Cue Biopharma Inc (CUE) 2024 Q2 法說會逐字稿

Good day and welcome to the Cue Biopharma second-quarter 2024 earnings call. (Operator Instructions) Please note this event is being recorded.

大家好，歡迎參加 Cue Biopharma 2024 年第二季財報電話會議。（操作員指示）請注意，此事件正在被記錄。

I would now like to turn the conference over to our Chief Executive Officer, Mr. Dan Passeri. Please go ahead, sir.

現在，我想將會議交給我們的執行長丹·帕塞里先生。先生，請繼續。

Hey. Thank you, and good afternoon, everyone. As a reminder, this presentation and discussion is being recorded and will be available on our website for the next 30 days. Also, please be aware that the slides accompanying today's update may be advanced directly by those listening in, and we will notify you on what slide we're on throughout the presentation.

嘿。謝謝大家，下午好。提醒一下，本次演示和討論將被錄製，並將在接下來的 30 天內在我們的網站上提供。此外，請注意，今天更新的幻燈片可能會由聽眾直接播放，我們將在整個簡報過程中通知您我們正在播放哪張投影片。

Joining me on today's call is Dr. Anish Suri, our President and Chief Scientific Officer; and Dr. Matteo Levisetti, our Chief Medical Officer. Shown here on slide 2, this presentation and overview may contain some forward-looking statements, and any forward-looking statements made during this call represents the company's views only as of today, August 19, 2024.

參加今天電話會議的有我們的總裁兼首席科學官 Anish Suri 博士和我們的首席醫療官 Matteo Levisetti 博士。如投影片 2 所示，本簡報和概述可能包含一些前瞻性陳述，本次電話會議期間所做的任何前瞻性陳述僅代表本公司截至今天（2024 年 8 月 19 日）的觀點。

I'd like to begin the call by providing you with some context pertaining to our recent announcement focused upon near-term developments with our autoimmune programs and associated corporate restructuring. I'll begin with a brief synopsis of the objectives underlying these measures and just to underscore, we carefully assessed our strategic positioning and evaluated various options for optimizing probabilities of success within the challenges and constraints of the current capital market conditions. The measures recently implemented aim to reduce our capital requirements while also achieving enhanced productivity through what we consider to be basically a balanced business model focusing upon accessing capital and additional resources through a series of anticipated strategic partnerships.

我想先向您介紹一些有關我們最近發布的公告的背景信息，重點介紹我們的自身免疫計劃和相關公司重組的近期發展。我將首先簡要概述這些措施背後的目標，並強調，我們仔細評估了我們的策略定位，並評估了在當前資本市場條件的挑戰和限制下優化成功機率的各種選擇。最近實施的措施旨在減少我們的資本需求，同時透過我們認為基本上平衡的商業模式來提高生產力，該模式專注於透過一系列預期的策略合作夥伴關係獲取資本和額外資源。

Furthermore, we've taken measures for our clinical data to further mature to enhance competitive positioning, particularly relating to patient survival data, enabling near-term cost savings and delaying the launch of a capital-intensive trial towards registration. This path provides a higher probability of success as more mature data should bolster the veracity of our mechanistic advantages for establishing the potential of a new standard of care for cancer patients.

此外，我們已採取措施進一步完善我們的臨床數據，以增強競爭地位，特別是與患者生存數據相關的數據，從而實現短期成本節約，並推遲啟動資本密集型試驗以進行註冊。這條途徑提供了更高的成功機率，因為更成熟的數據應該能夠增強我們機制優勢的真實性，從而為癌症患者建立新的護理標準。

As shown in slide number 3, we believe we've developed a breakthrough proprietary therapeutic approach to establish a new standard of care for treating both cancer and autoimmune diseases by restoring immune balance to the patient's immune system. As Matteo will elaborate upon shortly, our data from the ongoing CUE-101 Phase 1b trial clearly demonstrates evidence of substantial prolongation of survival in patients treated with monotherapy in the second-line-plus setting and emerging data from the combination trial in frontline with Keytruda -- that's pembrolizumab -- that also appears to be following a similar pattern as what we saw with the monotherapy trial.

如幻燈片 3 所示，我們相信我們已經開發出一種突破性的專有治療方法，透過恢復患者免疫系統的免疫平衡，為治療癌症和自體免疫疾病建立新的護理標準。Matteo 稍後會詳細闡述，我們正在進行的 CUE-101 第 1b 階段試驗的數據清楚地表明，在二線加治療中接受單一療法治療的患者的生存期顯著延長，並且與 Keytruda（即 pembrolizumab）在一線進行的聯合試驗的新數據似乎也遵循了與我們在單一療法試驗中看到的類似的試驗。

We believe this data to be quite remarkable, underscoring what we believe to be the true competitive positioning of our approach. As such, it's our intention with the measures taken to enable clinical data to further develop and mature in support of our foundational platform that we believe can induce effective and long-lasting antitumor activity or can be harnessed to rebalance the aberrant immune responses to address autoimmune disease.

我們認為這些數據非常了不起，強調了我們認為我們的方法的真正競爭定位。因此，我們採取措施的目的是使臨床數據進一步發展和成熟，以支持我們的基礎平台，我們相信該平台可以誘導有效和持久的抗腫瘤活性，或可以利用該平台重新平衡異常的免疫反應來治療自體免疫疾病。

We've also made significant progress with our lead autoimmune disease program, CUE-401, being developed in collaboration with our partner, Ono Pharmaceuticals, to address multiple autoimmune and inflammatory diseases such as rheumatoid arthritis, graft-versus-host disease, lupus, inflammatory bowel disease, psoriasis, multiple sclerosis, amongst others, representing large multibillion-dollar market potential, addressing significant unmet medical need.

我們的主要自體免疫疾病計畫 CUE-401 也取得了重大進展，該計畫由我們與合作夥伴小野製藥 (Ono Pharmaceuticals) 合作開發，旨在治療多種自體免疫性和發炎性疾病，如類風濕性關節炎、移植物抗宿主疾病、狼瘡、發炎性腸道疾病、牛皮癬、多發性硬化症等，代表著數十億美元的巨大市場，尚未滿足了市場的巨大潛力。

Through this partnership, we've made impressive progress to date and moving towards selection of a lead candidate, which we anticipate in the first quarter of the coming year. Our collaboration with Ono has been highly productive and supportive, resulting in a growing body of promising data, demonstrating the ability of CUE-401 to generate and expand regulatory T cells or T-regs fostering disease control in several disease models tested to date. As a reminder, Cue Biopharma has retained an option to a 50% US co-development co-marketing rights to CUE-401.

透過此次合作，我們迄今已取得了令人矚目的進展，並朝著選出主要候選人的方向邁進，我們預計將在明年第一季完成這一目標。我們與小野公司的合作卓有成效且相互支持，產生了越來越多有希望的數據，證明了 CUE-401 能夠在迄今為止測試的幾種疾病模型中生成和擴增調節性 T 細胞或 T-regs，從而促進疾病控制。提醒一下，Cue Biopharma 保留了 CUE-401 50% 美國共同開發共同行銷權的選擇權。

Turning to 501, this program continues to advance and progress forward with the potential of eliminating autoreactive B cells with a highly selective and well-tolerated biologic. This program has the promise of addressing multiple B-cell-mediated autoimmune diseases such as lupus, myasthenia gravis, Sjogren's disease, and myositis, amongst others, representing significant unmet medical needs with large multibillion-dollar market potential.

談到 501，該計劃繼續向前推進並取得進展，有可能透過高度選擇性和耐受性良好的生物製劑消除自身反應性 B 細胞。該計畫有望解決多種 B 細胞介導的自體免疫疾病，例如狼瘡、重症肌無力、乾燥症和肌肉炎等，代表著巨大的未滿足的醫療需求，具有數十億美元的巨大市場潛力。

Furthermore, the same mechanism of action that we would be seeing in B-cell ablation for autoimmune disease may be deployed to address B-cell malignancies such as B-cell lymphoma. We're presently assessing strategic partnering alternatives for furthering the development of this promising program and look forward to providing updates as they become available.

此外，我們在治療自體免疫疾病的 B 細胞消融中看到的相同作用機制可能被用於治療 B 細胞惡性腫瘤，例如 B 細胞淋巴瘤。我們目前正在評估戰略合作夥伴的替代方案，以進一步推動這一有前景的項目的發展，並期待在獲得最新資訊後立即提供。

We have positioned ourselves with a growing portfolio of highly promising drug candidates in both oncology and autoimmune disease, all of which represents significant market opportunities addressing major unmet medical needs. We believe we've derisked and validated our therapeutics platform with the existing datasets from our CUE-101 and CUE-102 programs and have established foundational preclinical data pertaining to our autoimmune programs with potential to rebalance the patient's immune system to restore health. We've implemented a cash-efficient business model, enabling a reduction of capital requirements with an emphasis on validating near-term partnering structures.

我們擁有一系列極具前景的腫瘤和自體免疫疾病候選藥物，這些藥物都代表著解決重大未滿足醫療需求的重要市場機會。我們相信，我們已經利用 CUE-101 和 CUE-102 計畫的現有數據集降低了風險並驗證了我們的治療平台，並且已經建立了與我們的自身免疫計畫相關的基礎臨床前數據，有可能重新平衡患者的免疫系統以恢復健康。我們實施了現金高效的商業模式，從而能夠減少資本需求，並專注於驗證近期的合作夥伴結構。

I'm going to now turn the call over to Anish, who will describe the core attributes and advantages of our approach to treating autoimmune disease as well as provide some additional context on our underlying platform developments for both oncology and autoimmune disease. After Anish, Matteo will provide further updates on the CUE-101 and 102 clinical trials and highlight the importance of the maturing data sets with particular attention to the survival metrics that are emerging. I'll then return for a brief summary before opening the call up to questions. Anish?

現在我將把電話轉給 Anish，他將描述我們治療自體免疫疾病的方法的核心屬性和優勢，並提供一些有關我們針對腫瘤學和自體免疫疾病的基礎平台開發的額外背景資訊。在 Anish 之後，Matteo 將提供有關 CUE-101 和 102 臨床試驗的進一步更新，並強調成熟數據集的重要性，特別關注正在出現的生存指標。然後，我將回來做一個簡短的總結，然後再開始提問。阿尼什？

Thanks, Dan, and good afternoon to all listening in on today's call. I'll start by briefly summarizing our platform and the significant potential of our approach for restoring immune balance for treating cancers and autoimmune diseases. As described previously, the Immuno-STAT platform enables selective modulation of disease-relevant immune cells while avoiding broad perturbations of the immune system. This approach allows us to maximize efficacy while preserving patient safety.

謝謝，丹，各位收聽今天電話會議的朋友們，大家下午好。我將首先簡要概述我們的平台以及我們恢復免疫平衡以治療癌症和自體免疫疾病的方法的巨大潛力。如前所述，Immuno-STAT 平台能夠選擇性調節與疾病相關的免疫細胞，同時避免免疫系統的廣泛幹擾。這種方法使我們能夠最大限度地提高療效，同時保障患者安全。

As Dan indicated, previously and as summarized on slide 3, we have now clinically validated Immuno-STAT's via the CUE-100 series that selectively and safely delivers the potent cytokine IL-2, along with the TCR-activating signal to preferentially activate tumor-specific T cells while sparing all other relevant T cells. This selective stimulation allows for the generation of a therapeutic index for IL-2, which has eluded many others trying to develop IL-2 based cancer therapies.

正如 Dan 先前指出的以及幻燈片 3 中總結的那樣，我們現在已經透過 CUE-100 系列對 Immuno-STAT 進行了臨床驗證，該系列可以選擇性地、安全地傳遞強效細胞因子 IL-2 以及 TCR 激活信號，優先激活腫瘤特異性 T 細胞，同時保留所有其他相關 T 細胞。這種選擇性刺激可以產生 IL-2 的治療指數，而許多試圖開發基於 IL-2 的癌症療法的人卻未能做到這一點。

In over 120 patients dosed, we have demonstrated a remarkable increase in efficacy with favorable tolerability. Matteo will provide further details on the latest clinical data that continue to demonstrate impressive benefit for patients being treated with CUE-101 and CUE-102.

在超過 120 名接受治療的患者中，我們已證明療效顯著提高且耐受性良好。Matteo 將提供有關最新臨床數據的更多詳細信息，這些數據繼續證明接受 CUE-101 和 CUE-102 治療的患者將獲得顯著益處。

On the autoimmune front, we have focused on two distinct and highly promising approaches to reset immune balance. CUE-401 is a novel bispecific that stimulates the generation and expansion of regulatory T cells. Regulatory T cells or T-regs possess the ability to dampen and control autoreactive lymphocytes, hence are an important cell type to maintain immune homeostasis and health. CUE-401 has been partnered with Ono Pharmaceuticals, and this collaboration continues to move forward strongly.

在自體免疫方面，我們專注於兩種截然不同且極具前景的重置免疫平衡的方法來。CUE-401 是一種新型雙特異性藥物，可刺激調節性 T 細胞的產生和擴增。調節性 T 細胞或 T-reg 具有抑制和控制自體反應性淋巴細胞的能力，因此是維持免疫穩態和健康的重要細胞類型。CUE-401 已與小野製藥 (Ono Pharmaceuticals) 合作，且這項合作持續強勁推進。

In addition to CUE-401, we've also made significant progress developing CUE-501 from the CUE-500 series to enable T-cell-mediated depletion of B cells. This approach has the potential to deliver CAR-T-like efficacy in a biologic while preserving patient safety, which offers significant differentiation from other competing approaches. Both CUE-401 and CUE-500 series are designed to address large patient populations across numerous autoimmune and inflammatory diseases with a multibillion-dollar market potential. We will expand on both programs in the next few slides.

除了 CUE-401 之外，我們還在開發 CUE-500 系列中的 CUE-501 方面取得了重大進展，以實現 T 細胞介導的 B 細胞耗竭。這種方法有可能在生物製劑中實現類似 CAR-T 的功效，同時確保患者的安全，這與其他競爭方法有顯著的差異。CUE-401 和 CUE-500 系列均旨在解決眾多自體免疫和發炎疾病的患者群體，具有數十億美元的市場潛力。我們將在接下來的幾張投影片中詳細闡述這兩個程序。

The next slide, slide 4, exemplifies the unique attributes of CUE-401 in induction and expansion of T-regs. CUE-401 is a bispecific composed of the two key cytokine IL-2 and TGF beta that are known to convert peripheral CD4 T cells into T-regs as well as expand pre-existing natural T-regs. This ability to induce new populations of T-regs provides CUE-401 with the prospects of significant superiority over other approaches, deploying IL-2 variants to focus on only the pre-existing natural T-regs.

下一張投影片，即投影片 4，展示了 CUE-401 在誘導和擴展 T-regs 方面的獨特屬性。CUE-401 是一種雙特異性藥物，由兩種關鍵細胞因子 IL-2 和 TGFβ 組成，已知它們能夠將週邊 CD4 T 細胞轉化為調節性 T 細胞，並擴增預先存在的天然調節性 T 細胞。這種誘導新 T 細胞調節細胞群的能力使得 CUE-401 比其他方法具有顯著的優勢，利用 IL-2 變異體僅關注預先存在的天然 T 細胞調節細胞。

As shown on slide 4, we believe the mechanism of action of CUE-401 to enhance T-regs is qualitatively and quantitatively superior to IL-2 muteins targeting CD25, which is a high-affinity subunit of the IL-2 receptor expressed on regulatory T cells.

如幻燈片 4 所示，我們認為 CUE-401 增強 T-regs 的作用機制在質量和數量上均優於針對 CD25 的 IL-2 突變蛋白，CD25 是在調節性 T 細胞上表達的 IL-2 受體的高親和力亞基。

Slide 5 highlights data sets that show superiority of CUE-401 over an IL-2 mutein analog currently in clinical development for T-reg generation. As shown on the left side of the slide, in an in vitro human MLR assay, which is an in vitro model for graft-versus-host disease, CUE-401 induces differentiation and expansion of T-regs. In contrast, a T-reg-directed IL-2 mutein is unable to achieve these effects. The bottom-left panel confirms that both IL-2 and TGF-beta signals are needed for T-reg generation; either alone is unable to achieve this effect.

幻燈片 5 重點介紹了顯示 CUE-401 優於目前在 T-reg 生成臨床開發中的 IL-2 突變蛋白類似物的數據集。如幻燈片左側所示，在體外人類 MLR 試驗（移植物抗宿主疾病的體外模型）中，CUE-401 誘導 T-regs 的分化和擴增。相反，T-reg 指導的 IL-2 突變蛋白無法達到這些效果。左下圖證實，IL-2 和 TGF-beta 訊號都是 T-reg 生成所必需的；單獨使用任何一種都無法達到這種效果。

As shown on the right side and as previously discussed, short-term administration of CUE-401 results in long-term protection from autoimmunity, in this case, autoimmune gastritis. In our ongoing collaboration with Ono Pharmaceuticals, we have further extended the in vivo efficacy with CUE-401 in several other disease models where we have noted a significant increase in T-regs accompanied by a notable decrease in pro-inflammatory cytokines.

如右側所示及先前所討論的，短期服用 CUE-401 可長期預防自體免疫疾病，在本例中為自體免疫性胃炎。在我們與小野製藥的持續合作中，我們進一步擴展了 CUE-401 在其他幾種疾病模型中的體內療效，我們注意到 T-regs 顯著增加，同時促炎細胞因子顯著減少。

Let's now move to slide 6 to provide an overview and update on the CUE-500 series for B-cell depletion. The primary goal behind the design of the CUE-500 T-cell engagers was to achieve T-cell-mediated depletion of B cells while avoiding the adverse effects of systemic immune activation and broad engagement of all T cells. Our approach enables the potential to achieve CAR-T-like efficacy while avoiding the safety pitfalls of pan T-cell engagers.

現在我們轉到投影片 6，概述並更新用於 B 細胞耗竭的 CUE-500 系列。CUE-500 T 細胞接合器設計的主要目標是實現 T 細胞介導的 B 細胞耗竭，同時避免全身免疫活化和所有 T 細胞廣泛參與的不利影響。我們的方法有可能達到類似 CAR-T 的功效，同時避免泛 T 細胞接合器的安全隱憂。

By design the CUE-500 series Immuno-STATs bind to CD19 on B cells and effectively paint the B-cells with the viral epitope such as CMV. These B-cells are then readily recognized and killed by the memory antiviral T cells as shown in this slide.

根據設計，CUE-500 系列免疫統計 (Immuno-STAT) 與 B 細胞上的 CD19 結合，並有效地將病毒表位（如 CMV）塗在 B 細胞上。然後，這些 B 細胞很容易被記憶抗病毒 T 細胞識別並殺死，如本幻燈片所示。

Engaging virus-specific T cells or VSTs offers several advantages. These are trained killer T cells present in high frequency across the human population. They are localized in disease tissue and perform rapid killing of targets. And due to the specificity of virus antigens, the VSTs avoid the risk of potential reactivity against cell tissue or systemic immune activation as would be with pan T-cell engagers.

利用病毒特異性 T 細胞或 VST 具有多種優勢。這些是經過訓練的殺傷性 T 細胞，在人類中頻率很高。它們位於疾病組織中並快速殺死目標。而且由於病毒抗原的特異性，VST 避免了像泛 T 細胞接合劑那樣對細胞組織或全身免疫活化產生潛在反應的風險。

Importantly, and as shown in slide 7, VSTs, in this case CMV-specific memory T cells, can achieve the same degree of killing of B-cells as pan T-cell engagers, in this case, an anti-CD19, anti-CD3 bispecific molecule. Note here that the killing is specific to the engagement of CMV T cells since CUE-500 molecule expressing an HIV epitope is unable to mediate B-cell killing since HIV-specific T cells are largely absent in most individuals.

重要的是，如幻燈片 7 所示，VST（在本例中為 CMV 特異性記憶 T 細胞）可以達到與泛 T 細胞接合劑（在本例中為抗 CD19、抗 CD3 雙特異性分子）相同程度的 B 細胞殺滅效果。請注意，這種殺傷作用是特定於 CMV T 細胞的參與，因為表達 HIV 抗原決定基的 CUE-500 分子無法介導 B 細胞殺傷，因為大多數個體中 HIV 特異性 T 細胞基本上不存在。

Slide 8 further exemplifies the difference in safety and cytokine production between CUE-501 and pan T-cell engagers. Due to their high selective engagement, the CUE-501 molecule does not result in copious production of inflammatory cytokines such as interferon gamma and TNF as shown here. In contrast, a pan T-cell engager molecule due to its anti-CD3 binding to all T cells results in significantly higher levels of cytokine release, which ultimately compromises patient safety and drug tolerability.

幻燈片 8 進一步體現了 CUE-501 和泛 T 細胞接合劑在安全性和細胞激素產生方面的差異。由於其高度選擇性參與，CUE-501 分子不會導致大量產生發炎細胞因子，例如乾擾素γ和TNF（如圖所示）。相較之下，泛 T 細胞接合分子因其抗 CD3 與所有 T 細胞結合，導致細胞激素釋放水平顯著升高，最終損害患者安全和藥物耐受性。

The following slide, slide 9, highlights some of the notable points of differentiation between CUE-500 CAR-T approaches and pan T-cell engager molecules. Note that all three approaches involve T-cell-mediated killing of target B-cells, but it's only the CUE-500 series that can selectively engage trained memory killer T-cells and redirect them to kill B-cells.

下面的幻燈片 9 重點介紹了 CUE-500 CAR-T 方法和泛 T 細胞接合分子之間的一些顯著差異。請注意，這三種方法都涉及 T 細胞介導的目標 B 細胞殺滅，但只有 CUE-500 系列可以選擇性地參與訓練有素的記憶殺死 T 細胞並重新引導它們殺死 B 細胞。

The selective engagement while avoiding systemic activation results in a significant reduction in cytokine release and related toxicities, which should favor patient safety while preserving efficacy. We believe the CUE-500 series of biologics are likely positioned as the best-in-class T-cell engagers for B-cell depletion and could address a very large segment of autoimmune patients across many indications.

選擇性參與同時避免全身活化導致細胞激素釋放和相關毒性顯著減少，這有利於患者安全同時維持療效。我們相信 CUE-500 系列生物製劑很可能被定位為 B 細胞耗竭的最佳 T 細胞接合劑，並可以解決多種適應症中大量自體免疫患者的問題。

In summary, there are three key takeaway messages. First, due to the shared core structural framework that clinical de-risking and validation of Immuno-STAT in oncology via CUE-101 and CUE-102, including lack of clinically relevant immunogenicity bolsters and supports the clinical application of CUE-500 series for B-cell depletion in autoimmunity. Second, selective harnessing of antiviral-memory T cells to kill B cells, circumvents the safety risks associated with systemic T-cell activation, as noted with pan T-cell engagers And third, data demonstrating comparable killing while avoiding high levels of pro-inflammatory cytokine production positions the CUE-500 series to achieve desirable efficacy while not compromising patient safety, which is of highest clinical relevance when considering therapeutic applications in autoimmune diseases.

總而言之，有三個關鍵訊息。首先，由於透過 CUE-101 和 CUE-102 對腫瘤學中的 Immuno-STAT 進行臨床去風險和驗證具有共同的核心結構框架，包括缺乏臨床相關的免疫原性，從而增強並支持了 CUE-500 系列在自體免疫中 B 細胞耗竭的臨床應用。其次，選擇性利用抗病毒記憶 T 細胞殺死 B 細胞，可避免與全身性 T 細胞活化相關的安全風險，正如泛 T 細胞接合劑所指出的那樣；第三，數據顯示，在避免高水平促炎細胞因子產生的同時，可比殺傷力使 CUE-500 系列能夠實現理想的療效，同時不損害患者的安全，這在考慮自身免疫性疾病的應用性應用時具有最高的臨床治療應用性。

With that background and update, I'll turn the call over to Matteo to describe the maturing clinical data from the ongoing oncology trials. Matteo?

在了解了這些背景和最新情況後，我將把電話轉給 Matteo，讓他描述正在進行的腫瘤學試驗的成熟臨床數據。馬特奧？

Thanks, Anish. Good afternoon to everyone listening in on today's call. The maturing clinical data from the ongoing CUE-101 trial continues to demonstrate highly encouraging and robust metrics of clinical benefit for patients newly diagnosed with recurrent metastatic HPV-positive head and neck cancer treated in combination with pembrolizumab and for heavily pre-treated recurrent metastatic HPV-positive head and neck cancer patients treated with monotherapy.

謝謝，阿尼什。收聽今天電話會議的各位下午好。正在進行的 CUE-101 試驗日趨成熟的臨床數據繼續證明，對於接受派姆單抗聯合治療的新診斷復發性轉移性 HPV 陽性頭頸癌患者，以及接受單一療法治療的接受過大量治療的複發性轉移性 HPV 陽性頭頸癌患者，均具有令人鼓舞且強勁的臨床獲益指標。

The latest data continues to bolster prior observations, further enhancing our confidence in CUE-101 as a potential new standard-of-care therapeutic to improve outcomes for patients battling HPV-positive head and neck cancer. As previously and consistently stated, we believe CUE-101's unique mechanism of action, as evidenced by the data generated to date enables effective and tolerated dosing and selective expansion of the targeted tumor-specific T cells.

最新數據繼續支持先前的觀察結果，進一步增強了我們對 CUE-101 作為一種潛在的新標準治療方法的信心，可以改善與 HPV 陽性頭頸癌作鬥爭的患者的治療效果。如同先前所述，我們相信 CUE-101 的獨特作用機制（迄今為止產生的數據證明）能夠實現有效且耐受的劑量以及針對性腫瘤特異性 T 細胞的選擇性擴增。

Pembrolizumab is approved as the current standard-of-care treatment of first-line patients with recurrent metastatic head and neck cancer that have tumors with a combined positive score or CPS score of greater than or equal to 1%, which is a measure of PDL expression. The approval of pembrolizumab in this setting was based on a median overall survival of 12.3 months and with an objective response rate of 19% as observed in the KEYNOTE 048 study.

派姆單抗被批准作為複發性轉移性頭頸癌患者的一線標準治療方法，這些患者的腫瘤綜合陽性評分或 CPS 評分大於或等於 1%，這是 PDL 表達的衡量標準。在此情況下核准使用 pembrolizumab 是基於 KEYNOTE 048 研究觀察到的 12.3 個月的中位總存活期和 19% 的客觀緩解率。

As presented at ASCO in June, the following combination treatment with CUE-101, the objective response rate of 46%, as shown on slide 10, observed in patients with CPS greater than or equal to 1, represents a greater than doubling compared to the historical ORR of 19% observed with pembrolizumab monotherapy. As shown on the waterfall plot, out of 24 evaluable patients, we have observed significant tumor reductions across many of these patients, including confirmed partial responses in 10 patients and a confirmed complete response in 1 patient. Importantly, four patients remain on treatment, including one with stable disease that exhibits a reduction in their target lesions of minus 28%.

如同 6 月在 ASCO 上所介紹的，與 CUE-101 聯合治療，在 CPS 大於或等於 1 的患者中觀察到的客觀反應率為 46%（如幻燈片 10 所示），與使用 pembrolizumab 單藥治療觀察到的歷史 ORR 19% 相比，提高了一倍多。如瀑布圖所示，在 24 名可評估患者中，我們觀察到許多患者的腫瘤顯著縮小，其中 10 名患者確認為部分緩解，1 名患者確認為完全緩解。重要的是，四名患者仍在接受治療，其中一名病情穩定，目標病變減少了-28%。

Notably, for patients with low CPS scores, or scores of 1 to 19, an ORR of 50% was observed with CUE-101 and pembrolizumab, which represents a greater than tripling of the historical ORR of approximately 15% observed with pembrolizumab alone. In totality, our data suggests that not only does CUE-101 appear to demonstrably enhance the response rate of PD-1 inhibition, but also does so by substantially enhancing responses in patients that are traditionally less likely to respond.

值得注意的是，對於 CPS 評分較低或評分為 1 至 19 的患者，使用 CUE-101 和 pembrolizumab 觀察到的 ORR 為 50%，這比單獨使用 pembrolizumab 觀察到的歷史 ORR 約 15% 增加了兩倍多。總體而言，我們的數據表明，CUE-101 不僅能夠顯著提高 PD-1 抑制的反應率，而且還能顯著增強傳統上不太可能產生反應的患者的反應。

This is particularly important since patients with low CPS scores represent approximately 50% of all patients that are CPS positive and eligible for treatment with pembrolizumab in the frontline setting. The responses observed in these patients have been durable, as reflected in the 12-month OS and median OS, which is shown on the next slide, slide 11.

這一點尤其重要，因為 CPS 評分低的患者約佔所有 CPS 陽性且有資格在一線環境中接受 pembrolizumab 治療的患者的 50%。在這些患者身上觀察到的反應是持久的，這反映在 12 個月的 OS 和中位數 OS 中，如下一張投影片（第 11 張）中所示。

For patients treated with CUE-101 and pembrolizumab as first-line treatment, the median PFS of 5.8 months compares favorably to the median PFS of 3.2 months that was observed in the pembrolizumab arm of the KEYNOTE 048 trial. Importantly, the 12-month OS of 90% and in the median OS of 21.8 months observed in patients with CPS greater than or equal to 1 treated with combination treatment is notable and substantially better than the historical data with pembrolizumab monotherapy, where 12-month OS and median OS were 51% and 12.3 months, respectively.

對於使用 CUE-101 和 pembrolizumab 作為第一線治療的患者，中位 PFS 為 5.8 個月，與 KEYNOTE 048 試驗中 pembrolizumab 組觀察到的中位 PFS 3.2 個月相比更為有利。重要的是，在接受聯合治療的 CPS 大於或等於 1 的患者中觀察到的 12 個月 OS 為 90%，中位 OS 為 21.8 個月，這一結果顯著優於使用 pembrolizumab 單藥治療的歷史數據，其中 12 個月 OS 和中位 OS 分別為 51% 和 1 個月。

These enhanced survival metrics, which continue to be followed, are particularly evident when looking at the patients with both low and high PD-L1 expression, as shown on slide 12. Consistent with the enhanced ORR observed in patients with low PD-L1 expression, treated with CUE-101 and pembrolizumab, these patients are demonstrating favorable metrics of survival. In CPS-low patients treated with CUE-101 and pembrolizumab, the 12-month OS of 82% and the median OS of 21.8 months is importantly notable given the historical values of 44% and 10.8 months observed for pembrolizumab in the KEYNOTE 048 study.

這些增強的生存指標將繼續受到關注，當觀察 PD-L1 表達低和高的患者時尤其明顯，如幻燈片 12 所示。與使用 CUE-101 和 pembrolizumab 治療的低 PD-L1 表達患者中觀察到的增強 ORR 一致，這些患者表現出良好的生存指標。對於接受 CUE-101 和 pembrolizumab 治療的 CPS 低患者，12 個月 OS 為 82%，中位 OS 為 21.8 個月，鑑於 KEYNOTE 048 研究中觀察到的 pembrolizumab 的歷史值為 44% 和 10.8 個月，這一點非常重要。

The benefit to CPS-high patients is also noteworthy with 12-month OS of 100% and a median OS that has not yet been reached in patients with CPS greater than or equal to 20, treated with CUE-101 and pembrolizumab compared to the historical values of 56% and 14.8 months, respectively. As a reminder, these maturing data from the combination trial appear to be following what we observed in the monotherapy second-line-plus setting, where CUE-101 demonstrated significant prolongation of survival as shown in the following slide, slide 13.

對於 CPS 高的患者來說，益處也值得注意，使用 CUE-101 和 pembrolizumab 治療的 CPS 大於或等於 20 的患者，12 個月 OS 為 100%，中位 OS 尚未達到，而歷史值分別為 56% 和 14.8 個月。提醒一下，這些來自組合試驗的成熟數據似乎與我們在單一療法二線加治療中觀察到的情況一致，其中 CUE-101 顯示出顯著延長生存期的效果，如下一張幻燈片 13 所示。

As shown on the left, the median OS observed in patients treated with CUE-101 monotherapy at 2 mgs per kg was 24.8 months and 20.8 months for those treated with CUE-101 at a dose of 4 mgs per kg. The survival observed in these patients is remarkable when compared to the median OS observed in the second line with checkpoint inhibitors, where median OS of 7.5 and 8.4 months were observed for nivolumab and pembrolizumab, respectively. We believe this enhancement of survival to be mediated by the durable and selective expansion of targeted tumor-specific T cells by CUE-101.

如左圖所示，接受 2 毫克/公斤 CUE-101 單藥治療的患者的中位 OS 為 24.8 個月，而接受 4 毫克/公斤 CUE-101 治療的患者的中位 OS 為 20.8 個月。與二線檢查點抑制劑治療的中位 OS 相比，這些患者的存活期非常顯著，其中 nivolumab 和 pembrolizumab 的中位 OS 分別為 7.5 個月和 8.4 個月。我們相信，這種生存率的提高是透過 CUE-101 對靶向腫瘤特異性 T 細胞的持久和選擇性擴增來介導的。

In totality, our data suggests that CUE-101 increases the number of patients benefiting from checkpoint inhibition and appears to have substantially improved survival in these patients. We continue to monitor and carefully follow the patients remaining on treatment as well as in survival follow-up and look forward to providing an update at SITC in November. The data continues to mature over time, and we believe the observations to date, particularly pertaining to what appears to be a substantial enhancement of survival will place CUE-101, and by implication, the CUE-100 series, in a favorable and competitive position to potentially become a new standard of care.

總體而言，我們的數據表明 CUE-101 增加了受益於檢查點抑制的患者數量，並且似乎顯著提高了這些患者的存活率。我們將繼續監測並密切追蹤仍在接受治療以及生存追蹤的患者，並期待在 11 月的 SITC 上提供最新消息。隨著時間的推移，數據不斷成熟，我們相信迄今為止的觀察結果，特別是關於生存率大幅提高的觀察結果，將使 CUE-101 以及 CUE-100 系列處於有利和競爭地位，有可能成為新的護理標準。

Moving on to the CUE-102 program, which is being explored in patients with WT1-expressing tumors, including colon, pancreatic, gastric and ovarian cancers, CUE-102 has been well tolerated to date and no DLTs have been observed. Preliminary and emerging data shows dose-dependent increases in exposure and activation and expansion of WT1-specific T cells.

接下來是 CUE-102 項目，該項目正在針對 WT1 表達腫瘤患者（包括結腸癌、胰腺癌、胃癌和卵巢癌）進行研究，迄今為止，CUE-102 耐受性良好，未觀察到 DLT。初步和新興數據顯示，WT1 特異性 T 細胞的暴露、活化和擴增呈劑量依賴性增加。

Patients in all four indications have been treated at the expansion dose of 4 mgs per kg and remain on treatment or an active follow-up. As previously reported, we've observed antitumor activity in gastric and ovarian patients as well as durable disease control in several tumor types, including pancreatic cancer. These data continue to mature, and we look forward to presenting updated data at SITC in November.

所有四種適應症的患者均已接受每公斤 4 毫克的擴展劑量治療，並且仍在接受治療或積極追蹤。如前所述，我們觀察到胃癌和卵巢癌患者的抗腫瘤活性以及包括胰腺癌在內的幾種腫瘤類型的持久疾病控制。這些數據正在不斷成熟，我們期待在 11 月的 SITC 上展示更新的數據。

With that, I will now turn the call back over to Dan. Dan?

說完這些，我現在將電話轉回給丹。擔？

Yeah. Thanks, Matteo. As conveyed throughout this update call and shown on the next slide, slide 14, we continue to make significant progress across our platform with programs in both oncology and autoimmune disease. We've demonstrated the ability to selectively modulate targeted T cells, providing what we believe to be a superior therapeutic approach in both oncology and autoimmune disease treatment.

是的。謝謝，馬特奧。正如本次更新電話會議中所傳達的以及下一張幻燈片（第 14 張）所顯示的，我們繼續在腫瘤學和自體免疫疾病項目方面在整個平台上取得重大進展。我們已經證明了選擇性調節靶向 T 細胞的能力，從而提供了我們認為在腫瘤學和自體免疫疾病治療中均更優越的治療方法。

We continue to generate data from our two lead oncology programs, CUE-101 and CUE-102, and believe the data will continue to strengthen and bolster our position as a potential new standard of care particularly supported by ongoing data generation pertaining to what appears to be highly meaningful and remarkable survival enhancement. We believe these observations support the premise that our approach is selectively activating and expanding tumor-specific T cells, providing a durable anticancer effect resulting in enhanced survival. We believe we have the potential of establishing a new standard of care in the battle against cancer as well as autoimmune disease.

我們繼續從我們的兩個主要腫瘤學項目 CUE-101 和 CUE-102 中產生數據，並相信這些數據將繼續加強和鞏固我們作為潛在新護理標準的地位，特別是透過持續產生的與看似非常有意義和顯著的生存增強相關的數據。我們相信這些觀察結果支持了我們的方法是選擇性活化和擴增腫瘤特異性 T 細胞的前提，從而提供持久的抗癌效果，從而提高存活率。我們相信，我們有潛力在對抗癌症和自體免疫疾病的鬥爭中建立新的護理標準。

Importantly, as oncology data continue to mature, we have recently taken measures to prioritize our near-term focus and resource deployment upon near-term development milestones in our autoimmune programs, including lead selection and advancement towards the clinic in our partnership with Ono for CUE-401, as well as positioning CUE-501 for strategic partnering to further extend our capital runway and to enhance our capacity.

重要的是，隨著腫瘤學數據的不斷成熟，我們最近採取措施，優先考慮我們自身免疫計劃的近期發展里程碑上的近期重點和資源部署，包括與小野公司合作為 CUE-401 進行先導物選擇和臨床推進，以及定位 CUE-501 進行戰略合作，以進一步延長我們的資本跑道並增強我們的能力。

As a reminder, we've retained a 50% co-development and co-marketing right to CUE-401, which has the potential application to multiple autoimmune diseases with multibillion-dollar market potential. Through various proactive measures taken, we have extended our runway to mid-2025, reduced our going forward cash burn from approximately $40 million per year to approximately $30 million per year. And importantly, additional partnering will further enhance our cash position with upfront milestone payments as well as reduce our operational cash burn requirements through sponsored full-time equivalent supports.

提醒一下，我們保留了 CUE-401 50% 的共同開發和共同行銷權，該藥物有可能應用於多種自體免疫疾病，具有數十億美元的市場潛力。透過各種積極措施，我們將業務發展路線延長至 2025 年中期，並將未來的現金消耗從每年約 4,000 萬美元減少至每年約 3,000 萬美元。重要的是，額外的合作將透過預付里程碑付款進一步增強我們的現金狀況，並透過贊助的全職等效支持減少我們的營運現金消耗需求。

Through these measures, we believe we'll be increasingly capable of sustaining operational continuity through partnerships and other means of support. As a result of these measures, combined with the ongoing progress with our maturing data across our programs, we believe we're very well positioned to realize a series of upcoming risk-reducing and value-driving milestones as we continue towards the goal of establishing a new standard of care for treating both cancer and autoimmune disease with our approach to restore health by restoring immune balance.

透過這些措施，我們相信我們將越來越有能力透過合作夥伴關係和其他支援手段來維持營運的連續性。透過採取這些措施，再加上我們各個計畫數據不斷成熟，我們相信，我們完全有能力實現一系列即將到來的降低風險和推動價值的里程碑，我們將繼續朝著建立一種新的標準的目標邁進，透過恢復免疫平衡來恢復健康，從而治療癌症和自體免疫疾病。

And with that, I'd now like to open the call up to questions. Operator?

現在，我想開始回答大家的提問。操作員？

Thank you. We will now begin the question-and-answer session.

謝謝。我們現在開始問答環節。

Stephen Willey, Stifel.

史蒂芬威利（Stephen Willey），Stifel。

Yeah, good afternoon. Thanks for taking the questions. Anish or Dan, was just wondering if you could speak to maybe what you know at this point about the trafficking capacity of CUE-501. And then also just what's your estimate of CMV-seropositivity in the general population? I know it's correlated to age. I think it tends to be lower in males versus females, but just wondering kind of what your general estimate of this would be and whether you would need to screen for CMV positivity in the context of a Phase 1 dose escalation trial.

是的，下午好。感謝您回答這些問題。Anish 或 Dan，我只是想知道您是否可以談談您目前所了解的有關 CUE-501 的販運能力的情況。那麼，您對普通人群中 CMV 血清陽性率的估計是多少？我知道這與年齡有關。我認為男性的比例往往低於女性，但我只是想知道您對此的總體估計是什麼，以及是否需要在第 1 階段劑量遞增試驗中篩檢 CMV 陽性。

Yeah. So both very good questions, Steve. CMV is an example we presented. But just to make the point, Steve, we have made CUE-500 molecules with SARS-CoV-2 and EPB and other viral epitopes as well. So we presented the case with CMV.

是的。這兩個問題都問得非常好，史蒂夫。CMV 是我們提出的例子。但只是為了說明這一點，史蒂夫，我們已經製造了含有 SARS-CoV-2 和 EPB 以及其他病毒表位的 CUE-500 分子。因此我們向 CMV 提交了此案。

In the particular case of CMV, seropositivity anywhere around 65% to 70%. In our experience, when we've screened donors for SARS-CoV-2 at this point in time in the history of mankind, virtually 100% have been SARS positive for obvious reasons.

在 CMV 的特殊情況下，血清陽性率約為 65% 至 70%。根據我們的經驗，當我們在人類歷史上的這個時間點對捐贈者進行 SARS-CoV-2 篩檢時，由於顯而易見的原因，幾乎 100% 的人都呈現 SARS 陽性。

From the trafficking, we are now doing in vivo studies, but with Immuno-STATs in general, Steve, we had published a paper in Nature Methods with Hidde Ploegh several years back, where we used immunoPET imaging to make the point that Immuno-STATs could penetrate solid tumor tissue as well as an infectious model and directly engage the relevant antigen-specific T cells, and we believe the same should hold true for the 500 series, where you can have extravasation and local engagement to essentially be able to recognize the pieces that are bound by these molecules.

從運輸角度來說，我們現在正在進行體內研究，但總體而言，對於 Immuno-STATs，史蒂夫，幾年前我們與 Hidde Ploegh 在《自然方法》雜誌上發表了一篇論文，其中我們使用免疫 PET 成像來表明 Immuno-STATs 可以穿透實體腫瘤組織以及感染模型，並直接與相關的抗原特異性 T 細胞結合，我們相信 500 系列也可以穿透實體腫瘤組織以及您基本上可以通過局部和局部來識別出來的部分，我們相信 500 系列。

Okay. That's helpful. And then maybe just a CUE-101 question. So I understand that you guys are obviously kind of pausing things for now and allowing the survival data to mature. But I guess in the context of frontline head and neck right now and what is capable with pembro monotherapy, I think that appears to be the subject of some increasing debate as a function of primarily, I guess, the LEAP-010 data.

好的。這很有幫助。然後可能只是一個 CUE-101 問題。所以我明白，你們現在顯然暫停了一些事情，並讓生存數據成熟。但我想，在目前頭頸一線治療的背景下，以及派姆單藥治療的效果如何，我認為這似乎是一些爭論的主題，主要原因在於 LEAP-010 數據。

So just curious if you think a more mature survival statistics could help attract strategic interest. And just curious if you can share anything in terms of the conversations that you've had thus far with potentially interested parties in terms of how they're thinking about what pembro monotherapy historically is capable of?

所以我只是好奇，您是否認為更成熟的生存統計數據有助於吸引戰略興趣。我很好奇，您是否可以分享您迄今為止與潛在感興趣的各方進行的對話，了解他們如何看待派姆單藥療法的歷史功效？

Sure. Thanks, Steve. This is Dan. So it's an important question. We've had dialogue with multiple potential partners on the data sets that we've had historically. When we look at the monotherapy data, we've actually had the comment of the data looks so promising that how do they know that we haven't biased by selecting healthy patients. And that's one of the reasons we emphasize the randomized strategy for the Phase 2.

當然。謝謝，史蒂夫。這是丹。所以這是一個重要的問題。我們已經與多個潛在合作夥伴就我們過去擁有的資料集進行了對話。當我們查看單一療法數據時，我們實際上已經得到了這樣的評論：數據看起來非常有希望，他們怎麼知道我們沒有透過選擇健康患者而產生偏見。這就是我們強調第二階段隨機策略的原因之一。

I think what's really important here when you look at the landscape of competing molecules, different kinase inhibitors, et cetera, in this space, we think the survival data is in a really differentiate and truly position CUE with an advantage and a competitive advantage in terms of the durability of triggering an immune response. So that survival data as it continues to mature, I think what we've seen in monotherapy is very impressive. What we're seeing emerge with the combination appears to be following suit. And I think that's going to be just positive in the long run.

我認為，當你觀察這個領域的競爭分子、不同的激酶抑制劑等的格局時，真正重要的是，我們認為生存數據確實具有區分性，並且真正使 CUE 在觸發免疫反應的持久性方面具有優勢和競爭優勢。隨著生存數據的不斷成熟，我認為我們在單一療法中看到的結果非常令人印象深刻。我們看到的組合似乎也出現了類似的情況。我認為從長遠來看這將是積極的影響。

I think ultimately, a randomized study is basically far more convincing, because you're going directly against pembro as a single agent. But it is an important topic, and it is being watched. And we do have ongoing dialogue with companies on 101.

我認為最終，隨機研究基本上更有說服力，因為你直接將派姆作為單一藥物進行對比。但這是一個重要的主題，而且受到關注。我們確實正在就 101 號條款與各公司進行對話。

Ren Benjamin, Citizens JMP. Please go ahead.

任本傑明（Ren Benjamin），公民 JMP。請繼續。

Hey, good afternoon, guys. Thanks for taking the questions. So thanks for the update on 101 in combination with Keytruda and as a monotherapy. I guess my first question would be how to think about these results given the current landscape and in particular kind of the developing landscape given the provocative data we saw at ASCO from Merus and some of the others that are also in the space.

嘿，大家下午好。感謝您回答這些問題。感謝您對 101 與 Keytruda 聯合使用以及作為單一療法的更新。我想我的第一個問題是，考慮到目前的情況，特別是考慮到我們在 ASCO 上看到的來自 Merus 和其他一些研究機構的啟發性的數據，如何看待這些結果。

And just as a follow-up to that, I'm kind of curious -- I don't think it was mentioned in the earlier comments -- Can you provide any sort of an update on the neoadjuvant study?

作為後續問題，我有點好奇——我認為之前的評論中沒有提到——您能提供有關新輔助研究的任何最新消息嗎？

Sure. Matto, why don't you take (multiple speakers) question, both of them.

當然。Matto，為什麼不回答（多位發言者）兩個問題呢？

Yeah. No, I will. And again, just to follow up on the prior question, again, I think this really -- the data from the LEAD-010 trial underscores the importance of looking at early survival metrics, specifically like a 12-month survival and also median OS as it matures. And so we actually look at the pembro mono data set from LEAD-010, the 12-month survival is 59%. If we look at the CUE-101 combination data, our current 12-month survival is 90%. And if you look at CPS high, it's 100% of patients are alive at 12 months.

是的。不，我會的。再次，只是為了跟進先前的問題，我再次認為這確實 - LEAD-010 試驗的數據強調了關注早期生存指標的重要性，特別是像 12 個月生存期以及成熟時的中位 OS。因此，我們實際上查看了 LEAD-010 的派姆單核細胞增多症資料集，12 個月存活率為 59%。如果我們查看 CUE-101 組合數據，我們目前的 12 個月存活率為 90%。如果你看一下 CPS 的高值，你會發現 100% 的患者在 12 個月時仍然存活。

And so with regards to the question now of the evolving landscape and with, I guess, in particular, Merus's compound, petosemtamab, again, it's really important to look at the data that they've shared with regards to their survival. And so in the second-line setting and beyond, they reported a survival of 11.5 months.

因此，關於現在不斷變化的情況的問題，特別是對於 Merus 的化合物 petosemtamab，再次，查看他們分享的有關其生存的數據非常重要。因此，在二線治療及以後，他們報告的存活期為 11.5 個月。

With CUE-101 mono, we're currently at 20.8 months and even 20 -- almost 5 months in the 2 mg per kg cohort. So although in the second-line-plus, they reported a response rate of 37%, their survival is about half as long as CUE monotherapy, where we observed a response rate of 5%. And again, this is fully consistent with patterns of clinical benefit that have been now well defined in immunotherapy. So if we look at Kimmtrak, recently approved for uveal melanoma, really modest response rate but a clear survival benefit led to its approval.

使用 CUE-101 單核細胞增多症，我們目前已達到 20.8 個月，甚至在 2 毫克/公斤的組別中也達到了 20--將近 5 個月。因此，儘管在二線加治療中，他們報告的反應率為 37%，但他們的生存期約為 CUE 單一療法的一半，我們觀察到的反應率為 5%。再次強調，這與免疫療法中現已明確定義的臨床益處模式完全一致。因此，如果我們看一下最近批准用於治療葡萄膜黑色素瘤的 Kimmtrak，其反應率確實不高，但明顯的生存益處使其獲得了批准。

And so back to petosemtamab now in the frontline setting, they, at ASCO, reported some very preliminary data. They actually only reported data on about half of the patients that were treated with very minimal follow-up. So with the follow-up -- a median follow-up, if you looked at the swimmer plot about 4 months.

現在回到 petosemtamab 目前在一線環境中的應用，他們在 ASCO 上報告了一些非常初步的數據。他們實際上只報告了大約一半接受過極少後續治療的患者的數據。因此，透過後續行動——中位後續行動，如果你查看大約 4 個月的游泳者圖。

So again, I would just use caution and clearly here the data needs to mature. And as I mentioned before, we have maturing metrics, both at 12-month OS and median OS that are established. So that's real data, and we'll have to see what happens going forward with petosemtamab. And perhaps one could hypothesize, it will be similar to different inhibitors of these pathways, for which they're inevitably pop-up bypass pathways, and hence, the advantages of engaging the immune system and inducing expansion of a durable antitumor T-cell population.

所以，我再次強調，我只是想謹慎行事，顯然這裡的數據需要成熟。正如我之前提到的，我們擁有成熟的指標，包括 12 個月的 OS 和已建立的中位 OS。這是真實的數據，我們必須看看 petosemtamab 的未來發展。也許有人會假設，它將類似於這些途徑的不同抑制劑，它們不可避免地會彈出旁路途徑，因此，具有參與免疫系統和誘導持久抗腫瘤 T 細胞群擴增的優勢。

Got it. And just --

知道了。而且只是--

I am sorry, Ren. I think there was one other question about the new adjuvant, if I recall. And so that study is progressing well. The investigators at Washington University are very close to completing enrollment in Schedule B, where patients are getting two doses of 101, and we're getting tissue pre- and post-treatment.

對不起，任。如果我沒記錯的話，我想還有一個關於新佐劑的問題。因此這項研究進展順利。華盛頓大學的研究人員即將完成 B 計畫的招募，該計畫中的患者將接受兩劑 101，我們將獲得治療前後的組織樣本。

Again, this is -- the preliminary data that we've seen looks very encouraging. The investigators really, I think, have -- I know have the intent of submitting this for publication in a very high-level journal. And so when this will become public and shared really depends on how they choose to proceed.

再說一次，我們看到的初步數據看起來非常令人鼓舞。我認為，研究人員確實——我知道他們有意將這項研究提交給高水準的期刊發表。因此，何時公開和分享這些資訊實際上取決於他們選擇如何進行。

Got it. And then just maybe a final question on kind of funding and your current cash position. Like can you maybe help us understand how you plan on bridging the gap between now and kind of initial milestone payments expected from the Ono opt-in versus selection of lead candidates and the like. How do you see that kind of unfolding? Thanks.

知道了。然後也許最後一個問題是關於資金類型和您當前的現金狀況。例如，您能否幫助我們了解您計劃如何彌補現在與 Ono 選擇加入與選擇主要候選人等預期的初始里程碑付款之間的差距。您如何看待這種情況的發生？謝謝。

Thanks, Ren. This is Dan. That's an important question. One thing I want to emphasize, we were very prudent and deliberate and basically looking at that question in a very dynamic way. The one thing we have not chosen to do historically with the cost of capital as the small-cap biotech sector has basically been compressed in terms of valuations, we have not chosen to go out and do a massively dilutive financing.

謝謝，Ren。這是丹。這是一個重要的問題。我想強調的一點是，我們非常謹慎和深思熟慮，基本上以非常動態的方式看待這個問題。從歷史上看，由於小型生物技術行業的估值基本上受到壓縮，因此我們沒有選擇對資本成本進行大規模稀釋融資。

So we've taken a look at our business model where we have programs that are all kind of moving over time. we have a partnered program right now, 401 with Ono. And if one looks back at that, it was actually a really nice design. They're helping -- they're subsidizing basically the preclinical development, working very closely with us. They're supporting our scientists. And that has resulted in a really good, high-quality body of data going forward to select a lead candidate of then with the objective of getting into the clinic. We have a 50% opt-in there.

因此，我們研究了我們的商業模式，其中我們所有的項目都是隨著時間推移而發展的。我們現在有一個合作項目，與 Ono 合作的 401 項目。如果回顧一下，那實際上是一個非常好的設計。他們正在提供幫助——他們基本上在資助臨床前開發，並與我們密切合作。他們正在支持我們的科學家。這就產生了一個非常好的、高品質的數據，可以用來選出當時的主要候選藥物，以進入臨床治療。我們有 50% 的人選擇加入。

Even with the 50% opt-in, we'll receive milestones. So if those milestones get triggered, they help subsidize the development of that program. We have 501 in late-stage discussions with several companies. The objective there is to consummate a transaction where we have an upfront. We have additional support of our scientists that are going to be committed to that program. That reduces our burn rate and then a series of milestones beginning obviously, with lead candidate selection, IND filing. Those milestones overlapped with the Ono milestones are really important to basically give us continuity.

即使只有 50% 的人選擇加入，我們也會取得里程碑式的進展。因此，如果這些里程碑被觸發，它們將有助於補貼該計劃的發展。我們與幾家公司正在進行 501 的後期討論。我們的目標是完成一筆有預付款的交易。我們得到了致力於該計劃的科學家的額外支持。這降低了我們的燒錢率，然後顯然開始了一系列里程碑，從主要候選人的選擇，到 IND 申請。這些里程碑與小野里程碑重疊，對於我們保持連續性非常重要。

So the measures we've taken for reducing our burn basically enabling 101 data to mature without going into a very costly Phase 2 and just being prudent about what we're focusing on in the near term, focusing on partnering 501 to supplement. So these milestones help extend the runway in a sort of tiered manner.

因此，我們為減少燒錢而採取的措施基本上是讓 101 個數據成熟，而無需進入成本高昂的第 2 階段，並且謹慎考慮我們近期的重點，專注於與 501 合作進行補充。因此，這些里程碑有助於以分層的方式延長跑道。

So if we do need to raise any capital -- and not sure right now if we're going to need to, but if we do, it's going to be a modest amount -- we're really trying to keep dilution down to a minimum because cost of capital is key. And ultimately, what we want to do is hit these milestones, further develop the pipeline, demonstrate further robustness of our clinical, competitive positioning. And ultimately, at some point in the future when the stock is a healthier valuation, cost of capital isn't as onerous.

因此，如果我們確實需要籌集任何資金——目前我們不確定是否需要，但如果需要，那將是一筆適度的資金——我們確實在努力將稀釋度保持在最低水平，因為資本成本是關鍵。最終，我們想要實現這些里程碑，進一步開發產品線，進一步展示我們臨床競爭定位的穩健性。最終，在未來某個時候，當股票估值更健康時，資本成本就不會那麼繁重。

So I hope that's a clear answer, but it's basically a dynamic analysis. And we have a lot of moving parts here, but it's basically building a -- that's why I met by a balanced business model, having a stream of capital options coming in with these milestones being triggered and looking at raising capital in a very sort of prudent, pragmatic manner based on cost of capital.

所以我希望這是一個明確的答案，但基本上它是一個動態分析。我們這裡有很多活動部件，但它基本上是在構建一個——這就是為什麼我遇到了一個平衡的商業模式，隨著這些里程碑的觸發，有一系列的資本選擇湧入，並根據資本成本以非常謹慎、務實的方式考慮籌集資金。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞集團（Jefferies）。

Hi. Congrats on the data update, and thanks for taking my questions. I will ask one on the CUE-500 series. For CUE-501, can you talk more about plans or options for next steps to position this program for partnering? Would it enhance potential for BD if you got regulator feedback or even key investigator buy-in to help define what the clinical development path could look like?

你好。恭喜數據更新，感謝您回答我的問題。我會問一個有關 CUE-500 系列的問題。對於 CUE-501，您能否詳細談談該計劃的合作下一步計劃或選擇？如果您獲得監管機構的回饋甚至關鍵研究人員的支持以幫助定義臨床開發路徑，這是否會增強 BD 的潛力？

Yeah. A very important question. I think obviously, the Ono partnership has enhanced our sort of insight on the autoimmune space. We have a very attractive sort of preclinical data set right now. We've been in discussions with several potential pharma partners on 501 various stages of diligence and progression. We're just highly confident that based on the feedback we have, it's a differentiated asset with very attractive based on -- basically being a biologic that mirrors what CAR-T was able to do with lupus, that's what the intent is, compares favorably with bispecifics, the CD3, CD19 molecules.

是的。一個非常重要的問題。我認為，與小野公司的合作顯然增強了我們對自身免疫領域的洞察力。我們現在擁有一組非常有吸引力的臨床前資料集。我們已經與幾個潛在的製藥合作夥伴就 501 個盡職調查和進展的不同階段進行了討論。我們非常有信心，根據我們得到的回饋，它是一種差異化資產，具有非常大的吸引力——基本上是一種生物製劑，可以反映 CAR-T 對狼瘡的作用，這就是目的，與雙特異性、 CD3、CD19 分子相比具有優勢。

So we think the data set presents a opportunity for us to partner in the near term. And in terms of indications with that molecule, we're obviously going to hold off until the asset is partnered, and we're able to engage in dialogue -- strategic dialogue with a partner on what to focus on in a sort of a series of indications.

因此我們認為該數據集為我們近期的合作提供了機會。就該分子的適應症而言，我們顯然會推遲，直到資產獲得合作夥伴，並且我們能夠進行對話——與合作夥伴進行戰略對話，討論在一系列適應症中應該關注的重點。

But for that program, we look at partnering as an important means of subsidizing development. We'd also aim to preserve a cell type, for instance, eosinophils or mass cells, something like that, where we retain control and upside of sort of a number of indications from those cell types. So I hope that answers your question, Maury.

但對於該計劃，我們將合作視為資助發展的重要手段。我們還旨在保留一種細胞類型，例如嗜酸性粒細胞或腫塊細胞等，我們保留對這些細胞類型的多種指徵的控制和優勢。所以我希望這能回答你的問題，莫里。

Yeah. Really helpful. And maybe just a follow-up on the financial side as well. I guess for the Ono opt-in, is there any room to negotiate and potentially accelerate milestones or opt-in potential based on the data that you've generated so far? Or would it not make sense to try do that at this point?

是的。真的很有幫助。或許也只是對財務的後續關注。我猜對於 Ono 選擇加入，根據您迄今為止生成的數據，是否有任何談判空間並可能加速里程碑或選擇加入的潛力？或者說現在嘗試這麼做沒有意義？

Yeah, I don't think it would make sense to try to modify it right now. We've been making really good progress. The partnership has actually been extremely productive. They've really been an outstandingly supportive partner, and we're aligned on what the next steps are. So I think we're very much seeing things from a similar perspective.

是的，我認為現在嘗試修改它是沒有意義的。我們已經取得了非常好的進展。此次合作其實非常富有成效。他們確實是一個非常支持的合作夥伴，我們對下一步的行動也達成了一致。所以我認為我們從非常相似的角度看待事物。

Leland Gershell, Oppenheimer.

利蘭·格謝爾，奧本海默。

Hey, good afternoon. Thanks for the update and taking my questions. Maybe just a few for you, Dan or Anish. It looks like you have a good base of preclinical data here for 401 and 501. I wanted to know what might be the next set of non-clinical data that we might be looking for that you might have to present to us. And in that, are there any particular studies you're doing that may guide your thought process with respect to the indications that you prioritize for both those assets? Thank you.

嘿，下午好。感謝您的更新和回答我的問題。對你來說也許只有幾個，丹或阿尼什。看起來您擁有 401 和 501 的良好臨床前數據基礎。我想知道我們可能正在尋找的下一組非臨床數據是什麼，您可能需要向我們提供這些數據。並且，您是否正在進行任何特定的研究，這些研究可以指導您思考這兩項資產優先考慮的跡象？謝謝。

Yeah. Thanks, Leland. This is Anish. So we continue to generate pretty exciting data for both programs in autoimmunity with 401 obviously, in collaboration with Ono, where we have seen efficacy and activity in several disease models. And in due time, collectively and collaboratively, we will release that in the public domain.

是的。謝謝，利蘭。這是阿尼什。因此，我們繼續與 Ono 合作，為 401 在自體免疫領域的兩個項目產生相當令人興奮的數據，我們已經看到了 401 在幾種疾病模型中的功效和活性。在適當的時候，我們將透過集體合作將其發佈到公共領域。

In total, the data does seem to reflect what I've mentioned, which is a molecule that generates copious amounts of regulatory T cells along with signatures for halting autoimmune processes, seizing and sort of reversing or minimizing proinflammatory cytokine production and related pathologies. For 500, we are in the process of in vivo experiments. And again, we hope to sort of release that as we start further understanding relationship between dosing, B-cell depletion, and some of the models that we're characterizing now.

總的來說，數據似乎確實反映了我所提到的內容，即一種能夠產生大量調節性 T 細胞的分子，同時還具有阻止自身免疫過程、控制和逆轉或減少促炎細胞因子產生及相關病理的特徵。對於500，我們正在進行體內實驗。再次，我們希望隨著我們開始進一步了解劑量、B 細胞耗竭以及我們現在正在描述的一些模型之間的關係，能夠發布這一點。

So both programs, the intentions are in this -- as we continue to go through this year to be able to talk about these data sets as they emerge.

因此，這兩個項目的目的都是這樣的——隨著今年的推進，我們將能夠隨時討論這些數據集。

Ted Tenthoff, Piper Sandler.

泰德·坦索夫、派珀·桑德勒。

Great. Thank you very much. To sort of the evolving world of targeting CD19 to deplete B cells for autoimmune disease, how much is the safety -- the potential safety profile that you've generated on the Immuno-STAT platform from 101 to 102 differentiating from the cell therapies. And is that something that investors are focused on? Thanks so much.

偉大的。非常感謝。對於不斷發展的以 CD19 為目標來消耗 B 細胞以治療自體免疫疾病的世界來說，其安全性如何？您在 Immuno-STAT 平台上產生的潛在安全性概況與細胞療法相比從 101 到 102 有何不同？這是投資人關注的重點嗎？非常感謝。

Yeah. Ted, again, very good question. And I think I tried to stress that, but the clinical de-risking and vulnerability of Immuno-STATs in mab, in general, what we've shown with 101 and 102, we believe, has an enormous positive implication of the 500 series of B-cell depletion. Simply, even if you look at the metrics of tolerability from immunogenicity, as you will know, we have not seen any clinically relevant immunogenicity 100 series trials with 101 or 102. We've had patients receiving drug up to two years. So again, that speaks to the nature of selective-TCR engagement via this framework.

是的。泰德，你又問了個非常好的問題。我想我曾試圖強調這一點，但總的來說，免疫統計在 mab 中的臨床去風險和脆弱性，正如我們在 101 和 102 中所展示的那樣，我們相信，這對 500 系列 B 細胞耗竭有著巨大的積極影響。簡單來說，即使您從免疫原性角度來衡量耐受性指標，您也會知道，我們還沒有看到任何針對 101 或 102 的臨床相關的免疫原性 100 系列試驗。我們有一些患者接受該藥物治療長達兩年。所以，這再次說明了透過該框架進行選擇性 TCR 參與的本質。

The second is the fact that -- by virtue of the fact that you're only co-opting a very small percentage of your peripheral T-cell repertoire in an individual and not carpet bombing all T cells with anti-CD3-based approaches, which we refer to as the pan T-cell engages, we believe should also offer superior safety and tolerability metrics. And some of that is evident from this in vitro assessment of cytokine release that we did where you saw this profound production of cytokines by pan T-cell engager molecules as opposed to CUE-500, but it was significantly reduced despite the fact that CUE-500 shows a very comparable metrics of killing efficacy of B-cells. So that's also quite important.

第二點是，由於你只利用了個體外周 T 細胞庫中很小一部分，而不是用基於抗 CD3 的方法對所有 T 細胞進行地毯式轟炸（我們稱之為泛 T 細胞參與），我們相信這也應該提供卓越的安全性和耐受性指標。從我們進行的細胞激素釋放體外評估中可以明顯看出這一點，與 CUE-500 相比，您可以看到泛 T 細胞接合分子產生了大量的細胞因子，但儘管 CUE-500 顯示出非常可比的 B 細胞殺傷效力指標，但細胞因子的產生量卻顯著減少。所以這也很重要。

Thirdly, I think we should sort of reemphasize the fact that through nature, your memory antiviral T cells is something that all of us have harbored from the time we're born through our life to provide us protective immunity. So there's no other better long-lasting killer T-cell population that one harbors as compared to what T cells offer. So we do think being able to redirect them to kill targets such as B cells provides a very exciting avenue for really harnessing the potential of what nature has already given the individual.

第三，我認為我們應該再次強調這樣一個事實，即透過大自然，記憶抗病毒 T 細胞是我們所有人從出生起就擁有的，可以為我們提供保護性免疫。因此，與 T 細胞相比，沒有其他更好的長效殺傷性 T 細胞群可供人體所用。因此，我們確實認為，能夠重新引導它們殺死 B 細胞等目標，為真正利用大自然賦予個體的潛力提供了一條非常令人興奮的途徑。

Very great. And obviously, a very different manufacturing approach than what we're seeing with the oncology side CAR-T (multiple speakers)?

非常棒。顯然，其製造方法與我們在腫瘤學 CAR-T（多位發言人）中看到的方法非常不同？

That's exactly right. Just to add to that, the manufacturability is exactly what we've seen with 101, 102, antibody-based biologics. The yields are in line with what we've seen at similar stages for Immuno-STAT, which are clinically grade -- products have yielded in grams per liter with very good show of stability of the GMP product. That's a very important point.

完全正確。補充一點，可製造性正是我們在基於抗體的 101、102 生物製劑中所看到的。產量與我們在 Immuno-STAT 類似階段看到的產量一致，它們是臨床級的——產品產量以每公升克為單位，並且表現出 GMP 產品的非常好的穩定性。這是非常重要的一點。

This concludes our question-and-answer session. I would like to turn the conference back over to Mr. Dan Passeri for any closing remarks. Please go ahead, sir.

我們的問答環節到此結束。我想將會議交還給丹·帕塞里先生，請他作最後發言。先生，請繼續。

Thank you. We just want to thank everyone for listening and your continued interest in our progress, and we look forward to keeping you updated with the progress we make going forward. So thank you very much and take care.

謝謝。我們只想感謝大家的聆聽以及對我們進展的持續關注，我們期待隨時向您通報我們未來的進展。非常感謝您，請保重。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。