Agenus Inc (AGEN) 2023 Q3 法說會逐字稿

Good morning. My name is Jeannie, I will be your conference operator today. At this time, I would like to welcome everyone to the Agenus Q3 2023 Earnings Conference Call. (Operator Instructions) Zack Armen, you may begin your conference.

早安.我叫珍妮，今天我將擔任你們的會議操作員。此時，我歡迎大家參加 Agenus 2023 年第三季財報電話會議。 （操作員指示）Zack Armen，您可以開始會議了。

Thank you, operator, and thank you all for joining us today. Today's call is being webcast and will be available on our website for replay.

謝謝運營商，也謝謝大家今天加入我們。今天的電話會議正在進行網路直播，並將在我們的網站上重播。

I'd like to remind you that this call will include forward-looking statements, including statements regarding our clinical development, regulatory and commercial plans and time lines as well as time lines for data release and partnership opportunities among other updates. These statements are subject to risks and uncertainties, and we refer you to our SEC filings available on our website for more details on these risks.

我想提醒您，本次電話會議將包括前瞻性聲明，包括有關我們的臨床開發、監管和商業計劃和時間表的聲明，以及數據發布和合作機會以及其他更新的時間表。這些聲明存在風險和不確定性，我們建議您參閱我們網站上提供的 SEC 文件，以了解有關這些風險的更多詳細資訊。

Joining me today are Dr. Garo Armen, Chairman and Chief Executive Officer; Dr. Steven O'Day, Chief Medical Officer; Dr. Todd Yancey, Chief Strategic Advisor; and Christine Klaskin, Vice President of Finance. Dr. Robin Taylor, Chief Commercial Officer, will be participating in the Q&A session.

今天與我一起出席的有董事長兼執行長 Garo Armen 博士； Steven O'Day 博士，首席醫療官； Todd Yancey 博士，首席策略顧問；克里斯汀‧克拉斯金 (Christine Klaskin)，財務副總裁。商務長 Robin Taylor 博士將參加問答環節。

Now I'd like to turn the call over to Garo to highlight our progress and speak to our outlook for the remainder of the year. Garo?

現在我想把電話轉給加羅，強調我們的進展並談論我們對今年剩餘時間的展望。加羅？

Thank you, Zack. Ladies and gentlemen, as we gather today for the earnings call, let's reflect on the remarkable patient outcomes from our botensilimab trials. As underscored by our leading experts and researchers, we're witnessing sustained benefits in treating some of the most challenging cancers. Based on these observations and for the sake of cancer patients, our urgent mission is to set a new benchmark in cancer care, providing patients with longer-term potentially curative benefit with some patients experiencing treatable toxicities.

謝謝你，扎克。女士們先生們，當我們今天聚集在一起參加財報電話會議時，讓我們回顧一下我們的博滕西利單抗試驗所取得的顯著的患者結果。正如我們的領先專家和研究人員所強調的那樣，我們正在見證治療一些最具挑戰性的癌症的持續益處。基於這些觀察結果，為了癌症患者的利益，我們的緊迫使命是在癌症護理方面樹立新的基準，為患者提供長期的潛在療效，並為一些經歷可治療毒性的患者提供幫助。

Our BOT therapy is showing promise across various cancer stages and types with benefits seen in some of the most treatment-resistant so-called cold tumors. In addition, recent data presented at our corporate event in Madrid during ESMO revealed BOT potential in earlier stages of cancer where remarkable rapid responses were observed with the possibility to prevent significant treatment-related morbidities, including the potential need for colostomy.

我們的 BOT 療法在各種癌症階段和類型中都顯示出前景，在一些最難治療的所謂冷腫瘤中也能看到好處。此外，ESMO 期間在馬德里舉行的公司活動上公佈的最新數據顯示了BOT 在癌症早期階段的潛力，觀察到顯著的快速反應，有可能預防與治療相關的重大發病率，包括潛在的結腸造口術需求。

Moving forward, we're concentrating on 3 key priorities: submitting our first biologics license application for colorectal cancer; prioritizing other clinical programs with the potential for rapid approval; and importantly, to mark reallocating resources to achieve our goals. Accordingly, we're gearing up our first BOT/BAL BLA submission in mid-2024 with a focus on late-stage colorectal cancer. Dr. Yancey will delve deeper into this topic shortly.

展望未來，我們將重點關注 3 個關鍵優先事項：提交我們的第一份大腸癌生物製劑許可申請；優先考慮其他有可能快速批准的臨床項目；重要的是，標誌著重新分配資源以實現我們的目標。因此，我們正在準備在 2024 年中期提交第一份 BOT/BAL BLA，重點關注晚期結直腸癌。 Yancey 博士很快就會更深入地研究這個主題。

The cancer community's enthusiasm and rapid enrollment in our Phase II clinical trial in MSS CRC highlights an urgent unmet need. To address this, we have started a compassionate use program with the aim of broadening it into an expanded access program next year.

癌症界對 MSS CRC II 期臨床試驗的熱情和快速註冊凸顯了迫切的未滿足需求。為了解決這個問題，我們啟動了一項同情使用計劃，旨在明年將其擴展為擴大訪問計劃。

With very limited options to treat patients with advanced colorectal cancer, the positive trends and lasting responses in our studies strengthen our conviction in BOT/BAL's potential. Our top priority is obtaining BOT/BAL's approval in MSS CRC in order to allow patients access to this important IO treatment, offering them new hope which does not exist today.

由於治療晚期大腸直腸癌患者的選擇非常有限，我們研究中的正面趨勢和持久反應增強了我們對 BOT/BAL 潛力的信心。我們的首要任務是在 MSS CRC 中獲得 BOT/BAL 的批准，以便患者能夠獲得這項重要的 IO 治療，為他們帶來今天還不存在的新希望。

Our second area of focus is advancing our prioritized clinical programs, which includes refractory pancreatic cancer and neoadjuvant setting in CRC. Dr. O'Day will detail the exciting data that showcases BOT potential in these cold solid tumors.

我們的第二個重點領域是推動我們的優先臨床項目，其中包括難治性胰腺癌和大腸癌的新輔助治療。 O'Day 博士將詳細介紹令人興奮的數據，以展示 BOT 在這些冷實體瘤中的潛力。

In addressing our financial capabilities to drive our objectives, we're already taking and continue to take steps to contain costs. These steps are important, particularly given the current challenging environment in the biotech sector. Our immediate prospects for additional cash infusion that does not involve stock issuance include the milestone payment from one of our partnered programs expected by the end of December 2023. That's this year.

在解決我們的財務能力以實現我們的目標時，我們已經並繼續採取措施來控製成本。這些步驟非常重要，特別是考慮到生物技術領域當前充滿挑戰的環境。我們不涉及股票發行的額外現金注入的直接前景包括預計在 2023 年 12 月底之前從我們的一項合作計劃中支付里程碑付款。那就是今年。

In addition to this expected milestone, we are in the process of the sale of 2 nonstrategic assets and pursuing the partial sale of milestones and royalties due to Agenus from our partnered programs. These 3 sales are expected to close by the end of the first half of 2024. The potential proceeds from these 4 transactions are estimated at approximately $200 million in total.

除了這一預期的里程碑之外，我們正在出售 2 項非戰略資產，並尋求部分出售我們合作項目中 Agenus 的里程碑和特許權使用費。這 3 筆交易預計將於 2024 年上半年末完成。這 4 筆交易的潛在收益估計總計約為 2 億美元。

With our cash balance at the end of Q3 along with these 4 planned transactions, we believe we are sufficiently funded through the end of 2024. In addition to these planned transactions, we're also in advanced discussions for a potential structured financing for BOT/BAL as well as a potential corporate collaboration with a large pharma or biotech company.

根據我們第三季末的現金餘額以及這 4 項計劃交易，我們相信到 2024 年底我們的資金充足。除了這些計劃交易之外，我們還在深入討論 BOT/ 的潛在結構性融資。BAL 以及與大型製藥或生物技術公司的潛在企業合作。

That ends my formal remarks, introductory remarks, and now I'll be handing it over to Dr. O'Day to shed light on our latest findings and data updates. Steven?

我的正式演講、介紹性演講到此結束，現在我將把它交給奧戴博士，以闡明我們的最新發現和數據更新。史蒂文？

Thank you, Garo. Together with our investigators and key opinion leaders, we presented updates from the BOT/BAL development program at a corporate event hosted during the Madrid ESMO Congress in October. I'll now briefly describe these data updates, beginning with colorectal cancer.

謝謝你，加羅。我們與我們的調查人員和關鍵意見領袖一起，在 10 月馬德里 ESMO 大會期間舉辦的企業活動上介紹了 BOT/BAL 開發計劃的最新情況。我現在將簡要描述這些數據更新，從大腸直腸癌開始。

We updated our Phase Ib cohort of 70 evaluable patients with BOT and BAL in refractory MS-stable colorectal cancer without active liver metastasis. This is the target population for our fully enrolled Phase II study and the population in which we've received Fast Track designation from the FDA.

我們更新了由 70 名可評估的 BOT 和 BAL 患者組成的 Ib 期隊列，這些患者患有難治性 MS 穩定結直腸癌，無活動性肝轉移。這是我們完全入組的 II 期研究的目標族群，也是我們獲得 FDA 快速通道指定的族群。

The RECIST confirmed overall response rate was 24%. The duration of response was not reached with 59% of responses ongoing and now a median follow-up updated to 12.3 months. These patients showed a 12-month overall survival rate of 74%, approximately twice that reported for standard of care.

RECIST 確認整體緩解率為 24%。 59% 的反應仍在持續，但尚未達到反應持續時間，現在中位追蹤時間更新為 12.3 個月。這些患者的 12 個月總存活率為 74%，約為標準護理報告的兩倍。

With longer follow-up, the median OS previously reported at 20.9 months is now no longer reached. Importantly, the OS curve plateau continues to emerge and strengthen as the data matures with the longest patient now alive at 3.5 years and 3 other patients who are alive beyond 21 months. We plan to file our initial BLA in this indication in mid-2024.

隨著追蹤時間的延長，先前報告的中位 OS 為 20.9 個月，現在已不再達到。重要的是，隨著數據的成熟，OS 曲線平台持續出現並加強，目前存活時間最長的患者為 3.5 年，另外 3 名患者的存活時間超過 21 個月。我們計劃在 2024 年中期提交該適應症的初始 BLA。

Next, we presented data from an investigator-sponsored trial at WOW Cornell, in which 12 patients with CRC were treated with 1 dose of BOT and 2 doses of BAL in the neoadjuvant therapy window of opportunity setting. Surgery was performed, on average, only 4 weeks after the initiation of immunotherapy.

接下來，我們提供了 WOW 康乃爾大學研究者資助的一項試驗的數據，其中 12 名 CRC 患者在新輔助治療機會窗口中接受 1 劑 BOT 和 2 劑 BAL 治療。平均而言，免疫治療開始後僅 4 週就進行了手術。

All 3 MSI high colorectal patients had complete or near complete pathologic responses and, even more importantly, 6 out of 9 patients with MS-stable colorectal cancer had pathologic responses of 50% or greater, including 2 complete pathologic responses. None of the 12 patients had tumor growth during the treatment interval and no surgeries were delayed due to immune-related toxicities.

所有3 名MSI 高的結直腸癌患者均具有完全或接近完全的病理緩解，更重要的是，9 名MS 穩定的結直腸癌患者中有6 名的病理緩解達到50% 或更高，其中包括2 例完全病理緩解。 12名患者在治療期間均未出現腫瘤生長，也沒有因免疫相關毒性而延誤手術。

These results represent an important opportunity to move into earlier lines of therapy with curative intent and change the treatment paradigm for MS-stable colorectal cancer, potentially avoiding the morbidity of late-line therapies.

這些結果代表了一個重要的機會，可以進入具有治療目的的早期治療，並改變 MS 穩定大腸癌的治療模式，從而有可能避免晚期治療的發生率。

In second-line pancreatic cancer, we have treated 6 patients with the combination of botensilimab, Gemzar and Abraxane triplet. All 6 patients had progressed following first-line metastatic FOLFIRINOX therapy, and all 6 have liver metastasis. Four of the 6 patients have achieved marked and sustained tumor marker reductions.

在二線胰臟癌方面，我們已經用 botensilimab、Gemzar 和 Abraxane 三聯療法聯合治療了 6 名患者。所有 6 名患者在一線轉移性 FOLFIRINOX 治療後均出現進展，且所有 6 名患者均出現肝轉移。 6 名患者中有 4 名實現了腫瘤標記顯著且持續的降低。

Two of the 4 patients have already achieved partial responses at 16 weeks with target lesion reduction of minus 47%, which has been confirmed and minus 37%, which is pending confirmation scans, and both responses are ongoing. Two other patients showed stable disease at their first 8-week scans with tumor reduction of minus 20% and minus 13%, and they remain on study awaiting 16-week scan.

4 名患者中的兩名患者在 16 週時已實現部分緩解，目標病變減少了 -47%（已確認）和 -37%（有待確認掃描），並且兩種緩解都正在進行中。另外兩名患者在第一個 8 週掃描中表現出疾病穩定，腫瘤縮小了負 20% 和負 13%，他們仍在研究中等待 16 週掃描。

A randomized Phase II study is currently enrolling and a data update is anticipated in the first half of 2024. Our other Phase II trial is in refractory metastatic melanoma, including PD-1 refractory as well as PD-1 CTLA-4 refractory disease. In a Phase Ib expansion cohort of 10 patients, botensilimab alone showed a 30% objective response rate and 60% disease control rate in these refractory patients.

目前正在進行一項隨機II 期研究，預計將於2024 年上半年進行數據更新。我們的另一項II 期試驗是針對難治性轉移性黑色素瘤，包括PD-1 難治性疾病以及PD- 1 CTLA-4 難治性疾病。在由 10 名患者組成的 Ib 期擴展隊列中，單獨使用 botensilimab 在這些難治性患者中顯示出 30% 的客觀緩解率和 60% 的疾病控制率。

In the Phase II study, the botensilimab monotherapy cohort is now fully enrolled, and the botensilimab/balstilimab combination cohort is enrolled with approximately 30 patients. A data update is anticipated in the second half of 2024.

在 II 期研究中，botensilimab 單藥治療隊列現已全部入組，而 botensilimab/balstilimab 聯合隊列則入組了約 30 名患者。預計 2024 年下半年進行數據更新。

In PD-L1 refractory non-small cell lung cancer, we reported on 9 patients who were treated with the combination of BOT and BAL. Five of the 9 patients in the combination achieved RECIST-confirmed partial responses for an ORR of 56% and a disease control rate of 89%. Approximately 50 patients have now been enrolled in 2 expansion cohorts, including PD-1 refractory as well as TKI driver mutation refractory disease. A data update is anticipated in mid-2024.

在 PD-L1 難治性非小細胞肺癌中，我們報告了 9 名接受 BOT 和 BAL 合併治療的患者。合併治療中的 9 名患者中有 5 名達到了 RECIST 確認的部分緩解，ORR 為 56%，疾病控制率為 89%。約 50 名患者現已入組 2 個擴展隊列，包括 PD-1 難治性疾病以及 TKI 驅動突變難治性疾病。預計數據更新將於 2024 年中期進行。

Dr. Bree Wilky, Director of the Sarcoma Medical Oncology, Deputy Associate Director for Clinical Research at the University of Colorado Cancer Center presented an update of botensilimab program in sarcomas at ESMO 2023. In 41 evaluable heavily pretreated sarcoma patients, the combination of BOT and BAL demonstrated an overall response rate of 20%, a median duration of response of 19.4 months and a 6-month progression-free survival of 40%. There were differential responses observed by dose level with 29% response rate in the 2-milligram per kilo BOT cohort compared to 15% in the 1 milligram per kilo BOT cohort.

科羅拉多大學癌症中心肉瘤腫瘤內科主任、臨床研究副主任 Bree Wilky 博士在 ESMO 2023 上介紹了 botensilimab 治療肉瘤計畫的最新進展。在 41 名經過嚴格預處理的肉瘤患者中，BOT 和BAL 的整體緩解率為20%，中位緩解持續時間為19.4 個月，6 個月無惡化存活率為40%。根據劑量水平觀察到不同的反應，每公斤 2 毫克 BOT 組的反應率為 29%，而每公斤 1 毫克 BOT 組的反應率為 15%。

In addition, we observed promising activity and difficult-to-treat subtypes of sarcoma, such as leiomyosarcoma and visceral angiosarcoma. The results we've achieved in cold tumors in both the refractory setting and, more recently, in early disease offers hope for patients and families where current standards of care are an adequate or limited benefit.

此外，我們觀察到有希望的活性和難以治療的肉瘤亞型，例如平滑肌肉瘤和內臟血管肉瘤。我們在難治性冷腫瘤和最近的早期疾病中取得的結果為當前護理標準足以或有限獲益的患者和家庭帶來了希望。

The robustness of our data broadly across tumor types resulting in deep and durable responses showcases a potential groundbreaking advancement in oncology for botensilimab. We remain committed to improving patient outcomes and are grateful for the support of our team, trial participants and stakeholders. I am confident in the positive impact we are making, and I'm excited about the future.

我們的數據廣泛應用於各種腫瘤類型，從而產生了深入而持久的反應，這表明博滕西利單抗在腫瘤學方面可能取得突破性進展。我們仍然致力於改善患者的治療效果，並感謝我們的團隊、試驗參與者和利害關係人的支持。我對我們正在產生的正面影響充滿信心，並對未來感到興奮。

Now I'll turn the call over to Todd to discuss our regulatory strategy.

現在我將把電話轉給托德，討論我們的監管策略。

Thank you, Steven. The landscape for MSS CRC patients who received 1 to 2 prior lines of therapy is challenging. There are limited effective options available, so our focus in our development and regulatory path is to bridge that gap.

謝謝你，史蒂文。對於先前接受過 1 至 2 種治療的 MSS CRC 患者來說，前景充滿挑戰。可用的有效選擇有限，因此我們的開發和監管路徑的重點是彌合這一差距。

At present, the available therapies in this setting, including monotherapy with regorafenib, monotherapy with Lonsurf and the newly introduced combination of Avastin and Lonsurf, offer only marginal reported improvements in survival, and response rates are low with survival curves going to 0.

目前，這種情況下可用的療法，包括瑞戈非尼單一療法、Lonsurf單一療法以及新推出的阿瓦斯丁和Lonsurf聯合療法，僅能提供有限的生存改善，且緩解率較低，生存曲線降至0。

Recognizing this, we've developed a differentiated investigational agent with botensilimab that has already demonstrated significant benefit over reported results for these standard of care therapies with survival curve plateaus consistent with substantial long-term benefit.

認識到這一點，我們開發了一種具有 botensilimab 的差異化研究藥物，該藥物已證明比這些標準護理療法的報告結果具有顯著的益處，其生存曲線平台與實質性長期益處一致。

In our studies, patients with a median of 4 prior lines of therapy, 1/4 of whom had received prior immunotherapy experienced a 24% RECIST response rate compared to the standard of care's reported rate of only 3%. Importantly, our median overall survival is currently exceeding 21 months, a significant leap from standard of care at 12.9 months as reported in the ARCAD database.

在我們的研究中，先前接受過 4 種治療的患者（其中 1/4 之前接受過免疫治療）的 RECIST 緩解率為 24%，而標準治療報告的緩解率為 3%。重要的是，我們的中位總生存期目前超過 21 個月，與 ARCAD 資料庫報告的 12.9 個月的標準護理相比顯著飛躍。

Our regulatory process is well underway, and we, as we have stated, plan to submit our first BLA as characterized in our Fast Track designation in the middle of 2024. This application is robust. It's targeted to include data from approximately 400 patients at 2 different doses, both 1 milligram per kilogram and 2 milligrams per kilogram and will be supported by safety data from several hundred additional patients across multiple indications where we have observed broad activity. And in this process, we're not leaving any stone unturned.

我們的監管流程正在順利進行，正如我們所說，我們計劃在 2024 年中期提交我們的第一份 BLA，正如我們的快速通道指定所描述的那樣。該申請非常穩健。它的目標包括來自大約400 名患者的2 種不同劑量（每公斤1 毫克和每公斤2 毫克）的數據，並將得到我們觀察到廣泛活動的多個適應症的另外數百名患者的安全數據的支持。在此過程中，我們不遺餘力。

We're conducting a comprehensive and full exploration of dosing schedule ranging from the lowest dose of 0.1 milligrams per kilogram to 3 milligrams per kilogram in our Phase I and Phase II studies. Additionally, we're investigating the contribution of components of the 2 experimental agents, BOT and BAL, in a randomized fashion within our now fully enrolled Phase II study. As we move forward, we are and we'll continue to proactively engage with regulatory authorities.

在我們的一期和二期研究中，我們正在對給藥方案進行全面、充分的探索，從最低劑量0.1毫克每公斤到3毫克每公斤。此外，我們正在以隨機方式研究 2 種實驗藥物（BOT 和 BAL）成分的貢獻，該研究現已完全納入 II 期研究。隨著我們的前進，我們正在並將繼續積極與監管機構合作。

While we await complete feedback from the FDA in EMEA, we have taken scientific advice from key European countries and are in the process of scheduling meetings with the CHMP and FDA representatives. These discussions are crucial as they regard our path forward toward approval. Our goal is clear. We aim to submit this package for potential approval by 2024 midyear, and we're optimistic about the opportunity for an accelerated review, which would allow us to bring this innovative solution to patients in need as soon as we can.

在我們等待歐洲、中東和非洲地區 FDA 的完整回饋的同時，我們已經聽取了主要歐洲國家的科學建議，並正在安排與 CHMP 和 FDA 代表的會議。這些討論至關重要，因為它們關係到我們走向批准的道路。我們的目標很明確。我們的目標是在 2024 年年中之前提交該方案以獲得批准，我們對加速審查的機會持樂觀態度，這將使我們能夠盡快將這項創新解決方案帶給有需要的患者。

Now I'd like to turn the call over to Christine to discuss the financials.

現在我想把電話轉給克里斯汀討論財務問題。

Thank you, Todd. We ended our third quarter of 2023 with a consolidated cash, cash equivalent and short-term investment balance of $100.63 million. This compares to $193.4 million at the end of last year.

謝謝你，托德。截至 2023 年第三季度，我們的合併現金、現金等價物及短期投資餘額為 1.0063 億美元。相比之下，去年底為 1.934 億美元。

For the 3 and 9 months ended September 30, 2023, we recognized revenue, which includes noncash revenue, of $24.3 million and $72.5 million, respectively. Including noncash expenses of $28.1 million, we incurred a net loss of $64.5 million for the third quarter. For the 9 months of 2023, we incurred a net loss of $208.9 million, which includes noncash expenses of $82 million.

截至 2023 年 9 月 30 日的 3 個月和 9 個月，我們確認的收入（包括非現金收入）分別為 2,430 萬美元和 7,250 萬美元。包括 2,810 萬美元的非現金費用，我們第三季的淨虧損為 6,450 萬美元。 2023 年 9 個月，我們的淨虧損為 2.089 億美元，其中包括 8,200 萬美元的非現金支出。

I'll now turn the call back to Garo.

我現在將電話轉回加羅。

Thank you, Christine. I want to express my gratitude for your support during this clinical phase of Agenus. Our striving cancer research highlighted by botensilimab signify a potential new era in cancer care.

謝謝你，克里斯汀。我想對您在 Agenus 臨床階段的支持表示感謝。博滕西利單抗強調的我們努力的癌症研究標誌著癌症治療的潛在新時代。

I also want to express my gratitude to our employees. I am confident in our team dedication and our ability to achieve our milestones. The success of balstilimab remains our top priority, and I assure you that our diligently managed finances will ensure the necessity for resources to be allocated for this very important endeavor.

我還要向我們的員工表示感謝。我對我們團隊的奉獻精神和實現里程碑的能力充滿信心。巴司替利單抗的成功仍然是我們的首要任務，我向您保證，我們勤奮管理的財務將確保為這項非常重要的努力分配資源的必要性。

With your continued support, we expect to meet and exceed our goals with the prospect of bringing hope and healing to those affected by cancer. Thank you for your support once again. Together, we are destined for remarkable achievements for the benefit of cancer patients, which will, in turn, create significant value for all of our stakeholders.

在您的持續支持下，我們期望能夠達到並超越我們的目標，為癌症患者帶來希望和治癒。再次感謝您的支持。我們一定會齊心協力，為癌症患者的利益取得非凡的成就，進而為我們所有利害關係人創造巨大的價值。

With that, I will now open the call for questions. Thank you very much.

現在，我將開始提問。非常感謝。

(Operator Instructions) Your first question comes from the line of Emily Bodnar with H.C. Wainwright.

（操作員說明）您的第一個問題來自 Emily Bodnar 和 H.C.溫賴特。

First one, just briefly, if you can comment on when we may expect to see initial Phase II data for the MSS CRC study. And then secondly, if you could talk about how you're thinking about strategy in neoadjuvant CRC. Are you kind of looking to evaluate broadly in CRC or just focus on MSS patients and maybe just discuss the regulatory pathway to potentially getting BOT/BAL approved in that setting?

第一個問題，請簡要說明一下，我們預計何時會看到 MSS CRC 研究的初始 II 期數據。其次，您是否可以談談您如何看待新輔助大腸癌的策略。您是否希望對 CRC 進行廣泛評估，或者只關注 MSS 患者，並可能只是討論在該情況下可能獲得 BOT/BAL 批准的監管途徑？

Thank you, Emily. So let me answer the question broadly, and I'll ask if Dr. O'Day has any additional comments. But -- so what I've said publicly is the fact that we have clearly disclosed the data on the first 70 patients, not because the rest of the data isn't satisfactory but the rest of the data needs to be cleaned up, and we need a little bit of work to do.

謝謝你，艾米麗。因此，讓我廣泛地回答這個問題，然後我會詢問奧戴博士是否有任何其他意見。但是——所以我公開說的是，我們明確披露了前70名患者的數據，不是因為其餘數據不令人滿意，而是其餘數據需要清理，並且我們需要做一些工作。

But our look at the data both in the second cohort and in our Phase II studies indicate that we should have a sustainable response rate, perhaps even an improving response rate as we disclose and analyze these data for regulatory and beyond purposes. So that is going to be more of a regulatory decision, when to disclose it, and the ideal circumstance for us will be certainly to publish the data at around the time of a potential BLA submission. To publish the data in peer-reviewed journal, that would be part of our plan.

但我們對第二組和第二階段研究中的數據的觀察表明，當我們出於監管和其他目的披露和分析這些數據時，我們應該擁有可持續的答复率，甚至可能提高答复率。因此，何時披露數據將更多是一個監管決定，對我們來說，理想的情況肯定是在潛在的 BLA 提交前後發布數據。在同行評審的期刊上發布數據，這將是我們計劃的一部分。

Now with regard to the neoadjuvant plans, we haven't quite crystallized it yet. Of course, the typical response for neoadjuvant studies is the fact that large studies, they take time. But we believe that depending on what patient populations we go after, we may be able to look at a subset of patients that would be the subject of high mobility with standards of care. And as you know, in these patients, even though the treatments are largely curative, they're not 100% curative standard of care, not a 100% curative, but they cure a quite substantial number of patients.

現在關於新輔助治療計劃，我們還沒有完全具體化。當然，新輔助研究的典型反應是大型研究需要時間。但我們相信，根據我們關注的患者群體，我們也許能夠專注於一部分具有高流動性和照護標準的患者。如你所知，在這些患者中，儘管治療在很大程度上是治癒的，但它們不是 100% 治癒的護理標準，不是 100% 治癒的，但它們治癒了相當多的患者。

But those cures come at a very high cost to the patients and that includes the potential use of colostomy bags, it involves sexual dysfunction and also involves the loss of muscle function in the area of the abdomen. And particularly, if you are a patient in your 30s, 40s, you don't want to be subject to these morbidity. So we're going to take a little bit of time, not too much time, to determine exactly what the patient population and the trial design would be with the aim of a very rapid trial execution and potentially rapid filing and approval.

但這些治療方法對患者來說代價非常高，其中包括可能使用結腸造口袋，涉及性功能障礙，也涉及腹部肌肉功能的喪失。特別是，如果您是 30 多歲、40 多歲的患者，您不想遭受這些發病率的困擾。因此，我們將花一點時間，而不是太多時間，來準確地確定患者群體和試驗設計，目的是非常快速地執行試驗，並可能快速提交和批准。

So I think we'll disclose some of these details in the first half of next year.

所以我認為我們將在明年上半年披露其中一些細節。

Your next question comes from the line of Colleen Kusy from Baird.

您的下一個問題來自貝爾德 (Baird) 的科琳·庫西 (Colleen Kusy)。

Congrats on the progress. For the randomized CRC study that's fully enrolled, can you just give us a sense of the regulatory bar there? Does the combination need to be better than the individual drug arms and standard of care and by what margin?

祝賀取得的進展。對於已全部入組的隨機 CRC 研究，您能否讓我們了解那裡的監管障礙？該組合是否需要優於單獨的藥物組和護理標準，差距是多少？

If I may ask Todd to answer that question.

我可以請托德回答這個問題嗎？

I think there are really 2 questions there. One is what do we expect in terms of performance versus standard of care and the second is really what do we expect to see in terms of incremental contribution in the doublet. So just to remind everybody about the design of the trial, the 5 arms, of which one is standard of care. And of course, patients are randomized across these arms.

我認為確實有兩個問題。一是我們對性能與護理標準的期望，二是我們對雙聯體增量貢獻的實際期望。因此，我想提醒大家有關試驗的設計，即 5 組，其中一個是標準護理。當然，患者被隨機分配到這些組別。

The other 4 arms all have botensilimab, which as monotherapy, we know to be active from the Phase I dose escalation. And 2 of those arms have botensilimab in combination with balstilimab. And as we've been observing in the data set that we've been presenting for the MSS CRC patients on active liver met since, well, for the last almost 18 months, there is a substantial benefit in the combination.

其他 4 個臂均使用博替尼單抗，作為單一療法，我們知道該藥物在 I 期劑量遞增中具有活性。其中 2 個臂將博替利單抗與巴斯蒂利單抗合併使用。正如我們在過去近 18 個月以來為患有活動性肝臟疾病的 MSS CRC 患者提供的數據集中觀察到的那樣，該組合具有顯著的益處。

And so as it relates to the first question versus standard of care, standard of care is for patients with 1 to 2 prior lines of therapy is offering a 3% overall response rate and an expected median overall survival of 12.9 months that's coming from the ARCAD database of over 18,000 patients. And currently, we're showing 24% versus 3% for response and over 21 months for median overall survival.

因此，由於它涉及第一個問題與標準護理，標準護理是針對先前接受過 1 到 2 種治療的患者，其總體緩解率為 3%，並且來自 ARCAD 的預期中位總生存期為 12.9 個月超過18,000 名患者的資料庫。目前，我們的反應率分別為 24% 和 3%，中位總存活期超過 21 個月。

So we need to be obviously meaningfully better than currently available standards of care. So looking at 3% versus 24% or 12.9 months versus over 21 months, I think it's clear to everyone that you could drive a truck through that.

因此，我們需要明顯優於目前可用的護理標準。因此，從 3% 與 24% 或 12.9 個月與 21 個月以上的情況來看，我認為每個人都清楚你可以駕駛卡車度過這段時期。

Now as it relates to the incremental contribution of balstilimab to botensilimab, given our mechanism of action, which is really multifactorial. First of all, we have obviously our optimized engagement with CTLA-4 and a receptor ligand interaction. But the back-end engineering is resulting in suddenly inactivation of both innate and adaptive immune response, has created a hot (inaudible), and we have -- we expect to see a substantial improvement in the combination, certainly at least a doubling of response when we add balstilimab.

現在，考慮到我們的作用機制，這涉及到 balstilimab 對 botensilimab 的增量貢獻，這實際上是多因素的。首先，我們顯然對 CTLA-4 和受體配體相互作用進行了最佳化。但後端工程導致先天性和適應性免疫反應突然失活，產生了熱（聽不清楚），我們期望看到組合的顯著改善，當然至少反應加倍當我們添加巴司替利單抗時。

And so I think that's what we want to be able to discern. Just for comprehensiveness, we'll also remind everyone that in that same clinical trial, we are looking at 2 active doses, 1 milligram per kilogram and 2 milligram per kilogram. And at the time of regulatory submission, we anticipate having approximately 175 patients in each of those 2 doses. So we'll be able to have a robust perspective on the activity of the doses, 1 and 2, and also on the tolerability of those two.

所以我認為這就是我們希望能夠辨別的。為了全面起見，我們也要提醒大家，在同一項臨床試驗中，我們正在研究 2 種活性劑量，即每公斤 1 毫克和每公斤 2 毫克。在向監管機構提交申請時，我們預計這 2 劑疫苗中的每劑將有大約 175 名患者接受治療。因此，我們將能夠對劑量 1 和 2 的活性以及這兩種劑量的耐受性有一個強有力的了解。

That's super helpful. And at the time of BLA submission, would you expect to have any sort of overall survival early data from this study?

這非常有幫助。在提交 BLA 時，您是否期望從這項研究中獲得任何類型的整體生存早期數據？

I think we would have certainly evident trends for patient benefit. What we've observed pretty consistently in the Phase I database, which is not small, remembering we've got 101 patients in total there for safety and we have 70 patients in the MSS CRC on active liver metastatic patient population for efficacy adjudication, we are obviously seeing that responses for patients and that response can be stable disease or better is translating to not only durable response but very substantial overall survival.

我認為我們肯定會有明顯的病患利益趨勢。我們在I 期資料庫中觀察到的情況相當一致，該資料庫並不小，記住我們總共有101 名患者用於安全性，我們在MSS CRC 中有70 名患者用於活性肝轉移患者群體的療效判定，我們顯然，我們看到患者的反應，並且這種反應可以是疾病穩定或更好，不僅轉化為持久的反應，而且還轉化為非常可觀的總體生存率。

So I certainly expect that we'd be able to demonstrate a point estimates for response, durability of response for patients with stable disease or better and that is trending toward a survival benefit. Remember also that the time of submission is not a moment in time that's frozen because we will be required to provide updates on safety and efficacy during agency review and that will allow time for additional maturation of the data set.

因此，我當然希望我們能夠證明對疾病穩定或更好的患者的反應、反應持久性的點估計，並且這有利於生存。還要記住，提交時間並不是凍結的時刻，因為我們將需要在機構審查期間提供有關安全性和有效性的更新，這將為資料集的進一步成熟留出時間。

And again, as has been consistent since we began to show data in June of 2022, the longer the study goes the more mature the observations have been around the durability of response and its translation to survival. So I think we have a very, very robust set of data to present to the agencies for their review.

再說一次，正如我們自 2022 年 6 月開始展示數據以來一直一致的那樣，研究時間越長，圍繞反應的持久性及其轉化為生存的觀察結果就越成熟。所以我認為我們有一組非常非常可靠的數據可以提交給各機構進行審查。

Got it. That makes sense. And on the cash guidance, can you maybe just provide a little bit more color on what's included in that in terms of the ongoing and planned studies?

知道了。這就說得通了。關於現金指導，您能否就正在進行的和計劃中的研究提供更多資訊？

If you can repeat the question on the latter part of your question?

能否重複一下您問題後半部的問題？

Yes. Just on the updated cash guidance?

是的。只是更新後的現金指導嗎？

I got it, I think. So as you know, we finished the quarter with a little over $100 million. My guidance for the fourth quarter burn is approximately $40 million. Now beyond that, as we've said earlier, we will have a milestone payment that is due to us by the end of this year. And we will sell 2 assets that are nonstrategic assets. We expect that to be completed in the first half of this -- next year. And then a third-party royalty transaction.

我想，我明白了。如您所知，本季結束時我們的收入略高於 1 億美元。我對第四季燒錢的指引約為 4000 萬美元。除此之外，正如我們之前所說，我們將在今年年底前支付一筆里程碑付款。我們將出售兩個非策略資產。我們預計這將在今年上半年——明年——完成。然後是第三方特許權使用費交易。

Now of course, the first 2 are entirely in our control, meaning the milestone payment and the asset sales. And the royalty transaction will require external investors for that kind of transaction. We had done that before some years ago; in fact, about 5 years ago. We consummated a transaction for third-party royalties when we had a much skinnier loyalty portfolio at the time. And we did this with XOMA Corporation.

當然，現在前兩項完全由我們控制，即里程碑付款和資產出售。特許權使用費交易將需要外部投資者進行此類交易。幾年前我們就這麼做過；事實上，大約5年前。當我們當時的忠誠度投資組合要薄弱得多時，我們就完成了第三方特許權使用費交易。我們與 XOMA Corporation 合作完成了這項工作。

So we're talking about a transaction that will be multiples of that transaction for a much larger and much more attractive portfolio that has had some very encouraging comments from our partners. So with those, we expect to bring in approximately $200 million of cash between now and middle of next year. That is through nonstock issuance transactions. Without any stock issuance, we expect to bring in approximately $200 million. And with that, it will take us where we are in the end of next year.

因此，我們正在談論的交易將是該交易的倍數，以獲得更大、更具吸引力的投資組合，我們的合作夥伴對此給予了一些非常令人鼓舞的評論。因此，從現在到明年年中，我們預計將帶來約 2 億美元的現金。即透過非股票發行交易。如果不發行任何股票，我們預計將帶來約 2 億美元的收入。這樣，我們就能在明年年底達到現在的目標。

Any other questions?

還有其他問題嗎？

Mayank Mamtani, your line is open.

Mayank Mamtani，您的電話已接通。

Helpful recap of ESMO-driven data. So maybe just to clarify on the second-line plus CRC accredited approval, are you able to talk to the specific guidance you may have on the design of the Phase III confirmatory study and maybe timing of initiation to just kind of round out the other updates you provided? And then I have a follow-up.

有用的 ESMO 驅動數據回顧。因此，也許只是為了澄清二線加 CRC 認可的批准，您能否談談您可能對 III 期驗證性研究的設計以及啟動時間的具體指導，以完善其他更新你提供了？然後我有一個後續行動。

So I'll just make a [broad] comment on the confirmatory studies, and then I'll ask Todd to provide additional color. With regard to confirmatory studies, we have 2 choices. One is to do a confirmatory study in the second or third-line setting. The other one is to do a confirmatory study in the first line.

因此，我將對驗證性研究發表[廣泛]評論，然後我會要求托德提供更多資訊。關於驗證性研究，我們有兩個選擇。一是在二線或三線環境中進行驗證性研究。另外一個就是在第一線做驗證性研究。

We have not made that decision yet. We've had discussions with the FDA on the latter-line confirmatory study. We have not yet had discussions on the first line because we're awaiting data from an [ISD] study, which is ongoing right now with studies (inaudible) FOLFOX. And we expect that data to be available in the first quarter of next year, and that will inform us better which way to go, whether we go the first line or third line.

我們還沒有做出這個決定。我們已經與 FDA 就後線驗證性研究進行了討論。我們尚未就第一線進行討論，因為我們正在等待 [ISD] 研究的數據，該研究目前正在與 FOLFOX 進行研究（聽不清楚）。我們預計這些數據將在明年第一季提供，這將更好地告訴我們該走哪條路，無論我們走第一線還是第三線。

Todd, would you like to add any additional color on this?

托德，你想為此添加一些額外的顏色嗎？

Yes. I just had a couple of points to that. We already -- Mayank, now that we have a clear understanding of how to preemptively manage or to intervene early on GI toxicity, you already have a higher level of comfort with regard to our ability to combine in the front-line with 5FU and oxaliplatin-based regimens, of course, which have associated GI toxicity. So that level of comfort is rising. But at City of Hope, we are conducting a study to determine what the best management paradigm would be for the combination.

是的。我對此只有幾點看法。我們已經 -- Mayank，現在我們已經清楚地了解如何先發製人地管理或早期幹預胃腸道毒性，您已經對我們在一線結合 5FU 和奧沙利鉑的能力感到更加放心當然，基於的治療方案具有相關的胃腸道毒性。所以舒適度正在上升。但在希望之城，我們正在進行一項研究，以確定合併後的最佳管理模式。

In addition to that, I think we have greater strength of evidence for incremental benefit in earlier lines of therapy derived from the preliminary data set we're seeing in the neoadjuvant setting. So I think our objective will be to optimize the development program to accelerate access for patients to a broader patient population.

除此之外，我認為我們有更有力的證據證明早期療法的增量益處來自我們在新輔助治療中看到的初步數據集。因此，我認為我們的目標是優化開發計劃，以加速患者接觸到更廣泛的患者群體。

And so there's a lot of regulatory precedent for doing a confirmatory trial in either a broader patient population than the accelerated approval indication and/or in an earlier line. And again, at the end of the day, the decision with regard to the design of the confirmatory trial will require alignment with both the U.S. and the European authorities, and we're basically looking at 2 potential options at least that we would present for their review.

因此，在比加速批准適應症更廣泛的患者群體和/或早期產品線中進行驗證性試驗有很多監管先例。再說一遍，最終，有關驗證性試驗設計的決定將需要與美國和歐洲當局保持一致，我們基本上正在考慮至少兩個潛在的選擇他們的評論。

Very helpful. And then on the new pancreatic cancer BOT chemo data, could you just clarify what number of patients you are targeting in the randomized control cohort? And if you are seeing any uptick in enrollment similar to what occurred in other colorectal cancer expansion cohort last year? And for the relatively warmer tumors in lung and melanoma, it seems like you have both mono and BOT/BAL combination data. So there is a theme here of mono BOT data and combination BOT/BAL.

很有幫助。然後，關於新的胰臟癌 BOT 化療數據，您能否澄清一下您在隨機對照隊列中針對的患者數量？您是否發現入學人數增加，類似於去年其他大腸癌擴張族群中發生的情況？對於相對溫暖的肺癌和黑色素瘤腫瘤，您似乎同時擁有單一數據和 BOT/BAL 組合數據。所以這裡有一個主題：單一BOT資料和組合BOT/BAL。

So how are you sort of thinking across tumor types where you may pursue BOT stand-alone versus maybe combination? If there's a view on that you could share? And I have one more financial question after this.

那麼，您如何看待不同腫瘤類型，您可能會尋求單獨使用 BOT 還是合併使用 BOT？如果您對此有什麼看法可以分享嗎？此後我還有一個財務問題。

Thank you. Dr. O'Day, would you like to take that first part, the first multi-part question.

謝謝。 O'Day 博士，您願意回答第一部分，也就是第一個由多個部分組成的問題嗎？

Yes. Mayank, can you repeat the very first part of it, I have the melanoma part, but...

是的。 Mayank，你能重複它的第一部分嗎，我有黑色素瘤部分，但...

The pancreatic cancer BOT chemo data, number of patients that you're targeting in the randomized control cohort. And if you've seen any uptick in enrollment like what happened with colorectal cancer.

胰臟癌 BOT 化療數據，您在隨機對照隊列中針對的患者數量。如果您看到入學人數增加，例如大腸癌的情況。

Yes. So we have a lot of enthusiasm around the data so far with both our PIs on the pancreas study, but more broadly KOLs. So we are expanding that and it is accruing, and we plan on treating another 60 patients in randomization in the coming months.

是的。因此，到目前為止，我們對胰臟研究的 PI 以及更廣泛的 KOL 的數據充滿熱情。因此，我們正在擴大這一範圍，並且它正在不斷增加，我們計劃在未來幾個月內隨機治療另外 60 名患者。

In terms of melanoma, obviously, we have single-agent activity in melanoma in PD-1 and PD-1 CTLA-4 refractory that we've reported in our Ib trial. We've now accrued a large number of patients to monotherapy in both the PD-1 refractory and PD-1 CTLA-4 refractory at 2 different doses. And as I said today, we're combining it with BAL, and that data will be maturing, and we look forward to presenting it in 2024.

顯然，就黑色素瘤而言，我們在 Ib 試驗中報告了對 PD-1 和 PD-1 CTLA-4 難治性黑色素瘤的單藥活性。我們現在已經有大量患者接受了兩種不同劑量的 PD-1 難治性和 PD-1 CTLA-4 難治性單一療法。正如我今天所說，我們正在將其與 BAL 結合起來，數據將會日益成熟，我們期待在 2024 年呈現它。

Got it. And maybe for Garo, this concept of structured financing or even corporate partnerships. I was just curious if there's any sort of segmentation you're thinking by indication or geographies? Are there any sort of constructs and new [townships] that are more preferred versus less? If you could provide some color there, that would be helpful.

知道了。或許對加羅來說，這種結構性融資甚至企業合作關係的概念。我只是好奇您是否正在考慮按指示或地理位置進行任何類型的細分？是否有任何類型的建築和新[城鎮]更受青睞而不是更受青睞？如果您可以在那裡提供一些顏色，那將會很有幫助。

The kinds of discussions that we're having and some of them are in advanced stages, as I said before, really encompass both a global collaboration across all indications as well as specific indication collaboration, for which infrastructure exists at some companies to be able to segregate products by indication. That's new technology, and we've been proposed the potential option of segregating certain indications that are of greater interest to certain partners. So we're looking at all of these options simultaneously, and I think a good deal for us would be driven by several things.

正如我之前所說，我們正在進行的討論（其中一些討論已進入後期階段）實際上既涵蓋了所有適應症的全球合作，也涵蓋了特定適應症的合作，一些公司為此建立了基礎設施，能夠依指示隔離產品。這是新技術，有人向我們提出了分離某些合作夥伴更感興趣的某些跡象的潛在選擇。因此，我們正在同時考慮所有這些選擇，我認為對我們來說，一筆划算的交易將由幾個因素推動。

Number one, the appropriateness of the collaborator, their conviction that our product could be a significant player in the immuno-oncology and broader oncology field. So that's number one because we believe that botensilimab plus balstilimab offers performance advantages that we not seen at any immuno-oncology and oncology treatment setting.

第一，合作者的適當性，他們相信我們的產品可以成為免疫腫瘤學和更廣泛的腫瘤學領域的重要參與者。所以這是第一，因為我們相信博替利單抗加巴斯蒂利單抗提供了我們在任何免疫腫瘤學和腫瘤學治療環境中都沒有看到的性能優勢。

So for example, when we talk about patients that have either failed all other therapies or do not respond to other therapies, not just immunotherapy but beyond immunotherapy, these are patients that are in dire need of a product that offers them a potentially curative option with toxicity that is transient. I think that there is an enormous need in the field for such a program. I think botensilimab offers that treatment option for patients.

例如，當我們談論對所有其他療法都失敗或對其他療法（不僅僅是免疫療法，而且超出免疫療法）沒有反應的患者時，這些患者迫切需要一種產品，為他們提供潛在的治療選擇暫時性的毒性。我認為該領域非常需要這樣一個計劃。我認為博滕西利單抗為患者提供了這種治療選擇。

Now -- so given this, the partner must have high conviction that this product could be a huge win for patients and a huge win commercially as a result. That's number one. Number two, the partner needs to make the appropriate financial commitments, not just for compensating us in terms of upfront and milestones but also a substantial financial commitment for the development of this product. And development has to be rapid because, as we've said before, we have seen clear clinical activity in so far 9 different cancers. You can't lie about that. It's real. It's been presented at major conferences.

現在，考慮到這一點，合作夥伴必須堅信該產品可以為患者帶來巨大的勝利，從而在商業上帶來巨大的勝利。這是第一名。第二，合作夥伴需要做出適當的財務承諾，不僅要在前期和里程碑方面向我們提供補償，還要為該產品的開發做出實質的財務承諾。而且開發必須是快速的，因為正如我們之前所說，迄今為止我們已經在 9 種不同的癌症中看到了明顯的臨床活性。你不能對此撒謊。它是真實的。它已在重大會議上發表過。

And so of course, there are regulatory and other questions about do overall response rates translate to longer-term benefit. We know they do. We need to demonstrate that with numbers, but with CTLA-4 binding antibodies and ours is a multifunctional broad-functioning molecule that binds the CTLA-4 as one of its 5 different activities, not just the center stage activity but one of 5 different activities.

因此，當然，存在著關於整體回應率能否轉化為長期利益的監管和其他問題。我們知道他們這樣做。我們需要用數字來證明這一點，但是用CTLA-4 結合抗體，我們的分子是一種多功能的廣泛功能分子，它結合CTLA-4 作為其5 種不同活性之一，不僅僅是中心階段活性，而是5 種不同活性之一。

So all of that means that this product needs to be rapidly developed across all indications. And if you pay attention to my quadrant slide, you will see that the opportunity for cancer, cancer patients is enormous. So the partnership has to be based on a commitment -- financial commitment for rapid development and, of course, other cultural compatibilities that will allow our A team to work with -- and partner's A team to bring this into a harmonious conclusion.

因此，所有這些都意味著該產品需要在所有適應症上快速開發。如果你注意我的象限幻燈片，你會發現癌症、癌症患者的機會是巨大的。因此，合作夥伴關係必須基於承諾——快速發展的財務承諾，當然還有其他文化兼容性，使我們的 A 團隊能夠與合作夥伴的 A 團隊合作，從而達成和諧的結果。

Your last question comes from the line of Kelly Shi with Jefferies.

你的最後一個問題來自凱莉·施（Kelly Shi）與杰弗里斯（Jefferies）的對話。

This is Claire on for Kelly. So just one question for the plan for CRC. So can you remind us what's your plan for those CRC patients with liver mets at the Phase III confirmatory study specifically in patients without liver mets? Or is there is an option to look at all-comer patients as well?

這是克萊爾為凱利代言的。那麼只有一個關於 CRC 計劃的問題。那麼您能否提醒我們，對於 III 期驗證性研究中出現肝代謝異常的 CRC 患者，特別是沒有肝代謝異常的患者，您有何計畫？或者是否也可以選擇查看所有患者？

So I will take a little crack at it, and I'll ask Dr. O'Day to also comment on this. So as you know, liver mets is a sort of a black box right now for everybody. There's no clear answer as to why liver mets patients don't respond. There is speculation about why they may not respond. And of course, liver is a privileged organ with a lot of immunosuppressive components to it.

所以我會對此進行一些嘗試，我會請奧戴博士也對此發表評論。如您所知，肝臟代謝症候群現在對每個人來說都是一個黑盒子。至於為什麼肝臟代謝症候群患者沒有反應，目前還沒有明確的答案。人們猜測他們為什麼可能不回應。當然，肝臟是一個特殊的器官，其中含有許多免疫抑製成分。

Now we are looking at a number of ways of what we're coming in. For example, if you look at our pancreatic data, all patients in the small number of patients that have been treated had had liver mets and all patients that have responded have had liver mets response. We don't know if any of the other chemotherapy components are contributing to this.

現在我們正在研究我們正在研究的多種方法。例如，如果您查看我們的胰腺數據，您會發現少數接受治療的患者中的所有患者都進行了肝臟代謝檢查，並且所有患者均做出了反應有肝臟代謝症候群反應。我們不知道其他化療成分是否會導致這種情況。

For example, there's some speculation that gemcitabine may play a role in this. We don't know that. But I think in the next coming months, we will have a very deliberate action plan in trying to answer this question with small trials, possibly [ISDs] that will be undertaken to see if we can translate some of what we have observed in pancreatic cancer can be also actualized in CRC. But right now, we're working with limited knowledge. But I think, as you said, this is an area that needs to be explored very diligently. Dr. O'Day?

例如，有人猜測吉西他濱可能在其中發揮作用。我們不知道這一點。但我認為在接下來的幾個月裡，我們將有一個非常深思熟慮的行動計劃，試圖透過小型試驗來回答這個問題，可能會進行[ISD]，看看我們是否可以轉化我們在胰腺癌中觀察到的一些東西也可以在CRC中實現。但目前，我們的知識有限。但我認為，正如你所說，這是一個需要非常努力探索的領域。奧戴博士？

Yes. So obviously, in the refractory colorectal patient population, the IO combination of BOT/BAL has its most profound signal to date in the nonactive liver met patients. These are patients who've never had liver metastasis or have had treated liver metastasis. But depending on alignment of the Phase III trial, as Todd said, if we do move to first line, obviously, we would treat all-comers. And so we will be aligning our Phase III trial in the coming weeks and months.

是的。顯然，在難治性結直腸患者群體中，BOT/BAL 的 IO 組合在非活動性肝病患者中具有迄今為止最深刻的信號。這些患者從未發生過肝轉移或接受過肝轉移治療。但正如托德所說，根據第三階段試驗的調整，如果我們確實進入第一線，顯然我們會對待所有人。因此，我們將在未來幾週和幾個月內調整我們的 III 期試驗。

There are no further questions at this time. Garo Armen, I turn the call back over to you.

目前沒有其他問題。加羅·阿曼，我把電話轉給你。

Thank you very much, everyone, for your attentiveness to our developments. This is a very exciting time, I believe, for cancer patients, certainly patients that are in desperate need of effective therapies, not just therapies that extend their life by a month or 2 at a very high cost of quality of life but potentially expand life much longer with potential curative outcomes in some patients and with a much, much more acceptable, more dignified quality of life with some gastrointestinal side effects that are typical to overactivation of the immune system, but they are reversible.

非常感謝大家對我們動態的關注。我相信，對於癌症患者來說，這是一個非常令人興奮的時刻，尤其是那些迫切需要有效治療的患者，而不僅僅是以非常高的生活品質成本延長生命一兩個月但有可能延長生命的治療方法有些患者的治療時間更長，並且具有更容易接受、更有尊嚴的生活質量，並且會出現一些胃腸道副作用，這些副作用是免疫系統過度激活的典型症狀，但它們是可逆的。

And I think if you look at our record, our physicians have learned that reversibility is a function of rapid intervention. And as our trials progress from earlier-stage Phase I trials for extended (inaudible) patients to Phase II trials, we will be seeing a significant improvement in a way our transient toxicities are managed. So it's a very exciting time for patients. And other than the obligations that we need to fulfill in order to bring these products to patients very rapidly, I think the future looks brighter than it has ever looked in our company's history and my career as an observant and an operator in this business. So thank you very much.

我認為，如果你看看我們的記錄，我們的醫生就會了解到，可逆性是快速介入的功能。隨著我們的試驗從針對擴展（聽不清楚）患者的早期 I 期試驗進展到 II 期試驗，我們將看到短暫毒性管理方式的顯著改善。因此，對於患者來說，這是一個非常令人興奮的時刻。除了我們需要履行的快速將這些產品帶給患者的義務之外，我認為未來看起來比我們公司的歷史以及我作為該行業的觀察者和經營者的職業生涯中所看到的更加光明。非常感謝。

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

今天的電話會議到此結束。您現在可以斷開連線。