Beam Therapeutics Inc (BEAM) 2024 Q3 法說會逐字稿

Good morning, and welcome to the Beam Therapeutics Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Beam's request.

早安，歡迎參加 Beam Therapeutics 電話會議。此時，所有參與者都處於只聽模式。最後將會有一個問答環節。請注意，本次通話是應 Beam 的要求進行錄音的。

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.

我現在想將電話轉給投資者關係和外部溝通副總裁 Holly Manning。

Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review third quarter 2024 business update, including Abstracts Accepted for Presentation at the American Society of Hematology Annual Meeting. You can access slides for today's call by going to the Investors section of our website, bmtx.com.

謝謝你，接線生。大家早安，歡迎參加 Beam 的電話會議，回顧 2024 年第三季的業務更新，包括在美國血液學會年會上接受演講的摘要。您可以造訪我們網站 bmtx.com 的投資者部分，查看今天電話會議的幻燈片。

With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Giuseppe Ciaramella, our President; and Dr. Amy Simon, our Chief Medical Officer.

今天與我一起參加電話會議並發表事先準備好的演講的是我們的執行長約翰·埃文斯 (John Evans)；我們的總裁 Giuseppe Ciaramella 博士；以及我們的首席醫療官 Amy Simon 博士。

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995.

在我們開始之前，我想提醒大家，我們在本次電話會議中所做的一些陳述將包括出於 1995 年《私人證券訴訟改革法案》安全港條款的目的而做出的前瞻性陳述。

Actual events and results could differ materially from those expressed or implied by any forward looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K, as updated by our quarterly reports on Form 10-Q and any other filings that we may make with the SEC.

由於各種風險、不確定性和其他因素，包括我們最新10-K 表格年度報告的風險因素部分中列出的因素，實際事件和結果可能與任何前瞻性陳述中明示或暗示的事件和結果存在重大差異，根據我們的 10-Q 表格季度報告以及我們可能向 SEC 提交的任何其他文件進行更新。

In addition, any forward-looking statements represent our views only as of today and should not be relied upon, as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change.

此外，任何前瞻性陳述僅代表我們截至今天的觀點，不應被依賴於代表我們截至任何後續日期的觀點。除法律要求外，Beam 特別聲明不承擔更新或修改任何前瞻性聲明的義務，即使我們的觀點發生變化。

With that, I will turn the call over to John.

這樣，我就把電話轉給約翰。

Thanks, Holly. Good morning, everyone, and thank you for joining us for this exciting moment for Beam, for our employees and for the patients we aim to serve. At Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. This vision has never felt more tangible than it does today, as we report the first clinical data from our portfolio of one-time treatments.

謝謝，霍莉。大家早安，感謝您加入我們，共同見證 Beam、我們的員工以及我們旨在服務的患者的激動人心的時刻。在 Beam，我們的願景是為患有嚴重疾病的患者提供終身治療。當我們報告一次性治療組合的第一份臨床數據時，這個願景從未像今天這樣更加切實。

From the beginning of Beam, we saw an opportunity to advance the gene editing field. CRISPR nucleases are able to precisely target a location in the DNA, but they lack the ability to precisely edit genes. With our innovative next generation technology called base editing, we can now make more precise single base changes at specific locations in genes, resulting in predictable edits in all cells, without needing to damage or make double stranded breaks in the DNA.

從 Beam 成立之初，我們就看到了推動基因編輯領域發展的機會。CRISPR核酸酶能夠精確定位DNA中的某個位置，但它們缺乏精確編輯基因的能力。借助我們稱為鹼基編輯的創新下一代技術，我們現在可以在基因的特定位置進行更精確的單鹼基變化，從而在所有細胞中進行可預測的編輯，而無需損壞DNA 或在DNA 中造成雙鏈斷裂。

The central hypothesis behind Beam is that this breakthrough could provide a superior way to modify genes and could open up entirely new applications in gene editing for a wide range of severe diseases. Given the incredible breadth of potential applications for base editing, it was critical to sharpen our focus and execution on areas where we can have the greatest impact in the near-term. This led to our two core franchises in hematology and liver genetic diseases.

Beam 背後的核心假設是，這項突破可以提供一種更好的基因修飾方法，並為多種嚴重疾病的基因編輯開闢全新的應用。鑑於鹼基編輯的潛在應用範圍令人難以置信，至關重要的是加強我們對短期內能產生最大影響的領域的關注和執行。這導致了我們在血液學和肝臟遺傳疾病方面的兩個核心專營權。

In both cases, we are advancing highly differentiated and potentially best-in-class lead programs with BEAM-101 in sickle cell disease and BEAM-302 in alpha-1 antitrypsin deficiency or AATD, each of which have increased probability of technical success based on strong preclinical validation as well as recent advances in the field.

在這兩種情況下，我們都在推進高度差異化且可能是同類最佳的先導項目，其中包括用於治療鐮狀細胞病的BEAM-101 和用於治療α-1 抗胰蛋白酶缺乏症或AATD 的BEAM-302，每個專案都增加了基於以下技術成功的可能性：強大的臨床前驗證以及該領域的最新進展。

In sickle cell disease, we have a validated regulatory pathway available for BEAM-101, which the BEACON trial is designed to pursue. We also have a next generation program using our ESCAPE technology designed to expand the addressable patient population by eliminating chemotherapy from transplant.

在鐮狀細胞疾病方面，我們有一條經過驗證的適用於 BEAM-101 的監管途徑，BEACON 試驗就是為了追求這一途徑而設計的。我們還有一個使用 ESCAPE 技術的下一代計劃，旨在透過消除移植中的化療來擴大可尋址的患者群體。

Beginning today and continuing at ASH, we're reporting the first clinical data from our hematology franchise. Initial data from our BEACON Phase 1/2 trial support the potential for meaningful clinical differentiation of BEAM-101 compared to currently available treatments for sickle cell disease. We will also be reporting non-human primate data for our ESCAPE technology that validate our vision of enabling gene editing and stem cell transplant, using only antibody based conditioning avoiding chemotherapy altogether.

從今天開始並在 ASH 繼續，我們將報告我們血液學專營權的第一份臨床數據。我們的 BEACON 1/2 期試驗的初步數據支持 BEAM-101 與目前可用的鐮狀細胞疾病治療方法相比具有有意義的臨床差異化潛力。我們還將報告我們的 ESCAPE 技術的非人靈長類動物數據，該數據驗證了我們實現基因編輯和乾細胞移植的願景，僅使用基於抗體的調理，完全避免化療。

In our liver franchise, BEAM-302 also has the potential for rapid proof-of-concept in the clinic and represents the first program with potential to be a one-time treatment with benefit for both lung and liver manifestations of the disease. We expect to report the first clinical data from our ongoing Phase 1/2 trial of BEAM-302 in patients with AATD in 2025, marking another potentially transformative event for the company, our platform and for patients. I'd like to highlight several important updates from our third quarter financial results press release.

在我們的肝臟專營權中，BEAM-302 還具有在臨床中進行快速概念驗證的潛力，並且代表了第一個有可能成為一次性治療的項目，對疾病的肺部和肝臟表現均有益。我們預計將於 2025 年報告我們正在進行的針對 AATD 患者的 BEAM-302 1/2 期試驗的第一份臨床數據，這標誌著公司、我們的平台和患者的另一個潛在的變革事件。我想強調一下我們第三季財務業績新聞稿中的幾項重要更新。

To-date, we have exceeded enrollment expectations in the BEACON trial with 35 sickle cell patients enrolled. Of these, eight patients have been treated with BEAM-101 with the remainder going through pre transplant stages including cell collection and drug product manufacturing. We are also excited to share that we have nominated development candidates for our ESCAPE technology, which Pino will detail shortly. For in-vivo therapies, this summer we dosed the first patient with BEAM-302 in AATD and have continued to enroll and treat patients while opening new sites globally.

到目前為止，我們在 BEACON 試驗中入組了 35 名鐮狀細胞患者，超出了入組預期。其中，8 名患者已接受 BEAM-101 治療，其餘患者正在經歷移植前階段，包括細胞收集和藥物製造。我們也很高興地告訴大家，我們已經提名了 ESCAPE 技術的開發候選者，皮諾很快就會詳細介紹這項技術。對於體內治療，今年夏天，我們在 AATD 中對首例 BEAM-302 患者進行了給藥，並在全球開設新站點的同時繼續招募和治療患者。

As of last month, we have completed dosing in the first cohort of the study. As I noted, we expect to share initial data for multiple cohorts in 2025. In addition, in June, we received US IND clearance for our second in-vivo program BEAM-301 for the treatment of glycogen storage disease 1a or GSD1a. Since then, our team has been preparing to advance BEAM-301 into the clinic with site activation underway and patient dosing expected to commence in early 2025. And importantly, we continue to be in a strong financial position.

截至上個月，我們已經完成了第一組研究的給藥。正如我所指出的，我們預計在 2025 年分享多個隊列的初始數據。此外，6 月，我們的第二個個體內項目 BEAM-301 獲得了美國 IND 批准，用於治療糖原貯積症 1a 或 GS​​MD1a。從那時起，我們的團隊一直在準備將 BEAM-301 推進臨床，正在進行現場激活，預計將於 2025 年初開始患者給藥。重要的是，我們繼續保持強勁的財務狀況。

Turning now to ASH. We are honored to have four abstracts accepted for presentation at the meeting in December. These include two oral presentations, one featuring initial clinical data from the BEACON trial and one with our non-human primate data for our ESCAPE technology as well as poster presentations showcasing exploratory biomarker data for BEAM-101 and preliminary clinical data for BEAM-201, our quad edited CAR-T cell for T-cell malignancies. Abstracts will be available on the ASH website at 9 A.M. Eastern Day.

現在轉向 ASH。我們很榮幸有四份摘要被接受並在 12 月的會議上發表。其中包括兩場口頭演講，一場以BEACON 試驗的初始臨床數據為特色，另一場以我們的ESCAPE 技術的非人靈長類動物數據為特色，以及展示BEAM-101 探索性生物標記數據和BEAM-201 初步臨床數據的海報演講，我們的四重編輯 CAR-T 細胞用於治療 T 細胞惡性腫瘤。摘要將於上午 9 點在 ASH 網站上提供。東日.

I'll now turn to sickle cell disease. At the JPMorgan Conference in January, I asked the question, what if we could develop better one-time therapies for people living with sickle cell disease. I'm pleased today to report that, yes we believe we are on the road to do just that. For sickle cell disease, we are pursuing a long-term stage development strategy that envisions three waves of innovation to progressively reach broader subsets of patients over time. Our Wave 1 approach is BEAM-101, a genetically modified investigational cell therapy administered via hematopoietic stem cell transplantation with busulfan conditioning.

現在我要談談鐮狀細胞疾病。在一月份的摩根大通會議上，我問了一個問題：如果我們能夠為鐮狀細胞疾病患者開發出更好的一次性療法會怎麼樣？我今天很高興地向大家報告，是的，我們相信我們正在實現這一目標。對於鐮狀細胞疾病，我們正在推行長期階段開發策略，設想三波創新，隨著時間的推移逐步覆蓋更廣泛的患者群體。我們的第一波方法是 BEAM-101，這是一種基因改造研究性細胞療法，透過造血幹細胞移植和白消安調理進行管理。

We believe BEAM-101 has the potential to be a best-in-class option for the roughly 10% of sickle cell patients, who have severe disease despite receiving standard of care treatments and are considered appropriate for a chemotherapy based transplant. Though the market for autologous genetic therapies in sickle cell disease is just getting started, it is important to note that allogeneic transplants for patients with severe sickle cell disease are already a reality with several 100 conducted annually in the U.S. And that number only represents those patients, who could find a suitable matched donor, which we know, represents a small minority of total eligible patients.

我們相信，BEAM-101 有潛力成為大約 10% 的鐮狀細胞患者的最佳選擇，這些患者儘管接受標準護理治療，但仍患有嚴重疾病，並被認為適合基於化療的移植。儘管鐮狀細胞疾病自體基因療法市場才剛起步，但值得注意的是，對嚴重鐮狀細胞疾病患者進行同種異體移植已經成為現實，美國每年進行數百例，而這個數字僅代表這些患者我們知道，能夠找到合適的匹配捐贈者的人只佔合格患者中的一小部分。

And finally, we know that autologous transplants are expected to have real advantages over allogeneic transplants, including a lack of graft versus host disease and no need to coordinate the procedure with a donor. Wave 2 takes the same BEAM-101 platform and now incorporates our ESCAPE technology to enable non-genotoxic condition. If successful, ESCAPE would eliminate chemotherapy, which we believe is one of the main hurdles for patients considering a transplant based therapy and thus meaningfully expand the patient population for ex-vivo gene editing by three-fold to two-fold.

最後，我們知道自體移植預計比同種異體移植具有真正的優勢，包括不存在移植物抗宿主疾病，且無需與捐贈者協調手術。Wave 2 採用相同的 BEAM-101 平台，現在結合了我們的 ESCAPE 技術以實現非基因毒性條件。如果成功，ESCAPE將消除化療，我們認為化療是考慮基於移植的治療的患者的主要障礙之一，從而有意義地將離體基因編輯的患者群體擴大三倍至兩倍。

A little further out is Wave 3, where we are using our leading capabilities in lipid nanoparticles to explore the potential for in-vivo based editing for sickle cell disease, which would eliminate the need for transplantation, thus enabling even broader patient access around the world.

更遠的是第三波，我們正在利用我們在脂質奈米顆粒方面的領先能力來探索鐮狀細胞病體內編輯的潛力，這將消除移植的需要，從而使世界各地的患者能夠獲得更廣泛的治療。

Now, let's start by reviewing BEAM-101. Sickle cell disease is a genetic disorder that affects hemoglobin, which delivers oxygen to cells throughout the body. People with this disease make abnormal hemoglobin molecules called hemoglobin S or HbS. This abnormal HbS can form stiff polymers, which distort red blood cells into a sickle or crescent shape, blocking the flow of blood and oxygen throughout the body.

現在，讓我們先回顧一下 BEAM-101。鐮狀細胞疾病是一種影響血紅素的遺傳性疾病，血紅素會向全身細胞輸送氧氣。患有這種疾病的人會產生異常的血紅蛋白分子，稱為血紅蛋白 S 或 HbS。這種異常的 HbS 可以形成僵硬的聚合物，使紅血球扭曲成鐮刀形或新月形，阻礙血液和氧氣在全身的流動。

Sickle cell disease begins in early childhood and leads to anemia, infections and episodes of severe pain, which can manifest as vaso-occlusive crises or VOCs. Patients also can experience life threatening complications such as stroke and significant organ damage, resulting in decreased life expectancy. While recently approved gene therapies have been shown to significantly reduce VOCs, patients are still generally left with HbS of more than 50%, suggesting there are opportunities for further improvement.

鐮狀細胞疾病始於兒童早期，導致貧血、感染和劇烈疼痛，可能表現為血管阻塞危機或 VOC。患者也可能經歷危及生命的併發症，例如中風和嚴重器官損傷，導致預期壽命縮短。雖然最近批准的基因療法已被證明可以顯著減少 VOC，但患者的 HbS 仍普遍超過 50%，這表明還有進一步改善的機會。

Elevating a protective form of hemoglobin called fetal hemoglobin or HbF is a clinically validated strategy to prevent the consequences of sickle cell disease by preventing HbS from polymerizing, thereby preventing red blood cell destruction and organ damage. BEAM-101 was designed to induce a more efficient editing leading to greater and more uniform induction of HbS, a deeper reduction of HbS and normalization of hemoglobin and red blood cell function.

升高稱為胎兒血紅蛋白或 HbF 的保護性血紅蛋白是一種經過臨床驗證的策略，可透過阻止 HbS 聚合來預防鐮狀細胞疾病的後果，從而防止紅血球破壞和器官損傷。BEAM-101 旨在誘導更有效的編輯，從而產生更大、更均勻的 HbS 誘導、更深層的 HbS 減少以及血紅蛋白和紅血球功能的正常化。

Moving to an ideal outcome what would an ideal outcome from genetic correction look like. As shown on slide 13, total hemoglobin for a person with sickle cell disease has 100% HbS in circulation, which causes sickling and results in decreased red blood cell lifespan, anemia, pain crises and organ damage. The disease threshold is exemplified by people with sickle cell trait or carriers with only one mutation and are typically asymptomatic. These people generally have about 60% normal hemoglobin and only 40% HbS.

走向理想的結果 基因校正的理想結果是什麼樣的。如投影片 13 所示，鐮狀細胞疾病患者的總血紅素在循​​環中含有 100% HbS，這會導致鐮狀細胞形成並導致紅血球壽命縮短、貧血、疼痛危機和器官損傷。疾病閾值以具有鐮狀細胞特徵的人或僅具有一種突變的攜帶者為例，並且通常無症狀。這些人的血紅素一般有60%左右是正常的，而HbS只有40%。

The recently approved gene therapies for sickle cell disease, though clearly providing significant benefit to patients, do not achieve this threshold. With base editing, we are aiming for a deeper correction of the hemoglobin profile that is at least on par with or even better than that of a typical person with sickle cell trait. HbF also has the additional biochemical benefit of being anti-sickling, which may provide additional protection.

最近批准的鐮狀細胞疾病基因療法雖然明顯為患者提供了顯著的益處，但並未達到此閾值。透過鹼基編輯，我們的目標是對血紅蛋白譜進行更深入的校正，使其至少與具有鐮狀細胞特徵的典型人相當甚至更好。HbF 還具有抗鐮狀化的額外生化益處，可提供額外的保護。

In pre-clinical models, BEAM-101 achieved these goals, potently inducing HbF to more than 60% and proportionally reducing sickle HbF to less than 40% without the need to make double stranded DNA breaks. Today, we are reporting the first data from our ongoing clinical trial at BEAM-101 in patients with sickle cell disease that validate our preclinical findings and support our goals for this program.

在臨床前模型中，BEAM-101 實現了這些目標，有效地將 HbF 誘導至 60% 以上，並將鐮狀 HbF 按比例降低至 40% 以下，而無需進行雙股 DNA 斷裂。今天，我們報告了我們正在進行的 BEAM-101 鐮狀細胞疾病患者臨床試驗的第一份數據，這些數據驗證了我們的臨床前研究結果並支持我們該計劃的目標。

Let me now turn the call over to Amy to review the BEACON trial and the initial clinical data in our ASH abstract.

現在讓我將電話轉給 Amy，回顧 BEACON 試驗以及 ASH 摘要中的初步臨床數據。

Thanks, John. Starting with the trial design, BEACON is a single-arm open-label study evaluating the safety and efficacy of a single dose of BEAM-101 in patients with sickle cell disease and severe VOCs. The trial is enrolling adult patients 18 to 35 years old with sickle cell disease, who have experienced four or more severe VOCs in the two years prior to screening.

謝謝，約翰。從試驗設計開始，BEACON 是一項單臂開放標籤研究，評估單劑量 BEAM-101 對鐮狀細胞疾病和嚴重 VOC 患者的安全性和有效性。該試驗招募 18 至 35 歲的鐮狀細胞疾病成年患者，這些患者在篩檢前的兩年內經歷過 4 次或更多嚴重的 VOC。

Patients are mobilized using plerixafor, after which autologous CD-34 positive hematopoietic stem and progenitor cells are collected by leukapheresis and genetically modified with our adenine based editor. Patients then receive myeloablative conditioning with busulfan, followed by a single infusion of BEAM-101. Key endpoints are outlined here on slide 16.

使用普樂沙福動員患者，然後透過白血球分離術收集自體 CD-34 陽性造血幹細胞和祖細胞，並使用我們基於腺嘌呤的編輯器進行基因修飾。然後患者接受白消安清髓調理，然後單次輸注 BEAM-101。第 16 張投影片概述了關鍵終點。

As John highlighted to date, we've exceeded enrollment projections with 35 patients having cleared screening and enrolled in the study. The data we'll review today are as of July 2, 2024 data cut and includes six patients in the safety analyses and four patients in the efficacy analyses. In our presentation at ASH, we'll share additional data with more patients and longer follow-up.

正如 John 迄今為止所強調的那樣，我們已經超越了入組預測，有 35 名患者通過了篩檢並參與了研究。我們今天將審查的數據截至 2024 年 7 月 2 日的數據截取，包括安全性分析中的 6 名患者和療效分析中的 4 名患者。在 ASH 的演講中，我們將與更多患者和更長的追蹤時間分享更多數據。

Baseline demographics are shown on slide 17 and were as follows. Five of the six patients were beta-S genotype and one patient was beta-S beta-zero genotype. All were self-reported as Black African American, 50% were female and ages ranged from 19 to 27 years. The BEAM-101 manufacturing process allows for efficient dose production with all six patients requiring just one or two cycles of mobilization to achieve a dose with a mean of 1.5 cycles.

第 17 張幻燈片顯示了基線人口統計數據，如下所示。6 名患者中有 5 名是 β-S 基因型，一名患者是 β-S β-0 基因型。所有人都自稱是非裔美國人，其中 50% 是女性，年齡從 19 歲到 27 歲不等。BEAM-101 製造流程可實現高效的劑量生產，所有 6 名患者只需進行一到兩個週期的活動即可獲得平均 1.5 個週期的劑量。

As a reminder, minimizing the number of cycles of mobilization is a key goal for both patients and providers to reduce days in hospital and the overall time required to manufacture a dose. Safety data were captured for all six patients. BEAM-101 was considered generally well tolerated and demonstrated a safety profile consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant.

提醒一下，最大限度地減少活動週期次數是患者和提供者減少住院天數和生產劑量所需的總時間的關鍵目標。收集了所有六名患者的安全資料。BEAM-101被認為總體上具有良好的耐受性，並表現出與白消安和自體造血幹細胞移植的清髓調理一致的安全性。

Of note, one patient died due to respiratory failure four months after their BEAM-101 infusion, which was determined by the investigator to be likely related to busulfan conditioning. Busulfan is a cytotoxic drug used in a transplant setting and is known to be associated with significant side effects, including lung injury and death.

值得注意的是，一名患者在輸注 BEAM-101 四個月後因呼吸衰竭死亡，研究人員確定這可能與白消安調理有關。白消安是一種用於移植環境的細胞毒性藥物，已知會導致嚴重的副作用，包括肺損傷和死亡。

This is a complex case and the unfortunate outcome while rare has been reported previously with stem cell transplant. The event was determined to be unrelated to BEAM-101 by the investigator. The case was reviewed by both the Data Safety Monitoring Committee and the FDA. In all patients dosed, there was no Grade B or higher adverse events or serious adverse events related to BEAM-101.

這是一個複雜的病例，其不幸的結果在先前的幹細胞移植報告中很少見。調查人員確定該事件與 BEAM-101 無關。該案件由資料安全監測委員會和 FDA 共同審查。在所有接受治療的患者中，沒有發生與 BEAM-101 相關的 B 級或以上不良事件或嚴重不良事件。

As shown on slide 19, time to engraftment is for the four patients with a follow-up period of one month or more. Rapid neutrophil engraftment was observed for all patients after BEAM-101 treatment with a median of 17 days and a range of 15 to 19 days. Platelet engraftment was achieved at a median of 20 days with a range of 11 to 34 days. These data are similar to what is seen in patients undergoing allogeneic stem cell transplantation with unedited stem cells.

如投影片 19 所示，四名患者的植入時間為追蹤期為 1 個月或更長。在 BEAM-101 治療後，所有患者均觀察到嗜中性球快速植入，中位數時間為 17 天，範圍為 15 至 19 天。血小板植入的中位數時間為 20 天，範圍為 11 至 34 天。這些數據與接受未經編輯的幹細胞同種異體幹細胞移植的患者的數據相似。

Neutrophil engraftment is particularly important, as this is one of the key factors that determine the length of hospital stay in patients after undergoing a transplant. Minimizing time to neutrophil engraftment is another important goal of transplant therapy in sickle cell disease because not only can it result in reduced hospital stays, but also to potentially decrease risk of developing opportunistic infections.

中性粒細胞植入尤其重要，因為這是決定患者接受移植後住院時間長短的關鍵因素之一。最大限度地縮短嗜中性球植入時間是鐮狀細胞疾病移植治療的另一個重要目標，因為它不僅可以減少住院時間，還可以潛在降低機會性感染的風險。

On slide 20, we detailed total hemoglobin for the four patients included in the efficacy analyses, where patients had six, five, two and one month of follow-up, respectively. After treatment with BEAM-101, we observed an early end market induction of HbF and a significant increase in total hemoglobin. The patient's total hemoglobin increased from a mean baseline of 9.3 grams per deciliter to 17.9, 18.2, 11 and 11.8 grams per deciliter at the last time point. No symptoms or interventions were undertaken for the patients with mild elevated total hemoglobin.

在第 20 張投影片上，我們詳細介紹了功效分析中包含的 4 名患者的總血紅素，其中患者分別進行了 6 個月、5 個月、2 個月和 1 個月的追蹤。使用 BEAM-101 治療後，我們觀察到 HbF 的早期終端市場誘導以及總血紅素的顯著增加。患者的總血紅素從平均基線 9.3 克/分升增加到最後一個時間點的 17.9、18.2、11 和 11.8 克/分升。對於總血紅素輕度升高的患者，沒有出現任何症狀或採取乾預措施。

Notably, all four patients achieved greater than 60% HbF of non-transfused hemoglobin at month one and sustained its elevation at the last time point. The percent of HbF in non-transfused blood dropped to less than 40% in all four patients, which again was sustained to the last time point as of the data cutoff. Importantly, these data are consistent with our pre-clinical results and was seen in individuals with sickle cell trait, whereas John mentioned, patients generally have 60% normal hemoglobin and 40% sickle globin.

值得注意的是，所有四名患者在第一個月的非輸血血紅素 HbF 均達到 60% 以上，並在最後一個時間點持續升高。所有四名患者中未輸血的 HbF 百分比均降至 40% 以下，這一情況再次持續到數據截止時的最後一個時間點。重要的是，這些數據與我們的臨床前結果一致，並且在具有鐮狀細胞特徵的個體中觀察到，而約翰提到，患者通常具有 60% 的正常血紅蛋白和 40% 的鐮狀細胞珠蛋白。

In addition, markers of hemolysis including lactate dehydrogenase, indirect bilirubin, haptoglobin and reticulocyte counts were seen to normalize or improve in all four patients. No VOCs were reported by investigators following BEAM-101 treatment.

此外，所有四名患者的溶血標記（包括乳酸脫氫酶、間接膽紅素、觸珠蛋白和網狀紅血球計數）均正常化或改善。BEAM-101 處理後，研究人員未報告任何 VOC。

Collectively, these findings represent a deep correction of the hemoglobin profile of the blood after BEAM-101 treatment. In addition to our primary BEACON clinical abstract, we have an additional abstract detailing exploratory biomarker assessment of red blood cells' hemoglobin expression, health and function.

總的來說，這些發現代表了 BEAM-101 治療後血液血紅蛋白譜的深度校正。除了我們的主要 BEACON 臨床摘要外，我們還有一份額外的摘要，詳細介紹了紅血球血紅蛋白表達、健康和功能的探索性生物標記評估。

As shown on slide 22, for the first two patients included in the analysis, 98% of red blood cells expressed HbF as early as month one with near complete elimination of red blood cells expressing solely HbF post treatment with BEAM-101. These HbS only cells are the cells, which would be most likely to sickle and cause pain crises and organ damage over time. Biomarker data also show that treatment with BEAM-101 restored red blood cell function across a range of parameters.

如幻燈片 22 所示，對於分析中包含的前兩名患者，早在第一個月就有 98% 的紅血球表達 HbF，並且在使用 BEAM-101 治療後幾乎完全消除了僅表達 HbF 的紅血球。這些僅含有 HbS 的細胞是最有可能隨著時間的推移而鐮狀生長並導致疼痛危機和器官損傷的細胞。生物標記數據也顯示，BEAM-101 治療可在一系列參數上恢復紅血球功能。

As shown on slide 23, maximum sickling was significantly reduced for the first two patients treated with BEAM-101 below the levels associated with sickle trait blood samples. Other improvements in blood function include decreased dense red blood cells, decreased hemolysis and decreased red blood cell adhesion, all of which are associated with disease severity.

如幻燈片 23 所示，使用 BEAM-101 治療的前兩名患者的最大鐮狀化顯著減少，低於與鐮狀特徵血液樣本相關的水平。血液功能的其他改善包括緻密紅血球減少、溶血減少和紅血球黏附減少，所有這些都與疾病嚴重程度相關。

In summary, we're encouraged by this emerging BEAM-101 clinical data, which we believe are consistent with our preclinical findings and demonstrate the potential for differentiation from other cell and gene therapies as outlined in the key takeaways on slide 24. Beam cell collection and manufacturing process were efficient, resulting in just one to two mobilization cycles. BEAM-101 was generally well tolerated with the safety profile consistent with the known effects of myeloblative conditioning and stem cell transplant.

總而言之，我們對這一新興的BEAM-101 臨床數據感到鼓舞，我們相信這些數據與我們的臨床前研究結果一致，並證明了與其他細胞和基因療法的差異化潛力，如幻燈片24 的關鍵要點所述。束流細胞收集和製造過程非常高效，只需一到兩個動員週期。BEAM-101 通常具有良好的耐受性，其安全性與清髓調理和幹細胞移植的已知效果一致。

Neutrophil engraftment is rapid with all patients engrafting in under 20 days. Both in grafting timing and cell collection efficiency contribute to shorter hospital stays and a faster path for treatment for patients. BEAM-101 effectively induced HbF to greater than 60% with HbF meaningfully reduced to less than 40% consistent with the profile of individuals with sickle cell trait. And finally, multiple biomarkers show the near elimination of HbF only cells and improved red blood cell health and functions following BEAM-101 treatment.

中性粒細胞植入速度很快，所有患者均在 20 天內植入。移植時間和細胞收集效率都有助於縮短患者的住院時間並加速患者的治療路徑。BEAM-101 有效誘導 HbF 達到 60% 以上，且 HbF 顯著降低至 40% 以下，與鐮狀細胞性狀個體的情況一致。最後，多種生物標記顯示，BEAM-101 治療後，僅 HbF 的細胞幾乎被消除，紅血球的健康和功能得到改善。

Taken together, we believe this initial data set demonstrates BEAM-101 has the potential to be best-in-class, one-time treatment for people living with sickle cell disease. We look forward to reporting data from a more recent data cut from our BEACON trial in oral presentation at ASH on December 8, which will feature additional patients and longer follow-up.

總而言之，我們相信這一初始資料集表明 BEAM-101 有潛力成為鐮狀細胞疾病患者的同類最佳一次性治療方法。我們期待在 12 月 8 日 ASH 口頭報告中報告從 BEACON 試驗中截取的最新數據，該試驗將包括更多患者和更長的追蹤時間。

I'll now pass the call over to Pino to go through our initial ESCAPE data.

現在我將把電話轉給 Pino 來檢查我們的初始 ESCAPE 資料。

Thank you, Amy. Returning to our overall vision for bringing new options to patients with sickle cell disease, ESCAPE forms the foundation of our Wave 2 sickle cell disease strategy, which aims to provide the same transformative efficacy potential seen with Wave 1, but with an alternative to genotoxic conditioning during the transplant process.

謝謝你，艾米。回到我們為鐮狀細胞疾病患者帶來新選擇的總體願景，ESCAPE 構成了我們Wave 2 鐮狀細胞疾病策略的基礎，該策略旨在提供與Wave 1 相同的變革功效潛力，但提供基因毒性調理的替代方案在移植過程中。

This approach offers significant upside, including the potential to improve patient safety and overall treatment experience and become a compelling option, not only for severe patients but also for more moderate disease patients. As a result, we believe that such a product would expand the eligible patient population for gene editing therapies by up to four-fold.

這種方法具有顯著的優勢，包括有可能提高患者的安全性和整體治療體驗，並成為一種引人注目的選擇，不僅適用於重症患者，也適用於病情較輕的患者。因此，我們相信這樣的產品將使符合基因編輯療法的患者群擴大四倍。

So why is conditioning so important? Conditioning is a critical component of a transplant. It is necessary to make space in a patient's body to receive the ex-vivo edited cells that need to graft in the patient's bone marrow in order to be effective. The field of stem cell transplant has generated dramatic outcomes for many hematology patients with upwards of 22,000 transplants now occurring in the US and even. However, all such transplants still rely on chemotherapy, most commonly busulfan to enable the replacement of blood cells.

那麼為什麼調理如此重要呢？調理是移植的關鍵組成部分。有必要在患者體內騰出空間來接收離體編輯的細胞，這些細胞需要移植到患者的骨髓中才能發揮作用。幹細胞移植領域為許多血液疾病患者帶來了巨大的成果，目前在美國甚至全世界進行了超過 22,000 例移植手術。然而，所有此類移植仍然依賴化療，最常見的是白消安來取代血球。

Busulfan was first approved in 1950s. And as Amy mentioned, it's associated with both acute and chronic toxicity that include infertility, the potential for increased rates of malignancy and in rare instances can be fatal. Improving upon that option represents the next frontier in hematology and could bring the transformative impact of transplant to many more patients with many more diseases.

白消安於 20 世紀 50 年代首次獲得批准。正如艾米所提到的，它與急性和慢性毒性有關，包括不孕症、惡性腫瘤發病率增加的可能性，在極少數情況下可能是致命的。對這一選擇的改進代表了血液學的下一個前沿，並且可以為更多患有更多疾病的患者帶來移植的變革性影響。

The ESCAPE technology has the potential to finally enable the vision of a non-genotoxic conditioner approach, thus bringing about the paradigm shift in transplant medicine for the first time in nearly 70 years. Our ESCAPE program consists of two investigational therapies, which we named the BEAM-103 and BEAM-104 as part of our development candidate nomination announced today. BEAM-103 is our conditioning antibody, designed to bind unedited hematopoietic cells in the marrow and eliminate them. BEAM-104 is a multiplex based edited cell product that includes two edits. The first is the same therapeutic edit as in BEAM-101 to elevate fetal hemoglobin.

ESCAPE 技術有可能最終實現非基因毒性調節劑方法的願景，從而帶來近 70 年來首次移植醫學的範式轉移。我們的 ESCAPE 計劃包括兩種研究療法，我們將其命名為 BEAM-103 和 BEAM-104，作為我們今天宣布的開發候選藥物提名的一部分。BEAM-103 是我們的調理抗體，旨在結合骨髓中未經編輯的造血細胞並消除它們。BEAM-104 是一種基於多重編輯的細胞產品，包括兩次編輯。第一個是與 BEAM-101 相同的治療編輯，以提高胎兒血紅蛋白。

The second is an additional edit to introduce a mid-sense mutation in the extracellular domain of CD117, a receptor expressed by hematopoietic stem and progenitor cells that regulates survival proliferation and differentiation of the cells. The CD117 edit does not alter CD170 biology, but only disrupts the binding of BEAM-103 to the receptor. This allows edited cells to ESCAPE the antibody with the goal of enabling engraftment in growth of edited cells and clearance of disease cells.

第二個是額外的編輯，在 CD117 的胞外結構域中引入中義突變，CD117 是造血幹細胞和祖細胞表達的受體，調節細胞的存活增殖和分化。CD117 編輯不會改變 CD170 生物學，只會破壞 BEAM-103 與受體的結合。這允許編輯的細胞逃避抗體，目的是使編輯的細胞能夠植入生長並清除疾病細胞。

In the data shown on the right, you can see that, in the presence of a mixed population of unedited and edited cells, increasing levels against about the cost of cell population to shift to become completely edited cells. We have evaluated the system extensively in mice, but to establish true growth concept, we wanted to conduct a comprehensive study in non-human primates. We are collaborating with multiple leading experts in the field and this initial study was conducted by Dr. John Tisdale of the NIH, a pre-eminent leader in autologous transplant and non-human primates model to a transplant.

在右側顯示的數據中，您可以看到，在存在未編輯和編輯的細胞的混合群體的情況下，細胞群體轉變為完全編輯的細胞的成本水平不斷提高。我們已經在小鼠身上廣泛評估了這個系統，但為了建立真正的生長概念，我們希望在非人靈長類動物中進行全面的研究。我們正在與該領域的多位領先專家合作，這項初步研究是由美國國立衛生研究院的 John Tisdale 博士進行的，他是自體移植和非人類靈長類移植模型領域的傑出領導者。

The data to be presented by Dr. Tisdale at ASH seek to answer two key fundamental questions: Can engraftment of hematopoietic stem cells be achieved without chemotherapy? And can a therapeutic level of fetal hemoglobin be achieved? As detailed on the right side of Slide 30, the monkey autologous transplant process being conducted here is comparable to an ex-vivo gene editing product in humans, with the caveat that by necessity various steps in the process have not been optimized to the same degree that we have done for humans.

ASH 的 Tisdale 博士將提供的數據旨在回答兩個關鍵的基本問題：無需化療能否實現造血幹細胞的植入？胎兒血紅素能否達到治療水準？正如幻燈片 30 右側所詳述的，這裡進行的猴子自體移植過程與人類體外基因編輯產品相當，但需要注意的是，該過程中的各個步驟必然沒有得到相同程度的優化我們為人類所做的一切。

We mobilized CD34 cells from two reasons macaque monkeys and edited them ex-vivo, incorporating both the HbF edit and the CD117 ESCAPE edit. The animals were conditioned with BEAM-103, CD117 antibody and then infused with the BM-104 edited cell product. Subsequently, these animals received monthly antibody treatments after transplantation to maximize the competitive advantage of edited cells and continue suppression of unedited cells.

我們從兩種獼猴中調動 CD34+ 細胞，並對其進行離體編輯，結合 HbF 編輯和 CD117 ESCAPE 編輯。這些動物以 BEAM-103、CD117 抗體進行調節，然後注射 BM-104 編輯的細胞產物。隨後，這些動物在移植後每月接受抗體治療，以最大限度地發揮編輯細胞的競爭優勢並繼續抑制未編輯的細胞。

The BEAM-103 antibody was well tolerated both doses and no supportive care was necessary for the antibody condition of animals. Importantly, they did not go through a period of myelobrasion, as is steady seen in chemotherapy condition. Remarkably, we observed significant reduction of HbF at 30-time points post-transplant. As cell levels rose to 61% in the periphery, as early as eight weeks post-transplant in one of the animals and stabilized at approximately 85% at week 35 for both animals.

BEAM-103 抗體在兩種劑量下均具有良好的耐受性，且動物的抗體狀況無需支持性治療。重要的是，他們沒有經歷一段骨髓磨削期，這在化療條件下是穩定的。值得注意的是，我們觀察到移植後 30 個時間點 HbF 顯著降低。其中一隻動物的周邊細胞水平早在移植後 8 週就上升至 61%，而兩隻動物在第 35 週時穩定在約 85%。

Early induction of HbF was also observed in the level of surpassing 50% in both animals in both ends. These unprecedented results established preclinical proof-of-concept for condition with a CD117 antibody and non-chemotherapy, leading to robust long-term engraftment and high levels of HbF expression for ex-vivo edited CD34 cell. If replicated in humans, these results will achieve our Wave 2 vision of non-genotoxin condition for gene editing in hematology.

在兩端的兩隻動物中也觀察到 HbF 的早期誘導水準超過 50%。這些前所未有的結果為 CD117 抗體和非化療條件建立了臨床前概念驗證，導致離體編輯的 CD34 細胞實現穩健的長期植入和高水平的 HbF 表達。如果在人類身上複製，這些結果將實現我們關於血液學基因編輯的非基因毒素條件的第二波願景。

Intriguingly, the lack of myeloplation also suggests the possibility that the transplant of ESCAPE edited CD34 cells could eventually become an outpatient procedure, further enhancing the access and scalability of these products for patients. On the back of the strong preclinical results, we are now accelerating the development of our ESCAPE technology towards the clinic.

有趣的是，缺乏骨髓移植也表明 ESCAPE 編輯的 CD34 細胞的移植最終有可能成為門診手術，從而進一步提高患者對這些產品的可及性和可擴展性。在強勁的臨床前結果的支持下，我們現在正在加速將 ESCAPE 技術開發到臨床。

We're currently conducting additional NHP studies to explore antibody dosing regimens, dose response and cannibalism and we're on track to initiate Phase I enabling studies by the end of the year. Once complete, we plan to conduct a Phase 1 healthy volunteer study of the BEAM-103 antibody before moving into studies of both BEAM-103 and BEAM-104 in sickle cell disease and beta thalassemia patients.

我們目前正在進行額外的 NHP 研究，以探索抗體給藥方案、劑量反應和自相殘殺，我們預計在今年年底啟動第一階段研究。完成後，我們計劃對 BEAM-103 抗體進行 1 期健康志願者研究，然後再對鐮狀細胞病和 β 地中海貧血患者進行 BEAM-103 和 BEAM-104 的研究。

As we now look forward to the development of this promising technology, I want to highlight the strong synergies between BEAM-101 and ESCAPE. With an identical edit and underlying base editing technology, today's BEAM-101 clinical data are also derisking for ESCAPE. In each investment and advancement, we make in manufacturing, clinical, regulatory and commercial preparedness for BEAM-101, a direct applicability to accelerate and derisk the future success of ESCAPE. The two programs therefore form a single integrated franchise, which we believe can deliver successful improvements to patients with sickle cell disease.

當我們現在期待這項有前途的技術的發展時，我想強調 BEAM-101 和 ESCAPE 之間的強大協同作用。憑藉相同的編輯和底層鹼基編輯技術，今天的 BEAM-101 臨床數據也消除了 ESCAPE 的風險。在每項投資和進步中，我們都為 BEAM-101 的製造、臨床、監管和商業做好準備，這是加速 ESCAPE 未來成功並降低風險的直接應用。因此，這兩個項目形成了一個單一的綜合特許經營項目，我們相信它可以為鐮狀細胞疾病患者帶來成功的改善。

I'll now turn the call back over to John to wrap up.

現在我將把電話轉回給約翰結束。

Thanks, Pino. As you can see, we are very encouraged by these emerging data sets. First, for BEAM-101 in patients with sickle cell disease, we are so far achieving a potentially differentiated clinical profile using base editing, consistent with our preclinical data and comparable to sickle cell trait, while also potentially requiring fewer days in the hospital for both mobilization and engraftment.

謝謝，皮諾。正如您所看到的，我們對這些新興資料集感到非常鼓舞。首先，對於鐮狀細胞疾病患者的BEAM-101，我們迄今為止透過鹼基編輯實現了潛在差異化的臨床特徵，與我們的臨床前數據一致並且與鐮狀細胞特徵相當，同時也可能需要更少的住院天數動員和植入。

Second, with ESCAPE achieving robust preclinical proof-of-concept and now moving rapidly towards the clinic, we are opening up the potential for non-genotoxic conditioning and transplant, which would expand the initial BEAM-101 market to reach a broader group of patients with a less myeloablative profile that even has the potential to become an outpatient procedure for conditioning and transplant.

其次，隨著 ESCAPE 實現了強有力的臨床前概念驗證並迅速走向臨床，我們正在開闢非基因毒性調理和移植的潛力，這將擴大最初的 BEAM-101 市場，涵蓋更廣泛的患者群體清髓性較低，甚至有可能成為調理和移植的門診手術。

And finally, these data sets support that base editing does appear to have significant advantages in predictability, efficiency and lack of double strand breaks with strong translation from preclinical to clinical data, minimal impact on cell viability and promising efficacy outcomes.

最後，這些數據集支持鹼基編輯確實在可預測性、效率和缺乏雙鏈斷裂方面具有顯著優勢，並且從臨床前數據到臨床數據的轉化能力很強，對細胞活力的影響最小，並且療效結果有希望。

Before I close, I'll provide a brief review of the clinical data on BEAM-201, which will be in a poster at ASH. Initial clinical data for BEAM-201, which is the first quadruplex edited allogeneic CAR T-cell therapy candidate in clinical development establishes clinical proof-of-concept for a high level of multiplex based editing.

在結束之前，我將簡要回顧 BEAM-201 的臨床數據，這些數據將出現在 ASH 的海報中。BEAM-201 是臨床開發中第一個四重編輯同種異體 CAR T 細胞療法候選藥物，其初始臨床數據為高水平多重編輯建立了臨床概念驗證。

The safety profile of BEAM-201 was consistent with these patients' advanced underlying disease as well as with lymphodepletion and CAR T-therapy. We also observed early evidence of clinical efficacy with two of three patients treated with BEAM-201 achieving a complete response, allowing them to pursue transplant, which is potentially curative.

BEAM-201 的安全性與這些患者的晚期基礎疾病以及淋巴細胞清除和 CAR T 療法一致。我們還觀察到臨床療效的早期證據，接受 BEAM-201 治療的三分之二的患者實現了完全緩解，使他們能夠進行移植，這有可能治癒。

While not a priority program given our decision to focus on hematology and liver-genetic diseases, we continue to seek a path forward for BEAM-201 with a partner and look forward to supporting the future advancement as well as other potential applications of multiplex-based editing in cell therapy.

雖然鑑於我們決定專注於血液學和肝臟遺傳疾病，這不是一個優先計劃，但我們將繼續與合作夥伴一起尋找 BEAM-201 的前進道路，並期待支持未來的進步以及基於多重的其他潛在應用細胞治療中的編輯。

Wrapping up, as you've heard, 2024 has been an incredibly fruitful time at Beam with broad-based execution and validating data across our portfolio of base editing programs. We have a number of meaningful catalysts on the horizon, starting with updated data at ASH in December. Again, I'd like thank the Beam team for their continued hard work and dedication to our shared vision, the patients and physicians, who participated in our clinical trials and to each of you for your continued support of Beam.

正如您所聽到的，2024 年是 Beam 碩果累累的一年，我們在鹼基編輯程式組合中進行了廣泛的執行和數據驗證。從 12 月 ASH 的更新數據開始，我們即將看到許多有意義的催化劑。我再次感謝 Beam 團隊的持續辛勤工作和對我們共同願景的奉獻，感謝參與我們臨床試驗的患者和醫生，並感謝你們每一個人對 Beam 的持續支持。

With that, operator, please open the line for Q&A.

那麼，接線員，請開通問答線。

(Operator Instructions)

（操作員說明）

Gena Wang with Barclays.

王吉娜與巴克萊銀行。

Thank you. Really impressive update. I have so many questions. Since I can only ask one question, maybe I'll ask a less exciting question. That's the safety. One patient’s death just a little bit puzzling. Why after four months and that patient die? And then, why that will could be due to the busulfan? If you can give a little bit more color there?

謝謝。確實令人印象深刻的更新。我有很多問題。由於我只能問一個問題，也許我會問一個不太令人興奮的問題。這就是安全性。一名患者的死亡有點令人費解。為什麼四個月後那個病人死了？那麼，為什麼這可能是由於白消安呢？如果你能給那裡多一點顏色嗎？

Sure. Maybe I'll start and then I'll have Amy give a little color on the time course and what we know about busulfan. Yes, it's a very sad outcome, of course. I think what it shows maybe at a high level is the very real risks of transplant and chemotherapy. We're using busulfan in this case that we use the same protocol and dosing regimen of busulfan as others do in the field, obviously, informed by world experts on our trial. But we know that chemotherapy and transplant do have significant toxicity and in rare cases can have mortality, something that the field continues to optimize, but it's a real choice that patients have to think about.

當然。也許我會開始，然後我會讓艾米介紹時間進程以及我們對白消安的了解。是的，這當然是一個非常悲傷的結果。我認為它在很大程度上顯示了移植和化療的真實風險。在這種情況下，我們使用白消安，我們使用與其他人在該領域所做的相同的白消安方案和給藥方案，顯然，這是由世界專家在我們的試驗中告知的。但我們知道化療和移植確實具有顯著的毒性，在極少數情況下可能會導致死亡，這是該領域不斷優化的領域，但這是患者必須考慮的真正選擇。

At the same time, I'd like to say that I think this also underscores the severity of severe sickle cell disease. We've seen sickle cell survival rates improve to about 50 years on median here in the U.S., but that's median. The most severe 10% are much sicker than that.

同時我想說，我認為這也強調了嚴重鐮狀細胞疾病的嚴重性。我們已經看到美國的鐮狀細胞存活率中位數提高到約 50 年，但這只是中位數。最嚴重的 10% 的病情比這嚴重得多。

And so, the severity of the disease really is what makes that transplant potentially compelling option despite the risks. Importantly, as Amy will outline, the case is consistent with our prior experience with busulfan and with transplant. So, we don't see any change in the risk benefit profile of our agent or of the field based on this.

因此，儘管存在風險，但疾病的嚴重程度確實使移植成為潛在的令人信服的選擇。重要的是，正如艾米將概述的那樣，該病例與我們之前使用白消安和移植的經驗一致。因此，我們認為我們的代理商或該領域的風險收益狀況不會因此而發生任何變化。

Our goal with BEAM-101 is ultimately to give a better option to patients and transplanters, who are seeking transplant that begins with the shift from allo to auto, which is happening now. And of course, with the data we're showing today, we believe that BEAM-101 is potentially best-in-class profile out of the autologous therapies. So maybe with that preamble, I'll ask Amy to say just a little bit about what we know about busulfan and the time course of this kind of toxicity.

我們的 BEAM-101 目標最終是為患者和移植者提供更好的選擇，他們正在尋求從異種移植到自動移植的移植，現在正在發生。當然，根據我們今天展示的數據，我們相信 BEAM-101 可能是自體療法中同類最佳的。因此，也許在序言中，我會請艾米簡單介紹一下我們對白消安的了解以及這種毒性的時間過程。

Sure. So it turns out busulfan is, as John mentioned, a chemotherapeutic and cytotoxic agent and it is known to be associated with dose dependent pulmonary toxicity. As you go up in higher doses, more toxicity and in some cases can actually be fatal. In general, myeloblade conditioning with agents such as busulfan can cause something that we refer to as the idiopathic pneumonia syndrome. This can occur in up to 6% of patients who have autologous transplant. And this idiopathic pneumonia syndrome really represents a spectrum of pulmonary diseases, including lung injury, respiratory failure that tend to start around day 20 or 30 post transplant and kind of manifest through about day 100.

當然。因此，正如約翰所提到的那樣，白消安是一種化療和細胞毒性藥物，已知它與劑量依賴性肺毒性有關。隨著劑量的增加，毒性也更大，在某些情況下實際上可能是致命的。一般來說，用白消安等藥物調節骨髓葉片可能會引起我們所謂的特發性肺炎綜合症。多達 6% 的接受自體移植的患者可能會出現這種情況。這種特發性肺炎症候群實際上代表了一系列肺部疾病，包括肺損傷、呼吸衰竭，這些疾病往往在移植後 20 或 30 天左右開始，並在移植後 100 天左右表現出來。

The rates, as I mentioned, are up to 6% and these can often wind up with multi kind of – multilobar opacities in the lung, respiratory failure and in some cases, as I mentioned be fatal. I think that the team at the site did an extensive workup. And usually, what you'll do is rule out other potential contributing causes, which they did, such as infection or other types of etiologies for pulmonary dysfunction.

正如我所提到的，該比率高達 6%，並且通常會導致肺部出現多種 — 多葉性混濁、呼吸衰竭，在某些情況下，正如我所提到的，甚至是致命的。我認為現場團隊進行了廣泛的檢查。通常，您要做的就是排除其他潛在的原因，例如感染或其他類型的肺功能障礙病因。

In the end, the timing of this dysfunction as well as the extensive clinical workup really point to the fact that, this is consistent with what has been seen previously in busulfan both in what is reported in the label as well as the literature about stem cell transplantation, complications with busulfan and other literature. Notably, the patient's blood was corrected and normalizing in line with what was seen in other patients. So while it's an unfortunate case, it is a known complication that myeloablative conditioning can have really kind of profound effects, even though it is required for a successful transplantation.

最後，這種功能障礙的發生時間以及廣泛的臨床檢查確實表明了這樣一個事實：這與先前在白消安的標籤中報導的內容以及有關幹細胞的文獻中所看到的一致。安併發症等文獻。值得注意的是，該患者的血液被糾正並正常化，與其他患者的情況一致。因此，雖然這是一個不幸的病例，但眾所周知的併發症是清髓性調節可能會產生真正深遠的影響，儘管這是成功移植所必需的。

And I think investigators take this into account, when thinking about selecting patients, who are appropriate for a risk benefit profile as well as talking with their patients, so that it's clear that the patients understand the risk benefit and that, they're signing up for something that they understand what they're getting into.

我認為研究人員在考慮選擇適合風險收益概況的患者以及與患者交談時考慮到這一點，以便患者清楚地了解風險收益並且他們正在註冊他們了解自己正在從事的事情。

[Yanin Zhu].

[朱亞寧].

Thanks for taking our questions and congrats on the data. Again a very impressive HbF induction. I was wondering, how would the higher HbF induction translate into additional clinical benefit compared with approved product and also other upcoming products in the pipeline? If you can shed some light, because I guess VOC has been -- data has been pretty strong for the approved product. So wondering where could we see additional clinical benefit?

感謝您提出我們的問題並祝賀我們獲得了數據。再次令人印象深刻的 HbF 感應。我想知道，與已批准的產品和其他即將推出的產品相比，更高的 HbF 誘導將如何轉化為額外的臨床益處？如果您能透露一些信息，因為我猜 VOC 已經——批准產品的數據相當強勁。那麼想知道我們在哪裡可以看到額外的臨床益處？

Sure. I'd like to Pino to cover this one.

當然。我希望皮諾來報道這一點。

Yes. As you can see, really, we do believe that this higher hemoglobin F is also associated with a concomitant decline of hemoglobin S to levels less than 40%. That 60 to 40 ratio is really the ratio that you typically see in sickle trait individuals, who obviously do not have symptoms unless in very sort of severe condition. We do feel that, that combination of 60 to 40 can be like a sickle trait and potentially even better since hemoglobin S is anticycline as opposed to hemoglobin A.

是的。正如您所看到的，我們確實相信血紅蛋白 F 升高也與血紅蛋白 S 下降至低於 40% 的水平有關。60 比 40 的比例實際上是鐮狀特徵個體中常見的比例，除非病情非常嚴重，否則他們顯然不會出現症狀。我們確實認為，60 到 40 的組合可能像鐮刀特徵，甚至可能更好，因為血紅蛋白 S 是抗環素，而不是血紅蛋白 A。

So that should lead to a variety of deeper resolution. We share some biomarkers that show that the blood is function is normalized to the extent that we can measure it. We also show that we have almost completely eliminated cells that express hemoglobin S on its own. These are really the cells that potentially can cause sickling under some severe conditions.

因此，這應該會導致各種更深層的解決方案。我們分享一些生物標記物，這些生物標記表明血液功能已正常化到我們可以測量的程度。我們還表明，我們幾乎完全消除了自身表達血紅蛋白 S 的細胞。這些確實是在某些嚴重條件下可能導致鐮狀細胞的細胞。

And so even though it is great to see a strong resolution of VOCs in the launch product so far, I think we have also potentially the opportunity to improve even upon that. And so, the overall combination of the parameters that we have really for the first time, reproduce the sickle trait that others have not yet done.

因此，儘管到目前為止我們很高興看到推出的產品對 VOC 有了很強的解決方案，但我認為我們也有可能在此基礎上進行改進。因此，我們第一次真正對參數進行整體組合，再現了其他人尚未完成的鐮刀特性。

Dae Gon Ha with Stifel.

Dae Gon Ha 與 Stifel。

Thanks for taking our questions and I'll add my congrats on the initial data as well. Look forward to your 302 update next year. Circling back on the efficacy side, question for either John or Amy. Patients three and four, the female patients, just wondering if you can comment on the progress you're seeing there, specifically on the fetal hemoglobin induction. And when you look at both across the board, it seems like month two seems to be sort of the start of a plateau, if you will, on the total hemoglobin. So just wondering how we should think about sort of a longer-term efficacy for these two patients and specifically on the patient floor side?

感謝您提出我們的問題，我也會對初始數據表示祝賀。期待明年的302更新。回到功效方面，向約翰或艾米提出問題。第三號和第四號患者，女性患者，只是想知道您是否可以評論您所看到的進展，特別是胎兒血紅蛋白誘導的進展。當你全面審視這兩個面向時，如果你願意的話，似乎第二個月似乎是總血紅素進入平台期的開始。所以只是想知道我們應該如何考慮這兩位患者的長期療效，特別是在患者樓層方面？

I think there's not much to see between the patients. There's going to be some variability. All of these patients have what I would consider to be a robust early induction of F. In patients three and four, it's also worth noting, they received their last transfusion closer to the month one-time point, which means you have more transfused blood around. That has to clear before the marrow is going to turn on its endogenous production quite as strongly. That's a subtle variable. I think ultimately, we'll just wait for a longer follow-up and we should be able to compare these datasets.

我認為病人之間沒有什麼好看的。會有一些變化。所有這些患者都具有我認為強有力的 F 早期誘導。大約。在骨髓開始如此強烈地啟動其內源性生產之前，必須澄清這一點。這是一個微妙的變數。我認為最終，我們只需等待更長的後續行動，我們應該能夠比較這些數據集。

Eric Joseph with JPMorgan.

摩根大通的艾瑞克‧約瑟夫。

Thanks for taking the questions. Just digging into the first two patients of one and two that the total hemoglobin count is fairly high at least at months five and six. So just wondering how we -- whether there's any concern about the total hemoglobin counts being sort of where they are, whether you sort of normalize or come back down with time. Any sort of concern, I guess, with long-term follow-up with persisting hemoglobin around that level?

感謝您提出問題。只要深入研究一號和二號的前兩名患者，總血紅素計數至少在第五個月和第六個月相當高。所以只是想知道我們如何 - 是否擔心總血紅蛋白計數是否在其所在位置，是否會隨著時間的推移而恢復正常或下降。我想，長期追蹤血紅蛋白持續保持在該水平附近有什麼擔憂嗎？

Yes. Thanks, Eric. Amy?

是的。謝謝，埃里克。艾米？

Yes. Two patients, as you noted, have experienced mild elevations in hemoglobin. Importantly, there have been no clinical signs or symptoms from those patients or medical interventions required. These are really considered laboratory abnormalities at this point by the investigators and have not even been considered as adverse events. Importantly, as Pino alluded to recently, with the elevated hemoglobin F to S ratio of 60 to 40, we feel that these patients are no longer patients who have sickle cell disease but in fact, with editing their blood health and function have improved to what would be similar to that of a trait or a healthy person.

是的。正如您所指出的，兩名患者的血紅素出現輕度升高。重要的是，這些患者沒有任何臨床徵兆或症狀，也沒有需要醫療介入。此時，研究人員確實認為這些是實驗室異常，甚至還沒有被視為不良事件。重要的是，正如皮諾最近提到的，隨著血紅蛋白F 與S 的比率升高到60 比40，我們認為這些患者不再是鐮狀細胞疾病患者，但事實上，透過編輯，他們的血液健康和功能已改善到與某個特徵或健康人的特徵相似。

And those include, as I already mentioned, the hemoglobin F to S ratio, the improvements or normalization in hemolysis, the decreased RBC sickling, RBC density and RBC adhesion. And for all those reasons, there has been really no concern by the investigators of these mild elevations seen to date. And as you mentioned, we'll continue to follow these, but at this point in time, this reflects really just a lab abnormality.

正如我已經提到的，這些包括血紅蛋白 F 與 S 的比率、溶血的改善或正常化、紅血球鐮狀化、紅血球密度和紅血球黏附的減少。由於所有這些原因，研究人員實際上並不擔心迄今為止所看到的這些輕微升高。正如您所提到的，我們將繼續追蹤這些情況，但目前，這實際上反映了實驗室的異常情況。

Appreciate it. Maybe just one quick follow-up, if I could, on the safety front. Any changes to either screening criteria or modifications to the conditioning regimen as a result of the unfortunate death attributed to busulfan?

欣賞它。如果可以的話，也許只是在安全方面進行快速跟進。由於白消安導致的不幸死亡，篩檢標準或預處理方案是否有任何變化？

Yes. There's been no change to our eligibility criteria. It was determined by the DMC and concurred with the FDA that the safety profile of the study had not changed after this event. However, we already had in place what's called therapeutic drug monitoring for busulfan, and that type of therapeutic monitoring is often done when there's a narrow therapeutic window for a drug.

是的。我們的資格標準沒有變化。經 DMC 確定，並與 FDA 一致認為，該研究的安全性在該事件發生後沒有改變。然而，我們已經對白消安進行了所謂的治療藥物監測，而這種類型的治療監測通常是在藥物治療窗口狹窄的情況下進行的。

This is typically done by all the various studies in gene editing as well as investigators who use busulfan for conditioning. And just to note that the patient's busulfan level was within the target range that we were basically trying to obtain -- to try to ensure both conditioning was appropriately done, but at the same time trying to guarantee safety.

這通常是由基因編輯領域的所有研究以及使用白消安進行調節的研究人員完成的。只是要注意，患者的白消安水平在我們基本上試圖獲得的目標範圍內 - 試圖確保適當地進行調節，但同時試圖保證安全。

Kostas Biliouris with BMO Capital Markets.

BMO 資本市場的 Kostas Biliouris。

Thanks for taking our question and congrats on the progress and the data here. One clarification and one question from us, please. I think you already kind of described that, but can you clarify whether you have observed any off target editing or busulfan editing in the patient who died? I know there is no clinical evidence for that, but this is a question that comes up from investors.

感謝您提出我們的問題，並對此處的進展和數據表示祝賀。請我們作出一項澄清並提出一個問題。我想你已經描述了這一點，但是你能澄清一下你是否在死亡的病人中觀察到任何脫靶編輯或白消安編輯嗎？我知道沒有臨床證據證明這一點，但這是投資人提出的問題。

And then a second question on commercialization of 101 and ESCAPE. How are you thinking about the sequencing of commercializing these two products and potential cannibalization of 111 from ESCAPE?

第二個問題是關於101和ESCAPE的商業化。您如何看待這兩種產品商業化的順序以及 ESCAPE 111 的潛在蠶食？

So I'll let Pino answer the first question and then I'll do the second.

所以我會讓皮諾回答第一個問題，然後我會回答第二個問題。

Yes, we have not noted any off target biology of concern in any of the studies that we've done. Specifically, we do not do off target biology on every single drug product but as part of our pre-clinical package, you do extensive off-target biology on several donors, including the adjustment in silico of looking at different genomic background, which was the context of the cash JV advisory board conversation that added. And through none of that activity, there was any off target biology of concern emerged.

是的，在我們所做的任何研究中，我們都沒有註意到任何脫靶生物學問題。具體來說，我們不會對每種藥物產品進行脫靶生物學，但作為我們臨床前方案的一部分，您會對多個供體進行廣泛的脫靶生物學，包括在計算機上調整查看不同的基因組背景，這是現金合資顧問委員會對話的背景。透過這些活動，沒有出現任何令人擔憂的脫靶生物學問題。

Yes, and then, on the market perspective, I think our plan has always been -- we consider this a lifecycle strategy across this franchise. So beginning with BEAM-101 then leading to ESCAPE, now BEAM-103 and 104 and ultimately, thinking about in-vivo as well. So we see this as a progression. I think if ESCAPE fully achieves its profile, which would be efficacy comparable to 101 or other gene therapies in the field, but without chemotherapy, I would expect that to overtake and replace 100 million of the market, but of course we'll have to see the profiles and consider that at the time.

是的，然後，從市場角度來看，我認為我們的計劃一直是——我們認為這是整個特許經營的生命週期策略。因此，從 BEAM-101 開始，然後到 ESCAPE，現在是 BEAM-103 和 104，最終也考慮體內。所以我們認為這是一個進步。我認為，如果 ESCAPE 完全實現其功效，其功效可與 101 或該領域的其他基因療法相媲美，但無需化療，我預計它將超越並取代 1 億的市場份額，但當然我們必須查看個人資料並當時考慮這一點。

In terms of the market progression, I think we've talked about this as well, and I had it in my slides, but we continue to believe that, the market for these sort of Wave 1 therapies as we call them is about 1 in 10 patients, really those patients who are severe enough to consider a transplant and there our goal is to give transplant as a better option.

就市場進展而言，我認為我們也討論過這一點，並且我在幻燈片中也提到了這一點，但我們仍然相信，我們所說的此類第一波療法的市場約為 1% 10 名患者，實際上是那些病情嚴重到需要考慮移植的患者，我們的目標是將移植作為更好的選擇。

It's quite clear that autologous will be preferred over allogeneic. There's already several 100 allogeneic transplants that occur every year in the U.S. for sickle cell patients with severe disease and that's after including the fact that most of those patients who might seek a transplant can't find a match seek a transplant can't find a match.

很明顯，自體同種異體將優於同種異體。美國每年已經為患有嚴重疾病的鐮狀細胞患者進行了數百例同種異體移植，這也包括大多數可能尋求移植的患者無法找到匹配的事實。

So, I think that implies a certain market size that we expect will be there and we believe with today's data, assuming it holds up over time, we'll show that BEAM-101 is the best-in-class option for patients in this first market. Once we can bring ESCAPE forward, of course, that really changes the game because now you have, of course, eliminated a lot of the risks of transplant and chemotherapy. You've also expanded the addressable patient population, so that many more patients who might not have been a good fit for transplant before now can come in. And as Pino said, we think that leads to an addressable population that's up to 4 times larger.

因此，我認為這意味著我們預計將存在一定的市場規模，我們相信根據今天的數據，假設它隨著時間的推移而持續下去，我們將證明 BEAM-101 是該領域患者的最佳選擇第一個市場。當然，一旦我們能夠推進 ESCAPE，這確實會改變遊戲規則，因為現在你當然已經消除了許多移植和化療的風險。您還擴大了可尋址的患者群體，以便更多以前可能不適合移植的患者可以進來。正如皮諾所說，我們認為這會導致可尋址人口增加 4 倍。

Final point to make in terms of the staging of the programs is the one that Pino highlighted as well, which is the ESCAPE program is almost identical to BEAM-101 plus one-single guide RNA to get to the CD117 edit and of course the antibody.

關於程序分期的最後一點也是 Pino 強調的一點，即 ESCAPE 程序幾乎與 BEAM-101 相同，加上單嚮導 RNA 來進行 CD117 編輯，當然還有抗體。

So from a regulatory preclinical package, the clinical trial sites and design, regulatory strategy and endpoints and ultimately even commercial infrastructure, all of that is shared between the two programs, which will make for a much more efficient development program and I think ultimately will accelerate what we can do with ESCAPE.

因此，從監管臨床前方案、臨床試驗地點和設計、監管策略和終點，甚至最終的商業基礎設施來看，所有這些都在兩個項目之間共享，這將有助於製定更有效率的開發計劃，我認為最終將加速我們可以用 ESCAPE 做什麼。

Samantha Semenkow with Citi.

花旗銀行的 Samantha Semenkow。

Thank you for taking the question. Sort of expanding on that last question, the NHP data that you shared today for ESCAPE, they look pretty encouraging on both engraftment and HbF injection. But given the safety advantage with avoiding chemotherapy, I'm just curious on your thoughts on the potential trade-off for a slightly less efficacious profile on the trade-off for the better safety profile. And then relatedly for BEAM-103, the CD117 antibody, are there any safety concerns for targeting CD117 that we should be aware of?

感謝您提出問題。在某種程度上擴展了最後一個問題，即您今天為 ESCAPE 分享的 NHP 數據，它們在植入和 HbF 注射方面看起來都非常令人鼓舞。但考慮到避免化療的安全優勢，我只是好奇你對潛在的權衡稍微低一些的效果和更好的安全性的權衡的想法感到好奇。那麼與 BEAM-103（CD117 抗體）相關，我們應該注意針對 CD117 的任何安全性問題嗎？

Yes. Maybe I'll have Pino answer the second question. I'll just highlight on the first question. I think, of course, if you have a safety advantage but lose some efficacy, then there's more of a debate to be had. I think what you see from the data that Pino shared is, we're achieving fairly full efficacy with ESCAPE and then we get that safety advantage. So, so far that looks quite compelling. Obviously, as I noted, it will take some time to evolve the full product profile, but maybe I'll hand over to Pino to expand on that.

是的。也許我會讓皮諾回答第二個問題。我只強調第一個問題。當然，我認為，如果你有安全優勢但失去了一些功效，那麼就會有更多的爭論。我認為您從皮諾分享的數據中看到的是，我們透過 ESCAPE 實現了相當全面的功效，然後我們獲得了安全優勢。所以，到目前為止，這看起來相當引人注目。顯然，正如我所指出的，需要一些時間來發展完整的產品概況，但也許我會交給皮諾來擴展它。

I'm sorry, could you repeat the second question just for a moment?

抱歉，您能重複第二個問題嗎？

Yes, of course. I was just thinking about as you move, BEAM-103 into the Phase 1 healthy volunteer study next year, Are there any safety concerns of targeting 117 that we should be aware of?

是的當然。我只是在想，隨著明年BEAM-103進入第一階段健康志願者研究，針對117是否有我們應該注意的安全問題？

Yes. There have been actually several studies already conducted with antibodies against CD117. Actually, Celldex was the latest company to reveal some of the data they're using anti CD117 for the treatment of urticaria. And basically what you see in those individuals is that, you see a transient but mild neutropenia being the major sort of outcome that you'll see.

是的。實際上已經進行了幾項針對 CD117 抗體的研究。事實上，Celldex 是最新一家披露他們使用抗 CD117 治療蕁麻疹的一些數據的公司。基本上，您在這些人身上看到的是，您會看到短暫但輕微的中性粒細胞減少症是您將看到的主要結果。

And so, really, these antibodies do not lead to myelblation, as you would see with chemotherapy. And that's why as John mentioned earlier, it opens the possibility actually that this kind of treatment may even become in the future outpatient treatment paradigm, because obviously they do not run the risk of opportunistic infections due to neutropenia.

因此，實際上，這些抗體不會導致髓鞘消融，就像化療時所看到的那樣。這就是為什麼正如約翰之前提到的，它實際上開啟了這種治療甚至可能成為未來門診治療範式的可能性，因為顯然它們不存在因中性粒細胞減少症而導致機會性感染的風險。

So, we think that, it really the healthy volunteer is a very healthy volunteer is a very expeditious and efficient way of quickly getting to a PK/PD understanding of the antibody, and then it gives us a more assured essentially dosing regimen for us to go into the sickle cell and beta thalassemia patient without having to have extensive, sort of treatment options, tested during those trials.

因此，我們認為，健康志願者確實是非常健康的志願者，這是快速了解抗體的 PK/PD 了解的一種非常迅速且有效的方法，然後它為我們提供了更放心的基本劑量方案進入鐮狀細胞和β地中海貧血患者，而無需在這些試驗期間進行廣泛的治療選擇。

Sami Corwin with William Blair.

薩米·科溫和威廉·布萊爾。

Congrats on the data and thank you for taking my questions. Pino, you just mentioned this and I noticed on the slide that you plan on exploring the ESCAPE technology and beta thalassemia in addition to sickle cell disease. I guess I was curious, what kind of prompted that expansion? And then, as you're thinking about the clinical trials for the ESCAPE platform, are you thinking about running those in the U.S. or would those likely be conducted ex-US?

恭喜您獲得數據，並感謝您回答我的問題。Pino，您剛剛提到了這一點，我在幻燈片上註意到，除了鐮狀細胞疾病之外，您還計劃探索 ESCAPE 技術和 β 地中海貧血。我想我很好奇，是什麼促使了這種擴張？然後，當您考慮 ESCAPE 平台的臨床試驗時，您是否考慮在美國進行這些試驗，或者這些試驗可能會在美國境外進行？

So, a couple of things on there. In terms of the beta thalassemia consideration, it's really a fact that, we think that ESCAPE essentially alters the risk benefit profile and in particular reduces the risk to the point that even in the beta thalassemia patients, a transplant might be justified, particularly in the broader beta thalassemia patient, which goes beyond the transfusion dependent thalassemia patients, which as you know is a relatively small number of patients, obviously very sick, but we think that ESCAPE opens up the opportunity to treat even beyond TDP.

所以，有幾件事。就β地中海貧血的考慮而言，事實上，我們認為ESCAPE本質上改變了風險收益狀況，特別是將風險降低到即使在β地中海貧血患者中，移植也可能是合理的，特別是在更廣泛的β地中海貧血患者，超出了輸血依賴性地中海貧血患者，正如您所知，後者的患者數量相對較少，顯然病情非常嚴重，但我們認為ESCAPE 開闢了甚至超越TDP 的治療機會。

And so, that's fundamentally the main reason to consider that. And then in terms of the various places where we'll go, the healthy volunteers, we have not yet decided exactly where US or ex-US We will just be really efficiency and rapid exploration of that Phase 1 is really what's going to guide us in the choice that we make.

因此，這從根本上來說是考慮這一點的主要原因。然後就我們要去的各個地方而言，健康的志願者，我們還沒有確切地決定美國或美國以外的地方，我們將只是真正高效和快速探索第一階段真正將指導我們在我們做出的選擇中。

Luca Issi with RBC Capital.

盧卡·伊西 (Luca Issi) 與加拿大皇家銀行資本 (RBC Capital) 合作。

Thanks so much for taking my question. Maybe John, big picture, it feels to me that ESCAPE is becoming increasingly more important now, especially in the context of the debt today, kind of reminding us the risk associated with busulfan. If a scenario where escape is actually not game-changing, are you still committed to commercialize BEAM-101 solo or would you be open to partner BEAM-101 or out license it similar to what Editas has recently communicated? Any color there. Much appreciated.

非常感謝您提出我的問題。也許約翰，從大局來看，我覺得現在逃脫變得越來越重要，特別是在今天的債務背景下，有點提醒我們與白消安相關的風險。如果逃生實際上並不能改變遊戲規則，您是否仍然致力於將 BEAM-101 單獨商業化，或者您是否願意與 BEAM-101 合作，或者像 Editas 最近傳達的那樣對其進行許可？那裡有任何顏色。非常感謝。

Yes. I think as you noted, we are playing the long game here in hematology and we see very exciting progression of technology that takes advantage of base editing, not to mention our now significant capabilities in CD34 manufacturing and these sorts of blood therapies to create a lot of impact for patients over time. And it is a progression that begins with 101 as potentially best-in-class product for this Wave 1 market leading to ESCAPE, which is no question, incredibly exciting and would be a really revolutionary product in the conditioning field, expanding us from sickle cells also include beta thalassemia, et cetera.

是的。我認為正如您所指出的，我們在血液學領域正在打一場持久戰，我們看到了利用鹼基編輯技術的非常令人興奮的進步，更不用說我們現在在CD34 製造和此類血液療法方面的重要能力，創造了許多隨著時間的推移對患者的影響。這是一個從101 開始的進步，它是第一波市場的潛在同類最佳產品，最終導致ESCAPE，毫無疑問，令人難以置信的令人興奮，並且將成為調理領域的真正革命性產品，使我們從鐮狀細胞擴展到鐮狀細胞還包括β地中海貧血等。

As I have noted before, I think a lot of the capabilities we build along the way there, now adding the ability to change your blood system potentially without chemotherapy could lead to a lot of other places, right? So, we see a lot of growth opportunity here in hematology over the long-term. That's why it's one of our two core pillars.

正如我之前指出的，我認為我們在過程中建立的許多能力，現在增加了無需化療即可改變血液系統的能力，可能會帶來很多其他的地方，對嗎？因此，從長遠來看，我們在血液學領域看到了許多成長機會。這就是為什麼它是我們的兩大核心支柱之一。

So, I think when it comes to partnering, I think we've always said that we have the luxury here of we don't have to partner for financial reasons. We would only partner strategically. And so, the partnership would be considered if a party could help us reach more patients more quickly than we could do ourselves and then it would be something that we would consider.

因此，我認為在合作方面，我們總是說我們很幸運，不必因為財務原因而合作。我們只會進行戰略合作。因此，如果一方能夠比我們自己更快地幫助我們接觸更多患者，那麼我們就會考慮建立合作關係。

To your hypothetical, I think if some of the elements of that pillar were to start to change, if we didn't have the ESCAPE technology for instance or it didn't work in some fundamental way, I do think that would change the long-term outlook in hematology that might change the balance of our strategic thinking. But in the near-term, I don't think it would change the value we have with BEAM-101 to potentially help a lot of patients who need help.

根據你的假設，我認為如果該支柱的某些要素開始改變，例如，如果我們沒有 ESCAPE 技術，或者它沒有以某種基本方式發揮作用，我確實認為這會改變長期的情況。前景可能會改變我們戰略思維的平衡。但在短期內，我認為這不會改變我們對 BEAM-101 的價值，也就是可能幫助許多需要幫助的患者。

So I think the calculus would basically be the same. It would be these are products that I think can make a big impact for patients and generate sustainable revenue and market value. If there's a party out there who can help us do any of this better without getting in the way of what we need to build that's a conversation that we'll entertain. Otherwise, we're prepared and well financed to do this ourselves.

所以我認為微積分基本上是相同的。我認為這些產品可以對患者產生重大影響，並產生可持續的收入和市場價值。如果有一個團體可以幫助我們做得更好，而不妨礙我們需要建立的東西，那麼我們將進行一場對話。否則，我們已經準備好並且有充足的資金來自己做這件事。

Michael Yee with Jefferies.

邁克爾·易和杰弗里斯。

If I may, since this is an earnings call as well, right, there are some other pipeline developments. You did announce that you had completed dosing the first cohort in AAT, which I think is a big achievement. Could you just remind us to what extent you believe that there would be material enough information to disclose and at what time point, given my understanding is the AAT levels should be rising pretty quickly. And certainly based on today's data, I'm sure you have more confidence in the editing here in-vivo. So at what point, would there be enough proof-of-concept for you to disclose and given you've already dosed three patients already?

如果可以的話，因為這也是一次財報電話會議，對吧，還有一些其他的進展。您確實宣布您已經完成了第一批 AAT 的給藥，我認為這是一項重大成就。鑑於我的理解是 AAT 水平應該會很快上升，您能否提醒我們您認為在何種程度上會有足夠的實質性資訊可以披露以及在什麼時間點披露。當然，根據今天的數據，我相信您對體內編輯更有信心。那麼，考慮到您已經給三名患者服用了藥物，那麼什麼時候會有足夠的概念驗證供您揭露呢？

So, you're absolutely right. We have a lot going on in the portfolio. We're very excited about the progress on liver side as well, as I noted in the Q results. With alpha-1, obviously, first cohort completed and now moving forward with that dose escalation. It is true as a reminder to everybody, we have dose escalating beginning at a low dose, but a low dose that is nonetheless expected to have biological activity that's important ethically and then we will seek to understand the optimal biological range, as we go.

所以，你是完全正確的。我們的投資組合中有很多事情要做。正如我在 Q 結果中指出的那樣，我們對肝臟的進展也感到非常興奮。顯然，對於 alpha-1，第一組已經完成，現在正在推進劑量遞增。確實，提醒大家的是，我們從低劑量開始逐漸增加劑量，但低劑量仍有望具有重要的生物活性，這在倫理上很重要，然後我們將尋求了解最佳的生物範圍。

We've guided to a 2025 data release on that program. I feel confident in that guidance. I think when we will narrow that as we can, obviously. I think what we've always said is, we would look to bring out data when there is a clear profile of the drug.

我們已指導該計劃於 2025 年發布數據。我對這項指導充滿信心。我認為顯然，我們什麼時候會盡可能縮小範圍。我認為我們一直說的是，當藥物有明確的概況時，我們會尋求提供數據。

And I think that, I think clearly means at least multiple cohorts, exactly how we define that will be TBD. But we'll be watching it closely. And as you know, this is a program that does have the potential for early clinical proof-of-concept based on levels of alpha-1 normal, M alpha-1 going up based on Z protein hopefully going down. And then, of course, we'll be looking at safety in a Phase 1 study. So stay tuned, but that's certainly an update that we'll be looking forward to in 2025.

我認為，我認為這顯然意味著至少有多個群體，具體如何定義還有待確定。但我們會密切關注。如您所知，這個計畫確實具有早期臨床概念驗證的潛力，其基礎是 alpha-1 正常水平，M alpha-1 水平上升，基於 Z 蛋白有望下降。當然，我們將在第一階段研究中關注安全性。請繼續關注，這肯定是我們在 2025 年期待的更新。

Rick Bienkowski with Cantor Fitzgerald.

里克·賓科斯基和康托·菲茨傑拉德。

Congrats on the update and thanks for taking the question. I was just hoping to get a little more color on the expected pace of dosing in BEACON. I believe you said there were 35 patients enrolled in the study and eight patients dosed to date. If we can just get a little more detail on where we are for cell collection of the 27 patients, who weren't dosed yet and the potential timeline for all of these patients to be dosed?

恭喜更新並感謝您提出問題。我只是希望對 BEACON 的預期給藥速度有更多了解。我相信你說過有 35 名患者參加了這項研究，迄今為止有 8 名患者接受了治療。我們能否更詳細地了解 27 名尚未接受給藥的患者的細胞收集地點以及所有這些患者接受給藥的潛在時間表？

Yes. So, I think as you rightly noted that we're quite pleased with the enrollment. It's actually exceeded expectations at this point. 35 patients now fully enrolled. That does not include additional patients who are in screening and consenting. So, it's a pretty robust pipeline and moving quite quickly now. As we had hoped, I think when we set up the clinical program that we did and thanks to Amy and her team for driving it. Dosing is now -- basically, as you know, it takes a long time to create the dose. At this point, we have doses rolling off the line fairly regularly. So, there is going to be a big uptick in doses in the near future as that trial commences.

是的。因此，我認為正如您正確指出的那樣，我們對註冊情況感到非常滿意。目前來看，確實已經超出了預期。 35 名患者現已全部入組。這不包括正在篩檢和同意的其他患者。所以，這是一個非常強大的管道，而且現在進展得很快。正如我們所希望的那樣，我認為當我們制定臨床計劃時我們就這麼做了，並感謝艾米和她的團隊推動了它。現在的劑量基本上，如您所知，需要很長時間才能產生劑量。目前，我們的劑量已經相當規律地下線了。因此，隨著試驗的開始，在不久的將來劑量將會大幅增加。

As a reminder, the overall trial, we're looking for 45 total patients, who will be dosed here. Clearly, we're well on our way to that. Also interestingly, we've always designed this trial as a potential to be a registration trial and our best understanding of that package based on the benchmark set by the XL program was 30 patients followed for about 15 months to get their endpoint assessed.

提醒一下，在整個試驗中，我們總共尋找 45 名患者，他們將在這裡接受給藥。顯然，我們正在朝著這個目標前進。另外有趣的是，我們一直將這項試驗設計為潛在的註冊試驗，並且根據XL 計劃設定的基準，我們對該方案的最佳理解是對30 名患者進行約15 個月的跟踪，以評估其終點。

And so, clearly, in this 35 patients, we've already got those patients moving. So, the clock has started at this point as we execute on these doses and look to enable, what could be a potential filing package for 101.

因此，很明顯，在這 35 名患者中，我們已經讓這些患者移動了。因此，當我們執行這些劑量並尋求啟用 101 的潛在歸檔包時，時鐘已經開始。

Debjit Chattopadhyay with Guggenheim.

Debjit Chattopadhyay 與古根漢。

This is [Rai Forsathon] on for Debjit. What are your human translational expectations from the NHP ESCAPE data? Do you expect outperformance or underperformance relative to 101? And does having BEAM-101 clinical data help bolster your confidence in escape's clinical performance?

這是 Debjit 的 [Rai Forsathon]。您對 NHP ESCAPE 資料的人類翻譯期望是什麼？您預計相對於 101 的表現會優於還是較差？擁有 BEAM-101 臨床數據是否有助於增強您對 escape 臨床表現的信心？

Yes. Pino?

是的。皮諾？

Yes. We expect frankly equivalent, if not better performance in human and that's driven by the sequence of the guide that we use is -- and the antibody being cross reactive actually between non-human primates and human. So, obviously, we are refining a little bit the treatment paradigm of the antibody, so that we can optimize it even further, but I think this non-human primate data gives us tremendous confidence that we can move forward to the clinical studies.

是的。坦白說，我們期望在人類中具有同等的（如果不是更好的）性能，這是由我們使用的指南的序列驅動的- 並且抗體實際上在非人類靈長類動物和人類之間發生交叉反應。因此，顯然，我們正在對抗體的治療範例進行一些改進，以便我們可以進一步優化它，但我認為這些非人靈長類動物數據給了我們巨大的信心，我們可以繼續進行臨床研究。

Mani Foroohar with Leerink Partners.

Mani Foroohar 與 Leerink Partners。

Thanks for taking the question, guys. A quick follow-up on Mike's question on AATD. As we think about the market opportunity in this indication, this is obviously a fairly heterogeneous population. How should we think about the path forward both in terms of enrollment and clinical data and then ultimate sort of commercial opportunity between patients with a predominantly lung phenotype and those with a liver phenotype? And how will your enrollment strategy reflect the opportunity set across those?

謝謝你們提出問題，夥伴們。快速跟進 Mike 關於 AATD 的問題。當我們考慮此適應症的市場機會時，這顯然是一個相當異質的族群。我們應該如何思考入組和臨床數據方面的前進道路，以及主要肺表型患者和肝臟表型患者之間的最終商業機會？您的招生策略將如何反映這些機會？

So, alpha-1, it is a somewhat heterogeneous population. You have, of course, the majority of patients are primarily lung involved a minority have primary liver involvement, and of course, there's a spectrum of patients who share both. The beauty of BEAM-302 is that it addresses both sides of that equation.

所以，α-1，它是一個有些異質的群體。當然，大多數患者主要涉及肺部，少數患者主要涉及肝臟，當然，有許多患者同時患有這兩種疾病。BEAM-302 的優點在於它解決了等式的兩邊。

So for every allele we add it, we are going to start secreting normal protein, which should benefit the lungs and be under normal regulation and we're going to decrease the production of this toxic C protein that is causing so much trouble to liver. So I think at the end of the day, we don't need to choose.

因此，對於我們添加的每個等位基因，我們將開始分泌正常的蛋白質，這應該有益於肺部並處於正常調節之下，我們將減少這種對肝臟造成很多麻煩的有毒C 蛋白的產生。所以我認為最終我們不需要選擇。

Now in the trial itself, we're initially studying this in patients, who are primarily lung just to make sure we have a clean profile given this is a liver delivered therapy, then, we will treat patients who have much more liver involvement.

現在在試驗本身中，我們最初在主要是肺部的患者中進行研究，只是為了確保我們有一個乾淨的輪廓，因為這是一種肝臟傳遞的療法，然後，我們將治療更多肝臟受累的患者。

But our expectation based on pre-clinical data and our goal would be to deliver a single dose that is usable across the entire population and develop the drug across the entire population. I think by the time we get to considering market potential, ultimately, all patients are in view here, both currently diagnosed and then continuing to identify additional patients, who have that Z phenotype and are in really severe need of new therapeutic options.

但我們基於臨床前數據的期望和我們的目標是提供可在整個人群中使用的單一劑量，並為整個人群開發藥物。我認為，當我們開始考慮市場​​潛力時，最終，所有患者都將被納入考慮範圍，包括目前已被診斷的患者，然後繼續識別其他患者，這些患者俱有Z 表型並且確實迫切需要新的治療選擇。

Can I get a quick follow-up here? It makes a lot of sense to me that the technology can address the underlying genetic cause of disease and therefore address the molecular genetics to drive all of these phenotypes. That makes a lot of sense to me, biologically and clinically. But from a regulatory perspective, the time horizon approval endpoints for these two phenotypes aren't necessarily aligned. If you give us a little bit of color on how you think about -- how to get approved for treatment for liver, mixed, long, et cetera, what that looks like from a regulatory practical perspective?

我可以在這裡得到快速跟進嗎？對我來說，這項技術可以解決疾病的潛在遺傳原因，從而解決驅動所有這些表型的分子遺傳學問題，這很有意義。這對我來說很有意義，無論是生物學上還是臨床上。但從監管角度來看，這兩種表型的時間範圍核准終點不一定一致。如果您給我們一些關於您的想法的資訊 - 如何獲得批准用於肝臟、混合型、長期等的治療，從監管實踐的角度來看，這是什麼樣的？

Yes, understood. And I mean, look, I think our first job here is to deliver a hopefully compelling Phase 1 data set, right, which shows the kind of fundamental correction of the gene in the body for the first time. That's step one. That of course, that data opens the door to the conversation with the regulators for a lot of the different options here.

是的，明白了。我的意思是，看，我認為我們在這裡的首要工作是提供一個令人信服的第一階段數據集，對吧，它首次顯示了體內基因的基本校正。這是第一步。當然，這些數據為與監管機構進行對話打開了大門，以獲得許多不同的選擇。

You're right that formally a lung endpoint may have a certain set of requirements and characteristics that may be different than a liver endpoint. Of course, the RNAi knockdown therapies have been exploring the liver pathway. We can learn from that. And so, certainly for the different kinds of patients, we may explore both.

您是對的，從形式上來說，肺部終點可能具有與肝臟終點不同的一組特定要求和特徵。當然，RNAi敲低療法一直在探索肝臟途徑。我們可以從中學習。因此，當然對於不同類型的患者，我們可以同時探索兩者。

At the same time across both of them, there's the opportunity to consider the use of just the biomarkers themselves and the protein deficiency, which defines this disease, as endpoints and markers of benefit that we would be exploring as well and that of course would be universal across patients. So, I definitely grant your point. I think it's early days. There's a lot to work through. I think our first step is to generate a compelling data set that will then drive the conversations with regulators and investigators on how to develop the drug.

同時，在這兩者中，有機會考慮僅使用生物標記本身和蛋白質缺乏（定義了這種疾病）作為我們也將探索的終點和益處標誌物，當然這將是在患者中普遍存在。所以，我絕對同意你的觀點。我認為現在還為時過早。還有很多工作要做。我認為我們的第一步是產生一個令人信服的數據集，然後推動與監管機構和研究人員就如何開發藥物進行對話。

This concludes the question-and-answer session. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

問答環節到此結束。感謝您參加今天的會議。這確實結束了該程式。您現在可以斷開連線。