AstraZeneca PLC (AZN) 2022 Q4 法說會逐字稿

Good morning to those joining from the U.K. and the U.S. Good afternoon to those in Central Europe, and good evening to those listening in Asia. Welcome, ladies and gentlemen, to AstraZeneca's Full Year and Q4 2022 Results Conference Call for investors and analysts.

早上好，來自英國和美國的聽眾。下午好，中歐的聽眾，晚上好，亞洲的聽眾。女士們，先生們，歡迎參加阿斯利康為投資者和分析師舉辦的全年和 2022 年第四季度業績電話會議。

Before I hand the call 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 forward-looking statements. Any forward-looking statements made on the 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 call. (Operator Instructions) I must advise that this conference is being recorded today.

在我將電話轉給阿斯利康之前，我想閱讀安全港聲明。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以就阿斯利康的運營和財務業績做出前瞻性陳述。儘管我們認為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前瞻性陳述所表達或暗示的結果存在重大差異的因素的影響。電話會議上所做的任何前瞻性陳述都反映了電話會議時可獲得的知識和信息。公司不承擔更新前瞻性陳述的義務。另請仔細閱讀本次電話會議隨附的幻燈片中的前瞻性聲明免責聲明。 （操作員說明）我必須告知今天正在錄製此會議。

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

那麼，我現在將把你交給公司。

Thank you, operator, and good afternoon, everyone. I'm Andy Barnett, Head of Investor Relations at AstraZeneca, and I'm pleased to welcome you to AstraZeneca's Fourth Quarter and Full Year Conference Call for 2022. We will also present our guidance for 2023 on today's call. As usual, all materials presented are available on our website.

謝謝接線員，大家下午好。我是阿斯利康投資者關係主管 Andy Barnett，很高興歡迎您參加阿斯利康 2022 年第四季度和全年電話會議。我們還將在今天的電話會議上介紹我們對 2023 年的指導意見。與往常一樣，所有展示的材料都可以在我們的網站上找到。

Please advance to Slide 2. This slide contains our usual -- this slide contains our usual safe harbor statement, where we'll 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 our results announcement, numbers are in million U.S. Dollars unless otherwise stated.

請轉到幻燈片 2。這張幻燈片包含我們通常的 - 這張幻燈片包含我們通常的安全港聲明，我們將在其中使用固定匯率或 CER、核心財務數據和其他非 GAAP 措施對我們的業績發表評論。非 GAAP 與 GAAP 對賬包含在我們的業績公告中，除非另有說明，否則數字以百萬美元為單位。

Please advance to the next slide. This slide shows the agenda for today's call. Following our prepared remarks, we will open the side for questions. We will try to address as many questions as we can during the allotted time. (Operator Instructions)

請轉到下一張幻燈片。這張幻燈片顯示了今天電話會議的議程。在我們準備好的發言之後，我們將開放提問環節。我們將在規定的時間內盡可能多地解決問題。 （操作員說明）

Please advance to the next slide. And with that, Pascal, I'll hand over to you.

請轉到下一張幻燈片。有了這個，帕斯卡，我就交給你了。

Thanks, Andy, and hello, everyone. Welcome to today's call. We can move to Slide 5. We delivered a strong 2022 performance, finishing the year with total revenue and EPS at the upper end of our guidance range, which I'm sure you will remember, we upgraded twice during the year.

謝謝，安迪，大家好。歡迎來到今天的電話。我們可以轉到幻燈片 5。我們在 2022 年取得了強勁的業績，以總收入和每股收益在我們指導範圍的上限結束了這一年，我相信你會記得，我們在這一年中升級了兩次。

We reported total revenue for the full year of $44.4 billion, which represents an increase of 25% at CER. Core EPS was $6.66, which is up 33% compared to the prior year. Our business fundamentals remain strong, supported by our diverse portfolio of products and also our broad geographic footprint. It is from this base of strength that we are announcing our 2023 guidance. We expect core EPS to increase by a high single-digit to low double-digit percentage given that we anticipate a very substantial decline in demand for our COVID medicines in 2023. This guidance is clear evidence of the strength of the underlying business as well as our commitment to delivering improved profitability.

我們報告全年總收入為 444 億美元，按 CER 計算增長 25%。核心每股收益為 6.66 美元，比上年增長 33%。在我們多樣化的產品組合和廣闊的地理足蹟的支持下，我們的業務基礎依然強勁。正是基於這一實力基礎，我們宣布了 2023 年的指導方針。鑑於我們預計 2023 年對我們的 COVID 藥物的需求將大幅下降，我們預計核心每股收益將以高個位數百分比增長至低兩位數百分比。該指南清楚地證明了基礎業務的實力以及我們致力於提高盈利能力。

Please advance to Slide 6. Excluding our COVID medicines, we now have 12 blockbuster medicines. And we've made remarkable progress in our pipeline over the year with 8 positive Phase III readouts and a record 34 regulatory approvals in key markets. Our pipeline momentum continues to build, and I'm pleased to tell you that we are planning to initiate more than 30 additional Phase III studies in 2023, and we believe 10 of these trials have blockbuster potential.

請轉到幻燈片 6。不包括我們的 COVID 藥物，我們現在有 12 種重磅炸彈藥物。一年來，我們在管道方面取得了顯著進展，有 8 個積極的 III 期讀數和在主要市場獲得創紀錄的 34 個監管批准。我們的管道勢頭繼續增強，我很高興地告訴你，我們計劃在 2023 年啟動 30 多項額外的 III 期研究，我們相信其中 10 項試驗具有重磅炸彈的潛力。

Here are just a few examples of Phase III trials we are initiating based on promising data we saw in the year. In oncology, we are moving our next-generation oral SERD camizestrant into the adjuvant breast cancer setting, and we are progressing 2 bispecific antibodies into several new Phase III trials. Following our proposed acquisition of CinCor, we intend to initiate a Phase III trial of baxdrostat in hypertension. And lastly, we have an opportunity in rare diseases to raise the standard of care once again for patients with hypophosphatasia with ALXN1850, our next-generation asfotase alfa.

以下是我們根據今年看到的有希望的數據啟動的 III 期試驗的幾個例子。在腫瘤學方面，我們正在將我們的下一代口服 SERD camizestrant 轉移到輔助乳腺癌環境中，並且我們正在將 2 種雙特異性抗體推進到幾個新的 III 期試驗中。在我們提議收購 CinCor 之後，我們打算啟動 baxdrostat 治療高血壓的 III 期試驗。最後，我們有機會在罕見疾病領域再次提高低磷酸酯酶症患者的護理標準 ALXN1850，我們的下一代 asfotase alfa。

Please advance to Slide 7. In order to stay at the forefront of scientific innovation, we are also making strategic investments in new platforms and technologies that have potential to drive additional waves of innovation with a few examples listed here.

請轉到幻燈片 7。為了保持在科學創新的前沿，我們還對新平台和技術進行戰略投資，這些平台和技術有可能推動更多的創新浪潮，這裡列出了一些例子。

To date, we have not only been able to build a sizable pipeline, but one with the potential to add significant value to patients and their treating physicians as is clearly evident from the many accolades that our medicines received this past year. So as you can see, we are working on today. We're working on tomorrow, which is 2025 to 2030. And we're also working on the long-term with those new investments in new technologies.

迄今為止，我們不僅能夠建立一個相當大的管道，而且有可能為患者及其治療醫生增加顯著價值，這從我們的藥物在過去一年中獲得的許多讚譽中可以清楚地看出這一點。如您所見，我們今天正在努力。我們正在為明天而努力，也就是 2025 年到 2030 年。我們也在著眼於對新技術的新投資的長期發展。

Please advance to Slide 8. Today, we are announcing our ambition to launch at least 15 new medicines by the end of the decade, which will support our ambition to deliver our industry-leading revenue growth over the long term. Looking first at 2023, we are confident that the strength of our underlying portfolio will enable us to outgrow expected revenue declines from our COVID-19 medicines. Over the midterm, excluding the COVID medicines, we are on track to deliver on our previously stated ambition of low double-digit total revenue CAGR growth for 2025, which is expected to come from our existing medicines and new launches.

請轉到幻燈片 8。今天，我們宣布了到本十年末推出至少 15 種新藥的雄心，這將支持我們實現行業領先的長期收入增長的雄心。首先展望 2023 年，我們相信我們基礎產品組合的實力將使我們能夠克服 COVID-19 藥物帶來的預期收入下降。在中期，不包括 COVID 藥物，我們有望實現我們之前提出的 2025 年低兩位數總收入 CAGR 增長的雄心，預計這將來自我們現有的藥物和新推出的藥物。

When we look to the long term, we are on track to deliver our industry-leading growth well beyond 2025. Underpinning this confidence is the strength of our commercial portfolio, but also the extensive pipeline we are developing. Additionally, while the portfolio has a relatively low exposure to loss of exclusivity compared to peers, we take a very proactive approach, which starts many years in advance.

從長遠來看，我們有望在 2025 年以後實現行業領先的增長。支撐這種信心的是我們商業組合的實力，以及我們正在開發的廣泛管道。此外，雖然與同行相比，該投資組合的排他性喪失風險相對較低，但我們採取了非常積極主動的方法，提前多年開始。

As you can see here, we have 3 examples where follow-on medicines have been identified and trials underway are being initiated to replace revenues that may be lost following the few patent expiries that are expected to occur before 2030. And of course, the focus here is on Farxiga franchise management, Lynparza replacement with the PARP1 and the switch of Soliris to Ultomiris.

正如您在這裡看到的，我們有 3 個例子，其中後續藥物已經確定，並且正在進行試驗以彌補預計在 2030 年之前發生的少數專利到期後可能損失的收入。當然，重點這是關於 Farxiga 特許經營權管理、用 PARP1 替代 Lynparza 以及從 Soliris 到 Ultomiris 的轉換。

Coupling the scale and promise of our pipeline with our strong track record of delivery and the growth outlook for our company is very exciting indeed. Importantly, we also have a clear trajectory to reduce greenhouse gas emissions with targets that have been verified by the science-based targets initiative. And finally, we remain focused on our ambition to improve operating margins, as we stated before.

將我們管道的規模和承諾與我們強大的交付記錄和我們公司的增長前景相結合，確實非常令人興奮。重要的是，我們還有一個明確的軌跡來減少溫室氣體排放，其目標已被基於科學的目標倡議所驗證。最後，正如我們之前所說，我們仍然專注於提高營業利潤率的雄心壯志。

And now I will hand over to Aradhana to take you through our financials and provide more insight into our 2023 guidance. Over to you, Aradhana.

現在，我將交給 Aradhana 來帶您了解我們的財務狀況，並更深入地了解我們的 2023 年指導方針。交給你了，Aradhana。

Thank you, Pascal, and good afternoon, everyone. As usual, I will start with our reported P&L. Please turn to Slide 9. As Pascal mentioned, total revenue increased by 25% in 2022, ahead of our fiscal year guidance of a low 20s percentage increase. Excluding COVID-19 medicine, total revenue increased by 15%. Collaboration revenue increased by 56%, partially driven by higher and hurdle sales. As a reminder, we book our share of gross profits from most major markets as collaboration revenue. For Test buyer, we book our share of gross profits from the U.S. collaboration revenue and ex-U.S. sales booked as product sales.

謝謝 Pascal，大家下午好。像往常一樣，我將從我們報告的損益開始。請轉到幻燈片 9。正如 Pascal 提到的，2022 年總收入增長了 25%，高於我們 20 多歲的低增長百分比的財政年度指導。不包括 COVID-19 藥物，總收入增長了 15%。協作收入增長了 56%，部分原因是更高的銷售額和障礙銷售額。提醒一下，我們將我們在大多數主要市場的毛利潤份額記為協作收入。對於測試買家，我們從美國合作收入和美國以外的收入中計入我們的毛利份額。銷售額記為產品銷售額。

Please turn to the next slide. Our core gross margin on product sales increased by 6 percentage points to 80% in 2022, driven by lower Vaxzevria sales compared to the prior year and favorable product sales margin with higher proportion of oncology and a full year of Alexion medicines. In the fourth quarter, a $335 million cost of inventory write-down and other termination fees negatively impacted core gross margin by approximately 3 percentage points. Core R&D costs increased by 24% in 2022, driven by initiation of a number of new late-stage trials in areas where we have seen promising data as well as a full year of Alexion R&D costs. We have also increased investments in early research, including discovery and new platforms and technologies to maintain scientific leadership.

請翻到下一張幻燈片。我們的產品銷售核心毛利率在 2022 年增長了 6 個百分點，達到 80%，這是由於 Vaxzevria 銷售額與上一年相比較低，以及較高的腫瘤學和 Alexion 藥物的全年銷售利潤率。第四季度，3.35 億美元的庫存減記成本和其他終止費用對核心毛利率產生了約 3 個百分點的負面影響。核心研發成本在 2022 年增加了 24%，這是由於在我們看到有希望的數據以及全年 Alexion 研發成本的領域啟動了許多新的後期試驗。我們還增加了對早期研究的投資，包括發現和新平台和技術，以保持科學領先地位。

R&D as a percentage of total revenue remained in line with our expectations around 21%. SG&A investment increased by 21%, reflecting a full year of Alexion costs as well as new launches and pre-launch support. As Pascal mentioned in his introduction, we received 34 regulatory approvals in major markets last year, which also impacts SG&A cost as we need to invest behind these launches.

研發佔總收入的百分比仍然符合我們的預期，約為 21%。 SG&A 投資增加了 21%，反映了 Alexion 全年的成本以及新產品發布和發布前支持。正如 Pascal 在他的介紹中提到的那樣，我們去年在主要市場獲得了 34 項監管批准，這也影響了 SG&A 成本，因為我們需要在這些發布後進行投資。

However, core SG&A cost as a percentage of total revenue decreased in line with our commitment to deliver operating leverage. Our core operating margin was 30% in 2022, an improvement over 2021 where our operating margin was 27%, reflecting the impact from Vaxzevria sales. We continue to focus on steadily improving our margins without compromising on our top line growth ambition.

然而，核心 SG&A 成本佔總收入的百分比有所下降，這符合我們提供運營槓桿的承諾。我們在 2022 年的核心營業利潤率為 30%，比 2021 年有所改善，當時我們的營業利潤率為 27%，反映了 Vaxzevria 銷售的影響。我們繼續專注於穩步提高利潤率，同時不影響我們的收入增長目標。

Core EPS of $6.66 was in the upper end of our full year guidance and was impacted by the Evusheld costs I previously mentioned, but benefited from a lower tax rate for the year, partly as a result of much lower tax rate in fourth quarter 2022. The core tax rate in the fourth quarter was 10% due to favorable one-off adjustments, IP incentive regimes, geographical mix of products and profits and adjustment to prior year tax liabilities.

6.66 美元的核心每股收益處於我們全年指導的上限，受到我之前提到的 Evusheld 成本的影響，但受益於全年較低的稅率，部分原因是 2022 年第四季度的稅率大幅降低。由於有利的一次性調整、知識產權激勵制度、產品和利潤的地域組合以及對上一年稅收負債的調整，第四季度的核心稅率為 10%。

Please turn to Slide 11. Our cash flow performance continues to improve. And in 2022, the net cash inflow from operating activities increased by $3.8 billion to $9.8 billion, driven by strong conversion and continuous focus on cash generation. We saw CapEx of $1.1 billion, driven by investment in manufacturing capacity, R&D equipment and Alexion integration. We anticipate CapEx to increase in 2023 to support business growth and sustainability priorities.

請轉到幻燈片 11。我們的現金流量表現繼續改善。 2022 年，在強勁的轉換和對現金產生的持續關注的推動下，經營活動產生的現金流入淨額增加了 38 億美元，達到 98 億美元。在對製造能力、研發設備和 Alexion 整合的投資推動下，我們看到資本支出為 11 億美元。我們預計資本支出將在 2023 年增加，以支持業務增長和可持續性優先事項。

In 2022, we had deal payments relating to past transactions of just above $2 billion, and we anticipate a similar level in 2023. Our net debt decreased by $1.4 billion to $22.9 billion. Our net debt-to-EBITDA ratio decreased to 2.5x. If adjusting for the Alexion inventory fair value adjustment, which does not impact our cash flow, the ratio decreased to 1.8x. Most of the fair value inventory from Alexion has now been expensed with just over $100 million more to come in 2023. Our capital allocation priorities remain unchanged with #1 priority being reinvestment in the business.

2022 年，我們與過去交易相關的交易付款略高於 20 億美元，我們預計 2023 年將達到類似水平。我們的淨債務減少 14 億美元至 229 億美元。我們的淨債務與 EBITDA 比率降至 2.5 倍。如果針對 Alexion 存貨公允價值調整進行調整（不影響我們的現金流），該比率降至 1.8 倍。 Alexion 的大部分公允價值存貨現已支出，2023 年將增加 1 億美元多一點。我們的資本配置優先事項保持不變，第一優先事項是對業務的再投資。

Please turn to Slide 12. I'm pleased to share our 2023 guidance with you. As a reminder, all our guidance is at constant exchange rates. We expect total revenue to increase by a low to mid-single-digit percentage. Excluding our COVID-19 medicines, we anticipate total revenue to increase by low double-digit percentage. As implied by the guidance, we anticipate a substantial decline in COVID-19 revenue with minimal Vaxzevria sales.

請轉到幻燈片 12。我很高興與您分享我們的 2023 年指南。提醒一下，我們所有的指導都是以固定匯率計算的。我們預計總收入將以中低個位數百分比增長。不包括我們的 COVID-19 藥物，我們預計總收入將以低兩位數的百分比增長。正如指南所暗示的那樣，我們預計 COVID-19收入將大幅下降，而 Vaxzevria 的銷售額將降至最低。

This guidance assumes some antibody sales, including revenue in 2023 from our next-generation antibody AZD3152. We anticipate the core gross margin will benefit from lower COVID revenue and then we will see a slight improvement versus pre-pandemic levels. We will continue to focus on continuous margin improvement while managing the impact of inflation on the cost of raw materials and goods.

本指南假設一些抗體銷售，包括我們下一代抗體 AZD3152 在 2023 年的收入。我們預計核心毛利率將受益於較低的 COVID 收入，然後我們將看到與大流行前水平相比略有改善。我們將繼續專注於持續提高利潤率，同時管理通貨膨脹對原材料和商品成本的影響。

In China, we expect to return to growth in 2023 with 2022 having been more of a transition year due to pricing dynamics relating to VBP and NRDL. Of course, the shorter-term impact of the current COVID wave in China is difficult to predict. While maintaining our strong focus on cost management and operating leverage, we will continue to invest in the pipeline and core operating expenses are anticipated to increase by low to mid-single-digit percentage.

在中國，由於與 VBP 和 NRDL 相關的定價動態，我們預計 2023 年將恢復增長，而 2022 年更像是一個過渡年。當然，目前中國 COVID 浪潮的短期影響很難預測。在保持我們對成本管理和運營槓桿的高度關注的同時，我們將繼續投資於管道，預計核心運營費用將以低至中個位數的百分比增長。

Collaboration revenue and other operating income are anticipated to increase versus 2022. Increase in collaboration revenue is partly driven by continued strength in HER2 sales as well as certain success-based milestone payments. Other operating income anticipate certain expected transactions that may or may not materialize during the course of the year. The core tax rate is anticipated to be between 18% and 22%. We have previously highlighted that the U.K. tax rate is anticipated to increase from 19% to 25% in April. We will also start seeing implementation of the global minimum tax rate in many countries.

與 2022 年相比，合作收入和其他營業收入預計將增加。合作收入的增加部分是由於 HER2 銷售的持續強勁以及某些基於成功的里程碑付款。其他營業收入預計某些預期交易可能會或可能不會在年內實現。核心稅率預計在 18% 至 22% 之間。我們之前曾強調，英國稅率預計在 4 月份從 19% 上調至 25%。我們還將開始在許多國家/地區實施全球最低稅率。

Core EPS is anticipated to grow by a high single, low double-digit percentage at constant exchange rates. Based on average January FX rates, we anticipate a low single-digit adverse FX impact on both total revenue and core EPS in 2023.

按固定匯率計算，核心每股收益預計將以高個位數、低兩位數的百分比增長。根據 1 月的平均匯率，我們預計 2023 年總收入和核心每股收益將受到低個位數的不利外匯影響。

With that, I will hand over to Dave to take you through our oncology performance.

有了這個，我將交給戴夫帶你了解我們的腫瘤學表現。

Thank you, Aradhana. We're pleased to report -- please turn to Slide 15. Oncology total revenues for the full year 2022 grew 20% year-over-year, underpinned by 19% growth in product sales. In the fourth quarter, oncology delivered total revenues of over $4 billion, reflecting a 12% increase year-over-year. We saw strong double-digit growth in product sales across the U.S., Europe and emerging markets with established rest of world impacted by rising COVID-19 hospitalization rates in Japan.

謝謝你，阿拉達納。我們很高興地報告——請轉到幻燈片 15。在產品銷售額增長 19% 的支持下，2022 年全年腫瘤學總收入同比增長 20%。第四季度，腫瘤學總收入超過 40 億美元，同比增長 12%。我們看到美國、歐洲和新興市場的產品銷售額實現兩位數的強勁增長，而世界其他地區則受到日本 COVID-19 住院率上升的影響。

Turning now to our individual medicines. Tagrisso global revenues grew by 12% in the fourth quarter. In the U.S., fourth quarter growth was fueled by continued ADAURA momentum and increased FLAURA duration of therapy. We saw solid growth of 17% in Europe despite impact from pricing clawbacks in certain markets.

現在轉向我們的個別藥物。 Tagrisso 全球收入在第四季度增長了 12%。在美國，第四季度的增長受到 ADAURA 持續增長勢頭和 FLAURA 治療持續時間增加的推動。儘管受到某些市場定價回扣的影響，我們在歐洲看到了 17% 的穩健增長。

China Tagrisso revenues in the fourth quarter were impacted by hospital budget management. Execution in China remains strong, and we expect demand to outpace the pricing impact following NRDL reenlistment, which will take effect in March. Lynparza remains the leading PARP inhibitor globally with fourth quarter product sales growth of 17%, and we received a milestone tied to the European approval of PROpel in the quarter. We saw double-digit sales growth in the U.S., Europe, established rest of world, and the emerging markets, supported by increased penetration in breast, ovarian and prostate cancers.

中國泰瑞沙第四季度的收入受到醫院預算管理的影響。中國的執行力依然強勁，我們預計需求將超過 NRDL 重新納入後的定價影響，該計劃將於 3 月生效。 Lynparza 仍然是全球領先的 PARP 抑製劑，第四季度產品銷售額增長 17%，我們在本季度收到了與歐洲批准 PROpel 相關的里程碑。我們在美國、歐洲、成熟的世界其他地區和新興市場看到了兩位數的銷售增長，這得益於乳腺癌、卵巢癌和前列腺癌的滲透率增加。

Turning now to Imfinzi. Revenues grew 27% in the fourth quarter, fueled by new indications in the U.S. and Europe. We saw robust U.S. growth of 37%, reflecting rapid launch uptake in biliary tract cancer. We saw strong initial demand for Imjudo for use in combination with Imfinzi following FDA approvals for HIMALAYA and POSEIDON. In the fourth quarter, we reported Calquence total revenues of $588 million reflecting 53% growth driven by increased penetration across key markets in the growing BTK inhibitor class.

現在轉向 Imfinzi。在美國和歐洲出現新跡象的推動下，第四季度收入增長了 27%。我們看到美國強勁增長了 37%，反映出膽道癌的快速上市。在 FDA 批准 HIMALAYA 和 POSEIDON 之後，我們看到了對 Imjudo 與 Imfinzi 聯合使用的強烈初始需求。在第四季度，我們報告 Calquence 的總收入為 5.88 億美元，反映了 53% 的增長，這是由於不斷增長的 BTK 抑製劑類在主要市場的滲透率增加所推動的。

In the U.S., we saw destocking in the quarter, which reduced by half the third quarter inventory build following the launch of the Maleate tablet formulation. We expect this inventory build to be fully depleted by the end of the first quarter this year. And finally, Enhertu total revenue was up 224% in the fourth quarter to $216 million. In the U.S., Enhertu achieved approximately 50% new patient share in second line HER2-positive metastatic breast cancer and over 40% of HR-positive HER2-low post-chemo new patient share.

在美國，我們在本季度看到去庫存，在馬來酸鹽片劑配方推出後，第三季度的庫存減少了一半。我們預計到今年第一季度末，這些庫存將完全耗盡。最後，Enhertu 第四季度的總收入增長了 224%，達到 2.16 億美元。在美國， Enhertu 在二線 HER2陽性轉移性乳腺癌中獲得了約50%的新患者份額，在 HR 陽性 HER2-low 化療後新患者份額中獲得了超過 40% 的份額。

Turning to Slide 16, you'll see important near-term performance drivers across our key oncology medicines. Turning first to Tagrisso, we anticipate gradual DoT expansion in the frontline setting and continued ADAURA momentum. As previously mentioned, we still anticipate a mandatory price reduction in Japan to take effect in 2023.

轉到幻燈片 16，您將看到我們主要腫瘤藥物的重要近期績效驅動因素。首先轉向塔格里索，我們預計 DoT 會在前線環境中逐漸擴展，並會持續保持 ADAURA 的勢頭。如前所述，我們仍預計日本的強制降價將於 2023 年生效。

To date, we've seen a strong launch for Imfinzi in biliary tract cancer and we're establishing Imfinzi in combination with Imjudo in lung and liver cancers. These are both tumor areas where we're building out our global presence and these investments will position us well to deliver on future launches across the portfolio.

迄今為止，我們已經看到 Imfinzi 在膽道癌中的強勁上市，我們正在將 Imfinzi 與 Imjudo 聯合用於治療肺癌和肝癌。這些都是我們正在建立全球影響力的腫瘤領域，這些投資將使我們能夠很好地交付未來的產品組合。

Lynparza remains the leading PARP inhibitor in first-line HRD-positive ovarian cancer, where we continue to improve HRD testing rates. In BRCA-mutated breast cancer, we continue to drive testing and share, particularly in early HR-positive breast. In late December, Lynparza in combination with abiraterone received European approval in prostate cancer with an all-comers label, reflecting the strength of the Phase III PROpel trial. In the U.S., we continue to work with the FDA on the PROpel approval following the agency's request for more time to conduct their review.

Lynparza 仍然是一線 HRD 陽性卵巢癌的主要 PARP 抑製劑，我們繼續提高 HRD 檢測率。在 BRCA 突變的乳腺癌中，我們繼續推動測試和分享，特別是在早期 HR 陽性乳腺癌中。 12 月下旬，Lynparza 聯合阿比特龍獲得了歐洲批准用於治療前列腺癌，並貼上了所有人都同意的標籤，這反映了 III 期 PROpel 試驗的實力。在美國，在 FDA 要求有更多時間進行審查後，我們繼續與 FDA 就 PROpel 的批准進行合作。

Calquence continues to gain momentum in frontline CLL and exited the fourth quarter with 64% new patient share in the U.S., which we expect to be durable in the face of competition. We're excited about the recent positive CHMP opinion for the maleate tablet formulation, which will address an important patient need and allows for combination with PPIs.

Calquence 在一線 CLL 領域繼續獲得發展勢頭，並在第四季度以 64% 的美國新患者份額結束，我們預計這將在競爭中保持持久。我們對最近 CHMP 對馬來酸鹽片劑配方的正面意見感到興奮，這將滿足患者的重要需求並允許與 PPI 聯合使用。

We see continued demand for Enhertu in second-line HER2-positive metastatic breast cancer and strong adoption Enhertu low. We're excited to expand Enhertu low in Europe following the recent approval of DB04.

我們看到二線 HER2 陽性轉移性乳腺癌對 Enhertu 的持續需求和 Enhertu 的強烈採用。在最近獲得 DB04 批准後，我們很高興在歐洲擴展 Enhertu。

Finally, as Susan will next recap, we look to file CAPItello291 for HR-positive advanced breast cancer patients following strong Phase III results.

最後，正如蘇珊接下來要回顧的那樣，我們希望在 III 期取得強勁結果後為 HR 陽性晚期乳腺癌患者提交 CAPItello291。

With that, I'll now hand it over to Susan, who will cover key pipeline progress since our last report as well as new opportunities we're progressing into late-stage development.

有了這個，我現在將它交給 Susan，她將介紹自我們上次報告以來的關鍵管道進展以及我們正在進入後期開發的新機會。

Thank you, Dave. Please turn to the next slide. We had our largest set of presence at the San Antonio Breast Cancer Symposium in December of last year, demonstrating the high potential of our breast cancer portfolio to redefine the treatment paradigm. A key highlight with Phase III data for CAPItello291, which demonstrated that capivasertib plus Faslodex led to a statistically significant and clinically meaningful improvement in progression-free survival versus an active control of placebo plus Faslodex, with a 40% reduction in the risk of disease progression or death in the overall trial population.

謝謝你，戴夫。請翻到下一張幻燈片。去年 12 月，我們在聖安東尼奧乳腺癌研討會上的出席人數最多，展示了我們的乳腺癌產品組合在重新定義治療模式方面的巨大潛力。 CAPItello291 III 期數據的一個關鍵亮點，表明與安慰劑加 Faslodex 的主動控制相比，capivasertib 加 Faslodex 導致無進展生存期有統計學意義和臨床意義的改善，疾病進展風險降低 40%或在整個試驗人群中死亡。

CAPItello291 validates the use of AKT inhibition to address acquired resistance to endocrine therapy and CDK4/6 inhibitors regardless of a biomarker and offers a potential new standard of care in second-line therapy for the patients with estrogen receptor driven disease. We look forward to the submission of the data with the U.S. FDA granting us a Fast Track designation.

CAPItello291 驗證了使用 AKT 抑制來解決對內分泌治療和 CDK4/6 抑製劑的獲得性耐藥，無論生物標誌物如何，並為雌激素受體驅動疾病患者的二線治療提供潛在的新護理標準。我們期待著向美國 FDA 提交數據，授予我們快速通道稱號。

The camizestrant, our potential best-in-class next-generation oral SERD -- the Phase II SERENA-2 trial showed improved progression-free survival, providing confidence that camizestrant can become the backbone endocrine therapy of choice across all ER-driven breast cancer with 2 pivotal Phase III trials in the metastatic setting ongoing SERENA-4 and SERENA-6.

camistrant，我們潛在的同類最佳的下一代口服 SERD——II 期 SERENA-2 試驗顯示無進展生存期有所改善，使人們相信 camistrant 可以成為所有 ER 驅動的乳腺癌的首選內分泌治療骨幹正在進行的 SERENA-4 和 SERENA-6 轉移環境中的 2 個關鍵 III 期試驗。

We'll soon initiate our first trial in the early setting with CAMBRIA-1. This is an extended adjuvant trial that will evaluate whether switching from standard of care endocrine therapy with or without abemaciclib to camizestrant after 2 to 5 years, improves invasive breast cancer-free survival in patients with ER positive and HER2-negative early breast cancer at high risk of recurrence. CAMBRIA-1 is a critical opportunity with the potential to increase cure rates in a population at moderate to high risk for metastatic recurrence. Plans for additional trials with camizestrant are at an advanced stage.

我們很快將在 CAMBRIA-1 的早期設置中啟動我們的第一個試驗。這是一項擴展的輔助試驗，將評估是否在 2 至 5 年後從含或不含 abemaciclib 的標準護理內分泌治療轉換為 camizestrant，提高 ER 陽性和 HER2 陰性早期乳腺癌患者的無浸潤性乳腺癌生存期復發的風險。 CAMBRIA-1 是一個重要的機會，有可能提高中高轉移復發風險人群的治愈率。與 camizestrant 進行額外試驗的計劃處於後期階段。

Please turn to Slide 19. Towards the end of 2022, we reported important data for our hematological portfolio at ASH. This included new long-term follow-up data from the Phase I/II trial, ACE-CL-001 for our BTK inhibitor, Calquence, in both the treatment-naive and the relapsed/refractory chronic lymphocytic leukemia settings.

請轉到幻燈片 19。到 2022 年底，我們報告了 ASH 血液學產品組合的重要數據。這包括針對我們的 BTK 抑製劑 Calquence 的 I/II 期試驗 ACE-CL-001 在初治和復發/難治性慢性淋巴細胞白血病環境中的新長期隨訪數據。

We also presented interim Phase I data for our AZD0486, our CD19/CD3 next-generation bispecific T-cell engager. We're very encouraged by the strong objective response rates and favorable tolerability profiles seen in heavily pre-treated patients with diffuse large B-cell and follicular lymphomas. Further development is planned as these results reinforce our belief that AZD0486 provides an opportunity to reach patient populations beyond those reached by current CD20 therapies.

我們還展示了我們的 AZD0486（我們的 CD19/CD3 下一代雙特異性 T 細胞接合器）的中期 I 期數據。我們對大量預先治療的瀰漫性大 B 細胞淋巴瘤和濾泡性淋巴瘤患者的強烈客觀反應率和良好的耐受性感到非常鼓舞。計劃進一步開發，因為這些結果強化了我們的信念，即 AZD0486 提供了一個機會，可以覆蓋當前 CD20 療法所達到的患者群體。

Please move to the next slide. As we have signaled the development program for our TROP2 ADC Dato-DXd continues to expand with a new Phase III trial in lung cancer. AVANZAR will evaluate Dato-DXd plus our PD-L1 inhibitor, Imfinzi, versus pembrolizumab plus chemotherapy in first-line advanced non-small cell lung cancer. This trial allows recruitment of patients regardless of their tumor histology or PD-L1 status and will be the first to use TROP2 as a biomarker in both the primary analysis and as a stratification factor with co-primary endpoints in both the TROP2 and ITT populations.

請移至下一張幻燈片。正如我們已經發出的信號，我們的 TROP2 ADC Dato-DXd 的開發計劃繼續擴大，在肺癌中進行了一項新的 III 期試驗。 AVANZAR 將評估 Dato-DXd 聯合我們的 PD-L1 抑製劑 Imfinzi 與 pembrolizumab 聯合化療在一線晚期非小細胞肺癌中的療效。該試驗允許招募患者，無論其腫瘤組織學或 PD-L1 狀態如何，並將首次在 TROP2 和 ITT 人群中使用 TROP2 作為主要分析中的生物標誌物和作為具有共同主要終點的分層因素。

AVANZAR complements two other ongoing trials that investigate combinations of Dato-DXd and pembrolizumab. TROPION-Lung07 in the PD-L1 less than 50% population and TROPION-Lung08 in the PD-L1 more than 50% group.

AVANZAR 補充了另外兩項正在進行的研究 Dato-DXd 和 pembrolizumab 組合的試驗。 TROPION-Lung07 用於 PD-L1 低於 50% 的人群，TROPION-Lung08 用於 PD-L1 高於 50% 的人群。

Please move to the next slide. Finally, I'm excited to update you on some progression for our bispecific programs, volrustomig and rilvegostomig, both of which will be moving into Phase III this year. Volrustomig is our PD-1/CTLA-4 bispecific. And based on the longer-term follow-up data for the 750-milligram dose, we're confident to move this into late-stage trials in CTLA-4 sensitive tumors. We will be initiating 5 Phase III trials with volrustomig this year, including in non-small cell lung cancer.

請移至下一張幻燈片。最後，我很高興向您介紹我們雙特異性項目 volrustomig 和 rilvegostomig 的一些最新進展，這兩個項目都將在今年進入 III 期。 Volrustomig 是我們的 PD-1/CTLA-4 雙特異性藥物。根據 750 毫克劑量的長期隨訪數據，我們有信心將其推進 CTLA-4 敏感腫瘤的後期試驗。今年我們將啟動 5 項 volrustomig 的 III 期試驗，包括非小細胞肺癌。

In addition, our PD-1/TIGIT bispecific, rilvegostomig is continuing to progress with the first patients being dosed in the Phase II cohort of the ARTEMIDE-01 trial in first-line non-small cell lung cancer.

此外，我們的 PD-1/TIGIT 雙特異性藥物 rilvegostomig 正在繼續取得進展，第一批患者在 ARTEMIDE-01 一線非小細胞肺癌試驗的 II 期隊列中接受給藥。

Our Phase II program continues to grow with the GEMINI trial in gastric cancer. We plan to start the first Phase III with more details available later in the year.

隨著 GEMINI 胃癌試驗的進行，我們的 II 期項目繼續發展。我們計劃啟動第一階段 III，並在今年晚些時候提供更多詳細信息。

Please advance to the next slide, and I'll hand over to Ruud to cover biopharmaceuticals.

請轉到下一張幻燈片，我將交給 Ruud 來介紹生物製藥。

Thanks, Susan. Please turn to Slide 22. Total revenue from biopharmaceuticals grew 11% at constant exchange rates to $20 billion in 2022. Total revenue from CVRM was $9.2 billion, growing at 90% in the year with Farxiga delivering over $1 billion in every quarter and growth of over 50%.

謝謝，蘇珊。請轉到幻燈片 22。按固定匯率計算，生物製藥的總收入在 2022 年增長了 11%，達到 200 億美元。CVRM 的總收入為 92 億美元，年增長率為 90%，其中 Farxiga 每個季度的收入都超過 10 億美元，並且增長了超過 50%。

In our Respiratory & Immunology business, we saw strong growth in our biological medicines such as Fasenra, Tezspire, and Saphnelo. Along with continued progress for Breztri, that growth offset the generic pressure on all the medicines such as Pulmicort, Symbicort and Daliresp. Overall, R&I total revenue grew 3%.

在我們的呼吸與免疫學業務中，我們看到了 Fasenra、Tezspire 和 Saphnelo 等生物藥物的強勁增長。隨著 Breztri 的持續進步，這種增長抵消了普米克、信必可和 Daliresp 等所有藥物的通用壓力。總體而言，R&I 總收入增長了 3%。

Total revenue from our V&I portfolio was up 8%, with COVID-19 broadly flat as expected.

我們 V&I 投資組合的總收入增長了 8%，COVID-19 與預期大致持平。

Please turn to Slide 23. In 2023, we are proud to be bringing the transformative benefits of our modern medicines to more patients around the world, and we will continue to expand a base into new geographies with plans for launches in over 30 countries for Tezspire and nearly 20 each for Breztri and Saphnelo. Tezspire has seen very strong momentum since its launch this time last year, and it has already achieved new-to-brand share of over 20% in the United States.

請轉到幻燈片 23。2023 年，我們很自豪能夠將我們現代藥物的變革性優勢帶給全球更多患者，我們將繼續將基地擴展到新的地區，併計劃在 30 多個國家/地區推出 Tezspire Breztri 和 Saphnelo 各有近 20 個。 Tezspire自去年這個時候推出以來勢頭非常強勁，在美國的新品牌份額已經超過20%。

In 2023, we will look to extend that trend and replicate it in other major markets. Breztri is also enjoying good growth, doubling revenues in 2022. In 2023, we intend to capitalize on the growth of the fixed-dose combination triple class and raise awareness among patients and pulmonologists of the benefits that this medicine brings.

到 2023 年，我們將尋求延續這一趨勢並將其複製到其他主要市場。 Breztri 也取得了良好的增長，到 2022 年收入翻了一番。到 2023 年，我們打算利用固定劑量組合三聯療法的增長，並提高患者和肺科醫生對這種藥物帶來的好處的認識。

Airsupra is the first and only rescue therapy to treat underlying inflammation in asthma. This year, we will educate practitioners and patients about this new class of medicine and building up market access ahead of commercial launch.

Airsupra 是第一個也是唯一一個治療哮喘潛在炎症的搶救療法。今年，我們將對從業者和患者進行有關這種新型藥物的教育，並在商業發布之前建立市場准入。

Saphnelo is the first new treatment for lupus SLE in over a decade and has quickly become the new-to-brand SLE in the intravenous segment in the United States. We have successfully launched in 8 markets at the end of 2022. And by expanding across Europe and other markets, we can bring this medicine to even more patients in 2023.

Saphnelo 是十多年來狼瘡 SLE 的第一個新療法，並迅速成為美國靜脈注射領域的新品牌 SLE。到 2022 年底，我們已成功在 8 個市場推出。通過在歐洲和其他市場的擴張，我們可以在 2023 年將這種藥物帶給更多的患者。

And of course, Farxiga is continuing its impressive growth, helped by its expansion into heart failure with preserved ejection fraction following the DELIVER results. With such a strong portfolio of innovative products, we remain very excited about the long-term prospects for our biopharmaceuticals business.

當然，Farxiga 正在繼續其令人印象深刻的增長，這得益於它在 DELIVER 結果後擴展到射血分數保持不變的心力衰竭。憑藉如此強大的創新產品組合，我們對生物製藥業務的長期前景感到非常興奮。

With that, I will now turn the call over to Mene to cover our pipeline.

有了這個，我現在將把電話轉給 Mene 來覆蓋我們的管道。

Thank you, Ruud. And please turn to Slide 24. I want to start by providing some highlights from our mid- to late-stage pipeline in CVRM, demonstrating the depths and breadths across our portfolio. .

謝謝你，魯德。請轉到幻燈片 24。我想首先提供 CVRM 中後期管道的一些亮點，展示我們產品組合的深度和廣度。 .

I won't go through all these assets in detail, but I wanted to draw your attention to the areas we're focusing on, namely cardiorenal, metabolic and liver diseases. Supporting our commitment to cardiorenal diseases, you will see in the quarter, we announced our plans to acquire SynCor adding baxdrostat, a novel aldosterone synthase inhibitor, which further strengthens our pipeline. And I'll go into more detail on this in the next slide.

我不會詳細介紹所有這些資產，但我想提請您注意我們關注的領域，即心腎、代謝和肝臟疾病。為了支持我們對心腎疾病的承諾，您將在本季度看到，我們宣布了收購 SynCor 的計劃，並添加了一種新型醛固酮合成酶抑製劑 baxdrostat，這進一步加強了我們的產品線。我將在下一張幻燈片中對此進行更詳細的介紹。

The other thing to point out is our progress with mitiperstat in Phase II for NASH. Mitiperstat is also being investigated in heart failure with preserved ejection fraction which is currently in Phase IIb and also in COPD, which is in Phase IIa. This is a mechanism, first-in-class mechanism targeting myeloperoxidase which is known to cause the formation of hypochlorous acid, which interferes with microvascular function. In our preclinical models we've seen robust efficacy, which reduced inflammation, fibrosis and also improves microvascular function. We see it as a very exciting first-in-class mechanism with broad application across our portfolio.

另一件需要指出的事情是我們在 NASH II 期使用 mitiperstat 取得的進展。 Mitiperstat 還在射血分數保留的心力衰竭中進行研究，目前處於 IIb 期，在 COPD 中也處於 IIa 期。這是一種針對髓過氧化物酶的一流機制，已知髓過氧化物酶會導致次氯酸的形成，從而乾擾微血管功能。在我們的臨床前模型中，我們已經看到了強大的功效，它可以減少炎症、纖維化並改善微血管功能。我們認為這是一個非常令人興奮的一流機制，在我們的產品組合中具有廣泛的應用。

I'm also very excited about some of the progress we've seen with our earlier stage assets, such as our long-acting relaxin in heart failure with pulmonary hypertension, PNPLA3, antisense oligonucleotide for genetically driven NASH and our small molecule oral PCSK9 inhibitor with dyslipidemia. And I look forward to sharing updates on these molecules with clinical data in the coming quarters.

我也對我們在早期資產中看到的一些進展感到非常興奮，例如我們在伴有肺動脈高壓的心力衰竭中的長效鬆弛素、PNPLA3、用於遺傳驅動的 NASH 的反義寡核苷酸和我們的小分子口服 PCSK9 抑製劑與血脂異常。我期待在未來幾個季度與臨床數據分享這些分子的更新。

Please turn to next slide. And I want to showcase in more detail our Farxiga combinations and how they're differentiated from each other. First, balcinrenone is a selective mineralocorticoid receptor modulator, which believe could have reduced risk of hyperkalemia versus conventional MR antagonists. We have an ongoing Phase II study looking at CKD patients with heart failure, a population which has limited treatment options.

請翻到下一張幻燈片。我想更詳細地展示我們的 Farxiga 組合以及它們之間的區別。首先，巴西利酮是一種選擇性鹽皮質激素受體調節劑，與傳統的 MR 拮抗劑相比，它被認為可以降低高鉀血症的風險。我們正在進行一項針對患有心力衰竭的 CKD 患者的 II 期研究，該人群的治療選擇有限。

Second is zibotentan, our endothelin A receptor antagonist, which has been shown to improve renal blood flow and reduce albuminuria and vascular stiffness. The selective profile of zibotentan in combination with Farxiga is expected to reduce significant side effects of fluid retention, a hallmark of traditional endothelin receptor antagonist. We have an ongoing Phase II trial in CKD patients with macro albuminuria. And this combination is also being investigated in liver cirrhosis than recently dosed in Phase II.

其次是 zibotentan，我們的內皮素 A 受體拮抗劑，已被證明可以改善腎血流量並減少蛋白尿和血管僵硬。 zibotentan 與 Farxiga 聯合使用的選擇性特徵有望減少體液瀦留的顯著副作用，這是傳統內皮素受體拮抗劑的一個標誌。我們正在進行一項針對患有大量白蛋白尿的 CKD 患者的 II 期試驗。並且這種組合也在肝硬化中進行研究，而不是最近在 II 期給藥。

And finally, baxdrostat, currently being investigated as a monotherapy for treatment-resistant hypertension. We believe when combined with Farxiga would significantly benefit patients with hypertension and several other cardiorenal diseases. Baxdrostat has shown to be effective at reducing systolic blood pressure without off-target inhibition of cortisol synthesis. And this treatment paradigm would offer a much-needed option for patients with CKD and hypertension. And we're planning to initiate Phase III trials for this molecule through the course of this year.

最後，baxdrostat，目前正在研究作為難治性高血壓的單一療法。我們相信，當與 Farxiga 聯合使用時，高血壓和其他幾種心腎疾病患者將顯著受益。 Baxdrostat 已顯示可有效降低收縮壓，而不會脫靶抑制皮質醇合成。這種治療模式將為 CKD 和高血壓患者提供急需的選擇。我們計劃在今年啟動該分子的 III 期試驗。

Please turn to the next slide. Here, I'm highlighting some key late-stage assets that have progressed or planned to progress during the year. Our IL-33 monoclonal antibody, tozorakimab entered Phase III trials for adults hospitalized with viral lung infections with acute respiratory failure. Emerging IL-33 signs in viral lung infections provided confidence to advance to Phase III. During the quarter, we also dosed our Phase I/III SUPERNOVA trial, which investigates the safety and efficacy of our next-generation, long-acting antibody, AZD3152 in COVID-19 pre-exposure prophylaxis settings in immunocompromised patients.

請翻到下一張幻燈片。在這裡，我重點介紹了一些在這一年中取得進展或計劃取得進展的關鍵後期資產。我們的 IL-33 單克隆抗體 tozorakimab 已進入針對因病毒性肺部感染並伴有急性呼吸衰竭住院的成人的 III 期試驗。病毒性肺部感染中出現的 IL-33 跡象為進入 III 期提供了信心。在本季度，我們還對 I/III 期 SUPERNOVA 試驗進行了給藥，該試驗研究了我們的下一代長效抗體 AZD3152 在免疫功能低下患者的 COVID-19 暴露前預防環境中的安全性和有效性。

AZD3152 neutralizes all known variants from Alpha, all the way to XBB.1.5 and the immunobridging trial design has been agreed in principle with both FDA and the EMA shortening the time between discovery and approval. We will aim to make the new lab available in the second half of 2023, subject to trial readouts and regulatory reviews. And finally, we're expanding Saphnelo into new autoimmune diseases, planning 2 new Phase III starts this year in scleroderma and polymyositis.

AZD3152 中和了從 Alpha 到 XBB.1.5 的所有已知變體，並且免疫橋接試驗設計原則上已與 FDA 和 EMA 達成一致，縮短了發現和批准之間的時間。我們的目標是在 2023 年下半年啟用新實驗室，具體取決於試驗結果和監管審查。最後，我們正在將 Saphnelo 擴展到新的自身免疫性疾病，計劃今年在硬皮病和多發性肌炎中啟動 2 個新的 III 期臨床試驗。

Please move to the next slide. Now I hand over to Marc to cover rare diseases.

請移至下一張幻燈片。現在我把報導罕見病的工作交給馬克。

Thank you, Mene. And please move to Slide 28. In 2022, Rare Disease total revenues grew 10% on a pro forma basis, contributing $7.1 billion. Throughout the year, we saw continued durable growth of our C5 franchise, which grew 7%. Ultomiris grew 42% in the year and 62% in the quarter, reflecting an accelerating and successful conversion from Soliris across PNH, atypical HUS, and MG. Consequently, Soliris declined 5% in the year, which was partially offset by the growth in NMO, where Soliris remain the market leader.

謝謝你，梅內。請轉到幻燈片 28。2022 年，罕見病總收入預估增長 10%，貢獻 71 億美元。全年，我們看到 C5 特許經營權持續持續增長，增長了 7%。 Ultomiris 在這一年增長了 42%，在本季度增長了 62%，反映出從 Soliris 到 PNH、非典型 HUS 和 MG 的加速和成功轉換。因此，Soliris 在這一年下降了 5%，這部分被 NMO 的增長所抵消，而 Soliris 仍然是市場領導者。

Beyond the C5 franchise, Strensiq delivered 18% in the year and 27% in the quarter due to increased awareness and diagnosis as well as geographical expansion. Koselugo contributed significant growth in the quarter and is now available in 28 markets.

除了 C5 特許經營權之外，由於意識和診斷的提高以及地域擴張，Strensiq 在年內實現了 18% 的增長，在本季度實現了 27% 的增長。 Koselugo 在本季度貢獻了顯著增長，現已在 28 個市場上市。

Our geographic expansion continues, leveraging AstraZeneca footprint, and we launched in 11 more countries in 2022. This figure includes China where Soliris has launched in PNH and atypical HUS late in 2022. Our rare disease medicines are now available in 57 countries, and we are well on track to achieve 100 countries by 2030.

我們的地域擴張繼續，利用阿斯利康的足跡，我們於 2022 年在另外 11 個國家/地區推出。這個數字包括 Soliris 在 PNH 和非典型 HUS 於 2022 年底推出的中國。我們的罕見病藥物現已在 57 個國家/地區上市，我們是有望在 2030 年實現 100 個國家。

Please move to the next slide. I wanted to spend some time discussing our approach to PNH, where our conversion from Soliris to Ultomiris is now well over 80% for both patients and payers who switch for both convenience and cost reasons. PNH is a little rare life threatening blood disorder characterized by intravascular hemolysis, IVH, which is caused by an uncontrolled activation of the complement system. Elevated LDH is a biomarker for IVH. And our C5 inhibitors have over 83,000 patient years of experience and long-term safety and efficacy data, demonstrating C5 continued and sustained LDH reduction for patients.

請移至下一張幻燈片。我想花一些時間討論我們對 PNH 的方法，對於出於方便和成本原因轉換的患者和付款人來說，我們從 Soliris 到 Ultomiris 的轉換現在已經超過 80%。 PNH 是一種罕見的危及生命的血液病，其特徵是血管內溶血 (IVH)，這是由補體系統不受控制的激活引起的。升高的 LDH 是 IVH 的生物標誌物。我們的 C5 抑製劑擁有超過 83,000 個患者年的經驗和長期安全性和有效性數據，證明 C5 持續和持續地減少患者的 LDH。

The large majority of the patient on Ultomiris are very well controlled. There is a subpopulation about 10% to 20% of patients that do experience clinically meaningful extravascular hemolysis, while they are on C5 inhibitors based on patient data from the 2 larger studies conducted in PNH patients. We have developed danicopan, a novel Factor D as an add-on therapy for these patients. And we plan to submit our data to regulators in the first half of this year.

Ultomiris 的大多數患者都得到了很好的控制。根據在 PNH 患者中進行的 2 項大型研究的患者數據，有大約 10% 至 20% 的患者亞群確實經歷了具有臨床意義的血管外溶血，而他們正在服用 C5 抑製劑。我們開發了 danicopan，一種新型 D 因子作為這些患者的附加療法。我們計劃在今年上半年將我們的數據提交給監管機構。

Please move to next slide. Here, I wanted to showcase 2 of our planned Phase III trials for the year. The first is Ultomiris in cardiac surgery associated acute kidney injury, part of label expansion plans for Ultomiris. Acute kidney injury is a high unmet medical need, causing patients to endure loss of kidney function, renal replacement therapy and risk or mortality.

請移至下一張幻燈片。在這裡，我想展示我們今年計劃的 III 期試驗中的 2 個。第一個是用於心臟手術相關急性腎損傷的 Ultomiris，這是 Ultomiris 標籤擴展計劃的一部分。急性腎損傷是一種高度未滿足的醫療需求，導致患者忍受腎功能喪失、腎臟替代治療以及風險或死亡。

For patients with CKD, the risk of AKI following cardiac surgery is increased by 60% to 80%. We will focus on the subset of those patients with kidney ischaemia, where complement plays a role. This program is unique as we plan to use Ultomiris in a preventative way, a single dose given prior to surgery in the CSA-AKI patients, an exciting opportunity with blockbuster potential.

對於 CKD 患者，心臟手術後發生 AKI 的風險增加 60% 至 80%。我們將重點關注腎缺血患者的子集，補體在其中發揮作用。該計劃是獨一無二的，因為我們計劃以預防方式使用 Ultomiris，在 CSA-AKI 患者手術前給予單劑量，這是一個具有重磅炸彈潛力的令人興奮的機會。

Another Phase III plan for this year is 1850, which is our next-generation asfotase alfa in hypophosphatasia. 1850 has been optimized by our researchers for longer half-life to allow for less frequent dosing. We have also built it to have a better enzymatic activity so that we can dose at lower volumes and to have a superior manufacturing process. We believe that this improved therapy will allow us to deliver more than 2x the addressable population relative to Strensiq. This gives us great opportunity for geographic expansion, bringing this medicine to more HPP patients where there are no other treatment options.

今年的另一個 III 期計劃是 1850，這是我們在低磷酸酯酶症中的下一代 asfotase alfa。我們的研究人員對 1850 進行了優化，以實現更長的半衰期，從而減少給藥頻率。我們還構建了它以具有更好的酶活性，以便我們可以以較低的體積給藥並擁有卓越的製造工藝。我們相信，這種改進的療法將使我們能夠提供比 Strensiq 多 2 倍的可尋址人群。這為我們提供了很好的地域擴張機會，將這種藥物帶給更多沒有其他治療選擇的 HPP 患者。

And with that, please turn to Slide 30, and I will hand the call back to Pascal.

然後，請轉到幻燈片 30，我會將電話轉回給 Pascal。

Thank you, Marc. Can you move please to slide -- to the next slide. As we said before, we delivered a great performance in 2022. And very importantly, we made significant progress with our pipeline. We are very confident that 2023 will be another great year for our company with the growth of our underlying business more than offsetting the decline in demand for our COVID medicines.

謝謝你，馬克。請移到下一張幻燈片。正如我們之前所說，我們在 2022 年取得了出色的表現。而且非常重要的是，我們在管道方面取得了重大進展。我們非常有信心，2023 年對我們公司來說將是又一個偉大的一年，因為我們基礎業務的增長足以抵消對我們 COVID 藥物需求的下降。

We're expecting to announce the results of at least 18 Phase III trials in 2023. And of course, had a handful of significant ones to look at for -- on this slide, as you can see on the left-hand side. Our pipeline progress, together with the strength of our strategic product portfolio makes us confident to deliver our industry-leading growth for many years to come. We expect to launch at least 15 new medicines by 2030.

我們預計將在 2023 年公佈至少 18 項 III 期試驗的結果。當然，還有一些重要的試驗值得關注——在這張幻燈片上，您可以在左側看到。我們的管道進展，加上我們戰略產品組合的實力，使我們有信心在未來許多年實現行業領先的增長。我們預計到 2030 年至少推出 15 種新藥。

Lastly, we have set bold targets for our company to reduce emissions. And I very much hope that leading by example, to address climate change will inspire others to do so as much as they can.

最後，我們為公司設定了大膽的減排目標。我非常希望以身作則，應對氣候變化將激勵其他人盡可能多地這樣做。

With that, I will hand the call back to Andy.

有了這個，我會把電話轉回給安迪。

Thank you, Pascal. And our speakers now will be joined by other members of our executive team to go to the Q&A. (Operator Instructions) With that, Pascal, I'll hand over to you to start the Q&A.

謝謝你，帕斯卡。我們的發言人現在將與我們執行團隊的其他成員一起參加問答環節。 （操作員說明）有了這個，帕斯卡，我將交給你開始問答。

Thank you, Andy, and we'll start with an online question by Andrew Baum. Andrew, go ahead.

謝謝安迪，我們將從安德魯鮑姆的在線問題開始。安德魯，繼續。

And apologies for the background noise. First question in relation to risk and this is an observation rather than a criticism. You're expediting a number of particular oncology programs into Phase III from Phase I. Obviously, you've been involved in by some of your prior experiences with Dato-DXd and low HER2, for example. But how do you think about managing that risk in the balance of return within the overall portfolio?

並為背景噪音道歉。第一個問題與風險有關，這是一個觀察而不是批評。你正在將一些特定的腫瘤學項目從第一階段加速到第三階段。顯然，你已經參與了一些你之前在 Dato-DXd 和低 HER2 方面的經驗，例如。但是，您如何看待在整個投資組合的回報平衡中管理風險？

And then second question in relation to your prophylactic COVID-19 antibodies. Do you hope to get approval under EUA or this full approval? And does that impact how you're able to use your field force to promote the drug. I note there's a significant uptick in the fourth quarter prior to the removal of the EUA. So I care about this from an ongoing revenue perspective.

然後是關於您的預防性 COVID-19 抗體的第二個問題。您希望獲得 EUA 下的批准還是完全批准？這是否會影響您如何使用現場力量來推廣藥物。我注意到在取消 EUA 之前的第四季度出現了顯著上升。所以我從持續收入的角度關心這一點。

Thanks, Andrew. So maybe Susan, you can cover the first question. And Iskra, you'll cover the second one, which is approval EUA and use your field force.

謝謝，安德魯。所以蘇珊，你可以回答第一個問題。 Iskra，你將涵蓋第二個，即批准 EUA 並使用你的現場力量。

Okay. Thanks for the question. So I think in terms of the acceleration of products from early phase into late phase, we do have efficacy expansions in all of the trials where we've moved products into late-phase decision-making. So we have a robust dose selection data sets, and we have robust both efficacy and safety data sets to support those investments.

好的。謝謝你的問題。因此，我認為就產品從早期階段到後期階段的加速而言，我們確實在所有將產品轉移到後期決策的試驗中進行了療效擴展。因此，我們擁有強大的劑量選擇數據集，並且我們擁有強大的療效和安全性數據集來支持這些投資。

And in the case of the ADCs we've got a clinically validated linker warhead combination. And based on the data we've already seen within HER2, which together with the data that we have, with datopotamab deruxtecan across multiple trials gives us confidence in the profile.

在 ADC 的情況下，我們有一個經過臨床驗證的鏈接器彈頭組合。基於我們已經在 HER2 中看到的數據，連同我們擁有的數據，datopotamab deruxtecan 在多個試驗中使我們對概況充滿信心。

And similarly, with the bispecifics, I would just comment that I think CTLA-4 is a very well-validated target. The challenge has been the tolerability and the design of volrustomig is designed to address specifically that challenge, and we're encouraged by the data that we've seen, particularly with longer follow-up to support that. So I feel that we're not just accelerating them. We're accelerating on the base of good data that always convinces us that this is a good balanced risk.

同樣，對於雙特異性抗體，我只想說我認為 CTLA-4 是一個經過充分驗證的目標。挑戰一直是耐受性和 volrustomig 的設計旨在專門解決這一挑戰，我們對我們所看到的數據感到鼓舞，特別是更長時間的後續行動來支持這一點。所以我覺得我們不僅僅是在加速它們。我們在良好數據的基礎上加速發展，這些數據總是讓我們相信這是一個很好的平衡風險。

Yes. So thanks, Andrew, for the question. As you fairly noticed, we are definitely advancing the development of our new antibody. And we do aim to make it available to the patient in the second half of this year. Obviously, while developing the clinical development program, we also consulted with the regulators, including FDA. And there is an agreement to basically look at the immunobridging data from the study and the grant emergency approval based on those data. And the key reason for that is the significant unmet need and this long-acting monoclonal antibody the same as Evusheld. They remain the only option at a given time for the protection for immunocompromised patient.

是的。謝謝安德魯提出的問題。正如您所注意到的，我們肯定正在推進我們新抗體的開發。我們的目標是在今年下半年將其提供給患者。顯然，在製定臨床開發計劃的同時，我們也諮詢了包括FDA在內的監管機構。並且有一項協議，主要是查看研究中的免疫橋接數據，並根據這些數據授予緊急批准。關鍵原因是未滿足的需求以及這種與 Evusheld 相同的長效單克隆抗體。在特定時間，它們仍然是保護免疫功能低下患者的唯一選擇。

On your second part of the question on the promotion, that is absolutely correct that any emergency approval dictates that how much you can do and the promotion with the field force in U.S. But it's also important to note that during the COVID and because of the high unmet needs, there were different exceptions. Because all stakeholders do understand the importance of education and raising awareness, both in a patient population that needs protection as well as with the health care professionals. And we do believe that, that will continue, again, given the high unmet need and given the fact that COVID is here to stay and those patients will need protection going forward.

關於晉升問題的第二部分，這是絕對正確的，任何緊急批准都規定了你能做多少以及在美國的現場工作人員的晉升。但同樣重要的是要注意，在 COVID 期間，由於高未滿足的需求，有不同的例外。因為所有利益相關者都明白教育和提高意識的重要性，無論是對需要保護的患者群體還是對醫療保健專業人員。我們確實相信，鑑於未滿足的需求很高，並且考慮到 COVID 將繼續存在，這些患者將需要保護，這將再次持續下去。

Thank you, Iskra. Mattias Häggblom at Handelsbanken. Mattias, over to you.

謝謝你，火星報。 Handelsbanken 的 Mattias Häggblom。馬蒂亞斯，交給你了。

Two questions, please. First, on manufacturing capabilities. The company is known as one of the strongest in small molecule manufacturing within the industry. But as the company moves into more complex modalities within R&D like cell therapies, I'm curious to hear if in the medium term, there is a need as well to step up your in-house capabilities within manufacturing for those areas as well?

請教兩個問題。第一，關於製造能力。該公司被譽為業內小分子製造領域實力最強的公司之一。但隨著公司在研發中進入更複雜的模式，如細胞療法，我很想知道在中期，是否也需要加強這些領域製造的內部能力？

And then secondly, when I look at consensus projections for both '24 and '25 top line is below double digit and for '26 and '27 around 45% growth, which I doubt would be enough to qualify as industry-leading growth. So which areas are perhaps beyond '25 areas where the company remains underestimated by the Street?

其次，當我查看 24 年和 25 年收入的共識預測時，收入低於兩位數，而 26 年和 27 年收入增長約 45%，我懷疑這是否足以成為行業領先的增長。那麼，哪些領域可能超出了 25 個公司仍被華爾街低估的領域？

Thank you, Mattias. So let me just try to cover the first one. We think we have strong manufacturing capabilities in small molecules, but also in large molecules, we have been developing this over the last number of years. And as you've seen from our presentation, we have now several biologics.

謝謝你，馬蒂亞斯。所以讓我試著介紹第一個。我們認為我們在小分子和大分子方面都有強大的製造能力，我們在過去幾年一直在開發這一點。正如您從我們的演示中看到的那樣，我們現在有幾種生物製劑。

Now in terms of new technologies, it is true that moving forward, we will need new capabilities, and we're working on this in cell therapy, of course, but in other fields as well. So we definitely are looking at this, and we will build the capabilities we need as the pipeline progresses, and we develop -- we get data from products that give us confidence that we need to scale up. But definitely, we are looking at it from a CMC view point already on with many technologies.

現在就新技術而言，向前邁進確實需要新的能力，當然，我們正在細胞治療領域開展這方面的工作，但在其他領域也是如此。因此，我們肯定會關注這一點，我們將隨著管道的進展構建我們需要的能力，我們會開發——我們從產品中獲取數據，這些數據讓我們有信心需要擴大規模。但可以肯定的是，我們已經從許多技術的 CMC 角度來看它。

The second question, we don't actually guide by products. So not exactly sure how to answer your question, really, in terms of your judgment based on the consensus. Consensus is looking at a variety of products. This -- I would only say that we think we can derive growth across the totality of our portfolio, first of all, managing dependent expiries, as we've explained here; secondly, launching new products; and thirdly, growing the existing products we have in the pipeline. Now I don't know if any of my colleagues want to add and he's saying, yeah, it's a little bit difficult to give you guidance by products.

第二個問題，我們其實不以產品為導向。因此，根據您基於共識的判斷，我不確定如何回答您的問題。共識正在研究各種產品。這——我只想說，我們認為我們可以在我們的整個投資組合中實現增長，首先，管理依賴到期，正如我們在這裡解釋的那樣；其次，推出新產品；第三，增加我們正在開發的現有產品。現在我不知道我的同事是否想補充他說，是的，通過產品給你指導有點困難。

Yeah. We have 15 new launches. And definitely, lots of growth in our so-called commercial portfolio are our existing products. But the 15 new launches of these are NMEs. And beyond this, we have a large range of line of life cycle management programs. We launched 30 new Phase III this year. A lot of those are life cycle management programs that will add sales to existing products, will become part of the consensus as people realize what those studies are. I think that's a much -- yes, we can't say much more than this.

是的。我們推出了 15 款新產品。當然，我們所謂的商業產品組合中的大量增長是我們現有的產品。但其中 15 個新推出的是 NME。除此之外，我們還有範圍廣泛的生命週期管理計劃。我們今年推出了 30 個新的三期。其中很多是生命週期管理計劃，將增加現有產品的銷售額，隨著人們意識到這些研究的意義，它們將成為共識的一部分。我認為這很多 - 是的，我們不能說更多。

The next question comes from Tim Anderson of Wolfe. Tim, over to you.

下一個問題來自 Wolfe 的 Tim Anderson。蒂姆，交給你了。

Two questions. On Dato-DXd, the decision to move into a new Phase III trial in frontline lung could be interpreted as you having even higher confidence in the pending TROPION-Lung01 readout in second line. Is that a fair read through that we can make? Or is the decision to move into a new frontline trial totally independent of what TROPION-Lung01 shows?

兩個問題。在 Dato-DXd 上，進入新的一線肺部 III 期試驗的決定可以解釋為您對二線待定的 TROPION-Lung01 讀數有更高的信心。這是我們可以做到的公平閱讀嗎？還是決定進入新的一線試驗完全獨立於 TROPION-Lung01 的表現？

And then second question is on earnings guidance. You're kind enough to give us revenue guidance for '23 excluding COVID revenues. The earnings guidance still contains COVID contribution and that distorts results year-on-year. Could you give us an idea of what that earnings guidance would be if you excluded COVID from base in 2022 as well as 2023?

然後第二個問題是關於收益指導。您非常友好地為我們提供了 23 年不包括 COVID 收入的收入指導。收益指引仍然包含 COVID 的貢獻，並且與去年同期相比扭曲了結果。如果您在 2022 年和 2023 年將 COVID 排除在基數之外，您能否告訴我們收益指導是什麼？

Great question, Tim. So the first one, Susan, you can cover on the second one, even though we don't split our EPS or our profit by product or franchise. I think Aradhana, you can give some color to this. Susan, do you want to cover the first one?

好問題，蒂姆。所以第一個，蘇珊，你可以涵蓋第二個，即使我們沒有按產品或特許經營權分割我們的每股收益或利潤。我認為 Aradhana，你可以給它一些顏色。蘇珊，你想報導第一個嗎？

Yes. Thanks for the question. So the confidence in Dato-DXd is monotherapy and the second line is built from the monotherapy experience that we've got previously. And the confidence to move into AVANZAR study is built from the -- some of the data that you've seen with the TROPION-Lung02 data set with the combination with different I/O immune checkpoint inhibitors.

是的。謝謝你的問題。因此，對 Dato-DXd 的信心是單一療法，而第二條線是建立在我們之前獲得的單一療法經驗的基礎上的。進入 AVANZAR 研究的信心來自——您在 TROPION-Lung02 數據集上看到的一些數據，結合不同的 I/O 免疫檢查點抑製劑。

So I think what that shows is there's also activity in PD-L1 low patient population with that combination as well. And then, of course, we've been working and developing TROP2 biomarker based on the initial data. So I think there's different elements that are involved in the AVANZAR study. But I would just say that we have confidence built across multiple data sets for the Dato-DXd program.

所以我認為這表明在 PD-L1 低患者人群中也有這種組合的活動。然後，當然，我們一直在根據初始數據開發 TROP2 生物標誌物。所以我認為 AVANZAR 研究涉及不同的元素。但我只想說，我們有信心為 Dato-DXd 計劃建立跨多個數據集。

Yes. And as it relates to COVID-related contribution for 2023, again, we don't break down profitability by product. But I can just say that the COVID contribution is not material to profitability in 2023. We did mention that we are advancing the next-generation antibody. Obviously, we have some expectations before year-end. But we're also obviously spending money on clinical trials and actively recruiting that. So the net contribution is not expected to be material.

是的。由於它與 2023 年與 COVID 相關的貢獻有關，因此我們不會按產品細分盈利能力。但我只能說 COVID 的貢獻對 2023 年的盈利能力並不重要。我們確實提到我們正在推進下一代抗體。顯然，我們在年底前有一些期望。但我們顯然也在臨床試驗上花錢並積極招募。因此，預計淨貢獻不會很大。

Thanks, Aradhana. So Tim, I'm sure you will triangulate those numbers. But if you do that and you combine what Aradhana told you, which is very minimal profitability for COVID in '23. And you look at what you could estimate for '22, I'm sure you will realize the underlying profit growth for the rest of the business is very substantial. So definitely, we are on track with growing sales and profitability from the underlying business.

謝謝，阿拉達納。所以蒂姆，我相信你會三角測量這些數字。但是，如果您這樣做並且將 Aradhana 告訴您的內容結合起來，那麼 23 年 COVID 的盈利能力非常小。你看看你對 22 年的估計，我相信你會意識到其餘業務的潛在利潤增長非常可觀。因此，可以肯定的是，我們正朝著基礎業務的銷售額和盈利能力增長的方向發展。

Luisa Hector at Berenberg. Luisa, over to you.

貝倫貝格的路易莎·赫克托。路易莎，交給你了。

On Alexion really. So one for Marc, just in terms of confidence in the complement area given some of the recent competitors launching and having data. And perhaps you could also highlight the advantages of your own subcutaneous C5 1720, which I think is just starting Phase III myasthenia gravis. So when might we see some data for that? And what are the advantages that you could offer?

真的在 Alexion 上。因此，對於 Marc 來說，考慮到一些最近推出並擁有數據的競爭對手，就對補充領域的信心而言。也許您還可以強調您自己的皮下注射 C5 1720 的優勢，我認為它剛剛開始 III 期重症肌無力。那麼我們什麼時候可以看到一些數據呢？您可以提供哪些優勢？

And on the cost side here, there's a lot of commentary around some of your savings after the deal. It looks like synergies are higher, but this seems to be on a gross level. So before any reinvestment, should we expect any of that increase in cost savings to fall to the bottom line? Or do you plan to reinvest?

在這裡的成本方面，有很多關於交易後您節省的一些費用的評論。看起來協同效應更高，但這似乎是在總體水平上。因此，在進行任何再投資之前，我們是否應該預期成本節約的增加會降到底線？或者你打算再投資？

Thank you. Thank you for the 3 question. I will take them in order. The first one is our confidence in C5. It is absolutely true that there are growing competition in C5, and we had always modeled that. We always said the -- our franchise -- our C5 franchise would be durable, sustainable, but it would not be static. In other words, we are going to lose to some competition in our earlier indications, but we are going to grow into new indication, and we are continuing to pioneer development on Ultomiris. But as you mentioned, 1720 and other products in the complement cascade to gain pioneering a new indication.

謝謝。謝謝你的第3個問題。我會把它們整理好。第一個是我們對C5的信心。 C5 中的競爭越來越激烈，這是絕對正確的，我們一直在模仿這一點。我們總是說——我們的專營權——我們的 C5 專營權將是持久的、可持續的，但它不會是靜態的。換句話說，我們將在早期的適應症中輸給一些競爭者，但我們將成長為新的適應症，我們將繼續引領 Ultomiris 的發展。但是正如你所提到的，1720和其他產品在補充級聯中獲得了新適應症的開拓。

Today, I described one of them, the cardiac surgery-associated AKI. But there are several other new indications that we would pioneer for the C5 inhibitors. Talking about 1720, it is absolutely right that we have initiated a Phase III trial in myasthenia gravis. The trial has initiated late last year. We expect to read out in a number of months. It's obviously a field we know well. It's a subcut formulation as you have emphasized. And we have a big hope with this product. We will also study potentially other indications for this bispecific 1720 in the coming months.

今天，我描述了其中之一，即心臟手術相關的 AKI。但是還有其他幾個新的跡象表明我們將率先開發 C5 抑製劑。說到1720，我們啟動重症肌無力III期試驗是完全正確的。該試驗於去年年底開始。我們預計將在數月內宣讀。這顯然是我們熟悉的領域。正如您所強調的，這是一個細分公式。我們對這款產品寄予厚望。我們還將在未來幾個月研究這種雙特異性 1720 的其他潛在適應症。

Talking about the synergies, it is a fact that we have been able to find quite a lot of synergies in manufacturing, in enabling functions, but also also synergies in the scientific world where we can -- when Alexion can now tap into many of the existing capabilities in research and development and a lot of exchange of animal models or chemical library, high scope screening. I mean, the variety of synergies is wide. And we do reinvest part of the synergies into beefing up our own research and development capabilities for us to develop more molecules. We expect to have by the end of 2023, about 10 products in Phase III trials. So far, this is a great increase in comparison to what we had in the past. And of course, we will provide when these products become ready for Phase III, we will provide visibility and explain what they are going to produce with this.

談到協同作用，事實上我們已經能夠在製造、啟用功能方面找到很多協同作用，而且在科學界我們也能找到協同作用——亞力兄現在可以利用許多現有的研發能力和大量交換動物模型或化學庫，高範圍篩選。我的意思是，協同作用的範圍很廣。我們確實將部分協同效應重新投資於增強我們自己的研發能力，以便我們開發更多的分子。我們預計到 2023 年底，大約有 10 種產品進入 III 期試驗。到目前為止，與過去相比，這是一個很大的增長。當然，當這些產品準備好進入第三階段時，我們將提供可見性並解釋他們將以此生產什麼。

Thank you, Marc. Probably maybe add just some other color with on Alexion. It is a very good company, a very strong company. It's a very strong team, good science, good products. So essentially, and then also very high profitability, as you know very well from past numbers that Alexion was publishing. So our goal is really not to try and optimize the cost base. We're generating a lot of cost synergies and we're investing quite a bit of this in the pipeline because our goal is to drive the top line. .

謝謝你，馬克。可能只是在 Alexion 上添加一些其他顏色。這是一家非常好的公司，非常強大的公司。這是一個非常強大的團隊，好的科學，好的產品。所以從本質上講，然後還有非常高的盈利能力，正如您從 Alexion 發布的過去數字中非常了解的那樣。所以我們的目標真的不是嘗試優化成本基礎。我們正在產生大量的成本協同效應，並且我們在管道中投入了大量資金，因為我們的目標是推動收入增長。 .

If we drive the top line, mechanically, we will improve the operating margin of the overall AstraZeneca. So we're really investing in the pipeline. We are investing in expanding the coverage globally in China, emerging markets, et cetera, et cetera. That's really the goal we have. Operating margin improvement as a percentage, they really have to come from other parts of the company. But for Alexion, it's really a top line-driven focus.

如果我們機械地推動收入增長，我們將提高整個阿斯利康的營業利潤率。所以我們真的在投資管道。我們正在投資擴大在中國、新興市場等全球的覆蓋範圍。這確實是我們的目標。營業利潤率的提高確實來自公司的其他部門。但對於 Alexion 來說，這確實是一個頂線驅動的焦點。

The next one is James Gordon, JPMorgan. James, over to you.

下一位是摩根大通的詹姆斯戈登。詹姆斯，交給你了。

James Gordon, JPMorgan. I'll try and restrain myself with a number of questions and just ask 2 about upcoming pipeline data points. The first one was on Dato-DXd and upcoming TL01 data. So this data is in refractory lung. And assuming you do show a significant benefit versus chemo, how should we extrapolate that to the TL07, TL08 and the AVANZAR trials that have been front line. Would we extrapolate just the absolute benefit on PFS and OS? Or would it be the proportional benefit, the hazard ratio that we would extrapolate? That will be the first question, please.

詹姆斯戈登，摩根大通。我會嘗試用一些問題來克制自己，只問 2 個關於即將到來的管道數據點的問題。第一個是關於 Dato-DXd 和即將發布的 TL01 數據。所以這個數據是在難治性肺中。假設你確實顯示出與化療相比有顯著益處，我們應該如何將其外推到 TL07、TL08 和一線的 AVANZAR 試驗。我們是否僅推斷 PFS 和 OS 的絕對優勢？或者它會是我們推斷的比例收益，即風險比？這將是第一個問題，請。

And then the second question, also upcoming, so you've got FLAURA2 data, Tagrisso and chemo. How confident are you that's going to show a clinically meaningful benefit to justify extra tox and extreme convenience from chemo? And how do you think now that might stack up versus what J&J might show from our poster with their combo approach where we're also going to get Phase III data at the end of this year?

然後是第二個問題，也即將到來，所以你有 FLAURA2 數據、Tagrisso 和化療。您對顯示臨床意義的益處以證明化療帶來的額外毒性和極端便利有多大信心？你認為現在這可能與強生公司可能從我們的海報中展示的組合方法相比如何，我們也將在今年年底獲得 III 期數據？

Susan, I think those are both for you.

蘇珊，我想這兩樣都適合你。

Okay. Thank you. Thanks for the questions. So the Dato-DXd, again, as I said, I think the data in the second line show the potential for improving on the current standard of care. But of course, you're going to get in the second line responses in a subset of the total patient population. It's really the durability of those responses that drives the confidence in that efficacy component. The first-line trial isn't just about Dato-DXd. It's about combinations of Dato-DXd with the immunotherapy agents. And again, we have seen is something where you're seeing enhanced response rates beyond what you would just look at from and what you would expect from the individual components. So I think that's really what gives us confidence about the first line, and I don't think it's a straightforward extrapolation from the data that you've just seen in TL01. It's taken into account the other data that we've got across the portfolio.

好的。謝謝。感謝您的提問。所以 Dato-DXd，正如我所說，我認為第二行的數據顯示了改善當前護理標準的潛力。但是，當然，您將在總患者群體的一部分中獲得二線反應。正是這些反應的持久性推動了人們對該功效成分的信心。一線試用不僅僅是關於 Dato-DXd。它是關於 Dato-DXd 與免疫治療藥物的組合。再一次，我們已經看到，您看到響應率的提高超出了您所看到的以及您對各個組件的期望。所以我認為這真的讓我們對第一行充滿信心，我不認為這是從你剛剛在 TL01 中看到的數據的直接推斷。它考慮了我們在整個投資組合中獲得的其他數據。

The FLAURA2, the confidence for that is based on the -- again, we've got a Phase II data set that's already been published, the Opel data set, which showed really high response rate of around 90% and a high durable progression-free survival, which if recapitulated in the FLAURA2 would represent a significant improvement over the standard of care and something that's in line with what the much smaller data set that we've seen from the amuvatinib combination has seen. So I think that's what gives us confidence.

FLAURA2，對此的信心是基於——再次，我們有一個已經發布的 II 期數據集，Opel 數據集，它顯示了大約 90% 的高響應率和高持久進展-免費生存，如果在 FLAURA2 中概括，這將代表對護理標準的顯著改進，並且與我們從 amuvatinib 組合中看到的更小的數據集所看到的一致。所以我認為這就是給我們信心的原因。

Yes, it does come at a tolerability profile, but there are some patients who are symptomatic in first line because of their disease that might want a higher response rate and the opportunity to have that longer time off therapy. And again, the chemotherapy is only given for a fixed duration in the FLAURA2. So I still think that it represents a reasonably convenient overall regimen for patients in that setting.

是的，它確實具有耐受性，但有些患者由於其疾病而在一線出現症狀，他們可能希望獲得更高的反應率並有機會延長治療時間。同樣，化療僅在 FLAURA2 中進行固定持續時間。所以我仍然認為，對於那種情況下的患者來說，它代表了一種相當方便的整體治療方案。

Thank you, Susan. Christopher Uhde at SEB. Chris, go ahead.

謝謝你，蘇珊。 SEB 的克里斯托弗·烏德 (Christopher Uhde)。克里斯，繼續。

One is just a follow-up on Evusheld, which is -- can you tell us what proportion of it roughly has actually made it from shelves into arms? I'm thinking about this stat article mid last year, but tracking sales for this one doesn't work like other drugs. Then -- so yes, is there are any ways that you can use to -- that you could share with us, that would be great to hear.

一個只是 Evusheld 的後續行動，也就是——你能告訴我們它實際上從貨架上變成武器的大致比例是多少嗎？我正在考慮去年年中的這篇統計文章，但跟踪這篇文章的銷售情況不像其他藥物那樣有效。然後 - 是的，有沒有什麼方法可以用來 - 你可以與我們分享，很高興聽到。

And then the second question, so Calquence going forward. I noted your remark about durability. But Obviously, the competition is sort of now better positioned than Calquence. So strategically, obviously, Calquence is supposed to be a backbone of, I think, a budding hematology franchise built on combos. So how do these recent competitive advances affect that strategy and your outlook for Calquence going forward?

然後是第二個問題，所以 Calquence 繼續前進。我注意到你關於耐用性的評論。但顯然，競爭現在比 Calquence 處於更有利的位置。所以在戰略上，顯然，Calquence 應該是，我認為，一個基於組合的新興血液學專營權的支柱。那麼，這些最近的競爭優勢如何影響該戰略以及您對 Calquence 未來的展望？

Thanks, Christopher. So maybe Iskra you can cover. The second one -- the second one is for you, Dave. It's a provocative question. We don't agree with the fact that competition is very stronger, but I'm sure you can elaborate on this. Over to you, Iskra.

謝謝，克里斯托弗。所以也許你可以報導《火星報》。第二個——第二個是給你的，戴夫。這是一個挑釁性的問題。我們不同意競爭非常激烈的事實，但我相信你可以詳細說明這一點。交給你了，火星報。

Let's start with a simple one. Thanks for the question. And when we look overall, I mean there are such huge differences across geography that is really difficult to give you 1 number. But it's also true that if you look at the countries where Evusheld was available earlier basically from December 2021, you will see the numbers that go up to 80% or 90% of the delivered doses that are utilized in the hospitals and obviously in the arms of the patients.

讓我們從一個簡單的開始。謝謝你的問題。當我們從整體上看時，我的意思是地域之間存在如此巨大的差異，很難給你 1 個數字。但同樣真實的是，如果你看看基本上從 2021 年 12 月開始就可以使用 Evusheld 的國家，你會看到這些數字高達 80% 或 90% 的交付劑量在醫院中使用，顯然在手臂中的病人。

There is also a note to mention that in some geographies, like, for example, Japan, where a few months ago, we actually got the approval, obviously, those numbers will be very, very low. All-in-all, I think what is really important is that as this is a new market and there is a huge need to increase education and awareness around the need and the availability of those options within the hospitals, it is important to continue helping patients and HCPs to understand that. And I do believe that, that will definitely then impact the utilization across the globe.

還有一個要注意的是，在某些地區，例如日本，幾個月前，我們實際上獲得了批准，顯然，這些數字會非常非常低。總而言之，我認為真正重要的是，由於這是一個新市場，因此非常需要加強對醫院內這些選擇的需求和可用性的教育和認識，因此繼續提供幫助非常重要患者和 HCP 了解這一點。我確實相信，這肯定會影響全球的利用率。

Okay. So I think on -- Chris, for the first piece and Pascal alluded to this, I mean, we really do believe that Calquence is well positioned within the next-generation BTKi class. And I think that it's worth spending a minute on a couple of the things that underscore that conviction and are also part of the readiness and training that we've got across the globe as we do come into a more competitive space.

好的。所以我認為 - Chris，對於第一篇文章和 Pascal 提到了這一點，我的意思是，我們確實相信 Calquence 在下一代 BTKi 類中處於有利地位。而且我認為值得花一分鐘時間在一些強調這種信念的事情上，這也是我們在進入更具競爭力的領域時在全球範圍內進行的準備和培訓的一部分。

I think first and foremost, it's important to note that we've done our own important work to be taking a look at a matched indirect comparison, which is important to do. And as you do that, ASCEND and ALPINE really do show very similar results. We're in the midst of doing a similar piece of work to look at ELEVATE-TN and SEQUOIA. And I think that the reason for this is pretty straightforward, which is that the indirect or the cross-trial comparisons that were being made between the 2 head-to-head studies where really not very appropriate comparisons to be made, because they're looking at very different treatment populations.

我認為首先，重要的是要注意我們已經完成了自己的重要工作來查看匹配的間接比較，這很重要。當您這樣做時，ASCEND 和 ALPINE 確實顯示出非常相似的結果。我們正在做一項類似的工作來研究 ELEVATE-TN 和 SEQUOIA。而且我認為這樣做的原因非常簡單，那就是在 2 項頭對頭研究之間進行的間接或交叉試驗比較確實不是很合適的比較，因為它們是著眼於非常不同的治療人群。

So on the efficacy dimension, we see very well positioned. I think also of note in terms of hypertension and also neutropenia, Calquence absolutely could have some opportunities for differentiation there. That's resonating with our advisers as well. So when we take a look at the exit share that we had in 2022 and the frontline CLL setting, we eclipsed 60%, getting close to 65%.

因此，在功效維度上，我們看到了非常好的定位。我認為在高血壓和中性粒細胞減少症方面也值得注意，Calquence 絕對可以在那裡有一些分化的機會。這也引起了我們顧問的共鳴。因此，當我們查看 2022 年的退出份額和前線 CLL 設置時，我們超過了 60%，接近 65%。

We see even in the early January movement, certainly that there's been uptake of zanubrutinib, but the uptake we believe, based on our charts is predominantly in later lines, which doesn't come out of some of the acute via claims data that you see. And we're well prepared to take on competition in the year ahead, but we think we are well positioned to be able to do it.

我們甚至在 1 月初的運動中也看到了 zanubrutinib 的吸收，但我們認為，根據我們的圖表，吸收主要出現在後面的幾行中，這並不是來自您看到的一些急性索賠數據.我們已經做好了迎接來年競爭的準備，但我們認為我們有能力做到這一點。

Thank you, Dave. Eric Le Berrigaud. Over to you, Eric. Eric, you might be on mute. We can't hear you.

謝謝你，戴夫。埃里克·勒貝里戈。交給你了，埃里克。埃里克，你可能靜音了。我們聽不到你的聲音。

Do you hear me now?

你現在聽到了嗎？

Yes.

是的。

Okay. Sorry. So a couple of questions. First, a couple on the financials. First on CapEx. The first growing companies those days are suggesting a significant increase in CapEx. Now there's a doubling CapEx this year versus last. Could you quantify maybe the level of increase in CapEx in '23 versus '22, please?

好的。對不起。所以有幾個問題。首先，一對夫婦的財務狀況。首先是資本支出。那些日子裡第一批成長型公司建議大幅增加資本支出。現在，今年的資本支出比去年翻了一番。您能否量化 23 年與 22 年資本支出的增長水平？

And a pretty similar question about OOI. You're expecting an increase in other operating income this year versus last. We're coming from very high level of $1.5 billion not so long ago. So how should we think about any figure between the $450 million last year and the $1.5 billion 2 years ago? So that's for the financial part.

關於 OOI 的一個非常相似的問題。您預計今年的其他營業收入會比去年有所增加。不久前，我們來自 15 億美元的非常高的水平。那麼我們應該如何看待去年的 4.5 億美元和兩年前的 15 億美元之間的任何數字呢？這就是財務部分。

And then maybe a question for Alexion and Marc. Thanks, Marc, for clarifying about the C5 franchise. Can I try to be even more specific about the incoming competition from iptacopan APPOINT-PNH since you show a slide on PNH. How do you see this new drug competing with Ultomiris and ultimately, there the kind of market share split between these drug and the existing C5 franchise of AstraZeneca, please?

然後也許有一個問題要問 Alexion 和 Marc。馬克，謝謝你澄清了 C5 的特許經營權。既然你在 PNH 上展示了一張幻燈片，我能否嘗試更具體地說明來自 iptacopan APPOINT-PNH 的即將到來的競爭。你如何看待這種新藥與 Ultomiris 的競爭，最終，這些藥物與阿斯利康現有的 C5 特許經營權之間的市場份額分配情況如何？

Thanks, Eric. So Aradhana, the first 2 are for you, I guess.

謝謝，埃里克。所以 Aradhana，我想前兩個是給你的。

Sure. So we do expect an increase in CapEx, and we won't give specific CapEx guidance, obviously, but I can give you some color on where that increase is coming from. So firstly, as you can imagine, we have the addition of the full year of Alexion CapEx. And as Pascal mentioned, we are investing more in Alexion.

當然。所以我們確實預計資本支出會增加，顯然我們不會給出具體的資本支出指導，但我可以給你一些關於增加來自何處的顏色。因此，首先，正如您所想像的，我們增加了 Alexion 資本支出的全年。正如 Pascal 提到的，我們正在對 Alexion 進行更多投資。

The second example is we did announce a new API facility that we're going to put in Ireland, and that CapEx is going to add to the CapEx. Thirdly, we do have, obviously, investments in several sustainability initiatives and including our next-gen propellant. So that's another investment that we're making both in propellant as well as other sustainability initiatives.

第二個例子是我們確實宣布了一個新的 API 設施，我們將在愛爾蘭投入使用，並且資本支出將添加到資本支出中。第三，顯然，我們確實對多項可持續發展計劃進行了投資，包括我們的下一代推進劑。因此，這是我們在推進劑和其他可持續發展計劃方面進行的另一項投資。

And then we are, as part of our sort of continuous improvement, making several systems and infrastructure investments in our operating systems that will also add to CapEx. Again, we're not giving a specific guidance, but those are some of the elements that go into potentially increasing CapEx.

然後，作為我們持續改進的一部分，我們對我們的操作系統進行了多項系統和基礎設施投資，這也將增加資本支出。同樣，我們沒有給出具體的指導，但這些是可能增加資本支出的一些要素。

As it relates to your question on other operating income, we're giving some color on that as part of our overall guidance based on what our current view is today. I did mention that we expect an increase in collaboration revenue as our partnered products are very successful. We expect some increase in milestones, and we do expect some increase in other income. I would say we're sort of past most of the bigger divestitures and the history, I'd say we're sort of through most of the portfolio reorganization, but there may be certain other transactions that happen this year potentially.

由於它與你關於其他營業收入的問題有關，我們根據我們目前的看法，作為我們總體指導的一部分，對此進行了一些說明。我確實提到過，由於我們的合作產品非常成功，我們預計合作收入會增加。我們預計里程碑會有所增加，我們確實預計其他收入會有所增加。我想說我們已經過去了大部分更大規模的資產剝離和歷史，我想說我們已經完成了大部分投資組合重組，但今年可能還會發生某些其他交易。

Thank you, Aradhana. Marc, before you cover the Alexion question. Let me just add a little bit on the PROpel and next-generation propellant is a sustainability initiative, but it's also a business continuity and a business expansion initiative. Because it's very clear that over the next few years, we don't know exactly when, but it's clear that over the next few years, propellant as they are known today will no longer be approved and lasts for market. There's already quite a number of initiatives in many countries to ban those products. So you can imagine that we definitely need to transition our propellant-based products to the next-generation propellant that have no impact on greenhouse gas emissions.

謝謝你，阿拉達納。馬克，在你回答亞力兄問題之前。讓我稍微補充一下 PROpel 和下一代推進劑是一項可持續發展計劃，但它也是一項業務連續性和業務擴展計劃。因為很明顯，在接下來的幾年裡，我們不知道確切的時間，但很明顯，在接下來的幾年裡，今天所熟知的推進劑將不再獲得批准並繼續投放市場。許多國家已經採取了相當多的舉措來禁止這些產品。所以你可以想像，我們肯定需要將基於推進劑的產品過渡到對溫室氣體排放沒有影響的下一代推進劑。

Marc, over to you.

馬克，交給你了。

Yes. Thank you for the question on iptacopan, Eric. So basically, we have -- I mean, Alexion has many years of data, I mentioned 89,000 years of data on this. So we know that the complete inhibition of the terminal -- the terminal complement is absolutely necessary to maintain efficacy, sustained efficacy in PNH. Now it is also true that a small proportion, and we -- in our data, we see that it's about 10% to 20% of this population has some extravascular hemolysis.

是的。感謝您提出有關 iptacopan 的問題，Eric。所以基本上，我們有 - 我的意思是，Alexion 有很多年的數據，我提到了 89,000 年的數據。所以我們知道完全抑制終末——終末補體是維持藥效、持續藥效在PNH中絕對必要的。現在，一小部分人也是如此，我們 - 在我們的數據中，我們看到大約 10% 到 20% 的人口有一些血管外溶血。

And the study that several companies have produced, we have produced our own with danicopan, and we are also doing other studies with other Factor D. The same for Novartis, have done studies in this extravascular hemolysis patients. And when you do provide a proximal complement inhibitor such as a Factor D or Factor B, you can improve on hemoglobin and you can improve on anemia and so on. So I think these are very interesting data. The strategy that we are following is to provide danicopan as an add-on on the backbone of Soliris or Ultomiris. And we have seen very good results there.

幾家公司進行的研究，我們自己進行了達尼可泮，我們也在用其他 D 因子進行其他研究。諾華公司也是如此，已經在這种血管外溶血患者中進行了研究。當您提供近端補體抑製劑（例如 D 因子或 B 因子）時，您可以改善血紅蛋白和貧血等。所以我認為這些是非常有趣的數據。我們遵循的策略是提供 danicopan 作為 Soliris 或 Ultomiris 主幹的附加組件。我們在那裡看到了非常好的結果。

The question for the treatment of proximal complement inhibitors in monotherapy, they do have short-term efficacy. The question is whether this long-term efficacy will be maintained and whether the patients who, of course, with an oral treatment, you need to ensure the complete compliance of the patient for -- in a therapy where the inhibition of the activation has to be complete and sustained. So that's going to be for long-term data to be proven. I think the overall therapies can open probably in a greater field in PNH for some patients. But of course, we will need -- we will be expecting longer-term data to be absolutely sure of that.

對於近端補體抑製劑單藥治療的問題，它們確實具有短期療效。問題是這種長期療效是否會維持，當然，對於接受口服治療的患者，您是否需要確保患者完全依從性——在必須抑制激活的治療中是完整和持續的。因此，這將需要長期數據來證明。我認為對於一些患者來說，整體療法可能會在 PNH 的更大領域中打開。但當然，我們將需要——我們將期待更長期的數據來絕對確定這一點。

Okay. Mark Purcell, Morgan Stanley. Mark, over to you.

好的。馬克·珀塞爾，摩根士丹利。馬克，交給你了。

Pascal. Two questions, one on Dato-DXd, the second one on Farxiga. On Dato-DXd TROPION-Lung01, there appears to be a bit of a debate at the moment given the layers to the top line data disclosure, which could be positive, it could be negative. But if we look back at PanTumour01 and the non-small cell lung cancer, cohort, the PFS was 6.9 months. And I don't believe we've seen an update since the ASCO 2021 data. Clearly, the duration of exposure was quite low, 5 months because these were peripheral patients, that is over 60% of them were third line plus.

帕斯卡。兩個問題，一個關於 Dato-DXd，第二個關於 Farxiga。在 Dato-DXd TROPION-Lung01 上，鑑於頂線數據披露的層次，目前似乎存在一些爭論，這可能是積極的，也可能是消極的。但如果我們回顧 PanTumour01 和非小細胞肺癌隊列，PFS 為 6.9 個月。而且我認為自 ASCO 2021 數據以來我們沒有看到更新。顯然，暴露的持續時間很短，只有 5 個月，因為這些患者是外圍患者，其中超過 60% 是三線以上患者。

So as you sort of go forward and these patients are better -- likely to better tolerate mucositis and stomatitis and things like that. How should we think about PFS benefit in the second line setting? I think we all well understand that dose it has should show a a 4- to 5-month benefit in this setting. But how should we think about the PFS benefit as you come forward in line? And should we expect these data to present at ASCO or ESMO this year?

因此，隨著你的進步，這些患者會更好——可能會更好地耐受粘膜炎和口腔炎等疾病。我們應該如何考慮二線設置中的 PFS 獲益？我想我們都很清楚，在這種情況下，它的劑量應該顯示出 4 到 5 個月的好處。但是，當您排隊時，我們應該如何考慮 PFS 收益？我們是否應該期待這些數據在今年的 ASCO 或 ESMO 上呈現？

And then second, in terms of Farxiga, it would be really useful for -- to help us understand how far SECA revenues are split between diabetes, CKD and heart failure? Obviously, we recognize there's overlap between those. But it's more in terms of thinking about the future. When we look at the sort of range of combination opportunities you have on Slide 24, it would be great to understand sort of where the bigger opportunities lie. And based on Phase II data, where you believe you will drive most differentiation versus SGL2 monotherapy.

其次，就 Farxiga 而言，它真的很有用——幫助我們了解 SECA 收入在糖尿病、CKD 和心力衰竭之間的分配有多遠？顯然，我們認識到它們之間存在重疊。但更多的是考慮未來。當我們查看幻燈片 24 上的各種組合機會時，最好了解更大的機會在哪裡。根據 II 期數據，您相信您將推動與 SGL2 單一療法的最大差異化。

Thanks, Mark. So Susan back to you again. And Ruud, do you want to cover the second one in terms of the potential?

謝謝，馬克。所以蘇珊再次回到你身邊。還有 Ruud，你想在潛力方面涵蓋第二個嗎？

So thanks, Mark, for the question. Well, you clearly are very familiar with the lung cohort from the TROPION and PanTumour study. As you say, it's close to a 7-month median PFS in a more heavily pretreated patient population. So again, one would expect that in an earlier line, you might do a little better than that, but that's -- we'll have to wait and see for the trial data to read out. And then in terms of the timing, it's an event-driven trial. We've guided to the first half that's what we're still expecting to see. And of course, depending on the timing, we'll then make the data available at an upcoming congress dependent on those timing.

馬克，謝謝你提出這個問題。那麼，您顯然非常熟悉 TROPION 和 PanTumour 研究中的肺隊列。正如您所說，在接受更大量預處理的患者群體中，它接近 7 個月的中位 PFS。因此，人們會再次期望在較早的一行中，您可能會做得更好一點，但那是——我們將不得不等待並等待試驗數據被讀出。然後就時間而言，這是一個事件驅動的試驗。我們已經引導到上半年，這是我們仍然期待看到的。當然，根據時間安排，我們將根據這些時間安排在即將召開的大會上提供數據。

Okay. And regarding your question about the split market, it's a bit of a difficult question because there are substantial differences across different geographies, primarily in the emerging markets, the international markets is still heavily driven by diabetes. But if you look at the United States and Europe, it's roughly 2/3 of the patients are coming from heart failure and CKD. But rightly mentioning there is a substantial overlap.

好的。關於你關於分裂市場的問題，這是一個有點困難的問題，因為不同地區之間存在很大差異，主要是在新興市場，國際市場仍然在很大程度上受到糖尿病的推動。但如果你看看美國和歐洲，大約有 2/3 的患者來自心力衰竭和 CKD。但正確地提到存在大量重疊。

Moving forward, we truly believe that there is a substantial opportunity for our combinations in the heart failure segment and the chronic kidney disease segment. Both segments are very well underserved, and we believe is the excellent profile of Farxiga and potentially also, of course, then the antihypertensive effects of baxdrostat as well as 9977, we have a unique opportunity to further expand that population in both CKD and heart failure.

展望未來，我們真的相信我們在心力衰竭領域和慢性腎臟疾病領域的組合有很大的機會。這兩個細分市場都沒有得到很好的服務，我們相信 Farxiga 的出色表現，當然還有 baxdrostat 和 9977 的抗高血壓作用，我們有一個獨特的機會進一步擴大 CKD 和心力衰竭人群.

Thanks, Ruud. Michael Leuchten at UBS -- unless Mene, you wanted to add something on?

謝謝，魯德。 UBS 的 Michael Leuchten——除非 Mene，你想補充一些東西嗎？

No, just about cirrhosis, the liver, I think, also has a very high in medical need and the efficacy. The data around that, I think, is pretty interesting. And so I think we'll get a readout there. And just to point out, and I know you know this, but the price points of diabetes versus heart failure, CKD, and some of these different types of CKD, because there are obviously various flavors of it, different price points relative to the diabetes price that placebo has been based on.

不，就肝硬化而言，我認為肝臟也有很高的醫療需求和療效。我認為，這方面的數據非常有趣。所以我想我們會在那裡得到讀數。只是要指出，我知道你知道這一點，但糖尿病與心力衰竭、CKD 以及其中一些不同類型的 CKD 的價格點，因為它顯然有多種口味，與糖尿病相關的不同價格點安慰劑所依據的價格。

Michael Leuchten at UBS. Over to you, Michael.

瑞銀的 Michael Leuchten。交給你了，邁克爾。

Two questions, please. One back to Susan. The AVANZAR trial is only asking an additional fixed-dose question of dato on top of carboplatin plus Imfinzi. Not a replacement question of chemotherapy, which is a question that Lung07 is asking.

請教兩個問題。一個回到蘇珊。 AVANZAR 試驗僅在卡鉑加 Imfinzi 的基礎上詢問額外的固定劑量 dato 問題。不是化療的替代問題，這是Lung07提出的問題。

Given that the biomarkers being looked at here, just wondering why you wouldn't also ask the replacement question in that Phase III? And then a question for (inaudible). Just wondering what the latest update would be for China given the NRDL process is now a yearly process. Are you happy with the pricing levels qualitatively that you've seen? Do you think it's a stable system that allows you to operate more predictably going forward after what we saw last year?

考慮到這裡正在研究的生物標誌物，只是想知道為什麼您不在第三階段提出替代問題？然後是一個問題（聽不清）。只是想知道鑑於 NRDL 流程現在是年度流程，中國的最新更新是什麼。您對所看到的定性定價水平滿意嗎？您是否認為這是一個穩定的系統，可以讓您在我們去年看到的情況之後更加可預測地向前發展？

Thanks, Michael. So Susan, if you want to cover this one, and we have Leon online. So the China question, Leon can take.

謝謝，邁克爾。蘇珊，如果你想報導這個，我們有萊昂在線。所以關於中國問題，Leon 可以接手。

So when adding carboplatin onto to DXD we don't see a substantial increased problem with the tolerability of that. And again, you're only giving the platinum for a set number of cycles. So this is a reasonably well-tolerated regimen. And as I said, the replacement question is being asked elsewhere across the program. So I think the question is really that we're focusing on for AVANZAR is we're going across histologies. We include squamous as well as non-squamous non-small cell lung cancer and across PD-L1 subgroups.

因此，當將卡鉑添加到 DXD 中時，我們沒有看到其耐受性出現實質性增加的問題。再說一遍，您只是在一定數量的周期內提供鉑金。因此，這是一個相當耐受的方案。正如我所說，替代問題正在整個計劃的其他地方提出。所以我認為問題是我們真正關注 AVANZAR 的是我們正在研究組織學。我們包括鱗狀和非鱗狀非小細胞肺癌以及跨 PD-L1 亞組。

And then asking the question about the benefit in the biomarker patient population TROP2 positive.

然後詢問有關生物標誌物患者群體 TROP2 陽性的益處的問題。

Thank you, Susan. Leon, over to you.

謝謝你，蘇珊。萊昂，交給你了。

Yes. I think this year, we have several major drugs getting to NRDL renewal. And also, we are applying for our Cmax drug from [brazikumab] it's a new entry. And also we have some application of new indication of Farxiga and also for Lynparza. So right now, I don't think we received the final result of price reduction level and also indication. But based on the latest information, I think the trend of NRDL is quite predictable and transparent, especially on the renewal. So based on the 2021 result, I think Farxiga, our anti-diabetes drug last year, I think, get quite a good result for revenue. And also, I think this year, we expect no big surprise on renewal and also quite many encouraging news on government encouragement on innovative drugs and also additional indictment and also our reimbursement renewal. So I think the trend on the China NRDL side is quite promising.

是的。我認為今年，我們有幾個主要藥物進入國家醫保目錄更新。而且，我們正在從 [brazikumab] 申請我們的 Cmax 藥物，這是一個新的條目。此外，我們還有 Farxiga 和 Lynparza 的一些新適應症的應用。所以現在，我認為我們還沒有收到降價水平的最終結果和指示。但是根據最新的信息，我覺得醫保目錄的走向是可以預見和透明的，尤其是在續保方面。因此，根據 2021 年的結果，我認為我們去年的抗糖尿病藥物 Farxiga 在收入方面取得了相當不錯的成績。而且，我認為今年，我們預計續簽不會有太大的驚喜，而且政府鼓勵創新藥物、額外起訴和我們的報銷續簽也有很多令人鼓舞的消息。所以我覺得中國醫保這邊的趨勢是很有希望的。

Thank you, Leon. Michael, the other good thing about the system is that it's becoming more formulaic, more driven by approaches or formulas that we can understand, and therefore, as Leon said it's a lot more predictable.

謝謝你，萊昂。 Michael，該系統的另一個好處是它變得更加公式化，更多地由我們可以理解的方法或公式驅動，因此，正如 Leon 所說，它更具可預測性。

Richard Parkes, Exane.

理查德帕克斯，Exane。

First one, just going back to Andrew's comments about risk profile in the Phase III starts and specifically thinking about the bispecifics. Obviously, the CTLA-4, PD-1, you've got very strong Phase II data. The TIGIT, PD-1 seems a bit more speculative based on what we're seeing with other TIGIT antibodies. So could you talk about what you've got in-house and what advantages you think that bispecific might have over TIGIT, PD-1 combinations that would be really helpful. And if you're planning to start Dato-DXd combinations as well would be helpful there.

第一個，回到安德魯關於 III 期開始風險狀況的評論，並特別考慮雙特異性抗體。顯然，CTLA-4、PD-1，你有非常強大的 II 期數據。根據我們對其他 TIGIT 抗體的觀察，TIGIT、PD-1 似乎更具推測性。那麼你能談談你在內部擁有的東西以及你認為雙特異性可能比 TIGIT 和 PD-1 組合有哪些真正有用的優勢。如果您也打算開始 Dato-DXd 組合，那將會很有幫助。

Then the second question. One of your ambitions is to extend the life cycle of your Lynparza franchise with your TROP1 selective. However, that currently falls outside of the Lynparza relationship with Merck. I'm just wondering if you could discuss any plans to bring the asset within that deal and when a decision might be made on that.

然後是第二個問題。您的目標之一是通過您的 TROP1 選擇性延長 Lynparza 特許經營權的生命週期。然而，這目前不屬於 Lynparza 與默克公司的關係。我只是想知道您是否可以討論將資產納入該交易的任何計劃，以及何時可以就此做出決定。

Thanks, Richard. So there's one for Susan and one for Dave, I guess.

謝謝，理查德。所以我猜，蘇珊和戴夫各一份。

Okay. Thanks for the question, Richard. So again, the PD-1 element of the bispecific programs that we've got is the same across the assets that we've got. So that's one element of it. And the PD-1 TIGIT doesn't add a challenge from a safety perspective on the background of PD-1.

好的。謝謝你的問題，理查德。因此，我們所擁有的雙特異性程序的 PD-1 元素在我們所擁有的資產中是相同的。所以這是其中的一個要素。而 PD-1 TIGIT 並沒有在 PD-1 的背景下從安全角度增加挑戰。

So obviously, with the PD-1 CTLA-4 dose selection has been important to get that right therapeutic window for the tolerability profile whilst driving the efficacy PD-1 TIGIT, this is a safe combination.

很明顯，PD-1 CTLA-4 的劑量選擇對於獲得正確的耐受性治療窗口非常重要，同時推動 PD-1 TIGIT 的療效，這是一個安全的組合。

And the preclinical data that we have does show some potential for differentiation, although as you're well aware, the extrapolation of that into the clinic is challenging with these models. So what I would just say is that by having both elements of the combination on one molecule, it does help us with a combination philosophy for other things that we want to put into that. And we'll be happy to share more of the plans for that when we start dosing the first patients in the Phase III.

我們擁有的臨床前數據確實顯示了一些差異化的潛力，儘管您很清楚，使用這些模型將其外推到臨床中具有挑戰性。所以我只想說的是，通過在一個分子上同時擁有組合的兩個元素，它確實幫助我們對我們想要放入其中的其他東西提出了組合理念。當我們開始為 III 期的第一批患者給藥時，我們將很樂意分享更多的計劃。

Richard, in terms of our plans moving forward around development and commercialization of AZD-5305, it's really consistent with what we had said in the past. We're developing it independently, it's an early development. Now just moving into Phase III, any commercial arrangements, we've really yet to decide and we'll wait for more data. With that said, we're minded to extend the collaboration and build on the joint success that we've had together with Merck on Lynparza. But of course, that depends on agreeing on any terms. But we really have benefited greatly from our collaboration together and the collective work that the 2 teams are doing.

理查德，就我們圍繞 AZD-5305 的開發和商業化推進的計劃而言，這與我們過去所說的完全一致。我們正在獨立開發它，這是一個早期的開發。現在剛剛進入第三階段，任何商業安排，我們真的還沒有決定，我們將等待更多的數據。話雖如此，我們有意擴大合作，並在我們與默克公司在 Lynparza 上取得的共同成功的基礎上再接再厲。但當然，這取決於就任何條款達成一致。但我們確實從我們的合作以及兩個團隊所做的集體工作中受益匪淺。

Thanks, Dave. Seamus Fernandez at Guggenheim. Seamus, over to you. Seamus, we don't hear you.

謝謝，戴夫。古根海姆的 Seamus Fernandez。西莫，交給你了。 Seamus，我們聽不到你的聲音。

Yes. Can you hear me now?

是的。你能聽到我嗎？

Yes, go ahead.

好，去吧。

Okay. Great. So first question is just on the sort of impact on some of the older products as it relates to the NRDL and the magnitude of the decline that we could see in Seroquel in China year-over-year. And then also the time when we might see Nexium generics actually introduced in Japan. I know those were 2 fairly large tail products for the company, where we'll see impacts year-over-year. And I just wanted to get a sense of at least the relative profitability of those products because I think it's important to gauging just how robust the overall performance of the company is outside of that.

好的。偉大的。因此，第一個問題只是關於與 NRDL 相關的一些舊產品的影響，以及我們在中國看到的 Seroquel 同比下降的幅度。然後也是我們可能會看到 Nexium 仿製藥實際在日本推出的時間。我知道這些是公司的 2 個相當大的尾部產品，我們將看到逐年產生的影響。我只是想至少了解一下這些產品的相對盈利能力，因為我認為衡量除此之外公司的整體業績有多強勁很重要。

And then the second question, just wanted to better understand the choice of stratifying by TROP2 expression. And if that is something that you're gaining learnings from in the -- from the second-line study or if you think that would apply in the second-line setting versus some of the disclosures that you made for the new Phase III in the first-line setting today?

然後是第二個問題，只是想更好地理解通過 TROP2 表達式進行分層的選擇。如果這是你從二線研究中獲得的東西，或者你認為這將適用於二線設置，而不是你在新的 III 期研究中所做的一些披露今天一線設置？

Thanks, Seamus. So Susan, can you cover maybe first this one? And I will ask Leon to cover the Seroquel question. And Ruud, you take the Nexium, Japan?

謝謝，西默斯。蘇珊，你能不能先介紹一下這個？我會請 Leon 回答有關 Seroquel 的問題。還有 Ruud，你拿 Nexium，日本？

So thanks for the question, Seamus. So the data to support the TROP2 biomarker comes from multiple different settings, including the early combination data. But yes, absolutely, we'll be looking at the TROPION-Lung01 data as well when that reads out. So I do think that, that's important. We do know that TROP2 is highly expressed in many different cancers. But I think optimizing for the expression and heterogeneity of expression is something that can potentially identify the patient populations that are more likely to respond and more likely to get a durable benefit. I think that's an important consideration, not just in lung cancer, but across other potential indications.

謝謝你的問題，Seamus。因此，支持 TROP2 生物標誌物的數據來自多個不同的設置，包括早期組合數據。但是，是的，當然，我們也會在讀出 TROPION-Lung01 數據時查看它。所以我確實認為，這很重要。我們確實知道 TROP2 在許多不同的癌症中高表達。但我認為針對錶達和表達的異質性進行優化可以潛在地識別出更有可能做出反應並更有可能獲得持久利益的患者群體。我認為這是一個重要的考慮因素，不僅在肺癌方面，而且在其他潛在適應症中也是如此。

Leon, do you want to cover the Seneca question? Thanks, Susan.

Leon，你想討論 Seneca 的問題嗎？謝謝，蘇珊。

Yes. Seroquel is quite a big product getting into VVP tender loss. And I think the last one is the Pulmicort. So actually, we are launching new products speeding up our portfolio and launch to offset these losses. But I think Seneca is a chronic disease product. It has 20 million, 30 million patients, actually the largest number of patients in China of AstraZeneca products in Seroquel. So actually, the price is low and has 3 indications and the chronic heart disease and hypertension and heart failure. So actually, it's a quite a good product, and classical and branded. So we will do a lot of consumerization and making sure loyal user of Seroquel will still be sticky brick and also the length of treatment for Seroquel is quite good, patients stick to it because of the heart rate. So we also will do a lot of digital channel education. And also, we have a quite successful business in China on retail pharmacy.

是的。 Seroquel 是一個相當大的產品，進入了 VVP 招標損失。我認為最後一個是 Pulmicort。因此，實際上，我們正在推出新產品以加快我們的產品組合併推出以抵消這些損失。但我認為Seneca是一種慢性病產品。它有2000萬、3000萬患者，實際上是思瑞康阿斯利康產品在中國患者數量最多的。所以其實價格低，而且有3個適應症，慢性心髒病和高血壓心力衰竭。所以實際上，這是一個非常好的產品，經典且品牌化。所以我們會做很多消費化，確保 Seroquel 的忠實用戶仍然是粘磚，而且 Seroquel 的治療時間相當長，患者會因為心率而堅持使用它。所以我們也會做很多數字渠道教育。而且，我們在中國的零售藥店業務非常成功。

So I think it will first drop quite significantly, but gradually, it will pick up because more and more patients will take the drug for long term and loyal customer will stay with the product. And we will still be promoting a lot of other cardiovascular products within the hospital. And AstraZeneca is the #1 company totally, but also #1 company in cardiovascular renal space. So we have a roxa, farxiga and so many other products still quite active. And also we have a new product in hypertension, which is coming. So I think all-in-all, I'm not too pessimistic about the Seroquel future.

所以我認為它首先會顯著下降，但逐漸會回升，因為越來越多的患者會長期服用該藥，而忠實的客戶會繼續使用該產品。我們仍將在醫院內推廣許多其他心血管產品。阿斯利康是全球排名第一的公司，也是心血管腎臟領域排名第一的公司。所以我們有 roxa、farxiga 和許多其他產品仍然非常活躍。我們還有一種治療高血壓的新產品即將上市。所以我認為總而言之，我對 Seroquel 的未來並不太悲觀。

Thank you, Leon. Just to illustrate what Leon was saying, you look at the Crestor in China, which we have consumerized and the price is low, as Leon said, those are chronic conditions and patients take these products over a long period of time. We have very extensive capabilities online and pharmacy-based activities. So we think we can consume Seroquel a little bit like we've done with Crestor.

謝謝你，萊昂。只是為了說明 Leon 所說的話，你看看中國的 Crestor，我們已經消費並且價格低，正如 Leon 所說，那些是慢性病，患者長期服用這些產品。我們擁有非常廣泛的在線和基於藥房的活動。所以我們認為我們可以像使用 Crestor 那樣使用一點 Seroquel。

Regarding the next Japan question, we have lost the exclusivity in Japan late last year. And instantly, we have seen generics coming into the marketplace. So the expectation for 2023 is a sharp decline in our Nexium business in Japan.

關於下一個日本問題，我們在去年年底失去了在日本的獨家經營權。很快，我們就看到了仿製藥進入市場。因此，對 2023 年的預期是我們在日本的 Nexium 業務將大幅下滑。

Thank you. Jo Walton, Crédit Suisse. Jo, over to you.

謝謝。 Jo Walton，瑞士信貸。喬，交給你了。

Thank you. A couple, please. On Tagrisso, I believe, Pascal, you've said that you're confident that you can keep going with that despite IRA, perhaps because of orphan drug elements. I wonder if you could tell us a little bit about that because Tagrisso, I guess, could be mentioned as one of the drugs when they give the list later this year. Aradhana, I wonder if I could ask an earlier question in a different way, just in terms of COVID. If you could give us some sense of how much COVID contributed to your earnings in 2022, we can all then make our decision about what we think could be in '23. It's just that sort of level that there has been today.

謝謝。請來一對關於 Tagrisso，我相信，Pascal，你說過你有信心儘管有 IRA，但你可以繼續這樣做，這可能是因為孤兒藥物成分。我想知道你是否可以告訴我們一些關於它的信息，因為我猜，當他們在今年晚些時候給出清單時，Tagrisso 可能會被提及為其中一種藥物。 Aradhana，我想知道我是否可以用不同的方式問一個較早的問題，就 COVID 而言。如果您能讓我們了解 2022 年 COVID 對您收入的貢獻有多大，那麼我們都可以就我們認為 23 年的情況做出決定。這就是今天的那種水平。

And my final question is just on your confidence in being able to control your operating costs. They were obviously growing much faster in 2022 than you're expecting them to in 2023. And I'm mindful of the incredible expansion of R&D that you're doing, all of which costs money and you do have new products that need a lot of marketing support. So are you going to be -- are you fully confident that you can provide all the support that you need in '23 with only mid-single-digit growth of your operating expenses?

我的最後一個問題是關於您對能夠控制運營成本的信心。他們在 2022 年的增長速度顯然比你預期的 2023 年要快得多。我注意到你們正在進行的令人難以置信的研發擴張，所有這些都需要花錢，而且你們確實有需要很多的新產品營銷支持。那麼，您是否會——您是否完全有信心能夠在 23 世紀提供您需要的所有支持，而您的運營費用僅需中等個位數的增長？

The last 2 questions are questions you love, Aradhana, for you. And then the first one, maybe, Dave, you can start with this one, Tagrisso, IRA.

最後 2 個問題是你喜歡的問題，Aradhana，給你。然後是第一個，戴夫，你可以從這個開始，愛爾蘭共和軍的塔格里索。

So Jo, on this, as you know, CMS is still in the midst of rule making to determine exactly how both the list of the first 10, which come out later this year, will be determined. And then also how the exclusions are going to be managed.

所以 Jo，關於這一點，正如你所知，CMS 仍在製定規則中，以確定如何確定今年晚些時候發布的前 10 個名單。然後還有如何管理排除項。

In terms of the list of the first 10, we'll see exactly how rule making goes through. My sense is that on a gross sales basis that Tagrisso would not likely make the first 10 in the first go through. But obviously, we'll have to see that. I do think that it would be likely to come in as you move through over the course of the years, which gets to the next question. And I think that there is absolutely an orphan drug designation exemption that's clear within the law. And I think that we certainly are minded that, that is one that could very well be applied to Tagrisso, and that's work that we'll be continuing to advance.

就前 10 名的列表而言，我們將確切地看到規則制定是如何進行的。我的感覺是，在總銷售額的基礎上，Tagrisso 不太可能在第一次通過時就進入前 10 個。但顯然，我們必須看到這一點。我確實認為隨著時間的推移，它很可能會出現，這就是下一個問題。而且我認為法律中絕對有明確的孤兒藥指定豁免。而且我認為我們當然注意到，這是一個可以很好地應用於 Tagrisso 的工作，我們將繼續推進這項工作。

Thanks, Jo, for your questions. So in terms of COVID contribution in 2022. Again, I won't give specific numbers, but I can give you some color that may help you. So if you look at our total COVID medicines in 2022, that was about $4 billion. Split almost half and half between Vaxzevria and Evusheld. Vaxzevria was -- majority of that, as you know, was initial contracts. So it was not really major contributor. And for Evusheld, we had guided, in 2022 that the gross margin for that is lower than our corporate gross margins. And then you also saw from today's results that we did take a charge for the Evusheld inventory and contract. So I think you can piece all of that together to see what that contributed in 2022.

喬，謝謝你的提問。所以就 2022 年的 COVID 貢獻而言。同樣，我不會給出具體數字，但我可以給你一些可能對你有幫助的顏色。因此，如果您看一下 2022 年我們的 COVID 藥物總額，那大約是 40 億美元。在 Vaxzevria 和 Evusheld 之間幾乎各佔一半。 Vaxzevria 是 - 如您所知，其中大部分是初始合同。所以它並不是真正的主要貢獻者。對於 Evusheld，我們在 2022 年指導其毛利率低於我們的公司毛利率。然後你也從今天的結果中看到，我們確實對 Evusheld 庫存和合同收取了費用。所以我認為你可以將所有這些拼湊起來，看看在 2022 年做出了什麼貢獻。

As it relates to your question on operating cost management, that is always an ongoing give and take and push and pull within the company. We are committed to our investment in R&D. And while you can see, obviously, the 30 clinical Phase III that we expect to start this year, we also had 34 approvals last year. So there are some trials that are sort of coming off their main phase of investment and other trials that are starting this year. That being said, we're constantly doing portfolio prioritization to make sure we are able to fund the most promising and the most value-generating assets in our portfolio. Also with those, for example, the 34 regulatory approvals, many of them were already in areas that we're in. So again, we try to get operating leverage in those areas.

由於它與您關於運營成本管理的問題有關，這始終是公司內部持續不斷的給予和接受以及推動和拉動。我們致力於研發投資。很明顯，雖然你可以看到我們預計今年開始的 30 項臨床 III 期，但去年我們也獲得了 34 項批准。因此，有些試驗已經結束了他們的主要投資階段，而其他試驗則從今年開始。話雖如此，我們一直在進行投資組合優先級排序，以確保我們能夠為我們投資組合中最有前途和最能產生價值的資產提供資金。此外，例如，34 項監管批准，其中許多已經在我們所處的領域。因此，我們再次嘗試在這些領域獲得運營槓桿。

Some of them are in new areas. So for example, with HIMALAYA and TOPAZ, we're building more in spaces that we were not in. But in the case of breast cancer, for example, we are leveraging infrastructure and sales force where we already are present. So again, we have operating leverage and in areas that we're new and entering we build as needed.

其中一些位於新區域。因此，例如，對於 HIMALAYA 和 TOPAZ，我們正在我們不在的空間中建造更多。但是在乳腺癌的情況下，例如，我們正在利用我們已經存在的基礎設施和銷售隊伍。因此，我們再次擁有運營槓桿，在我們新進入的領域，我們根據需要進行建設。

Thank you, Aradhana. Maybe just one addition on the Evusheld 2022. The cost base is not that great, really relative to typical pharmaceutical products that you have to launch and promote. So the profitability in '22 was actually pretty good. And in '23, as Aradhana said, it will be very minimal. So you will have to piece those elements together. But again, as I said earlier, if you do it, you will see that the underlying profitability of -- sorry, the profitability of the underlying business is improving very nicely from '22 to '23.

謝謝你，阿拉達納。也許只是 Evusheld 2022 的一個補充。成本基礎並不是那麼好，真的相對於你必須推出和推廣的典型醫藥產品而言。所以 22 年的盈利能力實際上相當不錯。而在 23 年，正如 Aradhana 所說，它將非常小。所以你必須將這些元素拼湊在一起。但同樣，正如我之前所說，如果你這樣做，你會看到潛在的盈利能力——抱歉，基礎業務的盈利能力從 22 年到 23 年都有很好的改善。

We'll take maybe the last question from Emmanuel Papadakis at Deutsche Bank. Over to you Emmanual.

我們可能會回答德意志銀行的 Emmanuel Papadakis 提出的最後一個問題。交給你 Emmanual。

Perhaps a follow-up question on margins. Given you finished 22% or 30%, you guided for see our growth of low to mid-single digits for both revenues and OpEx that implies pretty limited expansion in '23. So can you just reconfirm your commitment to the mid- to high 30s margin in the midterm and give us some sense of what the pathway looks like beyond 2023. When do we get to that mid-30s number, for example?

也許是關於利潤率的後續問題。鑑於你完成了 22% 或 30%，你指導我們的收入和運營支出都實現了中低個位數的增長，這意味著 23 年的擴張非常有限。那麼，您能否在中期再次確認您對 30 年代中高利潤率的承諾，並讓我們了解 2023 年以後的路徑是什麼樣的。例如，我們什麼時候達到 30 年代中期的數字？

And then maybe a second question on Lynparza ahead of the PROpel, the delayed PDUFA decision. Could you give us a sense of your current label expectations in light of both EMA decision and that slightly mixed overall survival data you presented us last year where there was an inversion of the early part of the curve. To what extent is that might to be a problem when considering prospects from all-comer label? And maybe since I'm the last person and I'll try and squeeze in it. Dave, I think you mentioned it, I may have missed it Enhertu market shares, in second line HER2-positive and HER2 low. Where are they now? Where could they go?

然後可能是在 PROpel 之前關於 Lynparza 的第二個問題，即延遲的 PDUFA 決定。根據 EMA 的決定和你去年向我們提供的略微混合的總體生存數據，你能否告訴我們你目前的標籤預期，其中曲線的早期部分出現倒轉。在考慮全能品牌的前景時，這在多大程度上可能成為一個問題？也許因為我是最後一個人，所以我會嘗試擠進去。戴夫，我想你提到過，我可能錯過了 Enhertu 市場份額，在二線 HER2 陽性和 HER2 低位。他們現在在哪裡？他們能去哪裡？

Aradhana, you want to -- thanks, Emmanuel. Aradhana, do you want to take the first one?

Aradhana，你想——謝謝，Emmanuel。 Aradhana，你想拿第一個嗎？

Yes. So we are remaining committed to our ambition. Just as a reminder, that is an ambition and not guidance. And you can see we are constantly operating -- improving our operating margins. You can see that 2022 operating margins were better than 2021. We are continuously working on productivity improvements. But again, there are various elements everything from sort of a mix shift and mix improvement, gross margin improvement and, again, operating leverage on the SG&A line, while not compromising on the investment in R&D. So again, it's a balance that we try to strike between steadily improving our operating margin while still investing for that strong growth post 2025.

是的。因此，我們將繼續致力於我們的雄心壯志。提醒一下，這是一種雄心，而不是指導。你可以看到我們一直在運營——提高我們的運營利潤率。你可以看到 2022 年的營業利潤率比 2021 年要好。我們一直致力於提高生產力。但同樣，有各種因素，包括混合轉變和混合改進、毛利率提高，以及 SG&A 系列的運營槓桿，同時不影響研發投資。因此，我們再次試圖在穩步提高營業利潤率與繼續為 2025 年後的強勁增長進行投資之間取得平衡。

Susan. Thanks, Aradhana.

蘇珊。謝謝，阿拉達納。

So in terms of the PROpel data, we are confident in the benefit risk, across the patient population, so in the ITT, so including the HRR and BRCA wild type. We also have confidence in the biological plausibility of the benefit of interaction between PARP inhibition and androgen receptor inhibition.

因此，就 PROpel 數據而言，我們對整個患者群體的獲益風險充滿信心，因此在 ITT 中，包括 HRR 和 BRCA 野生型。我們也對 PARP 抑制和雄激素受體抑制之間相互作用的益處的生物學合理性充滿信心。

Because actually, androgen receptor signaling is involved in DNA repair in AR-driven cancer cells. And we'll present not just -- we'll present some clinical data looking at this interaction in the ASR prostate cancer meeting, which is in March, I believe. So I think you have to understand what the rationale is for, why the interaction is relevant in the wild-type population as well as in the HRR mutated population. And then you have to look at the overall clinical benefit, which with a 5-month improvement in our PFS and a trend to improvement in OS with curves, yes, they're separate. But they look good. I think that we're confident in that overall population, and we're happy to see that we actually got that reflected in the EU label. So we'll continue to dialogue with the regulators around the world on this.

因為實際上，雄激素受體信號參與了 AR 驅動的癌細胞的 DNA 修復。我們不僅會展示——我們還會在 ASR 前列腺癌會議上展示一些臨床數據來研究這種相互作用，我相信這是在 3 月份舉行的。所以我認為你必須了解基本原理是什麼，為什麼相互作用與野生型種群以及 HRR 突變種群相關。然後你必須看看整體臨床效益，我們的 PFS 有 5 個月的改善，並且有曲線改善 OS 的趨勢，是的，它們是分開的。但他們看起來不錯。我認為我們對總體人口有信心，我們很高興看到我們實際上在歐盟標籤中反映了這一點。因此，我們將繼續就此與世界各地的監管機構進行對話。

With respect, Emmanuel, to Enhertu, in the U.S., we have gotten to approximately 50% new patient share in second line HER2-positive. So in the DBO 3 population, and over 40% in hormone receptor positive HER2 low post chemo new share. So that's the DESTINY-Breast04 population.

尊敬的 Emmanuel 和 Enhertu，在美國，我們已經在二線 HER2 陽性患者中獲得了大約 50% 的新患者份額。因此，在 DBO 3 人群中，超過 40% 的激素受體陽性 HER2 低化療後新份額。這就是 DESTINY-Breast04 人口。

Just 2 things. On your second question for how high could it go. There's still some Kadcyla use that exists in the marketplace today. There's a decent amount of fragmentation with various utilization of various HER2-directive agents and some chemotherapies. But I expect us to continue to grow in DB03. And if you look at in Europe, Kadcyla had at its peak as much as 70% share. So I think that it's important to note that as you get into marketplaces where Kadcyla actually had a greater percentage of the standard of care. I think that, that certainly represents the next goal that we have for those teams in terms of penetration, and then we'd like to go beyond that.

只有兩件事。關於你的第二個問題，它能走多高。今天市場上仍然存在一些 Kadcyla 用途。各種 HER2 導向劑和一些化學療法的各種使用存在相當數量的碎片。但我希望我們在 DB03 中繼續成長。如果你看看在歐洲，Kadcyla 的峰值份額高達 70%。因此，我認為重要的是要注意，當您進入 Kadcyla 實際上擁有更高百分比的護理標準的市場時。我認為，這肯定代表了我們在滲透方面對這些團隊的下一個目標，然後我們想超越這個目標。

In the DB-04 population, I again think that we've got with the overall survival results and the fact that systemic chemotherapy is just, frankly, not delivering adequate efficacy and safety for patients as a second chemo option with advanced breast cancer that we've got an opportunity to continue to grow. I do think you saw that the Q3 growth was aided by symbolus, but I think we continue to grow from where we are here. And looking forward, the launches across the globe, not just the U.S. throughout 2023.

在 DB-04 人群中，我再次認為我們已經獲得了總生存期結果，並且坦率地說，全身化療作為晚期乳腺癌的第二種化療選擇並不能為患者提供足夠的療效和安全性。有機會繼續成長。我確實認為你看到第三季度的增長得到了 symbolus 的幫助，但我認為我們將繼續從我們這裡的地方增長。展望未來，2023 年將在全球範圍內推出，而不僅僅是美國。

Thank you, and we probably will close for today here. Thank you so much for, again, your interest and your great questions. Let me just close by saying again that we're very much on track with our ambition to deliver a top line revenue that is the best of the -- one of the -- that is an industry-leading growth rate with a double -- low double-digit growth rate to 2025 and continued growth past '25 to 2030. We're working very hard on our pipeline. And importantly, also, we are working very hard on prioritizing constantly and improving our productivity. So we deliver also on our ambition to improve our operating margin over the next few years. Certainly, we are very much on track with that, too. In the long run, we'll stay true to it. But of course, we'll have to consider the evolution of the pipeline and the need for reinvestment as we see fit. But for now, we are focused on 2025 as a base camp 1 and very much on track with that. Thank you again for all your interest, and have a good day.

謝謝，我們今天可能會在這裡結束。再次非常感謝您的興趣和提出的重要問題。最後，讓我再說一遍，我們正朝著我們的雄心壯志邁進，實現最高收入，這是最好的——其中之一——行業領先的增長率是——到 2025 年保持兩位數的低增長率，並在 25 年後持續增長到 2030 年。我們正在努力開發我們的管道。同樣重要的是，我們正在非常努力地不斷確定優先次序並提高我們的生產力。因此，我們也實現了在未來幾年提高營業利潤率的雄心壯志。當然，我們也在這方面走上正軌。從長遠來看，我們會堅持下去。但當然，我們必須考慮管道的演變和我們認為合適的再投資需求。但就目前而言，我們專注於將 2025 年作為大本營 1，並且非常符合這一目標。再次感謝您的關注，祝您有美好的一天。