Jazz Pharmaceuticals PLC (JAZZ) 2023 Q4 法說會逐字稿

Good afternoon, ladies and gentlemen. My name is Abby, and I will be your conference operator today. At this time, I would like to welcome everyone to the Jazz Pharmaceuticals Fourth Quarter 2023 Earnings Conference Call. (Operator Instructions) Thank you. And I will now turn the conference over to Andrea Flynn, Head of Investor Relations. Ms. Flynn, you may begin.

女士們、先生們，午安。我叫艾比，今天我將擔任你們的會議操作員。現在，我歡迎大家參加爵士製藥 2023 年第四季財報電話會議。 （操作員說明）謝謝。我現在將會議交給投資者關係主管安德里亞·弗林 (Andrea Flynn)。弗林女士，您可以開始了。

Thank you, operator, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its fourth quarter and full year 2023 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors may also refer to the press release we issued earlier today, which is also posted to our website.

謝謝接線員，大家下午好。今天，Jazz Pharmaceuticals 公佈了其第四季度和 2023 年全年財務業績。本網路廣播附帶的幻燈片簡報可在我們網站的投資者部分取得。投資者還可以參考我們今天早些時候發布的新聞稿，該新聞稿也發佈在我們的網站上。

On the call today are Bruce Cozadd, Chairman and Chief Executive Officer; Renee Gala, President and Chief Operating Officer; and Robert Iannone, Executive Vice President, Global Head of R&D.

今天參加電話會議的是董事長兼執行長 Bruce Cozadd； Renee Gala，總裁兼營運長；執行副總裁兼全球研發主管 Robert Iannone。

On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential and anticipated development and commercialization milestones and goals, which involve risks and uncertainties that could cause actual events, performance and results to differ materially from those contained in these forward-looking statements.

在投影片2 上，我想提醒您，今天的網路廣播包含前瞻性陳述，例如與我們未來的財務和營運業績、成長潛力以及預期開發和商業化里程碑和目標相關的陳述，其中涉及可能存在的風險和不確定性。導致實際事件、績效和結果與這些前瞻性陳述中包含的內容有重大差異。

We encourage you to review the statements contained in today's press release, in our slide deck and the risks and uncertainties described in our SEC filings, which identify certain factors that may cause the company's actual events, performance and results to differ materially from those contained in the forward-looking statements made on today's webcast. We undertake no duty or obligation to update our forward-looking statements.

我們鼓勵您查看今天的新聞稿、我們的幻燈片中所包含的聲明以及我們向SEC 文件中描述的風險和不確定性，其中確定了可能導致公司的實際事件、業績和結果與其中包含的內容存在重大差異的某些因素。今天的網路廣播中所做的前瞻性陳述。我們不承擔更新前瞻性陳述的責任或義務。

As noted on Slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the Investors section of our website. I'll now turn the call over to Bruce.

如投影片 3 所示，我們將在此網路廣播中討論非 GAAP 財務指標。這些非 GAAP 財務指標的描述以及 GAAP 與非 GAAP 財務指標的調整包含在今天的新聞稿和我們網站投資者部分的幻燈片簡報中。我現在將把電話轉給布魯斯。

Thanks, Andrea. Good afternoon, everyone. Thank you for joining us today to discuss our fourth quarter and full year 2023 results and our excitement about 2024. I'll start on Slide 5. 2023 was a highly productive year for Jazz. Thanks to the passion and innovation of our talented employees around the world, we helped more patients, generated more than $3.8 billion in revenues and advanced multiple pipeline programs.

謝謝，安德里亞。大家下午好。感謝您今天加入我們，討論我們的 2023 年第四季度和全年業績以及我們對 2024 年的興奮。我將從幻燈片 5 開始。2023 年對於 Jazz 來說是高效的一年。由於我們世界各地才華橫溢的員工的熱情和創新，我們幫助了更多患者，創造了超過 38 億美元的收入，並推進了多個管道項目。

We believe these accomplishments position us well for success in 2024 as we focus on commercial execution and accelerating top line growth, delivering on key pipeline catalysts and remaining active in assessing corporate development opportunities to drive growth and value creation.

我們相信，這些成就使我們能夠在 2024 年取得成功，因為我們專注於商業執行和加速營收成長，提供關鍵的管道催化劑，並繼續積極評估企業發展機會，以推動成長和價值創造。

Before we move on, I want to highlight our announcement from last week that Phil Johnson is joining Jazz as our Chief Financial Officer, effective March 1. Phil comes to Jazz from Eli Lilly, where over the course of almost 3 decades, he led several finance functions and was most recently Group Vice President of Finance and Treasurer. As we move into 2024, we are excited to add Phil's industry experience, leadership and strategic approach to our executive team.

在我們繼續之前，我想強調一下我們上周宣布的菲爾·約翰遜(Phil Johnson) 將加入Jazz 擔任我們的首席財務官，該任命將於3 月1 日生效。菲爾從禮來(Eli Lilly ) 來到Jazz，在近3 年的時間裡，他領導了多個專案。擔任財務職能，最近擔任集團財務副總裁兼財務主管。邁入 2024 年，我們很高興將 Phil 的產業經驗、領導力和策略方法加入我們的執行團隊。

Turning to Slide 6. Our performance in 2023 is reflective of the strong execution that's transformed our business over the past several years. Highlighting a few commercial accomplishments in 2023, combined revenue from our key growth drivers, Xywav, Epidiolex and Rylaze increased 27% year-over-year. We drove more than $1.9 billion in revenue from our sleep therapeutic area, reinforcing our confidence in its durability.

轉向幻燈片 6。我們 2023 年的業績反映了過去幾年改變我們業務的強大執行力。 2023 年，我們的主要成長動力 Xywav、Epidiolex 和 Rylaze 的綜合收入年增了 27%，這凸顯了 2023 年的一些商業成就。我們從睡眠治療領域獲得了超過 19 億美元的收入，增強了我們對其耐用性的信心。

Epidiolex continues to grow, reflecting strong underlying demand and the execution by our commercial team. Epidiolex is now annualizing at more than $900 million and on track to deliver on its blockbuster potential. Our oncology therapeutic area surpassed $1 billion in revenue for the year, with Rylaze leading the way with 40% year-over-year growth.

Epidiolex 持續成長，反映出強勁的潛在需求和我們商業團隊的執行力。 Epidiolex 目前的年收入超過 9 億美元，並有望發揮其巨大的潛力。我們的腫瘤治療領域今年的收入超過 10 億美元，其中 Rylaze 以 40% 的年增長領先。

Moving to our R&D and pipeline efforts. We have multiple near-term late-stage catalysts targeting significant market opportunities. Given the strength of clinical data to date across multiple indications, we've used Zanidatamab as our most derisked asset, with more than a $2 billion peak potential.

轉向我們的研發和管道工作。我們有多個針對重大市場機會的近期後期催化劑。鑑於迄今為止跨多種適應症的臨床數據的強度，我們已將 Zanidatamab 作為我們風險最小的資產，其峰值潛力超過 20 億美元。

On the operational front, our disciplined capital allocation provides the financial strength to invest in our continued growth and diversification while generating healthy operating cash flow and margins. We have a strong track record of successful corporate development and remain focused on evaluating additional transactions.

在營運方面，我們嚴格的資本配置為我們的持續成長和多元化投資提供了財務實力，同時產生健康的營運現金流和利潤。我們擁有成功企業發展的良好記錄，並繼續專注於評估額外交易。

Turning to Slide 7. We made progress towards Vision 2025 based on our strong performance in 2023. On the commercial side, we've executed successful launches with leading therapies in narcolepsy and epilepsy and a growing oncology portfolio. Our investments in R&D have expanded our capabilities and the breadth and depth of our pipeline. And on operational excellence, disciplined capital allocation has put us in a strong financial position, and we continue to be mindful of making investments with the most impact to drive meaningful shareholder value.

轉向幻燈片 7。基於 2023 年的強勁表現，我們在 2025 年願景方面取得了進展。在商業方面，我們成功推出了嗜睡症和癲癇症領域的領先療法以及不斷增長的腫瘤學產品組合。我們對研發的投資擴大了我們的能力以及產品線的廣度和深度。在卓越營運方面，嚴格的資本配置使我們處於強大的財務狀況，我們將繼續注意進行最具影響力的投資，以推動有意義的股東價值。

I'll now turn the call over to Renee to review our commercial performance, after which Rob will share an update on our R&D progress. I will provide a financial overview, and then we'll open the call to Q&A. Renee?

現在，我將把電話轉給 Renee，回顧我們的商業表現，之後 Rob 將分享我們研發進展的最新情況。我將提供財務概覽，然後我們將開始問答電話。蕾妮？

Thanks, Bruce. We had a strong fourth quarter, generating quarterly revenue of more than $1 billion for the first time. This capped off a successful 2023, in which we achieved year-over-year double-digit growth across each of our key products, Xywav, Epidiolex and Rylaze.

謝謝，布魯斯。我們第四季表現強勁，季度營收首次超過 10 億美元。這為 2023 年的成功畫上了圓滿的句號，我們的每個主要產品 Xywav、Epidiolex 和 Rylaze 都實現了同比兩位數的成長。

I'll start on Slide 9 with our sleep therapeutic area. Total revenue from sleep, which includes Xywav and Xyrem net sales plus royalties from high sodium oxybate authorized generics, or AGs, was $483 million in the fourth quarter of 2023 and exceeded $1.9 billion for the full year. We believe we are well positioned to achieve our Vision 2025 goal of $2 billion in sleep revenue.

我將從幻燈片 9 的睡眠治療區開始。睡眠總收入（包括 Xywav 和 Xyrem 淨銷售額加上高羥丁酸鈉授權仿製藥（AG）的特許權使用費）在 2023 年第四季為 4.83 億美元，全年超過 19 億美元。我們相信，我們有能力實現 2025 年睡眠收入 20 億美元的願景目標。

Xywav revenue was $337 million for the fourth quarter of 2023 and approximately $1.3 billion for the full year 2023, which represented year-over-year annual growth of 33%. We have increasing visibility into oxybate market dynamics since the entry of branded and AG high sodium oxybates in 2023. We remain confident in the durability of our sleep therapeutic area and Xywav in particular. As the only low sodium oxybate and the only therapy approved to treat idiopathic hypersomnia, or IH, we expect Xywav to remain the oxybate of choice, including the #1 treatment for narcolepsy.

Xywav 2023年第四季的營收為3.37億美元，2023年全年的營收約為13億美元，年增33%。自 2023 年品牌和 AG 高羥丁酸鈉進入以來，我們對羥丁酸鹽市場動態的了解越來越多。我們對我們的睡眠治療領域，尤其是 Xywav 的耐用性仍然充滿信心。作為唯一的低鈉羥丁酸鹽和唯一被批准用於治療特發性嗜睡症(IH) 的療法，我們預計Xywav 仍將是首選的羥丁酸鹽，包括治療發作性睡病的第一號治療藥物。

Exiting 2023, there were approximately 9,525 narcolepsy patients taking Xywav. Our focus is on educating patients and prescribers around the lifelong burden of high sodium intake for narcolepsy patients. Based on positive feedback from the field about the benefits of reducing sodium intake, we believe that the majority of patients and health care providers will continue to prioritize long-term health when evaluating oxybate therapy.

截至 2023 年，約有 9,525 名發作性睡病患者服用 Xywav。我們的重點是教育患者和處方者了解嗜睡症患者的終身高鈉攝取負擔。根據該領域關於減少鈉攝取量益處的積極回饋，我們相信大多數患者和醫療保健提供者在評估羥丁療法時將繼續優先考慮長期健康。

Looking at IH, annual revenue from this indication doubled from 2022 to 2023, and we continue to view IH as a source of sustained growth for Xywav. Exiting 2023, there were approximately 2,775 active IH patients on Xywav. Given our confidence that the IH indication represents a durable growth opportunity for Xywav, we are continuing to invest in further building this market. We have expanded our sales force, adding field personnel who are focused on IH, with the primary directive to increase the depth and breadth of IH prescribers.

看看 IH，從 2022 年到 2023 年，該適應症的年收入翻了一番，我們繼續將 IH 視為 Xywav 持續增長的來源。截至 2023 年，Xywav 約有 2,775 名活躍 IH 患者。鑑於我們相信 IH 適應症代表了 Xywav 的持久成長機會，我們將繼續投資以進一步建立該市場。我們擴大了銷售隊伍，增加了專注於 IH 的現場人員，主要目標是增加 IH 處方者的深度和廣度。

Turning to Slide 10. We drove another quarter of Epidiolex growth with net product sales of approximately $241 million in the fourth quarter, representing a 16% increase compared to the same quarter in 2022. For the full year 2023, Epidiolex revenue was $845.5 million, up 15% year-over-year, driven by underlying demand and geographic expansion. We remain confident in the long-term growth prospects and blockbuster potential of Epidiolex, which is now annualizing at more than $900 million in revenue.

轉向投影片 10。我們推動 Epidiolex 又一個季度成長，第四季產品淨銷售額約為 2.41 億美元，與 2022 年同季相比成長 16%。2023 年全年，Epidiolex 營收為 8.455 億美元，受潛在需求和地理擴張的推動，較去年同期成長15%。我們對 Epidiolex 的長期成長前景和巨大潛力仍然充滿信心，該公司目前的年收入超過 9 億美元。

Key drivers of this demand growth in the U.S. include positive responses to data on the benefits of Epidiolex beyond seizure control, such as language and communication, cognition, executive function and emotional and social function, as well as increased penetration in the adult patient setting.

美國這項需求成長的主要驅動因素包括對Epidiolex 在癲癇控制之外的益處（如語言和溝通、認知、執行功能以及情緒和社交功能）的數據的積極反應，以及在成人患者環境中滲透率的增加。

Further opportunities for growth include continued education to support optimal dosing, focused data generation and geographic expansion beyond the more than 35 countries where Epidiolex is approved, with additional launches and market reimbursement expected in 2024.

進一步的成長機會包括繼續教育以支持最佳劑量、集中數據生成以及將 Epidiolex 批准的地區擴展到超過 35 個國家，預計 2024 年將有更多上市和市場補償。

Moving to oncology. Slide 11 highlights the strong performance of Rylaze in 2023, which contributed to our total oncology business exceeding $1 billion in annual revenue for the first time. Rylaze delivered net product sales of approximately $102 million for the fourth quarter of 2023 and approximately $394 million for the full year, representing 26% and 40% year-over-year increases in those periods, respectively.

轉向腫瘤學。幻燈片 11 強調了 Rylaze 在 2023 年的強勁表現，這使得我們的總腫瘤業務年收入首次超過 10 億美元。 Rylaze 2023 年第四季的產品淨銷售額約為 1.02 億美元，全年的產品淨銷售額約為 3.94 億美元，年比分別成長 26% 和 40%。

A number of factors are contributing to continued strong demand for Rylaze. Rylaze has been almost universally adopted in pediatric asparaginase-based oncology protocols in the U.S., and we continue to see strong adoption of the new Monday, Wednesday, Friday dosing regimen. We are also seeing increased usage of Rylaze in ALL patients due to some of the benefits of a short-acting profile relative to current first-line asparaginase therapies, including switches from these first-line therapies due to tolerability concerns and side effects.

許多因素導致對 Rylaze 的需求持續強勁。在美國，Rylaze 幾乎已被普遍採用在兒科基於天冬酰胺酶的腫瘤治療方案中，並且我們繼續看到新的週一、週三、週五給藥方案得到廣泛採用。我們也看到 Rylaze 在 ALL 患者中的使用增加，因為相對於目前的一線天冬酰胺酶療法，短效療法具有一些好處，包括由於耐受性問題和副作用而從這些一線療法中轉換。

In addition, we have an opportunity for continued growth with increasing use of Rylaze in the treatment of adolescents and young adults, or the AYA market.

此外，隨著 Rylaze 在青少年和年輕人治療或 AYA 市場中的使用增加，我們有機會持續成長。

Turning to Slide 12 on Zepzelca. Net product sales for the fourth quarter increased 3% year-over-year to $74 million. For the full year 2023, net product sales were $289.5 million, up 7% year-over-year. We have established Zepzelca as the #1 treatment for second-line small cell lung cancer patients, and we continue to hear positive feedback from health care providers on its clinical benefit and ease of use and administration for patients and their health care practices. Since its launch, Zepzelca has generated almost $900 million in revenue, and is proving to be a highly accretive and well-executed corporate development transactions.

轉向 Zepzelca 上的幻燈片 12。第四季產品淨銷售額年增 3%，達到 7,400 萬美元。 2023 年全年，產品淨銷售額為 2.895 億美元，較去年同期成長 7%。我們已將 Zepzelca 確立為二線小細胞肺癌患者的第一療法，並且我們繼續聽到醫療保健提供者對其臨床益處以及患者及其醫療保健實踐的易用性和管理的積極反饋。自推出以來，Zepzelca 已產生近 9 億美元的收入，並被證明是一項具有高度增值性且執行良好的企業發展交易。

In addition to the second-line setting, there remains an unmet need for patients in earlier lines of therapy. The ongoing Phase III trial in first-line small cell lung cancer provides a further opportunity to improve patient lives and outcomes as well as drive future growth. With that, I'll turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?

除了二線治療外，早期治療患者的需求仍未被滿足。正在進行的一線小細胞肺癌 III 期試驗為改善患者的生活和結果以及推動未來的成長提供了進一步的機會。這樣，我會將其交給 Rob，以獲取有關我們的管道和即將到來的里程碑的最新資訊。搶？

Thanks, Renee. 2024 represents an exciting time for us on the R&D front. And we anticipate multiple meaningful catalysts across oncology and neuroscience. On Slide 14, we've provided an overview of the key clinical programs in our diversified pipeline. And I'll highlight several milestones we expect to reach in the near term.

謝謝，蕾妮。 2024 年對於我們的研發來說是一個令人興奮的時刻。我們預期腫瘤學和神經科學領域將出現多種有意義的催化劑。在投影片 14 上，我們概述了我們多元化管道中的關鍵臨床項目。我將重點介紹我們預計在短期內實現的幾個里程碑。

Starting with oncology and Zanidatamab. We anticipate completing our rolling BLA submission for accelerated approval of Zanidatamab in second-line biliary tract cancer, or BTC, in the first half of this year. And I'm excited to report that we recently initiated our first-line BTC trial. Additionally, we are targeting late this year to report top line data from the ongoing Phase III first-line gastroesophageal adenocarcinoma, or GEA trial. If positive, we expect this trial would support a registration. I'll speak more to our Zanidatamab development plan in just a moment.

從腫瘤學和 Zanidatamab 開始。我們預計在今年上半年完成滾動 BLA 提交，以加速批准 Zanidatamab 用於二線膽道癌（BTC）。我很高興地向大家報告，我們最近啟動了一線 BTC 試驗。此外，我們計劃在今年稍後報告正在進行的 III 期一線胃食道腺癌 (GEA) 試驗的主要數據。如果結果積極，我們預計該試驗將支持註冊。稍後我將詳細介紹我們的 Zanidatamab 開發計劃。

We're also pleased with the progress of the Zepzelca first-line trial, which completed enrollment in January of this year. Top line progression-free survival data for Zepzelca in combination with Tecentriq in first-line extensive-stage small cell lung cancer is expected at the end of 2024 or early 2025. If approved, this indication would enable more patients with small cell lung cancer to potentially benefit from longer duration of therapy with Zepzelca.

我們也對 Zepzelca 一線試驗的進展感到高興，該試驗已於今年 1 月完成入組。 Zepzelca 聯合 Tecentriq 一線廣泛期小細胞肺癌一線無進展生存數據預計將於 2024 年底或 2025 年初獲得。如果獲得批准，該適應症將使更多小細胞肺癌患者能夠較長時間的 Zepzelca 治療可能會受益。

Turning to neuroscience. We expect top line data from our Phase III trial of Epidiolex in Japan in the second half of 2024. We also have ongoing trials for suvecaltamide, or JZP385, In both essential tremor and Parkinson's disease tremor, with top line data from the ET trial expected late in the first half of 2024. If trial findings are positive, we believe this trial could serve as part of a pivotal regulatory package.

轉向神經科學。我們預計 2024 年下半年在日本獲得 Epidiolex III 期試驗的頂線數據。我們也正在進行針對特發性震顫和帕金森氏症震顫的 Suvecaltamide 或 JZP385 試驗，預計 ET 試驗的頂線數據2024 年上半年末。如果試驗結果積極，我們相信該試驗可以成為關鍵監管計劃的一部分。

Slide 15 provides more detail on our development plan for Zanidatamab. We have meaningfully progressed Zanidatamab development across indications since bringing it to Jazz last year. And based on the totality of the data, we are highly confident in this molecule as a differentiated therapy for HER2-expressing cancers. I'll note that we are hosting an R&D Day on March 19 that will focus exclusively on Zanidatamab, including perspectives from GEA and breast cancer KOLs.

幻燈片 15 提供了有關 Zanidatamab 開發計劃的更多細節。自從去年將 Zanidatamab 引入 Jazz 以來，我們已經在各個適應症方面取得了有意義的進展。根據全部數據，我們對這種分子作為 HER2 表達癌症的差異化療法充滿信心。我要指出的是，我們將於 3 月 19 日舉辦研發日活動，並專注於 Zanidatamab，包括 GEA 和乳癌 KOL 的觀點。

Zanidatamab has shown compelling activity across a broad range of HER2-positive tumors, and our development plan represents a robust investigation of this molecule in multiple tumor types, as outlined on this slide. In addition to our BTC and GEA programs, we see meaningful opportunity for Zanidatamab to improve care for early and late-stage breast cancer patients.

Zanidatamab 在多種 HER2 陽性腫瘤中顯示出引人注目的活性，我們的開發計劃代表了對該分子在多種腫瘤類型中的深入研究，如本幻燈片所述。除了我們的 BTC 和 GEA 計畫之外，我們還看到 Zanidatamab 在改善早期和晚期乳癌患者的照護方面具有重要的機會。

Slide 16 highlights 1 of the most critical factors contributing to our enthusiasm around Zanidatamab. Specifically, the data generated to date has demonstrated Zanidatamab activity as monotherapy in combination with other agents, in patients previously treated with other HER2 agents, and results in durable responses with encouraging progression-free survival and overall survival data.

投影片 16 重點介紹了激發我們對 Zanidatamab 熱情的最關鍵因素之一。具體而言，迄今為止產生的數據已證明扎尼達單抗與其他藥物聯合作為單一療法，對於先前接受其他HER2 藥物治療的患者俱有持久的反應，並具有令人鼓舞的無進展生存期和總存活期數據。

Our development strategy for Zanidatamab starts with BTC, an area of high unmet patient need where there are currently no approved HER2 therapies. We believe coming to market in BTC will enable a fast-to-market strategy where we can leverage supplemental BLA findings and other indications.

我們的 Zanidatamab 開發策略從 BTC 開始，這是一個患者需求未被高度滿足的領域，目前尚無核准的 HER2 療法。我們相信，進入 BTC 市場將實現快速上市策略，我們可以利用補充的 BLA 調查結果和其他跡象。

GEA is the next potential indication to follow BTC, and we believe a prior approval in BTC may accelerate adoption into GEA treatment guidelines and protocols. Following discussions with FDA, we have elected to increase the enrollment target for the GEA trial to improve statistical power for the overall survival endpoint. This will not impact the time line to potential approval, which is still based on PFS from the original patient enrollment target.

GEA 是繼 BTC 後的下一個潛在適應症，我們相信 BTC 的事先批准可能會加速 GEA 治療指南和方案的採用。在與 FDA 討論後，我們選擇增加 GEA 試驗的入組目標，以提高整體存活終點的統計功效。這不會影響潛在批准的時間線，該時間線仍基於原始患者入組目標的 PFS。

We remain committed to rapidly advancing and expanding our development for a molecule that has the potential to transform the current standard of care in multiple HER2-positive cancers. Now I will turn the call over to Bruce for a financial update. Bruce?

我們仍然致力於快速推進和擴大我們對一種分子的開發，這種分子有可能改變多種 HER2 陽性癌症的當前護理標準。現在我將把電話轉給布魯斯，以了解最新的財務狀況。布魯斯？

Thanks, Rob. I'll start with our top line results on Slide 18. As a reminder, our full financial results are available in our press release and 10-K.

謝謝，羅布。我將從投影片 18 上的主要業績開始。提醒一下，我們的完整財務表現可在我們的新聞稿和 10-K 中找到。

In the fourth quarter of 2023, we achieved more than $1 billion in total revenues. And for full year 2023, we recorded more than $3.8 billion in total revenues, representing 5% growth over full year 2022. We were pleased to deliver growth despite headwinds from the introduction of both branded and AG high sodium oxybate competition, with our full year results driven by continued growth in both neuroscience and oncology, including double-digit growth from each of our 3 key growth drivers.

2023 年第四季度，我們的總營收超過 10 億美元。 2023 年全年，我們的總收入超過 38 億美元，比 2022 年全年增長 5%。儘管品牌和 AG 高羥丁酸鈉競爭的引入帶來了阻力，但我們很高興實現增長。神經科學和腫瘤學的持續成長推動了這一成果，包括我們的三個關鍵成長驅動力均實現了兩位數的成長。

Turning to Slide 19. Our full year 2023 non-GAAP adjusted net income was approximately $1.3 billion, and we reported non-GAAP adjusted EPS of $18.29. We continue to generate significant cash from our business, demonstrating the strength and diversity of our global portfolio. We recorded approximately $1.1 billion of cash from operations for the full year 2023 and ended the year with $1.6 billion in cash on hand.

轉向幻燈片 19。我們在 2023 年全年非 GAAP 調整後淨利潤約為 13 億美元，我們報告的非 GAAP 調整後每股收益為 18.29 美元。我們繼續從業務中產生大量現金，展示了我們全球投資組合的實力和多樣性。 2023 年全年，我們的營運現金約為 11 億美元，年底手頭現金為 16 億美元。

Our strong overall financial position and operating cash flows mean we have significant flexibility to invest in priority commercial and R&D programs as well as corporate development opportunities. We are pleased to share our full year financial guidance for 2024, beginning on Slide 20.

我們強勁的整體財務狀況和營運現金流意味著我們擁有極大的靈活性來投資優先商業和研發項目以及企業發展機會。我們很高興分享我們從幻燈片 20 開始的 2024 年全年財務指引。

Our 2024 total revenue guidance range of $4 billion to $4.2 billion represents 7% year-over-year top line growth at the midpoint. We expect double-digit percentage revenue growth of Xywav, Epidiolex and Rylaze combined to drive total revenue growth this year.

我們的 2024 年總收入指引範圍為 40 億至 42 億美元，中間值年增 7%。我們預計 Xywav、Epidiolex 和 Rylaze 的兩位數百分比營收成長將共同推動今年總營收成長。

Our 2024 neuroscience revenue guidance of $2.8 billion to $2.95 billion reflects the expected growth of Xywav in IH and Epidiolex, offset by the expected decline in Xyrem. I'll note this guidance is inclusive of AG royalties, which we expect to exceed $200 million in 2024. Our 2024 oncology revenue guidance range of $1.12 billion to $1.22 billion reflects expectations of continued double-digit growth for this therapeutic area.

我們的 2024 年神經科學收入指引為 28 億至 29.5 億美元，反映了 Xywav 在 IH 和 Epidiolex 中的預期成長，但被 Xyrem 的預期下降所抵消。我要指出的是，該指導意見包括AG 特許權使用費，我們預計2024 年將超過2 億美元。我們2024 年腫瘤學收入指導範圍為11.2 億美元至12.2 億美元，反映了該治療領域持續兩位數成長的預期。

I'd like to draw your attention to several items on Slide 21. With regard to operating expenses, our SG&A guidance range is $1.17 billion to $1.23 billion. The expected increase in SG&A in 2024 over 2023 will largely be a result of continued investments in our key growth drivers, including Xywav IH initiatives, commercial support for Epidiolex in the U.S., where we know the market is promotionally sensitive, geographic expansion of Epidiolex outside the U.S. and educational efforts for Rylaze in AYA.

我想提請您注意幻燈片 21 上的幾項。關於營運費用，我們的 SG&A 指導範圍為 11.7 億美元至 12.3 億美元。預計 2024 年 SG&A 較 2023 年成長將主要歸功於對我們關鍵成長動力的持續投資，包括 Xywav IH 計畫、對 Epidiolex 在美國的商業支持（我們知道該市場對促銷敏感）、Epidiolex 在美國以外的地理擴張美國以及Rylaze 在AYA 的教育工作。

Our R&D guidance range of $800 million to $850 million represents an increase of 5% at the midpoint compared to 2023, driven by planned continued investment in our robust Zanidatamab development program. Both SG&A and R&D guidance at the midpoint represent the same percentages of total revenue compared to 2023.

我們的研發指導範圍為 8 億美元至 8.5 億美元，與 2023 年相比，中位數成長了 5%，這得益於對我們強大的 Zanidatamab 開發項目的計畫持續投資。與 2023 年相比，SG&A 和研發指導的中位數佔總收入的百分比相同。

On the bottom line, we expect adjusted net income in 2024 to be in line with 2023 with a guidance range of $1.275 billion to $1.35 billion. This reflects anticipated investments in our commercial growth drivers and pipeline enabled by top line growth and disciplined and strategic capital allocation.

總體而言，我們預計 2024 年調整後淨利將與 2023 年持平，指引範圍為 12.75 億美元至 13.5 億美元。這反映了我們對商業成長驅動力和管道的預期投資，這些投資是由營收成長和嚴格的策略性資本配置所推動的。

I'll conclude our prepared remarks on Slide 23. In 2023, we delivered on our neuroscience, oncology and total revenue guidance. On the commercial side, our 2023 performance was driven by combined double-digit growth of key products Xywav, Epidiolex and Rylaze. On a combined basis, we expect these to grow by double digits again in 2024. This is a very exciting time for Jazz on the R&D front as we continue to advance our pipeline and invest in long-term growth, with multiple catalysts expected in the near term.

我將在幻燈片 23 上結束我們準備好的演講。2023 年，我們提供了神經科學、腫瘤學和總收入指導。在商業方面，我們 2023 年的業績是由關鍵產品 Xywav、Epidiolex 和 Rylaze 的兩位數綜合成長所推動的。綜合來看，我們預計這些成長將在2024 年再次實現兩位數成長。對於Jazz 來說，在研發方面這是一個非常令人興奮的時刻，因為我們將繼續推進我們的產品線並投資於長期成長，預計將在短期。

As always, we remain focused on operational excellence and strategic capital allocation, with corporate development remaining an opportunity for additional growth and diversification.

一如既往，我們仍然專注於卓越營運和策略資本配置，企業發展仍然是進一步成長和多元化的機會。

In summary, we are poised to deliver top line growth and multiple pipeline catalysts in 2024. And longer term, with our expanding product portfolio, R&D progress and focus on operational excellence, we believe we are well positioned to achieve Vision 2025 and deliver further diversification, sustainable growth and enhanced value to patients and shareholders. That concludes our prepared remarks. I would now like to turn the call over to the operator to open the line for Q&A.

總之，我們準備在2024 年實現營收成長和多種管道催化劑。從長遠來看，隨著我們不斷擴大的產品組合、研發進展和對卓越營運的關注，我們相信我們有能力實現2025 年願景並實現進一步多元化、永續成長並提高患者和股東的價值。我們準備好的演講到此結束。我現在想將電話轉給接線員以打開問答線。

(Operator Instructions) We'll take our first question from Jessica Fye with JPMorgan.

（操作員說明）我們將接受摩根大通的 Jessica Fye 提出的第一個問題。

We're seeing worries about Xywav's position in narcolepsy despite what looks like sleep neuro guidance clearly ahead of consensus. Can you talk about what you're seeing competitively in narcolepsy right now? And maybe set expectations for what you think the outlook is for Xywav in that setting?

我們看到人們對 Xywav 在嗜睡症中的地位感到擔憂，儘管看起來睡眠神經指導明顯領先於共識。您能談談您現在在發作性睡病方面看到的競爭情況嗎？也許您對 Xywav 在這種情況下的前景抱有期望？

Yes. Jess, thanks for the question. Renee, maybe I'll turn that one over to you.

是的。傑西，謝謝你的提問。蕾妮，也許我會把那個交給你。

Sure. Yes, happy to comment. Thanks, Jess. So at a high level, as we look at Xywav for 2024, as we noted on the call, we do expect it to be an important growth driver, 1 of 3 as we look at where we expect growth on the top line across the year.

當然。是的，很高興發表評論。謝謝，傑西。因此，從高水準來看，正如我們在電話會議上指出的那樣，當我們展望2024 年Xywav 時，我們確實預計它將成為一個重要的成長動力，當我們考慮全年營收成長時，它是3 個驅動因素中的第一個。

We do see Xywav continuing to resonate as a differentiated therapy as the only low sodium oxybate, the #1 treatment in narcolepsy and then, of course, the only drug approved for IH. What we're seeing in terms of the market is we are seeing the majority of new-to-oxybate patients starting on Xywav. We do believe it will remain the oxybate of choice. And that said, as we're looking at Q4, as we've said, we do expect some patients to try LUMRYZ. Given there are now many more patients on Xywav and Xyrem, naturally, we would expect some impact there.

我們確實看到 Xywav 作為一種差異化療法繼續引起共鳴，作為唯一的低羥丁酸鈉、發作性睡病的第一大治療方法，當然也是唯一被批准用於 IH 的藥物。我們在市場上看到的是，大多數新使用 oxybate 的患者都開始使用 Xywav。我們確實相信它仍將是首選的羥丁酸鹽。也就是說，正如我們所說，當我們專注於第四季度時，我們確實預計一些患者會嘗試 LUMRYZ。鑑於現在使用 Xywav 和 Xyrem 的患者數量更多，我們自然預計會產生一些影響。

So as we look at exiting the fourth quarter, we had more than 9,500 narcolepsy patients ending the year. Keep in mind also that our patient number is a net number. So it reflects the adds from the quarter, less any discontinuations that we had.

因此，當我們看到第四季結束時，我們有超過 9,500 名發作性睡病患者。另請記住，我們的患者編號是一個淨編號。因此，它反映了本季的新增業務，減去我們的停產業務。

Also in the fourth quarter, we did see an increase in our nonrevenue [vitals] as we continue to refine our patient support services program. We are seeing an increase in programs that essentially seek to take advantage of our affordability programs. This increase was seasonal, and we don't expect it to continue given how we're refining those programs.

同樣在第四季度，隨著我們繼續完善病患支援服務計劃，我們確實看到了非收入 [vitals] 的增加。我們看到本質上是尋求利用我們的負擔能力計劃的計劃有所增加。這種增長是季節性的，考慮到我們如何完善這些計劃，我們預計這種增長不會持續下去。

And then finally, keep in mind, within the fourth quarter as we continue to add new patients in both IH and narcolepsy, those patients need to titrate. So the revenue is lower upon starting, meaning that a patient that is starting therapy may not be as valuable upon starting therapy as a patient that's discontinuing.

最後，請記住，在第四季度內，隨著我們繼續增加新的 IH 和發作性睡病患者，這些患者需要進行滴定。因此，開始治療時的收入較低，這意味著開始治療的患者在開始治療時可能不如停止治療的患者那麼有價值。

And then I'll just say that as we look forward, we do believe that every high sodium patient is a potential Xywav patient. In particular, as we see decreasing commercial coverage for Xyrem, we expect those patients to shift therapy either to authorized generics, which, of course, we receive a significant royalty on, or to fixed dose high sodium branded therapy or importantly to Xywav, which will be an additional driver of growth in 2024 for narcolepsy, with probably more of our growth coming from idiopathic hypersomnia.

然後我只想說，當我們展望未來時，我們確實相信每個高鈉患者都是潛在的 Xywav 患者。特別是，隨著我們看到Xyrem 的商業覆蓋範圍不斷減少，我們預計這些患者將治療轉向授權的仿製藥（當然，我們會收取大量特許權使用費），或者轉向固定劑量高鈉品牌療法，或重要的是Xywav，這到 2024 年，嗜睡症將成為嗜睡症成長的另一個驅動力，其中更多的增長可能來自特發性嗜睡症。

And we will take our next question from Marc Goodman with Leerink Partners.

我們將回答 Leerink Partners 的 Marc Goodman 提出的下一個問題。

Yes, can you give us a little color just on the oncology portfolio? I mean you have products, Defitelio, Vyxeos, Zepzelca, Erwinaze -- I'm sorry, Rylaze, I still say that, Bruce, I apologize. Any color you can give us just on the quarter? I mean, Defitelio and Vyxeos obviously much higher than expected. The other 2 products, flattish quarter-to-quarter. So anything you can provide would be helpful.

是的，您能為我們介紹一下腫瘤學產品組合嗎？我的意思是你有產品，Defitelio、Vyxeos、Zepzelca、Erwinaze——對不起，Rylaze，我仍然這麼說，Bruce，我道歉。您能為我們提供本季度的任何顏色嗎？我的意思是，Defitelio 和 Vyxeos 顯然比預期高得多。其他兩種產品則是環比持平。所以你能提供的任何東西都會有幫助。

Yes, Marc, you're not the only one that occasionally refers to a prior product name. I'll say for some of our products, we do see significant quarter-to-quarter variability, particularly in the sort of very rare diseases. This has been true of Defitelio for years. So I wouldn't read too much in on the Defitelio, Vyxeos side. We've been more focused on the growth in Zepzelca, but particularly on our strong performance with Rylaze. And maybe I'll turn it over to Renee to comment a little bit on Rylaze.

是的，馬克，您並不是唯一一個偶爾提到以前的產品名稱的人。我想說，對於我們的一些產品，我們確實看到了顯著的季度變化，特別是在那種非常罕見的疾病中。德菲特里奧多年來一直都是這樣。所以我不會讀太多關於 Defitelio、Vyxeos 方面的內容。我們更加關注 Zepzelca 的成長，尤其是 Rylaze 的強勁表​​現。也許我會把它交給 Renee，讓她對 Rylaze 發表一些評論。

Yes. Thanks, Bruce, and thanks for the question, Marc. I would say, certainly echoing the variability with respect to Rylaze in particular, we did see some seasonality at the end of the fourth quarter going into the holidays. This is a relatively small market in terms of the rare population here with respect to the use that we see in Rylaze. Importantly, we do see Rylaze as a growth driver in 2024.

是的。謝謝布魯斯，也謝謝馬克的提問。我想說，特別是與 Rylaze 的變化相呼應，我們確實在第四季度末進入假期時看到了一些季節性。相對於我們在 Rylaze 看到的使用而言，這裡的人口稀少，這是一個相對較小的市場。重要的是，我們確實將 Rylaze 視為 2024 年的成長動力。

Just a reminder, due to supply constraints with Erwinaze, we were never really able to fully understand the market potential for that product, but we're continuing to see strong demand overall in the fourth quarter. And we also began a rolling launch in Europe late in the year. That is not an area as we think about Europe that we expect to see a strong contributor to growth in 2024, but we're pleased we were able to get that underway.

提醒一下，由於 Erwinaze 的供應限制，我們從未真正完全了解該產品的市場潛力，但我們在第四季度繼續看到整體強勁的需求。今年年底，我們也開始在歐洲滾動推出。在我們看來，這並不是一個對歐洲 2024 年成長做出強勁貢獻的領域，但我們很高興能夠實現這一目標。

And then with respect to Zepzelca, we've established this as the #1 treatment for second-line small cell lung cancer, and we do see future growth opportunity in first line as we look at reading out that study either late this year or early the next year. We continue to hear positive feedback from HCPs on the clinical benefit, the ease of use, as I mentioned, and seeing additional use there. But we do, as Bruce said, have some variability quarter-to-quarter in that area as well.

然後，就 Zepzelca 而言，我們已將其確定為二線小細胞肺癌的第一療法，當我們考慮在今年年底或年初宣讀該研究時，我們確實看到了一線藥物未來的增長機會下一年。正如我所提到的，我們不斷聽到 HCP 對臨床益處、易用性以及其他用途的正面回饋。但正如布魯斯所說，我們在該領域也存在一些季度與季度的變化。

And we will take our next question from Jason Gerberry with Bank of America.

我們將回答美國銀行 Jason Gerberry 的下一個問題。

My question, just how you foresee with zani, the frontline GEA differentiating in the PD-L1 negative subpopulation, if you aren't stratifying patients on the basis of PD-L1 status. So is the thought here that as long as that subpopulation doesn't produce a discordant result versus the all-comer group, that should facilitate a broader label than Merck secured with its KEYNOTE-811 regimen? Just kind of wondering how you can kind of paint that picture?

我的問題是，如果您不根據 PD-L1 狀態對患者進行分層，那麼您如何預見 zani（一線 GEA 區分 PD-L1 陰性亞群）的情況。那麼，這裡的想法是否是，只要該亞群不會產生與所有參與者群體不一致的結果，這應該會促進比默克公司透過其 KEYNOTE-811 療法獲得的更廣泛的標籤？只是想知道如何才能畫出那幅畫？

Thanks, Jason, for the question. Rob, you want to weigh in on that?

謝謝傑森的提問。羅布，你想對此發表意見嗎？

The PD-L1 biomarker wouldn't have any predictive value for Zanidatamab or any other HER2 therapies. So we think we can clearly define a benefit in the PD-L1 positive or negative subgroups.

PD-L1 生物標記對 Zanidatamab 或任何其他 HER2 療法沒有任何預測價值。因此，我們認為我們可以清楚地定義 PD-L1 陽性或陰性亞組的益處。

Of course, we have 2 experimental arms, one where zani is combined with standard of care chemo. And we also have an arm where we add PD-1 antagonist to that atezolizumab from Beijing. And so we have an opportunity to address both the PD-L1 negative group where the standard of care continues to be Herceptin chemo, and the PD-L1 positive group where PD-1s have been shown to benefit patients. And we think in that segment, we have the superior anti-HER2 drug. We don't think that there will be a differential based on which PD-1 is used.

當然，我們有兩個實驗組，其中一個將扎尼與標準護理化療結合。我們還有一個手臂，將 PD-1 拮抗劑添加到來自北京的 atezolizumab 中。因此，我們有機會解決 PD-L1 陰性組（護理標準仍然是赫賽汀化療）和 PD-L1 陽性組（PD-1 已被證明對患者有益）的問題。我們認為在這個領域，我們擁有更優越的抗 HER2 藥物。我們認為不會因使用 PD-1 而有差異。

And we will take our next question from Ami Fadia with Needham & Company.

我們將接受 Needham & Company 的 Ami Fadia 提出的下一個問題。

Going back to the oxybate market, can you talk about the market dynamics here, particularly with the entry of LUMRYZ? How has that impacted the total number of patients on oxybate? Do you believe that they are expanding the market or predominantly taking share? And how do you envision that evolving in 2024 in your guidance? And maybe just related to that, in IH, can you elaborate on where the increased sales force will focus on to drive additional prescribing depth?

回到羥丁酸鹽市場，您能否談談這裡的市場動態，特別是 LUMRYZ 的進入？這對接受奧昔丁治療的患者總數有何影響？您認為他們是在擴大市場還是佔據主導地位？您對 2024 年的指導有何展望？也許與此相關的是，在 IH 中，您能否詳細說明增加的銷售人員將集中在哪裡以推動額外的處方深度？

Thanks, Ami, for those questions. Renee, I'll turn that one over to you.

謝謝阿米提出這些問題。蕾妮，我把那份交給你。

Sure. Yes. And thank you, Ami. With respect to what we're seeing in narcolepsy, as I mentioned, new to oxybate patients today, we see the vast majority of those starting on Xywav. Now based on as we look at 2024, for example, we expect to see a continued decline of Xyrem. We said we expect AG royalties to exceed $200 million, and we expect to see Xywav as an important growth driver. But that growth will likely be greater in IH versus narcolepsy, as I've mentioned before, but the narcolepsy business is very important to us.

當然。是的。謝謝你，阿米。正如我所提到的，就我們在發作性睡病中所看到的情況而言，對於當今的 oxybate 患者來說是新的，我們看到絕大多數患者都是從 Xywav 開始的。例如，現在根據我們對 2024 年的展望，我們預計 Xyrem 將持續下滑。我們表示預計 AG 特許權使用費將超過 2 億美元，並且我們預計 Xywav 會成為重要的成長動力。但正如我之前提到的，與嗜睡症相比，IH 的成長可能會更大，但嗜睡症業務對我們來說非常重要。

As we think about what's happening in terms of narcolepsy, given that there are fewer patients that are on Xyrem today versus what are on Xywav, it would be natural to expect some impact to Xywav from patients starting on branded fixed dose high sodium LUMRYZ.

當我們思考發作性睡病方面正在發生的情況時，鑑於目前使用 Xyrem 的患者數量少於使用 Xywav 的患者，因此很自然地預計開始使用品牌固定劑量高鈉 LUMRYZ 的患者會對 Xywav 產生一些影響。

We do continue, though, to see as we look forward this opportunity for some growth within narcolepsy related to some market expansion. I think there's very little of that we're seeing right now. And just given if you're looking at a market opportunity, it would be much easier to go after patients that are already experienced on oxybate.

不過，我們確實繼續看到，因為我們期待與一些市場擴張相關的發作性睡病領域的一些成長機會。我認為我們現在看到的很少。如果您正在尋找市場機會，那麼尋找已經接受過羥丁酸治療的患者會更容易。

Now with respect to IH, as we look at what's happening with that market, we continue to see an opportunity to continue to educate on the entire condition of IH and the benefit of restorative sleep in terms of the improvement on that overall condition. We are looking at opportunities where we have both experienced oxybate prescribers, but those who are not currently doing a lot of prescribing for IH as well as broader opportunities to focus on prescribers that are less familiar with oxybate in general, but have a number of patients within their practice on IH.

現在，就 IH 而言，當我們觀察市場正在發生的情況時，我們繼續看到有機會繼續教育 IH 的整體狀況以及恢復性睡眠在改善整體狀況方面的益處。我們正在尋找機會，其中既有經驗豐富的羥丁酯處方者，也有目前沒有進行大量 IH 處方的處方者，以及更廣泛的機會來關註一般不太熟悉羥丁酯但有大量患者的處方者在他們的IH 實踐中。

We will take our next question from Ash Verma with UBS.

我們將回答瑞銀的 Ash Verma 提出的下一個問題。

So I wanted to just get your latest thoughts on what you're thinking about bridging to 2025 vision of $5 billion in sales. Do you think you need business development to get there? And is it possible that you could reconsider the target metrics for 2025 at some point? .

因此，我想了解您對於實現 2025 年 50 億美元銷售額願景的最新想法。您認為您需要業務發展才能實現這一目標嗎？您是否有可能在某個時候重新考慮 2025 年的目標指標？ 。

And then second question. So for Zepzelca on competitive front, there is a drug from Amgen, Tarlatamab, just if you can comment on how do you think the small cell lung cancer space might evolve?

然後是第二個問題。因此，對於 Zepzelca 來說，在競爭方面，安進有一種藥物 Tarlatamab，請您評論一下您認為小細胞肺癌領域可能會如何發展？

Yes, Ash, thanks for the questions. On the Vision 2025 target for revenue specifically, we had identified that as we came into 2022 as coming about $2 billion from oxybate. And I'll remind you that we had excellent progress with Xywav, in particular, in 2023. And we continue to expect additional growth in 2024. Last year, we had over $1.9 billion as we move towards the $2 billion target.

是的，阿什，謝謝你的提問。具體到 2025 年願景收入目標，我們已經確定，到 2022 年，Oxbate 將帶來約 20 億美元的收入。我要提醒您的是，我們在Xywav 方面取得了巨大進展，尤其是在2023 年。我們繼續預計2024 年會有進一步增長。去年，我們的收入超過19 億美元，我們正朝著20 億美元的目標邁進。

Epidiolex, we said would be a blockbuster product north of $1 billion in revenue. We're currently annualizing based on the last quarter at over $900 million and still showing nice growth both in the U.S. and outside the U.S. with Epidiolex. So we believe we're solidly on track for that. And we also said our oncology business will contribute north of $1 billion in 2025, with Epidiolex and oncology together contributing $2.5 billion. And we were very pleased, obviously, to see our oncology business grow to more than $1 billion in 2023, and we've again projected nice growth of that business, as you can see from our guidance for 2024.

我們曾說過 Epidiolex 將是一款收入超過 10 億美元的重磅產品。目前，我們基於上一季的年化收入超過 9 億美元，而 Epidiolex 在美國和美國以外的地區仍然顯示出良好的成長。因此，我們相信我們正在穩步實現這一目標。我們也表示，到 2025 年，我們的腫瘤業務將貢獻超過 10 億美元，其中 Epidiolex 和腫瘤業務合計貢獻 25 億美元。顯然，我們非常高興看到我們的腫瘤業務在 2023 年增長到超過 10 億美元，並且我們再次預計該業務將實現良好增長，正如您從我們對 2024 年的指導中看到的那樣。

So for the organic piece, $4.5 billion, we feel like we are on track for Vision 2025. We, of course, did include a placeholder of $500 million in 2025 revenues that could come from corporate development transactions done after the announced Vision 2025. Of course, that could include some revenue contribution from Zanidatamab, where we said we'll finish our rolling BLA submission in the first half of this year. And we're projecting that launch could come in 2025 or sooner.

因此，對於45 億美元的有機部分，我們感覺我們正在實現2025 年願景。當然，我們確實在2025 年收入中包含了5 億美元的佔位符，這些收入可能來自宣布的2025 年願景之後完成的企業開發交易。當然，這可能包括 Zanidatamab 的一些收入貢獻，我們表示將在今年上半年完成滾動 BLA 提交。我們預計該產品可能會在 2025 年或更早推出。

We're not suggesting that would make up all of that $500 million in 2025. But we are in a strong financial position with our cash and our cash flow to be active on the corporate development side, and we continue to review targets that would make for interesting additions to our business.

我們並不是說這將在 2025 年彌補全部 5 億美元。但我們的財務狀況強勁，我們的現金和現金流在企業發展方面非常活躍，並且我們將繼續審查目標，以實現為我們的業務增添有趣的內容。

I'll point out, we're not going to do a deal just to do a deal. We're going to do a deal if it's a good use of our capital, it furthers our strategy, adds an additional growth driver and provides sustainability over not just 2025, but as we look through the period, 2025 to 2030. So long answer Ash to a short question, but we're making excellent progress towards Vision 2025. And on the Zepzelca side, maybe Rob, I'll turn that one over to you.

我要指出的是，我們不會只是為了達成協議而達成協議。如果這筆交易能很好地利用我們的資本，我們就會達成一項交易，它將進一步推進我們的策略，增加額外的成長動力，並不僅在2025 年，而且在我們展望2025 年至2030 年期間提供可持續性。答案很長Ash 提出了一個簡短的問題，但我們在實現 2025 年願景方面正在取得巨大進展。在 Zepzelca 方面，也許是 Rob，我會把這個問題交給你。

Happy to, Bruce. As you know, Tarlatamab is a very different mechanism of action than Zepzelca. The data that will support -- that have supported a BLA or in the third line versus Zepzelca in the second line.

很高興，布魯斯。如你所知，Tarlatamab 的作用機制與 Zepzelca 非常不同。將支援的數據—支援 BLA 或第三行與第二行 Zepzelca 的比較。

And the safety profile for Tarlatamab is really quite different with a high risk of CRS and (inaudible), even including neurological effects. And that safety profile may well be a significant challenge, especially for community practitioners where many small cell lung cancer patients are treated.

Tarlatamab 的安全性確實非常不同，它具有高風險的 CRS 和（聽不清楚），甚至包括神經系統影響。這種安全性很可能是一個重大挑戰，特別是對於治療許多小細胞肺癌患者的社區從業者而言。

In contrast, Zepzelca has a very favorable safety profile, can be easily given as an infusion once every 3 weeks. And that really makes it an ideal candidate for add-on therapy in the frontline setting. And as you know, in partner with Genentech, we are running a frontline trial in small cell lung cancer. We expect top line PFS results as early as the end of this year. And that will allow a greater proportion of patients to receive therapy for a longer time.

相比之下，Zepzelca 具有非常有利的安全性，可以輕鬆地每 3 週輸註一次。這確實使其成為前線附加治療的理想候選人。如您所知，我們正在與基因泰克合作進行小細胞肺癌的第一線試驗。我們預計最快將於今年底獲得頂線 PFS 結果。這將使更多的患者能夠接受更長時間的治療。

And to build on that further. So as we look at that opportunity in first line, we also appreciate, as Rob had mentioned, the ease of use for Zepzelca currently in second line, just given the tolerability profile, the patient experience, the clinical activity. These patients that are coming in with second-line small cell lung cancer generally have quite a poor health prognosis. So they've already relapsed at this point. And so having a drug that's very easy to use is quite important in the treatment decision.

並在此基礎上進一步發展。因此，當我們在第一線尋找這個機會時，正如 Rob 所提到的，我們也欣賞 Zepzelca 目前在第二線的易用性，只要考慮到耐受性、患者體驗和臨床活動。這些患有二線小細胞肺癌的患者通常健康預後相當差。所以他們此時已經復發了。因此，擁有一種非常容易使用的藥物對於治療決策非常重要。

We will take our next question from Joseph Thome with TD Cowen.

我們將回答 Joseph Thome 和 TD Cowen 提出的下一個問題。

Congrats on the progress. Maybe just 1 on Zanidatamab, how should we think about continued investment in the program overall? I know you outlined the breast cancer opportunity in other HER2-expressing cancers. I guess, what's sort of the decision point to make that additional investment to start additional studies either in breast cancer or some of these other cancers? Is it the first kind of approval in BTC? Is it -- if it works in GEA or are you looking more at the landscape overall in competition? How should we think about the appetite to expand that?

祝賀取得的進展。也許 Zanidatamab 上只有 1，我們該如何考慮對該專案整體的持續投資？我知道您概述了其他表達 HER2 的癌症中發生乳癌的機會。我想，進行額外投資以開始針對乳癌或其他一些癌症的額外研究的決策點是什麼？這是BTC中的第一種批准嗎？如果它在 GEA 有效，或者您是否更關注競爭中的整體情況？我們該如何看待擴大這規模的需求？

Yes. I'll start, and then Renee and Rob, if you want to add anything in, you certainly can. While we don't give R&D guidance by program, you saw our R&D guidance for the full year represents about the same percentage of total revenues as we reported for 2023. With Zanidatamab having contributed a lot to the growth in R&D, 2023 over 2022, we have a little bit more of an apples-to-apples comparison between 2023 and 2024. I will say our guidance does assume activity in breast as well as BTC and GEA. And we'll certainly at our R&D Day in March be explaining a little bit more about our specific plans. But Rob, let me know if you want to say more now.

是的。我先開始，然後 Renee 和 Rob，如果你們想添加任何內容，你們當然可以。雖然我們沒有按專案提供研發指導，但您可以看到我們全年的研發指導與我們報告的2023 年總收入的百分比大致相同。由於Zanidatamab 對2023 年研發成長做出了巨大貢獻，較2022 年而言，我們對 2023 年和 2024 年進行了更多的同類比較。我想說的是，我們的指導確實假設了乳癌以及 BTC 和 GEA 的活動。我們肯定會在三月的研發日上對我們的具體計劃進行更多解釋。但是羅布，如果你現在想再說更多的話，請告訴我。

Yes. Only that of course, we're already working in areas outside of BTC and GEA. We've published data in the metastatic breast cancer setting, both HER2-positive and the combined HER2 ER-positive patients early in metastatic setting. So we already have data. And as Bruce mentioned, we are planning for additional work in breast cancer even now.

是的。當然，我們已經在 BTC 和 GEA 以外的領域開展工作。我們已經發表了轉移性乳癌的數據，包括早期轉移性 HER2 陽性和 HER2 ER 聯合陽性患者。所以我們已經有了數據。正如布魯斯所提到的，我們現在就計劃在乳癌方面進行更多工作。

And we will take our next question from Gregory Renza with RBC Capital Markets.

我們將回答加拿大皇家銀行資本市場部 Gregory Renza 提出的下一個問題。

Congrats on the progress. Maybe, Bruce, just adding on to some of the color that you provided around Vision '25 and that $500 million potentially through corporate development. Just curious if you could comment a bit on where you see valuations for some of the areas in which you're looking externally? Certainly, 2023, as you've noted, maybe put Jazz just based on where the markets were in a position of strength. I'm just curious how you see 2024 to date for competition, for attractiveness of assets that are in Jazz's power alley?

祝賀取得的進展。也許，Bruce，只是添加了您圍繞 Vision '25 提供的一些色彩，以及透過企業發展可能獲得的 5 億美元。只是好奇您是否可以評論一下您在外部尋找的某些領域的估值？當然，正如您所指出的，到 2023 年，爵士隊可能會根據市場處於強勢地位的位置來進行排名。我只是很好奇，您如何看待 2024 年迄今為止爵士樂勢力範圍內的競爭和資產的吸引力？

Greg, thanks for the question. We have quite a bit of experience on the corp dev side, having done a number of these transactions over the years and feel like there's a great set of opportunities out there across neuroscience and oncology, as well as some rare disease spaces that would build on capabilities we already have in-house based on a lot of our activities over recent years.

格雷格，謝謝你的提問。我們在公司開發方面擁有相當多的經驗，多年來已經完成了許多此類交易，並且感覺神經科學和腫瘤學以及一些罕見疾病領域存在大量機會基於近年來我們的大量活動，我們內部已經擁有了能力。

Being active in all of those spaces, looking at on-market and near-market products, including some in late-stage development, I think, gives us the ability to find things at valuations that work for us.

我認為，積極參與所有這些領域，專注於市場上和近市場的產品，包括一些處於後期開發的產品，使我們能夠以適合我們的估值找到合適的產品。

Now there can be pockets of areas where it seems like everyone's looking at the same time, valuations maybe a little high to earn a good return. If that's true, that's why we look at other areas as well. So with our team, with our strong financial position, we're confident we'll continue to find opportunities (inaudible) to work to drive that growth and sustainable growth over a longer period of time.

現在可能有一些領域似乎每個人都在同時關注，估值可能有點高才能獲得良好的回報。如果這是真的，這就是我們也關注其他領域的原因。因此，憑藉我們的團隊和強大的財務狀況，我們相信我們將繼續尋找機會（聽不清楚）來努力在更長的時間內推動成長和永續成長。

We will take our next question from Annabel Samimy with Stifel.

我們將回答 Annabel Samimy 和 Stifel 提出的下一個問題。

On zani, I know that you're still in the rolling BLA process, but can you talk about your launch plans there, how you might be preparing for it in terms of sales, what type of investment you need to make in the launch, the infrastructure to appropriately target GI cancers versus lung cancers? And could that potentially impact, say, Zepzelca?

關於 zani，我知道您仍處於滾動 BLA 流程中，但您能談談您的發布計劃嗎？您在銷售方面可能會如何做好準備，您需要在發布中進行什麼類型的投資，適當針對胃腸癌症和肺癌的基礎設施？這可能會影響 Zepzelca 等公司嗎？

And then, I guess, sort of related on the operating margin, Vision 2025, I guess, was supposed to be 5 points over where the guidance was set back in 2022. I think you're still at 43%, and that would have been 48%. So are you backing off of that operating margin guidance, given the number of investments that you have to make here? Or just if you can give a little color there, that would be great.

然後，我想，與營業利潤率有關，我想 2025 年願景應該比 2022 年設定的指導值高出 5 個點。我認為你仍然在 43%，這將有為 48%。那麼，考慮到您必須在這裡進行的投資數量，您是否會放棄營業利潤率指導？或者如果你能給那裡一點顏色，那就太好了。

Yes. Annabel, maybe I'll take the second part of your question first, and then we'll come back to Zanidatamab commercial launch thinking. When we set that target, it was coming off 43% margin back in 2021. I'll point out we essentially achieved that increase in margin as we moved through 2022. That's given us great flexibility to make the kinds of investments we wanted to make in the R&D portfolio and behind our key growth drivers on the commercial side. So we're glad to be making those investments today.

是的。 Annabel，也許我會先回答你問題的第二部分，然後我們再回到 Zanidatamab 商業上市的思考。當我們設定該目標時，2021 年的利潤率將下降43%。我要指出的是，隨著我們進入2022 年，我們基本上實現了利潤率的成長。這給了我們很大的靈活性來進行我們想要進行的投資研發組合以及商業方面的主要成長驅動力。因此，我們很高興今天進行這些投資。

We obviously haven't given guidance for 2025 specifically yet. I will point out, as we've pointed out before, that whether or not we do a corporate development transaction and spread our expenses over a greater revenue base does impact our margins. So we built that into our thinking as well. But for now, we think the investments we're making are investments that will lead to high return for our shareholders. Renee, you want to talk about Zanidatamab?

顯然我們還沒有具體給出 2025 年的指導。我要指出的是，正如我們之前指出的那樣，無論我們是否進行企業發展交易並將我們的支出分散到更大的收入基礎上，都會影響我們的利潤率。所以我們也將這一點納入了我們的想法中。但就目前而言，我們認為我們正在進行的投資將為股東帶來高回報。 Renee，你想談談 Zanidatamab 嗎？

Sure. Yes. Thanks for the question. So with respect to how we're thinking about BTC, we believe we have the ability to really effectively cover our BTC launch, which could happen as early as later this year. We'll be ready certainly, but we're looking at more than likely 2025. So the way we're thinking about the launch is we should be able to leverage our current field force that is out in the field right now with Zepzelca with a relatively small augment to that field force.

當然。是的。謝謝你的提問。因此，就我們如何看待 BTC 而言，我們相信我們有能力真正有效地應對 BTC 的發布，這最早可能會在今年晚些時候發生。我們肯定會做好準備，但我們的目標很可能是 2025 年。因此，我們考慮發布的方式是，我們應該能夠利用我們目前在 Zepzelca 上的現場力量對野戰部隊的增強相對較小。

The key is to enter the market with BTC to help HCPs get important experience with Zanidatamab. We do expect to have our GEA data as early as the end of this year. That's what we're targeting. And so by being in a position where we have our HCPs getting experience with zani, it's a more seamless transition when you're thinking about GEA. Also, if we're looking at an sBLA process for GEA, that's, of course, a bit faster as well.

關鍵在於用 BTC 進入市場，幫助 HCP 獲得 Zanidatamab 的重要經驗。我們預計最快在今年底獲得 GEA 數據。這就是我們的目標。因此，透過讓我們的 HCP 獲得 Zani 的經驗，當您考慮 GEA 時，這是一個更無縫的過渡。此外，如果我們正在研究 GEA 的 sBLA 流程，當然也會更快。

So we think it's a relatively small expansion to the footprint in the U.S. And we're also looking at zani as a global brand, an important global brand for us. So after the U.S., we're also looking at Europe as well as Japan.

因此，我們認為這是對美國業務的相對較小的擴張。我們也將 zani 視為一個全球品牌，對我們來說是一個重要的全球品牌。因此，繼美國之後，我們也關注歐洲和日本。

And while the BTC opportunity holistically from an epidemiology perspective is smaller, it's a high unmet need in terms of the severity of the cancer. And so we're looking at a build strategy, start with BTC, where we have around 12,000 patients worldwide, build into GEA with 63,000.

雖然從流行病學的角度來看，比特幣的整體機會較小，但就癌症的嚴重程度而言，這是一個未被滿足的需求。因此，我們正在研究一項建構策略，從 BTC 開始，我們在全球擁有約 12,000 名患者，然後建置到 GEA，擁有 63,000 名患者。

And when I say worldwide, I mean the U.S., Europe and Japanese markets. And then as we expand into breast, we're looking at a much larger population of more than 150,000 patients. So that's how we're looking at the broader opportunity.

當我說全球時，我指的是美國、歐洲和日本市場。然後，當我們擴展到乳房領域時，我們正在研究更多的患者群體，超過 150,000 名患者。這就是我們如何看待更廣泛的機會。

And we will take our next question from David Amsellem with Piper Sandler.

我們將回答 David Amsellem 和 Piper Sandler 提出的下一個問題。

Can you just add a little more about Epidiolex and what drove the performance? Is -- are you seeing double-digit volume growth both U.S. and ex-U.S.? And was there any stocking benefit that we should be aware of?

您能否補充更多有關 Epidiolex 的資訊以及推動性能的因素？您是否看到美國和美國以外地區的銷售量都出現兩位數成長？我們該注意什麼庫存好處嗎？

Thanks for the question, David. Renee, maybe I'll turn that one over to you.

謝謝你的提問，大衛。蕾妮，也許我會把那個交給你。

Sure. Yes, happy to comment. So as we look at Epidiolex, as we've said in the past, we tend to see a more gradual buildup over the second half of the year, and then that works off over the first half of the year. So we saw a very small amount of that in the fourth quarter in terms of buildup. But we are seeing continuing demand growth, and we're seeing that across both the U.S. as well as in Europe.

當然。是的，很高興發表評論。因此，當我們審視 Epidiolex 時，正如我們過去所說，我們往往會看到下半年的成長更加緩慢，然後在上半年開始發揮作用。因此，我們在第四季度看到了非常少量的累積。但我們看到需求持續成長，無論是在美國還是在歐洲。

We've said in the past, what continues to resonate with physicians, providers, patients is really the understanding of some of the beyond seizure benefits as well as the synergistic effect we're seeing with Clobazam. We see continued opportunity in the adult segment. That's an area we're starting to focus a bit more on. And that, we expect to be a driver of growth in 2024.

我們過去說過，繼續引起醫生、提供者和患者共鳴的是對一些超越癲癇發作的益處以及我們所看到的氯巴佔的協同效應的理解。我們看到成人市場存在持續的機會。這是我們開始更加關注的領域。我們預計這將成為 2024 年成長的推動力。

And then more broadly, as we look at how Epidiolex is viewed in the market as the #1 branded treatment, it continues to be seen as a very well-characterized and tolerated drug, which means that lends itself well to polypharmacy. That's the norm in this area. And the data that we continue to generate both -- as I just described in terms of with Clobazam and the data beyond seizures and just further understanding of these effects that you're seeing is creating greater demand from our physicians stating they intend to use it earlier in their process of this polypharmacy with patients.

從更廣泛的角度來看，當我們觀察Epidiolex 在市場上如何被視為第一品牌治療藥物時，它仍然被視為一種特性良好且耐受性良好的藥物，這意味著它非常適合多藥治療。這是該地區的常態。我們繼續產生的數據- 正如我剛才所描述的氯巴扎姆和癲癇發作之外的數據，以及對您所看到的這些影響的進一步了解正在對我們的醫生產生更大的需求，他們表示他們打算使用它在他們對患者進行多藥物治療的早期階段。

We are seeing growth outside the U.S. as well, as I mentioned. So we're continuing to both launch in new geographies and then add indications within existing geographies. And so that growth is proceeding nicely as well.

正如我所提到的，我們也看到了美國以外地區的成長。因此，我們將繼續在新的地區推出產品，然後在現有地區添加指示。因此，成長也進展順利。

We will take our next question from Joon Lee with Truist Securities.

我們將回答 Truist Securities 的 Joon Lee 提出的下一個問題。

Thanks for the update and for taking our questions. When you do report top line data from suvecaltamide and essential tremor, will you have a go/no-go decision when you report the top line? Or is that something that you still have to consult with the FDA and the Phase II meeting before being able to comment on a go/no-go decision? And is the advancement into Parkinson's disease dependent on the outcome of ET? Or are they independent events? And just quickly, anything you can share on the latest on the orexin program.

感謝您的更新並回答我們的問題。當您報告斯維卡胺和特發性震顫的頂線數據時，您在報告頂線時會做出繼續/不繼續的決定嗎？或者說，在對是否通過的決定發表評論之前，您仍然需要諮詢 FDA 和第二階段會議？帕金森氏症的進展是否取決於 ET 的結果？還是它們是獨​​立事件？很快，您就可以分享有關食慾素計劃的最新資訊。

So the first part of the question was around essential tremor. And I would say, in general, our practice has been to share top line data on a timely basis. Whether we comment precisely that time on that steps remains to be seen and remains to be -- remains dependent on the data. But in general, our view is we know what we need move this program forward. So I'm not sure that barring a surprise in the data, that would involve a different regulatory interaction. Rob, anything else you want to add on ET or on orexin?

所以問題的第一部分是關於特發性震顫。我想說，總的來說，我們的做法是及時分享頂線數據。我們是否對該步驟進行準確評論還有待觀察，仍取決於數據。但總的來說，我們的觀點是我們知道需要什麼來推動這個計劃。因此，我不確定除非數據出現意外，否則是否會涉及不同的監管互動。 Rob，您還想為 ET 或食慾素添加什麼內容嗎？

I would just say that with regard to ET, I agree with you that we'll see the data, and we're not expecting to have to talk to FDA before providing some guidance on that. It certainly is positioned as a pivotal trial. We're very excited about it, given the high unmet need. There hasn't been an approved drug in 50 years, and what's available there is pretty poor.

我只想說，關於 ET，我同意你的觀點，我們會看到數據，我們不希望在提供一些指導之前與 FDA 交談。它無疑被定位為一個關鍵的試驗。鑑於未滿足的需求很高，我們對此感到非常興奮。 50 年來沒有一種藥物獲得批准，可用的藥物也相當匱乏。

We think we have a differentiated mechanism of action and a best-in-class calcium channel modulator. Certainly, this trial was built to be part of a pivotal program. So I think it will be quite informative, and we do see the data. I don't think PD -- Parkinson's disease tremor is a direct read through, but certainly strong data and essential tremor would give us more confidence in this target overall.

我們認為我們擁有差異化的作用機制和一流的鈣通道調節劑。當然，這項試驗是關鍵計畫的一部分。所以我認為這將提供相當豐富的信息，而且我們確實看到了這些數據。我不認為 PD——帕金森氏症震顫是直接通讀的，但肯定的是，強有力的數據和特發性震顫會讓我們對這個整體目標更有信心。

And then finally, on the question of orexin. There are no updates there. We're on pause while we're examining the safety findings that we previously characterized.

最後，關於食慾素的問題。那裡沒有更新。當我們檢查我們之前描述的安全結果時，我們暫停了。

We will take our next question from Gary Nachman with Raymond James.

我們將回答加里·納赫曼和雷蒙德·詹姆斯提出的下一個問題。

So on zani, just what's the time line for expanding further into breast cancer? Will you be doing that in parallel with BTC and GEA? And then regarding increasing the size of the GEA trial, just describe what you hope to see from that interim OS data. And next year, is it possible that GEA could contribute to the sales of zani and not just BTC?

那麼札尼，進一步擴展到乳癌的時間線是什麼？你們會與 BTC 和 GEA 並行這項工作嗎？然後，關於增加 GEA 試驗的規模，只需描述您希望從臨時作業系統資料中看到什麼。明年，GEA 是否有可能為 zani 的銷售做出貢獻，而不僅僅是 BTC？

Rob, I'm going to turn this one over to you.

羅布，我要把這個交給你。

Yes. So similar to the answer I gave previously. We have been working in breast cancer already, both in the metastatic setting for HER2-positive cancer and then we published recently on HER2-positive, ER-positive breast cancer at San Antonio last year, we published on early stage disease. So we have been working in breast cancer and publishing on those data. And we are progressing further development plans in those areas. It's not dependent on any other readout.

是的。與我之前給出的答案非常相似。我們已經在乳癌領域開展工作，包括 HER2 陽性癌症的轉移性乳癌，去年我們在聖安東尼奧發表了關於 HER2 陽性、ER 陽性乳癌的文章，我們發表了關於早期疾病的文章。因此，我們一直致力於乳癌研究並發布這些數據。我們正在這些領域推進進一步的發展計畫。它不依賴任何其他讀數。

With regard to the changes to the GEA study. Again, we made those changes to ensure better power for the overall -- the final overall survival end point. We plan to read out the progression-free survival based on the original sample size so -- to have no impact on the overall time line.

關於 GEA 研究的變化。同樣，我們做出這些改變是為了確保整體有更好的動力——最終的整體生存終點。我們計劃根據原始樣本量讀出無惡化存活期，這樣就不會對整體時間線產生影響。

And we know from health authority interactions that in this setting, PFS is adequate to support approval. It's usual and typical to do an interim analysis, albeit early on OS at the time that you're looking at PFS. And generally, health authorities just want to be sure that something funky is not happening, that you're not seeing somehow a detriment in the OS, but there's not an expectation that OS on that first interim would be well powered.

我們從衛生當局的互動中得知，在這種情況下，PFS 足以支持批准。儘管在您查看 PFS 時還處於作業系統早期，但進行中期分析是常見且典型的做法。一般來說，衛生當局只是想確保不會發生一些奇怪的事情，確保你沒有看到操作系統受到某種損害，但並不期望操作系統在第一個過渡時期能夠得到良好的支持。

And then of course, we have the second interim analysis, which is occurring around the time that it would have on the original trial, which is why we believe we sort of have our cake and eat it too with this change. And then on the mature OS data, we'd have more power.

當然，我們還有第二次中期分析，該分析是在最初試驗的時間左右進行的，這就是為什麼我們相信，透過這一變化，我們可以說是魚與熊掌兼得。然後在成熟的作業系統資料上，我們會有更多的能力。

And then...

進而...

Yes. I mean in terms of -- so I didn't get to the -- didn't address the question on revenue in 2025. There is a scenario where we are, given what we've shared around BTC, that we are on the market for BTC. And as we read out the data for GEA, we certainly have a faster path as a supplemental in the U.S. to get an update to the label, but we certainly will also publish and seek compendia listing even while we are progressing the supplemental BLA.

是的。我的意思是——所以我沒有談到——沒有解決 2025 年收入的問題。有一種情況是，考慮到我們圍繞 BTC 分享的內容，我們正處於比特幣市場。當我們讀出 GEA 的數據時，我們當然有一個更快的途徑作為美國的補充來更新標籤，但即使我們正在推進補充 BLA，我們也肯定會發布並尋求概要列表。

We will take our next question from Akash Tewari with Jefferies.

我們將接受 Jefferies 的 Akash Tewari 提出的下一個問題。

This is Amy on for Akash. Just a quick one on zani and GEA. So given the mechanism similarity between Herceptin and PERJETA combo and zani, why do you think their Phase III GEA trial JACOB failed? It doesn't seem to be like HER2 expression related given the treatment arm enrolled roughly similar HER2, 3 population compared to the comparator arm, which is Herceptin plus chemo. So is there anything you are doing differently in your trial?

這是艾米為阿卡什主持的節目。簡單介紹一下 Zani 和 GEA。那麼，鑑於赫賽汀和 PERJETA 組合以及扎尼之間的機制相似，您為什麼認為他們的 III 期 GEA 試驗 JACOB 失敗了？鑑於治療組招募的 HER2, 3 族群與比較組（赫賽汀加化療）大致相似，因此似乎與 HER2 表現無關。那麼您在試驗中是否做了什麼不同的事情？

Rob, do you want to take that?

羅布，你想接受這個嗎？

Yes, happy to, Bruce. So first of all, while the epitopes on Zanidatamab do correspond to the same epitopes that Herceptin and PERJETA independently bind, the reason Zanidatamab is differentiated is that when they occur -- when they're positioned on the same antibody, what you get is binding of the 2 FAB fragments of the antibody on different receptors. And it causes receptor clustering, which enhances interference signaling, whether that be through HER2 or interference of dimerization with HER3 and therefore, interference is signaling with HER3 internalization. And marking the cells for immune destruction.

是的，很高興，布魯斯。因此，首先，雖然 Zanidatamab 上的表位確實對應於赫賽汀和 PERJETA 獨立結合的相同表位，但 Zanidatamab 不同的原因是，當它們出現時 - 當它們位於同一抗體上時，您得到的是結合不同受體上抗體的2 個FAB 片段。它會引起受體聚集，從而增強幹擾訊號傳導，無論是透過 HER2 或乾擾 HER3 的二聚化，因此，幹擾是透過 HER3 內化的訊號傳導。並標記細胞以進行免疫破壞。

A lot of this experimental data was published in Nature Communications and includes some really nice data showing this clustering effect that occurs with the biparatopic antibody and showing that it induces complement-dependent cytotoxicity, which is unique amongst any HER2 antibodies and also some experimental data comparing head-to-head to just combining those 2 antibodies separately.

許多實驗數據發表在Nature Communications 上，其中包括一些非常好的數據，顯示雙互補位抗體發生的這種聚類效應，並顯示它誘導補體依賴性細胞毒性，這在任何HER2 抗體中都是獨一無二的，也包括一些比較實驗數據直接將這兩種抗體單獨組合。

So we think we actually have a differentiated drug that will be more effective than giving the combination. And our clinical data, by the way, support that. So we have activity in patients who have progressed on the combination of Herceptin and PERJETA with breast cancer. So I think our preclinical data show the differentiated mechanism and the clinical data are showing better results, whether it be in breast cancer or also in BTC, where we seem to have better results than when you give Herceptin, Perjeta to BTC patients.

因此，我們認為我們實際上有一種差異化藥物，比合併用藥更有效。順便說一句，我們的臨床數據也支持這一點。因此，我們對赫賽汀和帕妥珠單抗聯合用藥後病情進展的乳癌患者開展了活動。所以我認為我們的臨床前數據顯示了差異化機制，臨床數據顯示出更好的結果，無論是在乳癌還是BTC 中，我們似乎比給BTC 患者服用赫賽汀、帕妥珠單抗更有好的結果。

And we will take our next question from Charles Duncan with Cantor Fitzgerald.

我們將回答查爾斯鄧肯和坎托菲茨杰拉德提出的下一個問題。

This is Asiya on for Charles. We have a question on Epidiolex. So given the Phase III readout in the second half of this year, can you talk a little bit about the addressable market and opportunity in Japan compared to the opportunity in the U.S. And also, you did mention additional market launches this year. So I was wondering if you can provide a bit more color on this?

這是阿西亞為查爾斯代言的。我們有一個關於 Epidiolex 的問題。因此，鑑於今年下半年的第三階段數據，您能否談談日本的潛在市場和機會與美國的機會相比。而且，您確實提到了今年的其他市場啟動。所以我想知道你是否可以對此提供更多的顏色？

Yes, Renee, let me turn that one over to you.

是的，蕾妮，讓我把那份交給你。

Sure. Yes, I'm happy to jump in there. So for Japan, we're excited to be able to have made the progress that we have in that geography. There's about 20,000 patients across 3 different indications that we think provide quite an important opportunity.

當然。是的，我很高興跳進去。因此，對於日本來說，我們很高興能夠在該地區取得進展。大約 20,000 名患者有 3 種不同的適應症，我們認為這提供了一個非常重要的機會。

And Japan, obviously, is the second largest pharmaceutical market in the world. We have now the opportunity not only with Epidiolex, but also Zanidatamab to be able to have meaningful opportunities in that market. So we do expect the top line results in the second half of this year.

顯然，日本是世界第二大醫藥市場。我們現在不僅有機會獲得 Epidiolex，還有 Zanidatamab，能夠在該市場獲得有意義的機會。因此，我們確實預期今年下半年會出現頂線業績。

And we're pleased also with the progress we've made to be able to see changes to the Cannabis Control Act underway, which will enable that eventual launch. And then in terms of outside the U.S. as we think about the progress that we're making there, we're already approved in more than 35 different countries. We do have some additional launches and reimbursements anticipated through the end of 2024. And I would think of that as gradual updates as we go, we are already approved and reimbursed in the 5 main large markets in Europe. So what we've been doing over the course of '23 and '24 is really focused on ensuring we have the full indication set available in each of the countries.

我們也對我們所取得的進展感到高興，我們能夠看到《大麻控制法案》正在進行的修改，這將使最終的啟動成為可能。然後就美國以外的地區而言，當我們考慮我們在那裡取得的進展時，我們已經在超過 35 個不同的國家/地區獲得批准。預計到 2024 年底，我們確實會有一些額外的推出和報銷。我認為這是我們逐步更新的結果，我們已經在歐洲 5 個主要市場獲得批准和報銷。因此，我們在 23 年和 24 年期間所做的工作實際上集中在確保我們在每個國家/地區都有完整的適應症集。

We're continuing to be able to execute partnership agreements to ensure that either if we're not going direct, we're making the product available through our partners and we'll expect that to continue over the course of 2024. And given we're now in a place where we're annualizing at more than $900 million, we see the product as being very much on track for blockbuster status.

我們將繼續能夠執行合作夥伴協議，以確保如果我們不直接合作，我們將透過我們的合作夥伴提供產品，我們預計這種情況將在 2024 年繼續下去。目前我們的年收入已超過9 億美元，我們認為該產品非常有望成為重磅產品。

And we will take our next question from Jeff Hung with Morgan Stanley.

我們將回答摩根士丹利的 Jeff Hung 提出的下一個問題。

This is Michael Riad on for Jeff Hung. On the high sodium authorized generics, what evidence generation is needed to support the long-term health messaging and drive patients like towards the switch to low sodium? Or do you think that the majority of the narcolepsy and IH community are more or less aligned with the benefits given the need for lifelong treatment?

我是邁克爾·裡亞德 (Michael Riad) 代表傑夫·洪 (Jeff Hung)。對於高鈉授權仿製藥，需要提供哪些證據來支持長期健康資訊並推動患者轉向低鈉？或者您認為大多數發作性睡病和 IH 社群或多或少都認同需要終身治療的好處？

Yes. I would say the evidence surrounding impact of sodium on cardiovascular health is pretty incontrovertible. Certainly, they underlie the original orphan drug exclusivity decision by FDA determining that Xywav was clinically superior to Xyrem on the basis of that lower sodium. The same thing could be said for LUMRYZ, which has the same sodium level as Xyrem. It doesn't mean there aren't opportunities to bring out more data as we have already, including with our presentation at the neurology meeting last year that within a period of 180 days of starting sodium oxybate therapy, we saw patients have a significantly increased either diagnosis of hypertension or beginning anti-hypertensive med.

是的。我想說，有關鈉對心血管健康影響的證據是無可爭議的。當然，它們是 FDA 最初孤兒藥獨佔性決定的基礎，該決定確定 Xywav 由於鈉含量較低而在臨床上優於 Xyrem。 LUMRYZ 的情況也是如此，它的鈉含量與 Xyrem 相同。這並不意味著我們沒有機會提供更多數據，包括我們去年在神經病學會議上的演講，即在開始羥丁酸鈉治療的 180 天內，我們看到患者的病情顯著增加診斷高血壓或開始服用抗高血壓藥物。

So even in a short period of time, you see that impact on people, even if they aren't already diagnosed as being hypertensive patients, which is, again, why that original determination was that Xywav will be a safer product in all narcolepsy patients who are known to be at high cardiovascular risk to begin with.

因此，即使在很短的時間內，你也會看到這種對人們的影響，即使他們還沒有被診斷為高血壓患者，這也是為什麼最初的決定是Xywav 對於所有發作性睡病患者來說將是一種更安全的產品已知心血管風險較高的人。

And we will take our next question from Joel Beatty with Baird.

我們將回答喬爾·比蒂和貝爾德提出的下一個問題。

For Zanidatamab, how much of the $2 billion in peak sales potential projection comes from breast cancer? And are you able to give a sense of when we might see data in that setting from the I-SPY 2 and MD Anderson collaboration trials?

對於 Zanidatamab 而言，預計 20 億美元的峰值銷售潛力中有多少來自乳癌？您能透露一下我們什麼時候可以看到 I-SPY 2 和 MD 安德森合作試驗中的數據嗎？

I'll take the first part of that, and then Rob, Renee and the data part of it over to you. We have not provided a breakdown of the opportunity set for Zanidatamab, which we believe is extensive. And certainly, in our slides, you can see that while we have made the most commentary thus far on BTC and GEA and breast cancer, it certainly has potential beyond those indications as well, which is why we say north of $2 billion. We haven't fully quantified how big the product could be as we determine where else to take it. We've got our near-term priorities worked out and looking forward to sharing a little more information at our R&D Day. But on timing of data, Rob, maybe I'll turn that one over to you.

我將把第一部分交給你，然後 Rob、Renee 和資料部分交給你。我們尚未提供 Zanidatamab 機會的詳細信息，我們認為該機會是廣泛的。當然，在我們的幻燈片中，您可以看到，雖然我們迄今為止對BTC 和GEA 以及乳癌做出了最多的評論，但它肯定也具有超越這些適應症的潛力，這就是為什麼我們說超過20 億美元。當我們決定將其帶到其他地方時，我們還沒有完全量化該產品的規模。我們已經確定了近期的優先事項，並期待在研發日分享更多資訊。但關於數據的時間安排，羅布，也許我會把那個交給你。

Yes, for the MD Anderson neoadjuvant study, some data were already published, you may be aware of that December at San Antonio. That trial is ongoing, and I would expect some updates. They haven't indicated exactly when the updates will be published. On I-SPY, which is a little bit late, has started a little bit after that trial, really depends on the enrollment rate and the results and when that might graduate from that phase.

是的，對於 MD 安德森新輔助研究，一些數據已經發布，您可能知道去年 12 月在聖安東尼奧的研究。該試驗正在進行中，我期待一些更新。他們沒有具體說明何時發布更新。 I-SPY 有點晚了，在試驗之後才開始，這實際上取決於入學率和結果，以及何時可以從該階段畢業。

And so we don't have any specifics at this point. But we are pleased that the trials are ongoing, and we're excited to see how that may inform next steps in that early-stage. Space where we think zani is particularly well positioned to provide better tolerated option for women with curative breast cancer.

所以我們目前沒有任何細節。但我們很高興試驗正在進行中，並且很高興看到這將如何為早期階段的後續步驟提供資訊。我們認為扎尼特別適合為患有治癒性乳癌的女性提供更好的耐受性選擇。

And ladies and gentlemen, we have no further questions at this time. I will now turn the call back to Mr. Bruce Cozadd for closing remarks.

女士們、先生們，我們目前沒有其他問題。現在，我將把電話轉回給布魯斯·科薩德先生，讓其致閉幕詞。

Thank you, operator. I'd like to close today's call by recognizing our Jazz colleagues for their efforts and thank our partners and shareholders for their continued confidence and support. Thank you all for joining us today.

謝謝你，接線生。在結束今天的電話會議時，我想對 Jazz 同事的努力表示認可，並感謝我們的合作夥伴和股東一直以來的信任和支持。感謝大家今天加入我們。

And ladies and gentlemen, this concludes today's call, and we thank you for your participation. You may now disconnect.

女士們、先生們，今天的電話會議到此結束，我們感謝你們的參與。您現在可以斷開連線。