AstraZeneca PLC (AZN) 2023 Q3 法說會逐字稿

Good morning to those joining from the U.S., good afternoon to those in the U.K. and Central Europe, and good evening to those listening in Asia. Welcome, ladies and gentlemen, to AstraZeneca's 9 months and Q3 Results 2023 Conference Call and webinar for investors and analysts.

來自美國的聽眾早安，英國和中歐的聽眾下午好，亞洲的聽眾晚上好。女士們、先生們，歡迎參加阿斯特捷利康為投資者和分析師舉辦的 9 個月和 2023 年第三季業績電話會議和網路研討會。

Before I hand over to AstraZeneca, I'd like to read the safe harbor statement. The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these working statements.

在我移交給阿斯特捷利康之前，我想閱讀安全港聲明。該公司打算利用 1995 年美國私人證券訴訟改革法案的安全港條款。本次電話會議的參與者可能會就阿斯特捷利康的營運和財務表現做出前瞻性陳述。儘管我們相信我們的預期是基於合理的假設，但就其本質而言，前瞻性陳述涉及風險和不確定性，並且可能受到可能導致實際結果與這些工作陳述中明示或暗示的結果存在重大差異的因素的影響。

Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webinar. (Operator Instructions)

本次電話會議中所做的任何前瞻性陳述均反映了本次電話會議時可獲得的知識和資訊。該公司不承擔更新前瞻性陳述的義務。請同時仔細閱讀本簡報和網路研討會附帶的幻燈片中的前瞻性聲明免責聲明。 （操作員說明）

And with that, I will now hand you over to the company.

現在我就把你交給公司了。

Thank you, operator. I'm Andy Barnett, Head of Investor Relations at AstraZeneca, and I'm very pleased to welcome you to AstraZeneca's 9 Months and Third Quarter 2023 Conference Call. All -- as usual, all materials presented are a on our website. This slide contains our usual safe harbor statement. We will be making comments on our performance using constant exchange rates, or CER, core financial numbers and other non-GAAP measures. A non-GAAP to GAAP reconciliation is contained within the results announcement. Numbers used today are in millions of U.S. dollars unless otherwise stated.

謝謝你，接線生。我是阿斯特捷利康投資者關係主管安迪·巴尼特 (Andy Barnett)，我非常高興地歡迎您參加阿斯特捷利康 9 個月和 2023 年第三季的電話會議。像往常一樣，所有提供的材料都在我們的網站上。這張投影片包含我們通常的安全港聲明。我們將使用固定匯率（CER）、核心財務數據和其他非公認會計準則衡量標準對我們的業績進行評論。績效公告中包含非公認會計原則與公認會計原則的調節。除非另有說明，今天使用的數字均以百萬美元為單位。

This slide shows our agenda for today's call. Following our prepared remarks, we will open the line for questions. As usual, we will try and address as many questions as we can during the allotted time, although I'd ask participants to limit the number of questions you ask to allow others a fair chance to participate in the Q&A. (Operator Instructions)

這張投影片顯示了我們今天電話會議的議程。在我們準備好的發言之後，我們將開通提問熱線。像往常一樣，我們將嘗試在規定的時間內解決盡可能多的問題，但我會要求參與者限制提出的問題數量，以便其他人有公平的機會參與問答。 （操作員說明）

And with that, Pascal, I will hand it over to you.

帕斯卡，我就把它交給你了。

Thank you, Andy. Hello, everyone. Please advance to the next slide. Total revenue in the first 9 months of the year increased 5% to $33.8 billion, with 15% growth from our non-COVID-19 medicines, offsetting a $2.9 billion decline in revenue from our COVID-19 medicines. Core earnings per share increased 17% to $5.80. This increase is reflecting -- reflective of our robust company performance, our financial discipline as well as again in other operating income that we announced with our half year results. We continue to benefit from our diverse commercial portfolio and our broad global footprint. Given our confidence in the remainder of the year, we have upgraded our 2023 guidance. We now anticipate total revenue ex-COVID to increase by low teens percentage and core EPS to increase by low double digit to low teens percentage. Aradhana will provide more details on our financials shortly.

謝謝你，安迪。大家好。請前進到下一張幻燈片。今年前 9 個月的總收入成長了 5%，達到 338 億美元，其中非 COVID-19 藥品收入成長了 15%，抵消了 COVID-19 藥品收入下降的 29 億美元。每股核心收益成長 17% 至 5.80 美元。這一成長反映了我們強勁的公司業績、我們的財務紀律以及我們在半年業績中宣布的其他營業收入。我們繼續受益於我們多元化的商業投資組合和廣泛的全球足跡。鑑於我們對今年剩餘時間充滿信心，我們升級了 2023 年指引。我們現在預計，除新冠疫情之外的總收入將以低十幾歲的百分比增長，核心每股收益將以低兩位數的低十幾歲的百分比增長。 Aradhana 將很快提供有關我們財務狀況的更多詳細資訊。

Next slide, please. Taking a closer look at the performance of our non-COVID revenue across our regions and disease areas, we saw double-digit growth in the U.S. and Europe in the period, reflecting strong demand for our medicines and continued commercial execution. Our growth in the emerging markets continues to impress, particularly outside of China, which was up 37% in the year-to-date. This sustained growth underscores our confidence that these markets will become increasingly important for our company.

請下一張投影片。仔細觀察我們在各地區和疾病領域的非新冠收入表現，我們發現美國和歐洲在此期間實現了兩位數增長，反映出對我們藥品的強勁需求和持續的商業執行。我們在新興市場的成長持續令人印象深刻，尤其是在中國以外的市場，今年迄今成長了 37%。這種持續成長凸顯了我們的信心，即這些市場對我們公司將變得越來越重要。

On the right-hand side, of this slide, you will see that we delivered robust double-digit growth across oncology, CVRM and rare disease and as expected, with declines in V&I. R&I medicines growth more than -- compensated for the impact of generic competition to Symbicort launched in the U.S. during the third quarter. We saw a reduction in promotional activities in China in Q3 which created some demand softness for certain medicines in the quarter, but I have already seen recovery beginning October. We remain confident in delivering our total revenue guidance for China for the full year, which we upgraded with our half year results.

在這張投影片的右側，您將看到我們在腫瘤學、CVRM 和罕見疾病領域實現了強勁的兩位數成長，正如預期的那樣，V&I 出現了下降。 R&I 藥品的成長超過——彌補了第三季在美國推出的 Symbicort 仿製藥競爭的影響。我們看到第三季中國的促銷活動減少，導致本季某些藥品的需求疲軟，但我已經看到從 10 月開始出現復甦。我們仍然對實現中國全年總收入指引充滿信心，並調高了半年業績。

Please move to the next slide. Unlike many of our peers, we have relatively low exposure to patent expiries. We have a broad, diverse portfolio of commercialized medicines, and we have an industry-leading late-stage pipeline, which includes several high-potential assets. However, our vision is not short term. We are also striving to deliver sustainable industry-leading growth for many years to come. And while we are maintaining a focus on discovering new small and large molecules, we have taken a strategic decision to increase investment behind new modalities that we believe have the potential to revolutionize items for patients.

請移至下一張投影片。與許多同業不同，我們面臨專利到期的風險相對較低。我們擁有廣泛、多樣化的商業化藥品組合，並且擁有業界領先的後期研發管線，其中包括多項高潛力資產。然而，我們的願景並不是短期的。我們也努力在未來許多年實現領先業界的永續成長。在我們繼續專注於發現新的小分子和大分子的同時，我們做出了一項策略決定，增加對新模式的投資，我們相信這些新模式有可能徹底改變患者的產品。

With our ADC portfolio, we are aiming to replace the use of traditional chemotherapy across the board. Combinations of our ADCs with our next-generation IO bispecific portfolio, offers the promise of more durable benefits for patients with improved tolerability. We are pioneering new modalities such as epigenetic, oligonucleotides and RNA therapies to unlock entirely new treatment approaches. And we are excited by the curative potential of cell and gene therapies.

透過我們的 ADC 產品組合，我們的目標是全面取代傳統化療的使用。我們的 ADC 與下一代 IO 雙特異性產品組合相結合，有望為患者帶來更持久的益處，並提高耐受性。我們正在開創表觀遺傳學、寡核苷酸和 RNA 療法等新模式，以解鎖全新的治療方法。我們對細胞和基因療法的治療潛力感到興奮。

I'm pleased with the progress we are making in each of these areas, and I look forward to sharing updates with you in the coming years. With that, please advance to the next slide, and I will hand over to Aradhana, who will take you through our financials and also provide a closer look at how we are leveraging AI in the commercial part of our company.

我對我們在每個領域的進展感到高興，並期待在未來幾年與您分享最新進展。接下來，請繼續觀看下一張投影片，我將把時間交給 Aradhana，他將帶您了解我們的財務狀況，並進一步了解我們如何在公司的商業部分利用人工智慧。

Thank you, Pascal. Please advance to the next slide. As usual, I will start with our reported P&L. As Pascal highlighted, total revenue increased by 5% in the first 9 months and product sales increased by 4% at constant exchange rates. Excluding COVID-19 medicines, total revenue and product sales increased by 15%. Alliance revenue of $1 billion was driven by increased Enhertu profit sharing from geographies where Daiichi Sankyo books product sales. As a reminder, Daiichi will book product sales in the U.S. and main European countries.

謝謝你，帕斯卡。請前進到下一張幻燈片。像往常一樣，我將從我們報告的損益表開始。正如 Pascal 所強調的那樣，以固定匯率計算，前 9 個月的總收入增長了 5%，產品銷售額增長了 4%。不包括 COVID-19 藥品，總收入和產品銷售額成長了 15%。聯盟收入達 10 億美元，主要得益於第一三共 (Daiichi Sankyo) 登記產品銷售地區的 Enhertu 利潤分成增加。需要提醒的是，第一一將在美國和歐洲主要國家預訂產品銷售。

Please advance to the next slide. Looking at our core P&L, we saw the product sales gross margin increased by 2 percentage points to 82.4% driven by lower COVID sales compared to the prior year. We anticipate a lower gross margin in the fourth quarter driven by higher FluMist sales, which has a very low gross margin. Beyfortus, which we supply to Sanofi also has a dilutive impact on our product sales gross margins. Over time, the gross margin percentage will be diluted by both increased profit sharing for partnered products such as Tezspire and Enhertu in territories where we book revenue and higher emerging market revenue, partly offset by favorable product sales mix.

請前進到下一張幻燈片。從我們的核心損益表來看，由於新冠肺炎銷售額較前一年下降，產品銷售毛利率成長了 2 個百分點，達到 82.4%。我們預計第四季度的毛利率會下降，原因是毛利率非常低的 FluMist 銷售額增加。我們向賽諾菲供應的 Beyfortus 也對我們的產品銷售毛利率產生稀釋影響。隨著時間的推移，毛利率百分比將被我們預訂收入的地區的 Tezspire 和 Enhertu 等合作產品的利潤分享增加以及新興市場收入的增加所稀釋，部分被有利的產品銷售組合所抵消。

Our core operating expenses increased 7% over the period. Similar to previous years, we expect a step-up in absolute cost in the fourth quarter driven by SG&A spend phasing and the number of new Phase III starts. For the full year, we anticipate operating expenses around the upper end of our previous indication of low to mid-single-digit increase driven by continued investment in our business to support the strong top line growth seen into year-end. Core EPS of $5.80 represents a CER growth of 17%.

在此期間，我們的核心營運費用增加了 7%。與往年類似，我們預計第四季度的絕對成本將在 SG&A 支出分階段和新的第三期專案啟動數量的推動下上升。就全年而言，我們預計營運費用將在我們先前預測的低至中個位數成長的上限附近，這是由於對我們業務的持續投資所推動，以支持年底的強勁收入成長。核心每股收益為 5.80 美元，相當於固定匯率 (CER) 成長 17%。

Next slide, please. Our cash flow continues to improve and net debt increased -- decreased quarter to $23.4 billion despite an interim dividend payment of $1.5 billion. Our net debt-to-EBITDA now stands at 1.7x with the Alexion fair value inventory adjustment now behind us.

請下一張投影片。我們的現金流繼續改善，淨債務增加——儘管支付了 15 億美元的中期股息，但季度減少至 234 億美元。我們的淨債務與 EBITDA 比率目前為 1.7 倍，Alexion 公允價值庫存調整現已過去。

Turning to our full year guidance. We now anticipate total revenue to increase by a mid-single-digit percentage, up from previously low to mid-single digit. Excluding COVID-19 medicines, we now anticipate a growth in the low teens percentage range. For core EPS, we now anticipate to grow by low double-digit to low teens percentage, which is an upgrade versus prior guidance of a high single-digit to low double-digit percentage increase.

轉向我們的全年指導。我們現在預計總收入將以中個位數百分比成長，從先前的低點上升到中個位數。不包括 COVID-19 藥物，我們現在預計成長率將在青少年百分比範圍內。對於核心每股收益，我們現在預計將以低兩位數百分比到低兩位數百分比增長，這是對先前指導的高個位數到低兩位數百分比增長的升級。

Based on current FX rates, we anticipate a low single-digit adverse FX impact on total revenue. For core EPS, we now anticipate a mid-single-digit adverse impact on core EPS, which is a change versus last quarter, reflecting current FX rates.

根據目前匯率，我們預期外匯對總收入的不利影響較低，為個位數。對於核心每股收益，我們現在預計核心每股收益將受到中個位數的不利影響，這與上季度相比有所變化，反映了當前的匯率。

Please advance to the next slide. Our capital allocation priorities remain unchanged. The #1 priority is to reinvest in the business. By the end of the year, we will have started more Phase III trials than in prior years. Our high R&D productivity will also impact SG&A costs as we will have a number of new products to launch in the coming year, including Airsupra in the U.S. and eplontersen and also preparation for potential new launches of Dato-DXd following the positive data presented at ESMO just a couple of weeks ago. We're continuing to expand Alexion's rare disease products into more international markets now present in 64 countries.

請前進到下一張幻燈片。我們的資本配置重點維持不變。第一要務是對業務進行再投資。到今年年底，我們將開始比往年更多的 III 期試驗。我們的高研發效率也將影響銷售、管理和管理成本，因為我們將在來年推出許多新產品，包括美國的 Airsupra 和 eplontersen，並在 ESMO 上公佈積極數據後為可能新推出的 Dato-DXd 做準備就在幾週前。我們正在繼續將 Alexion 的罕見疾病產品擴展到更多國際市場，目前已遍佈 64 個國家。

Many of the new modalities we're investing in as well as the growth in our portfolio will require further investment in CapEx. In addition, we're investing in our manufacturing network, optimizing our global footprint and investing in upgrading our systems. We also remain focused on value-enhancing business development, where we believe we can best leverage our R&D and commercial capabilities. We have done a number of deals this year, including CinCor and Neogene. And today with Eccogene and we will continue to do so where and when we see attractive opportunities.

我們投資的許多新模式以及我們投資組合的成長將需要進一步投資資本支出。此外，我們正在投資我們的製造網絡，優化我們的全球足跡並投資升級我們的系統。我們也繼續專注於提高價值的業務發展，我們相信我們可以最好地利用我們的研發和商業能力。今年我們完成了多項交易，包括 CinCor 和 Neogene。今天，我們將與 Eccogene 合作，只要我們看到有吸引力的機會，我們就會繼續這樣做。

We have also a number of successful partnerships, including with Daiichi and Enhertu and Dato and Merck on Lynparza and Ionis on eplontersen. Overall, we will continue to invest to support growth drive innovation and bring innovative medicines to patients quicker.

我們也建立了許多成功的合作夥伴關係，包括與 Daiichi 和 Enhertu、Dato 和 Merck 合作開發 Lynparza，以及與 Ionis 合作開發 eplontersen。總體而言，我們將繼續投資以支持成長驅動創新，並更快地將創新藥物帶給患者。

Please advance to the next slide. continuing our commitment to showcase the use of AI across our business, in prior calls, I've covered some examples of the use in R&D and manufacturing operations. Today I'll highlight the use of AI and advanced analytics to drive faster decision-making with our commercial organization.

請前進到下一張幻燈片。為了繼續我們在整個業務中展示人工智慧的使用的承諾，在先前的電話會議中，我介紹了一些在研發和製造業務中使用的範例。今天，我將重點介紹如何使用人工智慧和進階分析來推動我們的商業組織更快地做出決策。

Starting first with data and analytics. Our in-house proprietary platform called AZBrain analyzes multiple large data sets enriching the data to correct for inaccuracies, duplication and data gaps to generate actionable insights. Next, we leverage AI to improve patient diagnosis and personalized treatment approaches. Even today, roughly 6% of EMR data is still unstructured. Application of novel technology to lung cancer screening enabled analysis of over 6 million handwritten documents in just 1 day and led to over 25,000 high-risk patients being reassessed. We plan to scale this technology to additional health systems and tumor types, including breast cancer.

首先從數據和分析開始。我們的內部專有平台 AZBrain 會分析多個大型數據集，豐富數據，修正不準確、重複和數據缺口，產生可行的見解。接下來，我們利用人工智慧來改善患者診斷和個人化治療方法。即使在今天，大約 6% 的 EMR 數據仍然是非結構化的。將新技術應用於肺癌篩檢，短短 1 天就可以分析超過 600 萬份手寫文檔，並導致超過 25,000 名高風險患者重新評估。我們計劃將這項技術擴展到其他衛生系統和腫瘤類型，包括乳癌。

We also apply large multimodal data sets to our clinical trials to help by the right patient population for trials and to deliver more personalized precision medicines and improve the success rate of our studies.

我們也將大型多模式資料集應用於臨床試驗，以幫助選擇合適的患者群體進行試驗，並提供更個人化的精準藥物並提高我們研究的成功率。

Finally, we're using AI and predictive analytics to inform more precise, tailored engagement with physicians using the preferred communication channel at a time when they're most likely to engage with potentially eligible patients. Our investments in AI have yielded important actionable insights into how we can continue to best serve our patients globally.

最後，我們使用人工智慧和預測分析，當醫生最有可能與潛在合格患者接觸時，使用首選溝通管道與醫生進行更精確、量身定制的接觸。我們對人工智慧的投資為我們如何繼續為全球患者提供最佳服務提供了重要的、可行的見解。

And with that, please advance to the next slide, and I will hand over to Dave.

接下來，請前進到下一張投影片，我將把它交給戴夫。

Thank you, Aradhana. Next slide, please. Oncology delivered solid performance in the year-to-date period with total revenues of over $13.5 billion, an increase of 20% versus the prior year, driven by strong global demand reinforcing both the value of our portfolio as well as the continued execution by our global teams.

謝謝你，阿拉達納。請下一張投影片。在強勁的全球需求的推動下，腫瘤學在年初至今表現強勁，總收入超過 135 億美元，比上年增長 20%，這既增強了我們的投資組合價值，又加強了我們的持續執行力。全球團隊。

Turning now to our key medicines. In the third quarter, Tagrisso global revenues grew 6%, fueled by continued demand for ADAURA and FLAURA. In China, we saw some market impact from the anticorruption campaign, but we have already observed recovery into the fourth quarter. Lynparza delivered 8% product sales growth in the third quarter, driven by double-digit growth in Established Rest of World and emerging markets. Lynparza extended its leadership position in the PARP inhibitor class globally, despite decreasing class use and the second-line label restriction in ovarian cancer in the United States.

現在轉向我們的關鍵藥物。第三季度，在 ADAURA 和 FLAURA 持續需求的推動下，Tagrisso 全球營收成長了 6%。在中國，我們看到反貪腐運動對市場產生了一些影響，但我們已經觀察到第四季的復甦。在世界其他成熟市場和新興市場兩位數成長的推動下，Lynparza 第三季的產品銷售成長了 8%。儘管在美國卵巢癌中該類藥物的使用量有所減少且二線標籤受到限制，但 Lynparza 仍擴大了其在全球 PARP 抑制劑類別中的領導地位。

We continue to accelerate our IO portfolio with a competitive class in the third quarter. Imfinzi total revenues, inclusive of Imjudo, delivered 54% growth driven by new launches. Calquence's total revenues increased 15%, driven both by expanded access in Europe and demand growth globally.

我們在第三季繼續以具有競爭力的水平加速我們的 IO 投資組合。在新產品推出的推動下，Imfinzi 總收入（包括 Imjudo）實現了 54% 的成長。由於歐洲市場准入範圍擴大和全球需求成長，Calquence 的總收入成長了 15%。

Enhertu total revenues of $339 million in the third quarter increased 86% year-on-year. And in the U.S., Enhertu new patient share in HER2-positive metastatic breast cancer and HER2 low post-chemo metastatic breast cancer remain above 50%. We continue to see strong demand growth globally, particularly in European markets, driven by recent launches of DESTINY-Breast03 and DESTINY-Breast04. In the quarter, Enhertu became the first antibody drug conjugate approved for lung cancer in Europe and Japan, and we received approval for Calquence in China. At ESMO, we presented updated FLAURA2 data, which Susan will cover shortly, and we are excited to have been granted priority review for FLAURA2 in the United States. We also received FDA acceptance for AEGEAN. These 2 important potential treatment regimens in our ambitions in lung cancer.

Enhertu第三季總營收為3.39億美元，年增86%。而在美國，Enhertu 在 HER2 陽性轉移性乳癌和 HER2 低化療後轉移性乳癌中的新患者比​​例仍保持在 50% 以上。在最近推出的 DESTINY-Breast03 和 DESTINY-Breast04 的推動下，我們繼續看到全球需求強勁成長，特別是在歐洲市場。本季度，Enhertu 成為歐洲和日本第一個獲準用於肺癌的抗體藥物偶聯物，我們的 Calquence 在中國獲得批准。在 ESMO 上，我們展示了更新的 FLAURA2 數據，Susan 很快就會介紹這些數據，我們很高興能夠在美國獲得 FLAURA2 的優先審查。我們也獲得了 FDA 對 AEGEAN 的認可。這兩種重要的潛在治療方案是我們治療肺癌的目標。

Next slide, please. Looking ahead, we're well positioned within our oncology portfolio, focusing on 2 medicines in increasingly competitive markets, Tagrisso and Calquence, we are confident in sustained leadership and future growth. We're well on our way to establishing Tagrisso at every stage for patients with EGFR-mutated non-small cell lung cancer, supported by its best-in-class once-daily oral regimen leading benefit risk profile. With ADAURA, we have the opportunity to further accelerate testing, referral and treatment rates in the resectable setting and to expand access through global reimbursements.

請下一張投影片。展望未來，我們在腫瘤學產品組合中處於有利地位，重點關注競爭日益激烈的市場中的兩種藥物：Tagrisso 和 Calquence，我們對持續的領導地位和未來的成長充滿信心。我們正在為 EGFR 突變非小細胞肺癌患者在各個階段建立 Tagrisso，並得到其一流的每日一次口服療法領先的獲益風險狀況的支持。借助 ADAURA，我們有機會進一步加快可切除環境中的檢測、轉診和治療率，並透過全球報銷擴大可及性。

The LAURA trial anticipated to read out in the first half of the next year, presents the opportunity to leverage our existing presence in unresectable Stage III with PACIFIC and offer a targeted therapy for EGFR mutated patients.

LAURA 試驗預計將於明年上半年公佈，該試驗提供了機會，利用我們在不可切除的 III 期 PACIFIC 中現有的優勢，為 EGFR 突變患者提供標靶治療。

Next, in the frontline metastatic setting, we continue to see increased real-world duration of treatment driven by patients gaining sustained benefit on Tagrisso monotherapy. FLAURA2 represents the opportunity to build on FLAURA, further extending duration of treatment and offering a best-in-class offer the subset of patients that may require more intensive treatment upfront. Novel life cycle management and combination opportunities allow for continued reinforcement of Tagrisso as the backbone TKI of choice in non-small cell lung cancer.

接下來，在第一線轉移治療中，我們繼續看到，由於患者從 Tagrisso 單藥治療中獲得持續獲益，實際治療持續時間增加。 FLAURA2 代表了在 FLAURA 基礎上發展的機會，進一步延長了治療持續時間，並為可能需要預先進行更強化治療的患者提供了一流的治療方案。新穎的生命週期管理和組合機會使 Tagrisso 能夠持續強化作為非小細胞肺癌選擇的骨幹 TKI。

Calquence remains the leading BTK inhibitor across all indications in the face of increasing class competition, and we've seen clear recovery in the relapsed/refractory setting. Going forward, we're confident Calquence will continue to maintain leadership globally despite increased competitive pressures, reinforced by strong efficacy and differentiated safety.

面對日益激烈的類別競爭，Calquence 仍然是所有適應症中領先的 BTK 抑制劑，我們已經看到復發/難治性治療的明顯恢復。展望未來，我們相信，儘管競爭壓力不斷增加，但強大的功效和差異化的安全性增強了卡爾昆斯將繼續保持全球領先地位。

With that, please advance to the next slide, and I'll hand over to Susan to cover key R&D highlights in the quarter.

接下來，請前往下一張投影片，我將由 Susan 介紹本季的主要研發亮點。

Thank you, Dave. Over the past quarter, we've had a significant presence of key oncology congresses, including the World Conference on Lung Cancer and ESMO. We continue to consolidate our leadership position in lung cancer with data from FLAURA2 unveiled at World Congress on Lung Cancer. The data demonstrated that Tagrisso plus chemotherapy extended the median progression-free survival by 9 months compared to Tagrisso alone in patients with first-line EGFR mutated non-small cell lung cancer. This is the longest median PFS that's been seen to date in this setting.

謝謝你，戴夫。在過去的季度中，我們大量參加了重要的腫瘤學大會，包括世界肺癌大會和 ESMO。利用世界肺癌大會上公佈的 FLAURA2 數據，我們繼續鞏固我們在肺癌領域的領導地位。數據表明，在一線 EGFR 突變非小細胞肺癌患者中，與單獨使用 Tagrisso 相比，Tagrisso 聯合化療將中位無惡化存活期延長了 9 個月。這是迄今為止在此環境中觀察到的最長的中位 PFS。

Further data at ESMO underscored the critical importance this regimen has for patients with the greatest unmet need, including those with CNS metastases at diagnosis. In these patients, Tagrisso plus chemotherapy resulted in more than 50% complete responses. FLAURA2 reinforces Tagrisso as the backbone therapy in EGFR mutated lung cancer, and the data have now been published in the New England Journal of Medicine.

ESMO 的進一步數據強調了該方案對於需求未得到最大滿足的患者（包括診斷時患有中樞神經系統轉移的患者）的至關重要性。在這些患者中，Tagrisso 合併化療取得了超過 50% 的完全緩解。 FLAURA2 強化了 Tagrisso 作為 EGFR 突變肺癌的骨幹療法，該數據現已發表在《新英格蘭醫學雜誌》上。

At ESMO, we expanded on our footprint in gynecological cancers presentation of the DUO-E data. This trial is the first to show increased benefit of combining both an immune checkpoint inhibitor and PARP inhibitor in the first-line advanced endometrial cancer setting, and demonstrated a deeper benefit with Lynparza in the proficient MMR and PD-L1 positive populations. We're in discussions with regulatory agencies around planned submission.

在 ESMO，我們擴大了 DUO-E 數據在婦科癌症展示中的足跡。該試驗首次顯示了在一線晚期子宮內膜癌治療中聯合使用免疫檢查點抑制劑和PARP 抑制劑可帶來更大的益處，並證明奧拉帕尼對MMR 和PD-L1 陽性人群具有更深入的益處。我們正在與監管機構就計劃提交進行討論。

We also had the first 2 positive Phase III presentations for Dato-DXd with data from both TROPION-Lung01 and TROPION-Breast01 presented at ESMO. These underscore its potential to replace backbone chemotherapy in these settings with both trials demonstrating the clear efficacy improvement of data Dato-DXd versus conventional chemotherapy, together with an improved safety profile.

我們還對 Dato-DXd 進行了前 2 次積極的 III 期演示，其中包括在 ESMO 上展示的 TROPION-Lung01 和 TROPION-Breast01 的數據。這些都強調了它在這些情況下取代骨幹化療的潛力，兩項試驗都證明了 Dato-DXd 的數據與傳統化療相比明顯提高了療效，並且安全性也得到了改善。

Dato-DXd best-in-class profile opens up future opportunities for combination with both IO and platinum chemotherapy and builds confidence, there is potential in earlier lines and other tumor types. We're moving to filing in both lung and breast cancer.

Dato-DXd 一流的配置為未來與 IO 和鉑類化療相結合開闢了機會，並建立了信心，認為在早期細胞系和其他腫瘤類型中具有潛力。我們正著手歸檔肺癌和乳癌。

Next slide, please. Our bispecific portfolio is designed to displace current standard of care immune checkpoint inhibition. These molecules are engineered to simultaneously inhibit 2 immune checkpoints, eliciting different biological effects compared with existing concurrent combinations. An early data suggest potential both as monotherapy and in combination with existing treatments such as chemotherapy. We are also combining our bispecifics with our ADC portfolio in Phase II trials.

請下一張投影片。我們的雙特異性產品組合旨在取代目前的免疫檢查點抑制護理標準。這些分子經過工程設計，可同時抑制 2 個免疫檢查點，與現有的同時組合相比，可產生不同的生物效應。早期數據顯示其既可以作為單一療法，也可以與化療等現有療法合併使用。我們也在 II 期試驗中將我們的雙特異性藥物與我們的 ADC 產品組合結合。

We're encouraged by the early data for volrustomig our PD-1 CTLA-4 bispecific. In first-line advanced lung cancer for volrustomig at 750 milligrams plus chemotherapy resulted in similar objective response rate as the higher 1,500-milligram dose with improved tolerability. In treatment-naive advanced renal cell carcinoma, data at ESMO demonstrated deep and durable responses at the 750-milligram dose, with a response rate of 48%, a complete response rate of 10% and a 12-month percussion free survival rate of 52%. Again, we saw improved tolerability compared to the higher 1,500-milligram dose.

我們對 volrustomig PD-1 CTLA-4 雙特異性抗體的早期數據感到鼓舞。在第一線晚期肺癌中，750 毫克 volrustomig 加化療的客觀緩解率與較高劑量 1,500 毫克相似，且耐受性有所改善。在未經治療的晚期腎細胞癌中，ESMO 的數據表明，750 毫克劑量可產生深度且持久的緩解，緩解率為 48%，完全緩解率為 10%，12 個月無衝擊生存率為 52% %。與更高的 1,500 毫克劑量相比，我們再次看到了耐受性的改善。

Patients with PD-L1 low lung cancer remain a group of high unmet need, and we continue to see that current PD-1 and PD-L1 agents have more limited benefit even when combined with chemotherapy within this patient population. Previous data such as those from our Phase III POSEIDON trial of Imfinzi plus Imjudo, demonstrate that CTLA-4 inhibition can improve the benefit in this group. This is the basis for our Phase III trial, eVOLVE-Lung02, which investigates whether volrustomig plus chemotherapy can improve outcomes versus standard of care pembrolizumab plus chemotherapy. eVOLVE-Lung02 is just 1 of the 4 bispecific trials we've announced this year, with 2 others for volrustomig and 1 for rilvegostomig.

PD-L1 低度肺癌患者仍然是一個未滿足的需求較高的群體，我們繼續看到，目前的PD-1 和PD-L1 藥物即使與該患者群體中的化療聯合使用，其益處也更加有限。先前的數據（例如 Imfinzi 聯合 Imjudo 的 III 期 POSEIDON 試驗的數據）表明 CTLA-4 抑制可以提高該組的益處。這是我們 III 期試驗 eVOLVE-Lung02 的基礎，該試驗研究 volrustomig 聯合化療與標準護理 pembrolizumab 聯合化療相比是否可以改善預後。 eVOLVE-Lung02 只是我們今年宣布的 4 項雙特異性試驗之一，另外 2 項針對 volrustomig，1 項針對 rilvegostomig。

Next slide, please. Our industry-leading ADC development program continues to move at pace, with 5 wholly owned antibody-drug conjugates now in the clinic and many more in preclinical development. Recent data shared at the ASCO Virtual Plenary illustrates the potential of our Claudin 18.2 directed antibody drug conjugate. Patients with Claudin 18.2 positive gastric or gastroesophageal cancer treated with AZD0901 showed an encouraging 33% confirmed response rate and a median progression-free survival of around 5 months.

請下一張投影片。我們業界領先的 ADC 開發計畫持續快速推進，目前已有 5 種全資抗體藥物偶聯物進入臨床，還有更多處於臨床前開發階段。 ASCO 虛擬全體會議上分享的最新數據說明了我們的 Claudin 18.2 定向抗體藥物偶聯物的潛力。使用 AZD0901 治療的 Claudin 18.2 陽性胃癌或胃食道癌患者顯示出令人鼓舞的 33% 確認緩解率，中位無惡化存活期約為 5 個月。

Claudin 18.2 is highly expressed in 50% to 60% of gastric cancers. And AZD0901 has potential to build on the important data we've already delivered with Enhertu in HER2-positive gastric cancer. And the emerging data for MATTERHORN for Imfinzi in resectable gastric cancer, thus accelerating our leadership in GI cancers.

Claudin 18.2 在 50% 至 60% 的胃癌中高表達。 AZD0901 有潛力建立在我們已經與 Enhertu 一起提供的 HER2 陽性胃癌的重要數據的基礎上。 Imfinzi 在可切除胃癌方面的 MATTERHORN 的新數據，從而加速了我們在胃腸道癌症領域的領先地位。

Next slide, please. Finally, I want to touch on our expanding presence in cell therapy. We now have 3 CAR-Ts in development, all of which include our transforming growth factor receptor [B] service armoring. This armoring is designed to resist the immunosuppressive tumor marker environment and enhance the potential effectiveness in solid tumors. We've seen encouraging data in humans with our GPC3 CAR-T, AZD7003, which demonstrates that this armoring is likely important for CAR-T when compared to other CAR-Ts targeting GPC3 without armoring.

請下一張投影片。最後，我想談談我們在細胞治療領域不斷擴大的業務。我們現在正在開發 3 個 CAR-T，所有這些都包括我們的轉化生長因子受體 [B] 服務裝甲。這種裝甲旨在抵抗免疫抑制腫瘤標記環境並增強實體瘤的潛在有效性。我們在人類身上看到了 GPC3 CAR-T AZD7003 令人鼓舞的數據，這表明與其他針對沒有裝甲的 GPC3 的 CAR-T 相比，這種裝甲對於 CAR-T 可能很重要。

We're also exploring the potential of our T-cell receptor therapies following the acquisition of Neogene Therapeutics. These [CAR-Ts] are our emerging modality that enable the identification of the intracellular targets unlocking biology that was previously inaccessible by cell therapy. Neogene already reopened INDs, 2 of which have moved into clinical development.

收購 Neogene Therapeutics 後，我們還在探索 T 細胞受體療法的潛力。這些 [CAR-T] 是我們的新興模式，能夠識別細胞內靶標，從而解鎖以前細胞療法無法實現的生物學功能。 Neogene 已重新開放 IND，其中 2 個已進入臨床開發階段。

Finally, we recently announced our collaboration and investment agreement with Cellectis. This collaboration leverages the Cellectis talent technology, which has been successfully used in the clinic to solve key challenges with allogeneic CAR-Ts and can precisely edit the genome in vivo to target the source of the genetically defined disease or tumor. We believe this collaboration will accelerate our development pipeline and unlock new ways to precisely target a broader range of cancers as well as other types of disease.

最後，我們最近宣布了與 Cellectis 的合作和投資協議。此次合作利用了 Cellectis 人才技術，該技術已成功應用於臨床，解決了同種異體 CAR-T 的關鍵挑戰，並且可以在體內精確編輯基因組，以靶向遺傳定義的疾病或腫瘤的來源。我們相信，此次合作將加速我們的開發進程，並開闢新的方法來精確靶向更廣泛的癌症以及其他類型的疾病。

And with that, please advance to the next slide, and I'll pass it over to Ruud to BioPharmaceuticals performance.

接下來，請轉到下一張投影片，我將把它交給 Ruud 來介紹生物製藥的表現。

Thank you, Susan. Next slide, please. BioPharmaceuticals delivered total revenue of $13.6 billion in the first 9 months of 2023 driven by growth of 19% in CVRM and 9% in R&I. Key highlights from the quarter included another record-breaking performance of Farxiga, now annualizing at more than $6 billion per year. Farxiga is truly a global brand with double-digit growth across all our main regions and the fastest expansion coming from emerging markets outside of China. In R&I, revenue growth from launches has more than offset the impact of generic competition for Symbicort in the United States.

謝謝你，蘇珊。請下一張投影片。在 CVRM 成長 19% 和 R&I 成長 9% 的推動下，生物製藥在 2023 年前 9 個月實現了 136 億美元的總收入。該季度的主要亮點包括 Farxiga 的業績再創紀錄，目前年銷售額超過 60 億美元。 Farxiga 是一個真正的全球品牌，在我們所有主要地區都實現了兩位數的成長，其中成長最快的來自中國以外的新興市場。在研發和創新領域，上市帶來的收入成長遠遠抵消了美國 Symbicort 仿製藥競爭的影響。

Emerging markets continues to generate strong growth particularly for inhaled products such as Breztri, which grew by 69% in the quarter. And in V&I, the first commercial sales of Beyfortus generated $67 million of product sales and Alliance revenue for AstraZeneca. And we also received our final regulatory milestone from our partner, Sanofi, following approval by the FDA.

新興市場持續強勁成長，尤其是 Breztri 等吸入產品，本季成長了 69%。在 V&I 中，Beyfortus 的首次商業銷售為阿斯特捷利康帶來了 6,700 萬美元的產品銷售額和聯盟收入。在 FDA 批准後，我們也從我們的合作夥伴賽諾菲那裡收到了最終的監管里程碑。

Next slide, please. We continue to invest in long-term research that can change clinical practices and differentiate our medicines. This is a particularly important part of our growth strategy for R&I with its portfolio of relatively young and fast-growing medicines with many years of [actuality] remaining. Combined, the key medicines that will drive R&I revenues grew by 42% year-on-year in quarter 3. This is being driven by a combination of class expansion for modern biological medicines and inhaled therapies and our share gains within those growing markets.

請下一張投影片。我們繼續投資長期研究，以改變臨床實踐並使我們的藥物脫穎而出。這是我們 R&I 成長策略的一個特別重要的部分，我們的 R&I 擁有相對年輕和快速成長的藥物組合，並且還具有多年的[實際]價值。總的來說，推動研發和創新收入的關鍵藥物在第三季度同比增長了42%。這是由現代生物藥物和吸入療法的類別擴展以及我們在這些不斷增長的市場中的份額增長共同推動的。

On the slide here, we have one example. Tezspire has quickly established a leading share in the first year of its launch in countries such as Germany and Japan. In other examples, Breztri is now the fastest growing medicine within the triple therapy class. And Fasenra remains the leading biologic for severe is eosinophilic asthma. We anticipate continued growth for Fasenra following recent positive readouts from MANDARA in EGPA and the MIRACLE trial for severe eosinophilic asthma in China.

在這裡的幻燈片上，我們有一個例子。 Tezspire在推出第一年就迅速在德國、日本等國家建立了領先的市場份額。在其他例子中，Breztri 現在是三聯療法類別中成長最快的藥物。 Fasenra 仍然是治療嚴重嗜酸性細胞性氣喘的領先生物製劑。繼近期 EGPA 中的 MANDARA 和中國針對嚴重嗜酸性粒細胞性氣喘的 MIRACLE 試驗取得正面結果後，我們預期 Fasenra 將持續成長。

The growth in our 4 key R&I medicines has more than offset the impact of generics on all the medicines, and they now make up nearly half of the therapy areas total revenue. And of course, we look forward to adding a fifth new medicine to this list when the Airsupra launches in 2024.

我們的 4 種關鍵 R&I 藥物的成長遠遠抵消了仿製藥對所有藥物的影響，它們現在佔治療領域總收入的近一半。當然，我們期待在 2024 年 Airsupra 推出時在此列表中添加第五種新藥。

In CVRM, Farxiga maintained its position as the fundamental treatment in heart failure and CKD and it continues to broaden its use among physicians. One of the drivers behind its recent growth has been the increase in diagnosis rates for CKD. Early diagnosis is an important factor for improving outcomes for patients and we hope to see this trend continue with more patients being identified at an earlier stage of their disease.

在 CVRM 領域，Farxiga 保持了其作為心臟衰竭和 CKD 基本治療藥物的地位，並繼續擴大其在醫生中的使用範圍。其近期成長背後的驅動因素之一是 CKD 診斷率的提高。早期診斷是改善患者預後的重要因素，我們希望看到這一趨勢持續下去，更多的患者在疾病的早期階段得到診斷。

Like R&I, our CVRM portfolio is evolving in a way that can generate long-term sustainable growth. And after today's blockbuster products inevitably reach the end of their exclusivity period. Our cohort of development medicines includes eplontersen for ATTR and the PDUFA date for our ATTR-PN submission is in quarter 4. Assuming approval, we expect to launch that indication in early 2024.

與 R&I 一樣，我們的 CVRM 產品組合正在以能夠產生長期可持續成長的方式不斷發展。如今的熱門產品不可避免地會達到其獨佔期的終點。我們的開發藥物隊列包括用於 ATTR 的 eplontersen，我們 ATTR-PN 提交的 PDUFA 日期為第四季度。如果獲得批准，我們預計將在 2024 年初推出該適應症。

We're also developing novel molecules that target hyperkalemia, high proteinuria and hypertension. These are areas of high unmet medical needs in patients with heart failure and CKD. For further details on the progress of those programs, I will now hand over to Sharon.

我們也正在開發針對高血鉀、高蛋白尿和高血壓的新型分子。這些是心臟衰竭和慢性腎臟病患者醫療需求未被滿足的領域。有關這些計劃進展的更多詳細信息，我現在將交給沙龍。

Thanks, Ruud. Next slide, please. I am delighted to be joining my first quarterly call in my new role and I would first like to thank Mene and the teams for your continued support and for helping me settle in. In the third quarter, we made significant progress on our fixed-dose combinations with Farxiga or dapagliflozin, which address pockets of high unmet medical need and where we aim to show significant benefit versus standard of care. Balcinerone is our selective mineralocorticoid receptor modulator. And in combination with dapagliflozin, we see opportunity to see lower of hyperkalemia in heart failure patients with chronic kidney disease.

謝謝，路德。請下一張投影片。我很高興能參加我擔任新職務後的第一次季度電話會議，首先我要感謝 Mene 和團隊的持續支持並幫助我適應。第三季度，我們在固定劑量方面取得了重大進展與Farxiga 或dapagliflozin的組合，可解決部分未滿足的醫療需求，我們的目標是顯示相對於標準護理的顯著益處。 Balcinerone 是我們的選擇性鹽皮質激素受體調節劑。與達格列淨併用，我們發現有機會降低患有慢性腎臟病的心臟衰竭患者的高血鉀症。

Preclinical data has shown separation of organ protective effects from acute effects on electrolytes, which predicts a reduced hyperkalemia risk. The Phase IIb MIRACLE trial aims to confirm the additive benefit of balcinerone combined with dapagliflozin, and we will have data later this year.

臨床前數據顯示，器官保護作用與對電解質的急性作用是分開的，這預示著高血鉀風險降低。 IIb 期 MIRACLE 試驗旨在確認 balcinerone 與 dapagliflozin 聯合使用的附加益處，我們將在今年稍後獲得數據。

We have shown significant benefit of zibotentan, our selective endothelin receptor antagonist in combination with dapagliflozin in improving fluid dynamics and reducing the risk of adverse kidney events. We presented data from our Phase IIb ZENITH-CKD trial at the American Society of Nephrology, which I will cover in the next slide.

我們已經證明，我們的選擇性內皮素受體拮抗劑 zibotentan 與達格列淨聯合使用可顯著改善體液動力學並降低腎臟不良事件的風險。我們展示了美國腎臟病學會 IIb 期 ZENITH-CKD 試驗的數據，我將在下一張投影片中介紹這些數據。

And finally, we are in advanced stages of planning Phase III trials for baxdrostat monotherapy in patients with treatment-resistant uncontrolled hypertension and in combination with dapagliflozin for patients with CKD and hypertension. Baxdrostat has been shown to be effective at reducing systolic blood pressure without off-target inhibition of cortisol synthesis. This treatment paradigm would offer needed option for patients with CKD and hypertension.

最後，我們正處於計劃 III 期試驗的後期階段，該試驗針對難以控制的高血壓患者進行 Baxdrostat 單藥治療，並與 CKD 和高血壓患者聯合使用達格列淨。 Baxdrostat 已被證明可有效降低收縮壓，且不會脫靶抑制皮質醇合成。這種治療模式將為 CKD 和高血壓患者提供所需的選擇。

We have already initiated a Phase III trial for zibotentan and dapagliflozin with plans to initiate baxdrostat monotherapy by the end of the year. We are also in advanced stages of planning Phase III trials for the other 2 combinations. Our ambition is to develop these 4 potential new medicines to extend cardiorenal protection while addressing specific symptoms of disease.

我們已經啟動了 zibotentan 和 dapagliflozin 的 III 期試驗，並計劃在今年年底啟動 baxdrostat 單藥治療。我們也處於規劃其他 2 種組合的 III 期試驗的後期階段。我們的目標是開發這 4 種潛在的新藥，以擴展心腎保護，同時解決疾病的特定症狀。

Next slide please. Data from the Phase II ZENITH-CKD trial investigating zibotentan and dapagliflozin in patients with CKD and residual high proteinuria showed clear benefit in reducing the urine albumin/creatinine ratio, a key indicator for kidney function. Zibotentan improves fluid dynamics and reduces the risk of adverse kidney events. When combined with dapagliflozin's ability to reduce extra vascular volume, these 2 medicines have been shown to provide significant benefit over endothelin receptor antagonist alone where fluid retention been a barrier to uptake.

請下一張投影片。 II 期 ZENITH-CKD 試驗研究了 zibotentan 和達格列淨治療 CKD 和殘餘高蛋白尿患者的數據，結果顯示在降低尿液白蛋白/肌酸酐比（腎功能的關鍵指標）方面有明顯的益處。 Zibotentan 改善流體動力學並降低腎臟不良事件的風險。當與達格列淨減少額外血管容量的能力相結合時，這兩種藥物已被證明比單獨使用內皮素受體拮抗劑具有顯著的益處，因為液體滯留是吸收的障礙。

The complementary mechanisms delivers superior efficacy and acceptable tolerability. Both doses were well tolerated and offer benefits across glomerular filtration rate, supporting our path to Phase III. On the right-hand side, our IL-33 inhibitor, tozorakimab, has proven ability to inhibit dual pathways, ST2 and RAGE/EGFR. This is important as these independent pathways are involved in different inflammatory cascades. Disregulation of ST2 pathway drives airway inflammation. While disregulation of RAGE/EGFR pathway, linked to epithelial remodeling and mucus overproduction, hallmarks of chronic lung diseases.

互補機制提供卓越的功效和可接受的耐受性。兩種劑量均具有良好的耐受性，並在腎小球濾過率方面提供益處，支持我們進入 III 期臨床試驗。在右側，我們的 IL-33 抑制劑 tozorakimab 已被證明能夠抑制雙通路 ST2 和 RAGE/EGFR。這很重要，因為這些獨立的途徑涉及不同的發炎級聯反應。 ST2 通路失調會導致氣道發炎。 RAGE/EGFR 路徑失調與上皮重塑和黏液過度產生有關，這是慢性肺部疾病的標誌。

This September data was presented from the ACCORD-2 trial for patients hospitalized with COVID-19. Patients receiving tozorakimab had a substantially lower risk of respiratory failure or death at day 29 versus standard of care alone. These data build confidence in tozorakimab and its mechanism of action in inflammatory lung diseases. The recently dosed MIRANDA trial updates the range of doses being investigated across our COPD program, which includes the ongoing OBERON and TITANIA Phase III trials. We will have data from our Phase II FRONTIER-3 trial in asthma as well FRONTIER-4 in COPD, which we hope to present in due course.

今年 9 月，針對因 COVID-19 住院的患者進行的 ACCORD-2 試驗提供了數據。與僅接受標準護理的患者相比，接受 tozorakimab 治療的患者在第 29 天出現呼吸衰竭或死亡的風險顯著降低。這些數據增強了人們對 tozorakimab 及其治療發炎性肺部疾病的作用機制的信心。最近進行的 MIRANDA 試驗更新了我們 COPD 計劃中正在研究的劑量範圍，其中包括正在進行的 OBERON 和 TITANIA III 期試驗。我們將獲得治療氣喘的 II 期 FRONTIER-3 試驗以及治療慢性阻塞性肺病的 FRONTIER-4 試驗的數據，我們希望在適當的時候公佈這些數據。

Please advance to the next slide. As announced this morning, we have licensed an oral glucagon-like peptide 1 receptor agonist for the treatment of obesity, type 2 diabetes and other cardiovascular renal and metabolic diseases. ECC5004 is a once-daily oral small molecule, and preliminary results have shown a potentially differentiated clinical profile. Obesity is a significant and growing market with over 1 billion patients living with obesity today. The majority of these patients are suffering with comorbidities, such as type 2 diabetes, heart failure, hypertension and renal disease.

請前進到下一張幻燈片。正如今天早上宣布的那樣，我們已獲得口服胰高血糖素樣勝肽 1 受體激動劑的許可，用於治療肥胖、2 型糖尿病和其他心血管腎臟和代謝疾病。 ECC5004是一種每日一次的口服小分子，初步結果顯示出潛在的差異化臨床特徵。肥胖是一個重要且不斷成長的市場，目前有超過 10 億患者患有肥胖症。這些患者大多患有合併症，如第2型糖尿病、心臟衰竭、高血壓和腎臟疾病。

We are well placed to address the spectrum of disease associated with obesity with potential oral combinations in our existing and pipeline medicines. For example, we have recently seen data on our oral PCSK9 where the product profile is in line with our expectations and is differentiated with limited food interactions. We are excited about the opportunity for a monotherapy in dyslipidemia as well as in combination with ECC5004. We are building a robust portfolio of novel medicines to address a broad range of cardiovascular, renal and metabolic diseases.

我們完全有能力透過現有和正在研發的藥物中潛在的口服組合來解決與肥胖相關的一系列疾病。例如，我們最近看到了有關口服 PCSK9 的數據，其中產品概況符合我們的預期，並且與有限的食物交互作用有所區別。我們對血脂異常單一療法以及與 ECC5004 聯合療法的機會感到興奮。我們正在建立強大的新藥組合，以解決廣泛的心血管、腎臟和代謝疾病。

Please move to the next slide, and I will now hand over to Marc, who will cover our rare disease portfolio.

請移至下一張投影片，我現在將交給 Marc，他將負責我們的罕見疾病組合。

Thank you, Sharon. Can we go to next slide, please. Rare Disease delivered total revenue of $5.8 billion in the first 9 months of 2023, up 12% year-over-year, driven by increased patient demand and new launches globally. Ultomiris grew 49% in the third quarter, driven by patient demand, particularly patient naive to branded treatment in generalized d myasthenia gravis as well as successful conversion on Soliris across all indications. As a consequence of this conversion dynamic, Soliris declined 12%.

謝謝你，莎倫。我們可以轉到下一張投影片嗎？在患者需求增加和全球新產品上市的推動下，罕見疾病在 2023 年前 9 個月的總收入為 58 億美元，年增 12%。在患者需求的推動下，Ultomiris 在第三季度成長了 49%，尤其是那些未接受全身性重症肌無力品牌治療的患者，以及所有適應症在 Soliris 上成功轉換的患者。由於這種轉換動態，Soliris 下降了 12%。

Beyond C5, both Strensiq and Koselugo grew 21% and 81%, respectively, reflecting strong underlying patient demand. Looking at the regional breakdown in the middle, I want to highlight the performance of emerging markets, which grew 70% in the quarter. Global expansion is an important part of our strategy. And we continue to benefit significantly from the AstraZeneca footprint. We have now launched in 64 countries globally and are on track to delivering on our ambition to reach 100 countries by 2030.

除了 C5 之外，Strensiq 和 Koselugo 分別成長了 21% 和 81%，反映出患者潛在的強勁需求。從中間的區域細分來看，我想強調新興市場的表現，該市場在本季成長了 70%。全球擴張是我們策略的重要組成部分。我們繼續從阿斯特捷利康的足跡中獲益匪淺。目前，我們已在全球 64 個國家/地區開展業務，並預計將實現 2030 年覆蓋 100 個國家的宏偉目標。

Lastly, I wanted to provide some context regarding our C5 franchise across neurological diseases, myasthenia gravis as well NMOSD as well as on ultra-rare disease, atypical HUS and PNH. We continue to see neurology indication grow as launches continue globally. And in the case of the MG, the patient population is significantly larger than our ultra-rare disease. The pie chart on the right panel represent revenues in the U.S. whereas the 2 other panels show global sales.

最後，我想提供一些關於我們的 C5 專營權的背景信息，包括神經系統疾病、重症肌無力、NMOSD 以及超罕見疾病、非典型 HUS 和 PNH。隨著全球範圍內產品的不斷推出，我們繼續看到神經科適應症的增長。就重症肌無力而言，患者人數明顯多於我們極為罕見的疾病。右側面板上的圓餅圖代表美國的收入，而其他兩個面板則顯示全球銷售額。

Please advance to the next slide. Last week, we presented Phase II data at the American Society of Nephrology demonstrating the clinically meaningful efficacy of Ultomiris in IgA nephropathy. Ultomiris demonstrated rapid, complete and sustained complement inhibition, characterized by significant and potentially disease-modifying reduction in proteinuria. From week 4 as well as a stable mean globular filtration rate over 26 weeks.

請前進到下一張幻燈片。上週，我們在美國腎臟病學會公佈了 II 期數據，證明 Ultomiris 對 IgA 腎病具有臨床意義的療效。 Ultomiris 表現出快速、完全和持續的補體抑制，其特徵是蛋白尿顯著且可能緩解疾病。從第 4 週開始，平均球濾過率在 26 週內保持穩定。

IgA nephropathy is characterized by the deposition of immune complexes in the kidney that activate the complement system, which then triggers inflammation and causes glomerular damage. The most prevalent primary glomerular disease related to other rare disease in the renal area, IgA nephropathy is associated with substantial morbidity and mortality with approximately half of patients experiencing end-stage kidney disease or death. We see the opportunity for Ultomiris as an add-on on therapy to patient, optimize on standard of care, renin-angiotensin-aldosterone system inhibitors and SGLT2s.

IgA 腎病的特徵是免疫複合物在腎臟中沉積，激活補體系統，然後引發發炎並導致腎小球損傷。 IgA 腎病變是與腎臟區域其他罕見疾病相關的最常見的原發性腎小球疾病，與大量的發病率和死亡率相關，大約一半的患者會經歷末期腎病或死亡。我們看到了 Ultomiris 作為患者附加療法、優化護理標準、腎素-血管緊張素-醛固酮系統抑制劑和 SGLT2 的機會。

This data not only affirms the role of complement in IgA nephropathy, it provides confidence for Phase III, but also accelerates our ambition to expand Ultomiris into additional indication and broader patient population.

這些數據不僅肯定了補體在 IgA 腎病中的作用，為 III 期臨床試驗提供了信​​心，而且加速了我們將 Ultomiris 擴展到其他適應症和更廣泛患者群體的雄心。

With that, please advance to the next slide. And I will hand over the call back to Pascal for his closing remarks.

接下來，請前進到下一張投影片。我將把電話轉回給帕斯卡，讓他發表閉幕詞。

Thank you, Marc. Next Slide, please. I spoke at the half of this call -- at the start of this call about how we are building a pipeline for the future and are aimed to deliver sustainable industry-leading growth for the long term. Our recent acquisition and partnership with Eccogene is a good example of this, where we hope to deliver differentiated treatments for patients, not only addressing obesity but developing combinations with other small molecule for a broad range of cardiovascular, renal, metabolic diseases.

謝謝你，馬克。請下一張投影片。我在本次電話會議的一半時——在本次電話會議開始時談到了我們如何為未來建立管道，並旨在實現行業領先的長期可持續增長。我們最近與Eccogene 的收購和合作就是一個很好的例子，我們希望為患者提供差異化的治療，不僅解決肥胖問題，而且開發與其他小分子的組合，治療廣泛的心血管、腎臟、代謝疾病。

In the near term, we have a rich catalyst pass with more than 20 Phase III studies due to readout before the end of 2024. On this slide, I have called out just a few. This includes LAURA, which Dave spoke to earlier, DESTINY-Breast06, which has the potential to bring Enhertu one line earlier for the treatment of hormone receptor positive breast cancer, as well as answer the question about how low HER2 expression can [be for patient] still to the have meaningful benefit from this important medicine.

短期內，我們有豐富的催化劑通過，有 20 多項第三階段研究，將於 2024 年底之前公佈。在這張投影片上，我隻列出了其中的一些。這包括 Dave 之前採訪過的 LAURA，以及 DESTINY-Breast06，該公司有可能將 Enhertu 提前推出一種治療激素受體陽性乳腺癌的產品線，並回答了關於 HER2 表達低到什麼程度的問題。 ] 仍然可以從這種重要的藥物中獲得有意義的益處。

We should also see the first Phase III results of anselamimab in light chain amyloidosis a WAYPOINT trial investigating test fire for the treatment of chronic rhinosinusitis with nasal polyps. Dato-DXd will be an important medicine in our portfolio, and we are investing heavily behind this medicine. TROPION-Breast02 will be the next Phase III study for Dato in TNBC. This is thought to be highly responsible to TROP2 directed therapies.

我們還應該看到安塞拉單抗治療輕鏈澱粉樣變性的第一個 III 期結果，這是一項 WAYPOINT 試驗，該試驗調查了治療鼻息肉慢性鼻竇炎的試驗。 Dato-DXd 將成為我們投資組合中的重要藥物，我們正在大力投資該藥物。 TROPION-Breast02 將是 Dato 在 TNBC 的下一個 III 期研究。這被認為與 TROP2 定向療法密切相關。

Before concluding, I would like to Welcome, Sharon, to this call. See how happy I have -- I am to have Sharon on board in our senior executive team, and I also want to thank Mene for his contributions over many, many years.

在結束之前，我想歡迎莎倫參加這次電話會議。看看我有多高興——我想讓沙龍加入我們的高級管理團隊，我還要感謝梅內多年來的貢獻。

And with that, I will hand back to Andy, and we'll move to the Q&A.

接下來，我將把問題交還給安迪，然後我們將進入問答環節。

Thank you, Pascal. We will now go to the Q&A with all of our executive participants shown here. (Operator Instructions) And with that, we'll move to the Q&A and the first question.

謝謝你，帕斯卡。我們現在將與此處顯示的所有高階主管參與者進行問答。 （操作員說明）接下來，我們將進入問答和第一個問題。

Okay. Thanks, Andy. The first question is from Steve Scala at Cowen.

好的。謝謝，安迪。第一個問題來自 Cowen 的 Steve Scala。

Two questions. To the extent that the oral GLP-1 will be developed as a monotherapy for obesity, should that suggest to us that AstraZeneca believes obesity is a therapeutic opportunity that is here to stay, and we are in the early innings despite access and other challenges that it may present? And secondly, apologies if I missed it, but longer-term financial targets, both total revenue growth and margin guidance, is that still intact?

兩個問題。在某種程度上，口服GLP-1 將被開發為肥胖症的單一療法，這是否表明阿斯特捷利康認為肥胖症是一種治療機會，並且將繼續存在，儘管存在准入和其他挑戰，但我們仍處於早期階段。它可能會呈現？其次，如果我錯過了，我深表歉意，但長期財務目標，包括總收入成長和利潤指引，是否仍然完好無損？

Thanks, Steve. So maybe Ruud could take the first question. And Sharon, if you want to add anything, step in. And then the next one will be favorite question.

謝謝，史蒂夫。所以也許路德可以回答第一個問題。莎倫，如果你想添加任何內容，請介入。然後下一個將是最喜歡的問題。

Yes, of course. And thank you so much, Steve, for the question. Yes, it's obvious that we believe that obesity is here to stay. I think in the prepared remarks of Sharon, she was alluding to the very substantial number of 1 billion people around the world suffering from overweight. More importantly, we truly believe that there's a unique opportunity, not only to help patients lose weight but also to help the cardiometabolic disorders associated with overweight. And I think we are in a unique position based on our broad portfolio of products. Of course, a lot of focus on Farxiga, but many other products in our portfolio, which makes it relatively easy to combine this -- in-licensing of the GLP-1 with other products like an oral PCSK9. We are very pleased to see first results coming out of our R&D pipeline and hopefully, in the near future, you will see those results. So it makes it very attractive for combination products as well.

是的當然。非常感謝史蒂夫提出這個問題。是的，很明顯，我們相信肥胖將繼續存在。我認為莎倫在準備好的發言中提到了全世界有 10 億人患有超重問題。更重要的是，我們堅信這是一個獨特的機會，不僅可以幫助患者減肥，還可以幫助治療與超重相關的心臟代謝紊亂。我認為，基於我們廣泛的產品組合，我們處於獨特的地位。當然，我們的重點是 Farxiga，但我們的產品組合中還有許多其他產品，這使得將 GLP-1 的許可與口服 PCSK9 等其他產品相結合相對容易。我們很高興看到我們的研發管道取得了第一批成果，希望在不久的將來，您會看到這些成果。因此，它對於組合產品也非常有吸引力。

Steve, on your second question, I think the long-term investment thesis remains very much intact. So we've talked about the growth ambition that we have sort of in that '21 to '25 time frame and you've seen us deliver on a double-digit CAGR. So that remains intact. And then post 2025 -- 2025 to 2030, we've said we would be we would have industry-leading top line growth. And what you today in the pipeline, whether it's the proprietary ADCs or the bispecifics or some of the new readouts on studies. I think all of that points to our confidence in that growth rate in the 2025 to '30 time frame.

史蒂夫，關於你的第二個問題，我認為長期投資論點仍然完好無損。因此，我們已經討論了我們在 21 至 25 年時間範圍內的成長雄心，您已經看到我們實現了兩位數的複合年增長率。所以這仍然完好無損。然後在 2025 年之後——2025 年到 2030 年，我們說過我們將實現業界領先的營收成長。以及您今天正在開發的產品，無論是專有的 ADC、雙特異性抗體或一些新的研究讀數。我認為所有這些都表明我們對 2025 年至 30 年間的成長率充滿信心。

As it relates to operating margins, that continues to be a focus for the company. And again, we have not given guidance on that. That is our ambition, and we continue to improve on our operating margins as we continue to invest in new product launches and new Phase III studies.

由於它與營業利潤率有關，因此這仍然是公司關注的焦點。再說一遍，我們沒有就此提供指導。這是我們的雄心，隨著我們繼續投資於新產品的推出和新的第三階段研究，我們將繼續提高我們的營業利潤。

Thank you, Aradhana. The next question is Gonzalo Artiach at ABG.

謝謝你，阿拉達納。下一個問題是 ABG 的 Gonzalo Artiach。

Gonzalo Artiach from ABG Sundal Collier. The first one is regarding the new drug candidate for diabetes and obesity license from Eccogene. This licensing has been announced with quite exciting today. So could you give us some color on what are the key points on the drug candidate that you consider more interesting to potentially position the small molecule as best-in-class, specifically given the fact that you have already an amylin analog in development?

來自 ABG Sundal Collier 的貢薩洛·阿蒂亞赫 (Gonzalo Artiach)。第一個是關於 Eccogene 獲得的治療糖尿病和肥胖症的新候選藥物許可。今天宣布這項許可非常令人興奮。那麼，您能否向我們介紹一下您認為候選藥物的哪些關鍵點更有趣，有可能將小分子定位為同類最佳藥物，特別是考慮到您已經在開發胰島澱粉樣多肽類似物？

And my second on is on the results from on the EMERALD-1 study. I don't know if you could give us some color here on the plans going forward with this indication. Are you planning to file on PFS results? Or will you wait for OS? And also if I'm not wrong, the study had a third arm of Imfinzi combined with TACE only without bevacizumab, which is not reported in the press release today. So I don't know if you could comment on that, too.

我的第二個問題是 EMERALD-1 研究的結果。我不知道您是否可以給我們一些關於此指示的後續計劃的資訊。您打算提交 PFS 結果嗎？或者你會等待作業系統嗎？另外，如果我沒記錯的話，該研究的第三個組是 Imfinzi 聯合 TACE，僅聯合使用貝伐珠單抗，這一點在今天的新聞稿中沒有報導。所以我不知道你是否也可以對此發表評論。

So maybe, Sharon, you could take the first one and Susan, the EMERALD question.

莎倫，也許你可以回答第一個問題，蘇珊則回答翡翠問題。

Sure, I'd love to, and thank you for the question. I think you heard the excitement in my voice as we talked the in-licensing of ECC5004, which we think is a best-in-class orally bioavailability -- orally bioavailable GLP-1 receptor agonist. And we are excited about what we view as a differentiated clinical profile for this molecule. It demonstrates greater tolerability than other molecules in the class with a lower reported rate of GI adverse events. We also believe that it has a simplified CMC path with a relative lower COGS relative to the competitors. And we have seen efficacy on par with competitors in this class, which we think will allow us to deliver an ideal target product profile to patients.

當然，我很樂意，謝謝你的提問。當我們談論 ECC5004 的許可時，我想您聽到了我聲音中的興奮，我們認為 ECC5004 是同類最佳的口服生物利用度——口服生物可利用的 GLP-1 受體激動劑。我們對這種分子的差異化臨床特徵感到興奮。它表現出比同類其他分子更高的耐受性，並且報告的胃腸道不良事件發生率較低。我們還認為，與競爭對手相比，它具有簡化的 CMC 路徑和相對較低的 COGS。我們已經看到了與同類競爭對手相當的功效，我們認為這將使我們能夠為患者提供理想的目標產品概況。

Amylin -- do you want to...

胰淀素——你想...

Sure. So as you mentioned, also in our portfolio, we have a long-acting amylin as well as a GLP-1 glucagon dual agonist. So we are targeting both incretin and non-incretin pathways as we identify a robust cardiometabolic profile that we think will serve the complexity of disease.

當然。正如您所提到的，在我們的產品組合中，我們還有長效胰島澱粉樣多肽和 GLP-1 胰高血糖素雙重激動劑。因此，我們的目標是腸促胰島素和非腸促胰島素途徑，因為我們確定了強大的心臟代謝特徵，我們認為這將服務於疾病的複雜性。

Thank you. Susan?

謝謝。蘇珊？

Yes, sure. So EMERALD-1, as you say, a 3-arm study the 600 patients that were randomized to TACE alone plus placebo, TACE plus Imfinzi and then TACE plus Imfinzi plus bevacizumab. So it's a local regional hepatocellular carcinoma, and it's exciting that this is the first positive Phase III study in this setting. I would say to your question about Imfinzi plus TACE, of course, it's important for us to show the potential for contribution of components.

是的，當然。 EMERALD-1，正如你所說，是一項 3 臂研究，有 600 名患者被隨機分配到單獨 TACE 加安慰劑、TACE 加 Imfinzi、然後 TACE 加 Imfinzi 加貝伐珠單抗。這是一種局部區域性肝細胞癌，令人興奮的是，這是該領域第一個積極的 III 期研究。對於您關於 Imfinzi 加 TACE 的問題，我想說，當然，展示元件貢獻的潛力對我們來說很重要。

And in terms of your question on filing on PFS. So we're excited that what we've got is a clinically meaningful improvement in progression-free survival. But given this is a local regional setting, it's always important to have data on overall survival. So as is typical, what we will do is we'll discuss with regulatory authorities. It may well be possible to file on PFS and then wait for OS to be supplemented during the follow-up period and during the review period.

至於你關於 PFS 備案的問題。因此，我們很高興我們在無進展生存方面取得了具有臨床意義的改善。但鑑於這是當地的區域環境，擁有整體存活率的數據始終很重要。因此，按照慣例，我們將與監管機構進行討論。很有可能先在PFS上備案，然後等待後續期間和審核期間OS補充。

The next question is from Andrew Baum at Citi.

下一個問題來自花旗銀行的安德魯·鮑姆。

A couple of questions. First to Sharon. Could you quantify and characterize any liver enzyme elevations you saw in the Phase I with ECC5004?

有幾個問題。首先是莎朗。您能否量化和表徵您在 I 期使用 ECC5004 時看到的任何肝臟酵素升高？

And the second for Ruud, with the removal of the AMP cap from Medicaid in 2024. Could you quantify for us the net impact on your revenues associated once you've taken that mitigate defensive measures?

第二個是 Ruud，2024 年取消了醫療補助的 AMP 上限。您能否為我們量化一下，一旦您採取緩解防禦措施，對您的收入產生的淨影響？

Sure. So I'll jump in with the answer regarding liver toxicity and ECC5004. In preclinical studies, we saw no evidence of liver toxicity. And in the clinical Phase I study to date, we have seen no evidence of elevated ALT or AST, which we think is an additional feature that helps us differentiate this molecule from other competitors in the class.

當然。因此，我將立即回答有關肝毒性和 ECC5004 的問題。在臨床前研究中，我們沒有發現肝毒性的證據。在迄今為止的臨床 I 期研究中，我們沒有看到 ALT 或 AST 升高的證據，我們認為這是一個額外的特徵，可以幫助我們將該分子與同類其他競爭對手區分開來。

So I'll take the second one, Pascal, here. So regarding your question, Andrew, about the impact of AMP cap, you have seen in the presentation of Pascal that we are very pleased with the very strong U.S. growth, and that's primarily driven by volume growth, including for Farxiga. Yes, we are expecting an impact of AMP cap in 2024, but we have very specific brand strategies in place. Overall, we think the impact is manageable. And it will be factored in the guidance we're going to give for 2024.

所以我將選擇第二個，帕斯卡，在這裡。因此，安德魯，關於 AMP 上限影響的問題，您在 Pascal 的演示中看到，我們對美國的強勁增長感到非常滿意，這主要是由銷量增長推動的，包括 Farxiga 的銷量增長。是的，我們預期 AMP 上限會在 2024 年產生影響，但我們制定了非常具體的品牌策略。整體而言，我們認為影響是可控的。我們將在 2024 年提供的指導中考慮這一因素。

Thank you, Ruud. Next question is from Sachin Jain, Bank of America.

謝謝你，路德。下一個問題來自美國銀行 Sachin Jain。

I have a couple for Ruud -- sorry for Dave and then one for Aradhana. So Dave, capivasertib launch due from the end of the year as that you talked about much. I wonder if you could just comment to your optimism for the assets and size of the initial indication. Secondly, on Enhertu, I wonder if you just flesh out the comments on the slowdown in the U.S. on the DB04 bolus and implications for growth of the asset in '24?

我為 Ruud 準備了幾張，為 Dave 表示抱歉，然後為 Aradhana 準備了一張。 Dave，capivasertib 將於今年年底推出，正如您所談到的。我想知道您是否可以評論一下您對最初跡象的資產和規模的樂觀態度。其次，關於 Enhertu，我想知道您是否只是充實了 DB04 增補中對美國經濟放緩的評論以及對 24 年資產增長的影​​響？

And then just 1 for Aradhana, I know you're not going to like the question, but any early thoughts for '24 growth outlook. Consensus has '24 EPS faster than '23. I'm not asking for guide but just pushes and pulls in the ability to accelerate growth in '24 relative to '23.

然後，對於 Aradhana，只有 1，我知道您不會喜歡這個問題，但是對於 24 世紀增長前景的任何早期想法。共識是「24 EPS」比「23」快。我並不是尋求指導，而是只是推動和拉動 24 年相對於 23 年加速成長的能力。

Dave?

戴夫？

Great. Sachin, I'm going to take the questions that you asked me just in reverse order. So if I start first with Enhertu. When we take a look at both DB03 and DB04, we are seeing continued opportunity for growth across the globe on both of those. On DB04 specifically, we had seen increase or a bolus effect at launch where patients in multiple lines of therapy. So multiple lines of post chemo, coming on to Enhertu just really due to a lack of options for patients in these later-line advanced stages.

偉大的。薩欽，我將以相反的順序回答你問我的問題。所以，如果我先從 Enhertu 開始。當我們審視 DB03 和 DB04 時，我們發現這兩者在全球都有持續成長的機會。特別是對於 DB04，我們在啟動時發現接受多線治療的患者出現增加或推注效應。因此，在 Enhertu 進行多線化療後，實際上是因為處於後期晚期階段的患者缺乏選擇。

What I'm pleased to say, and I think this is actually a really important aspect of Enhertu, the duration of therapy that those patients were able to stay on Enhertu is actually longer than we had even thought. So the bolus actually has been around, if you will, as part of the TRXs for a longer period of time than we had originally anticipated it might be. We continue to see nice growth in now the incident share.

我很高興地說，我認為這實際上是 Enhertu 的一個非常重要的方面，這些患者能夠接受 Enhertu 治療的持續時間實際上比我們想像的要長。因此，如果你願意的話，推注實際上作為 TRX 的一部分存在的時間比我們最初預期的要長。我們現在繼續看到事件份額的良好增長。

So I think the DB04 continues to grow, and we'll be moving based upon growth in 2 factors. One will be incident new patient share growth, but then also DOT which I expect will continue to grow. That DOT comment, if I could, just for a second, I think also holds for DB03, where you may recall that in 03, we had 18 months of duration of therapy within the study itself. But we know that more than 1/3 of patients were staying on therapy for greater than 24 months. So we're continuing to see the 03 DOTs extend, and I think that that's a positive piece within that.

因此，我認為 DB04 會繼續成長，我們將根據兩個因素的成長來採取行動。其中之一是新患者份額的成長，但我預計 DOT 也會繼續成長。如果可以的話，請稍等一下，DOT 的評論也適用於 DB03，您可能還記得，在 03 年，我們在研究本身中進行了 18 個月的治療持續時間。但我們知道超過 1/3 的患者接受治療的時間超過 24 個月。因此，我們將繼續看到 03 DOT 的擴展，我認為這是其中的積極因素。

As we take a look at CPI, I share enthusiasm that capivasertib could be a very important part of our breast cancer portfolio. And then perhaps Susan can talk a little bit about some of the thoughts around the CDP that goes beyond that. I do think that it's most likely that we will see biomarker labels across the globe, though we do be that the benefit in the ITT population was an important one there's a pretty significant number of people with breast cancer who can continue to benefit from endocrine-based therapies in that advanced setting. And biomarker is still 40% to 50% of that marketplace. So it's a sizable opportunity. And we are looking forward, hopefully, any day now to an FDA announcement and approval.

當我們審視 CPI 時，我同樣熱衷於 capivasertib 可能成為我們乳癌產品組合中非常重要的一部分。然後也許蘇珊可以談談關於 CDP 的一些超出此範圍的想法。我確實認為我們很可能會在全球範圍內看到生物標記標籤，儘管我們確實認為 ITT 人群的獲益是一個重要因素，有相當多的乳腺癌患者可以繼續從內分泌中受益——在這種在先進的環境中建立基礎療法。生物標記物仍佔該市場的 40% 至 50%。所以這是一個相當大的機會。我們希望隨時期待 FDA 的公告和批准。

Before we move to -- thank, Dave. Before we move to 2024, maybe Susan, you could comment on other indications that we are considering for capi?

在我們開始之前——謝謝戴夫。在我們進入 2024 年之前，也許 Susan，您可以評論一下我們正在考慮使用 capi 的其他跡象嗎？

Yes. Sure. So I do think this is an opportunity in a number of settings where the AKT pathway is important in limiting benefit, either in combination with endocrine therapy in both breast and prostate cancer but also in combination with chemotherapy as well. As well as the 291 study, we have CAPItello-290 in triple-negative breast cancer. CAPItello-292 is in combination with palbociclib and other CDK4/6 inhibitor potential in -- as well as hormonal therapy backbone in the first line. So it's got Faslodex as the hormone therapy backbone in the first line in the CAPItello-292.

是的。當然。因此，我確實認為，在許多情況下，這是一個機會，AKT 路徑在限制益處方面非常重要，無論是與乳癌和攝護腺癌的內分泌治療相結合，還是與化療相結合。除了 291 研究之外，我們還有用於治療三陰性乳癌的 CAPtello-290。 CAPtello-292 與 palbociclib 和其他具有潛力的 CDK4/6 抑制劑以及第一線荷爾蒙治療骨幹藥物合併使用。因此，在 CAPtello-292 的第一行中，Faslodex 作為荷爾蒙治療的支柱。

And then in prostate cancer, we have CAPItello-281 where capivasertib is combined with abiraterone. And again, that's focused in P10 deficient hormone sensitive prostate cancer based on the Phase II study there. But we also have a combination with docetaxel. And again, the AKT pathway limits the response to chemotherapy and limits the apoptotic response to chemotherapy. So that's also an important study. And based on the [ProCADE] data set, there's activity again across the spectrum of patients, both with and without P10 deficiency in that setting.

然後在前列腺癌方面，我們有 CAPtello-281，其中 capivasertib 與阿比特龍聯合使用。再次強調，根據 II 期研究，研究的重點是 P10 缺乏荷爾蒙敏感的前列腺癌。但我們也有與多西紫杉醇的組合。同樣，AKT 途徑限制了對化療的反應，並限制了對化療的細胞凋亡反應。所以這也是一項重要的研究。根據 [ProCADE] 資料集，各種患者再次出現活動，無論是否患有 P10 缺乏症。

Aradhana?

阿拉達納？

So thanks for the question. Obviously, we won't give guidance for 2024 on this call. We'll have to wait for early next year for that. We're actually going through our budget process right now. And as that concludes towards year-end, and we present that to the Board and then we'll give our guidance next year. Some of the things that, obviously, you need to take into account some of the pushes and pulls in the 2024 and midterm, including currency movements. As you know, we've had very strong growth momentum with our underlying brands, but then we also have launches Airsupra and eplontersen that Ruud mentioned that we'll be investing behind. And then the Phase III opportunities as well as some of these new BD opportunities, including the current product that we talked on Eccogene. So lots of moving parts, and we look forward to talking to you about that in early '24.

謝謝你的提問。顯然，我們不會在這次電話會議上給予 2024 年的指導。我們必須等到明年初。我們現在實際上正在經歷預算流程。當年底結束時，我們將其提交給董事會，然後我們將在明年提供指導。顯然，你需要考慮 2024 年和中期的一些推動和拉動，包括貨幣走勢。如您所知，我們的基礎品牌擁有非常強勁的成長勢頭，但我們也推出了 Airsupra 和 eplontersen，Ruud 提到我們將對其進行投資。然後是第三階段的機會以及一些新的 BD 機會，包括我們在 Eccogene 上討論的當前產品。有很多變化的部分，我們期待在 24 年初與您討論這個問題。

Maybe some quick addition to 2024. Actually, going back to the question, Andrew asked about AMP cap. Since the announcement of this new regulation, we've really come up with very modest price increases always below inflation. So of course, the calculation goes back many years, but we still believe that we will have an impact that is substantially lower than many other companies. And as Ruud said, it can be suddenly managed in the overall forecasting budget, forecasting for the company.

也許是對 2024 年的一些快速補充。實際上，回到問題，Andrew 詢問了 AMP 上限。自從宣布這項新規定以來，我們確實提出了非常溫和的價格上漲，始終低於通貨膨脹率。當然，計算可以追溯到很多年前，但我們仍然相信我們的影響力將大大低於許多其他公司。正如路德所說，它可以突然在整體預測預算中進行管理，為公司進行預測。

So the next question is Tim Anderson at Wolfe.

所以下一個問題是沃爾夫的提姆·安德森。

A couple of questions. On Tagrisso FLAURA2, in the New England Journal last night, editorial fairly positive based on PFS benefit. It really said it kind of comes down to how survival plays out. So the question for you is your view on whether it hits on survival in a clinically meaningful way?

有幾個問題。昨晚《新英格蘭雜誌》關於 Tagrisso FLAURA2 的社論基於 PFS 益處相當積極。它確實說這取決於生存的結果。因此，您面臨的問題是您對它是否以具有臨床意義的方式影響生存有何看法？

And then the second question is on obesity. Just further business development from here? It seems like if you're going to push into the space with external assets like today's announcement. Maybe you go all in and do more external deals. There are other assets out there. Do you take a much broader portfolio approach -- or conversely, -- is this kind of one and done, this is going to be your main asset from the outside world?

第二個問題是關於肥胖。只是從這裡進一步發展業務嗎？看起來你是否打算利用像今天宣布的那樣的外部資產進入這個領域。也許你會全力以赴並進行更多的外部交易。還有其他資產。你是否採取了更廣泛的投資組合方法——或者相反，——這種方法已經完成了嗎？這將成為你來自外部世界的主要資產嗎？

Thanks, Tim. So the first question, maybe we could start with Susan. And then, Dave, I think you could also comment on the commercial relevance of FLAURA2, which we believe is important for many patients. And then Second question, Sharon, you could take. And anything you want to add? Or would also please jump in.

謝謝，蒂姆。所以第一個問題，也許我們可以從蘇珊開始。然後，戴夫，我想你也可以評論一下 FLAURA2 的商業相關性，我們認為這對許多患者來說很重要。第二個問題，莎倫，你可以回答。還有什麼想補充的嗎？或者也請跳進去。

Progression-fee survival benefit that we've seen is very clinically meaningful with FLAURA2. Of course, the comparator is something that's already proven overall survival benefit in the first-line setting of lung cancer, which is monotherapy Tagrisso. So I think what we're hoping to see is maintenance of the improvement in PFS being carried through to the PFS 2 and a trend in OS. I think is very reasonable to expect. But obviously, as the data mature, we'll continue to look at the OS endpoint.

我們所看到的 FLAURA2 的進展費生存獲益非常具有臨床意義。當然，比較藥物是在肺癌一線治療中已被證明具有整體生存益處的藥物，即單藥治療 Tagrisso。因此，我認為我們希望看到的是 PFS 2 中 PFS 的改進得以維持，並且作業系統也呈現出趨勢。我認為這是一個非常合理的預期。但顯然，隨著資料的成熟，我們將繼續關注作業系統端點。

And -- thanks, Susan. And Tim, I think maybe just to build off of this. I think there's also an important tangential question just in general around the importance of overall survival as there's consideration for choices. And I think that you referenced the editorial, I think you hear this in the editorial, but also we hear this from the community as well that in selecting a treatment the benefit risk profile inclusive, of course, of efficacy, the side effect profile -- as well as the administration are all important factors that will come into this.

還有──謝謝，蘇珊。提姆，我想也許只是以此為基礎。我認為整體上還有一個重要的切線問題，就是整體生存的重要性，因為需要考慮選擇。我認為您引用了這篇社論，我想您在社論中聽到了這一點，而且我們也從社區中聽到了這一點，即在選擇治療方法時，受益風險概況當然包括功效和副作用概況 - - 以及政府都是影響這一切的重要因素。

So within that context, FLAURA2 is certainly something that we have heard very much as an option for those patients who would benefit from intensification, brain mets, L858R. And on top of that clinician are pretty well versed in the side effects that are associated with chemo and there's the ability to discontinue the chemo on FLAURA2, if approved, and continue on with the monotherapy.

因此，在這種背景下，FLAURA2 肯定是我們經常聽到的，對於那些將從強化、腦轉移、L858R 中受益的患者來說，FLAURA2 是一種選擇。除此之外，臨床醫生非常熟悉與化療相關的副作用，如果獲得批准，可以停止 FLAURA2 的化療，並繼續單一療法。

But we hear and know that the monotherapy is an option that we anticipate will continue to be a really important option for the majority of patients, all oral greater than 3 years, overall survival demonstrated proven and understood and a tolerability profile that's well managed.

但我們聽說並知道單一療法是一種選擇，我們預計將繼續成為大多數患者的真正重要選擇，所有口服療法均超過3 年，總生存期已得到證實和理解，並且耐受性狀況得到良好管理。

Thanks very much, Dave. Sharon?

非常感謝，戴夫。莎倫？

Sure. And thank you for the question about continuing to build our portfolio. I hope this morning, I'm conveying a story that we continue to build a strong cardiovascular, renal and metabolic portfolio with multiple medicine to treat obesity, type 2 diabetes, dyslipidemia, hypertension, chronic kidney disease and heart failure. So where we see opportunities to further strengthen that portfolio, we will move forward with a sense of urgency. We never comment on business development deals that are in progress or our future opportunities that we continue to scan the landscape and understand what might fit best into this growing portfolio.

當然。感謝您提出有關繼續建立我們的產品組合的問題。我希望今天早上我要傳達的故事是，我們繼續利用多種藥物建立強大的心血管、腎臟和代謝產品組合，以治療肥胖、2 型糖尿病、血脂異常、高血壓、慢性腎臟病和心臟衰竭。因此，當我們看到進一步加強該投資組合的機會時，我們將帶著緊迫感繼續前進。我們從不評論正在進行的業務發展交易或我們未來的機會，我們會繼續審視形勢並了解什麼最適合這個不斷增長的投資組合。

Thanks, Sharon. And maybe let me add that biopharma cardiovascular in particular remains very important to this company. And for the legal internal friendly competition, we have Ruud beat Dave by $100 million in the first 9 months of the year. So a very important part of the company. Anything you want to add on that?

謝謝，莎倫。也許讓我補充一點，生物製藥心血管疾病對這家公司仍然非常重要。而在合法的內部友好競爭中，我們在今年前 9 個月就以 1 億美元的價格擊敗了戴夫。所以是公司非常重要的一環。您還想補充什麼嗎？

No, no. Just to reinforce that, of course, we are excited about our internal pipeline also in obesity with the long-acting amylin. The GLP-1 glucagon dual agonist. But as Sharon said, we are always looking around for something that can add value, is making strategically sense. But all in all, I think we're very pleased with the progress we are making in our pipeline.

不，不。當然，為了強調這一點，我們對長效胰淀素在肥胖症中的內部管道感到興奮。 GLP-1 胰高血糖素雙重激動劑。但正如莎倫所說，我們一直在尋找能夠增加價值、具有戰略意義的東西。但總而言之，我認為我們對管道中取得的進展感到非常滿意。

Next question is Emily Field at Barclays.

下一個問題是巴克萊銀行的艾米麗·菲爾德。

I wanted to ask about volrustomig. Actually, I saw you started the Phase III in cervical in lung, and you also had renal data at ESMO. Just -- how broad of a Phase III program are you tending on running? How many tumor types?

我想問一下 volrustomig 的事。事實上，我看到你開始了頸肺的III期臨床研究，而且你在ESMO也有腎臟數據。只是—您打算運行的第三階段專案的範圍有多大？腫瘤有多少種類型？

Secondly, when could we see the combination arm from the TL04 study that combines volrustomig with Dato-DXd? And then my last one, just how much broader in terms of addressable patients would LAURA add to the Tagrisso patient pool?

其次，我們什麼時候可以看到 TL04 研究中將 volrustomig 與 Dato-DXd 結合的組合臂？然後是我的最後一個問題，LAURA 會在 Tagrisso 患者庫中添加多少可尋址患者？

Thank you, Emily. Susan, could you cover the first 2 volrustomig questions? And Dave, you can address the LAURA question.

謝謝你，艾米麗。蘇珊，你可以回答一下前兩個 volrustomig 問題嗎？戴夫，你可以回答勞拉的問題。

Yes. Again, I would say that we see the positioning of both volrustomig and rilvegostomig as being appropriate in different segments of the patient population that are currently treated with checkpoint inhibitors. So I think volrustomig has a place where CTLA-4 inhibition particularly adds value, and those are the areas that we will concentrate on. I also think that the emerging data from rilvegostomig, which will probably share a congress next year. And again, we -- please note that we have actually started our first Phase III trial with rilvegostomig building on the great data we saw with TOPAZ in the biliary tract setting. .

是的。我想說，我們認為 volrustomig 和 rilvegostomig 的定位適合目前接受檢查點抑制劑治療的不同患者群體。因此，我認為 volrustomig 在 CTLA-4 抑制方面具有特別增加的價值，而這些正是我們將重點關注的領域。我還認為來自 rilvegostomig 的新數據可能會在明年召開一次大會。再次強調，請注意，我們實際上已經開始了第一個 rilvegostomig 的 III 期試驗，該試驗建立在我們在 TOPAZ 在膽道環境中看到的大量數據的基礎上。 。

So I think there's great potential for this. We will -- we are examining both rilvo and volrustomig combinations with our ADCs in different tumor types. And we will, again, probably share updates on those in the next 12 to 24 months.

所以我認為這有很大的潛力。我們正在研究 rilvo 和 volrustomig 與我們的 ADC 在不同腫瘤類型中的組合。我們可能會在未來 12 到 24 個月內再次分享相關更新。

On LAURA, Emily, just in terms of the opportunity here, let me start with the headline, which is I think this is a sizable opportunity and an important chance for us to, if positive and approved, be able to kind of meaningfully catalyze the growth in the area. We know from the PACIFIC work that we've done that there is a significant number of patients that are diagnosed that are Stage III unresectable. We also know that many of these patients are not getting for very understandable reasons treatment with -- who are EGFR mutated with IO. And so there's a very good opportunity that's there. And I think that this will be probably the most significant Tagrisso growth driver that I would see as incremental coming into the near term, and we look forward to next year's readout.

關於勞拉，艾米麗，就這裡的機會而言，讓我從標題開始，我認為這是一個相當大的機會，對我們來說是一個重要的機會，如果積極並得到批准，能夠有意義地促進該地區的成長。我們從 PACIFIC 所做的工作中得知，有大量被診斷為無法切除的 III 期患者。我們也知道，其中許多患者由於 EGFR 突變並伴隨 IO 突變而沒有接受治療，原因是可以理解的。所以這是一個非常好的機會。我認為這可能是最重要的泰瑞沙成長驅動力，我認為這是近期增量的成長動力，我們期待明年的數據。

Yes. Important growth driver across the world, very much, of course, in Japan, where this eGFR mutations are common. And I think in China also beyond the growth potential, also a very nice differentiation in a market, as you know, is very, very competitive -- the eGFR market is very competitive. So clearly, an important addition from a differentiation viewpoint and promotional opportunity for the Chinese team.

是的。這是全世界重要的成長動力，當然，在日本，這種 eGFR 突變很常見。我認為在中國，除了成長潛力之外，市場上也有一個非常好的差異化，如你所知，競爭非常非常激烈——eGFR 市場競爭非常激烈。顯然，從差異化的角度來看，這對中國隊來說是一個重要的補充和晉昇機會。

Next question is James Gordon, JPMorgan.

下一個問題是摩根大通的詹姆斯戈登。

First question was on the oral GLP-1. And the question was, do you think the products are going to be competitive on weight loss versus other orals that are well ahead in terms of development? Or is the differentiation it will be much more about the combinability with other oral agents? And if so, which of the combos is it that you're most excited about? That's the first question, please. .

第一個問題是關於口服 GLP-1。問題是，您認為這些產品在減肥方面與其他在開發方面遙遙領先的口服產品相比是否具有競爭力？或者它的差異化更在於與其他口服製劑的組合性？如果是這樣，您對哪一個組合最興奮？這是第一個問題，請。 。

Second question would be (inaudible) 3, I think you started on high dose (inaudible) Phase III, [MIRANDA] trial, -- So do you -- this new higher dose trial you're now seeing Phase II that says that the first 2 studies overall the (inaudible) lower doses are perhaps under dosed so it should be less problem and then I think we've got to wait for this third trial. And if I could just squeeze in the (inaudible), on that, I think you mentioned potential launch next year. So is the expectation that launch in both lung and breast cancer? So you file both of those in this year, then they could go to those in next year?

第二個問題是（聽不清楚）3，我認為您開始進行高劑量（聽不清楚）第三階段，[米蘭達]試驗，--您也是如此--您現在正在看到的第二階段試驗表明，前兩項研究總體而言（聽不清楚）較低劑量可能劑量不足，因此問題應該較少，然後我認為我們必須等待第三次試驗。如果我能插話一下（聽不清楚），我想你提到了明年可能推出的產品。那麼，對於肺癌和乳癌的治療是否有希望呢？所以你今年都提交了這些，然後他們可以去明年？

Thanks, James. I'm really so happy that delegated the task to Andy to ask -- before to ask only one question at a time. So maybe, Sharon, you could take the first one. And again, if you have anything you want to add? And then the second one, so actually, and then Susan will take Dato question.

謝謝，詹姆斯。我真的很高興將這項任務委託給安迪來提問——之前一次只問一個問題。所以莎倫，也許你可以選擇第一個。再說一遍，您還有什麼要補充的嗎？然後是第二個問題，實際上，然後蘇珊將回答拿督問題。

Yes. Thank you for the questions. So your first was do we believe that this ECC5004 is competitive in weight loss. And yes, we do, based on the Phase I data that lines up very favorably with competitors in this class, which was very encouraging data, that gave us confidence in our ability to drive forward this molecule and see a differentiated target product profile in the clinic.

是的。謝謝你的提問。所以你的第一個問題是我們是否相信這款ECC5004在減肥方面具有競爭力。是的，我們確實這麼做了，基於第一階段的數據，該數據與同類競爭對手非常有利，這是非常令人鼓舞的數據，這使我們對推動該分子的能力充滿信心，並在該領域看到了差異化的目標產品概況。診所。

You also asked about which of the combinations we are most excited about. And it's a little like asking me to choose a favorite child because we have such a broad portfolio that has the potential to combine with this molecule. That said, thinking about Farxiga and our ability to manage hypertension, driven by obesity is a very appealing combination. Thinking about our emerging oral PCSK9 with very encouraging data in Phase I, we see an opportunity to limit dyslipidemia while managing obesity in overweight patients.

您也詢問了我們對哪些組合最感興趣。這有點像是要求我選擇一個最喜歡的孩子，因為我們有如此廣泛的產品組合，有可能與這種分子結合。也就是說，考慮 Farxiga 和我們控制肥胖驅動的高血壓的能力是一個非常有吸引力的組合。考慮到我們新興的口服 PCSK9 在第一階段的數據非常令人鼓舞，我們看到了在控制超重患者肥胖的同時限制血脂異常的機會。

And also thinking about how we're managing diabetes and the associated comorbidities gives us opportunities to also consider other mechanisms for managing heart failure and renal disease in combination with ECC5004. So we will be testing this molecule both in preclinical and clinical studies moving forward and identifying the most favorable combinations for patients.

思考我們如何管理糖尿病和相關的合併症，讓我們有機會考慮與 ECC5004 相結合來管理心臟衰竭和腎臟疾病的其他機制。因此，我們將在臨床前和臨床研究中測試這種分子，並確定對患者最有利的組合。

So nothing to add. Are you also going to take the question about [Tozo] or do I need to comment on that? So James, a good question. Of course, as always, time will tell and the data will tell, which dose is the most effective one. But we truly believe that we have a drug which is effective. The 600 is now tested in the MIRANDA trial. Let me remind you that also the competition is testing different dosing regimens. And you see it also a little bit as an insurance premium. We think that the 300 will be effective. But of course, we try to push the effectiveness to the highest level. So hopefully, both doses will work. But time will tell when the data will readout.

所以沒什麼好補充的。您也要回答有關 [Tozo] 的問題，或者我需要對此發表評論嗎？詹姆斯，這是個好問題。當然，一如既往，時間會證明一切，數據會證明哪種劑量是最有效的。但我們堅信我們有一種有效的藥物。 600 現已在 MIRANDA 試驗中進行測試。讓我提醒您，比賽也在測試不同的劑量方案。你也可以將其視為保險費。我們認為300將會有效。但當然，我們努力將效率提升到最高水準。因此希望兩種劑量都能發揮作用。但時間會告訴我們數據何時會被讀出。

Maybe going back to the oral GLP-1 agents, the -- first of all, one of the 2 oral agents that maybe you have in mind is a twice a day agent, this one will be once a day. And as Sharon explained earlier, we believe that the tolerability profile would be good. But the important thing to keep in mind is obesity by itself is one thing, but I think the more sustainable part of that market is really obesity, patients with complicating factors, people who have cardiometabolic risk factors. And so in that scenario, really combinations are critical. I mean, if you look at kidney disease, the Farxiga results are really exciting. They are great, but patients still see their kidney function decline over time. .

也許回到口服 GLP-1 藥物，首先，您可能想到的 2 種口服藥物之一是每天兩次，這個是每天一次。正如莎倫之前解釋的那樣，我們相信耐受性會很好。但要記住的重要一點是，肥胖本身是一回事，但我認為該市場中更永續的部分實際上是肥胖、有複雜因素的患者、有心臟代謝危險因子的人。因此，在這種情況下，真正的組合至關重要。我的意思是，如果你關注腎臟疾病，Farxiga 的結果確實令人興奮。它們很棒，但患者的腎功能仍然會隨著時間的推移而下降。 。

So we talk a lot about combinations in cancer, but I also think that in many of those cardiovascular metabolic conditions, combination treatment will be the future. So a combination for kidney disease, combination for the control of hypertension, possibly a combination for -- well, actually a combination for the management of hyperlipidemia. So that's where we believe that our pipeline also can -- is best positioned and can play a role. So with that, maybe, Dave, do you want to -- or Susan, maybe cover the Dato question.

因此，我們談論了很多癌症聯合治療，但我也認為，在許多心血管代謝疾病中，聯合治療將是未來。因此，治療腎臟疾病的組合，控制高血壓的組合，可能是——嗯，實際上是控制高血脂症的組合。因此，我們相信我們的管道也可以在這一領域處於最佳位置並發揮作用。因此，也許戴夫（Dave），你想－－或者蘇珊（Susan），也許可以回答拿督的問題。

Sure. So in the United States, we didn't have to wait for bundling the 2 trials together. So we will file those 2 separately. In Europe, it's better to bundle the 2 applications together. But I think is a good opportunity for -- depending on the review time lines for the review to be completed during the course of next year.

當然。因此，在美國，我們不必等待將兩項試驗捆綁在一起。因此，我們將分別歸檔這兩個文件。在歐洲，最好將這兩個應用程式捆綁在一起。但我認為這是一個很好的機會——具體取決於明年期間完成的審查時間表。

So the next one is Mattias Häggblom at Handelsbanken.

下一位是德國商業銀行的馬蒂亞斯‧赫格布洛姆 (Mattias Häggblom)。

So firstly with regard to the oral GLP-1 (inaudible) Because I'm asking how long into '24 or perhaps even '25 depending on the duration of such trial without (inaudible) have to wait before we can jump to today's comments around the different change of profile.

首先，關於口服GLP-1（聽不清楚）因為我問「24 年甚至25 年」需要多長時間，具體取決於此類試驗的持續時間，而無需（聽不清楚）必須等待我們才能跳轉到今天的評論輪廓的不同變化。

And then secondly, (inaudible) China, where lung cancer patients and physicians were asked for their preference for monotherapy or combination therapy survey which showed a close to 80% preference for the monotherapy regimen despite the combination was set in the survey to prolonged time to recurrence. So I would be curious to hear if the company has and the (inaudible) surveys based on other geographies. Again, trying to think of the mono versus combination trials in these setting?

其次，（聽不清楚）中國，肺癌患者和醫生被問及對單一療法或聯合療法的偏好調查顯示，儘管調查中將聯合療法設定為延長治療時間，但接近 80% 的人偏好單一療法。復發。因此，我很想知道該公司是否進行了基於其他地區的（聽不清楚）調查。再次，嘗試考慮在這些環境中進行單一試驗與組合試驗？

Thanks, Mattias. You were breaking up a little bit. The first question, did you get fully Sharon? otherwise, maybe...

謝謝，馬蒂亞斯。你們分手了一點。第一個問題，你完全了解莎朗了嗎？不然的話，也許…

It sounds like it was around the time lines for the ECC5004 clinical studies. But maybe if you could repeat the question one more time?

聽起來好像是在 ECC5004 臨床研究的時間表附近。但也許你可以再重複這個問題嗎？

Can you repeat the question, the first one, actually, the second one was FLAURA2 China and 80% preference for monotherapy is it or also in other geographies. But the first one, if you could repeat?

你能重複這個問題嗎，第一個，實際上，第二個是FLAURA2中國，80%的人對單一療法的偏好是它還是在其他地區。但是第一個，你能重複嗎？

Sure. The question is along Phase II trials in obesity, it's reasonable to expect before -- the market could judge today's comments that you have a differentiated profile. We see Phase II trials in obesity short as 5 weeks up to 16 plus -- so I'm just trying to frame the expectations for when we can get data in obese patients, which we have yet to see.

當然。問題是，隨著肥胖的第二階段試驗，先前有合理的預期——市場可以判斷今天的評論，即你有一個與眾不同的形象。我們看到針對肥胖症的 II 期試驗時間短至 5 週，最長可達 16 週以上——所以我只是試圖建立我們何時可以獲得肥胖患者數據的預期，但我們還沒有看到這一點。

Okay. Thanks. So Dave, do you want to take the FLAURA2 questions?

好的。謝謝。 Dave，你想回答 FLAURA2 的問題嗎？

Yes, I'd be happy to. So -- I've spoken to the discussions that we've had with physicians, both in the academic but also now, especially within the community setting post -- both WCLC and ESMO. And I think that what you see in the editorial is very consistent with what we are hearing across the globe. And I think that just maybe if I put into context within this, I mean, at the U.S., you've got 70-plus percent of non-small cell lung cancer patients who are with advanced disease being treated in the community. And I think that within that community context, the benefit risk that I had spoken to before of efficacy, oral convenience, tolerability profile that's really well understood and considered to be one that's well able to be managed. This is something that really does result in the monotherapy being -- I think really kind of the first port of call, that first real opportunity to look at.

是的，我很樂意。所以 - 我已經談到了我們與醫生進行的討論，無論是在學術界還是現在，特別是在社區設置帖子中 - WCLC 和 ESMO。我認為您在社論中看到的內容與我們在全球範圍內聽到的內容非常一致。我認為，如果我結合上下文來看，我的意思是，在美國，70% 以上的晚期非小細胞肺癌患者正在社區接受治療。我認為，在社區背景下，我之前談到的功效、口服便利性、耐受性等益處風險確實得到了很好的理解，並且被認為是能夠很好管理的。這確實導致了單一療法的出現——我認為這確實是第一個停靠點，第一個真正的觀察機會。

We do also know, and I think that this is something that comes through as well in the commentary that there are patients who can benefit from a more intensified approach to it. And within that context, I think that the editorial and others comment on that within this context, we expect FLAURA2, if approved, to be an option for certain patients that is going to be put on the table, but it's going to be put on the table in the context of multiple criteria for making the decision, not just based upon a single efficacy end point.

我們也知道，我認為評論中也提到了這一點，即有些患者可以從更強化的治療方法中受益。在這種背景下，我認為社論和其他人評論說，在這種背景下，我們預計FLAURA2 如果獲得批准，將成為某些患者的一個選擇，並將被放在桌面上，但它將被放在該表在做出決定的多個標準的背景下，而不僅僅是基於單一功效終點。

Sharon?

莎倫？

Sure. So your question regarding time lines for clinical development for ECC5004, obviously, front of mind for all of us. Thank you for the question. So as I mentioned earlier, we are in Phase I now, and we expect to have Phase I data in hand by the end of this year. And so we'll be moving rapidly towards Phase II. We expect to initiate 2 Phase II studies, one in obesity and one in type-II diabetes by the end of 2024. You are correct that these studies can vary in length, but we really want to be able to generate the outcome data that we think will add value to this program. So we are planning for studies that will span in the neighborhood of 18 minutes within interim analysis that will give us an early look at the data and will give us some confidence in our differentiation strategy.

當然。因此，您關於 ECC5004 臨床開發時間表的問題顯然是我們所有人首先考慮的問題。感謝你的提問。正如我之前提到的，我們現在處於第一階段，預計到今年年底我們將掌握第一階段的數據。因此，我們將迅速邁向第二階段。我們預計到2024 年底啟動2 項II 期研究，一項針對肥胖症，一項針對II 型糖尿病。你說得對，這些研究的長度可能會有所不同，但我們確實希望能夠產生我們希望的結果數據。認為將為該計劃增加價值。因此，我們計劃在中期分析中進行約 18 分鐘的研究，這將使我們能夠及早了解數據，並使我們對我們的差異化策略有一定的信心。

Next one is Mark Purcell at Morgan Stanley.

下一位是摩根士丹利的馬克·珀塞爾。

Two questions. The first one is on your bispecific T-cell engagers (inaudible). You talked in the press release around the potential to replace first-generation checkpoint inhibitors. So how should we think about the magnitude of benefit you expect to see versus KEYTRUDA, for example, in the eVOLVE-Lung02 trial. So what level of (inaudible) are you seeking? And smart chemotherapy platform, your organic platform (inaudible) We should get some data, I guess, for assets such as the B7H4, maybe the EGFR [cMET] in 2024. So could you give an update in terms of when we should see these data? And when do you expect to potentially move into pivotal trials with these assets?

兩個問題。第一個是雙特異性 T 細胞接合器（聽不清楚）。您在新聞稿中談到了取代第一代檢查點抑制劑的潛力。那麼，我們應該如何考慮您期望看到的與 KEYTRUDA 相比的益處程度，例如在 eVOLVE-Lung02 試驗中。那您想要什麼程度（聽不清楚）？智慧化療平台，您的有機平台（聽不清楚）我想，我們應該獲得一些數據，例如B7H4 等資產，也許是2024 年的EGFR [cMET]。所以您能否提供有關我們何時應該看到這些的最新資訊數據？您預計什麼時候可以對這些資產進行關鍵試驗？

Thanks, Mark. So I think the first question was the bispecific immune checkpoint inhibitor volrustomig. Susan you could take this one. And the second one is also for you in terms of the B7H4.

謝謝，馬克。所以我認為第一個問題是雙特異性免疫檢查點抑制劑 volrustomig。蘇珊，你可以拿走這個。第二個也是為您準備的 B7H4。

So just to be clear, the bispecifics are -- bispecifics, PD-1 that you said T-cell engagers. We do have T-cell engagers in our portfolio, but I think we're talking about volrustomig and rilvegostomig. So volrustomig in terms of the eVOLVE-02 study, you can imagine the context of first-line non-small cell lung cancer. A clinically meaningful benefit, is something where you're looking for some months of improvement on median PFS and often an improvement of the hazard ratio with that tail. And of course, CTLA-4 inhibition is particularly potent producing that tail inhibition. So I can't tell you what the design criteria for the study, but you'll see the size of the study, and I'm sure you can work that out. .

需要明確的是，雙特異性抗體是雙特異性抗體，也就是您所說的 T 細胞接合劑 PD-1。我們的產品組合中確實有 T 細胞參與者，但我認為我們正在談論 volrustomig 和 rilvegostomig。因此，根據 eVOLVE-02 研究的 volrustomig，您可以想像一線非小細胞肺癌的背景。具有臨床意義的益處是指您希望中位 PFS 能有幾個月的改善，並且通常會改善尾部的風險比。當然，CTLA-4 抑制特別有效地產生尾部抑制。因此，我無法告訴您該研究的設計標準是什麼，但您會看到該研究的規模，並且我相信您可以解決這個問題。 。

So -- but we're confident based on the data that we've seen. We've got the potential to improve on it. In the patient population where checkpoint inhibitors don't currently work as well, which is clearly that lower end of the PD-L1 expression level.

所以——但根據我們所看到的數據，我們有信心。我們有潛力改進它。在檢查點抑制劑目前效果不佳的患者群體中，這顯然是 PD-L1 表達水平的較低端。

And then for B7H4 lead ADC. This is an important molecule for us because, first of all, it's the first molecule that's come out of our proprietary ADC discovery platforms. We've got a proprietary link and topo warhead on that. You saw some data presented for B7H4 targeted ADCs at ESMO. So I think this is going to be an important target. It's overexpressed in parts of ovarian cancer, endometrial cancer, breast cancer and some biliary tract cancer. We're exploring cohorts in multiple of those cancers, and we look forward to sharing data next year on this. But we're excited by what we've seen so far. We will, obviously, because there's a competitive landscape over there, we're going to move at pace.

然後是 B7H4 主導 ADC。這對我們來說是一個重要的分子，因為首先，它是我們專有的 ADC 發現平台中產生的第一個分子。我們有一個專有的連結和拓撲彈頭。您在 ESMO 上看到了針對 B7H4 靶向 ADC 的一些數據。所以我認為這將是一個重要的目標。它在部分卵巢癌、子宮內膜癌、乳癌和一些膽道癌中過度表現。我們正在探索多種癌症的隊列，我們期待明年分享這方面的數據。但我們對迄今為止所看到的感到興奮。顯然，我們會的，因為那裡存在競爭格局，我們將加快步伐。

The next one is Eric Le Berrigaud at Stifel.

下一位是 Stifel 的 Eric Le Berrigaud。

Two questions, please. First, you're presenting the catalyst flow for 2024, probably you pick just a few of those. So just because SERENA-6 is not on it, just to confirm that it's still on schedule. We're hearing from physicians that it may come quite early and maybe as early as the turn of the year. So just to get your level of excitement and see that there is no decrease here?

請教兩個問題。首先，您將介紹 2024 年的催化劑流程，您可能只選擇其中的幾個。所以只是因為 SERENA-6 不在上面，只是為了確認它仍然按計劃進行。我們從醫生那裡得知，它可能會很早就到來，甚至可能最早在年初。那麼只是為了讓您的興奮程度並看到這裡沒有減少嗎？

The second question is about V&I. We're hearing a lot about the investment -- significant investment on CVRM, adding to oncology. And so you made a quick and pragmatic investment here around COVID vaccine and antibody. How much do Astra need V&I. And how much is it a distraction now to oncology, CVRM and rare disease in terms of resource allocation?

第二個問題是關於V&I。我們聽到了很多有關投資的消息——對 CVRM 的重大投資，增加了腫瘤學。因此，你們圍繞著新冠疫苗和抗體進行了快速、務實的投資。 Astra 需要多少 V&I。就資源分配而言，現在對腫瘤學、CVRM 和罕見疾病的干擾有多大？

Thank you, Eric. So maybe Susan, you could take the first one.

謝謝你，埃里克。所以也許蘇珊，你可以選擇第一個。

So again, we don't guide on interims, the SERENA-6 outcome is currently guided for beyond 2024. I would just say that our camizestrant trials overall are going really well, and we're pleased with the investigator feedback we've had from the investigators who are participating in these trials.

再說一遍，我們不會提供中期指導，SERENA-6 結果目前指導的是 2024 年以後。我只想說，我們的 camizestrant 試驗總體進展非常順利，我們對研究者的反饋感到滿意來自參與這些試驗的研究人員。

Thank you, Susan. So maybe to V&I, let me just make a couple of comments, and I could ask Iskra also to jump in. It is not a distraction. I mean our focus really has been and continues to be on antibodies -- on particular antibodies for patients who are immunocompromised and we work on 3152, and we do believe that there is an unmet need out there that is not addressed and needs to be addressed. The mortality in patients who are hematology patients, transplant patients, patients who are immunocompromised is very high, actually, 30%, 40% chance of dying if you if you have a blood cancer and you are infected with COVID.

謝謝你，蘇珊。因此，也許讓我對 V&I 發表一些評論，我可以請《火星報》也加入進來。這並不是分散注意力。我的意思是，我們的重點確實一直並將繼續放在抗體上——針對免疫功能低下患者的特定抗體，我們致力於3152，我們確實相信存在未得到滿足的需求，該需求尚未得到解決，需要得到解決。血液疾病患者、移植患者、免疫功能低下患者的死亡率非常高，實際上，如果您患有血癌並且感染了新冠病毒，死亡的可能性為 30%、40%。

I'm not even talking about being hospitalized, the risk of dying if you're hospitalize, I'm talking about the risk of dying if you are infected. So this is very high, and there is a need for those patients. In fact, we know many countries are ready to order is 3152 if it works. So of course, as always, we cannot guarantee success in anything we do. But we believe there is an opportunity for 3152, if it does work.

我甚至不是在談論住院，如果你住院就有死亡的風險，我是說如果你被感染就有死亡的風險。所以這是非常高的，並且對這些患者有需求。事實上，我們知道許多國家都準備好訂購 3152（如果有效的話）。因此，當然，一如既往，我們不能保證我們所做的任何事情都會成功。但我們相信，如果 3152 確實有效，它就有機會。

And we're working on other antibodies. And for vaccines, we have a very focused strategy on new technologies that for now, we really are disclosed because we need more data. But the last thing I would say is that there is actually a synergy with our other actives. If you think of hematology cancer again, doctors, hematologists, they need -- they want to protect their patients against COVID, especially during periods of increasing COVID infections. So for us, it's really a door opener if we have antibody to offer -- a door opener for the team that is promoting Calquence and the same is true for immune diseases. So there is a clear commercial strategy. And from a resource viewpoint, overall, it's limited investments in other distraction. Iskra, if you want to comment a little bit more on where we are and what we do.

我們正在研究其他抗體。對於疫苗，我們對新技術有一個非常集中的策略，目前我們確實公開了這些技術，因為我們需要更多數據。但我要說的最後一件事是，實際上與我們的其他活性物質有協同作用。如果你再次想到血液癌症，醫生、血液學家，他們需要——他們想要保護他們的病人免受新冠病毒感染，特別是在新冠病毒感染增加的時期。因此，對我們來說，如果我們能提供抗體，這確實是一個開門機會——對於推廣 Calquence 的團隊來說是一個開門機會，對於免疫疾病也是如此。所以有一個明確的商業策略。從資源的角度來看，整體而言，對其他幹擾的投資有限。 Iskra，如果您想對我們的現狀和我們所做的事情發表更多評論。

Thanks, Pascal, for the comments. So just to add, I think looking beyond the immunocompromise and I think you described the unmet need very clearly. I mean, you can also see an unprecedented demand, we see with Beyfortus that we are commercializing together with our partner, Sanofi, and there is a clear unmet need with RSV in the infant population. So I really believe that we can build and leverage our -- in-house knowhow of how the building long-acting monoclonal antibody is definitely has a need across the different populations.

謝謝帕斯卡的評論。所以補充一下，我認為超越免疫妥協，我認為你非常清楚地描述了未滿足的需求。我的意思是，你還可以看到前所未有的需求，我們看到 Beyfortus 正在與我們的合作夥伴賽諾菲一起商業化，並且嬰兒群體中 RSV 的需求明顯未得到滿足。因此，我堅信我們可以建立並利用我們的內部專業知識來建立不同人群確實需要的長效單株抗體。

And then also, I think, Pascal, as you mentioned, looking at the kind of what is next generation platform and how we can potentially contribute to bringing the new and differentiated vaccine is something that we are constantly focused on. And obviously, I will be very pleased to share more information with you in the due course.

然後，我認為，帕斯卡，正如您所提到的，研究下一代平台以及我們如何為帶來新的差異化疫苗做出貢獻是我們一直在關注的事情。顯然，我將非常高興在適當的時候與您分享更多資訊。

Maybe last point is Vaxzevria was really a different story. It was really to help the world deal with this terrible pandemic. But outside of this, what we focus on its products where we can actually be differentiated and address an unmet need. And of course, it's true for these antibodies. On the vaccine side, we would actually only go into large investments if we believe we have something that is totally differentiated.

也許最後一點是 Vaxzevria 確實是一個不同的故事。這確實是為了幫助世界應對這場可怕的流行病。但除此之外，我們專注於我們實際上可以實現差異化並解決未滿足需求的產品。當然，對於這些抗體也是如此。在疫苗方面，如果我們相信我們擁有完全差異化的東西，我們實際上只會進行大規模投資。

So next one is Richard Parkes at BNP.

下一位是法國巴黎銀行 (BNP) 的理查德·帕克斯 (Richard Parkes)。

Hopefully you can hear me okay. I've got 1 for Aradhana and 1 for Susan.

希望你能聽到我的聲音。我有 1 個給 Aradhana，1 個給 Susan。

Firstly, for Aradhana. Just on R&D spend, actually as you go into that budgeting negotiation later this year, you've had an incredible number of new Phase III starts this year. You're also investing in new technology platforms, you managed to keep R&D spend growth to mid-single digits, I think, in the third quarter. So I'm just wondering if you could talk about the moving parts of how that growing pipeline can be funded? How much of it can be funded through reinvestment as you -- and kind of the previous Phase III trials versus need for a step-up in the R&D spend growth trajectory into next year? I ask the question partly because we've seen other companies with -- surprising investors negatively with a step-up in R&D spend. So that's the first one.

首先，對於阿拉達納。就研發支出而言，實際上，當您在今年稍後進入預算談判時，今年啟動的新三期專案數量令人難以置信。您還投資了新技術平台，我認為，您在第三季設法將研發支出成長保持在中個位數。所以我想知道您是否可以談談如何為不斷增長的管道提供資金的移動部分？其中有多少可以透過再投資來資助──以及先前第三階段的試驗與明年研發支出成長軌跡的需要？我問這個問題的部分原因是我們看到其他公司的研發支出增加，令投資者感到驚訝。這是第一個。

Then secondly, for Susan, I can see you're starting a Phase III of the PARP1 selective inhibitor in prostate cancer. But obviously, there's a huge potential for that drug if you can unlock potential for synergy with an ADC, with a DNA damaging payload. So I just wondered if you could talk about your enthusiasm and optimism of that program? And potential, more broadly, and what we might see, I guess, insight to that -- your plans?

其次，Susan，我可以看到您正在開始針對前列腺癌的 PARP1 選擇性抑制劑的 III 期試驗。但顯然，如果您能夠釋放與具有 DNA 破壞性有效負載的 ADC 協同作用的潛力，那麼該藥物就有巨大的潛力。所以我想知道您是否可以談談您對該計劃的熱情和樂觀？更廣泛地說，還有潛力，以及我們可能會看到的，我想，對此的洞察力——你的計劃？

In terms of R&D, we obviously go through a very detailed process that is both bottoms-up and top-down. And I think we've obviously said in the past that we expect R&D to be somewhere in the low 20s percentage of revenue, and what that helps us with is actually provide some discipline in terms of which projects to prioritize and so forth.

在研發方面，我們顯然經歷了一個非常詳細的過程，既自下而上又自上而下。我認為我們過去曾明確表示，我們預計研發佔收入的比例將在 20 多歲左右，這對我們有幫助的實際上是在優先考慮哪些項目等方面提供了一些紀律。

Also, I would say, as we have started a number of Phase III studies. But when you look at Phase III studies, there's also been a number of studies that we have -- we're tapering down or we've read out and so forth. So it's a constant phase and all the Phase III expense doesn't come necessarily in 1 year, right? It's phased over the entire study period. We start a number of Phase III studies, for example, this year, but some of that expense -- a lot of that expense also goes in study starts, in the site recruitment, in the clinical study supply, et cetera. So I think we manage that and we provide that the top-down discipline, but it's a tough situation. I think if you asked Marc or Susan or Sharon, they'll always tell me we don't have enough money for all the exciting projects that we have. So -- so we try to maintain that balance.

另外，我想說的是，我們已經開始了一些 III 期研究。但是當你看一下第三階段的研究時，我們也進行了許多研究——我們正在逐漸減少或者我們已經讀出了等等。所以這是一個持續的階段，所有第三階段的費用不一定會在一年內到來，對吧？它在整個研究期間分階段進行。例如，我們今年啟動了一些 III 期研究，但其中一些費用——其中許多費用也用於研究啟動、場地招募、臨床研究供應等。所以我認為我們可以做到這一點，並且我們提供自上而下的紀律，但這是一個艱難的情況。我想如果你問馬克、蘇珊或莎倫，他們總是會告訴我，我們沒有足夠的錢來開展所有令人興奮的計畫。所以——所以我們努力保持這種平衡。

Thanks, Aradhana. Maybe a couple of additional points. First of all, beyond the prioritization that Aradhana covered very well and the use of technology to make ourselves more productive, we also have launched and are implementing a redeployment of our footprint. And so we are, for instance, leveraging Canada, Toronto in North America, Barcelona in Europe. So we've got -- we are going through a process by which we locate in the strategic centers jobs that are -- should be located there. And then we have a nearshore and a far shore strategy, so we are leveraging our sites in Guadalajara and also in India for some roles, so we're doing all sorts of things that help us manage the cost of R&D. We've been internalizing the conduct of our clinical trials. First of all, we believe that we'll deliver a better execution of our trials if we do it with our own clinical teams, but also, it reduces our cost when we internalize.

謝謝，阿拉達納。也許還有幾點。首先，除了 Aradhana 很好地涵蓋的優先事項以及利用技術來提高我們的生產力之外，我們還啟動並正在實施我們的足跡的重新部署。例如，我們正在利用加拿大、北美的多倫多、歐洲的巴塞隆納。因此，我們正在經歷一個流程，透過這個流程，我們可以在策略中心找到應該位於那裡的工作。然後我們有近岸和遠岸策略，所以我們正在利用我們在瓜達拉哈拉和印度的基地來發揮一些作用，所以我們正在做各種事情來幫助我們管理研發成本。我們一直在內部化我們的臨床試驗的進行。首先，我們相信，如果我們與自己的臨床團隊一起進行試驗，我們將更好地執行試驗，而且，當我們內部化時，它也會降低我們的成本。

So ultimately, we stick to what we said before, which is low 20s R&D on revenues. Some people have said what is it mean if low 20s is low 20s. If we meant more than this, we probably would say mid-20s or something like this. So it's low 20s, and I just want to reconfirm this is our ongoing target.

因此，最終，我們堅持之前所說的，即研發收入低於 20 美元。有人說了低20就是低20是什麼意思。如果我們的意思不止於此，我們可能會說 20 多歲或類似的東西。所以現在只有 20 多歲，我只是想再次確認這是我們持續的目標。

PARP1, Susan?

PARP1，蘇珊？

Yes. So for the question about saruparib, this is another program that I'm really excited about. I think we've learned a lot about the right patient populations to treat with PARP inhibitors during the development of Lynparza. But saruparib has this improved profile which enables clear improvement and tolerability, enables you to hit the target even harder, and I think that has the potential to lead to actually better efficacy than we see with olaparib.

是的。因此，對於有關 saruparib 的問題，這是另一個讓我非常興奮的項目。我認為在 Lynparza 的開發過程中，我們已經了解了很多關於使用 PARP 抑制劑治療的合適患者群體的資訊。但 saruparib 具有這種改進的特性，可以實現明顯的改善和耐受性，使您能夠更加努力地達到目標，我認為這有可能帶來比我們在奧拉帕尼看到的更好的療效。

So it's great to see the first Phase III trial starting, you'll see more coming, and I think 1 interesting area is the potential for this to have combinations. So saruparib in combination with ADCs is absolutely something that we're exploring, and we're encouraged by the early data that we've got, but it's a little early to be sharing those externally at the moment. Probably it will be another 12 months before we show those, I'd expect.

所以很高興看到第一個第三階段試驗開始，你會看到更多的試驗即將到來，我認為一個有趣的領域是這種組合的潛力。因此，saruparib 與 ADC 的結合絕對是我們正在探索的東西，我們對所獲得的早期數據感到鼓舞，但目前向外部分享這些數據還為時過早。我預計，我們可能還需要 12 個月才能展示這些內容。

Thanks, Susan.

謝謝，蘇珊。

Next question is from Christopher Uhde at SEB.

下一個問題來自 SEB 的 Christopher Uhde。

Christopher, we can't hear you.

克里斯多福，我們聽不到你的聲音。

Can you hear me now?

你聽得到我嗎？

Yes. Perfect. Go ahead.

是的。完美的。前進。

All right. Great. So my first question is for Sharon. Now that you taken over, I think we have a pretty good idea of what the strategy is for CVRM. Perhaps you could talk a little bit about what the R&I sort of big picture strategy is overall? And in terms of -- so R&D strategy and integrating that with commercial strategy and how to execute on it?

好的。偉大的。我的第一個問題是問莎倫的。現在您接手後，我認為我們已經非常清楚 CVRM 的策略是什麼。也許您可以談談 R&I 整體策略是什麼？就研發策略而言，並將其與商業策略結合，以及如何執行？

And then my second question is on Farxiga. And maybe here, I'd like to start by congratulating Mene and his team, even though he's not here today, on the successful readout for zibotentan. I guess it's his brainchild and arguably the zenith of his achievements at AZ.

我的第二個問題是關於 Farxiga 的。也許在這裡，我想首先祝賀梅內和他的團隊，儘管他今天不在場，但祝賀 zibotentan 的成功宣讀。我想這是他的創意，也可以說是他在 AZ 成就的巔峰。

But -- so a small percentage of patients that are eligible for SGLT2 actually get it across the each approved indication. Is the NRx split still even across the indicated patient groups? And how much gas is left in the tank in the U.S. and EU across those indications? We've got dapa, MI toplining positively, so how much impact can that have? And beyond it, are there any remaining steps you can take to convince prescribers or payers that a larger proportion of patients should be adding on SGLT2 on top of metformin or statin or BP meds or whatever before you start to bring Farxiga combos into the picture? So like -- the specific patient subgroups, for example?

但是，一小部分符合 SGLT2 資格的患者實際上能夠滿足每個批准的適應症。 NRx 在指定患者組的分佈是否仍均勻？根據這些指標，美國和歐盟的油箱還剩下多少汽油？我們已經得到了 dapa、MI 的積極支持，那麼這能產生多大的影響呢？除此之外，在您開始使用Farxiga 組合之前，您是否還可以採取任何剩餘步驟來說服處方者或付款人，更大比例的患者應該在二甲雙胍、他汀類藥物或血壓藥物或其他藥物的基礎上加入SGLT2？例如，特定的患者亞群？

And there's a logical follow-through. When the SGLT2s lose exclusivity, do you anticipate any substantial step-up in breadth of use? What might that look like? And does that impact how you view the opportunity for the novel Farxiga combo regimens like zibotentan?

並且有一個合乎邏輯的後續行動。當 SGLT2 失去排他性時，您預期使用範圍會出現實質的提升嗎？那會是什麼樣子呢？這是否會影響您如何看待 zibotentan 等新型 Farxiga 組合療法的機會？

So Sharon, R&I?

那麼莎倫，R&I？

Yes. So I'm in a very lucky position of stepping into a very strong biopharma organization with a foundation that was built over many years by Mene, and I'm grateful for both the incredible portfolio that was established as well as the extraordinary team of scientific leaders that I have the privilege of working with.

是的。因此，我非常幸運地進入了一個非常強大的生物製藥組織，該組織的基礎是梅內多年來建立的，我很感激所建立的令人難以置信的產品組合以及非凡的科學團隊我有幸與之共事的領導者。

So as we look forward to how we're going to continue to grow and invest in R&I, let's think a little bit about the successes that are already beginning to drive value for the portfolio. So looking towards Saphnelo, we have 3 Phase III studies ready to initiate. In fact, the DAISY study in sclerosis just dosed, so that's a Phase III study already initiated with 2 more, which we expect to launch early next year. So we're very proud of the potential of Saphnelo, which was put in place through internal discovery and development programs, and we're beginning to see delivery of that promise.

因此，當我們期待如何繼續發展和投資研發時，讓我們思考一下已經開始為投資組合帶來價值的成功。因此，針對 Saphnelo，我們已經準備好啟動 3 項 III 期研究。事實上，DAISY 針對硬化症的研究剛剛完成，因此這項 III 期研究已經啟動，還有另外 2 項研究，我們預計將於明年初啟動。因此，我們對 Saphnelo 的潛力感到非常自豪，它是透過內部發現和開發計劃實現的，我們開始看到這項承諾的兌現。

Also, a strong contender in our portfolio is tozorakimab which, as we mentioned earlier, is differentiated for the competitors because it is able to inhibit both the ST2 and the RAGE/EGFR pathways. And so we really see a wonderful opportunity there to target the breadth of respiratory disease and to be able to offer a better outcome for patients.

此外，我們產品組合中的一個強有力的競爭者是 tozorakimab，正如我們之前提到的，它與競爭對手不同，因為它能夠抑制 ST2 和 RAGE/EGFR 通路。因此，我們確實看到了一個絕佳的機會，可以針對呼吸系統疾病的廣泛範圍，並能夠為患者提供更好的結果。

So as we think about how we continue to build on our success and move forward, as we've mentioned, we're very interested in growing our footprint in treatments for immune-mediated diseases, and this is a continued build within the group as we expand both our capabilities as well as our capacity and we think about the new modalities that will best serve patients moving forward.

因此，正如我們所提到的，當我們思考如何繼續鞏固我們的成功並向前邁進時，我們對擴大我們在免疫介導疾病治療方面的足跡非常感興趣，這是集團內部的持續建設我們擴大了我們的能力和容量，並考慮了能夠最好地為患者提供未來服務的新模式。

So we continue to expand our pipeline and to think about what the treatment of the future maybe, and for a hint of the way we are thinking, Susan told you earlier about investments in cell therapy and the promise of those who have demonstrated in oncology. And we have seen early clinical data published by academic experts who have demonstrated the promise for cell therapy in patients with autoimmune disease, so we'll continue to explore these capabilities and evaluate the potential for that within our portfolio.

因此，我們繼續擴大我們的產品線，並思考未來的治療方法，為了暗示我們的思考方式，蘇珊早些時候告訴您有關細胞療法的投資以及那些在腫瘤學領域已證明的承諾。我們已經看到學術專家發表的早期臨床數據，他們證明了細胞療法對自體免疫疾病患者的前景，因此我們將繼續探索這些功能並評估我們產品組合中的潛力。

I hope that gives you some color that will also help us share our excitement and growth in respiratory and immunology.

我希望這能給您一些啟發，也能幫助我們分享我們在呼吸和免疫學領域的興奮和成長。

And let's not forget, before I come to the Farxiga question, there's still a high unmet medical need in our core indications in asthma and COPD despite all the progress we have made in the last few decades, but many patients are still suffering from severe exacerbation, lung damage, so there's still a very big untapped opportunity in those diseases.

我們不要忘記，在我談到Farxiga 問題之前，儘管我們在過去幾十年中取得了所有進展，但我們在氣喘和慢性阻塞性肺病的核心適應症中仍然存在很高的未滿足的醫療需求，但許多患者仍遭受嚴重惡化的痛苦、肺損傷，所以這些疾病還有很大的未開發機會。

Coming back to your question regarding the growth potential in -- of Farxiga, it's still very substantial, Christopher. Just to give you some numbers, currently, almost 1/3 of the new prescriptions are going to Type-2 diabetes, but more than 2/3 are going to CKD and heart failure. And the penetration in those 2 diseases is at the moment, despite all our efforts and also from the competition, is only 15% to 20%. And hence, there's still a very substantial upside moving forward. Very pleasing to see that most of the guidelines around the world have now adjusted their guidelines and SGLT2 are now one of the fundamental pillars of the treatment of heart failure patients, and the same is true for chronic kidney disease. So in that sense, the volume opportunity is very substantial.

回到你關於 Farxiga 成長潛力的問題，克里斯托弗，它仍然非常巨大。給你一些數字，目前，幾乎 1/3 的新處方用於治療 2 型糖尿病，但超過 2/3 的處方用於治療 CKD 和心臟衰竭。儘管我們付出了所有努力，也受到了競爭的影響，目前這兩種疾病的滲透率僅為 15% 至 20%。因此，未來仍有非常可觀的上行空間。非常高興地看到，世界上大多數指南現在都調整了指南，SGLT2 現在成為心臟衰竭患者治療的基本支柱之一，慢性腎臟病也是如此。因此從這個意義上來說，成交量機會非常可觀。

And your question about LOE, and let me reiterate again, we have a very, let's say, fragmented period of LOEs with Farxiga, 2026 the United States, but only 2028 in Europe. And beyond that, we see a very strong growth in emerging markets wherein some of those markets, roughly 10 markets, we have already lost LOE but still -- the brand is still growing very fast. So I'm not going to say that there's no impact on LOE, of course, there will be an impact of LOE. But clearly, the combination products hopefully will compensate for that loss in the second part of the decade. And we remain very bullish about the growth potential of the products in -- let's say, in the next few years.

關於你關於 LOE 的問題，讓我再次重申，我們與 Farxiga 的 LOE 非常分散，美國 2026 年，但歐洲只有 2028 年。除此之外，我們看到新興市場的成長非常強勁，其中一些市場（約 10 個市場）我們已經失去了 LOE，但該品牌仍然成長非常快。所以我不會說對LOE沒有影響，當然LOE會有影響。但顯然，組合產品有望在本世紀後半段彌補這一損失。我們仍然非常看好這些產品在未來幾年的成長潛力。

Thank you, Ruud. And Mene is not with us in the room is keeping an eye on us, so reminded us that we still have a number of readouts, our last cycle management opportunities in R&I, with (inaudible), with Fasenra, with (inaudible), so still quite a lot to come in R&I, in particular respiratory.

謝謝你，路德。梅內沒有和我們一起在房間裡，而是在關注我們，所以提醒我們，我們仍然有一些讀數，我們在R&I 的最後一個週期管理機會，與（聽不清），與Fasenra，與（聽不清），所以研究與創新領域還有很多工作要做，特別是呼吸領域。

So we move to the next question, Simon Baker at Redburn. Can I ask -- we only have a few minutes left, so can I ask everybody to ask 1 question, if you don't mind? Over to you, Simon.

那麼我們轉向下一個問題，雷德伯恩的西蒙貝克 (Simon Baker)。我可以問一下──我們只剩下幾分鐘了，如果你們不介意的話，我可以請大家問一個問題嗎？交給你了，西蒙。

Thanks, Pascal, and I'll behave myself.

謝謝，帕斯卡，我會好好表現的。

On -- (inaudible) returning to Emily's questions for you, Susan. The current use of CTLA-4 is really defined by acceptable levels of toxicity, and if your bispecific is better tolerated, that broadens the scope. I'm specifically thinking about lung cancer and PD-L1 greater than 50%. If all of Lung02 is focusing on less than 50%, are you planning to look at PD-L1 high as well?

關於－－（聽不清楚）回到艾蜜莉向你提出的問題，蘇珊。 CTLA-4 目前的使用實際上是由可接受的毒性水平來定義的，如果您的雙特異性抗體具有更好的耐受性，那就會擴大範圍。我特別考慮的是肺癌和 PD-L1 大於 50% 的情況。如果 Lung02 的全部關注點低於 50%，您是否也打算關注 PD-L1 高值？

So I think in the PD-L1 high group, this is the place where at the moment, based on the current data that we have, that the addition of TIGIT seems to make a particular difference in that setting. So we obviously look at the emerging data across our bispecific portfolio, but what we're doing in terms of the initial Phase III trials that you're seeing is focusing on the area where we think -- get that added benefit from CTLA-4 inhibition.

因此，我認為在 PD-L1 高組中，根據我們現有的數據，目前 TIGIT 的添加似乎在該設定中產生了特殊的差異。因此，我們顯然會關注我們的雙特異性產品組合中的新興數據，但就您所看到的初始III 期試驗而言，我們正在做的重點是我們認為的領域——從CTLA-4 中獲得額外的好處抑制。

It is better tolerated than just any co-administration of the 2 antibodies separately rather than in 1 drug, where you've -- only binding CTLA-4 in the presence of PD-1. However, if you compare, you are still getting some increase in toxicity. So I think we've got a much, much lower rate of the diarrhea and colitis that you see with CTLA-4 inhibition, but we have still seen some increases in liver enzyme elevation, and that's really what we try to optimize for when we're optimizing for the dose at 750. So we have an acceptable way of drug discontinuation and holidays based on that.

它比單獨聯合施用 2 種抗體（而不是在 1 種藥物中）具有更好的耐受性，後者僅在 PD-1 存在的情況下結合 CTLA-4。然而，如果您進行比較，您仍然會發現毒性增加。所以我認為，與 CTLA-4 抑制相比，我們的腹瀉和結腸炎發生率要低得多，但我們仍然看到肝酵素升高增加，這確實是我們嘗試優化的目標。我們正在優化750 的劑量。因此，我們有一個可接受的停藥和基於此的假期方式。

So I think we still need to make sure that we're optimizing the patient population that we're choosing for the relevant checkpoint inhibition profile, and that's what we're aiming to do across our bispecific portfolio.

因此，我認為我們仍然需要確保優化我們為相關檢查點抑制譜選擇的患者群體，這就是我們的雙特異性產品組合的目標。

This is the viability of this portfolio, and volrustomig is a more logical option for PD-L1 high, Simon, and the CTLA-4 combination of volrustomig is a better option for PD-L1 low in lung cancer.

這就是這個組合的可行性，對於PD-L1高Simon來說，volrustomig是一個更合理的選擇，而volrustomig的CTLA-4組合對於PD-L1低的肺癌來說是更好的選擇。

So we'll move to the next one. Rajeev Kumar, HSBC.

那麼我們將進入下一個。拉吉夫·庫馬爾，匯豐銀行。

Just 1 question on the long-term financial targets, you indicated that you want to achieve faster than the industry growth. Can you run us through how you're thinking about capital allocation today in terms of, for example, you highlighted GLP-1 acquisition or you just started trials on bispecific that will position you to be there. So what is the capital allocation algorithm you're following today that gets you to an answer? Whether there is -- you won't get success in every everything, but what gives you the confidence that you can deliver that industry-leading growth?

在關於長期財務目標的 1 個問題中，您表示希望實現比產業成長更快的目標。您能否向我們介紹一下您今天如何考慮資本配置，例如，您強調了 GLP-1 收購，或者您剛開始了雙特異性試驗，這將使您能夠實現這一目標。那麼，您今天遵循的資本分配演算法是什麼，可以讓您找到答案呢？是否有—您不會在所有事情上都取得成功，但是是什麼讓您有信心實現業界領先的成長？

Thanks, Rajeev. Aradhana had to step out for a minute, so let me address your question. First of all, we don't give long-term guidance. The only thing I will say about the long term is what we said before remains our goal, so there's not much change there. And in terms of a specific question about capital allocation, as Aradhana said a bit earlier during her comments, the priorities for us are to invest in our pipeline, reduce debt and pay our dividend, so there's no change there. And certainly, we want to continue building our pipeline.

謝謝，拉吉夫。阿拉達納必須出去一會兒，所以讓我回答你的問題。首先，我們不提供長期指導。關於長期，我唯一要說的是我們之前所說的仍然是我們的目標，因此沒有太大變化。至於資本配置的具體問題，正如阿拉達納早些時候在評論中所說，我們的首要任務是投資我們的管道、減少債務和支付股息，所以這方面沒有變化。當然，我們希望繼續建造我們的管道。

But the -- each time we build the pipelines for (inaudible) like we've just announced this morning, this additional (inaudible), we believe that we can deliver industry-leading growth from '25 to '30 and beyond based on what we have today. So anything we had actually will help us grow even more during the period and beyond. So we're always looking at today, tomorrow and the day after, the day after being new technologies like cell therapy that we want apply to oncology but also immune diseases. As Sharon mentioned, T-cell engagers, gene therapy for rare diseases. In the midterm, of course, which is what I call tomorrow, is actually a large Phase III pipeline. So that's really what we try to do.

但是，每次我們為（聽不清楚）建造管道時，就像我們今天早上剛剛宣布的那樣，這個額外的（聽不清），我們相信我們可以在25 年到30 年及以後實現行業領先的成長，基於什麼我們有今天。因此，我們實際上擁有的任何東西都將幫助我們在此期間及之後獲得更大的成長。因此，我們總是著眼於今天、明天和後天，我們希望將細胞療法等新技術應用於腫瘤學和免疫疾病。正如 Sharon 所提到的，T 細胞參與者，罕見疾病的基因治療。當然，中期，也就是我明天所說的，其實是一個大型的第三階段管道。這就是我們真正嘗試做的事情。

The next question is Emmanuel Papadakis, I'm rushing a little bit, from Deutsche Bank. But we only have a few minutes, and I'd like to give everybody a chance to ask their question.

下一個問題是來自德意志銀行的 Emmanuel Papadakis，我有點著急。但我們只有幾分鐘的時間，我想讓每個人都有機會提出問題。

This Luisa Hector from Berenberg actually, I was unmuted...

實際上，這個來自貝倫貝格的路易莎·赫克托，我沒有靜音…

It's not what the screen that I have in front of me says, but it's great to hear you. Go ahead Luisa and then we'll look back to Emmanuel, if that's okay.

這不是我面前的螢幕所說的，但很高興聽到你的聲音。繼續吧，路易莎，然後我們再看看伊曼紐爾，如果可以的話。

So on Dato at ESMO, it became clear that this drug is absolutely delivering on the promise of ADPs in the EGFR subgroup of lung cancer. I just wondered why you think this is? And whether you need to see any more data before you could consider starting Phase III in frontline EGFR in combination with Tagrisso?

因此，ESMO 的 Dato 明確表示，該藥物絕對兌現了 ADP 在肺癌 EGFR 亞群中的承諾。我只是想知道你認為這是為什麼？您是否需要查看更多數據才能考慮開始一線 EGFR 合併 Tagrisso 的 III 期臨床試驗？

Thanks. So it's a good question for Susan.

謝謝。所以這對蘇珊來說是一個很好的問題。

Yes, sure. So yes, in the EGFR subgroup, we did see really good activity with the hazard ratio of [0.389] group in the randomized study of TL01. So we've also got data from the ORCHARD platform study looking at the combinability of Dato-DXd with Tagrisso, so I think that's an important piece to also put in place. So I think it is encouraging. Obviously, as we've already said, we're going to be expanding the portfolio of Phase III trials that we have for Dato-DXd, and you'll see more of those trials in the coming months. But this is a place that obviously we can build on the great data that we just see with FLAURA2 by looking at the combination of Tagrisso with chemo, and you have the potential then to improve on the chemo piece. So I think it's an interesting area. Obviously, we'll be posting more trials in the coming months.

是的，當然。所以，是的，在 EGFR 亞組中，我們確實看到了 TL01 隨機研究中風險比為 [0.389] 組的良好活性。因此，我們也從 ORCHARD 平台研究中獲得了有關 Dato-DXd 與 Tagrisso 組合性的數據，所以我認為這也是需要落實的重要部分。所以我認為這是令人鼓舞的。顯然，正如我們已經說過的，我們將擴大 Dato-DXd 的 III 期試驗組合，並且您將在未來幾個月看到更多此類試驗。但顯然，我們可以透過觀察 Tagrisso 與化療的組合，以我們剛剛在 FLAURA2 中看到的大量數據為基礎，然後您就有潛力改進化療部分。所以我認為這是一個有趣的領域。顯然，我們將在未來幾個月內發布更多試驗。

Thanks, Susan. Emmanuel over to you.

謝謝，蘇珊。以馬內利交給你。

Quick question on [vemircopan] discontinuation for lack of efficacy in PNH. What cross read does that have to the ongoing myasthenia gravis and renal studies? And where does that leave your overall strategy and ability to defend against potentially newcomers like (inaudible), et cetera?

關於 [vemircopan] 因 PNH 缺乏療效而停藥的快速問題。這與正在進行的重症肌無力和腎臟研究有何交叉解讀？那麼，您的整體策略和抵禦潛在新來者（如（聽不清楚）等）的能力將在哪裡？

And then if I've got a very quick follow-up for (inaudible). You didn't mention China BBP for Farxiga next year. Are you no longer expecting that to be a headwind for revenues?

然後，如果我有一個非常快速的跟進（聽不清楚）。您沒有提到明年 Farxiga 的中國 BBP。您是否不再認為這會成為收入的阻力？

Okay. Marc, do you want to cover the first one?

好的。馬克，你想報道第一個嗎？

Yes, yes. So to answer your first question on vemircopan in PNH. I mean, PNH, it's absolutely essential to have a very high control of the disease, and we recommend in PNH the dual therapy between vemircopan and Ultomiris. Ultomiris has a very sustained and strong efficacy over time. I believe it's going to remain the standard of care. Vemircopan has shown efficacy but not as high as we want it to be.

是的是的。因此，請回答您關於 PNH vemircopan 的第一個問題。我的意思是，對於 PNH，對疾病進行高度控制是絕對必要的，我們建議在 PNH 中使用 vemircopan 和 Ultomiris 之間的雙重治療。隨著時間的推移，Ultomiris 具有非常持續且強大的功效。我相信它將繼續保持護理標準。 Vemircopan 已顯示出功效，但沒有我們希望的那麼高。

Regarding the read across other indications, we are still continuing Phase II studies in MG, as you mentioned, but also in several renal indication, and we are hopeful that this indication will be successful.

關於其他適應症的閱讀，正如您所提到的，我們仍在繼續 MG 的 II 期研究，但也在一些腎臟適應症中進行，我們希望該適應症能取得成功。

Maybe just 1 quick addition to what Marc said. I mean the -- at the (inaudible), you probably saw (inaudible) showed some sign of potential right through [IBH]. So that's why we believe C5 potentially combined with danicopan is really the best option here. Over to you Marc -- Ruud, sorry.

也許只是對 Marc 所說的內容進行快速補充。我的意思是——在（聽不清楚），您可能會看到（聽不清楚）透過 [IBH] 顯示出一些潛力的跡象。這就是為什麼我們相信 C5 與 danicopan 結合可能確實是最佳選擇。交給你了，馬克——路德，抱歉。

Yes, so Emmanuel, so it's -- clearly Farxiga is not listed in so-called batch 9. It could go into the [VBP] batch 10, but that impact will be only seen then in late 2024, so we simply need to wait til batch 10 is announced.

是的，Emmanuel，所以很明顯 Farxiga 沒有被列入所謂的第 9 批中。它可能會進入 [VBP] 第 10 批，但這種影響要到 2024 年末才能看到，所以我們只需要等待直到第10批公佈。

Nothing with China, and Farxiga is we will, as we've said before, we will what we call consumerize it just like we did with Crestor. It's really -- I mean the volume potential is still gigantic in China. The price is relatively low, so we can definitely consumerize it and operate in a private market and deliver to patients at home for a very low cost. So we believe we should be able to transition. There will be -- when we go [VBP] and we don't know exactly when because as Ruud said, it could be further delayed. When we go to VBP , we should have an initial drop and like we saw with Crestor, I hope, and believe that it can after that grow in volume.

與中國無關，Farxiga 是，正如我們之前所說，我們將把它消費化，就像我們對 Crestor 所做的那樣。我的意思是，中國的銷售潛力仍然巨大。價格相對較低，所以我們完全可以消費它，並在私人市場上運營，以非常低的成本送到患者家中。所以我們相信我們應該能夠轉型。當我們去[VBP]時，我們不知道確切的時間，因為正如路德所說，它可能會進一步推遲。當我們進入 VBP 時，我們應該會出現最初的下降，就像我們在 Crestor 中看到的那樣，我希望並相信之後它的數量會增長。

We take the last 1 question from Peter Welford with Jefferies.

我們回答 Peter Welford 和 Jefferies 提出的最後一個問題。

Just coming back to the oral GLP-1. I just wonder if, firstly, you could perhaps comment on how important is it that this could potentially get to market at a time when you do have a successful life cycle management or other strategies for Farxiga in the U.S. market? And overall, sort of presence, I guess, a significant presence in your CVRM portfolio in the U.S.? And how does it leave the weekly amylin, perhaps a question for Sharon? Is it actually possible to potentially reformulate the oral as well as an injectable for an amylin combination? Or is the amylin (inaudible) to remain a monotherapy at this point within your portfolio?

回到口服 GLP-1。我只是想知道，首先，您是否可以評論一下，當您在美國市場為 Farxiga 制定了成功的生命週期管理或其他策略時，該產品可能進入市場有多重要？整體而言，我想，您在美國的 CVRM 產品組合中佔有重要地位？每週的胰淀素是如何留下來的，這也許是莎倫的問題？是否真的有可能重新配製胰淀素組合的口服劑型和注射劑型？或者胰淀素（聽不清楚）目前在您的投資組合中仍然是單一療法嗎？

And I apologize. I know I'm last, but if I've done it, just step back again. Could you just quick -- can you reiterate the mid- to high 30% longer-term margin target? Because that wasn't actually mentioned, but it's come up for a lot of people's questions.

我道歉。我知道我是最後一個，但如果我做到了，就再退一步吧。您能否快速重申 30% 的中高長期利潤率目標？因為實際上並沒有提到這一點，但很多人都提出了這個問題。

Okay. So Peter, let me do my best in order to answer your first question regarding the importance of this new assets in the combination with Farxiga. It's fair to say that we are getting more and more excited about the other combinations in our portfolio as well. Sharon mentioned the combination with zibotentan. We hope to show results with (inaudible) in combination with Farxiga. And last but not least, of course, we have the baxdrostat combination. The Phase III trial has already started for the mono component, and hopefully early next year, we will also start to Phase III in the combination of Farxiga. So those 3 will enter the market earlier than the combination with the obesity. But of course, we will gladly do everything in order to accelerate the development also of the combination of the Eccogene compounds with Farxiga, if that makes sense.

好的。 Peter，讓我盡力回答您的第一個問題，即與 Farxiga 結合的這項新資產的重要性。可以公平地說，我們對產品組合中的其他組合也越來越感興趣。 Sharon提到了與zibotentan的組合。我們希望展示（聽不清楚）與 Farxiga 結合的結果。最後但並非最不重要的一點是，我們當然有 baxdrostat 組合。單組分的 III 期試驗已經開始，希望明年初，我們也能開始 Farxiga 組合的 III 期試驗。因此，這三種藥物將比與肥胖者的組合更早進入市場。當然，如果有意義的話，我們很樂意盡一切努力加速 Eccogene 化合物與 Farxiga 組合的開發。

So that's what I can say at the moment. It's high speed. There's a lot ongoing in order to make sure that we will mitigate the potential effect of an LOE in the United States as much as possible.

這就是我現在能說的。速度很快。為了確保我們能夠盡可能減輕 LOE 對美國的潛在影響，我們正在進行許多工作。

And I'll answer your second question, which -- sorry. Go ahead, Sharon. Yes.

我將回答你的第二個問題，抱歉。繼續吧，莎倫。是的。

Yes. I think we'll follow up. There was a question there about how this fits into our portfolio in which we already have a long-acting amylin agonist. So it's an excellent question, but let's just say that nobody thinks that the unmet medical need for diabetes has been fully met at this point. And so we have multiple opportunities to address both type-2 diabetes and obesity with the molecules in our portfolio as well as with this acquisition of ECC5004. So there is still a place for our long-acting amylin molecule, and it is a small molecule so we anticipate that it would be combinable with a molecule like ECC5004. So we continue to build on our portfolio, not subtract from.

是的。我想我們會跟進。有一個問題是，這如何適合我們已經有長效胰淀素激動劑的產品組合。這是一個很好的問題，但我們只能說，沒有人認為糖尿病未滿足的醫療需求目前已被充分滿足。因此，我們有許多機會利用我們產品組合中的分子以及此次收購 ECC5004 來解決第 2 型糖尿病和肥胖問題。因此，我們的長效胰島澱粉樣多肽分子仍然有一席之地，而且它是一種小分子，因此我們預計它可以與 ECC5004 這樣的分子結合。因此，我們將繼續擴大我們的投資組合，而不是減少投資組合。

And with amylin, the idea is really to combine, not replace GLP-1. If you want to combine and provide a product that is well tolerated, add further -- either further weight loss or enable reduction of GLP-1 and better tolerability of the combination, and also more durable effect. But of course, only time will tell them whether we can deliver this, and that's why we do the clinical development.

對於胰淀素，我們的想法實際上是結合而不是取代 GLP-1。如果您想組合並提供耐受性良好的產品，請進一步添加 - 進一步減輕體重或減少 GLP-1 以及組合的更好耐受性，以及更持久的效果。當然，只有時間才能告訴他們我們是否能夠實現這一點，這就是我們進行臨床開發的原因。

So the last question, operating margin remains certainly our key focus. But of course, we will always consider the opportunities we have. As I said before, with what we have in our hands, we can deliver industry-leading growth post-2025, which we've said before. And if we find other additional opportunities to grow even faster, certainly, we may consider adjusting operating margin target. But the one thing we will not do is compromise the profitability and the cash flow in absolute value.

因此，最後一個問題，營業利潤率仍然是我們的重點。但當然，我們將始終考慮我們擁有的機會。正如我之前所說，憑藉我們手中的資源，我們可以在 2025 年後實現領先業界的成長，這一點我們之前也說過。如果我們發現其他更快成長的機會，當然，我們可能會考慮調整營業利潤率目標。但我們不會做的一件事就是犧牲獲利能力和現金流的絕對值。

So we will only trade an adjustment in operating margin if we thought we can deliver faster, even faster growth profit and more cash flow. So that's sort of the bottom line, and we want to deliver for shareholders at the end of the day.

因此，只有當我們認為能夠實現更快、更快的利潤成長和更多現金流時，我們才會對營業利潤率進行調整。這就是底線，我們希望最終為股東帶來回報。

So with this, maybe we want to call it a day. And thank you very much for all your great questions, and have a good day, everybody. Thank you.

至此，也許我們就到此為止了。非常感謝大家提出的所有好問題，祝大家有美好的一天。謝謝。