025. In addition to KOMET-007, we continue dosing patients in our ongoing KOMET-008 study of ziftomenib, in combination with additional standards of care, including the FLT3 inhibitor, gilteritinib, as well as FLAGIDDA and low-dose cytarabine.

我們預計在 2025 年的醫學會議上分享 Ib 期擴展研究的初步數據。除了 KOMET-007 之外，我們還在正在進行的 KOMET-008 ziftomenib 研究中繼續給患者用藥，並結合其他標準護理，包括 FLT3 抑制劑、gilteritinib、以及 FLAGIDDA 和低劑量阿糖胞苷。

Roughly half of all patients with relapsed or refractory NPM1 mutant AML have co-occurring FLT3 mutations, and the prognosis for these patients is poor. Preclinical data for ziftomenib in combination with FLT3 inhibitors has shown strong synergistic effects compared to either single agent alone.

大約一半的復發或難治性 NPM1 突變 AML 患者同時存在 FLT3 突變，這些患者的預後很差。ziftomenib 與 FLT3 抑制劑聯合使用的臨床前數據顯示，與單獨使用任何一種藥物相比，具有強大的協同作用。

When we look across the fit, unfit and FLT3 mutant AML frontline populations, we believe a best-in-class safety and efficacy profile and optimal pharmaceutical properties could enable ziftomenib to become a cornerstone of therapy for patients with acute leukemias.

當我們審視健康、不健康和 FLT3 突變 AML 第一線人群時，我們相信，一流的安全性和有效性以及最佳的藥物特性可以使齊夫托美尼成為治療急性白血病患者的基石。

Ultimately, our mission is to develop ziftomenib across the continuum of care for all eligible patients with acute leukemias whose disease is driven by the menin pathway. A critical first step toward that mission is establishing ziftomenib as the best-in-class menin inhibitor for patients with relapsed and refractory NPM1 mutant AML.

最終，我們的使命是為所有符合條件的急性白血病患者（其疾病由 menin 途徑驅動）開發 ziftomenib 的連續護理。實現這項使命的關鍵第一步是將 ziftomenib 確立為治療復發難治性 NPM1 突變 AML 患者的同類最佳 menin 抑制劑。

As a reminder, ziftomenib is the first and only investigational therapy to be granted breakthrough therapy designation for treatment of relapsed and refractory NPM1 mutant AML. NPM1-mutant AML represents approximately 30% of new AML cases annually and is a disease of significant unmet need for which there is no approved targeted therapy.

需要提醒的是，ziftomeni 是第一個也是唯一一個被授予突破性療法稱號的治療復發性和難治性 NPM1 突變 AML 的研究療法。NPM1 突變 AML 約佔每年新發 AML 病例的 30%，是一種需求未被滿足的疾病，尚無核准的標靶治療。

FDA awarded BTD based on data from our KOMET-001 trial, recognizing ziftomenib's potential as an innovative medicine for patients with this devastating disease. Supporting data from the Phase I portion of KOMET-001 were recently featured in a leading clinical oncology journal, The Lancet Oncology.

FDA 根據我們 KOMET-001 試驗的數據授予 BTD，認可齊夫托美尼作為治療這種毀滅性疾病患者的創新藥物的潛力。KOMET-001 I 期部分的支持數據最近發表在領先的臨床腫瘤學雜誌《柳葉刀腫瘤學》上。

We completed enrollment in the registration-directed portion of KOMET-001 earlier this year, enrolling more than 85 NPM1 mutant patients in fewer than 16 months. We look forward to sharing top line results from this pivotal study next year as we continue to work closely with FDA to expedite development and review of ziftomenib as a monotherapy.

我們在今年稍早完成了 KOMET-001 註冊導向部分的入組，在不到 16 個月的時間內入組了超過 85 名 NPM1 突變患者。我們期待明年分享這項關鍵研究的主要結果，因為我們將繼續與 FDA 密切合作，以加快齊夫托美尼作為單一療法的開發和審查。

Meanwhile, we've generated a growing body of preclinical data that supports opportunities for menin inhibitors beyond acute leukemias, including the potential for ziftomenib in the treatment of certain solid tumors.

同時，我們已經產生了越來越多的臨床前數據，支持 Menin 抑制劑在急性白血病之外的應用機會，包括齊夫托美尼在治療某些實體瘤中的潛力。

Last month, at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, we reported preclinical data supporting the combination of ziftomenib and imatinib for the treatment of advanced gastrointestinal stromal tumors or GIST.

上個月，在巴塞隆納舉行的EORTC-NCI-AACR 分子標靶和癌症治療研討會上，我們報告了支持齊夫托美尼和伊馬替尼聯合治療晚期胃腸道間質瘤或GIST 的臨床前數據。

The combination showed unexpectedly robust and durable antitumor activity in both imatinib-sensitive and imatinib-resistant GIST patient-derived xenograft models. And in all cases, the combination was significantly superior to imatinib monotherapy.

該組合在伊馬替尼敏感和伊馬替尼抗藥性的胃腸道間質瘤患者來源的異種移植模型中顯示出出乎意料的強大和持久的抗腫瘤活性。在所有情況下，聯合療法均明顯優於伊馬替尼單一療法。

Mechanistically, the data reveal a KIT-dependent mechanism with ziftomenib and imatinib combining to sharply reduce KIT expression and/or activity, effectively silencing both the ERK and AKT mTOR signaling pathways and driving robust cell cycle arestin apoptosis.

從機制上講，數據揭示了KIT 依賴性機制，齊夫托美尼和伊馬替尼聯合使用可大幅降低KIT 表達和/或活性，有效沉默ERK 和AKT mTOR 信號通路並驅動強勁的細胞週期arestin凋亡。

Given that imatinib is well established as the frontline standard of care in patients with GIST and generic versions are available, we believe imatinib represents a promising combination partner for ziftomenib. In August, we received FDA clearance of our investigational new drug application for ziftomenib for treatment of advanced GIST.

鑑於伊馬替尼已被確立為胃腸道間質瘤患者的一線治療標準，並且已有仿製藥，我們相信伊馬替尼代表了齊夫托美尼的一個有前途的組合夥伴。8 月，我們獲得 FDA 批准用於治療晚期 GIST 的 ziftomenib 新藥研究申請。

We're now prepared to initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST after imatinib failure in the first half of 2025. If successful, the potential opportunity in GIST appears to be agnostic to the mutational status of KIT in GIST, suggesting an opportunity to explore the combination for nearly all patients, including those in the frontline setting.

我們現在準備啟動一項概念驗證研究，評估齊夫托美尼和伊馬替尼在 2025 年上半年伊馬替尼失敗後對晚期 GIST 患者的療效。如果成功，GIST 中的潛在機會似乎與 GIST 中 KIT 的突變狀態無關，這表明​​有機會為幾乎所有患者（包括第一線患者）探索該組合。

Earlier this year, we reported preclinical data supporting the potential therapeutic utility of menin inhibitors in the treatment of diabetes. We are advancing multiple next-generation menin inhibitor drug candidates targeting diabetes and other metabolic diseases, and we expect to nominate the first of these next-generation development candidates in the first half of 2025.

今年早些時候，我們報告了臨床前數據，支持 menin 抑制劑在糖尿病治療中的潛在治療效用。我們正在開發多種針對糖尿病和其他代謝疾病的下一代 Menin 抑制劑候選藥物，我們預計將在 2025 年上半年提名這些下一代開發候選藥物中的第一個。

Now let's quickly turn our attention to our farnesyl transferase inhibitor programs. Despite the success of targeted therapies, a considerable need remains to drive enhanced antitumor activity, while blunting the effects of innate and adaptive resistance.

現在讓我們快速將注意力轉向我們的法呢基轉移酶抑制劑計劃。儘管標靶治療取得了成功，但仍迫切需要增強抗腫瘤活性，同時削弱先天性和適應性抵抗的影響。

We're developing our next-generation farnesyl transferase inhibitor, KO-2806, to address this need. 2806 was designed to improve upon the potency, pharmacokinetic and physical chemical properties of earlier FTI drug candidates.

我們正在開發下一代法尼基轉移酶抑制劑 KO-2806 來滿足這項需求。 2806 旨在改善早期 FTI 候選藥物的效力、藥物動力學和物理化學特性。

We've generated a growing body of preclinical and clinical data that demonstrate the potential for KO-2806 as a companion therapeutic to augment the antitumor activities of targeted therapies, including tyrosine kinase inhibitors, KRAS inhibitors and pan-RAS inhibitors.

我們已經產生了越來越多的臨床前和臨床數據，證明 KO-2806 作為伴隨療法增強標靶療法（包括酪胺酸激酶抑制劑、KRAS 抑制劑和泛 RAS 抑制劑）抗腫瘤活性的潛力。

Late last year, we began dosing patients with KO-2806 as a monotherapy in a Phase I dose escalation trial that we call FIT-001. FIT-001 uses an innovative design that enabled us to begin dose escalation of KO-2806 in combination cohorts very early in the study while continuing to dose escalate concurrently as a single agent.

去年年底，我們開始在一項稱為 FIT-001 的 I 期劑量遞增試驗中將 KO-2806 作為單一療法給患者服用。FIT-001 採用創新設計，使我們能夠在研究的早期就開始在聯合隊列中增加 KO-2806 的劑量，同時繼續作為單一藥物同時增加劑量。

Earlier this year, we dosed the first patient with KO-2806, in combination with cabozantinib in clear cell renal cell carcinoma. And in August, we dosed the first patient in combination with adagrasib in KRAS G12C mutated non-small cell lung cancer.

今年早些時候，我們對第一位患者進行了 KO-2806 聯合卡博替尼治療透明細胞腎細胞癌的治療。今年 8 月，我們為首例 KRAS G12C 突變非小細胞肺癌患者合併阿達拉西給藥。

As a reminder, the study of KO-2806 and adagrasib is supported by a clinical collaboration and supply agreement with Mirati, now a Bristol-Myers Squibb company. If successful, we believe KO-2806 could drive enhanced antitumor activity and become a combination partner to multiple targeted therapies in large solid tumor indications.

提醒一下，KO-2806 和 adagrasib 的研究得到了與 Mirati（現為 Bristol-Myers Squibb 公司）的臨床合作和供應協議的支持。如果成功，我們相信 KO-2806 可以增強抗腫瘤活性，並成為大型實體瘤適應症中多種標靶療法的組合夥伴。

Meanwhile, we continue to evaluate the combination of tipifarnib with the targeted therapy, alpelisib, in PIK3CA-dependent head and neck squamous cell carcinoma in a study we call KURANT-HN. We believe there may be a meaningful opportunity to combine an FTI with a PI3-kinase alpha inhibitor and look forward to presenting preliminary clinical data from the current-HN trial at a medical meeting in the first half of 2025. With that, I'll now turn the call over to Tom for a discussion of our financial results.

同時，我們在一項名為 KURANT-HN 的研究中繼續評估替比法尼 (tipifarnib) 與標靶療法 alpelisib 的聯合治療 PIK3CA 依賴性頭頸鱗狀細胞癌的效果。我們相信，將 FTI 與 PI3 激酶 α 抑制劑結合可能是一個有意義的機會，並期待在 2025 年上半年的醫學會議上展示目前 HN 試驗的初步臨床數據。現在，我將把電話轉給湯姆，討論我們的財務表現。

Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the third quarter of 2024. Research and development expenses for the third quarter of 2024 were $41.7 million compared to $29.3 million for the third quarter of 2023.

謝謝特洛伊，大家下午好。我很高興簡要概述我們 2024 年第三季的財務表現。2024 年第三季的研發費用為 4,170 萬美元，而 2023 年第三季的研發費用為 2,930 萬美元。

The increase in R&D expenses was primarily due to the increases in clinical trial costs related to our ziftomenib and KO-2806 programs. General and administrative expenses for the third quarter of 2024 were $18.2 million compared to $13.1 million for the third quarter of 2023.

研發費用的增加主要是因為與我​​們的 ziftomenib 和 KO-2806 計畫相關的臨床試驗成本增加。2024 年第三季的一般及管理費用為 1,820 萬美元，而 2023 年第三季為 1,310 萬美元。

Net loss for the third quarter of 2024 was $54.4 million compared to a net loss of $38.6 million for the third quarter of 2023. This included noncash share-based compensation expense of $8.3 million compared to $7.1 million for the same period in 2023.

2024 年第三季的淨虧損為 5,440 萬美元，而 2023 年第三季的淨虧損為 3,860 萬美元。其中包括 830 萬美元的非現金股份補償費用，而 2023 年同期為 710 萬美元。

As of September 30, 2024, we had cash, cash equivalents and short-term investments of $455.3 million compared to $424 million as of December 31, 2023. We believe that our cash, cash equivalents and short-term investments will be sufficient to fund our current operating plan into 2027. With that, I now turn the call back over to Troy.

截至 2024 年 9 月 30 日，我們的現金、現金等價物和短期投資為 4.553 億美元，而截至 2023 年 12 月 31 日為 4.24 億美元。我們相信，我們的現金、現金等價物和短期投資將足以為我們目前到 2027 年的營運計畫提供資金。說完，我現在把電話轉回特洛伊。

Thanks, Tom. Before closing, I'd like to thank -- I'd like to take this opportunity to welcome Dr. Michael Vasconllis to our Board of Directors. Mike is an accomplished biopharmaceutical executive with more than 25 years of oncology drug development experience and industry leadership.

謝謝，湯姆。在結束之前，我要感謝——我想藉此機會歡迎 Michael Vasconllis 博士加入我們的董事會。Mike 是一位卓有成就的生物製藥主管，擁有超過 25 年的腫瘤藥物開發經驗和產業領導地位。

His extensive experience in R&D and regulatory affairs, combined with his leadership across both large and emerging companies are invaluable as we advance our menin inhibitor and FTI programs to market while continuing to create value for patients and shareholders.

他在研發和監管事務方面的豐富經驗，加上他在大型和新興公司的領導力，對於我們將menin 抑制劑和FTI 項目推向市場，同時繼續為患者和股東創造價值而言，是非常寶貴的。

Now before we jump into the question-and-answer session, let me lay out our anticipated upcoming milestones. For our menin inhibitor program, present updated data from the KOMET-007 trial of ziftomenib in combination with ven/aza and 7+3 at ASH in December 2024, report top line results from the KOMET-001 registration-directed trial of ziftomenib in NPM1 mutant relapsed/refractory AML in early 2025,

現在，在我們進入問答環節之前，讓我列出我們預期即將到來的里程碑。對於我們的menin 抑制劑項目，提供2024 年12 月在ASH 上的ziftomenib 聯合ven/aza 和7+3 的KOMET-007 試驗的最新數據，報告ziftomenib 在NPM1 中的KOMET-001 註冊指導試驗的頂線結果2025 年初突變復發/難治性 AML，

present preliminary data from the Phase Ib expansion portion of KOMET-007 at a medical meeting in 2025, initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST in the first half of 2025 and nominate a next-generation menin inhibitor development candidate targeting diabetes in the first half of 2025.

在2025 年的一次醫學會議上展示KOMET-007 Ib 期擴展部分的初步數據，在2025 年上半年啟動一項概念驗證研究，評估ziftomenib 和伊馬替尼對晚期GIST 患者的療效，並提名下一代menin 2025 年上半年針對糖尿病的抑制劑開發候選人。

For our farnesyl transferase inhibitor programs, identify the maximum tolerated dose for KO-2806 as a monotherapy by the end of this year, initiate one or more expansion cohorts for the combination of KO-2806 and cabozantinib in renal cell carcinoma in the first half of 2025 and present data from the current HN trial of tipifarnib in combination with alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma in the first half of 2025.

對於我們的法呢基轉移酶抑制劑項目，將在今年年底前確定KO-2806 作為單一療法的最大耐受劑量，並在今年上半年啟動一個或多個KO-2806 和卡博替尼聯合治療腎細胞癌的擴展隊列。

With that, Bo, we're now ready for questions.

Bo，我們現在準備好提問了。

Li Watsek, Cantor.

李·瓦塞克，康托爾。

On the progress. Troy, I guess, how are you thinking about the potential of using MRD negativity as part of the frontline endpoints? And then for the MRD data, negativity data that was just presented in your ASH abstract, is there any difference in the methodology used by you versus your peers?

論進展。Troy，我想，您如何看待使用 MRD 陰性作為前線終點的一部分的潛力？那麼對於 MRD 數據，也就是您剛剛在 ASH 摘要中提出的負面數據，您與同儕使用的方法有什麼不同嗎？

Yes. Great question, Li. I'll give you my answer, and then I'll ask Mollie to comment if she -- if she can. So for everybody's benefit, I mean, the base case scenario for these frontline studies is that you're using survival as the endpoint. There may be an opportunity to use MRD negativity as a surrogate endpoint in an accelerated design, but I wouldn't consider that the base case.

是的。很好的問題，李。我會給你我的答案，然後我會請莫莉發表評論，如果她——如果她可以的話。因此，為了每個人的利益，我的意思是，這些第一線研究的基本案例場景是使用生存作為終點。可能有機會在加速設計中使用 MRD 陰性作為替代終點，但我不認為這是基本情況。

I think although there's good evidence to support it, that's not yet sort of a path that has been given the green light by the health authorities. It is something that we intend on discussing with them here in the relatively near future.

我認為，儘管有充分的證據支持這一點，但這還不是衛生當局批准的道路。我們打算在不久的將來在這裡與他們討論這個問題。

So I think, Li, we'll be able to come back to you and others on this call probably early next year with an update on the regulatory strategy, the trial design and endpoints. We're certainly going to try to reach for that. I don't know if we'll be successful.

所以我認為，李，我們可能會在明年初透過這次電話會議向您和其他人提供有關監管策略、試驗設計和終點的最新資訊。我們當然會努力實現這個目標。我不知道我們是否會成功。

I think we can make a strong case, but we're using survival as the base case and MRD negativity, excuse me, as the upside case. I'll let Mollie add her thoughts to that. And Mollie, if you could also maybe comment to Lee's question on how our methodology may differ from others.

我認為我們可以提出一個強有力的案例，但我們使用生存作為基本案例，而 MRD 負面（請原諒）作為上行案例。我會讓莫莉添加她的想法。莫莉（Mollie），您是否也可以對李提出的關於我們的方法與其他方法有何不同的問題發表評論。

Sure. So Troy is exactly right. While we know that we'll be able to use a survival endpoint in each of the frontline indications we wish to pursue. MRD negativity is a clear and obvious new way to be looking at the benefit for these patients. We've seen it in other studies as they're pursuing their indications turn out to be an excellent surrogate.

當然。所以特洛伊是完全正確的。雖然我們知道我們將能夠在我們希望追求的每個一線適應症中使用生存終點。MRD 陰性是一種明確且明顯的新方法來看待這些患者的益處。我們在其他研究中看到了這一點，因為他們正在追求他們的適應症，結果證明這是一個很好的替代品。

So we do think there's a good argument to be made with the health authorities to use it as part of the study, but how we can use it and to what extent it would be able to be allowed to be used as an endpoint is very much up for discussion and nothing we are able to confirm or deny at this point because we have yet to have those discussions.

因此，我們確實認為，可以向衛生當局提出一個很好的論據，將其用作研究的一部分，但我們如何使用它以及在多大程度上可以允許將其用作終點是非常重要的。 ，目前我們無法確認或否認任何內容，因為我們尚未進行這些討論。

With regards to our MRD data in our abstracts, you'll notice we were more quiet about it in the relapsed/refractory setting due to the fact that it's -- we get less samples in that setting, and they're a much more varied type of methodology used to assess them, as you might imagine.

關於我們摘要中的 MRD 數據，您會注意到我們在復發/難治性環境中對此更加安靜，因為我們在該環境中獲得的樣本較少，而且它們的多樣性要大得多正如您可能想像的那樣，用來評估它們的方法類型。

So what our plan to do is to actually do a central analysis of those samples so that we can actually give a uniform answer to what our MRD negativity looks like in these particular patients. Frontline setting, we did provide the local test results.

因此，我們的計劃是對這些樣本進行集中分析，以便我們能夠對這些特定患者的 MRD 陰性情況給出統一的答案。前線設置，我們確實提供了當地的測試結果。

They are done more consistently because they're used to make standard of care decisions with regards to transplant, et cetera. So we did provide those site-based tests, but we do plan also on running those centrally so that we can give a much more uniform result on the MRD negativity.

它們的執行更加一致，因為它們用於制定有關移植等的標準護理決策。因此，我們確實提供了這些基於站點的測試，但我們也計劃集中運行這些測試，以便我們可以針對 MRD 陰性給出更統一的結果。

Okay. And then for the 6 mg data that you'll present at ASH, I just wonder if you can give us a sense of number of patients, follow-up and what types of data that we might see?

好的。然後，對於您將在 ASH 上展示的 6 毫克數據，我只是想知道您能否讓我們了解患者數量、隨訪情況以及我們可能會看到什麼類型的數據？

Yes. Li, thanks for that. So we've said we're anticipating showing data on more than 100 patients at this point. That will -- I think you can see by the abstract, we're kind of halfway there. You'll see additional patients at the different dose levels.

是的。李，謝謝你。所以我們說過，我們預計此時會顯示 100 多名患者的數據。我想你可以從摘要中看出，我們已經完成了一半。您會看到更多處於不同劑量水平的患者。

We're planning on really updating every patient on the study as of their status with respect to response as well as duration of any clinical benefit. In terms of what to expect, given that the activity is pretty robust at 200 and 400, we're expecting to see sort of pretty consistent activity.

我們計劃真正更新研究中的每位患者的反應狀況以及任何臨床效益的持續時間。就預期而言，鑑於 200 和 400 的活動相當強勁，我們預計會看到相當一致的活動。

We get asked a lot, do we expect a dose response? Not clear one expects a dose response with these high levels of activity. But something that you'll see is we actually do see interestingly a dose response with respect to safety and tolerability, i.e., as you go higher in dose, the safety and tolerability actually improves, which might seem counterintuitive, but that helps to support, as you know, we've moved forward now into the expansion cohorts at 600 milligrams across all the cohorts, and that's partly driven by activity.

我們常被問到，我們是否期望劑量反應？尚不清楚這些高活性水平會產生劑量反應。但你會看到的是，我們實際上確實有趣地看到了安全性和耐受性方面的劑量反應，即，當劑量增加時，安全性和耐受性實際上會提高，這可能看起來違反直覺，但這有助於支持，如您所知，我們現在已將所有隊列的劑量調整為 600 毫克，部分是由活動推動的。

It's also a significant component of safety and tolerability. So you'll see that -- you'll see sort of that -- it will actually be, I think, a meaningful update even relative to what you see in the abstracts.

它也是安全性和耐受性的重要組成部分。所以你會看到——你會看到類似的情況——我認為，即使相對於你在摘要中看到的內容，這實際上也是一個有意義的更新。

Jonathan Chang, Leerink Partners.

喬納森·張 (Jonathan Chang)，Leerink 合夥人。

As we're starting to see longer-term data for zifto and other menin inhibitors in the space, how has that impacted your thinking on what the opportunity could be for the class? And what do you see as the key factors determining how long patients can stay on treatment and benefit?

當我們開始看到該領域 zifto 和其他 menin 抑制劑的長期數據時，這對您對該類機會的思考有何影響？您認為決定患者能夠接受治療多長時間並受益的關鍵因素是什麼？

Yes, Jonathan, thanks for that question. That's actually -- while I appreciate that there are a significant number of folks that sort of want to get into the scrum of comparing one relapsed/refractory data set against another, one of the big take-home messages from our abstract is something I think you're alluding to, which is the -- what's beginning to emerge in the frontline setting.

是的，喬納森，謝謝你提出這個問題。事實上，雖然我很欣賞有很多人想要將一個復發/難治性資料集與另一個資料集進行比較，但我認為我們摘要中最重要的資訊之一是你提到的，這就是前線環境中開始出現的情況。

So just for everybody's benefit, if you go and you read the abstract for the frontline 7+3, you'll notice as of the data cutoff in June, 15 out of 15 NPM1 mutant patients and 16 out of 19 KMT2A rearranged patients remained on study, on therapy as of the data cutoff.

因此，為了大家的利益，如果您閱讀前線7+3 的摘要，您會注意到截至6 月份的數據截止，15 名NPM1 突變患者中的15 名和19 名KMT2A 重排患者中的16 名仍處於治療狀態研究，截至資料截止時的治療。

And for some of those patients, that study had been going at that point for a year. So what we've said consistently, Jonathan, is there is clearly a significant unmet need in the relapsed/refractory population. Those patients are in dire need of options.

對於其中一些患者來說，這項研究當時已經進行了一年。因此，喬納森，我們一直在說的是，復發/難治性人群顯然存在顯著的未滿足需求。這些患者迫切需要選擇。

But as one thinks about the commercial opportunity, clearly, if we can intercept patients early in their treatment journey and provide clinical benefit, whether that is in the form of continuation therapy, i.e., they get a response, they stay on ziftomenib, don't necessarily go to transplant or in the alternative, they get a response, they go to transplant and then they go back on zifto in a post-transplant maintenance. That's what we're seeing, we think, beginning to emerge in the 7+3 adverse risk frontline population.

但當人們想到商業機會時，顯然，如果我們能夠在患者治療過程的早期攔截並提供臨床益處，無論是持續治療的形式，即他們得到反應，他們繼續服用齊夫托美尼，不一定要進行移植，或在替代方案中，他們會得到反應，他們會進行移植，然後在移植後維持中重新使用zifto。我們認為，這就是我們所看到的，在 7+3 不利風險一線人群中開始出現。

The fact that you have 90-plus percent of the patients, again, as of the data cutoff, staying on study, that's not even survival, right? That's on study. That's significant. I think that the way I've always thought about it is adverse risk 7+3 is about as hard as it gets in the frontline setting.

事實上，截至數據截止時，90％以上的患者仍在繼續研究，這甚至不是生存，對吧？那是在學習中這很重要。我認為我一直認為逆風險 7+3 是在前線環境中最困難的。

We're hopeful that, that trend continues now that we're in the expansion cohorts for the frontline 7+3 without adverse risk, i.e., all comers as well as the frontline ven/aza. If we can take these frontline patients, keep them on in a response and keep them on therapy for a year, 18 months, potentially even longer, that's where you really begin to see significantly inflecting the disease.

我們希望這種趨勢能夠持續下去，因為我們處於前線 7+3 的擴展隊列中，沒有不利風險，即所有來者以及前線 ven/aza。如果我們能夠接收這些前線患者，讓他們繼續接受治療一年、18 個月，甚至可能更長，那麼你就真正開始看到疾病發生顯著變化。

And that's what in our thinking and our models really helps drive the commercial case. And I think we're excited to share with you the update for both the relapsed/refractory and the frontline, but that frontline picture is beginning to come into focus. And I think it looks pretty attractive relative to the competition.

這就是我們的思維和模型真正有助於推動商業案例的原因。我認為我們很高興與您分享復發/難治性和前線患者的最新情況，但前線情況開始成為焦點。我認為相對於競爭對手來說它看起來相當有吸引力。

Jason Zemansky, Bank of America.

傑森澤曼斯基，美國銀行。

Congratulations on the progress. Regarding the combination updates at ASH, what should we be thinking in terms of benchmarking a win here? Is safety still the focus? Or do you expect the data at that point to be mature enough to gain key insights into efficacy? And then a follow-up.

祝賀取得的進展。關於 ASH 的組合更新，我們應該考慮什麼來衡量這裡的勝利？安全仍然是重點嗎？或者您期望此時的數據足夠成熟，能夠獲得對功效的關鍵見解？然後是後續行動。

Yes. So let's start with that, Jason. And Mollie, maybe you want to take Jason's question in terms of how we think about benchmarking. Maybe we can start with the relapsed/refractory and then we can talk a little bit about the frontline and sort of what the benchmarks would be.

是的。那麼就讓我們從這個開始吧，傑森。莫莉，也許你想回答傑森關於我們如何看待基準測試的問題。也許我們可以從復發/難治性開始，然後我們可以談談前線以及基準是什麼。

Sure. Realistically, in the relapsed/refractory setting, these patients have, for the most part, failed venetoclax. And as we know, that's an extremely poor prognostic factor for doing well on any therapy. For KMT2A, you'd probably set the bar at less than 10% potential response rate for NPM1 slightly higher, but the data tends to suggest that overall, the survival would only be 2.4 months or so in these particular subsets of patients. So that helps see how bleak the situation is.

當然。實際上，在復發/難治性情況下，這些患者大部分都未能使用維奈托克。正如我們所知，對於任何治療效果良好來說，這都是一個極差的預後因素。對於 KMT2A，您可能會將 NPM1 的潛在緩解率設定為略高一些，低於 10%，但數據往往表明，總體而言，這些特定患者亞群的生存期僅為 2.4 個月左右。這有助於了解情況有多黯淡。

And so we think any improvement, obviously, over that would be very significant. But as you point out, really, the goal is safety and tolerability with a Phase I dose escalation. And the fact that we've been able to safely escalate through the 600-milligram dose without DLTs. And as Troy referred to, see not only the ability to escalate safely, but to see improved safety as we escalate is an extremely strong sign that we're getting good activity as we increase in doses. Troy, is there anything you would add?

因此，我們認為任何改進顯然都將是非常重要的。但正如您所指出的，實際上，目標是第一階段劑量遞增的安全性和耐受性。事實上，我們已經能夠在不使用 DLT 的情況下安全地增加 600 毫克劑量。正如特洛伊所提到的，不僅要看到安全升級的能力，而且要看到隨著我們升級而安全性的提高，這是一個非常強烈的跡象，表明我們隨著劑量的增加而獲得了良好的活動。特洛伊，你還有什麼要補充的嗎？

No, not to that, Mollie. But maybe we could -- you could help set expectations for frontline and how we think about that in the adverse risk population.

不，不是這樣，莫莉。但也許我們可以——你可以幫助設定對前線的期望，以及我們如何看待不良風險族群的期望。

Absolutely. So our best comparison for the frontline is the Vyxeos control arm, which put the response rate at about, for a composite response rate at about 60%. So that would be your CR, your complete response, your complete response with partial hematologic recovery and your complete response with incomplete hematologic recovery.

絕對地。因此，我們對前線的最佳比較是 Vyxeos 控制臂，它的響應率約為 60%，綜合響應率約為 60%。這就是您的 CR、您的完全緩解、部分血液學恢復的完全緩解以及血液學不完全恢復的完全緩解。

So about 60% there and an overall survival of about 6 months. So again, in these adverse risk patients, not a good setting to see. But again, we're seeing excellent ability to be able to escalate the dose. These patients are staying on for very significant periods of time.

約有 60% 的患者存活，總存活期約 6 個月。再說一次，對於這些有不良風險的患者來說，這不是一個好的環境。但我們再次看到了增加劑量的出色能力。這些患者要住院很長一段時間。

As Troy alluded to, very few have come off study even in our 200-milligram cohort, which has been going on for well over a year. So, so far, I think we're seeing signs that make us encouraged to keep moving forward.

正如特洛伊所提到的，即使在我們的 200 毫克隊列中，也很少有人退出研究，該研究已經持續了一年多。所以，到目前為止，我認為我們看到了鼓勵我們繼續前進的跡象。

Got it. That's helpful. And maybe to circle back on your comments on tolerability and safety. The team has been guiding away from a 0% DS rate, which makes sense. But I'm curious, is there a level that you think would be especially encouraging in both the 7+3 and ven/aza settings?

知道了。這很有幫助。也許再回顧一下您對耐受性和安全性的評論。團隊一直在指導遠離 0% DS 率，這是有道理的。但我很好奇，您認為在 7+3 和 ven/aza 設定中是否有一個特別令人鼓舞的等級？

And is there a ceiling here as well?

這裡也有上限嗎？

Go ahead, Mollie. Why don't you take that?

來吧，莫莉。為什麼不接受那個呢？

Sure. Yes, we traditionally thought that as long as it was easily controllable, easily addressed, 20% or less DS rate is extremely tolerable. What I always like to remind people is that for the grading of differentiation syndrome, Grade 3 simply means that a patient was hospitalized for the event.

當然。是的，我們傳統上認為只要容易控制、容易解決，20%或更低的DS率是非常可以容忍的。我總是想提醒人們的是，對於分化症候群的分級，3級僅僅意味著病人因該事件而住院。

And in these patients, they're extremely fragile and tend to have fevers of unknown significance, and other symptoms that might need urgent intervention, they're hospitalized all the time. So a Grade 3DS is not necessarily associated with extremely severe symptoms.

在這些患者中，他們極度脆弱，往往會出現不明程度的發燒，以及其他可能需要緊急幹預的症狀，他們一直住院。因此，3DS 級不一定與極為嚴重的症狀相關。

And what we're seeing is grades 2 and 3DS that are very easily controlled. And what's different from the monotherapy is it doesn't even appear that we need to interrupt drug to be able to control them. Steroids and supportive care do seem to be sufficient.

我們看到的是非常容易控制的 2 級和 3DS。與單一療法的不同之處在於，我們甚至不需要中斷藥物來控制它們。類固醇和支持治療似乎確實足夠了。

So just to summarize, a reasonable severity level, probably about 20% and with the ability to treat easily and quickly get these patients continued on therapy is where we would set the bar.

總而言之，合理的嚴重程度（可能約為 20%）以及能夠輕鬆快速地治療這些患者並繼續接受治療的能力是我們設定的標準。

I'll just add to that. Yes, Jason, I'll just add to that. You'll expect to see when we give the full data, the DS rate drop to single-digit percentages. So I think we're encouraged. We've seen it primarily, as Mollie indicated in the KMT2 rearranged in the relapsed/refractory setting, seems to be well managed with these combinations.

我就補充一下。是的，傑森，我補充一下。您會期望看到，當我們提供完整數據時，DS 率會下降到個位數百分比。所以我認為我們受到了鼓勵。正如 Mollie 在 KMT2 中在復發/難治性環境中重新排列的那樣，我們主要看到了這一點，這些組合似乎得到了很好的管理。

Roger Song, Jefferies.

羅傑·宋，杰弗里斯。

Congrats for all the progress. Maybe one question related to the -- again, back to the potential pivotal plan, understanding you're discussing with the FDA right now.

祝賀所有的進步。也許有一個問題與——再次回到潛在的關鍵計劃，了解您現在正在與 FDA 討論。

Just curious about the timing for the pivotal study initiation versus your expansion data release. Do you need to see more dose-dependent efficacy at the higher dose or RP2D dose, 600 milligram versus the others? Or the current dose exposure or the total package sufficient for you to move into the pivotal once you finalize the design?

只是好奇關鍵研究啟動的時間與擴展資料發布的時間。與其他劑量相比，您是否需要在更高劑量或 RP2D 劑量（600 毫克）下看到更多的劑量依賴性療效？或者當前的劑量暴露或總劑量足以讓您在最終確定設計後進入關鍵階段？

Yes, Roger, thanks for the question. We already have those trials designed and are preparing to engage the health authorities in discussion. So if that helps address your question, as Mollie indicated, both the clinical activity and the safety and tolerability support that 600 milligrams is going to represent the dose that we recommend to FDA and other global health authorities as the dose in combination

是的，羅傑，謝謝你的提問。我們已經設計了這些試驗，並準備與衛生當局進行討論。因此，如果這有助於解決您的問題，正如 Mollie 指出的那樣，臨床活性以及安全性和耐受性都支持 600 毫克將代表我們向 FDA 和其他全球衛生當局推薦的組合劑量。

The health -- in addition to the dose selection, as Mollie indicated in an answer to one of the previous questions, we'll talk about endpoints. The powering, the design, I mean, that's really up to us, but the endpoints are a critical question, and we'll want to have a robust discussion there.

健康—正如莫莉在回答之前的問題時指出的那樣，除了劑量選擇之外，我們還將討論終點。我的意思是，動力、設計，這實際上取決於我們，但端點是一個關鍵問題，我們希望在那裡進行深入的討論。

We're currently thinking that we'll kick off those studies middle of next year. We believe there's an opportunity to combine ziftomenib in both 7+3 and ven/aza. And so we've designed trials for each of those 2 settings. Something that I think has been an interesting surprise to us is before we had dosed a patient, I don't think we really appreciated the opportunity in the frontline 7+3.

我們目前正在考慮將於明年年中開始這些研究。我們相信有機會在 7+3 和 ven/aza 中結合齊夫托美尼。因此，我們為這兩種設定分別設計了試驗。我認為對我們來說一個有趣的驚喜是，在我們給病人服藥之前，我認為我們並沒有真正珍惜在前線 7+3 的機會。

We sort of naively assumed patients would enter that cohort. They would go through 2 or 3 cycles, go to transplant, and then we might or might not get them back. That's really not what we're seeing. And you don't necessarily see it in the abstract, but you'll see it in the more fulsome data set. Patients are -- as Mollie indicated, they're staying on therapy for prolonged periods of time. Many of them are not going to transplant.

我們天真地假設患者會進入該隊列。他們會經歷 2 到 3 個週期，然後進行移植，然後我們可能會也可能不會把他們找回來。這確實不是我們所看到的。你不一定會在抽像中看到它，但你會在更豐富的資料集中看到它。正如莫莉所說，患者要長期接受治療。他們中的許多人不打算移植。

And we'll -- obviously, you need to see the data to understand this. But what that's led us to is an appreciation that whereas we may have thought that venetoclax, azacitidine was the much larger commercial opportunity, it is meaningful.

顯然，您需要查看數據才能理解這一點。但這讓我們認識到，雖然我們可能認為維奈托克、阿扎胞苷是更大的商業機會，但它是有意義的。

There's no question, and we'll pursue that. But 7+3 plus zifto appears to be nearly equally important. And we can see that in terms of enrollment. We can also see that just in terms of the clinical benefit profile that's beginning to emerge.

毫無疑問，我們將追求這一點。但 7+3 加上 zifto 似乎幾乎同樣重要。我們可以從入學率方面看到這一點。我們也可以從開始出現的臨床效益方面看到這一點。

So we're rolling all of that in, think about regulatory discussions in the early part of next year with a goal towards starting a combination study or studies middle of next year. Hopefully, that helps answer your question.

因此，我們正在推進所有這些工作，考慮在明年初進行監管討論，目標是在明年年中開始一項或多項聯合研究。希望這有助於回答您的問題。

Excellent. That's very helpful. And similar in terms of the time line regarding your -- the monotherapy NPM1, the data continue to be early 2025. And how should we think about the NDA filing for that monotherapy?

出色的。這非常有幫助。與單一療法 NPM1 的時間線類似，數據仍然是 2025 年初。我們應該如何看待該單一療法的 NDA 申請？

Yes. Another -- thank you for that question. So yes, once the data has been collected and cleaned and locked, we'll be in a position to provide the top line results. Within some period of time, measured by a few months, we'll be ready to submit that NDA to the agency. We would be looking for ideally, if all goes well with the submission and review for an approval in the second half of next year.

是的。另一個——謝謝你提出這個問題。所以，是的，一旦資料被收集、清理和鎖定，我們就能夠提供最重要的結果。在一段時間內（以幾個月為單位），我們將準備好向該機構提交 NDA。如果明年下半年提交和審查一切順利的話，我們將尋找理想的情況。

We'll be in a better position, Roger, to guide on that more specific timing next year when we're a little bit closer, but that should give you a rough idea of how to think about it.

羅傑，明年當我們更接近時，我們將處於一個更好的位置來指導更具體的時間，但這應該讓您大致了解如何考慮它。

Charles Zhu, LifeSci Capital.

Charles Zhu，生命科學資本。

Congrats on the progress. A couple from us. First, could you remind us what proportion of patients are adverse risk? And if you're including this a broader population beyond adverse risk in your Phase Ib expansion cohorts, how should we be thinking about enrollment speed there?

祝賀取得的進展。我們的一對。首先，您能否提醒我們有多少比例的患者有不良風險？如果您將這一超出不利風險的更廣泛人群納入 Ib 期擴展隊列中，那麼我們應該如何考慮那裡的入組速度？

Sure, Charles. Thanks for the questions. Mollie, can you speak to that sort of how we think about adverse risk versus the broader population? And then what, if anything -- I don't know, what, if anything, we can say about enrollment?

當然，查爾斯。感謝您的提問。莫莉，您能談談我們如何看待相對於更廣泛人群的不利風險嗎？然後，如果有的話，我不知道，關於入學，我們可以說些什麼？

Sure. So the way we've defined adverse risk is older patients with -- that may also have a complex cytogenetic or be treatment-related AML. And so that is how we define adverse risk. And realistically, it does comprise a fair amount of patients.

當然。因此，我們定義不良風險的方式是老年患者，他們也可能患有複雜的細胞遺傳學或與治療相關的 AML。這就是我們定義不良風險的方式。事實上，它確實包含相當數量的患者。

I don't know exact numbers, but my estimate would be about 30%. And with regards to how that affects enrollment being able to open it up, I can tell you that our enrollment in the a where we did have the adverse risk was extraordinarily brisk.

我不知道具體數字，但我估計大約是 30%。至於這如何影響招生能夠開放它，我可以告訴你，我們在確實存在不利風險的領域的招生非常活躍。

As you can see with the fact that we're able to now share 105 patients' worth of data after just over a year. It is now just as brisk, if not more so, as we move into the Phase Ib. So we are very encouraged by the excitement of the investigators and the desire of the patients to participate in our trials.

正如您所看到的，僅僅一年多後，我們現在就能夠共享 105 名患者的數據。當我們進入 Ib 階段時，現在的情況同樣活躍，甚至更加活躍。因此，研究人員的興奮和患者參與我們試驗的願望讓我們深受鼓舞。

Got it. Great. And regarding your ASH abstract, one clarifying question here. Is there a response deepening effect that we could be seeing at the lower 200-milligram dose given that it has longer follow-up versus the 400? And granted, these are very small end, but how should we be thinking about what appears to be a numerically inverse dose response between 200 and 400 milligrams in combination?

知道了。偉大的。關於您的 ASH 摘要，這裡有一個澄清問題。鑑於 200 毫克劑量比 400 毫克劑量有更長的追蹤時間，我們是否可以看到反應加深效應？當然，這些都是非常小的結果，但是我們應該如何考慮 200 至 400 毫克組合之間的數字逆劑量反應？

Mollie, do you want to take that?

莫莉，你想要那個嗎？

Sure. I think there's a combination of reasons. I think the biggest one is exactly as you point out, small numbers. And within those small numbers, when I look at the demographic details, there's varying baseline characteristics as well that can complicate the interpretation.

當然。我認為有多種原因。我認為最大的一個正如你所指出的，是小數字。在這些小數字中，當我查看人口統計詳細資訊時，也存在不同的基線特徵，這可能會使解釋變得複雜。

So you'll have different ECOG medians for different dose levels, different numbers of priors for different dose levels. So ultimately, it really does become the totality of evidence that helps us determine what the correct dose to carry forward should be.

因此，不同劑量等級的 ECOG 中位數不同，不同劑量等級的先驗數量也不同。因此，最終，它確實成為了幫助我們確定應繼續使用的正確劑量的全部證據。

And I should clarify that we have both the safety monitoring committee and an independent data monitoring committee that have been involved consistently throughout the study, not only in helping to decide when and if we should dose escalate, but also helping to decide what the totality of data tells us about the right dose for these patients.

我應該澄清的是，我們有安全監測委員會和獨立數據監測委員會，他們一直參與整個研究，不僅幫助決定何時以及是否應該增加劑量，而且還幫助決定總體劑量數據告訴我們這些患者的正確劑量。

And ultimately, both of those committees agreed that it is 600 milligrams that should be taken into the expansion cohort based upon not just the response rates, taking into account the baseline characteristics, especially the safety and tolerability, the count improvements, the speed to response, a myriad of different data pieces. So we -- while it could appear to be an inverse dose response, we don't think that is actually the reality of this particular study.

最終，這兩個委員會都同意，應將 600 毫克納入擴展隊列，不僅基於回應率，還考慮基線特徵，特別是安全性和耐受性、計數改進、反應速度，無數不同的數據片段。所以我們——雖然它可能看起來是一種反劑量反應，但我們認為這實際上並不是這項特定研究的現實。

Perfect. Great. Makes sense. If you could humor maybe just one last one from me. Regarding the on-target menin resistance mutations, we've heard a few things from some third parties out there, but could you clarify the assay that you used relative to one of your peers/competitor's assays when they reported their 38.7% rate of mutations and how similar or different are the sensitivities of those assays? And what does that mean with the rate of emergent menin resistance on zifto?

完美的。偉大的。有道理。如果你能幽默一下，也許只是我的最後一篇。關於目標menin 抗性突變，我們從一些第三方那裡聽到了一些消息，但是您能否澄清一下您使用的檢測方法與您的同行/競爭對手的檢測方法（當他們報告38.7% 的突變率時）的比較這些檢測的靈敏度有何相似或不同？這對於 zifto 上新出現的 menin 抗藥性意味著什麼？

So I think you're referring to the difference between digital droplet PCR and RT-PCR that we used. We also use different sources, DNA versus RNA for examining that data. However, the patients that we looked at for mutations would have been detectable at even a less sensitive assay.

所以我認為您指的是我們使用的數位液滴 PCR 和 RT-PCR 之間的差異。我們也使用不同的來源（DNA 與 RNA）來檢查這些數據。然而，我們所觀察的患者的突變即使在靈敏度較低的檢測中也能被檢測到。

So we didn't need digital droplet PCR in order to determine if these mutations were there. So we do think that our data is highly reliable and that we're able to compare to these other data. And remember, they were using the digital droplet PCR to determine if these were present at baseline rather than things that developed over time.

因此，我們不需要數位液滴 PCR 來確定這些突變是否存在。因此，我們確實認為我們的數據高度可靠，並且我們能夠與其他數據進行比較。請記住，他們使用數位液滴 PCR 來確定這些是否存在於基線，而不是隨著時間的推移而發展的東西。

In addition, we've obviously continued to do our work on this topic, and we have continued to confirm through more and more sensitive analyses that our findings are extraordinarily consistent with what we presented at EHA.

此外，我們顯然繼續在這個主題上開展工作，並且透過越來越多的敏感分析繼續確認我們的發現與我們在 EHA 上提出的內容非常一致。

Philip Nadeau, TD Cowen.

菲利普·納多，TD·考恩。

We were intrigued by your comments about safety improving for zifto as the doses increase. Is there a mechanistic rationale as to why safety should improve with increased exposure?

我們對您關於 zifto 隨著劑量增加安全性提高的評論感興趣。是否有機械原理來解釋為什麼安全性會隨著暴露量的增加而增加？

Yes, Phil, there is actually. And I'll let Mollie give you more color.

是的，菲爾，確實有。我會讓莫莉給你更多的色彩。

Yes. It's actually a little bit more obvious than you'd even think. We are seeing faster count recoveries with increased dose. Obviously, faster count recoveries mean these patients have less time to be susceptible to infections, have less time to be susceptible to bleeds, have less need for transfusions. So there does seem to be a very good basis for why we are seeing the improved safety at increased dose.

是的。它實際上比你想像的更明顯。我們看到隨著劑量的增加，計數恢復得更快。顯然，更快的計數恢復意味著這些患者容易受到感染的時間更短，容易出血的時間更短，對輸血的需求也更少。因此，似乎有一個很好的基礎來解釋為什麼我們看到增加劑量後安全性有所改善。

That is very helpful. And then second question on the next-generation menin inhibitors. I think you mentioned specifically that you will nominate a candidate for diabetes in the first half of 2025. Are there efforts underway to identify next-generation menin inhibitors to advance in heme malignancies as well?

這非常有幫助。然後是關於下一代 Menin 抑制劑的第二個問題。我想您特別提到您將在 2025 年上半年提名一名糖尿病候選人。是否正在努力尋找下一代 menin 抑制劑來治療血紅素惡性腫瘤？

Yes. Good question, Phil. There could be. I mean we have molecules. It's -- you always think your baby is the most beautiful, right? It's hard to imagine improving on zifto. The one thing you might say is, could we actually develop a molecule that was active against all the known gatekeeper mutations.

是的。好問題，菲爾。可能有。我的意思是我們有分子。你總是認為你的寶寶是最漂亮的，對嗎？很難想像在 zifto 上進行改進。你可能會說的一件事是，我們是否真的可以發展出對所有已知的看門人突變都有活性的分子。

We have such molecules. It's not obvious to us now that we're in combinations. And as Mollie said, we continue to see very, very low rates of induction of gatekeeper mutations that that's an advantage. So at the moment,

我們有這樣的分子。現在我們處於組合狀態對我們來說並不明顯。正如莫莉所說，我們繼續看到非常非常低的看門人突變誘導率，這是一個優點。所以此刻，

I would say we have the molecules, we're holding them and really putting the bets on zifto going into combinations initially in the front line as well as doing work, for example, with the FLT3 inhibitors. We are, however, looking at menin inhibitors potentially for other solid tumors.

我想說的是，我們擁有這些分子，我們正在持有它們，並真正把賭注押在 zifto 上，最初在第一線進行組合，並開展工作，例如與 FLT3 抑製劑合作。然而，我們正在尋找可能用於其他實體腫瘤的 menin 抑制劑。

And we put out what I think is some very nice preclinical data combining ziftomenib with imatinib in GIST. We're doing the work to determine, is that an isolated example? Or are there other solid tumor applications? And if there are, you want the optionality of having a distinct next generation menin inhibitor for those solid tumor applications. As we continue to do more work, Phil, we'll begin to fill that picture in probably next year.

我們發布了我認為結合齊夫托美尼和伊馬替尼治療胃腸道間質瘤的一些非常好的臨床前數據。我們正在努力確定這是一個孤立的例子嗎？或是有其他實體腫瘤應用嗎？如果有的話，您希望可以選擇為這些實體腫瘤應用提供獨特的下一代 menin 抑制劑。菲爾，隨著我們繼續做更多的工作，我們可能會在明年開始填補這一空白。

Peter Lawson, Barclays.

彼得·勞森，巴克萊銀行。

Just as we think about expectations for kind of prior then treated patients in the pivotal study, how should we think about that versus what we saw in the Phase I data that was published?

正如我們在關鍵研究中考慮對先前接受治療的患者的期望一樣，與我們在已發布的第一階段數據中看到的情況相比，我們應該如何考慮這一點？

Yes. Mollie, do you want to speak to Peter's question?

是的。莫莉，你想回答彼得的問題嗎？

Sure. Obviously, the published data was on a very small data set, and we'll continue to analyze the monotherapy data as we put out our Phase II data set as well and probably gain a better picture as to exactly what these patients look like post venetoclax failure and if we're able to resensitize and get these patients back able to respond to therapies.

當然。顯然，所發表的數據是在一個非常小的數據集上，我們將在發布 II 期數據集時繼續分析單一療法數據，並可能更好地了解這些患者在使用 Venetoclax 後的具體情況失敗以及我們是否能夠重新敏感並讓這些患者恢復對治療的反應。

In the combination setting, we will be presenting more data on that as we get to ASH. We do think that there is still the good potential for patients to respond post venetoclax failure. Again, is that due to our ability to resensitize these patients to venetoclax?

在組合設定中，我們將在 ASH 中提供更多相關數據。我們確實認為，患者在 Venetoclax 失敗後仍有良好的反應潛力。再說一次，這是因為我們有能力讓這些病人對維奈托克重新敏感嗎？

Is it a synergistic effect between the 2 molecules? We don't know. It's too early, but we'll continue to analyze the data. All I can say is we continue to be encouraged.

這是兩個分子之間的協同效應嗎？我們不知道。現在還為時過早，但我們將繼續分析數據。我只能說我們繼續受到鼓勵。

Perfect. Really interesting. On the 7+3 adverse risk patients, what would the duration of response? How could that differ between do you think the NPM1 versus the KMT2A patients?

完美的。真的很有趣。對於7+3不良風險患者，反應持續時間是多久？您認為 NPM1 患者與 KMT2A 患者有何不同？

Yes. Mollie, do you want to take that question as well?

是的。莫莉，你也想回答這個問題嗎？

What's nice is that the answer to this question is we don't know yet because all of these patients are realistically still ongoing therapy. So thankfully, we haven't reached our median duration of response for these groups. And we hope that it continues on that way. And so that this question continues to be difficult to answer.

令人高興的是，這個問題的答案我們還不知道，因為所有這些患者實際上仍在接受治療。值得慶幸的是，我們尚未達到這些群體的反應持續時間中位數。我們希望這種情況能夠持續下去。所以這個問題仍然很難回答。

There's no kind of fundamental difference do you think between the NPM1 and KMT2A patients?

您認為 NPM1 和 KMT2A 患者之間沒有根本差異嗎？

I do. I think KMT2A are much harder to permanently control. They have just a much more aggressive monocytic disease that is so invasive. But I think that's where a molecule like ziftomenib becomes so important because our drug is able to actually accumulate in tissues as well and find some of these areas

我願意。我認為 KMT2A 更難永久控制。他們只是患有一種更具侵襲性的單核細胞疾病，這種疾病具有強烈的侵襲性。但我認為這就是像齊夫托美尼這樣的分子變得如此重要的地方，因為我們的藥物實際上也能夠在組織中累積並找到其中一些區域

where the KMT2A rearranged cells have been able to already invade at the time of diagnosis even in the front line. So yes, definitely a fundamental difference in the level of aggression between the 2, but we hope that menin becomes -- menin inhibitors at least become the great equalizer for them.

即使在前線，KMT2A 重排細胞在診斷時就已經能夠侵入。所以，是的，兩者之間的攻擊性水平肯定存在根本差異，但我們希望 menin 成為——menin 抑製劑至少成為他們的偉大均衡器。

Justin Zelin, BTIG.

賈斯汀·澤林，BTIG。

Congrats on the progress. Maybe following up on an earlier question about resistance mutations. Would you look to do that analysis in your combination and earlier line studies? And just expectations there if you think that it might differ in those settings?

祝賀取得的進展。也許是在跟進之前關於抗性突變的問題。您是否希望在您的組合和早期的生產線研究中進行這種分析？如果您認為這些設定可能有所不同，那麼只是期望？

Mollie, do you want to take that?

莫莉，你想要那個嗎？

Yes. Obviously, in frontline settings, we don't expect to see at least a baseline existence of these resistance mutations, although they could very well be in your relapsed/refractory setting after exposure to other menin inhibitors.

是的。顯然，在前線環境中，我們預計至少不會看到這些抗藥性突變的基線存在，儘管它們很可能在暴露於其他 menin 抑制劑後出現在復發/難治性環境中。

But with regards to a differential ability to develop these mutations, once you get into combination, your risks are going to decrease enormously. It's the monotherapy that's really the big risk for developing these types of mutations

但就產生這些突變的差異能力而言，一旦組合起來，你的風險就會大大降低。單一療法確實是發生這些類型突變的最大風險

because you're just not hitting it hard enough, fast enough, and you're giving it time just like with bacteria to grow out resistant colonies. So I think that you're just going to see a decrease overall in these mutations becoming an issue for patients that are able to have successful outcomes on the combinations.

因為你擊打它的力道不夠、速度不夠快，你給了它時間，就像細菌生長出抗性菌落一樣。所以我認為你會看到這些突變的總體減少成為能夠透過組合獲得成功結果的患者的一個問題。

Brad Canino, Stifel.

布拉德·卡尼諾，斯蒂菲爾。

Just one for me. Wondering, given we've seen one of the peer med companies initiate a frontline trial in collaboration with one of the European cooperative groups.

只給我一個。很奇怪，因為我們已經看到一家同行醫療公司與歐洲合作團體之一合作發起了一項前線試驗。

Just what's your current thinking about employing a similar strategy? How do you think about the pros and cons of using such a collaboration versus, say, doing a full company-sponsored one?

您目前對採用類似策略有何想法？您如何看待使用這種合作與完全由公司贊助的合作相比的利弊？

Yes. Thanks, Brad, for the question. So cooperative groups play a really important role in the ecosystem. They do some terrific work. In our view, and you can see this reflected in the development plan, we are establishing data packages for safety, tolerability, combinability, clinical activity across a range of different combinations.

是的。謝謝布拉德提出的問題。因此，合作團體在生態系統中扮演著非常重要的角色。他們做了一些很棒的工作。在我們看來，您可以在開發計劃中看到這一點，我們正在建立一系列不同組合的安全性、耐受性、可組合性、臨床活動的資料包。

Much of the focus, obviously, in the run-up to ASH is around 7+3 and ven/aza. But hopefully, next year, we'll talk more about 008, which is gilteritinib, LDAC, FLAGIDDA. And so to the extent that for some of these perhaps either smaller opportunities or populations where it's more difficult to identify these patients for treatment, those are ideal for cooperative groups.

顯然，在 ASH 之前的大部分焦點都集中在 7+3 和 ven/aza 上。但希望明年我們能多談008，即gilteritinib、LDAC、FLAGIDDA。因此，對於其中一些可能機會較小或難以識別這些患者進行治療的人群來說，這些對於合作團體來說是理想的選擇。

And I think you really want to take full advantage. And in that context, you probably know we have a collaboration with LLS' pedal in the pediatric indications because they're huge unmet need, difficult to find those patients.

我認為你真的想充分利用這一優勢。在這種情況下，您可能知道我們與 LLS 的踏板在兒科適應症方面進行了合作，因為它們有巨大的未滿足需求，很難找到這些患者。

It's not a huge commercial opportunity, but it is unquestionably one of the most important things you can do. And we are very happy to be collaborating with LLS. The downside to a cooperative group study is it's their design, it's their timeline. They dictate data release.

這不是一個巨大的商業機會，但無疑是您可以做的最重要的事情之一。我們很高興與 LLS 合作。合作小組研究的缺點是他們的設計和時間表。他們決定數據發布。

They dictate how you interpret that data, any amendments you make to the study. I don't think you're going to see us using cooperative group studies for either our 7+3 or ven/aza trials because that's where 90% of the value is, to be honest, right? We all we all know this.

它們決定了您如何解釋這些數據以及您對研究所做的任何修改。我認為您不會看到我們在 7+3 或 ven/aza 試驗中使用合作小組研究，因為說實話，這才是 90% 的價值，對吧？我們都知道這一點。

The big money here is get patients on study right at the get-go and ideally keep them on 12, 18, perhaps even 24 months. So you're going to see us, Brad, do Ca-sponsored studies, but we'll continue to work and have studies planned for cooperative groups where those smaller indications may be appropriate. We'll do a mix of both.

這裡最重要的是讓患者從一開始就接受研究，最好讓他們持續 12、18、甚至 24 個月。所以你會看到我們，布拉德，進行加州資助的研究，但我們將繼續工作，並為合作團體計劃研究，這些較小的適應症可能是合適的。我們將兩者混合。

David Dye, UBS.

大衛戴伊，瑞銀集團。

This is Xiaochuan on for David. Congrats on the quarter. So I guess our first question is kind of like for the pin data, ziftomenib pivotal data in relapsed or refractory NPM1 mutated AML in early 2025. So just curious if you could set some expectations on the clinical meaningful efficacy as well as duration bar.

這是大衛的小川。恭喜本季。所以我想我們的第一個問題有點像是 2025 年初復發或難治性 NPM1 突變 AML 的 pin 資料、ziftomenib 關鍵資料。所以只是好奇您是否可以對臨床上有意義的功效和持續時間設定一些期望。

And the second one, I think for your ASH abstract for the ziftomenib plus aza cohort, so we saw there were around like 25% patients who actually have prior Menin inhibitor. So just curious if we are going to see the efficacy profile from the set of patients at the presentation? Yes, I think it's just like related to potentially like higher activity against some mutation resistance to the patient..

第二個，我認為對於 ziftomenib 加 aza 隊列的 ASH 摘要，我們看到大約 25% 的患者實際上曾經患有 Menin 抑制劑。那麼只是好奇我們是否能在演示中看到一組患者的療效概況？是的，我認為這與患者對某些突變抗性的潛在更高活性有關。

Sure. Thanks, Xiochuan, for the question. So with respect to the monotherapy pivotal data, I think even before we ever dosed a patient, we've always given the same guidance, which is the regulatory bar in our view, the bar to approval is 20% to 30% CR/CRh and 4 to 6 months median duration of response.

當然。謝謝小川的提問。因此，關於單一療法的關鍵數據，我認為即使在我們給患者用藥之前，我們也總是給出相同的指導，這在我們看來是監管門檻，批准的門檻是 20% 至 30% CR/CRh中位緩解持續時間為4 至6 個月。

I don't think I've ever varied from when I've been asked that question. Certainly, to this point, nothing has changed. Now that is the bar that the agency uses to consider approvability. As Mollie has already indicated to you, there are a lot of other factors.

我不認為我被問到這個問題的時候有什麼不同。當然，到目前為止，一切都沒有改變。現在，這是該機構用來考慮批准性的標準。正如莫莉已經向你指出的那樣，還有很多其他因素。

So -- and some of those have been spoken to by competitors of ours. So CRC rate, overall response rate, things such as that as well as safety and tolerability, it all factors in. But that's how we're continuing to think about the monotherapy data.

所以——我們的競爭對手已經談過其中一些問題。因此，CRC 率、整體緩解率等因素以及安全性和耐受性都是因素。但這就是我們繼續思考單一療法數據的方式。

As far as data on activity in patients who have experienced prior menin inhibitors, yes, there will be some additional data in the materials that are presented at ASH that in the relapsed/refractory setting, it's part of the story.

至於先前接受過 Menin 抑制劑的患者的活動數據，是的，在 ASH 上展示的材料中將會有一些額外的數據，在復發/難治性情況下，這是故事的一部分。

It is, as Mollie indicated, still kind of an evolving part of the story. Because these patients are -- because the patient population is so heterogeneous, i.e., ECOG status, lines of therapy, what they've seen previously, I think we can -- I don't think we yet fully have the rules of the road, but we are encouraged to see activity in patients who have progressed on prior menin inhibitors and learning what, if anything, can we do to increase that when we treat them with ziftomenib.

正如莫莉所指出的，這仍然是故事不斷發展的一部分。因為這些患者——因為患者群體是如此的異質性，即 ECOG 狀態、治療方案、他們以前見過的情況，我認為我們可以——我認為我們還沒有完全掌握道路規則，但我們很高興看到使用先前的menin 抑制劑取得進展的患者的活動，並了解當我們用齊夫托美尼治療他們時，我們可以做些什麼來增加這種活動（如果有的話）。

George Farmer, Scotiabank.

豐業銀行的喬治法默。

This is (inaudible) on for George. Can you hear me okay?

這是喬治的（聽不清楚）。你聽得到我說話嗎？

We can.

我們可以。

Okay. Great. Curious about your diabetes program and how this next gen menin inhibitor that we're going to get more information on next year is going to be different from diclomenib and from this other competitor molecule from which we expect some critical Phase II data by year-end?

好的。偉大的。對您的糖尿病計畫感到好奇，以及我們將於明年獲得更多資訊的下一代 Menin 抑制劑將如何不同於雙氯美尼和其他競爭對手分子，我們預計到年底將獲得一些關鍵的 II 期數據？

And I guess they'll be setting the benchmark for the potential of menin inhibition in diabetes and what you'll need to see from your own program eventually down the road. So in what ways are you hoping to be similar or differentiate from that other program? And then I have a follow-up.

我想他們將為糖尿病中的 Menin 抑制潛力設定基準，以及您最終需要從自己的計劃中看到的內容。那麼您希望在哪些方面與其他計劃相似或有所不同？然後我有一個後續行動。

Yes. Okay. Yes, great question. So in our hands, and when we do these experiments away from AML, whether it's GIST, whether it's diabetes, folks should understand we evaluate not only ziftomenib, but competitor compounds as well as next-generation compounds in our portfolio. So we try to get a holistic picture.

是的。好的。是的，很好的問題。因此，在我們手中，當我們在 AML 之外進行這些實驗時，無論是 GIST 還是糖尿病，人們應該明白我們不僅評估齊夫托美尼，還評估我們產品組合中的競爭對手化合物以及下一代化合物。所以我們試著獲得一個整體的了解。

And for example, in GIST, zifto is uniquely active in GIST. And we think in part due to its tissue penetrant. In diabetes, it also seems to be extremely active Francis Burrows, who is not with us on the call, who is our Senior Vice President of Translational Research, he characterizes zifto as it hits menin as hard as you can hit it. It provides very potent knockdown.

例如，在 GIST 中，zifto 在 GIST 中具有獨特的活性。我們認為部分原因在於它的組織滲透劑。在糖尿病方面，它似乎也非常活躍，弗朗西斯·伯羅斯（Francis Burrows）沒有與我們一起參加電話會議，他是我們轉化研究的高級副總裁，他將 zifto 描述為它對人類的打擊是最大的。它提供非常有效的擊倒。

It's a menin degrader, which is a property that is shared by some of the other compounds, not all. We're not I think we can actually say we probably don't have to hit menin quite as hard as one hits it with leukemia in order to drive the sort of pharmacology that you're seeing in the diabetes models that we showed at the ADA meeting in June.

它是一種menin降解劑，這是其他一些化合物（並非全部）所共有的特性。我們不是，我認為我們實際上可以說，我們可能不必像對待白血病那樣嚴厲地打擊男性，以推動我們在糖尿病模型中看到的那種藥理學作用，就像我們在糖尿病模型中看到的那樣。

As we think about the properties of a next-gen compound, most important is safety. safety and tolerability. In the type 2 setting, honestly, these patients are not that sick, right? They are -- we're not talking about leukemia patients. We're talking about diabetic patients.

當我們考慮下一代化合物的特性時，最重要的是安全性。安全性和耐受性。老實說，在第 2 型環境中，這些患者的病情並沒有那麼嚴重，對嗎？他們是——我們不是在談論白血病患者。我們談論的是糖尿病患者。

That's not to take anything away, but the hurdle for safety and tolerability is much higher. So you're going to see us put a real emphasis on not only activity in the appropriate animal models, but really trying to create as large a therapeutic window as we can.

這並不是要拿走任何東西，但安全性和耐受性的障礙要高得多。因此，您將看到我們不僅真正重視適當動物模型中的活動，而且真正努力創造盡可能大的治療窗口。

The other interesting thing, and we've benchmarked this against other compounds that you may be aware of. What we see with zifto is when you add zifto, it takes several weeks for the activity to kick in. When you remove zifto, it takes several weeks for the activity to decay.

另一件有趣的事情是，我們已經將其與您可能知道的其他化合物進行了基準測試。我們在 zifto 中看到的是，當您新增 zifto 時，活動需要幾週的時間才能啟動。當您去除 zifto 後，活性需要幾週的時間才會減弱。

Does that make sense? Yes, it does because this is an epigenetic mechanism. With certain other competitor compounds, you do not see that. As soon as you remove the competitor compounds, the pharmacology goes away almost immediately, suggesting that maybe that's not acting entirely viaenin.

這樣有道理嗎？是的，確實如此，因為這是一種表觀遺傳機制。對於某些其他競爭對手的化合物，您看不到這一點。一旦去除競爭化合物，藥理學幾乎立即消失，這表明這可能不完全是維埃寧的作用。

And so we're going to want to make sure we understand that as well. The final thing I'll say is there are very sophisticated parties out there that know this space, and we are not shy about consulting them on what they would want to see as far as preclinical and clinical data that would ultimately allow you to do the right sort of diabetes study.

因此，我們希望確保我們也理解這一點。我要說的最後一件事是，有非常成熟的各方了解這個領域，我們並不羞於諮詢他們希望看到的臨床前和臨床數據，這些數據最終將使您能夠做正確的糖尿病研究。

So we'll have much more to talk about that. Again, looking forward to nominating probably the first compound, maybe of a couple in diabetes first half of next year. And then happy to walk people through that data as it continues to evolve. And you said you had a follow-up.

所以我們將會有更多的話題來討論這個問題。再次期待提名第一個化合物，可能是明年上半年一對患有糖尿病的夫婦的化合物。然後很樂意引導人們了解這些不斷發展的數據。你說你有後續行動。

Yes. Very, very helpful color there. Does your current cash runway estimate include this early clinical work -- early Phase I work in diabetes as you enter the clinic?

是的。那裡的顏色非常非常有用。您目前的現金跑道估算是否包括這項早期臨床工作——當您進入診所時，早期針對糖尿病的一期工作？

Yes. Let me ask Tom actually if he can speak to that question.

是的。讓我實際上問湯姆他是否可以回答這個問題。

Thank you. It does -- our cash runway does include the meta next-generation work in diabetes.

謝謝。確實如此——我們的現金跑道確實包括糖尿病領域的下一代元研究。

And it appears Dr. Wilson, we have no further questions today. I'd like to turn the conference back to you, sir, for any closing comments.

看來威爾遜博士，我們今天沒有其他問題了。先生，我想將會議轉回給您，請您發表閉幕詞。

Thank you, Bo, and thank you all once again for joining our call today. We'll be participating across the pond at the Jefferies London Healthcare Conference in a couple of weeks, and look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Tom or me. Thank you all again, and have a good evening, everyone.

謝謝你，Bo，並再次感謝大家今天加入我們的電話會議。幾週後，我們將參加大洋彼岸的傑富瑞倫敦醫療保健會議，並期待在那裡見到你們。同時，如果您有任何其他問題，請隨時聯繫皮特、湯姆或我。再次感謝大家，祝大家晚上好。

Thank you, Dr. Wilson. Again, ladies and gentlemen, that will conclude the Kura Oncology Third Quarter Financial Results Call. Again, thanks so much for joining us, and we wish you all a great evening. Goodbye.

謝謝你，威爾遜博士。女士們先生們，庫拉腫瘤學第三季財務業績電話會議到此結束。再次非常感謝您加入我們，並祝大家有個愉快的夜晚。再見。