IGM Biosciences Inc (IGMS) 2022 Q4 法說會逐字稿

Good day, everyone, and welcome to IGM Biosciences Fourth Quarter and Full Year 2022 Financial Results and Corporate Update Call. Today's call is being recorded.

大家好，歡迎參加 IGM Biosciences 2022 年第四季和全年財務業績和公司更新電話會議。今天的通話正在錄音。

At this time, I would like to turn the call over to Fred Schwarzer, Chief Executive Officer of IGM.

現在，我想把電話轉給 IGM 執行長 Fred Schwarzer。

Thank you, operator, and thanks to all of you joining us on this call. On behalf of IGM, I'm joined today by Misbah Tahir, Chief Financial Officer; Dr. Chris Takimoto, Chief Medical Officer; Dr. Bruce Keyt, Chief Scientific Officer; and Dr. Mary Beth Harler, President, IGM Autoimmunity and Inflammation.

謝謝您，接線員，也謝謝大家參加這次電話會議。今天，我代表 IGM 與財務長 Misbah Tahir 一起出席會議。 Chris Takimoto 博士，首席醫療官； Bruce Keyt 博士，首席科學官；以及 IGM 自體免疫和發炎總裁 Mary Beth Harler 博士。

Please note that we will be making forward-looking statements on this call including statements about IGM's plans, expectations and forecasts and about future events. Actual results may differ materially as a result of various risks and uncertainties including those discussed in the company's most recent annual report on Form 10-K as well as its other filings with the SEC.

請注意，我們將在本次電話會議中做出前瞻性聲明，包括有關 IGM 的計劃、期望和預測以及未來事件的聲明。由於各種風險和不確定性，包括公司最近的 10-K 表格年度報告以及向 SEC 提交的其他文件中討論的風險和不確定性，實際結果可能會存在重大差異。

Any forward-looking statements represent IGM's view as of today, March 30, 2023, only, and the company disclaims any obligation to update these statements, except as required by law.

任何前瞻性聲明僅代表 IGM 截至今天（2023 年 3 月 30 日）的觀點，除法律要求外，該公司不承擔任何更新這些陳述的義務。

Following this call, a replay will be available on the company's website, www.igmbio.com.

這次電話會議之後，將在公司網站 www.igmbio.com 上提供重播。

I would like to start with a few introductory remarks, and then I will turn the call over to Misbah to take you through our 2022 financial results. After Misbah's update, Chris will update you on clinical development of IGM-8444, our Death Receptor 5 agonist antibody. Next, Mary Beth will update you on our development plans for imvotamab and autoimmune diseases. We will then turn it back over to Chris to discuss the 2 most recent product candidates in our oncology pipeline. IGM-7354, our IGM targeted immunostimulatory IL-15 cytokine and IGM-2644, our CD38 x CD3 T cell engager, a next-generation CD38 antibody for multiple myeloma.

我想先做一些介紹性發言，然後我會將電話轉給米斯巴，向您介紹我們 2022 年的財務表現。 Misbah 更新後，Chris 將向您介紹我們的死亡受體 5 激動劑抗體 IGM-8444 的臨床開發。接下來，Mary Beth 將為您介紹我們針對 imvotamab 和自體免疫疾病的開發計劃。然後，我們會將其轉回給 Chris 討論我們腫瘤學管道中的 2 個最新候選產品。 IGM-7354 是我們的 IGM 標靶免疫刺激性 IL-15 細胞因子，IGM-2644 是我們的 CD38 x CD3 T 細胞接合劑，是治療多發性骨髓瘤的下一代 CD38 抗體。

Looking back, 2022 was a transformational year for IGM. At the end of the first quarter, we entered into an important collaboration with Sanofi to develop novel IGM agonist antibodies to address 3 oncology targets and 3 autoimmune targets. Throughout the year, we also continued the clinical development of our Death Receptor 5 agonist antibody IGM-8444, particularly in combination with FOLFIRI for the treatment of colorectal cancer.

回顧過去，2022 年對 IGM 來說是轉型的一年。第一季末，我們與賽諾菲達成重要合作，開發新型 IGM 激動劑抗體，以解決 3 個腫瘤學標靶和 3 個自體免疫標靶。在這一年中，我們也持續進行死亡受體 5 激動劑抗體 IGM-8444 的臨床開發，特別是與 FOLFIRI 合併用於治療大腸直腸癌。

We're very pleased with the data we have seen from those clinical development efforts as we announced in January of this year. These data have provided the basis for our decision to immediately move into a randomized study of IGM-8444 in second-line metastatic colorectal cancer in combination with FOLFIRI and bevacizumab, which is the standard of care in second-line colorectal cancer.

我們對今年 1 月宣布的臨床開發工作所獲得的數據感到非常滿意。這些數據為我們決定立即進行 IGM-8444 聯合 FOLFIRI 和貝伐珠單抗治療二線轉移性結直腸癌的隨機研究提供了基礎，貝伐珠單抗是二線結直腸癌的護理標準。

We are hopeful that this randomized study will show a significant improvement in progression-free survival relative to the standard of care chemotherapy control arm.

我們希望這項隨機研究將顯示相對於標準護理化療對照組，且無惡化存活期有顯著改善。

As we announced today, we have now treated the first patient in this randomized study. We also made great progress during 2022 in developing our understanding of the potential role of our T-cell engagers such as imvotamab in treating autoimmune diseases. We are encouraged by the expanded safety and efficacy data for imvotamab at 100 milligrams that we have developed through our clinical studies in non-Hodgkin's lymphoma, and we believe that imvotamab's safety profile may be an important differentiating factor in the exciting new field of T-cell engagers in autoimmune disease.

正如我們今天所宣布的，我們現在已經治療了這項隨機研究中的第一位患者。 2022 年，我們在了解 Imvotamab 等 T 細胞參與劑在治療自體免疫疾病中的潛在作用方面也取得了巨大進展。我們對透過非何杰金氏淋巴瘤臨床研究開發的 100 毫克 imvotamab 的安全性和有效性數據感到鼓舞，我們相信，imvotamab 的安全性可能是令人興奮的 T 細胞新領域的一個重要差異化因素。自體免疫疾病中的細胞參與者。

Building on our success in 2022, we expect that 2023 will also be an important year for the expansion and validation of IGM's platform. Already this year, we have treated the first patients in our clinical study of IGM-7354, an IgM targeted immunostimulatory IL-15 cytokine, which could be used for the treatment of patients with solid and hematologic malignancies. We are particularly excited about the potential to use IGM-7354 and in combination with cellular therapies such as CAR-T and CAR-NK cells.

在 2022 年成功的基礎上，我們預計 2023 年也將是 IGM 平台擴展和驗證的重要一年。今年，我們在 IGM-7354 臨床研究中治療了第一批患者，IGM-7354 是一種 IgM 靶向免疫刺激性 IL-15 細胞因子，可用於治療實體瘤和血液惡性腫瘤患者。我們對使用 IGM-7354 以及與 CAR-T 和 CAR-NK 細胞等細胞療法相結合的潛力感到特別興奮。

We are also initiating studies of IGM-2644 and our CD38 x CD3 bispecific IgM antibody, which we hope will be a safe and more potent form of anti-CD38 therapy for multiple myeloma, including for patients who have previously been treated with daratumumab. We also plan to file investigational new drug applications and initiate clinical studies for imvotamab in multiple autoimmune diseases this year, beginning with lupus and rheumatoid arthritis.

我們也正在啟動 IGM-2644 和 CD38 x CD3 雙特異性 IgM 抗體的研究，我們希望這將成為治療多發性骨髓瘤的安全且更有效的抗 CD38 療法，包括對於先前接受過 daratumumab 治療的患者。我們也計劃今年提交研究性新藥申請，並啟動 imvotamab 在多種自體免疫疾病的臨床研究，首先是狼瘡和類風濕性關節炎。

At this point, I'd like to turn the call over to Misbah to review our financial results for 2022.

現在，我想將電話轉給 Misbah，以審查我們 2022 年的財務業績。

Thank you, Fred. In addition to the brief financial overview, I will provide on the call today, you can read additional detail on our fourth quarter and year-end financial results in our press release issued prior to this call and in our 10-K, which was filed with the SEC.

謝謝你，弗雷德。除了我將在今天的電話會議上提供的簡要財務概述之外，您還可以在本次電話會議之前發布的新聞稿以及我們已提交的10-K 中閱讀有關我們第四季度和年終財務業績的更多詳細資訊與美國證券交易委員會。

We are fortunate to be in a strong financial position. In the second quarter of 2022, we received an upfront payment of $150 million from Sanofi related to our collaboration agreement and raised gross proceeds of $230 million in a follow-on public equity offering. As a result, our cash and investments totaled $427.2 million as of December 31, 2022.

我們很幸運擁有強大的財務狀況。 2022 年第二季度，我們從賽諾菲收到了與我們的合作協議相關的 1.5 億美元預付款，並在後續公開股權發行中籌集了 2.3 億美元的總收益。截至 2022 年 12 月 31 日，我們的現金和投資總額為 4.272 億美元。

In the fourth quarter, our research and development expenses were $45 million. For the full year 2022, R&D expenses were $179.3 million. General and administrative expenses for the fourth quarter of 2022 were $11.6 million and $49.7 million for the full year 2022. Collaboration revenues for the fourth quarter of 2022 were $0.4 million and $1.1 million for the full year 2022. Our net loss for the fourth quarter of 2022 was $52.6 million or a loss of $1.19 per share. For the full year 2022, our net loss was $221.1 million or a loss of $5.32 per share.

第四季度，我們的研發費用為4500萬美元。 2022 年全年，研發費用為 1.793 億美元。 2022 年第四季的一般及管理費用為1,160 萬美元，2022 年全年為4,970 萬美元。第四季的淨虧損2022 年為 5,260 萬美元，即每股虧損 1.19 美元。 2022 年全年，我們的淨虧損為 2.211 億美元，即每股虧損 5.32 美元。

Turning now to the financial guidance for 2023. We expect our full year 2023 GAAP operating expenses to be between $290 million and $300 million. This includes estimated noncash stock-based compensation expense of approximately $50 million. For the full year 2023, we also expect to recognize approximately $3 million of collaboration revenue related to last year's upfront payment from Sanofi.

現在轉向 2023 年的財務指引。這包括估計約 5000 萬美元的非現金股票補償費用。對於 2023 年全年，我們也預計將確認與賽諾菲去年預付款相關的約 300 萬美元的合作收入。

Finally, we expect to end 2023 with a balance of approximately $200 million in cash and investments, providing IGM with an expected cash runway into the second half of 2024.

最後，我們預計到 2023 年底，現金和投資餘額約為 2 億美元，為 IGM 提供到 2024 年下半年的預期現金跑道。

With that, I'll now turn the call over to Chris, our Chief Medical Officer.

現在，我將把電話轉給我們的首席醫療官克里斯。

Thank you, Misbah. As Fred mentioned, 2022 was a very important year for the clinical development of IGM-8444, I am pleased to announce that we have now dosed more than 100 patients with IGM-8444 in our broad multi-indication multi-combination Phase I study, and we're very excited about the safety and clinical activity profile that we've seen to date in our combination with the standard FOLFIRI chemotherapy regimen in colorectal cancer patients.

謝謝你，米斯巴。正如Fred 所提到的，2022 年對於IGM-8444 的臨床開發來說是非常重要的一年，我很高興地宣布，我們現在已經在廣泛的多適應症多組合I 期研究中給100 多名患者服用了IGM-8444，我們對迄今為止在結直腸癌患者中與標準 FOLFIRI 化療方案相結合所看到的安全性和臨床活性狀況感到非常興奮。

In January, we shared our initial data from our FOLFIRI combination cohort, which is available in detail in our current corporate overview presentation.

一月份，我們分享了 FOLFIRI 組合隊列的初始數據，該數據的詳細資訊可在我們目前的公司概述演示中找到。

To summarize, these data showed an encouraging safety profile that was broadly comparable to that expected from chemotherapy alone. Specifically, no signs of drug-related clinically significant hepatotoxicity were observed was only grade 1 and grade 2 transient drug-related liver enzyme elevations we're seeing.

總而言之，這些數據顯示出令人鼓舞的安全性，與單獨化療的預期效果大致相當。具體來說，沒有觀察到與藥物相關的臨床顯著肝毒性的跡象，我們僅看到 1 級和 2 級短暫的藥物相關肝酵素升高。

The substantial majority of our patients with metastatic colorectal cancer have been treated with 3 milligrams per kilogram of IGM-8444 in combination with FOLFIRI. And thus far, we have seen promising activity at that dose level with multiple confirmed responses even in patients who had previously progressed on prior FOLFIRI.

我們絕大多數的轉移性大腸直腸癌患者均接受了 3 毫克/公斤的 IGM-8444 與 FOLFIRI 合併治療。到目前為止，我們已經看到該劑量水平的有希望的活性，即使在先前接受 FOLFIRI 治療後出現進展的患者中也有多種確認的反應。

We also saw encouraging progression-free survival in third and fourth line patients, with 1 patient continuing for over a year without progression. These data have encouraged us to start treating patients with FOLFIRI plus bevacizumab, which is the current standard of care treatment for second line colorectal cancer.

我們也看到三線和四線患者的無惡化存活期令人鼓舞，其中一名患者持續一年多沒有進展。這些數據鼓勵我們開始使用 FOLFIRI 加貝伐珠單抗治療患者，這是目前二線大腸直腸癌的護理治療標準。

I am pleased to announce today that we have now treated nearly 20 patients in combination with bevacizumab, and we've not seen any additional toxicity signals arising from the addition of bevacizumab to the combination. These early safety and efficacy observations have encouraged us to proceed immediately into a randomized clinical study of FOLFIRI and bevacizumab plus or minus IGM-8444 in second-line colorectal cancer. We are pleased to announce today that we have now dosed the first patient in this randomized clinical trial.

我今天很高興地宣布，我們現在已聯合貝伐單抗治療了近 20 名患者，我們沒有看到因在聯合用藥中添加貝伐單抗而產生任何額外的毒性信號。這些早期的安全性和有效性觀察結果鼓勵我們立即進行一項 FOLFIRI 和貝伐單抗加或減 IGM-8444 治療二線大腸直腸癌的隨機臨床研究。我們今天很高興地宣布，我們現在已對這項隨機臨床試驗中的第一位患者進行了給藥。

We're also excited to announce today that our analysis of the cell death biomarker, caspase-3 in patients treated with IGM-8444 across multiple dose levels, both as monotherapy and in combination showed a consistent increase post treatment in 60 of 64 patients analyzed. In addition, a dose-dependent increase was seen at the 2 highest dose levels tested of 3 and 10 milligrams per kilogram. A summary of these data is available in our current corporate overview slide deck available on our website.

我們今天也很高興地宣布，我們對接受IGM-8444 多種劑量水平（單一療法和聯合療法）治療的患者的細胞死亡生物標誌物caspase-3 進行的分析顯示，在分析的64 名患者中，有60 名患者在治療後持續增加。此外，在測試的 2 個最高劑量水平（每公斤 3 毫克和 10 毫克）觀察到劑量依賴性增加。這些數據的摘要可在我們網站上目前的公司概述幻燈片中找到。

This biomarker signal has led us to add an additional 10-milligram per kilogram dose cohort to our randomized combination study. This protocol is currently being amended to randomize patients to 3 groups, either 3 or 10 milligrams per kilogram of IGM-8444 with FOLFIRI plus bevacizumab or standard of care chemotherapy alone.

這個生物標記訊號促使我們在隨機組合研究中額外添加每公斤 10 毫克的劑量組。該方案目前正在修訂，將患者隨機分為 3 組，每公斤 3 毫克或 10 毫克 IGM-8444 合併 FOLFIRI 加貝伐單抗或單獨標準護理化療。

Our primary endpoint for this study will be progression-free survival with overall survival and response rate as secondary end points.

我們這項研究的主要終點是無惡化存活期，總存活期和緩解率作為次要終點。

We are exploring with the FDA potential randomized pathways to accelerated approval in accordance with their recently released guidance on this topic. We also announced today that we are now treating patients in our fifth birinapant combination dose escalation cohort. To date, there have not been any observed dose limiting toxicities in combination with birinapant.

我們正在與 FDA 一起探索潛在的隨機途徑，以根據他們最近發布的有關該主題的指南來加速批准。我們今天也宣布，我們現在正在治療第五個 birinapant 組合劑量遞增隊列中的患者。迄今為止，與 birinapant 聯合使用時尚未觀察到任何劑量限制性毒性。

We also announced today that we've treated the first patient in our IGM-8444 plus venetoclax and azacytidine combination in subjects with acute myeloid leukemia.

我們今天也宣布，我們的 IGM-8444 聯合 Venetoclax 和氮胞苷組合治療了第一位急性髓性白血病患者。

Finally, we've also conducted extensive preclinical studies with other chemotherapeutic agents in combination with IGM-8444 in a variety of different cancer types. We plan to clinically evaluate one or more of these chemotherapy combinations with IGM-8444 as our development program expands.

最後，我們也對其他化療藥物與 IGM-8444 合併治療多種不同癌症類型進行了廣泛的臨床前研究。隨著我們開發計劃的擴展，我們計劃對 IGM-8444 中的一種或多種化療組合進行臨床評估。

At this point, I'd like to turn the call over to Mary Beth, our President of Autoimmunity and Inflammation. Mary Beth will be leading our clinical development efforts for imvotamab in autoimmune diseases and as the clinical development in autoimmune diseases will be our focus going forward, she will be sharing today's interim clinical updates about the imvotamab NHL program. Mary Beth?

現在，我想將電話轉給我們的自體免疫和發炎部門總裁瑪麗貝絲 (Mary Beth)。 Mary Beth 將領導我們針對自體免疫疾病的 imvotamab 臨床開發工作，由於自體免疫疾病的臨床開發將成為我們未來的重點，她將分享今天有關 imvotamab NHL 計畫的臨時臨床更新。瑪麗貝絲？

Thank you, Chris. As you mentioned, we are announcing some encouraging safety and clinical activity data for imvotamab, which we think could offer a compelling and differentiated profile in the exciting new area of T-cell engagers in autoimmune disease. We think there is an important opportunity to bring forward a readily accessible therapy that offers deeper B-cell depletion than achievable with currently available anti-CD20 therapies.

謝謝你，克里斯。正如您所提到的，我們宣布了一些令人鼓舞的imvotamab 安全性和臨床活性數據，我們認為這些數據可以在自身免疫性疾病T 細胞參與者這一令人興奮的新領域提供引人注目的差異化概況。我們認為，這是一個重要的機會，可以提出一種易於使用的療法，比目前可用的抗 CD20 療法可提供更深層的 B 細胞耗竭。

Also, you may recall hearing about some recent very encouraging data using CAR-T cells for B-cell depletion in lupus. We believe that imvotamab may have clear advantages over CAR-T therapies in autoimmune disease in terms of safety, cost and logistics.

此外，您可能還記得最近聽說過一些使用 CAR-T 細胞消除狼瘡 B 細胞的非常令人鼓舞的數據。我們認為，在自體免疫疾病方面，imvotamab 可能在安全性、成本和物流方面比 CAR-T 療法具有明顯的優勢。

We announced today that as of our most recent data assessment, the incidence of cytokine release syndrome was 9% overall safety evaluable patients treated with the 100-milligram titration dosing regimen in our Phase I and Phase II non-Hodgkin's lymphoma studies, and it was 13% overall safety evaluable patients treated with either 100 milligrams or 300-milligram titration dosing in these Phase I and Phase II lymphoma studies. All cases of CRS seen in the 100-milligram and 300-milligram titration dose cohorts were grade 1 other than 1 grade 2.

我們今天宣布，根據我們最新的數據評估，在我們的I 期和II 期非何杰金氏淋巴瘤研究中，接受100 毫克滴定劑量方案治療的整體安全性可評估患者中細胞激素釋放症候群的發生率為9%，在這些 I 期和 II 期淋巴瘤研究中，13% 的整體安全性可評估患者接受 100 毫克或 300 毫克滴定劑量治療。在 100 毫克和 300 毫克滴定劑量組中觀察到的所有 CRS 病例均為 1 級（1 例 2 級除外）。

We also announced today, although the patient numbers are very small and additional patients currently on treatment may respond as of the most recent data assessment, imvotamab has achieved a combined complete response rate of greater than 30% overall efficacy evaluable, diffuse large B-cell lymphoma or DLBCL and patients in our Phase I and Phase II studies treated with the 100-milligram titration weekly dosing regimen. Although the patient numbers are too small to make a statistical assessment, currently, the response rate in DLBCL continues to be -- continues to appear to be lower at the 300-milligram dose.

我們今天也宣布，儘管患者數量非常少，並且截至最近的數據評估，目前正在接受治療的其他患者可能會有所反應，但imvotamab 已實現了超過30% 的綜合完全緩解率，總體療效可評估，瀰漫性大B 細胞淋巴瘤或 DLBCL 以及我們的 I 期和 II 期研究中接受每週 100 毫克滴定給藥方案治療的患者。儘管患者數量太少而無法進行統計評估，但目前，DLBCL 的反應率在 300 毫克劑量下仍然較低。

As you may recall, we have previously announced that we have seen complete responses with imvotamab in all 4 major NHL subtypes; diffused large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and marginal zone lymphoma. While it is not possible to directly extrapolate these encouraging efficacy data in NHL to what we might observe in autoimmune disease, it's worth noting a couple of points. First, CD20 is a well-established target in multiple autoimmune diseases. And secondly, the imvotamab data in NHL clearly demonstrates that imvotamab effectively depletes B cells, even rapidly growing lymphoma cells.

您可能還記得，我們​​之前曾宣布，我們已經在所有 4 種主要 NHL 亞型中看到了 imvotamab 的完全緩解；瀰漫性大B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤及邊緣區淋巴瘤。雖然不可能直接將 NHL 中這些令人鼓舞的療效數據推斷為我們在自體免疫疾病中可能觀察到的結果，但有幾點值得注意。首先，CD20 是多種自體免疫疾病的既定標靶。其次，imvotamab 在 NHL 中的數據清楚地表明，imvotamab 可以有效地消耗 B 細胞，甚至快速生長的淋巴瘤細胞。

In combination with these strong signs of clinical activity, we believe that imvotamab's safety profile will be an important differentiating factor in the treatment of autoimmune diseases with T-cell engagers, together with the potential to more effectively deplete pathogenic B cells deep within tissues that may be refractory to current therapies. We believe there are significant unmet medical needs and commercial opportunities that imvotamab may address across a range of autoimmune diseases.

結合這些強烈的臨床活性跡象，我們相信 imvotamab 的安全性將成為 T 細胞接合劑治療自體免疫疾病的一個重要差異因素，並且具有更有效地消除組織深處致病性 B 細胞的潛力，從而可能對目前的治療方法無效。我們相信，imvotamab 可以解決一系列自體免疫疾病方面存在大量未滿足的醫療需求和商業機會。

We have also announced today that we plan to file IND applications in the second quarter to begin clinical testing of imvotamab in both severe systemic lupus erythematosus, or SLE, and in severe rheumatoid arthritis or RA. We are also evaluating a variety of additional autoimmune diseases for a potential third IND application later this year.

我們今天也宣布，計劃在第二季提交 IND 申請，開始對 imvotamab 在嚴重系統性紅斑狼瘡 (SLE) 和嚴重類風濕關節炎 (RA) 中進行臨床測試。我們也正在評估多種其他自體免疫疾病，以便在今年稍後進行第三次 IND 申請。

With that, I'll turn the call back over to Fred.

這樣，我會將電話轉回給弗雷德。

Thank you, Mary Beth. We are pleased with the safety and clinical activity profile that we have seen with imvotamab at 100 milligrams in our non-Hodgkin's lymphoma clinical studies to date, and we're excited to move forward aggressively in developing imvotamab for multiple autoimmune diseases.

謝謝你，瑪麗貝絲。到目前為止，我們在非何杰金氏淋巴瘤臨床研究中使用 100 毫克的 imvotamab 獲得的安全性和臨床活性狀況令我們感到滿意，並且我們很高興能夠積極推進針對多種自體免疫疾病的 imvotamab 開發。

Given the relative size of the potential autoimmune markets, and imvotamab's potential competitive advantage in autoimmune disease resulting from its safety profile, we believe that the unmet medical needs and the commercial opportunities for imvotamab in autoimmune diseases are substantially greater than those in non-Hodgkin's lymphoma, particularly those as monotherapy in relatively late lines of lymphoma treatment.

考慮到潛在自體免疫市場的相對規模，以及imvotamab 由於其安全性而在自體免疫疾病領域的潛在競爭優勢，我們認為，imvotamab 在自體免疫疾病中未滿足的醫療需求和商業機會遠大於非霍奇金淋巴瘤，特別是在相對晚期的淋巴瘤治療中作為單一療法的那些。

As a result, we are announcing today that we are redirecting our clinical development efforts for imvotamab to autoimmune diseases and that we have decided to cease further monotherapy clinical development efforts for imvotamab in non-Hodgkin's lymphoma.

因此，我們今天宣布，我們將把 imvotamab 的臨床開發工作轉向自體免疫疾病，並決定停止針對非何杰金氏淋巴瘤的 imvotamab 進一步單藥臨床開發工作。

We continue to believe that the safety and efficacy profile of imvotamab could position it well as a combination partner for the treatment of non-Hodgkin's lymphoma. And we will be focusing our future efforts in NHL on evaluating combination opportunities and partnerships for imvotamab.

我們仍然相信，imvotamab 的安全性和有效性特徵可以使其成為治療非何杰金氏淋巴瘤的組合夥伴。我們未來在 NHL 的工作重點將是評估 imvotamab 的組合機會和合作夥伴關係。

With that, I'd like to turn the call back to Chris to discuss our exciting early-stage clinical development efforts in oncology.

說到這裡，我想把電話轉回克里斯，討論我們在腫瘤學方面令人興奮的早期臨床開發工作。

Thank you, Fred. As we announced in January, we're excited to have initiated a clinical trial exploring the safety, efficacy and pharmacodynamic activity of IGM-7354, an IGM-targeted immunostimulatory IL-15 cytokine in the treatment of patients with solid tumors.

謝謝你，弗雷德。正如我們在一月份宣布的那樣，我們很高興啟動了一項臨床試驗，探索IGM-7354 的安全性、有效性和藥效活性，IGM-7354 是一種IGM 靶向免疫刺激性IL-15 細胞因子，用於治療實體腫瘤患者。

We are announcing today that we've successfully dosed our first 2 patients with no drug-related safety issues. We believe that IGM-7354 has the potential to be used in combination with a broad range of other drugs, which rely on CD8-positive cells or NK cells for their activity including combinations with CAR-T and CAR-NK cells.

我們今天宣布，我們已成功對首批 2 名患者進行了給藥，沒有出現與藥物相關的安全問題。我們相信 IGM-7354 有潛力與多種其他藥物合併使用，這些藥物的活性依賴 CD8 陽性細胞或 NK 細胞，包括與 CAR-T 和 CAR-NK 細胞聯合使用。

We are also announcing that the FDA has cleared our IND application for IGM-2644, a CD38 x CD3 IGM T-cell engager, which allows us to commence a Phase I dose escalation trial in patients with recurrent or refractory multiple myeloma.

我們也宣布FDA 已批准我們的IGM-2644（一種CD38 x CD3 IGM T 細胞接合劑）的IND 申請，這使我們能夠在復發性或難治性多發性骨髓瘤患者中開始I 期劑量遞增試驗。

This study will allow us to investigate the initial safety and efficacy of our next T cell engaging IGM molecule.

這項研究將使我們能夠研究下一個 T 細胞參與 IGM 分子的初始安全性和有效性。

Our ultimate clinical development goal for IGM-2644 is to establish it as a safe and more potent anti-CD38 therapy even for patients who have received prior daratumumab treatment.

我們對 IGM-2644 的最終臨床開發目標是使其成為一種安全且更有效的抗 CD38 療法，即使對於先前接受過 daratumumab 治療的患者也是如此。

We are very excited by the potential for IGM-2644 to provide the next-generation form of an anti-CD8 therapy. As you may recall, in December of last year, we presented preclinical data at the 2022 ASH meeting, showing that IGM-2644 achieved potent T-cell directed cellular cytotoxicity in multiple myeloma patient samples and in daratumumab resistant cell lines with minimal cytokine release.

我們對 IGM-2644 提供下一代抗 CD8 療法的潛力感到非常興奮。您可能還記得，去年12 月，我們在2022 年ASH 會議上公佈了臨床前數據，顯示IGM-2644 在多發性骨髓瘤患者樣本和daratumumab 抗藥性細胞系中實現了有效的T 細胞定向細胞毒性，且細胞激素釋放最少。

With that, I'd like to turn the call back over to Fred.

說到這裡，我想把電話轉回給弗雷德。

Thank you, Chris. In closing, I'd like to thank all of the employees of IGM for their work over the past year. All of our principal investigators, their teams and their institutions and most importantly, the patients and their families, all of whom have made the progress we've described today possible. We're very excited about the progress that we hope to make in 2023 towards our goal of bringing new and important treatments to patients. We appreciate your interest in IGM, and we look forward to keeping you all informed as to our progress.

謝謝你，克里斯。最後，我要感謝IGM所有員工在過去一年所做的工作。我們所有的主要研究人員、他們的團隊和機構，最重要的是病人及其家屬，所有人都使我們今天所描述的進展成為可能。我們對 2023 年為患者提供新的重要治療方法的目標所取得的進展感到非常興奮。我們感謝您對 IGM 的興趣，並期待向您通報我們的進展。

With that, operator, I'd like to open the call for questions.

接線員，我想開始提問。

(Operator Instructions) Our first question is from Stephen Willey with Stifel.

（操作員說明）我們的第一個問題來自 Stifel 的 Stephen Willey。

I guess a lot going on here. So the decision to add the 10 mg per kg dose to the randomized Phase II, can you maybe just -- can you answer the question, I guess, as to whether or not you've conducted any dose expansion with the 10 mg per kg dose in combination with bev and FOLFIRI before you're entering it into the randomized Phase II? And then just any updated thoughts on when we might get a look at the remaining dose expansion of patients? I guess those treated at the 3 mg per kg dose and any that you may have treated at the 10 mg dose.

我想這裡發生了很多事情。因此，決定將每公斤 10 毫克的劑量添加到隨機 II 期試驗中，我想，您能否回答這個問題，即您是否對每公斤 10 毫克的劑量進行了任何劑量擴展？ ，與bev 和FOLFIRI 合併使用的劑量？然後，關於我們何時可以查看患者剩餘劑量擴展的任何最新想法？我猜那些接受過每公斤 3 毫克劑量治療的患者以及您可能接受過 10 毫克劑量治療的患者。

Chris, would you like to take that one?

克里斯，你想買那個嗎？

Sure. Yes. Steve, thank you for the question. So the -- really the experience that we have with IGM-8444 at 10 milligrams per kilogram, as you're aware, we explored a number of patients during the monotherapy dose escalation and then when we started to combine with FOLFIRI, we did the expansion at 3 milligrams per kilogram, although we did treat 3 patients at 10 milligrams per kilogram with FOLFIRI. But it was really the biomarker data that we're sharing with you now that really showed this increase in plasma caspase-3 levels that continue to increase as we went from to 10 milligrams per kilogram.

當然。是的。史蒂夫，謝謝你的提問。因此，如您所知，我們在每公斤 10 毫克的 IGM-8444 方面的經驗是，我們在單藥治療劑量遞增期間對一些患者進行了研究，然後當我們開始與 FOLFIRI 聯合使用時，我們做了儘管我們確實用FOLFIRI 以每公斤10 毫克的劑量治療了3 名患者，但以每公斤3 毫克的劑量進行了擴展。但我們現在與您分享的生物標記數據確實顯示了血漿 caspase-3 水平的增加，隨著我們從每公斤 10 毫克增加到這一水平，這種水平繼續增加。

And that was one of the major factors that led us to incorporate and make the decision to add 10 milligrams per kilogram to the randomized study. Plus we did get additional feedback from the FDA that was, again, very supportive of doing formal dose exploration and optimization in the study. So those were the things, the new biomarker data and that really prompted us to make this addition to the study.

這是導致我們納入並決定在隨機研究中添加每公斤 10 毫克的主要因素之一。另外，我們確實從 FDA 獲得了額外的回饋，這些回饋再次非常支持在研究中進行正式的劑量探索和優化。這些就是新的生物標記數據，這確實促使我們對研究進行了補充。

Okay. And then I guess as a follow-up, does the addition of the third arm to the randomized Phase II change your powering assumptions? And I know that you're kind of guiding to potentially having a conversation with FDA regarding an accelerated approval pathway. So should we think about patient enrollment then as kind of a moving target?

好的。然後我想作為後續行動，將第三臂添加到隨機第二階段是否會改變您的動力假設？我知道您正在指導與 FDA 就加速審批途徑進行對話。那麼我們是否應該將患者入組視為一個移動目標？

Yes. So this study is built with a certain degree of flexibility. And again, the study is really designed to confirm the signal that we have seen in our single-arm experience in combining 8444 with FOLFIRI. But it's also written so that when we can actually evaluate the impact of dose as well as looking at the primary endpoint, which is going to be progression-free survival.

是的。因此本研究的建構具有一定的彈性。再說一遍，這項研究的真正目的是為了證實我們在將 8444 與 FOLFIRI 結合使用的單臂經驗中看到的訊號。但它的編寫也是為了讓我們能夠實際評估劑量的影響以及查看主要終點，即無進展生存期。

And so we've left things somewhat open in terms of if we get a strong signal that allows us to pick a dose and also confirm the magnitude of the benefit over the control arm, there's the potential that we can either stop this early and initiate a more formal registrational trial or alternatively, we could potentially, with regulatory feedback, expand this study to increase the number of patients on each of the arms and potentially use this as a randomized accelerated approval trial. So those possibilities are all things that we are considering as we move forward.

因此，如果我們得到一個強烈的信號，允許我們選擇劑量，並確認相對於控制臂的益處的大小，我們就保留了一些開放性，我們有可能可以提前停止並啟動或者，我們可以根據監管反饋擴大這項研究，以增加每組的患者數量，並可能將其用作隨機加速批准試驗。因此，這些可能性都是我們在前進過程中正在考慮的事情。

Okay. And then maybe just lastly, real quickly. I know obviously, imvotamab is getting prioritized for AI disease, but maybe for Mary Beth, can you just kind of speak to, I guess, your interest in potentially looking at IGM-2644 in autoimmune disease as well?

好的。然後也許是最後，很快。我顯然知道，imvotamab 正在優先用於治療 AI 疾病，但也許對於 Mary Beth，您能否談談，我猜，您也有興趣研究 IGM-2644 在自體免疫疾病中的應用？

Yes. No, absolutely. Thanks, Steve. As you know, we are thinking about our T-cell engager assets morph through a portfolio lens than individual opportunities. And we are very excited about how these assets may come together to afford multiple therapeutic approaches to treating B-cell and plasma cell mediated diseases.

是的。不，絕對是。謝謝，史蒂夫。如您所知，我們正在考慮透過投資組合鏡頭而不是個人機會來改變我們的 T 細胞參與資產。我們對這些資產如何結合起來提供多種治療方法來治療 B 細胞和漿細胞介導的疾病感到非常興奮。

As we discussed, obviously, CD20, a well-established target in autoimmune disease, CD38, some -- there is a smaller but very interesting data set, particularly in the setting of diseases such as lupus to support the potential utility of CD8 -- CD38 targeting therapies. I think it is very important that we understand what the safety of our own CD38 x CD3 molecule looks like in multiple myeloma.

正如我們所討論的，顯然，CD20（自身免疫性疾病中的一個既定目標）、CD38，還有一些——有一個較小但非常有趣的數據集，特別是在狼瘡等疾病的背景下，以支持CD8 的潛在效用— CD38標靶治療。我認為了解我們自己的 CD38 x CD3 分子在多發性骨髓瘤的安全性非常重要。

As we've discussed, Steve, safety is clearly a very important consideration in the management of chronic diseases such as autoimmune disorders.

正如我們所討論的，史蒂夫，安全顯然是治療自體免疫疾病等慢性疾病的一個非常重要的考慮因素。

I will note, however, that even as we await those initial human data in multiple myeloma with 2644, we are in parallel performing preclinical studies to understand how this molecule could differentiate not only from imvotamab, but also other potential competitors in this space. So in summary, a lot of activity as we await that human data.

然而，我要指出的是，即使我們在等待2644 在多發性骨髓瘤中的初步人體數據，我們也在並行進行臨床前研究，以了解該分子如何不僅與imvotamab 區分開來，而且還與該領域的其他潛在競爭對手區分開來。總而言之，當我們等待人類數據時，有很多活動。

And our next question is from Greg Harrison with Bank of America.

我們的下一個問題來自美國銀行的格雷格·哈里森。

Congrats on the progress. First off, maybe could you give some additional color on the transition towards autoimmune indications for imvotamab? What was the decision process that led to the choice of lupus and RA and how broadly do you think imvotamab could be applied across the autoimmune disease?

祝賀取得的進展。首先，您能否對 imvotamab 向自身免疫適應症的過渡提供一些額外的資訊？導致選擇狼瘡和 RA 的決策過程是什麼？

Well, Mary Beth, I think that's probably a question for you. It's one we spend a lot of time thinking about it. It's very broad. So I'll leave you to go at it, Mary Beth.

好吧，瑪麗貝絲，我想這可能是你的問題。這是我們花了很多時間思考的問題。它非常廣泛。所以我就讓你自己去做吧，瑪麗貝絲。

Indeed, and thank you for that question. Again, the CD20 as a target in autoimmune disease, well established and a very broad data set out there in the literature with respect to how various approaches to CD20 and B-cell depletion may look in the management of different B-cell and autoantibody-mediated diseases.

確實如此，謝謝你提出這個問題。同樣，CD20 作為自體免疫疾病的靶標，在文獻中已得到充分證實，並且提供了非常廣泛的數據，涉及各種 CD20 和 B 細胞耗竭方法在不同 B 細胞和自身抗體的管理中的效果。導的疾病。

As I think back to the conversations that were taking place, as our company contemplated the choice of continued investment in NHL versus beginning to invest in autoimmunity, you heard the key points of that rationale earlier in the presentation. Given the level of competition, given the change in the regulatory and therefore, the commercial environment in the lymphoma space, right? The upside on the autoimmune front, again, given that this is a well-characterized target and one that could absolutely benefit from deeper B-cell depletion. Those are the things that really got us excited.

當我回想起正在進行的對話時，當我們公司考慮選擇繼續投資 NHL 而不是開始投資自身免疫時，您在演講的前面聽到了這一基本原理的要點。考慮到競爭程度、監管變化以及淋巴瘤領域的商業環境，對嗎？自體免疫方面的優勢再次顯現，因為這是一個特徵明確的目標，絕對可以從更深層的 B 細胞耗竭中受益。這些才是真正讓我們興奮的事。

If you have not seen the publication from Georg Schett at all from the University of Erlangen in September of 2022. Looking at an anti-CD19 CAR-T and 5 patients with severe lupus that really catalyzed a deeper look at what is possible through deep B-cell depletion, right? And we think that imvotamab, which we believe will enable deeper B-cell depletion than currently available anti-CD20s because we are not dependent upon local complement and local NK cells. We know from our preclinical data that imvotamab will deplete in the spleen, in the lymph nodes, in the bone marrow where reservoirs of pathogenic B cells can sometimes hide and basically continue to drive autoimmune disorders.

如果您根本沒有看過埃爾蘭根大學Georg Schett 於2022 年9 月發表的論文。 透過觀察抗CD19 CAR-T 和5 名患有嚴重狼瘡的患者，這確實催化了更深入地了解透過深B的可能性-細胞耗盡，對嗎？我們認為 imvotamab 能夠比目前可用的抗 CD20 更深地消除 B 細胞，因為我們不依賴局部補體和局部 NK 細胞。從臨床前數據我們得知，imvotamab 會在脾臟、淋巴結和骨髓中耗盡，而這些地方有時會隱藏致病性 B 細胞的儲存庫，並基本上繼續導致自體免疫疾病。

So our hope is that imvotamab will deliver that level of deep B-cell depletion that was suggested by the CAR-T data, but do so with an off-the-shelf product with a better safety profile, clearly lower cost and fewer logistical considerations. So we're quite excited and moving quickly.

因此，我們希望 imvotamab 能夠實現 CAR-T 數據所建議的深度 B 細胞消除水平，但使用具有更好安全性、明顯更低成本和更少後勤考慮的現成產品來實現這一點。所以我們非常興奮並且行動迅速。

So I might add there that in terms of -- Greg, to your question, why lupus and RA as the first 2 indications and where might we go beyond that. Lupus obviously, as Mary Beth mentioned, you've got the proof of concept with Georg Schett, and that paper of real immune modulation. That's obviously a great place for us to start because we think we've got advantages over CD19 CAR-Ts there. RA is a place where we think we can get a signal very quickly in terms of biomarkers and so forth.

所以我可能會補充一點，格雷格，對於你的問題，為什麼狼瘡和 RA 作為前兩個適應症，以及我們可以在哪裡超越這個適應症。顯然，狼瘡，正如瑪麗貝絲所提到的，你已經得到了喬治謝特的概念證明，以及那篇關於真正免疫調節的論文。這顯然對我們來說是一個很好的起點，因為我們認為我們比 CD19 CAR-T 更有優勢。 RA 是我們認為可以非常快速地獲得生物標記等訊號的地方。

But in terms of where we go after those 2, I think you can think more broadly. First, any place where CD20 has shown signs of clinical activity or efficacy. Those are good places and any place across the entire landscape of autoimmune diseases where you've got autoantibodies implicated in disease. And as was mentioned earlier, that includes not just B cells that you might be able to take out with a CD20 T-cell engager, but also B cells you might be able to take out with a CD38 or a combination of the 2.

但就我們在這兩個之後的發展方向而言，我認為你可以更廣泛地思考。首先，CD20已顯示出臨床活性或功效跡象的任何地方。這些都是好地方，也是整個自體免疫疾病領域中與疾病有關的自身抗體的任何地方。如前面所提到的，這不僅包括您可以使用 CD20 T 細胞接合器取出的 B 細胞，還包括您可以使用 CD38 或兩者的組合取出的 B 細胞。

So our landscape is just really, really broad here in terms of what we might be able to do with a portfolio of T-cell engagers in autoimmune disease. And we think we're in a -- we have the potential to be in a real leadership position here. And we think our safety is perhaps the most important differentiating factor.

因此，就我們利用 T 細胞參與者組合在自體免疫疾病中的應用而言，我們的前景非常非常廣闊。我們認為我們有潛力在這裡處於真正的領導地位。我們認為我們的安全可能是最重要的差異化因素。

Mary Beth, did you want to add to that?

瑪麗貝絲，你想補充一下嗎？

Yes. No. Thank you. I think those are absolutely critical comments, right? We expect these initial studies in patients this year to inform on which development programs make the most sense for this particular mechanism, right? And I think any -- for those of you who have been in the autoimmune space in the past, right, there is a lengthy list of potential diseases here.

是的。不，謝謝。我認為這些絕對是批評性的評論，對嗎？我們希望今年對患者進行的這些初步研究能告知哪些開發計畫對這種特定機制最有意義，對嗎？我認為，對於那些過去一直在自體免疫領域工作的人來說，這裡有一長串潛在的疾病。

We could also think about in addition to the anti-CD20s and where the CAR-Ts are currently going in autoimmune disease, we could even contemplate perhaps where the SCRMs are going. So there is, as Fred indicated, there is a very broad range of opportunities.

除了抗 CD20 和 CAR-T 目前在自體免疫疾病中的發展方向之外，我們還可以考慮 SCRM 的發展方向。因此，正如弗雷德所指出的，存在著非常廣泛的機會。

And I will come back to his last remark, right? We not only have a very active molecule, but we think we've got a safety profile that will define the bar for this new class of therapies around T-cell engagers in autoimmunity. So it's an exciting place to be.

我會回到他的最後一句話，對吧？我們不僅擁有非常活躍的分子，而且我們認為我們已經擁有了安全性，它將定義這種圍繞自身免疫 T 細胞參與劑的新型療法的標準。所以這是一個令人興奮的地方。

Great. Great. That's super helpful. Maybe just one other, if I can, a much narrower question on 8444, the biomarker data that you discussed looks encouraging, you're seeing in almost every patient. How would you expect that to correlate into a clinical response?

偉大的。偉大的。這非常有幫助。如果可以的話，也許只是另一個關於 8444 的更狹窄的問題，您討論的生物標誌物數據看起來令人鼓舞，您幾乎在每個患者身上都看到了這一數據。您認為這與臨床反應有何關聯？

Chris, do you want to take that one?

克里斯，你想買那個嗎？

Yes. No, great question, Greg. So obviously, this is something that we're looking at very carefully. I think, though, when you first -- when you think about caspase-3, it's a cell death biomarker. It really is an indication of how well your agent is engaging the target and target pathway. And so the most important information is that it's telling us that the signal of engagement in modulating the extrinsic apoptotic pathway is quite strong at 10 milligrams per kilogram.

是的。不，很好的問題，格雷格。顯然，這是我們正在非常仔細地研究的事情。不過，我認為，當您第一次想到 caspase-3 時，它是一種細胞死亡生物標記。它確實表明您的代理參與目標和目標路徑的程度。因此，最重要的訊息是，它告訴我們參與調節外源性細胞凋亡途徑的訊號在每公斤 10 毫克時非常強烈。

We're obviously looking at how this correlates with other clinical parameters. And again, the data are still very early, so we can't really draw any direct conclusions there. But again, in terms of pharmacodynamic marker, we think it's very, very positive and very informative.

顯然，我們正在研究這與其他臨床參數的相關性。再說一次，數據還很早期，所以我們不能真正得出任何直接的結論。但同樣，就藥效學標記而言，我們認為它非常非常積極且資訊豐富。

Great. That's helpful. And congrats again on all the progress.

偉大的。這很有幫助。再次恭喜所有的進展。

Thank you.

謝謝。

And our next question is from Michael Schmidt with Guggenheim.

我們的下一個問題來自古根漢的邁克爾·施密特。

I had 2, perhaps the one on 8444, you updated us on your combination arm with birinapant as well, which seems to be progressing in dose escalation. Can you just remind us which types of patients are likely to respond to that particular combination? Just curious how you think about that. And then on CD20, obviously, a large commercial opportunity across a huge number of indications here. Does that shift in development strategy affect how you think about partnerships for this program that perhaps could maximize the opportunity if you have a large company on board for that?

我有 2 個，也許是 8444 上的那個，您也向我們更新了您的 birinapant 聯合用藥，劑量似乎正在逐步增加。您能否提醒我們哪些類型的患者可能會對這種特定組合產生反應？只是好奇你對此有何看法。然後在 CD20 上，顯然，這裡有一個跨越大量適應症的巨大商業機會。發展策略的轉變是否會影響您對該計劃的合作夥伴關係的看法，如果您有一家大公司參與其中，也許可以最大限度地利用機會？

So Chris, why don't you take the first question, and I'll take the second one?

那麼克里斯，為什麼你不回答第一個問題，我來回答第二個問題呢？

Sure. Yes. So with regards to the birinapant combination, so obviously, we're in a dose escalation part of the study. And just to be clear, we're escalating the dose of birinapant in this study. And we're conducting this in patients with all different types of solid tumors. So it's a standard solid tumor Phase I dose escalation study that is continuing to go on.

當然。是的。因此，對於 birinapant 組合，顯然我們正處於研究的劑量遞增部分。需要明確的是，我們在這項研究中增加了 birinapant 的劑量。我們正在對所有不同類型的實體瘤患者進行這項研究。因此，這是一項標準的實體腫瘤 I 期劑量遞增研究，仍在繼續進行。

The -- in terms of where we might take this, again, our strong interest in birinapant in this combination, was really built on the preclinical models that showed strong synergy as well as the scientific mechanistic understanding of how a SMAC mimetic could obviously combine very well with a stimulator agonist of the extrinsic apoptotic pathway. And so we've seen activity in a range of different preclinical models.

就我們可能採取的方式而言，我們對這種組合中的birinapant 的強烈興趣實際上是建立在臨床前模型的基礎上的，這些模型顯示出強大的協同作用，以及對SMAC 模擬物如何明顯地結合起來的科學機制理解。因此，我們已經看到了一系列不同臨床前模型的活動。

I don't know, Bruce, do you want to comment a little bit to that in terms of where we think this is promising.

我不知道，布魯斯，你是否想就我們認為這是有希望的方面對此發表一些評論。

Yes, yes. Michael, thank you for the question. I mean we have tested literally hundreds of different cell lines and patient samples in tumors. And we are, of course, always interested in any mechanism action type signals, but as well as prognostic indicators that might steer us. But what is really exciting, as Chris mentioned, is we do see with the treatment of FOLFIRI, particularly 5-FU and irinotecan, you get the synergy, but you also get upregulation of DR5, which may combine well and set us up for success with 8444 treatment.

是的是的。邁克爾，謝謝你的提問。我的意思是，我們已經在腫瘤中測試了數百種不同的細胞系和患者樣本。當然，我們總是對任何機制動作類型訊號感興趣，但也對可能引導我們的預後指標感興趣。但真正令人興奮的是，正如Chris 所提到的，我們確實看到FOLFIRI 的治療，特別是5-FU 和伊立替康，不僅能產生協同作用，而且還能上調DR5，這可能會很好地結合起來，為我們的成功奠定基礎。

Now still having that, we'll, of course, have to do the studies. But the combination -- the clinical study is to show where and when, which patients result in the best therapy. But we -- our preclinical data says that we're going to see a broad spectrum response in this and other indications.

現在仍然有這個，我們當然必須進行研究。但臨床研究的結合是為了顯示在何時何地哪些患者可以獲得最佳治療。但我們的臨床前數據表明，我們將在這種適應症和其他適應症中看到廣泛的反應。

And I think with respect to the specific question of birinapant, we think that, that very much could be broadly applicable against a lot of different solid tumors. And hopefully, with the combination of 8444 and birinapant, little or no additional toxicity. And so there may be multiple combinations here that are possible going forward. So very encouraging to -- as Michael, as you know, with those 2 agents, we're hitting both the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. And we think that's a real important 1, 2 punch that could be -- with no seeming additional toxicity could be very, very helpful.

我認為，關於 birinapant 的具體問題，我們認為，它可以廣泛適用於許多不同的實體腫瘤。希望 8444 和 birinapant 結合使用時，幾乎沒有或沒有額外的毒性。因此，未來可能會有多種組合。非常令人鼓舞的是——正如邁克爾，如你所知，透過這兩種藥物，我們同時達到了外在細胞凋亡途徑和內在細胞凋亡途徑。我們認為這是一個真正重要的一、二拳，沒有看似額外的毒性可能會非常非常有幫助。

Right. I mean we clearly have quite a body of data showing that we have high safety in both of these. And now preclinically, we see, again, a series of animal models and in vitro where the combination with birinapant intrinsic and 8444 intrinsic really combine well.

正確的。我的意思是，我們顯然有大量數據表明我們在這兩個方面都具有很高的安全性。現在，在臨床前，我們再次看到一系列動物模型和體外實驗，其中 birinapant 內在蛋白和 8444 內在蛋白的組合確實很好地結合在一起。

And thanks for your question about strategic partnerships for imvotamab, and I might expand it out to say imvotamab and our T-cell engagers for autoimmune perhaps more broadly. As you say, the opportunities there are large in number, large in size and could take a lot of money to pursue but with a lot of potential upside at the end of the pathway.

感謝您提出有關 imvotamab 戰略合作夥伴關係的問題，我可能會將其擴展為 imvotamab 和我們用於自身免疫的 T 細胞接合器，也許更廣泛。正如你所說，那裡的機會數量多、規模大，可能需要大量資金才能實現，但最終有很大的潛在上升空間。

So I think that strategically finding a partner that was looking to join us to explore this really new opportunity of T-cell engagers in autoimmune disease would be a really good thing for us as a company. Now exactly what the timing of that is, we'll have to wait and see. But long term, I think the opportunities are so large and so many different things we could do. I think a partner would be a really good idea for that franchise, if you will.

因此，我認為策略性地尋找一個希望與我們一起探索 T 細胞參與自體免疫疾病這一真正新機會的合作夥伴對於我們公司來說是一件非常好的事情。現在具體的時間是什麼，我們必須拭目以待。但從長遠來看，我認為機會非常大，我們可以做很多不同的事情。如果你願意的話，我認為合作夥伴對於該系列來說是一個非常好的主意。

And our next question is from Roger Song with Jefferies.

我們的下一個問題來自 Jefferies 的 Roger Song。

Great. Congrats on all the progress across broad IGM pipeline. So maybe 2 quick clarification from us. So one is for 8444 DR5. As you are focused on the randomized trial for 3 mg and the 10 mg, would you keep enjoying higher dose in your single-arm study considering you may -- maybe just test the safety and the PD marker. And also if or when you will report additional data from the single-arm day trial?

偉大的。恭喜 IGM 廣泛管道取得的所有進展。我們可能需要快速澄清一下。所以其中一個適用於 8444 DR5。當您專注於 3 毫克和 10 毫克的隨機試驗時，考慮到您可能——也許只是測試安全性和 PD 標誌物，您會在單臂研究中繼續享受更高劑量嗎？另外，您是否或何時會報告單臂日間試驗的額外數據？

And also for the imvotamab, I noticed your -- when you talk about the lupus and RA, you use the nomenclature severe form of the disease. Just curious, as you position your T-cell engager for autoimmune disease, what is the real target population for each indication? It will be the last line of the therapy at the starting point or you will potentially move into the early stage of the disease for those autoimmune disease? That's 2 questions we have.

對於 imvotamab，我注意到，當您談論狼瘡和 RA 時，您使用了該疾病的嚴重形式的術語。只是好奇，當您針對自體免疫疾病定位 T 細胞接合器時，每種適應症的真正目標族群是什麼？這將是起點治療的最後一行，還是您可能會進入那些自體免疫疾病的早期階段？這是我們的兩個問題。

Sure. Well, Chris, do you want to take the first one and then hand off to Mary Beth to take the second one?

當然。好吧，克里斯，你想拿第一個然後交給瑪麗貝絲拿第二個嗎？

Sure. So Roger, your question was really about the dose of 8444, now that we're exploring 10 milligrams per kilogram in the randomized study. And as you're probably aware and we've talked about before in our monotherapy part of the study, we went as high as 10 milligrams per kilogram, but we did not go higher.

當然。所以羅傑，你的問題實際上是關於 8444 的劑量，現在我們正在隨機研究中探索每公斤 10 毫克。正如您可能知道的那樣，我們之前在研究的單一療法部分中也談到過，我們的劑量高達每公斤 10 毫克，但並沒有更高。

There were no -- any safety signals that arose. We didn't define dose-limiting toxicities or a maximum tolerated dose. And that was also true going up to 10 milligrams per kilogram in combination with FOLFIRI chemotherapy. So there are really no safety issues there.

沒有出現任何安全訊號。我們沒有定義劑量限制毒性或最大耐受劑量。與 FOLFIRI 化療合併使用高達 10 毫克/公斤時也是如此。所以那裡確實不存在安全問題。

But as we look across the program and the experience, particularly the preclinical experience, the -- in terms of the efficacy and exposures that we're achieving that show activity in preclinical models, we feel that 10 milligrams per kilogram is a good dose, and we don't feel that there is a strong need to explore higher doses. It is something we would potentially leave open, but at least in our thinking today, we're really pleased with what we're seeing at 3 milligrams per kilogram. We want to get more experience in combination at 10 milligrams per kilogram and really start to think about how we optimize the dose in that range.

但當我們縱觀整個計畫和經驗，特別是臨床前經驗時，就我們所實現的功效和暴露量而言，我們在臨床前模型中顯示出活性，我們認為每公斤10 毫克是一個不錯的劑量，我們認為沒有強烈的必要去探索更高的劑量。我們可能會對此保持開放態度，但至少在我們今天的想法中，我們對每公斤 3 毫克的情況感到非常滿意。我們希望獲得更多每公斤 10 毫克的組合經驗，並真正開始思考如何優化該範圍內的劑量。

Roger, this is Mary Beth -- sorry.

羅傑，這是瑪麗貝絲——抱歉。

Well, I think there was the additional question of when we might show some of the monotherapy data there. And I think we just have not made a decision as to when and in what context we would produce additional monotherapy data. I think we're very focused on the randomized data. We're certainly not seeing anything in the monotherapy data that's inconsistent with what we've seen to date that would cause us to question our decision to move forward into this randomized study. So -- but at some point, we will present those data. We just haven't made a decision when, Roger.

嗯，我認為還有一個問題是我們什麼時候可以在那裡展示一些單一療法的數據。我認為我們只是還沒有決定何時以及在什麼情況下我們將產生額外的單一療法數據。我認為我們非常關注隨機數據。我們當然沒有在單一療法數據中看到任何與我們迄今為止所看到的不一致的東西，這會導致我們質疑我們繼續進行這項隨機研究的決定。所以，但在某個時候，我們將展示這些數據。我們只是還沒做出決定，羅傑。

And Mary Beth, do you want to go -- the second question?

瑪麗貝絲，你想參加第二個問題嗎？

Yes. No, sure. Thanks, Roger, for the question. You're absolutely correct. We are focusing initially on severe SLE and severe RA. Our intention is to establish initial safety and activity in those populations and then move into milder population. So obviously, a much more expansive group of patients on both fronts.

是的。不確定。謝謝羅傑的提問。你是完全正確的。我們首先關注嚴重的 SLE 和嚴重的 RA。我們的目的是在這些人群中建立初步的安全性和活動性，然後進入較溫和的人群。顯然，這兩個方面的患者群體都更加廣泛。

This is true particularly in light of the potential for disease modification through this approach as suggested by that CAR-T data from George Schett. So thanks for the question.

正如 George Schett 的 CAR-T 數據所表明的那樣，考慮到透過這種方法改變疾病的潛力，這一點尤其正確。謝謝你的提問。

Great. Maybe just a quick follow-up, maybe a clarification for Fred. So what I meant is for the additional single-arm data from the combination -- also from a combination you have been doing the monotherapy. But I believe the answer is similar. You haven't decided when you will...

偉大的。也許只是一個快速的跟進，也許是對弗雷德的澄清。所以我的意思是來自組合的額外單臂數據 - 也來自您一直在進行單一療法的組合。但我相信答案是相似的。你還沒決定什麼時候...

Yes. We have not decided that we'll -- at some point, we'll be presenting additional single-arm data on the FOLFIRI combination. At some point, we're presenting additional -- we'll be presenting our initial single-arm data on the birinapant combination. And at some point, we'll be presenting our initial single-arm data on the venetoclax combination. But we have not made a decision on when those data disclosures might happen where we're still all in progress on all of those studies right now.

是的。我們尚未決定在某個時候提供有關 FOLFIRI 組合的額外單臂資料。在某個時候，我們將展示更多關於 birinapant 組合的初始單臂資料。在某個時候，我們將展示有關 Venetoclax 組合的初始單臂資料。但我們尚未決定何時披露這些數據，目前所有這些研究仍在進行中。

Our next question is from Joel Beatty with Baird.

我們的下一個問題來自喬爾·比蒂和貝爾德。

Great. The first one is on the DR5 randomized study. How would you define success from that study?

偉大的。第一個是 DR5 隨機研究。您如何定義研究的成功？

I think we'll certainly know it when we see it, but I'm going to leave it to Chris to talk more about what we've got in mind.

我想當我們看到它時我們肯定會知道，但我會讓克里斯更多地談論我們的想法。

Yes. So thanks, Joel. Yes. So the study is designed with PFS as the primary endpoint. Obviously, we will be also looking at response rate and overall survival. The reason why we're really focusing on PFS though is that, one, that's much more strongly correlated with overall survival. And at least in the eyes of the FDA is much more an endpoint, which is -- has a much higher track record in terms of actually being a registration -- potential registrational endpoint.

是的。所以謝謝，喬爾。是的。因此，研究的設計以 PFS 作為主要終點。顯然，我們還將關注回應率和整體存活率。我們真正關注 PFS 的原因是，第一，它與整體生存期的相關性更強。至少在 FDA 看來，它更像是一個終點，在實際註冊方面擁有更高的追蹤記錄，是潛在的註冊終點。

And as we start to think about now randomized data supporting accelerated approval, that's really what has led us to design the study in the current way.

當我們開始考慮現在支持加速批准的隨機數據時，這確實是導致我們以當前方式設計研究的原因。

In terms of what the success look like, again, we don't -- I never like to give really specific targets, but we -- our expectation is that if you look at historical second line colorectal cancer data will FOLFIRI control arms for large randomized studies.

就成功的情況而言，再次強調，我們不會——我從來不喜歡給出真正具體的目標，但我們——我們的期望是，如果你看看二線結直腸癌的歷史數據，FOLFIRI 將會控制大範圍的癌症。

The PFS tends to be 5, 6 months or so in those studies and things in the not-too-distant past. So those -- that kind of gives you a floor, but we think where we need to be better and where we expect to be substantially better -- but that's kind of the thinking that has gone into the design of the trial.

在這些研究和不太遙遠的過去的事情中，PFS 往往是 5、6 個月左右。因此，這些——這給了你一個底線，但我們認為我們需要在哪些方面做得更好，以及我們期望在哪些方面做得更好——但這就是試驗設計中所考慮的。

Yes. I mean we really are looking for, hopefully, a significant improvement on PFS over control here, something that's clinically meaningful so...

是的。我的意思是，我們確實希望在 PFS 控制方面取得顯著改善，這是有臨床意義的，所以…

Got it. Okay. Sounds great. And then also on the same agent, now that you're focusing more on the 10-milligram dose, is there a risk of seeing some of the liver issues that we're seeing with other agents targeting the target?

知道了。好的。聽起來很棒。然後，同樣的藥物，現在您更專注於 10 毫克劑量，是否存在我們在其他針對目標的藥物中看到的一些肝臟問題的風險？

Joel, what I would say is, again, based on our monotherapy experience, we did not see any dose-related issues. We didn't see any issues around treatment-related liver toxicity in general, and we certainly didn't see anything that emerged at higher doses. So our expectation is that, that would not be an issue, and it hasn't been and we don't expect it to be an issue in the future.

喬爾，我想說的是，根據我們的單一治療經驗，我們沒有看到任何劑量相關的問題。一般來說，我們沒有發現任何與治療相關的肝毒性問題，我們當然也沒有看到更高劑量時出現的任何問題。因此，我們的期望是，這不會成為問題，而且過去也不是，我們預計它將來也不會成為問題。

Yes. And we dosed, as we said, 3 patients in combination with FOLFIRI didn't see anything there. We have dosed some patients in combination with birinapant and 10 mg/kg too and did not see any signal there. So we're not expecting to see a safety signal, a liver hepatotoxicity signal. But I guess that's why you do the study, but not expecting it.

是的。正如我們所說，我們給 3 名與 FOLFIRI 聯合用藥的患者沒有看到任何東西。我們也給一些患者聯合服用 birinapant 和 10 mg/kg，但沒有看到任何訊號。因此，我們不希望看到安全訊號、肝毒性訊號。但我想這就是你進行這項研究但沒有想到的原因。

And our next question is from Noah Eisenberg with JPMorgan.

我們的下一個問題來自摩根大通的諾亞艾森伯格。

This is Noah on for Eric. Just kind of looking at the second line randomized trial for 8444. Noticing that you're stratifying by KRAS status. So based on that, I'm wondering, is there any synergistic potential between DR5 activation and EGFR inhibition and to what -- and to what extent are you interested in evaluating EGFR combos or KRAS inhibitor combinations as part of the bev development strategy?

這是諾亞為埃里克做的。只要查看 8444 的二線隨機試驗。因此，基於此，我想知道DR5 活化和EGFR 抑制之間是否存在任何協同潛力，以及您對評估EGFR 組合或KRAS 抑制劑組合作為bev 開發策略的一部分感興趣到什麼程度以及在多大程度上感興趣？

So maybe I can start. Obviously, the colorectal cancer space, there are -- we're starting to see molecular profiling, obviously, have a big treatment impact on different treatment options. But one of the things that's been very clear to us, at least preclinically and also thus far in the clinic, is that through our mechanism, we think we should work well in a variety of different molecular subtypes, so KRAS wild-type, KRAS mutant. We expect and what we're seeing so far, again, small numbers, and we'll obviously look at this further but we don't expect to see really any differences in terms of just we expect to be active in all those subpopulations.

所以也許我可以開始了。顯然，在大腸直腸癌領域，我們開始看到分子分析顯然對不同的治療方案有很大的影響。但我們非常清楚的一件事是，至少在臨床前以及迄今為止的臨床中，我們認為透過我們的機制，我們應該在各種不同的分子亞型中表現良好，因此 KRAS 野生型、KRAS突變體。我們預計，到目前為止我們所看到的，再次是小數字，我們顯然會進一步研究這一點，但我們預計不會在我們期望在所有這些亞人群中活躍方面看到真正的任何差異。

That being said, as we think about really having a maximal impact on this disease and where do we go if we can confirm the signal and then where else do we go, we would obviously be open to exploring other combinations in the space as we start to broaden the program. But at least the development and plans now is to try and go more broadly across different molecular subtypes.

話雖這麼說，當我們考慮真正對這種疾病產生最大影響，如果我們能夠確認信號，我們該去哪裡，然後我們還能去哪裡，我們顯然會在開始時願意探索該領域的其他組合擴大該計劃。但至少現在的發展和計劃是嘗試更廣泛地跨越不同的分子亞型。

And I don't know, Bruce, there was kind of a mechanistic question there that maybe you can...

我不知道，布魯斯，那裡有一個機械問題，也許你可以...

Yes. No, it's a very good question. It's certainly an active area of research. We -- as Chris mentioned, we haven't seen differences due to KRAS positive or negative, but it could -- likely we'd work in both. But the opportunity to combine still is a good opportunity. We're investigating preclinically.

是的。不，這是一個非常好的問題。這無疑是一個活躍的研究領域。正如 Chris 所提到的，我們還沒有看到 KRAS 陽性或陰性造成的差異，但我們可能會在這兩種情況下工作。但結合的機會仍然是一個很好的機會。我們正在臨床前研究。

And our next question is from Brian Abrahams with RBC Capital Markets.

我們的下一個問題來自加拿大皇家銀行資本市場部門的布萊恩亞伯拉罕斯 (Brian Abrahams)。

It's Leo on for Brian. I had maybe a couple on the pipeline. So maybe starting with 7354, can you talk about, given the initial clean safety data there in 2 patients. Is this a dose you think could be active? And then I guess, when do you think we may get to doses where we'll have more activity? And where is the preclinical data steering you in terms of what doses you want to reach, what tumor types might be most active? And do you think you can also target low PD-1 expressing cells? Or is your strategy still going to be enriched. And then I had maybe a follow-up on 2644 as well.

萊奧 (Leo) 替補布萊恩 (Brian)。我可能還有幾個正在醞釀。考慮到 2 名患者的初步安全數據，您可以從 7354 開始談談嗎？您認為這個劑量可以發揮作用嗎？然後我想，你認為我們什麼時候可以達到可以進行更多活動的劑量？臨床前數據在哪裡引導您達到什麼劑量，哪些腫瘤類型可能最活躍？您認為您也可以針對低 PD-1 表現細胞嗎？或者你的策略還會變得豐富嗎？然後我可能還有關於 2644 的後續行動。

Chris, do you want to take the -- that question?

克里斯，你想回答這個問題嗎？

Yes. So yes. So obviously, one of the things we do when we start a Phase I study is we -- based on the preclinical data, make estimations of where we think an efficacious exposure level is. And obviously, for safety reasons and things in a dose escalation study, you generally start low and escalate. But I will say that -- so in terms of our expectation going into the study, we would have thought that maybe in dose cohort 3 or 4 we would be sort of entering the range that we saw clear actions in preclinical models.

是的。所以是的。顯然，當我們開始第一階段研究時，我們要做的一件事就是根據臨床前數據，估計我們認為有效的暴露程度。顯然，出於安全原因和劑量遞增研究中的原因，通常從低劑量開始逐漸增加。但我要說的是，就我們對這項研究的期望而言，我們會認為，也許在第 3 或第 4 組劑量中，我們會進入我們在臨床前模型中看到的明顯作用的範圍。

But I think the other factor is that IL-15 is a potent agonist and we've shown, certainly our molecules have been able to hit the target. So the safety, we think is good, but we -- we're also through our biomarkers looking at pharmacodynamic effects even at the lowest dose levels. And I think we're off to a good start, and we'll have more to talk about in the future about this. But there is certainly the potential that we could start seeing evidence that we're hitting the target even at the lowest dose levels in the study.

但我認為另一個因素是 IL-15 是一種有效的激動劑，我們已經證明，我們的分子確實能夠擊中目標。因此，我們認為安全性很好，但我們也透過生物標記來研究藥效學效應，即使在最低劑量水平下也是如此。我認為我們有了一個好的開端，將來我們將有更多的主題來討論這個問題。但我們肯定有可能開始看到證據，表明即使在研究中的最低劑量水平下，我們也能達到目標。

Got it. And then maybe one on 2644. Obviously, there's a few different bispecifics in multiple myeloma now BCMA, GPRC5D. How are you thinking about how 2644 is going to play in the space and the advantages that you might have over some of the other offerings?

知道了。然後可能是 2644 上的一個。您如何看待 2644 將如何在該領域發揮作用以及您相對於其他一些產品可能擁有的優勢？

Maybe I'll start with that and then let Chris take over. But we see 2644 as pretty different, at least the way we're intending to develop it as hopefully quite differentiated from those other bispecifics. We would like to see this as a next-generation CD38 molecule. And so we would like to, assuming safety and efficacy, we'd like to randomize against dara as fast as we can in order to show that we can potentially work better than dara in some of those patients who've maybe seen dara previously and then maybe eventually moving up. So the focus here for 2644 is a, hopefully, a next-generation CD38.

也許我會從這個開始，然後讓克里斯接手。但我們認為 2644 非常不同，至少我們打算開發它的方式希望與其他雙特異性抗體完全不同。我們希望將其視為下一代 CD38 分子。因此，在假設安全性和有效性的情況下，我們希望盡快對 dara 進行隨機分組，以表明我們可能比 dara 在一些以前可能見過 dara 的患者中效果更好，並且然後也許最終會上升。因此，2644 的焦點有望是下一代 CD38。

Chris, you want to add to that?

克里斯，你想補充嗎？

Yes. And it is a crowded space with bispecifics, but about 10 or 12 of those are all BCMA CD3 bispecifics and you have the BCMA CAR-T cells coming into this space. And I can tell you that the fact that we're not a BCMA bispecific is actually an important differentiating factor. Obviously, there's been reported cases of resistance to CAR-T cell therapy in multiple myeloma through loss of the BCMA antigen and things. And so it's not necessarily clear you'd want to use the BCMA targeting bispecific before you would use the CAR T cell or that you could use it afterwards.

是的。這是一個充滿雙特異性細胞的擁擠空間，但其中大約 10 或 12 個都是 BCMA CD3 雙特異性細胞，而 BCMA CAR-T 細胞進入這個空間。我可以告訴您，我們不是 BCMA 雙特異性抗體這一事實實際上是一個重要的差異化因素。顯然，有報告指出多發性骨髓瘤患者因 BCMA 抗原的缺失而對 CAR-T 細胞療法產生抗藥性。因此，在使用 CAR T 細胞之前或之後使用它，您不一定要使用 BCMA 靶向雙特異性抗體。

So the fact CD38 bispecifics. There are many fewer out there. There are a handful of other targets in multiple myeloma for bispecifics too, but it's not anywhere near as crowded as BCMA. So we think there's a way to differentiate there. And then Fred has already outlined a major tenant to our strategy here, and that is to really think about this as potentially the best CD38 targeting agent in this class. So that's really kind of driving our strategic thinking at this point.

事實上CD38是雙特異性的。那裡的人少很多。多發性骨髓瘤中還有一些雙特異性標靶，但它並不像 BCMA 那麼擁擠。所以我們認為有一種方法可以實現差異化。然後 Fred 已經在這裡概述了我們策略的一個主要租戶，那就是真正將其視為此類中潛在的最佳 CD38 靶向劑。因此，這確實推動了我們目前的戰略思維。

And our last question is from Asthika Goonewardene with Truist.

我們的最後一個問題來自 Asthika Goonewardene 和 Truist。

And I appreciate all the color you provided today. So Chris, I have a couple of questions for you here. On your slide where you have the caspase-3 increase, what was the on treatment -- when was the on-treatment measurement made at which cycle perhaps again tells that? And then do you expect a change in baseline to increase with subsequent cycles? And then related to that, you had 4 patients that you profile, the 5 patient profiles, including 4 with PRs and then 1 went on to curative surgery, what's the level of increase in caspase-3 that you noted in those profile patients? And then I've got a couple of follow-ups.

我很欣賞你今天提供的所有顏色。克里斯，我有幾個問題想問你。在你的幻燈片上，caspase-3 增加，治療中的情況是什麼——治療中的測量是什麼時候在哪個週期進行的，也許再次說明了這一點？那麼您預期基線的變化會隨著後續週期的增加而增加嗎？與此相關的是，您對4 名患者進行了分析，這5 名患者分析，其中4 名患者獲得PR，然後1 名繼續進行根治性手術，您在這些分析患者中註意到caspase-3 的增加水平是多少？然後我有一些後續行動。

Sure. Yes. No, thanks for the question. So just to be clear on our biomarker slide, what we're doing -- so these are our normalized data. So not surprisingly, caspase-3 levels in the plasma are -- came very highly at baseline from our patients. So what we've done is taken the pretreatment sample, normalized that to one and then showed the relative change.

當然。是的。不，謝謝你的提問。因此，為了在我們的生物標記幻燈片上清楚地表明我們正在做什麼——這些是我們的標準化數據。因此，毫不奇怪，我們患者的血漿中 caspase-3 水平在基線時非常高。因此，我們所做的就是取得預處理樣本，將其歸一化為 1，然後顯示相對變化。

And actually, the data that we're showing you here. So we monitor the caspase levels during the first cycle, second cycle. And what we're actually showing here is actually the maximum change that we see in the caspase-3 levels in patients who are on study. Now that could vary somewhat at different time points. So though we do tend to see a very immediate rise in the caspase-3 levels with treatment. So it's something that's very consistent that we're seeing across our patients. But there is some noise to the -- and the timing of this. But in general, it goes up in essentially all of the patients that are on treatment.

實際上，我們在這裡向您展示的數據。因此，我們在第一個週期和第二個週期期間監測 caspase 水平。我們在這裡實際展示的是我們在研究患者中看到的 caspase-3 水平的最大變化。現在，在不同的時間點可能會有所不同。因此，儘管我們確實傾向於看到治療後 caspase-3 水平立即升高。因此，我們在患者身上看到的情況非常一致。但對於這事件及其時機，存在一些噪音。但總體而言，幾乎所有接受治療的患者都會出現這種情況。

Got it. And then...

知道了。進而...

And also how we looked at those specific patients and how their relative hold increase in caspase.

還有我們如何觀察這些特定患者以及他們的半胱天冬酶相對含量如何增加。

Yes. So we have those data. We've looked at things in terms of those patients that have shown seem to see clinical benefit and things. And again, it's just small numbers, so we really can't draw any conclusion. So we don't really have anything to share with you right now, although, obviously, we're going to be looking at this pharmacodynamic biomarker and correlating that with all different sort of other clinical endpoints in the study, particularly as we move forward.

是的。所以我們有這些數據。我們已經從那些似乎看到了臨床益處的患者的角度來看待事情。再說一遍，這只是很小的數字，所以我們真的無法得出任何結論。因此，我們現在確實沒有任何資訊可以與您分享，但顯然，我們將研究這種藥效生物標記物，並將其與研究中所有不同類型的其他臨床終點相關聯，特別是在我們前進的過程中。

Got it. Okay. And then, Chris, I mean, the slide with the biomarker suggest that there's 17 patients or so who have been treated at 10 milligrams per kg, could you maybe give us some color on that about what -- how many of those patients had colorectal cancer? Or if you can't tell us that was the distribution, similar the percentage of colorectal cancer patients, was the distribution similar to that seen at 3 mg per kg dose?

知道了。好的。然後，克里斯，我的意思是，帶有生物標誌物的幻燈片表明大約有17 名患者接受了每公斤10 毫克的治療，您能否給我們一些關於這些患者中有多少人患有結直腸癌症的資訊？或者，如果您不能告訴我們這就是分佈，類似於大腸直腸癌患者的百分比，那麼該分佈是否與每公斤劑量 3 毫克時觀察到的分佈類似？

Yes, yes. So the answer to the last part of your question is no, it's actually different. So the data that we're showing you here is a combination of the monotherapy dose escalation patients, which were in all tumor types as well as patients that were in the FOLFIRI combination arm. And we previously disclosed that we only treated 3 patients with 10 milligrams per kilogram in combination with FOLFIRI and only one of those was a colorectal cancer patient.

是的是的。所以你問題最後一部分的答案是否定的，它其實是不同的。因此，我們在這裡向您展示的數據是單一療法劑量遞增患者的組合，這些患者屬於所有腫瘤類型以及 FOLFIRI 組合組中的患者。我們之前披露過，我們僅用 10 毫克/公斤與 FOLFIRI 聯合治療了 3 名患者，其中只有一名是結直腸癌患者。

And because of the expansion at 3 milligrams per kilogram with FOLFIRI, the majority of patients that we're showing you with these biomarker changes in the 3-milligram per kilogram cohort are actually colorectal cancer patients that are being treated with -- in combination with FOLFIRI.

由於 FOLFIRI 的劑量擴大到每公斤 3 毫克，我們向您展示的每公斤 3 毫克隊列中的這些生物標記變化的大多數患者實際上是正在接受聯合治療的結直腸癌患者福爾菲里。

But that being said, one of the things obviously, that is a key question is how much, particularly for the combination patients, how much of this biomarker change is being driven by our 8444 molecule and how much is being driven just by chemotherapy. And we'll say, again, with small numbers, but when we look at this in our data set, we don't see much of an effect of FOLFIRI chemotherapy on this market. So we think it is likely more specific for the action of 8444. But in our randomized study, where we will have a control arm, and we will obviously continue to measure this, we will have more definitive data to share with you to really address that question.

但話雖如此，顯然，一個關鍵問題是，這種生物標記的變化有多少是由我們的 8444 分子驅動的，有多少是由化療驅動的，特別是對於聯合用藥的患者。我們會再說一遍，雖然數量很少，但當我們在資料集中查看這一點時，我們沒有看到 FOLFIRI 化療對這個市場有太大影響。因此，我們認為 8444 的作用可能更具體。問題。

Great. Fred, I got one last for you. You said at some point, I'm using air quotes here, for presenting data from the Phase I study on the different cohorts. Can I (inaudible) to say, at least one of them in some point this year?

偉大的。弗雷德，我為你準備了最後一張。您曾說過，我在這裡使用空氣引用來展示不同群體的第一階段研究的數據。我可以（聽不清楚）說，今年的某個時候至少有其中一個嗎？

On what are you talking -- the imvotamab study?

你在說什麼——imvotamab 研究？

No.

不。

8444.

8444。

8444. We have -- I've been really honest in saying we have not made a decision when we would do that. I would say that sometime this year is -- would be a reasonable hope, at least for some of those. But we honestly just have not decided. We've been so focused on getting the randomized study up and running and these new biomarker data that's really been our focus. And we'll turn to that question that you've asked shortly, I think.

8444. 我們已經－我非常誠實地說，我們還沒有決定何時這樣做。我想說，今年的某個時候——這將是一個合理的希望，至少對其中一些人來說是這樣。但老實說我們還沒決定。我們一直非常專注於隨機研究的啟動和運行，這些新的生物標記數據才是我們真正關注的焦點。我想我們很快就會討論您提出的這個問題。

Thank you. And I would now like to turn the conference back to Fred Schwarzer, Chief Executive Officer, for the closing remarks.

謝謝。現在我想請執行長弗雷德‧施瓦澤 (Fred Schwarzer) 致閉幕詞。

I'd like to thank you all for joining us on today's call, and we greatly appreciate your support. Thank you.

我要感謝大家參加今天的電話會議，我們非常感謝你們的支持。謝謝。

And this concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。