Vir Biotechnology Inc (VIR) 2024 Q2 法說會逐字稿

Hello. Welcome to Vir Biotechnology’s Second Quarter 2024 Financial Results and Business Update Call. As a reminder, this conference call is being recorded. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. (Operator Instructions)

你好。歡迎參加 Vir Biotechnology 的 2024 年第二季財務業績和業務更新電話會議。提醒一下，本次電話會議正在錄音中。此時，所有參與者都處於只聽模式。演講者演講結束後，將進行問答環節。（操作員說明）

I will now turn the call over to Richard Lepke, Senior Director of Investor Relations. You may begin Mr. Lepke.

我現在將把電話轉給投資者關係高級總監理查德·萊普克 (Richard Lepke)。您可以開始了，萊普克先生。

Thank you, operator and hello everyone. I am Richard Lepke, Senior Director of Investor Relations at Vir Biotechnology. Joining me on the call are Dr. Marianne De Backer, our Chief Executive Officer; Dr. Jennifer Towne, our Chief Scientific Officer; Dr. Mark Eisner, our Chief Medical Officer; and Brent Sabatini, our Chief Accounting Officer.

謝謝接線員，大家好。我是理查德·萊普克 (Richard Lepke)，Vir Biotechnology 投資者關係高級總監。與我一起參加電話會議的還有我們的執行長 Marianne De Backer 博士；我們的首席科學官 Jennifer Towne 博士；我們的首席醫療官 Mark Eisner 博士；以及我們的首席會計官布倫特·薩巴蒂尼 (Brent Sabatini)。

Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under applicable securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements, to differ significantly from those expressed or implied by such forward looking statements. These risks and uncertainties and risks associated with our business are described in today's press releases and the company's reports filed with the Securities and Exchange Commission, including Forms 10-K, 10-Q and 8-K.

在開始之前，我想提醒大家，我們今天發表的一些聲明是適用證券法規定的前瞻性聲明。這些前瞻性陳述涉及重大風險和不確定性，可能導致我們的臨床開發計畫、未來結果、績效或成就與此類前瞻性陳述所明示或暗示的內容有顯著差異。這些風險和不確定性以及與我們業務相關的風險在今天的新聞稿和公司向美國證券交易委員會提交的報告（包括表格 10-K、10-Q 和 8-K）中進行了描述。

With that, I will turn the call over to Marianne. Please go ahead.

這樣，我會將電話轉給瑪麗安。請繼續。

Good afternoon, everyone, and thank you for joining us today. At Vir, our mission is powering the immune system to transform lives. During today's earnings call, we will discuss two significant announcements that mark critical milestones on our journey to realize this vision.

大家下午好，感謝您今天加入我們。在 Vir，我們的使命是為免疫系統提供動力，改變生活。在今天的財報電話會議上，我們將討論兩個重要的公告，它們標誌著我們實現這一願景的旅程中的關鍵里程碑。

Before we dive into these announcements, let me quickly highlight some key achievements from the second quarter. We presented promising Phase 2 SOLSTICE data in chronic hepatitis delta at the EASL Congress, which generated significant interest from both scientific as well as the medical community. These preliminary data underscore the potential of our combination therapy to tobevibart and elebsiran to revolutionize the treatment landscape for people living with hepatitis delta. We are now preparing to engage with regulatory authorities to discuss the registrational path forward. We also recently received FDA IND clearance and fast track designation for this combination therapy.

在我們深入討論這些公告之前，讓我快速強調一下第二季的一些關鍵成就。我們在 EASL 大會上展示了慢性丁型肝炎的 2 期 SOLSTICE 數據，該數據很有前景，引起了科學界和醫學界的極大興趣。這些初步數據強調了我們的 tobevibart 和 elebsiran 聯合療法有可能徹底改變丁型肝炎患者的治療模式。我們現在正準備與監管機構接洽，討論未來的註冊路徑。我們最近也獲得了 FDA IND 批准和該聯合療法的快速通道指定。

In parallel, we remain focused on advancing our functional cure program for chronic hepatitis B, and we eagerly anticipate reporting 48-week end of treatment data from the Phase 2 MARCH Part B study at the major medical congress in the fourth quarter.

同時，我們仍然專注於推進慢性乙型肝炎的功能性治癒計劃，並且我們熱切期待在第四季度的主要醫學大會上報告 2 期 3 月 B 部分研究的 48 週結束治療數據。

Now let me turn to the two significant announcements that will be the main focus of today's call. First, I'm excited to announce that Vir has entered into an exclusive worldwide license agreement with Sanofi for three clinical-stage masked T-cell engagers and the exclusive use of the PRO-XTEN protease-cleavable masking platform for oncology and infectious diseases. This license agreement is subject to HSR review and clearance, which we expect will take about 30 days from signing.

現在讓我談談將成為今天電話會議主要焦點的兩個重要公告。首先，我很高興地宣布，Vir 已與賽諾菲就三個臨床階段的掩蔽T 細胞接合器簽訂了全球獨家許可協議，並獨家使用PRO-XTEN 蛋白酶可裂解掩蔽平台用於腫瘤學和傳染病。該許可協議需要經過 HSR 審查和批准，我們預計簽署後大約需要 30 天。

Second, we will be providing a corporate update on our strategic restructuring. To provide you with a comprehensive overview of these announcements and their impact on our company, we have structured today's call as follows. First, I will summarize the strategic rationale behind the Sanofi license agreement and the corporate restructuring. Then, Jen will provide details on the masking platform and its potential applications. Mark will discuss the clinical stage assets we have licensed. Brent will provide financial overview, including the terms of the agreement and our capital allocation priorities in light of the restructuring. And finally, I will offer some closing remarks before we open the call for questions.

其次，我們將提供有關策略重組的公司最新情況。為了讓您全面了解這些公告及其對我們公司的影響，我們將今天的電話會議安排如下。首先，我將總結賽諾菲授權協議和公司重組背後的策略理由。然後，Jen 將提供有關屏蔽平台及其潛在應用的詳細資訊。馬克將討論我們已許可的臨床階段資產。布倫特將提供財務概況，包括協議條款以及我們根據重組進行的資本分配優先事項。最後，在我們開始提問之前，我將發表一些結束語。

Let me now provide more details on our exclusive worldwide license agreement with Sanofi and the strategic measures we have announced today. First, the agreement adds three potentially best-in-class clinical stage assets. SAR446309 or AMX-818, a dual-masked HER2-targeted T-cell engager in Phase 1 development. SAR446329 or AMX-500, a dual-masked PSMA-targeted T-cell engager in Phase 1 clinical development and SAR446368 or AMX-525, a dual-masked EGFR-targeted T-cell engager with a cleared IND scheduled to begin Phase 1 in early 2025. For the duration of the call, we will refer to these assets by the last four digits of their drug candidate code, 6309, 6329 and 6368, respectively. Looking ahead, these assets have multiple near-term key catalysts expected in the next nine to 18 months.

現在讓我提供有關我們與賽諾菲的全球獨家許可協議以及我們今天宣布的戰略措施的更多詳細資訊。首先，該協議增加了三項可能是同類最佳臨床階段資產。SAR446309 或 AMX-818，一種雙重掩蔽 HER2 靶向 T 細胞參與劑，處於 1 期開發中。SAR446329 或AMX-500 是一種雙掩蔽PSMA 標靶T 細胞接合劑，處於1 期臨床開發階段；而SAR446368 或AMX-525 是一種雙掩蔽EGFR 標靶T 細胞接合劑，已獲得批准的IND，計劃於2019 年開始1 期臨床開發。在通話期間，我們將透過候選藥物代碼的最後四位數字（分別為 6309、6329 和 6368）來引用這些資產。展望未來，這些資產預計在未來 9 至 18 個月內將有多個近期關鍵催化劑。

Second, we obtained the exclusive license to Sanofi's PRO-XTEN protease-cleavable masking platform for oncology and infectious diseases. T-cell engagers are, in essence, engineered by specific monoclonal antibodies. And given our deep antibody protein engineering and T-cell biology expertise, we believe that we can unlock meaningful synergies and create new best-in-class therapies.

其次，我們獲得了賽諾菲用於腫瘤學和傳染病的PRO-XTEN蛋白酶切割掩蔽平台的獨家許可。T 細胞接合器本質上是由特定的單株抗體設計的。憑藉我們深厚的抗體蛋白工程和 T 細胞生物學專業知識，我們相信我們可以釋放有意義的協同效應並創造新的一流療法。

Upon closing, we are also excited to strengthen Vir's capabilities by welcoming the team of key Sanofi employees with extensive scientific and oncology development expertise. Finally, we are strategically reprioritizing our pipeline, which has led to a restructuring of our organization.

交易結束後，我們也很高興透過歡迎擁有廣泛科學和腫瘤學開發專業知識的賽諾菲關鍵員工團隊來加強 Vir 的能力。最後，我們正在策略性地重新確定我們的管道的優先順序，這導致了我們組織的重組。

To better understand the potential impact of the licensed assets, let's first discuss the current landscape of cancer therapeutics and the unmet needs that still exist. Despite advances in cancer research, the global burden of cancer remains high with 10 million deaths annually and a five-year survival rate of just 5% for some cancers. T-cell engagers have shown promise as a potent therapeutic modality, but they often have lower tolerability because of off-tumor on-target toxicity in healthy tissue, systemic toxicity, such as cytokine release syndrome and the inability to achieve therapeutically active doses in the tumor microenvironment. These limitations have hindered the widespread adoption of T-cell engagers to date.

為了更好地了解許可資產的潛在影響，我們首先討論癌症治療的當前前景以及仍然存在的未滿足的需求。儘管癌症研究取得了進展，但全球癌症負擔仍然很高，每年有 1000 萬人死亡，某些癌症的五年存活率僅為 5%。T細胞接合劑已顯示出作為一種有效的治療方式的前景，但由於健康組織中的非腫瘤靶向毒性、系統毒性（例如細胞因子釋放綜合徵）以及無法在正常組織中達到治療活性劑量，因此它們通常具有較低的耐受性。迄今為止，這些限制阻礙了 T 細胞接合器的廣泛採用。

Our solution to addressing these challenges is the potential best-in-class to extend protease activating masking technology. This proprietary platform allows T-cell engagers, cytokines and auto molecules to be selectively activated in the tumor microenvironment. By masking the T-cell engagers, this technology aims to minimize off-tumor toxicities and systemic side effects while enabling the achievement of therapeutically active doses directly in the tumor tissue. This technology has the potential to significantly improve the safety and efficacy profile of future treatments.

我們應對這些挑戰的解決方案是擴展蛋白酶活化掩蔽技術的潛在最佳解決方案。此專有平台可讓 T 細胞接合劑、細胞激素和自體分子在腫瘤微環境中選擇性活化。透過掩蓋 T 細胞接合者，該技術旨在最大限度地減少腫瘤外毒性和全身副作用，同時能夠直接在腫瘤組織中實現治療活性劑量。該技術有可能顯著提高未來治療的安全性和有效性。

Now this strategic transaction not only enhances our clinical pipeline, but also augments our core R&D capabilities and upon closing will bring a complementary platform to the company. At Vir, we have always prided ourselves on our world-class immunology and biology expertise, which has enabled us to uniquely discover and engineer monoclonal antibodies to address serious infectious diseases. With the anticipated addition of the PRO-XTEN masking platform, we will be even better positioned to develop innovative therapies that selectively target disease-causing cells while sparing healthy tissue. Our leading data science capabilities, including machine learning and AI will further support our efforts to bring transformative therapies to patients faster.

現在，這項策略交易不僅增強了我們的臨床產品線，也增強了我們的核心研發能力，交易完成後將為公司帶來一個補充平台。在 Vir，我們一直為自己世界一流的免疫學和生物學專業知識感到自豪，這使我們能夠獨特地發現和設計單株抗體來應對嚴重的傳染病。隨著 PRO-XTEN 掩蔽平台的預期增加，我們將能夠更好地開發創新療法，選擇性地針對致病細胞，同時保護健康組織。我們領先的數據科學能力，包括機器學習和人工智慧，將進一步支持我們更快為患者提供變革性療法的努力。

An important component of the agreement is that we are adding a team of key employees who offer extensive expertise in oncology clinical development, in-depth knowledge of the proprietary masking platform and valuable expertise in manufacturing dual mask molecules. By combining our existing strengths with this new expertise, we will create a powerful synergy to drive innovation, and we look forward to working together to advance our mission following closing of the transaction.

該協議的一個重要組成部分是，我們將增加一個由關鍵員工組成的團隊，他們在腫瘤臨床開發方面提供廣泛的專業知識、對專有掩蔽平台的深入了解以及在製造雙掩蔽分子方面的寶貴專業知識。透過將我們現有的優勢與新的專業知識相結合，我們將創造強大的協同效應來推動創新，我們期待在交易完成後共同努力推進我們的使命。

As we anticipate integrating the licensed assets into our pipeline, we are taking decisive steps to focus on the highest value near-term opportunities. First, we are focusing our resources on our core programs in hepatitis delta, hepatitis B and upon closing the newly licensed masked T-cell engager clinical portfolio.

當我們預計將許可資產整合到我們的管道中時，我們正在採取果斷措施，專注於近期最高價值的機會。首先，我們將資源集中在丁型肝炎、B型肝炎的核心項目上，並在關閉新獲得許可的蒙蔽 T 細胞參與臨床組合後。

Second, we are phasing out programs in influenza and COVID-19 as well as our T-cell-based viral vector platform and programs. Where appropriate, these programs will be made available for partnering. Third, we are implementing a workforce restructuring that will result in a reduction of approximately 25% of our employees. These actions are expected to yield significant cost savings while allowing us to effectively utilize our strong balance sheet to advance our strategic priorities.

其次，我們正在逐步淘汰流感和 COVID-19 計畫以及基於 T 細胞的病毒載體平台和計畫。在適當的情況下，這些計劃將可供合作夥伴使用。第三，我們正在實施勞動力重組，這將導致我們的員工人數減少約25%。這些行動預計將顯著節省成本，同時使我們能夠有效地利用我們強大的資產負債表來推進我們的策略重點。

By streamlining our operations and allocating our capital efficiency, we are positioning Vir for long-term success and sustainable growth. In addition, we are revising our 2024 expense guidance lower. Brent will summarize the details later on the call.

透過簡化我們的營運和分配我們的資本效率，我們使 Vir 能夠實現長期成功和永續成長。此外，我們正在下調 2024 年費用指引。布倫特將在稍後的電話會議中總結細節。

I do want to take a moment to express my deepest gratitude to all our employees, including those who will be leaving the company for their dedication and their significant contributions to our mission. These decisions, while difficult, are necessary to ensure that we are allocating our capital and our talent in the most effective way possible to bring transformative therapies to patients. We believe that this strategic restructuring will enable us to deliver on that promise more effectively than ever before.

我確實想花點時間向我們所有員工表示最深切的謝意，包括那些即將離開公司的員工，感謝他們的奉獻精神以及對我們使命的重大貢獻。這些決定雖然困難，但卻是必要的，以確保我們以最有效的方式分配我們的資本和人才，為患者帶來變革性的治療。我們相信，這次策略重組將使我們能夠比以往更有效地兌現這項承諾。

With that, I would now like to turn the call over to Jen, who will provide more details on the masking platform and its potential applications in oncology and in infectious diseases.

現在，我想將電話轉給 Jen，她將提供有關屏蔽平台及其在腫瘤學和傳染病方面的潛在應用的更多詳細資訊。

Thank you, Marianne, and hello, everyone. As you can see on the slide, the PRO-XTEN technology consists of a protease releasable XTEN mask that can be universally applied to various protein therapeutic modalities. The PRO-XTEN technology has two key features. First, it implies the universal mask, which in the case of a T-cell engager is applied to both arms, masking both the part of molecule that targets the tumor-associated antigen and the part that activates the T-cell, the CD3 arm.

謝謝你，瑪麗安，大家好。正如您在幻燈片上看到的，PRO-XTEN 技術由蛋白酶可釋放的 XTEN 掩模組成，可普遍應用於各種蛋白質治療方式。PRO-XTEN 技術有兩個關鍵特性。首先，它意味著通用掩模，在 T 細胞接合器的情況下，該掩模應用於雙臂，從而掩蓋了靶向腫瘤相關抗原的分子部分和激活 T 細胞的部分，即 CD3 臂。

Second, the technology utilizes a protease-cleavable linker, which enables preferential and masking and drug activation, specifically in the tumor microenvironment. This is possible because the tumor microenvironment is known to have high levels of specific proteases that concludes the linker, releasing the active drug from the XTEN mask.

其次，該技術利用蛋白酶可切割的連接體，可以實現優先、掩蔽和藥物激活，特別是在腫瘤微環境中。這是可能的，因為已知腫瘤微環境具有高水平的特定蛋白酶，這些蛋白酶可連接接頭，從 XTEN 掩模中釋放活性藥物。

The PRO-XTEN technology can be applied to T-cell engagers, cytokines and likely other modalities. This masking technology allows for the selective activation of potent immune modulators at the site of the tumor, while minimizing their activity in healthy tissues. The XTEN mask has been clinically proven with ALTUVIIIO, an approved drug to provide half-life extension to the mask molecule.

PRO-XTEN 技術可應用於 T 細胞接合劑、細胞激素和可能的其他方式。這種掩蔽技術可以選擇性活化腫瘤部位的有效免疫調節劑，同時最大限度地減少它們在健康組織中的活性。XTEN 面膜已通過 ALTUVIIIO 的臨床驗證，ALTUVIIIO 是一種已批准的藥物，可延長面膜分子的半衰期。

Now let's take a closer look at how this technology can overcome the historical limitation of T-cell engagers and unlock new opportunities in cancer treatment. In blood circulation, the molecule remains fully masked with all of its components, including the XTEN mask, the linker and the tumor targeting and T-cell engaging components, all intact and connected. This mask configuration allows for a long half-life in the blood, which is essential for effective drug delivery to the tumor site.

現在讓我們仔細看看這項技術如何克服 T 細胞參與者的歷史限制並釋放癌症治療的新機會。在血液循環中，該分子仍然被其所有組件完全遮蔽，包括 XTEN 遮罩、接頭以及腫瘤靶向和 T 細胞接合組件，全部完整且連接。這種面罩配置可以延長血液中的半衰期，這對於有效地將藥物輸送到腫瘤部位至關重要。

As the masked T-cell engager reaches healthy tissue, the dual masking of both the tumor-associated antigen and the CD3 arms limit binding to healthy cells and T-cells. This unique feature reduces T-cell mediated cytotoxicity, thereby improving the tolerability of the treatment. However, when the masked T-cell engager enters the tumor microenvironment, a critical transformation occurs. The tumor microenvironment is characterized by high levels of tumor-associated proteases. These proteases recognize and cleave the protease-cleavable linkers on the PRO-XTEN mask T-cell engager and therefore, unmask and activate the molecule specifically in the tumor tissue.

當被掩蔽的 T 細胞接觸者到達健康組織時，腫瘤相關抗原和 CD3 臂的雙重掩蔽限制了與健康細胞和 T 細胞的結合。這項獨特功能可降低 T 細胞介導的細胞毒性，進而提高治療的耐受性。然而，當掩蔽的 T 細胞接合者進入腫瘤微環境時，就會發生關鍵的轉變。腫瘤微環境的特徵是高水平的腫瘤相關蛋白酶。這些蛋白酶可辨識並切割 PRO-XTEN 掩蔽 T 細胞接合器上的蛋白酶可切割接頭，從而在腫瘤組織中特異性地揭開並活化該分子。

The selective unmasking and activation in the tumor microenvironment allows for higher concentration of active drug where it's needed most, while minimizing exposure and toxicity in the healthy tissues. Once unmapped, the active T-cell engager can engage T-cells and tumor cells promoting potent antitumor activity resulting in killing of the tumor cells.

腫瘤微環境中的選擇性揭露和活化允許在最需要的地方提高活性藥物的濃度，同時最大限度地減少健康組織中的暴露和毒性。一旦未定位，活性 T 細胞接合器可以接合 T 細胞和腫瘤細胞，促進有效的抗腫瘤活性，從而殺死腫瘤細胞。

Importantly, any unmasked molecules that exit the tumor microenvironment are rapidly eliminated from the body due to a short half-life once unmasked, further reducing the risk of off-tumor toxicity. We believe that this approach has the potential to revolutionize the field of T-cell engagers and other immunotherapies.

重要的是，任何離開腫瘤微環境的未掩蔽的分子，由於半衰期較短，一旦暴露，就會迅速從體內消除，從而進一步降低腫瘤外毒性的風險。我們相信這種方法有可能徹底改變 T 細胞接合劑和其他免疫療法領域。

Now I'd like to share some compelling preclinical proof-of-concept data that demonstrate the ability of the PRO-XTEN masked HER2 T-cell engager to be conditionally activated in the tumor microenvironment. Let's start with the graph on the left, which shows the in vitro T-cell-dependent killing of HER2-positive tumor cells in the presence of PRO-XTEN masked and unmasked T-cell engagers. As you can see, the masked HER2 T-cell engager leads to a 10,000-fold shipped in cytotoxicity compared to the unmapped HER2 T-cell engager in vitro. In other words, the masked T-cell engager is essentially fitted in the absence of the proteases found in the tumor microenvironment, which is exactly what we want to minimize off-target toxicity.

現在我想分享一些令人信服的臨床前概念驗證數據，這些數據證明了 PRO-XTEN 掩蔽的 HER2 T 細胞接合器在腫瘤微環境中有條件活化的能力。讓我們從左圖開始，該圖顯示了在 PRO-XTEN 屏蔽和未屏蔽 T 細胞接合劑存在的情況下，HER2 陽性腫瘤細胞的體外 T 細胞依賴性殺傷。正如您所看到的，在體外，與未映射的 HER2 T 細胞接合器相比，屏蔽的 HER2 T 細胞接合器導致的細胞毒性高出 10,000 倍。換句話說，掩蔽的 T 細胞接合器本質上是在腫瘤微環境中不存在蛋白酶的情況下安裝的，這正是我們想要最大限度地減少脫靶毒性的原因。

Looking to the middle graph, we see the in vivo antitumor efficacy in a HER2-positive tumor model following treatment with masked or unmasked HER2 T-cell engagers. The masked HER2 T-cell engager induces robust tumor regression, demonstrating equivalent efficacy to the unmasked molecule. This provides strong evidence that the unmasking process is occurring as intended in the tumor tissue.

從中間的圖表中，我們看到了 HER2 陽性腫瘤模型在使用掩蔽或未掩蔽的 HER2 T 細胞接合劑治療後的體內抗腫瘤功效。掩蔽的 HER2 T 細胞接合劑可誘導腫瘤的強勁消退，證明與未掩蔽的分子具有相同的功效。這提供了強有力的證據，證明腫瘤組織中的揭露過程正在如預期中發生。

Finally, the graph on the right shows the relative levels of masked and unmasked T-cell engager present in tumors versus healthy tissues, 48 hours after treatment with the masked HER2 T-cell engager. As predicted, the only site where we see an accumulation of unmasked active T-cell engager is in the tumor. In contrast, the masked inactive molecule is present across many tissue types. This preferential unmasking in the disease site with minimal to no exposure of active molecule in normal tissue is critical to reduce off-tumor toxicity.

最後，右圖顯示了使用掩蔽 HER2 T 細胞接合劑治療 48 小時後，腫瘤與健康組織中存在的掩蔽和未掩蔽 T 細胞接合劑的相對水平。正如預測的那樣，我們看到未掩蔽的活性 T 細胞接合者累積的唯一部位是腫瘤中。相較之下，被掩蓋的非活性分子存在於許多組織類型中。這種在疾病部位的優先暴露，而正常組織中活性分子的暴露最少甚至不暴露，對於減少腫瘤外毒性至關重要。

Now, let's explore how this technology can also maximize the therapeutic index. Starting with the graph on the left, we see that the masked HER2 T-cell engager demonstrates extended pharmacokinetics as compared to the unmasked molecule. The prolonged circulation time of the masked molecule allows the drug to reach the tumor tissue while the rapid clearance of any unmasked molecule in the periphery helps to minimize off-target toxicity.

現在，讓我們探討一下這項技術如何能最大化治療指數。從左圖開始，我們發現與未掩蔽的分子相比，掩蔽的 HER2 T 細胞接合劑表現出更廣泛的藥物動力學。掩蔽分子的循環時間延長，使藥物能夠到達腫瘤組織，而周邊任何未掩蔽分子的快速清除有助於最大限度地減少脫靶毒性。

Moving to the middle graph, we observed minimal cytokine release with the masked T-cell engager as indicated by the low levels of IL-6. Cytokine-release syndrome has been a major limitation for the current T-cell engagers, and this is evidence is highly encouraging for the platform.

轉向中間的圖表，我們觀察到掩蔽 T 細胞接合器釋放的細胞因子最少，如 IL-6 水平低所示。細胞激素釋放症候群一直是目前 T 細胞參與者的主要限制，這項證據對該平台來說非常令人鼓舞。

Finally, the box on the right showcases the improvement in therapeutics index achieved. In nonhuman primate studies, the maximum tolerated dose of the masked HER2 T-cell engager was 43 milligrams per kilogram compared to just 0.2 milligrams per kilogram for the unmasked HER2 molecule. This represents a greater than 100-fold improvement in therapeutic index. Notably, the unmasked HER2 T-cell engager was lethal due to cytokine release syndrome at a dose of 0.3 milligrams per kilogram, highlighting the significant safety challenges associated with conventional T-cell engagers.

最後，右側的方框展示了治療指數的改善。在非人類靈長類動物研究中，屏蔽 HER2 T 細胞接合劑的最大耐受劑量為每公斤 43 毫克，而未屏蔽 HER2 分子的最大耐受劑量僅為每公斤 0.2 毫克。這代表治療指數提高了 100 倍以上。值得注意的是，未遮蔽的 HER2 T 細胞接合劑在每公斤 0.3 毫克的劑量下會因細胞激素釋放症候群而致命，這凸顯了與傳統 T 細胞接合劑相關的重大安全挑戰。

As we anticipate integrating the PRO-XTEN masking platform and the talented team from Sanofi and Vir, I'd like to highlight the synergistic capabilities and expertise that this deal brings together. First, at Vir, we have a deep understanding of T-cell biology and how to optimize their activity to kill cells in infectious diseases. This expertise can be directly applied to maximizing the ability of the masked T-cell engagers to eliminate tumor cells.

由於我們預計將 PRO-XTEN 掩蔽平台以及賽諾菲和 Vir 的才華橫溢的團隊整合在一起，我想強調這筆交易所帶來的協同能力和專業知識。首先，在 Vir，我們對 T 細胞生物學以及如何優化其活性以殺死傳染病中的細胞有深入的了解。這種專業知識可以直接應用於最大限度地提高掩蔽 T 細胞接合者消除腫瘤細胞的能力。

Second, our monoclonal antibody platform enables the rapid generation of novel antibodies for identified tumor targets. By combining our antibody discovery capabilities with the PRO-XTEN masking technology, we can rapidly create a new generation of masked T-cell engagers that can address a broad range of tumor antigens, expanding the potential impact of this modality.

其次，我們的單株抗體平台能夠快速產生針對已辨識腫瘤標靶的新型抗體。透過將我們的抗體發現能力與 PRO-XTEN 掩蔽技術結合，我們可以快速創建新一代掩蔽 T 細胞接合劑，可以處理廣泛的腫瘤抗原，從而擴大了這種模式的潛在影響。

Third, our next-generation protein engineering capabilities, which leverage proprietary AI and machine learning tools and high-throughput wet lab selection, enable us to optimize the properties of any protein. This expertise allows us to fine-tune and enhance multiple protein characteristics simultaneously. We can potentially create masked molecule with optimized stability, pharmacokinetics and tumor-specific activations, further improving their therapeutic potential.

第三，我們的下一代蛋白質工程能力利用專有的人工智慧和機器學習工具以及高通量濕實驗室選擇，使我們能夠優化任何蛋白質的特性。這種專業知識使我們能夠同時微調和增強多種蛋白質特性。我們有可能創造出具有優化穩定性、藥物動力學和腫瘤特異性活化的掩蔽分子，進一步提高其治療潛力。

Now let's discuss how the unique combination of properties offered by this proprietary platform sets it apart from other masking technologies. First, the PRO-XTEN platform employs a dual masking approach, where both the tumor-associated antigen and CD3 binding domains are masked. This feature maximizes the therapeutic index by decreasing both the Optum activity and the systemic immune activation.

現在讓我們討論一下這個專有平台提供的獨特特性組合如何使其與其他掩模技術區分開來。首先，PRO-XTEN 平台採用雙重掩蔽方法，其中腫瘤相關抗原和 CD3 結合域都被遮蔽。這一特徵透過降低 Optum 活性和全身免疫活化來最大化治療指數。

Second, the platform is designed to provide a short half-life of the active drug while maintaining a long half-life of the masked drug. This allows the masked drug to reach site of action before being removed, enhancing associated potential. Once activated, the short half-life of the active drug provides a safety advantage by limiting systemic exposure.

其次，該平台旨在提供活性藥物的短半衰期，同時保持掩蔽藥物的長半衰期。這使得掩蔽藥物能夠在被移除之前到達作用部位，從而增強相關的潛力。一旦被激活，活性藥物的半衰期短，透過限制全身暴露而提供安全優勢。

Third, the platform features universal tunable masks that can be applied to any T-cell engager. This innovative plug-and-play format allows us to use the same mask across multiple therapeutic candidates, saving time and resources compared to developing new mask for each antibody and expediting the development process.

第三，該平台具有通用可調掩模，可應用於任何 T 細胞接合器。這種創新的即插即用格式使我們能夠在多種候選治療藥物中使用相同的掩模，與為每種抗體開發新掩模相比節省了時間和資源並加快了開發過程。

Fourth, the platform has broad applicability as it can be used to mask not only T-cell engagers, but also cytokines and other therapeutic modalities. This versatility expands the potential impact of the technology and allows us to explore a wide range of immune targeting approaches.

第四，該平台具有廣泛的適用性，因為它不僅可用於掩蓋 T 細胞接合者，還可用於掩蓋細胞激素和其他治療方式。這種多功能性擴大了該技術的潛在影響，並使我們能夠探索廣泛的免疫標靶方法。

Finally, the masking technology has been validated in human clinical studies, providing a strong foundation for its use in our pipeline. We believe that with the unique properties of the platform and our combined expertise, we are uniquely positioned to develop a next-generation of masked T-cell engagers and cytokines. This powerful combination will set Vir apart and strengthen our position as a leader in the development of transformative immunotherapies.

最後，掩蔽技術已在人體臨床研究中得到驗證，為其在我們的管道中的使用奠定了堅實的基礎。我們相信，憑藉該平台的獨特特性和我們綜合的專業知識，我們在開發下一代掩蔽 T 細胞接合劑和細胞因子方面處於獨特的地位。這一強大的組合將使 Vir 脫穎而出，並鞏固我們作為變革性免疫療法開發領導者的地位。

With that, I'd like to hand the presentation over to Mark.

說到這裡，我想將簡報交給馬克。

Thank you, Jen, and hello, everyone. I'll now provide an overview of these programs and our plans for clinical development.

謝謝你，Jen，大家好。我現在將概述這些項目和我們的臨床開發計劃。

Following closing, the licensing agreement would provide us with a robust portfolio of assets targeting clinically validated antigens in oncology. These assets include three dual masked T-cell engagers each targeting a different antigen HER2, PSMA and EGFR.

交易完成後，許可協議將為我們提供腫瘤學中經過臨床驗證的抗原的強大資產組合。這些資產包括三個雙掩蔽 T 細胞接合器，每個接合器針對不同的抗原 HER2、PSMA 和 EGFR。

6309 is a dual masked HER2 CD3 T-cell engager. This asset has the potential to address significant unmet needs in HER2-expressing cancers with initial indications, including third line or later HER2-positive metastatic colorectal cancer and second to third line HER2-positive metastatic breast cancer.

6309 是一種雙重遮蔽 HER2 CD3 T 細胞接合劑。該資產有潛力解決具有初始適應症的 HER2 表達癌症中未滿足的重大需求，包括三線或更高版本的 HER2 陽性轉移性結直腸癌和二線至三線 HER2 陽性轉移性乳癌。

6329 is a dual masked PSMA CD3 T-cell engager. This asset is initially being developed for the treatment of third line or later metastatic castration-resistant prostate cancer, the disease with limited treatment options and poor outcomes. 6368 is a dual masked EGFR CD3 T-cell engager. This outset has the potential to address multiple EGFR-expressing tumors with initial indications, including third line or later metastatic colorectal cancer, second to third line metastatic non-small cell lung cancer and second to third line metastatic head and neck carcinoma.

6329 是一種雙掩蔽 PSMA CD3 T 細胞接合劑。該資產最初是為了治療第三線或晚期轉移性去勢抵抗性前列腺癌而開發的，這種疾病的治療選擇有限且預後不佳。 6368 是一種雙掩蔽 EGFR CD3 T 細胞接合劑。這一起點有可能解決具有初步適應症的多種表達 EGFR 的腫瘤，包括三線或後期轉移性結直腸癌、二線至三線轉移性非小細胞肺癌和二線至三線轉移性頭頸癌。

While we refer to specific lines of therapy and initial indications for these assets, it's important to note that our goal is ultimately to move up to earlier lines over time as the data support. HER2, PSMA and EGFR are all known to be important targets in a variety of solid tumors and existing therapies against these targets have demonstrated clinical benefit. However, existing therapies often come with significant toxicities, which can limit their ability to be dosed high enough to achieve optimal efficacy. In the following slides, I will provide more details on each of these assets, including their current clinical development plans.

雖然我們提到了這些資產的具體治療方案和初步適應症，但值得注意的是，我們的目標最終是隨著時間的推移，在數據支持下轉向更早的治療方案。眾所周知，HER2、PSMA 和 EGFR 都是多種實體瘤的重要靶點，而針對這些標靶的現有療法已證明具有臨床益處。然而，現有的療法通常具有顯著的毒性，這可能會限制它們以足夠高的劑量達到最佳療效的能力。在下面的幻燈片中，我將提供有關每項資產的更多詳細信息，包括它們當前的臨床開發計劃。

Now let's dive deeper into 6309, the dual masked HER2 CD3 T-cell engager. As you can see on the left side of this slide, there's a significant disease burden associated with HER2-positive cancers, particularly in metastatic colorectal cancer, breast cancer and gastroesophageal junction cancer. We estimate that annually, there are tens of thousands of newly diagnosed patients with metastatic HER2-positive cancers in key regions.

現在讓我們更深入地了解 6309，即雙掩蔽 HER2 CD3 T 細胞接合器。正如您在這張投影片左側所看到的，HER2 陽性癌症會帶來巨大的疾病負擔，特別是轉移性大腸直腸癌、乳癌和胃食道交界癌。我們估計，重點地區每年新診斷出數萬名轉移性 HER2 陽性癌症患者。

Despite the availability of HER2 targeting agents, there remains a significant unmet need in the treatment of HER2-positive tumors. While these therapies have improved outcomes for patients, mortality rates remain high due to disease progression. Additionally, there are major safety concerns associated with current HER2-targeted therapies, particularly cardiac dysfunction, interstitial lung disease and pneumonitis.

儘管已有 HER2 標靶藥物，但 HER2 陽性腫瘤的治療需求仍未滿足。儘管這些療法改善了患者的預後，但由於疾病進展，死亡率仍然很高。此外，目前的 HER2 標靶療法還存在重大安全問題，特別是心臟功能障礙、間質性肺病和肺炎。

In the HER2 low seven, which represents the majority of breast cancers, the treatment options are even more limited. There's only one approved HER2-targeted therapy for this population Enhertu, highlighting the need for additional effective and well-tolerated treatment options. The current Phase 1 study design for 6309 is carefully crafted to optimize the dose, demonstrating proof-of-concept with a dual masking platform and evaluate its potential across multiple HER2-expressing solid tumors.

在代表大多數乳癌的 HER2 低七位癌症中，治療選擇更加有限。對於這一人群，只有一種核准的 HER2 標靶療法 Enhertu，這凸顯了對其他有效且耐受性良好的治療方案的需求。目前 6309 的 1 期研究設計經過精心設計，以優化劑量，展示雙掩蔽平台的概念驗證，並評估其在多種表達 HER2 的實體瘤中的潛力。

The study began with a single-agent dose escalation phase to optimize the dose of 6309. Patients are enrolling at increasing dose levels until an optimized dose is determined. The study also includes a combination dose escalation phase with pembrolizumab. In addition, there are potential expansion cohorts to evaluate the efficacy and safety of 6309 in specific tumor types, such as HER2-positive metastatic colorectal cancer, HER2-positive breast cancer and HER2 low breast cancer. The data from these expansion cohorts will inform further development in these indications.

研究從單藥劑量遞增階段開始，以優化 6309 的劑量。患者以不斷增加的劑量水平入組，直到確定最佳劑量。研究也包括與派姆單抗合併劑量遞增階段。此外，還有潛在的擴展隊列來評估6309在特定腫瘤類型中的療效和安全性，例如HER2陽性轉移性大腸直腸癌、HER2陽性乳癌和HER2低乳癌。這些擴展隊列的數據將為這些適應症的進一步發展提供資訊。

We are excited about the potential of 6309 to transform the treatment landscape for patients with HER2-expressing cancers. As the only masked HER2 T-cell engager currently in clinical development, 6309 is designed to offer lower off-tumor and systemic toxicity, allowing for higher doses, potentially improved efficacy and benefit risk profile compared to existing HER2-targeted therapies.

我們對 6309 改變 HER2 表達癌症患者治療格局的潛力感到興奮。作為目前臨床開發中唯一的掩蔽HER2 T 細胞接合劑，6309 旨在提供較低的腫瘤外和全身毒性，與現有的HER2 標靶療法相比，可以使用更高的劑量，潛在地改善療效和獲益風險狀況。

The Phase 1 study is currently being conducted at 10 active sites in Europe and Australia. Monotherapy and combination therapy data is anticipated to be available in the second half of 2025, which will be a key catalyst for the program.

第一階段研究目前正在歐洲和澳洲的 10 個活動地點進行。單一療法和聯合療法數據預計將於 2025 年下半年提供，這將成為該計劃的關鍵催化劑。

Now let's shift our focus to 6329, a dual masked PSMA directed T-cell engager. Metastatic castration-resistant prostate cancer represents a significant disease burden with a large number of patients across lines of therapy. Despite currently available treatments, approximately 50% of patients with non-metastatic castration-resistant prostate cancer experienced metastatic recurrence within three years. Furthermore, only 34% of patients with metastatic prostate cancer are alive five years after diagnosis, highlighting the need for more effective therapies.

現在讓我們將焦點轉移到 6329，這是一種雙重掩蔽的 PSMA 定向 T 細胞接合劑。轉移性去勢抵抗性前列腺癌對大量接受不同治療的患者來說是一個重大的疾病負擔。儘管目前有可用的治療方法，但大約 50% 的非轉移性去勢抵抗性前列腺癌患者在三年內經歷了轉移性復發。此外，只有 34% 的轉移性前列腺癌患者在診斷後五年內仍存活，這突顯出需要更有效的治療方法。

We believe that 6329 is a highly differentiated asset by leveraging the PRO-XTEN masking technology, 6329 targets PSMA, a highly expressed antigen on prostate cancer cells to drive T-cell-mediated intratumor responses in the TME. As the only dual masked PSMA directed T-cell engager currently in clinical development, 6329 is designed to offer lower off-tumor toxicity, allowing for higher doses and potentially improved efficacy compared to existing PSMA-targeted therapies.

我們相信，6329 是一種高度差異化的資產，透過利用 PRO-XTEN 掩蔽技術，6329 的目標是 PSMA（前列腺癌細胞上高表達的抗原），可驅動 TME 中 T 細胞介導的腫瘤內反應。作為目前臨床開發中唯一的雙掩蔽 PSMA 定向 T 細胞接合劑，6329 旨在提供較低的腫瘤外毒性，與現有的 PSMA 標靶療法相比，可以使用更高的劑量，並可能提高療效。

Consequently, we believe that 6329 can offer patient benefit in third line metastatic castration-resistant prostate cancer with the potential to move into earlier lines of therapy in combination with antiandrogen therapies, which are the standard-of-care for these patients.

因此，我們相信 6329 可以為第三線轉移性去勢抵抗性前列腺癌患者帶來益處，並有可能與抗雄激素療法聯合進入早期治療，而抗雄激素療法是這些患者的標準治療。

The Phase 1 study is ongoing, evaluating 6329 as monotherapy in a dose escalation design with the potential to advance into monotherapy and combination therapy expansion cohorts. A key advantage of the PRO-XTEN technology is universal masking. This allows the use of the safety experience, especially about the risk of cytokine release syndrome from the 6309 Phase 1 study. This knowledge enabled 6329 to start at higher dose and potentially dose titrate faster, accelerating the development time line. The Phase 1 study is currently being conducted at six active sites in Europe and Australia. Monotherapy data is expected to be available in the second half of 2025. This data readout will be a key catalyst for the program.

1 期研究正在進行中，評估 6329 作為劑量遞增設計中的單一療法，並有可能進入單一療法和聯合療法擴展隊列。PRO-XTEN 技術的一個關鍵優勢是通用屏蔽。這使得可以利用安全經驗，特別是關於 6309 第一階段研究中細胞激素釋放症候群風險的經驗。這些知識使 6329 能夠以更高的劑量開始，並且可能更快地調整劑量，從而加快了開發時間。第一階段研究目前正在歐洲和澳洲的六個活動地點進行。單藥治療數據預計將於 2025 年下半年提供。該數據讀出將成為該計劃的關鍵催化劑。

Now let's turn our attention to 6368, a dual masked EGFR CD3 T-cell engager with IND clearance. EGFR-expressing solid tumors represent a significant disease burden with a large number of newly metastatic patients diagnosed each year. EGFR is broadly expressed across a wide range of tumor types, making it an attractive target for cancer therapy.

現在讓我們把注意力轉向 6368，這是一種具有 IND 許可的雙掩蔽 EGFR CD3 T 細胞接合劑。表達 EGFR 的實體腫瘤代表著重大的疾病負擔，每年診斷出大量新轉移患者。EGFR 在多種腫瘤類型中廣泛表達，使其成為癌症治療的有吸引力的標靶。

While the graph on the left highlights some of the most prevalent EGFR-expressing cancers, it's important to note that EGFR is also expressed in many other tumor types. Despite available treatments, the unmet need for patients with EGFR-expressing tumors remains high. The five-year survival rate for metastatic patients range from near 3% to 38% and second and third line settings to these tumor types, the outcomes are dismal.

雖然左圖突顯了一些最常見的 EGFR 表達癌症，但值得注意的是，EGFR 也在許多其他腫瘤類型中表達。儘管有可用的治療方法，但表達 EGFR 的腫瘤患者的未滿足需求仍然很高。轉移性患者的五年存活率約為 3% 至 38%，而這些腫瘤類型的二線和三線治療結果令人沮喪。

Leveraging the PRO-XTEN masking technology, we believe that 6368 has the potential to provide a safe and tolerable treatment option for patients in the second line and beyond settings for this difficult-to-treat cancers. The preclinical data for 6368 provides similar validation as seen with the previous PRO-XTEN masked T-cell engagers, demonstrating the platform's ability to minimize off-target toxicity while maintaining prudent antitumor activity in the TME.

利用 PRO-XTEN 掩蔽技術，我們相信 6368 有潛力為二線及其他治療這種難以治療的癌症的患者提供安全且可耐受的治療選擇。6368 的臨床前數據提供了與先前的 PRO-XTEN 掩蔽 T 細胞接合器類似的驗證，證明該平台能夠最大限度地減少脫靶毒性，同時在 TME 中保持審慎的抗腫瘤活性。

In vitro, the masking of 6368 leads to a 10,000-fold shift in cytotoxicity compared to the unmasked EGFR T-cell engager, highlighting the ability of the PRO-XTEN technology to prevent off-target immune synapse formation. In vivo, the PRO-XTEN masked EGFR T-cell engager demonstrated similar antitumor activity to the unmasked EGFR T-cell engager effectively inhibiting tumor growth compared to the control. This selective activation in the TME is consistent with the preclinical data shown for the other PRO-XTEN masked T-cell engagers.

在體外，與未掩蔽的 EGFR T 細胞接合劑相比，6368 的掩蔽導致細胞毒性發生 10,000 倍的變化，凸顯了 PRO-XTEN 技術防止脫靶免疫突觸形成的能力。在體內，PRO-XTEN 掩蔽的 EGFR T 細胞接合劑表現出與未掩蔽的 EGFR T 細胞接合劑相似的抗腫瘤活性，與對照組相比，可有效抑制腫瘤生長。TME 中的這種選擇性活化與其他 PRO-XTEN 掩蔽 T 細胞接合劑顯示的臨床前數據一致。

These preclinical findings support the clinical development of 6368. And with IND clearance, this asset is well-positioned to rapidly advance into a Phase 1 clinical study in patients with metastatic head and neck squamous cell carcinoma, non-small cell lung cancer and colorectal cancer. The Phase 1 clinical study for 6368 is targeted to begin in the first quarter of 2025.

這些臨床前研究結果支持6368的臨床開發。隨著 IND 的批准，該資產有望迅速進入針對轉移性頭頸鱗狀細胞癌、非小細胞肺癌和大腸直腸癌患者的 1 期臨床研究。6368的一期臨床研究計劃於2025年第一季開始。

Importantly, EGFR-expression in healthy tissues posted a significant challenge that potential therapeutics must minimize off-tumor toxicity to be clinically viable. The dual masking technology employed in 6368 can potentially offer a critical advantage over conventional EGFR-targeted approaches. The rapid clearance of 6368 achieved through shortened half-life outside the tumor microenvironment enhances its safety profile and suggest that it could be a transformative treatment option for these patients.

重要的是，健康組織中的 EGFR 表現提出了重大挑戰，即潛在的治療方法必須最大限度地減少腫瘤外毒性才能在臨床上可行。6368 所採用的雙重掩蔽技術可能比傳統的 EGFR 標靶方法具有關鍵優勢。透過縮短腫瘤微環境外的半衰期來實現 6368 的快速清除，增強了其安全性，並表明它可能成為這些患者的變革性治療選擇。

To conclude, the PRO-XTEN masking platform and the clinical assets licensed from Sanofi will, following closing, represent a significant step forward in our mission to develop innovative therapies that address the unmet needs of people living with cancer.

總而言之，PRO-XTEN 遮蔽平台和賽諾菲授權的臨床資產在交易完成後將代表我們在開發創新療法以滿足癌症患者未滿足的需求的使命中向前邁出的重要一步。

With that, I would like to hand the presentation over to Brent.

說到這裡，我想把演講交給布倫特。

Thank you, Mark. I would now like to discuss the financial aspects of this transaction and how it aligns with our strategic priorities. Following closing, our license agreement with Sanofi will provide us with exclusive rights to three clinical-stage dual masked T-cell engagers. In addition to these clinical-stage assets, the agreement will also provide us with exclusive use of Sanofi's protease cleavable masking platform for oncology and infectious diseases.

謝謝你，馬克。我現在想討論這項交易的財務方面以及它如何與我們的策略重點保持一致。交易完成後，我們與賽諾菲的許可協議將為我們提供三種臨床階段雙掩模 T 細胞接合劑的獨家權利。除了這些臨床階段的資產外，該協議還將為我們提供賽諾菲用於腫瘤學和傳染病的蛋白酶可裂解掩蔽平台的獨家使用權。

After HSR clearance, which we expect will take about 30 days from deal signing, Vir will be responsible for and have sole decision-making authority over all development and commercialization activities related to these assets. In exchange for these rights, Sanofi will be eligible for future development, regulatory and commercial net sales-based milestone payments as well as tiered royalties on worldwide net sales. These payments are structured to allow Sanofi to benefit from Vir's successful advancement and commercialization of these assets.

HSR 批准後（預計交易簽署後大約需要 30 天），Vir 將負責與這些資產相關的所有開發和商業化活動，並擁有唯一決策權。作為這些權利的交換，賽諾菲將有資格獲得基於未來開發、監管和商業淨銷售額的里程碑付款以及全球淨銷售額的分級特許權使用費。這些付款的目的是讓賽諾菲能夠從 Vir 的這些資產的成功推進和商業化中受益。

As part of the agreement, at closing, we will make an upfront payment of $100 million as well as a near-term escrow milestone payment of $75 million, which is subject to 6368, achieving first-in-human dosing totaling $175 million in near-term payments.

作為協議的一部分，交易完成時，我們將支付 1 億美元的預付款以及 7500 萬美元的近期託管里程碑付款，該款項受 6368 約束，在近期實現首次人體給藥總計 1.75 億美元。

As we anticipate integrating the newly licensed assets into our pipeline, we are also taking steps to prioritize our R&D portfolio and restructure our workforce to ensure that we are allocating our resources to the opportunities with the highest potential for patient impact. By concentrating our efforts on our key programs, we believe we can maximize value creation.

當我們預計將新許可的資產整合到我們的管道中時，我們也採取措施確定我們的研發組合的優先順序並重組我們的員工隊伍，以確保我們將資源分配給對患者影響最大的機會。我們相信，透過將精力集中在關鍵項目上，我們能夠最大限度地創造價值。

As part of this prioritization, we have made the decision to stop our R&D programs in Influenza, COVID-19 and the T-cell-based viral vector platform, where appropriate, we will seek strategic partners to continue development of these assets. We are also implementing a workforce restructuring that will result in a reduction of approximately 25% or approximately 140 employees. This reduction excludes the onboarding post-closing of approximately 50 key employees from Sanofi. We expect to end 2024 with around 435 employees, a reduction of close to 200 employees versus our peak in 2023.

作為這項優先事項的一部分，我們決定停止流感、COVID-19 和基於 T 細胞的病毒載體平台的研發項目，在適當的情況下，我們將尋求戰略合作夥伴來繼續開發這些資產。我們也正在實施勞動力重組，這將導致裁員約 25%，約 140 名員工。這一減少不包括交易結束後賽諾菲約 50 名關鍵員工的入職。我們預計到 2024 年底員工數量將達到約 435 名，與 2023 年的高峰相比減少近 200 名。

We estimate this workforce restructuring will result in the reduction of our cost structure by approximately $50 million annually, with savings expected to begin to be fully realized in the first quarter of 2025. In addition, we anticipate cost savings of approximately $50 million through the end of 2025 from the phaseout programs. These cost reductions will allow us to allocate more resources to our core programs while maintaining strong financial position.

我們估計，此次員工重組將導致我們的成本結構每年減少約 5,000 萬美元，預計節省的成本將在 2025 年第一季開始完全實現。此外，我們預計到 2025 年底，逐步淘汰計畫將節省約 5,000 萬美元的成本。這些成本削減將使我們能夠為核心專案分配更多資源，同時保持強勁的財務狀況。

Combined with the strategic restructuring efforts announced in late 2023, we have successfully streamlined our operations and reduced our annual cost structure by an estimated $90 million in total from our peak, positioning Vir for enhanced financial resilience, we remain committed to identifying additional cost saving measures as we move forward.

結合 2023 年底宣布的戰略重組工作，我們已成功簡化運營，並將年度成本結構比高峰期減少了約 9,000 萬美元，從而增強了 Vir 的財務彈性，我們仍致力於確定其他成本節約措施當我們前進時。

I'll now briefly touch on some key financial highlights for the second quarter of 2024. R&D expenses for the second quarter of 2024 were $105.1 million compared to $168.1 million for the same period in 2023. The decrease was primarily driven by lower clinical development costs and manufacturing costs associated with Vir 2482, lower manufacturing costs associated with our hepatitis programs and lower personnel costs related to cost savings initiatives implemented in 2023.

我現在將簡要介紹 2024 年第二季的一些關鍵財務亮點。2024 年第二季的研發費用為 1.051 億美元，而 2023 年同期為 1.681 億美元。這一下降主要是由於與 Vir 2482 相關的臨床開發成本和製造成本降低、與我們的肝炎項目相關的製造成本降低以及與 2023 年實施的成本節約計劃相關的人員成本降低。

SG&A expenses for the second quarter of 2024 were $30.3 million compared to $45.5 million for the same period in 2023. The decrease was primarily related to cost savings initiatives implemented during the second half of 2023. Restructuring, long-lived asset impairment and related charges for the second quarter of 2024 were $26.3 million compared to $5.4 million for the same period in 2023. The increase was primarily related to impairment charges related to closing our St. Louis, Missouri facility previously announced on December 13, 2023.

2024 年第二季的銷售、管理及行政費用為 3,030 萬美元，而 2023 年同期為 4,550 萬美元。這項下降主要與 2023 年下半年實施的成本節約措施有關。2024 年第二季的重組、長期資產減損和相關費用為 2,630 萬美元，而 2023 年同期為 540 萬美元。這一增長主要與先前於 2023 年 12 月 13 日宣布關閉密蘇裡州聖路易斯工廠相關的減損費用有關。

We ended the second quarter of 2024 with cash, cash equivalents and investments of $1.43 billion compared to $1.51 billion at the end of the first quarter of 2024, representing a $78 million decline quarter-over-quarter.

截至 2024 年第二季末，我們的現金、現金等價物和投資為 14.3 億美元，而 2024 年第一季末為 15.1 億美元，季減 7,800 萬美元。

I'll now summarize our revised financial guidance for 2024, which takes into account the anticipated impact of the licensing agreement and the workforce restructuring. We now expect our 2024 full year GAAP operating expenses to be in the range of $580 million to $610 million. Our revised expense guidance reflects a $70 million reduction compared to our prior guidance and demonstrates our commitment to financial discipline.

現在，我將總結我們修訂後的 2024 年財務指引，其中考慮了許可協議和勞動力重組的預期影響。我們現在預計 2024 年全年 GAAP 營運費用將在 5.8 億至 6.1 億美元之間。與先前的指導相比，我們修訂後的費用指導減少了 7000 萬美元，並體現了我們對財務紀律的承諾。

When excluding noncash stock-based compensation and restructuring expenses from the GAAP operating expense range, the resulting range of $450 million to $500 million, which represents a 26% year-over-year decline at the midpoint.

當從 GAAP 營運費用範圍中排除非現金股票薪酬和重組費用時，最終範圍為 4.5 億美元至 5 億美元，中點年減 26%。

From a cash perspective, our cash utilization in the second half of 2024 is expecting to be similar to the first half of 2024. The expense and cash guidance includes anticipated operating expenses associated with the license agreement. However, they exclude the impact of the previously mentioned $100 million upfront payment due to Sanofi at closing and the $75 million escrow payment, we will incorporate any associated impact on our guidance during our third quarter 2021 earnings press release. As we move forward, we remain confident in our ability to execute on our strategic priorities and create long-term value for our shareholders.

從現金角度來看，我們 2024 年下半年的現金利用率預計與 2024 年上半年相似。費用和現金指導包括與許可協議相關的預期營運費用。然而，它們排除了前面提到的賽諾菲在交割時支付的1 億美元預付款和7500 萬美元託管付款的影響，我們將在2021 年第三季收益新聞稿中納入對我們指導的任何相關影響。隨著我們的前進，我們對執行策略重點並為股東創造長期價值的能力充滿信心。

With that, I will now turn the call back over to Marianne for closing remarks.

現在，我將把電話轉回給瑪麗安，讓她發表結束語。

Thank you, Brent. As we have shared previously, our goal is to become a sustainable, fully integrated commercial company, and we have committed to utilize our strong cash position to invest in complementary attractive clinical stage assets.

謝謝你，布倫特。正如我們之前所分享的，我們的目標是成為一家可持續發展的、完全一體化的商業公司，我們致力於利用我們強大的現金狀況來投資具有互補吸引力的臨床階段資產。

We have committed to leverage our scientific expertise, our proprietary antibody platform and our capabilities to broaden our aperture beyond infectious diseases. We have committed to increase our financial discipline and build a more fit-for-purpose organization, and we have committed to sharpen our investment focus on areas where we can make the greatest impact on patients as value creation.

我們致力於利用我們的科學專業知識、我們專有的抗體平台和我們的能力來拓寬我們的視野，超越傳染病。我們致力於加強我們的財務紀律，建立一個更適合目標的組織，我們致力於將投資重點集中在能夠為患者創造價值、產生最大影響的領域。

Starting the close of the license agreement with Sanofi and coupled with our strategic restructuring, we will have successfully delivered on all of these commitments. Looking ahead, we will be positioned well with a focused set of development priorities to accelerate near-term value creation. Our development priorities include promising programs in hepatitis delta, hepatitis B and the newly licensed T-cell engagers. We are looking forward to sharing more with you on these programs as well as our earlier stage programs during our R&D Day in late November.

從與賽諾菲簽署許可協議開始，加上我們的策略重組，我們將成功兌現所有這些承諾。展望未來，我們將做好準備，制定一系列重點發展重點，以加速短期價值創造。我們的開發重點包括丁型肝炎、B型肝炎和新許可的 T 細胞接合劑方面有前景的項目。我們期待在 11 月底的研發日期間與您分享更多有關這些項目以及早期階段項目的資訊。

As we look to the future, we are excited about the multiple value-driving catalysts anticipated across our pipeline in the next four to 18 months. We expect to report additional clinical data from our hepatitis delta and our hepatitis B program later this year, as well as share updates subject to closing on the progress of our newly licensed T-cell engagers during the course of 2025 and 2026. These milestones highlight the potential of our pipeline to deliver meaningful near-term value.

展望未來，我們對未來 4 到 18 個月內預計將出現的多種價值驅動催化劑感到興奮。我們預計將在今年稍後報告我們的丁型肝炎和乙型肝炎項目的更多臨床數據，並分享更新信息，具體取決於我們新許可的T 細胞參與者在2025 年和2026 年期間的進展情況。這些里程碑凸顯了我們的管道提供有意義的近期價值的潛力。

In conclusion, today marks a pivotal moment for Vir as we embark on a new chapter in our journey of powering the immune system to transform lives. With a strengthened pipeline, our talented team and a clear vision for the future, we are well-positioned to deliver on our mission and create long-term value for all our stakeholders.

總之，今天對 Vir 來說是一個關鍵時刻，我們開啟了增強免疫系統改變生活之旅的新篇章。憑藉更強大的產品線、才華橫溢的團隊和對未來的清晰願景，我們有能力履行我們的使命，為所有利害關係人創造長期價值。

Thank you for your continued support and your interest in Vir. We look forward to keeping you updated on our progress.

感謝您對 Vir 的持續支持和興趣。我們期待向您通報我們的最新進展。

And with that, I'll turn the call back to Rich to begin the Q&A session.

然後，我會將電話轉回給 Rich，開始問答環節。

Thank you, Marianne. We will now start the Q&A session. Please limit questions to two per person so we get to all of our covering analysts.

謝謝你，瑪麗安。我們現在開始問答環節。請將問題限制為每人兩個，以便我們聯繫到所有覆蓋分析師。

I'll turn it over to you, operator.

我會把它交給你，接線生。

Thank you, Rich. At this time, we will begin conducting our analyst Q&A session. (Operator Instructions)

謝謝你，里奇。此時，我們將開始進行分析師問答環節。（操作員說明）

Phil Nadeau, TD Cowen.

菲爾·納多，TD·考恩。

Good afternoon. Thanks for taking our questions and congratulations on the deal. Two for us on the new molecules. I guess, first, on 6309 and 6329, the dose escalation phases that are ongoing now from which we'll get data next year. Are those in unselected patient populations kind of all comer refractory patients? Or are they being -- are HER in PSMA specific patients being enrolled in those trials. That's the first question.

午安.感謝您回答我們的問題並祝賀這筆交易。給我們兩個關於新分子的資訊。我想，首先是 6309 和 6329，現在正在進行劑量遞增階段，我們明年將從中獲得數據。未經選擇的患者群體中的患者是否都是難治性患者？或者他們是否正在招募 PSMA 特定患者中的 HER 參加這些試驗。這是第一個問題。

And then second, more broadly, can you give us some idea of the framework by which you'll evaluate all three of the TCEs to continue investment and move forward. This sounds very, very interesting. Nonetheless, there are other agents, obviously already in the market or in development targeting PSMA, HER and EGFR. So what -- broadly, what do you hope to see? Do you want to see best-in-class, simply competitive enough or do you expect there to be populations in which these work that some of the other agents do. Thank you.

其次，更廣泛地說，您能否給我們一些關於評估所有三個傳統文化表現形式以繼續投資並向前推進的框架的想法。這聽起來非常非常有趣。儘管如此，還有其他針對 PSMA、HER 和 EGFR 的藥物，顯然已經上市或正在開發中。那又怎樣——概括地說，你希望看到什麼？您是否希望看到一流的、具有足夠競爭力的產品，或者您是否期望在某些人群中這些藥物能夠像其他一些藥物一樣發揮作用。謝謝。

Thank you, Phil. Appreciate the question. So maybe I'll ask Mark, our CMO, to address your first question.

謝謝你，菲爾。感謝這個問題。所以也許我會請我們的首席行銷長馬克回答你的第一個問題。

Sure. And I appreciate the question. I think it's a really good one. For both 6309 and 6329, we are, as you said, enrolling tumor types that are heavily pretreated. In the case of 6309, both HER2-positive -- HER2 high and HER2 low patients are being enrolled. For the PSMA program, there's not a specific requirement for PSMA positivity, but that certainly will be something that's looked at.

當然。我很欣賞這個問題。我認為這是一個非常好的。對於 6309 和 6329，正如您所說，我們正在招募經過嚴格預處理的腫瘤類型。就 6309 而言，HER2 陽性、HER2 高和 HER2 低的患者均已入組。對於 PSMA 計劃，對 PSMA 積極性沒有具體要求，但這肯定會受到關注。

In terms of your question about the framework for how the assets will be evaluated. The Phase 1 studies allow both dose escalation to test the hypothesis that we can achieve a superior therapeutic index with better safety and efficacy than unmasked TCEs can achieve. So that's one point. The second point is that it allows for potential expansion cohorts in the different diseases, both in monotherapy and in combination therapy. So as the data evolve, we'll be able to determine what are the most promising tumor types combinations versus monotherapy.

關於您關於如何評估資產的框架的問題。第一階段研究允許劑量遞增來檢驗這樣的假設：我們可以實現比未掩蔽的 TCE 更好的治療指數，並且具有更好的安全性和有效性。這是一點。第二點是它允許在不同疾病中進行潛在的擴展隊列，無論是單一療法還是聯合療法。因此，隨著數據的發展，我們將能夠確定與單一療法相比最有希望的腫瘤類型組合。

In terms of very specific hurdles or bars, I think that's something I'll have to get back to you on a subsequent call. But what I would end with saying is that the way the program is currently designed will allow a very intensive interrogation of monotherapy, combination therapy in a variety of tumor types and in the case of PSMA in prostate cancer.

就非常具體的障礙或障礙而言，我認為這是我必須在後續電話中回覆您的內容。但我最後想說的是，該計劃目前的設計方式將允許對多種腫瘤類型以及前列腺癌中的 PSMA 的單一療法、聯合療法進行非常深入的研究。

That’s very helpful.

這非常有幫助。

Yeah. The only thing I would add there, Phil, is as we discussed, I mean, the unmet medical need is still incredibly high in each of these areas for two cancers and PSMA cancers. And there is no TCEs approved in either of the areas that we are discussing today.

是的。Phil，我唯一要補充的是，正如我們所討論的，我的意思是，在這些領域中，兩種癌症和 PSMA 癌症的未滿足醫療需求仍然非常高。我們今天討論的兩個領域都沒有批准任何傳統文化表現。

That's very helpful. Congrats on the deal and thanks for taking our questions.

這非常有幫助。恭喜這筆交易，並感謝您提出我們的問題。

Thank you.

謝謝。

Roanna Ruiz, Leerink.

羅安娜·魯伊斯，萊林克。

Hey, good afternoon. This is Nick Gasic on for Roanna. Thanks for taking our questions. Maybe first from us on the new deal with Sanofi. I guess what are the three T-cell engager programs are you most excited about? I'm curious what your thoughts are on the competitive positioning across the three? And I have a follow-up on HDV.

嘿，下午好。我是羅安娜的尼克·加西克。感謝您回答我們的問題。也許首先是我們與賽諾菲的新協議。我想您最感興趣的三個 T 細胞參與計劃是什麼？我很好奇您對這三者之間的競爭定位有何看法？我對 HDV 有後續報導。

Yeah. Thank you for that question. I'll start and then also ask Mark to chime in. Just again to reiterate for HER2 PSMA and EGFR, even though those are obviously biologically well-validated targets, and there's a lot of activity that has been going on, on these targets. I think that if you look at the landscape today, again, there's still a very high unmet medical need, high mortality for people diagnosed with HER2 cancers. Again, we talked about only 34% of patients being alive after five years diagnosed with PSMA prostate cancer and then only a five-year survival -- a 5-year survival rate of really being very low between 3% and 38% for EGFR-related cancers. So the unmet need despite everything that might be approved or in development is incredibly high.

是的。謝謝你提出這個問題。我先開始，然後請馬克插話。再次重申 HER2 PSMA 和 EGFR，儘管這些顯然是經過生物學驗證的靶標，並且針對這些標靶正在進行大量活動。我認為，如果你再看看今天的情況，仍然存在非常高的未滿足的醫療需求，被診斷出患有 HER2 癌症的人的死亡率很高。再次，我們談到只有34% 的患者在被診斷為PSMA 前列腺癌五年後還活著，然後只有五年存活率——對於EGFR 來說，5 年存活率確實非常低，在3% 到38%之間——相關癌症。因此，儘管一切可能被批准或正在開發，但未滿足的需求仍然非常高。

There are no T-cell engagers for each -- any of these targets that are currently being approved. And again, despite other modalities being approved, especially for HER2 PSMA, you are still faced with this high mortality and a lot of challenging side effects for patients. So the unmet need remains and we think that's really in each -- for each of these therapeutic agents an opportunity to potentially really drive the differentiating impact for patients.

目前正在批准的這些目標中的任何一個都沒有 T 細胞參與者。再說一次，儘管其他治療方式已獲得批准，尤其是 HER2 PSMA，但患者仍然面臨高死亡率和許多具有挑戰性的副作用。因此，未滿足的需求仍然存在，我們認為這確實是每種治療藥物都有可能真正為患者帶來差異化影響的機會。

Mark, do you want to add?

馬克，你要添加嗎？

Sure. Thanks, Marianne. So what I would note that these are all clinically validated targets. So we're very excited about all three of them. They are in different phases of development. The HER2 program is furthest along in the clinic, and so we're getting efficacy -- preliminary efficacy and safety data in these patients with multiple tumor types. And I think there's an opportunity to be first to achieve clinical proof-of-concept within a TCE. For PSMA, we're in Phase 1 as well, GenX [ph] offers a powerful proof point for the approach, which is another asset also in Phase 1.

當然。謝謝，瑪麗安。所以我要指出的是，這些都是經過臨床驗證的目標。所以我們對他們三個都感到非常興奮。它們處於不同的發展階段。HER2 計畫在臨床上走得最遠，因此我們正在獲得療效——針對這些患有多種腫瘤類型的患者的初步療效和安全性數據。我認為有機會成為第一個在 TCE 內實現臨床概念驗證的機會。對於 PSMA，我們也處於第一階段，GenX [ph] 為此方法提供了強有力的證明點，這也是第一階段的另一個資產。

And the other thing I would add is that because of the universal masking, we're able to leverage to 6309 HER2 program to dose escalate more quickly in the PSMA program. And then EGFR, which as we have said before, is looking to go to Phase 1 early next year in Q1 is a potential high risk, high reward opportunity. There's multiple competitors in the clinic three, but there's multiple tumor types that are EGFR positive. And I think here, the potential of the masking is really impactful because this is such a widely expressed marker or a molecule that in order to achieve a therapeutic index that can actually treat the cancers with acceptable safety. This is where I think the exciting aspect of the EGFR program is.

我要補充的另一件事是，由於通用掩蔽，我們能夠利用 6309 HER2 計劃在 PSMA 計劃中更快地增加劑量。然後，正如我們之前所說，EGFR 預計在明年初第一季進入第一階段，這是一個潛在的高風險、高回報的機會。三號診所有多個競爭對手，但有多種 EGFR 陽性腫瘤類型。我認為在這裡，掩蔽的潛力確實具有影響力，因為這是一種廣泛表達的標記物或分子，為了達到實際上可以以可接受的安全性治療癌症的治療指數。我認為這就是 EGFR 計劃令人興奮的地方。

Got it. Thanks for that color. Maybe second question just on HDV. Curious how your interactions with the FDA has been going after the recent HDV data at EASL. And maybe curious what your latest outlook is on a potentially accelerated approval pathway here. Thanks.

知道了。謝謝那個顏色。也許第二個問題只是關於 HDV。好奇在 EASL 最近的 HDV 數據之後，您與 FDA 的互動情況如何。也許好奇您對這裡可能加速的批准途徑的最新看法是什麼。謝謝。

Yeah. So good question. So we already announced that we have fast track designation from the FDA, which I think speaks to the high unmet medical need and the very compelling clinical data. We are pursuing other accelerated clinical development pathways such as breakthrough therapy designation, and we are pursuing an engagement with FDA starting this quarter, Q3 to talk about the registrational program. So we're very excited about the Delta program. We're moving quickly to fit into registrational studies.

是的。好問題。因此，我們已經宣布獲得 FDA 的快速通道指定，我認為這說明了未滿足的醫療需求和非常引人注目的臨床數據。我們正在尋求其他加速臨床開發途徑，例如突破性療法指定，並且我們正在尋求從本季度（第三季度）開始與 FDA 接觸，討論註冊計劃。因此，我們對達美計畫感到非常興奮。我們正在迅速採取行動以適應註冊研究。

That’s helpful. Thanks.

這很有幫助。謝謝。

Paul Choi, Goldman Sachs.

保羅‧崔，高盛。

Hi. Thank you. Good afternoon, and let me also offer my congratulations on the deal. My first question, either for Jennifer or for Mark is, can you maybe share any additional insights with regard to the safety profile of our -- of the T-cell engagers that you just in-licensed with from Sanofi, particularly with regard to anything in healthy volunteers that would suggest that you can avoid some of the issues with cytokine release syndrome that have been a hallmark of the class and just any other evidence you can share with regard to the safety profile?

你好。謝謝。下午好，我也對這筆交易表示祝賀。我的第一個問題，無論是對珍妮佛還是對馬克來說，您能否分享有關我們剛剛從賽諾菲獲得許可的 T 細胞接合器的安全性的任何其他見解，特別是在任何方面在健康在志工中，這是否表明您可以避免細胞因子釋放綜合徵的一些問題，這些問題一直是該課程的標誌，以及您可以分享有關安全性的任何其他證據嗎？

And then my second question, more for Mark probably is, as you think about prosecuting next stage clinical trials after the dose escalation studies, can you comment on your ability and the company's ability to pursue multiple drugs here, I guess, in the clinic at the same time? Or will you prioritize one over the other, depending on the dose escalation data?

然後我的第二個問題，更多的是馬克可能是，當你考慮在劑量遞增研究後進行下一階段的臨床試驗時，你能否評論一下你的能力和公司在這裡尋求多種藥物的能力，我猜，在診所同時？還是您會根據劑量遞增數據優先考慮其中一項？

Go ahead, Mark.

繼續吧，馬克。

Sure. Thanks, Paul, for the questions. In terms of the safety data, the first thing I would mention is the preclinical data that Jen described in detail that shows the fact that there's a 10,000-fold reduction in potency in the mass state as opposed to in the tumor microenvironment where the molecules are activated and form immune synopsis with the tumor cells.

當然。謝謝保羅提出的問題。就安全性數據而言，我首先要提到的是 Jen 詳細描述的臨床前數據，這些數據表明，與分子所處的腫瘤微環境相比，質量狀態下的效力降低了 10,000 倍。腫瘤細胞形成免疫概要。

We have had the opportunity during the diligence to look at preliminary clinical data, including safety data. It's been very valuable to be able to see that. We're not on the able to comment on that today, but I can say that we gained some valuable insights that gave us confidence to move into prosecuting the deal.

在盡職調查期間，我們有機會查看初步臨床數據，包括安全數據。能夠看到這一點非常有價值。今天我們無法對此發表評論，但我可以說，我們獲得了一些寶貴的見解，這使我們有信心著手執行該交易。

In terms of the next stage clinical trial, it's great questions about that. In terms of our development capabilities, I think Vir has demonstrated that we can run large trials at scale, including the peninsula trial of influenza prevention, 3,000 or so patients, multiple Phase 1 and 2 studies subcutaneously in Delta. And we -- bringing on the Sanofi employees, I think we see a lot of synergies between what we can provide in terms of clinical operations, regulatory and other infrastructure and their knowledge and in-depth experience with these assets and their deep relationships with the KOLs and the sites. I feel confident that we'll be able to prosecute multiple trials simultaneously. That, of course, we'll follow the data. We'll prioritize programs that have the most compelling clinical data as those data evolve.

就下一階段的臨床試驗而言，這是一個很大的問題。就我們的開發能力而言，我認為Vir已經證明了我們可以進行大規模的大型試驗，包括預防流感的半島試驗、3000名左右的患者、在達美進行的多項1期和2期皮下研究。我們——引入賽諾菲員工，我認為我們在臨床運營、監管和其他基礎設施方面所能提供的服務與他們對這些資產的知識和深入經驗以及他們與公司的深厚關係之間看到了很多協同作用。我相信我們能夠同時進行多項審判。當然，我們會追蹤數據。隨著這些數據的發展，我們將優先考慮擁有最引人注目的臨床數據的項目。

Okay. Great. Thank you for taking our questions.

好的。偉大的。感謝您接受我們的提問。

Eric Joseph, J.P. Morgan.

艾瑞克‧約瑟夫，摩根大通。

Hi. Thanks for taking the question. Maybe just one or two on 6309. As the trial is designed, it contemplates a combination with PD-1 pembrolizumab, maybe you can shed some light on the biological rationale behind that combination. Is -- are any PD-1 thought to be potentiators of T-cell engagers and any visibility that you might have at this stage on the safety of that combination so far.

你好。感謝您提出問題。也許 6309 上只有一兩個。在設計試驗時，它考慮與 PD-1 pembrolizumab 組合，也許您可以闡明該組合背後的生物學原理。是否有任何 PD-1 被認為是 T 細胞接合劑的增強劑，以及您在現階段對該組合的安全性可能有的了解。

Hi. This is Jen. I can start with that. So maybe I'll start and then hand it over to Mark along the ideas of the safety. So I think fundamentally, what a T-cell engager requires is both the targeting the tumor with the tumor-associated antigen and an activation of the T-cells through the CD3 arm. This informs the immune synapse allows the T-cells to directly kill the tumor cells.

你好。這是珍。我可以從那裡開始。所以也許我會開始，然後按照安全的想法交給馬克。因此，我認為從根本上來說，T 細胞接合者需要的既是用腫瘤相關抗原靶向腫瘤，也是透過 CD3 臂活化 T 細胞。這通知免疫突觸允許 T 細胞直接殺死腫瘤細胞。

This requires that you have T-cells there that can be activated. And so there's where I think you have real synergy with something like a PD-1, which really removes a break on a T-cell and it allows them to be active. So that's really the fundamental concept behind us of a checkpoint inhibitor with a T-cell engager.

這需要您那裡有可以激活的 T 細胞。因此，我認為與 PD-1 等藥物具有真正的協同作用，它確實消除了 T 細胞的斷裂，並使它們變得活躍。這確實是帶有 T 細胞接合器的檢查點抑制劑背後的基本概念。

Yeah. In terms of the safety of dose escalation in combination with pembro, I'll just refer to my prior statement, which is we have had the opportunity to see preliminary clinical data, including safety data and preliminary efficacy data. And we found this information really valuable. We're not really able to comment in detail on that at this point, but this is information we'll be providing as a subsequent interaction.

是的。關於劑量遞增合併pembro的安全性，我就參考我先前的說法，就是我們有機會看到初步的臨床數據，包括安全性數據和初步療效數據。我們發現這些資訊非常有價值。目前我們還無法對此進行詳細評論，但這是我們將在後續互動中提供的資訊。

Okay. Great. Well, thanks for the great color and congrats on the deal.

好的。偉大的。好吧，感謝您的出色色彩，並祝賀這筆交易。

Thanks Eric.

謝謝埃里克。

Mike Ulz, Morgan Stanley.

麥克烏爾茲，摩根士丹利。

Yep. Hey guys, thanks for taking the question. Maybe just now that you have this PRO-XTEN masking platform, you mentioned the potential to leverage it with your own monoclonal antibody platform. Can you maybe just give us a sense where you initially think you might go with your next-generation antibodies that could be masked now or any particular targets you might be interested in? Thanks.

是的。嘿夥計們，感謝您提出問題。也許剛剛您擁有了這個 PRO-XTEN 掩蔽平台，您提到了將其與您自己的單株抗體平台結合使用的潛力。您能否讓我們了解您最初認為您可能會使用現在可以被掩蓋的下一代抗體或您可能感興趣的任何特定目標？謝謝。

Jen, do you want to take that?

珍，你想接受這個嗎？

Yeah. No, thank you for the question. So I do think there are real synergies. I mean, fundamentally what the T-cell engagers are is that they are built off of the antibodies. And so these single-chain SVs, which are the binding portion of the antibody. So our antibody discovery engine really does provide quite complementary and synergistic at power to developing the next stage of T-cell engagers.

是的。不，謝謝你的提問。所以我確實認為存在真正的協同效應。我的意思是，從根本上來說，T 細胞接合者是由抗體建構的。這些單鏈 SV 是抗體的結合部分。因此，我們的抗體發現引擎確實為開發下一階段的 T 細胞接合者提供了相當互補和協同的力量。

I think as you can see by the first three molecules, and they really have focused in on ones that -- for which there is biological proof-of-concept for these being bonafied tumor-associated antigens. And frankly, there's a number of others that one could consider developing. I think that's where it will start.

我認為正如你所看到的前三個分子，他們確實專注於那些與腫瘤相關的抗原有生物學概念驗證的分子。坦白說，還有很多其他的東西可以考慮開發。我想這就是一切的開始。

I do think the platform has really broad potential and brought up facility. The first time in XTEN was used with this molecule ALTUVIIIO, which was really just used to extend its half-life. I think from that, it's been shown that it can be applied to not only T-cell engagers, but also to other biologics, including cytokines and probably antibodies as well. So I think there really is a broad potential of this, but I think focusing first on those that have biological proof-of-concept and an extent from there.

我確實認為該平台具有非常廣泛的潛力並提供了便利。XTEN 中第一次使用的是 ALTUVIIIO 這種分子，它實際上只是用來延長其半衰期。我認為由此看來，它不僅可以應用於 T 細胞接合劑，還可以應用於其他生物製劑，包括細胞因子，可能還有抗體。所以我認為這確實有廣泛的潛力，但我認為首先要關注那些具有生物學概念驗證和一定程度的潛力。

Got it. Thank you.

知道了。謝謝。

Yeah. The only thing I would add is if you think about these as T-cell engagers and the components of it, as Jen was saying, I mean, on the T-cell engagement side itself, the therapeutic modality, I think we can contribute tremendously with our antibody engineering expertise. And then what is also, I think, very encouraging is that both on the masked side, as Jen said, there's a considerable amount derisking that has happened given that there's a drug on the market that has been using this month. And also on the cleavable linker side, I think you have seen what Jen presented on the preclinical data, which is very convincingly showing, of course, preclinically in vitro and in vivo that this actually works. So I think there's a lot of derisking that has been on the platform. And as it relates to then really going for new targets, I think we can add a really unique capability.

是的。我唯一要補充的是，如果你將這些視為 T 細胞接合者及其組成部分，正如 Jen 所說，我的意思是，在 T 細胞接合本身、治療方式方面，我認為我們可以做出巨大貢獻憑藉我們的抗體工程專業知識。然後，我認為非常令人鼓舞的是，正如 Jen 所說，鑑於市場上有一種藥物本月一直在使用，因此在蒙面方面，已經發生了相當大的風險降低。同樣在可裂解連接體方面，我想您已經看到了 Jen 提出的臨床前數據，這非常令人信服地表明，當然，在臨床前體外和體內這實際上是有效的。所以我認為這個平台上有很多去風險的措施。由於它與真正追求新目標有關，我認為我們可以添加一個真正獨特的功能。

Great.

偉大的。

Joseph Stringer, Needham & Company.

約瑟夫‧斯金格，李約瑟公司。

Hi. Thanks for taking our questions. You mentioned the broad potential of the platform and the in-licensed assets. Just curious if you could provide some additional color behind the decision for the in-licensing and with the move into oncology intentional, were there other assets and other therapeutic areas that were considered?

你好。感謝您回答我們的問題。您提到了該平台和許可資產的廣泛潛力。只是好奇您是否可以在許可決定背後提供一些額外的信息，並且有意進入腫瘤學領域，是否考慮了其他資產和其他治療領域？

And then lastly, does the update -- corporate update here, does that affect any of the timelines or any of the resources that you can devote to the HBV or HDV programs? Thank you.

最後，公司的更新是否會影響您可以投入 HBV 或 HDV​​ 專案的任何時間表或任何資源？謝謝。

Yeah. Thank you for that question, Joe. So the corporate update, absolutely no impact on our time lines for the hepatitis delta and hepatitis B studies. I mean, our focus will be on clinical execution that is really a strategic priority for hepatitis programs and then after closing of this transaction also the newly licensed T-cell engagers.

是的。謝謝你提出這個問題，喬。因此，公司更新絕對不會影響我們丁型肝炎和B型肝炎研究的時間表。我的意思是，我們的重點將放在臨床執行上，這確實是肝炎計畫的策略重點，然後在本次交易結束後，還有新獲得許可的 T 細胞參與者。

Now coming to your earlier question about how we came about the decision. So during the course of, I think, the last year, we have said that we want to be really strategic and thoughtful about how we would be using our cash balance, which, as Brent mentioned, was $1.43 billion at the end of the second quarter. and that we would be looking for potentially bringing in a clinical stage asset or assets and really look for opportunities that would build strongly on our existing expertise. So really opportunities where there would be strong synergy.

現在回到你之前提出的問題，即我們是如何做出這個決定的。So during the course of, I think, the last year, we have said that we want to be really strategic and thoughtful about how we would be using our cash balance, which, as Brent mentioned, was $1.43 billion at the end of the second四分之一.我們將尋找可能引入臨床階段資產的機會，並真正尋找能夠在我們現有專業知識的基礎上建立強有力的機會。因此，確實存在具有強大協同效應的機會。

So obviously, we have looked at a lot of opportunities that would fit that mold. But I would say that we really believe this is a very, very unique fit for a lot of different reasons. Obviously, the start -- the opportunity addresses a very high unmet need. We talked about it. And we did very rigorous due diligence, and we came away very convinced about the value of the clinical assets, but also really the value of the platform and the signs behind it.

顯然，我們已經研究了很多適合這種模式的機會。但我想說的是，出於很多不同的原因，我們確實相信這是一個非常非常獨特的契合。顯然，這個機會解決了一個非常高的未滿足的需求。我們討論過。我們進行了非常嚴格的盡職調查，我們非常相信臨床資產的價值，也非常相信平台的價值及其背後的標誌。

As we said, the targets, the biological targets on the three clinical assets are derisked. The masking is, to some extent, derisked and the cleavable linkers, again, we have very strong preclinical data in vitro and in vivo to show that this actually all. So -- and again, in addition, highly synergistic, as we discussed with every capability that we have here in-house, our antibody expertise, our clinical development organization that has proven to be very, very strong in operating on clinical trials and also our deep immunology expertise and B and T-cell expertise, which we haven't talked about that much.

正如我們所說，三個臨床資產的目標、生物目標都沒有風險。在某種程度上，掩蔽是消除了風險的，並且可切割的接頭再次，我們有非常強大的體外和體內臨床前數據來表明這實際上是全部。因此，此外，高度協同，正如我們討論的那樣，我們內部擁有的每一項能力，我們的抗體專業知識，我們的臨床開發組織已被證明在臨床試驗運營方面非常非常強大，而且我們深厚的免疫學專業知識以及B 和T 細胞專業知識，我們對此還沒有過多討論。

And then finally, this deal brings a number of near-term catalysts and value infraction points for the company. Within the next nine to 18 months, we will really be able to see data on these clinical stage T-cell engagers. So that's all taken together, very, very excited and a great moment for us here at Vir.

最後，這筆交易為該公司帶來了一些近期催化劑和價值違規點。在接下來的 9 到 18 個月內，我們將真正能夠看到這些臨床階段 T 細胞接合者的數據。總而言之，這對我們 Vir 來說非常非常興奮，也是一個偉大的時刻。

Alec Stranahan, Bank of America.

亞歷克·斯特拉納漢，美國銀行。

Thanks, and appreciate you taking more questions. Two from us. First, just on the new TC assets. Just trying to understand the competitive positioning a bit more. Anything unique that you could point us to in terms of the design of the mask versus, say, a GenX or CytomX? Or is it more due to the fact that you're using a mask on both the antitumor and the anti-CD3 arms versus the actual structure of the mask itself? And then I've got a follow-up.

謝謝，並感謝您提出更多問題。我們兩個。首先，關於新的 TC 資產。只是想多了解競爭定位。您可以向我們指出面罩的設計與 GenX 或 CytomX 相比有何獨特之處嗎？或者更多的是因為您在抗腫瘤臂和抗 CD3 臂上都使用了面罩，而不是面罩本身的實際結構？然後我有一個後續行動。

Jen, do you want to take that?

珍，你想接受這個嗎？

Yes, sure, happy to. So really, I think that the uniqueness is actually in the combination of attributes for this platform. And so I spoke about this, but it was at a fairly high level. So let me elaborate a little bit more.

是的，當然，很高興。所以說真的，我認為獨特之處實際上在於這個平台的屬性組合。所以我談到了這個，但這是一個相當高的水平。讓我詳細說明一下。

So I think there's some major components. One you hit upon. One is the dual masking. So I think there provides a real advantage to masking both the tumor-associated antigen as well as the CD3 arm and both arms can because of safety issues. And so masking both of them really has the best potential to eliminate those issues.

所以我認為有一些主要組成部分。你偶然發現的一個。一是雙重掩蔽。因此，我認為，由於安全問題，掩蓋腫瘤相關抗原以及 CD3 臂和兩個臂都可以提供真正的優勢。因此，掩蓋它們確實最有可能消除這些問題。

Importantly, this is also different design, and it's a universal mask. So that's where it comes with this like plug-and-play concept, and that the same mask can be used across multiple different therapeutics. So essentially, the same mask is on all three of the T-cell engagers that are in or close to the clinic. And this allows for rapid execution, both preclinically, but also rapid execution in the clinic. As Mark highlighted, this does make a quicker path towards dose escalation for PSMA because the mask itself has been derisked.

重要的是，這也是不同的設計，並且是通用的面具。這就是它的即插即用概念，而同一個面罩可以用於多種不同的治療方法。因此，本質上，診所內或診所附近的所有三個 T 細胞接合器都戴著相同的面罩。這不僅可以在臨床前快速執行，而且可以在臨床中快速執行。正如 Mark 所強調的那樣，這確實為 PSMA 的劑量升級提供了更快的途徑，因為面罩本身已經消除了風險。

And ALTUVIIIO itself does also derisk the mask. So there has been an approved product for which this mask is used, providing additional concept around its safety as well as lack of immunogenicity.

ALTUVIIIO 本身也確實消除了面具的風險。因此，已經有一種使用該口罩的批准產品，提供了有關其安全性以及缺乏免疫原性的額外概念。

And then finally, I think the other component that we've hit on that I think is also quite exciting is this broader applicability of the masks, not only for T-cell engagers, but also potentially for other molecules like cytokine or potentially other protein therapeutics like antibodies.

最後，我認為我們發現的另一個我認為也非常令人興奮的部分是面罩的更廣泛的適用性，不僅適用於 T 細胞接合者，還可能適用於其他分子，如細胞因子或潛在的其他蛋白質抗體等療法。

Okay.

好的。

Alec, I would just add that from a competitive landscape perspective, for HER2, there's no other masked T-cell engagers in development. For PSMA, there is one mask TC in development and for EGFR, there are three. So I mean, in the broader context of things here, where TCEs, as we discussed, have a lot of shortcomings and a lot of toxicity and really challenging profiles for patients. We have an opportunity here through this masked TCEs to really drive the difference and the competitive landscape is really not that intense.

Alec，我想補充一點，從競爭格局的角度來看，對於 HER2，沒有其他蒙面 T 細胞參與者正在開發中。對於 PSMA，有一種正在開發的掩模 TC，對於 EGFR，有 3 種。所以我的意思是，在更廣泛的背景下，正如我們所討論的，傳統文化表現形式有很多缺點和很多毒性，對患者來說確實具有挑戰性。我們有機會透過這種掩蓋的傳統文化表現形式來真正推動差異化，而且競爭格局實際上並不那麼激烈。

Okay. Thanks. That's clear. And then maybe one quick one, just putting a finer point on the applications in immunology. Would this mostly be through half-life extension for, say, cytokines? Or are there any targets or indications you think could be the most apt initial avenues for development? Thanks.

好的。謝謝。很清楚。然後也許是一個快速的，只是對免疫學中的應用進行更詳細的闡述。這主要是透過延長細胞激素的半衰期來實現嗎？或者您認為有哪些目標或跡象可能是最合適的初始發展途徑？謝謝。

Yeah. So we can't extend the half-life, but I think actually, there are two attributes. So the way that the mask is used in ALTUVIIIO is purely fixed on the half-life. The way the mask is used for the T-cell engagers is that it does extend the half-life and allows them to get to the site of action. However, once they are cleaved, they don't have a very short half-life, which then allows them to act in that tumor microenvironment, because they're right there with their target antigen. It activates the T-cells, which then have a longer list and activation profile. But that active molecule once it circulates, then has a very short half-life, and that provides an avid safety benefit.

是的。所以我們不能延長半衰期，但我認為實際上有兩個屬性。所以ALTUVIIIO中mask的使用方式純粹是固定在半衰期上的。面罩用於 T 細胞接合器的方式是，它確實延長了半衰期並允許它們到達作用部位。然而，一旦它們被切割，它們的半衰期就不會很短，這使得它們能夠在腫瘤微環境中發揮作用，因為它們就與目標抗原在一起。它激活 T 細胞，然後 T 細胞具有更長的清單和活化曲線。但這種活性分子一旦循環，半衰期就非常短，這提供了強烈的安全益處。

You can envision the same type of thing being applied to a cytokine, having it be activated only at the site where you want it to be activated and then having that short half-life be an attribute, because we all know that these cytokines will incredibly potent and beneficial for activating immune cells, they often have very high associated toxicity themselves. So while they have a short half-life, you don't want them to have too long at half-life or you're going to have greater toxicity. So I think those both are true. Thank you for the question.

您可以想像將相同類型的東西應用於細胞因子，使其僅在您希望其被激活的位點被激活，然後將短半衰期作為一個屬性，因為我們都知道這些細胞因子將令人難以置信地它們對活化免疫細胞有效且有益，但它們本身通常具有非常高的相關毒性。因此，雖然它們的半衰期很短，但您不希望它們的半衰期太長，否則會產生更大的毒性。所以我認為這兩者都是正確的。謝謝你的提問。

Thank you.

謝謝。

All right. This concludes the Q&A session of the call. Thank you for participating, and I'll turn the call back over to Marianne.

好的。電話問答環節到此結束。感謝您的參與，我會將電話轉給瑪麗安。

Yes, apologies. Thanks everyone for your interest in listening to our earnings call today, and people [ph] will put that close call. Thank you.

是的，抱歉。感謝大家有興趣收聽我們今天的財報電話會議，人們[ph]將進行這次千鈞一發的比賽。謝謝。