福泰製藥 (VRTX) 2024 Q4 法說會逐字稿

Good day and welcome to the Vertex Pharmaceuticals fourth quarter of 2024 earnings call. (Operator Instructions) Please note this event is being recorded.

大家好，歡迎參加 Vertex Pharmaceuticals 2024 年第四季財報電話會議。（操作員指示）請注意，此事件正在被記錄。

I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead, ma'am.

現在我想將會議交給蘇西麗莎女士。請繼續，女士。

Good evening, all. My name is Susie Lisa. And as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our fourth-quarter 2024 financial results conference call.

大家晚上好。我的名字是 Susie Lisa。身為投資者關係資深副總裁，我很高興歡迎您參加我們的 2024 年第四季財務業績電話會議。

On tonight's call making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating Officer; and Charlie Wagner, Chief Financial Officer.

在今晚的電話會議上發表準備好的發言的有 Vertex 執行長兼總裁 Reshma Kewalramani 博士； Stuart Arbuckle，營運長；以及財務長查理·瓦格納（Charlie Wagner）。

We recommend that you access the webcast site as you listen to this call. The call is being recorded and a replay will be available on our website.

我們建議您在收聽此通話時造訪網路廣播網站。這次通話正在錄音，重播將在我們的網站上提供。

We will make forward-looking statements on this call that are subject to risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including without limitation, those regarding in Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia, and moderate-to-severe acute pain.

我們將在本次電話會議上做出前瞻性陳述，這些陳述可能會受到今天的新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性的影響。這些聲明包括但不限於有關 Vertex 上市銷售的治療囊性纖維化、鐮狀細胞疾病、β 地中海貧血以及中度至重度急性疼痛的藥物的聲明。

Our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

我們的產品線和 Vertex 的未來財務表現均基於管理層目前的假設。實際結果和事件可能會有重大差異。

I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis.

我還要指出的是，我們將在今晚的電話會議上審查的部分財務結果和指引是以非 GAAP 為基礎呈現的。

I'll now turn the call over to Reshma.

現在我將電話轉給 Reshma。

Thanks, Susie. Good evening, all, and thank you for joining us on the call today. Before diving into Q4 and full-year earnings, I'd like to provide a quick update on some leadership changes planned for mid-2025, as noted in our press release.

謝謝，蘇西。大家晚上好，感謝您今天的電話會議。在深入探討第四季度和全年收益之前，我想先簡要介紹一下我們新聞稿中提到的計劃於 2025 年中期進行的一些領導層變動。

Stuart Arbuckle will be retiring on July 1 of this year, after an almost 40-year career in biopharma and a stellar dozen-plus years at Vertex, first as Chief Commercial Officer and then as COO. Stuart reimagined the Vertex commercial organization as the company transitioned from hepatitis C and INCIVEK to establishing itself in CF. And since then, he has led as Vertex's Chief Commercial Officer and Chief Operating Officer with greater scale and innovation.

斯圖爾特·阿巴克爾 (Stuart Arbuckle) 將於今年 7 月 1 日退休，他在生物製藥領域擁有近 40 年的職業生涯，並在 Vertex 度過了十幾年輝煌的時光，先是擔任首席商務官，然後擔任首席營運官。隨著公司從丙型肝炎和 INCIVEK 轉向 CF 領域，史都華重新構思了 Vertex 的商業組織。此後，他擔任 Vertex 的首席商務官和首席營運官，帶領公司不斷擴大規模並進行創新。

Stuart has been at the helm through the launches and commercialization of all of our CFTR modulators, beginning with KALYDECO and all the way through to ALYFTREK. He has also helped develop and lead the organization into this new era of commercial diversification with the launches of CASGEVY and JOURNAVX.

從 KALYDECO 到 ALYFTREK，史都華一直負責我們所有 CFTR 調節劑的推出和商業化。透過推出 CASGEVY 和 JOURNAVX，他也幫助並帶領該組織進入商業多元化的新時代。

Anyone who's had the privilege to work with Stuart as I have know Stewart to be a consummate professional, an incredible leader, and an excellent developer of talent. He's uncommonly poised, leads with integrity, and always puts patients first.

任何有幸與史都華共事的人都知道，史都華是一位完美的專業人士、一位出色的領導者和優秀的人才開發者。他異常鎮定、誠信領導，並且始終把病人放在第一位。

As part of our carefully planned succession, Stuart is fully on board at Vertex until July, which will allow for a seamless transition. While we still have many months before he retires, I want to take this opportunity to convey my deep gratitude for his partnership and for all that Stuart has done for Vertex. We are very thoughtful and deliberate in how we plan for senior leader succession, and we always do so with a long time horizon in mind.

作為我們精心策劃的繼任計劃的一部分，史都華將在 Vertex 任職至七月，以確保無縫過渡。雖然距離他退休還有好幾個月的時間，但我想藉此機會對他的合作以及斯圖爾特為 Vertex 所做的一切表達深深的謝意。我們對高階領導繼任的規劃非常深思熟慮，並且始終著眼於長遠利益。

Thanks to this careful planning, we have never been in a stronger position to pass the baton from Stuart to other experienced senior leaders, and we are very confident that the transition will enable us to execute seamlessly on the significant opportunities ahead.

由於這一周密的規劃，我們從未有過比現在更好的機會將接力棒從斯圖爾特移交給其他經驗豐富的高級領導人，而且我們非常有信心，這一過渡將使我們能夠無縫地把握未來的重大機遇。

In that regard, I am very pleased to announce that Charlie Wagner, who join as CFO in April of 2019 and whom all of you know very well, will take on the additional role of CEO on July 1.

在這方面，我很高興地宣布，大家非常熟悉的查理·瓦格納 (Charlie Wagner) 將於 7 月 1 日兼任首席執行官一職。

I am equally pleased to announce that Duncan McKechnie, our long-time SVP and Head of the North American commercial team, will be promoted to EVP and Chief Commercial Officer also on July 1. Duncan had over 20 years experience in the industry across a wide range of strategic, operational, and commercial roles in multiple disease areas and geographies at both GSK and Novartis prior to joining Vertex 12 years ago. Duncan has been working side by side with Stuart since 2013, during which time he played an instrumental role architecting the successful launches of all of our CF medicines as well as the CASGEVY and JOURNAVX launches in the US.

我同樣高興地宣布，我們長期擔任高級副總裁兼北美商業團隊負責人的 Duncan McKechnie 也將於 7 月 1 日晉升為執行副總裁兼首席商務官。12 年前加入 Vertex 之前，鄧肯曾在葛蘭素史克和諾華公司擔任過多個疾病領域和地區的策略、營運和商業等職務，擁有超過 20 年的行業經驗。鄧肯自 2013 年以來一直與史都華並肩工作，在此期間，他為我們所有 CF 藥物以及 CASGEVY 和 JOURNAVX 在美國成功上市發揮了重要作用。

In addition to his role as the Commercial Head of North America since 2022, Duncan has also led the global health economics as well as the global value and access functions across the entire Vertex portfolio.

除了自 2022 年起擔任北美商業主管外，鄧肯還領導了整個 Vertex 投資組合的全球健康經濟學以及全球價值和准入職能。

I'm proud of the deep bench of outstanding talent we have at Vertex, and I'm looking forward to working directly with Duncan as he joins the executive committee and steps into the CCO role and as Charlie continues as CFO and adds COO responsibilities in July.

我為 Vertex 擁有的眾多傑出人才感到自豪，並期待與 Duncan 直接合作，他將加入執行委員會並擔任首席商務官一職，Charlie 將繼續擔任首席財務官，並在 7 月份承擔首席運營官的職責。

Moving to earnings. Fourth-quarter performance wrapped up another strong year as the continued outstanding commercial execution in CF helped us drive double-digit revenue growth for our tenth consecutive year and the launch of CASGEVY set us on the course of revenue diversification. We continue to reach more patients and delivered $2.91 billion in revenue in the fourth quarter, representing 16% growth versus Q4 2023.

轉向收益。第四季的業績又取得了強勁的成績，CF 持續出色的商業執行幫助我們連續第十年實現兩位數的收入增長，而 CASGEVY 的推出使我們走上了收入多元化的道路。我們繼續接觸更多患者，並在第四季度實現了 29.1 億美元的收入，較 2023 年第四季成長了 16%。

For the full-year 2024, revenue reached a new milestone of just over $11 billion, plus 12% versus 2023 and exceeded our full-year product revenue guidance of $10.8 billion to $10.9 billion. From this strong base, in 2025, we are focused on driving a significant expansion in the patients we serve with the ongoing launch of CASGEVY and two recent US NDA approvals, ALYFTREK, our next-generation fifth CF medicine approved on December 20; and JOURNAVX, approved for moderate-to-severe acute pain on January 30.

2024 年全年營收達到了新的里程碑，略高於 110 億美元，比 2023 年增長 12%，並超過了我們預期的 108 億至 109 億美元的全年產品收入。在此堅實基礎上，到 2025 年，我們將專注於推動我們服務的患者群體的大幅擴張，包括持續推出 CASGEVY 以及最近獲得兩項美國 NDA 批准，即於 12 月 20 日獲得批准的我們的第五代 CF 藥物 ALYFTREK；以及 JOURNAVX，於 1 月 30 日獲準用於治療中度至重度急性疼痛。

The JOURNAVX approval is landmark as it represents the first oral non-opioid pain signal inhibitor and the first new class of pain medicine in over 20 years. We see this approval as significant for millions of patients, for Vertex, and for society as an important option to support public health efforts to curb the opioid epidemic. Our R&D teams have worked on this program for many years, and it is indeed my privilege to acknowledge their efforts and also to thank the patients and healthcare providers who participated in the clinical trials and made this approval possible.

JOURNAVX 的核准具有里程碑意義，因為它是第一個口服非鴉片類疼痛訊號抑制劑，也是 20 多年來第一類新型止痛藥。我們認為此項批准對數百萬患者、對 Vertex 以及對社會都具有重要意義，是支持公共衛生工作遏制鴉片類藥物氾濫的重要選擇。我們的研發團隊已在該專案上工作多年，我很榮幸能夠認可他們的努力，同時也感謝參與臨床試驗並使該批准成為可能的患者和醫療保健提供者。

With these two recent approvals for ALYFTREK and JOURNAVX in hand and the continuing CASGEVY global launch, we have a keen focus on commercialization and our teams are working to secure broad access and reimbursement for patients who are waiting.

隨著 ALYFTREK 和 JOURNAVX 最近獲得批准以及 CASGEVY 繼續在全球推出，我們熱衷於商業化，我們的團隊正在努力為等待的患者確保廣泛的使用和報銷。

As I detailed in January, as the number of in-line approved medicines grow and the late-stage pipeline advances, we anticipate significantly expanding the number of patients we serve over the coming years. In 2024, our transformative therapies have the potential to serve approximately 160,000 patients with CF, sickle cell disease, and transfusion-dependent beta thalassemia. Now we can add 80 million acute pain patients to that reach, thanks to the approval of JOURNAVX.

正如我在一月份詳細說明的那樣，隨著批准的藥物數量的增長和後期研發管線的推進，我們預計未來幾年我們服務的患者數量將顯著增加。到 2024 年，我們的變革性療法有可能為大約 16 萬名 CF、鐮狀細胞疾病和輸血依賴性β地中海貧血患者提供服務。現在，由於 JOURNAVX 的批准，我們可以將這一範圍擴大到 8,000 萬名急性疼痛患者。

And beyond moderate-to-severe acute pain, focusing just on the mid- and late-stage pipeline, we seek to serve more than 5 million more patients including those with type 1 diabetes and certain renal diseases and then another 10 million-plus patients with peripheral neuropathic pain in the US alone.

除了中度至重度急性疼痛之外，我們僅關注中後期研發管線，尋求為超過 500 萬名患者提供服務，其中包括患有 1 型糖尿病和某些腎臟疾病的患者，然後僅在美國就為另外 1000 多萬患有周圍神經性疼痛的患者提供服務。

To give you a sense of our momentum, we are on track for key clinical development milestones in three pivotal studies this year. First, completing enrollment and dosing in the zimislecel Phase 1/2/3 study in type 1 diabetes which would position us to file for regulatory approval once this cohort has follow-up with one year of insulin independence.

為了讓您了解我們的發展勢頭，我們今年的三項關鍵研究有望實現關鍵的臨床發展里程碑。首先，完成 1 型糖尿病 zimislecel 1/2/3 期研究的招募和給藥，這將使我們能夠在該群體進行一年的胰島素獨立隨訪後申請監管部門批准。

Second, completing enrollment in the interim analysis cohort of povetacicept in IgAN, which would position us to file for potential US accelerated approval once that cohort reaches 36 weeks of treatment. And third, completing enrollment in the interim analysis cohort for inaxaplin for AMKD, which would position us to file for potential US accelerated approval once that cohort reaches 48 weeks of treatment.

其次，完成 Povetacicept 在 IgAN 治療中的中期分析隊列的招募，這將使我們能夠在該隊列達到 36 週的治療後申請美國加速批准。第三，完成 inaxaplin 治療 AMKD 的中期分析隊列的招募，一旦該隊列達到 48 週的治療，我們就可以申請美國加速批准。

In addition, we continue to execute the Phase 3 study of suzetrigine in patients with diabetic peripheral neuropathy. We're also making strong progress with VX-993, the next-generation NaV1.8 inhibitor in both moderate-to-severe acute pain and diabetic peripheral neuropathy. We also have ongoing trials of potentially transformative medicines like VX-670 in myotonic dystrophy type 1, povetacicept in a basket study in indications beyond IgAN and expect to move VX-407 for autosomal dominant polycystic kidney disease into Phase 2 this summer.

此外，我們仍在繼續對糖尿病週邊神經病變患者進行 Suzetrigine 的 3 期研究。我們也在 VX-993（下一代 NaV1.8 抑制劑）治療中度至重度急性疼痛和糖尿病週邊神經病變方面取得了重大進展。我們也正在進行具有潛在變革性的藥物試驗，例如用於治療 1 型強直性肌肉營養不良症的 VX-670、用於治療 IgAN 以外適應症的籃子研究中的 povetacicept，並且預計今年夏天將用於治療常染色體顯性多囊腎病的 VX-407 推進到第 2 階段。

It's truly an exciting area of broad diversification at Vertex in terms of the revenue base, our pipeline, and our geographic presence. Given the detailed clinical update we provided in January, I'll focus the R&D updates tonight on CF and our clinical-stage renal pipeline.

從收入基礎、產品線和地理分佈等方面來看，這確實是 Vertex 廣泛多元化的一個令人興奮的領域。鑑於我們在一月份提供的詳細臨床更新，今晚我將重點介紹 CF 和我們的臨床階段腎臟管線的研發更新。

Starting with CF. The US launch is underway for ALYFTREK, the fifth Vertex CFTR modulator regimen, while we are also working to secure approval in international regions. As we work to get ALYFTREK to patients around the globe, we are already in the clinic with our next-generation CFTR modulator regimen. With each CFTR modulator regimen that gains approval, we raised the bar ever higher for ourselves and the field as a whole as we continue our mission to bring all patients with CF to normal levels of CFTR function.

從 CF 開始。Vertex 的第五種 CFTR 調節劑方案 ALYFTREK 目前正在美國上市，同時我們也努力爭取國際地區的批准。在我們努力將 ALYFTREK 推廣至全球患者的同時，我們已經在臨床上推出了下一代 CFTR 調節劑方案。隨著每種 CFTR 調節劑方案獲得批准，我們對自己和整個領域的標準都提高了越來越高，我們將繼續我們的使命，讓所有 CF 患者的 CFTR 功能達到正常水平。

We term TRIKAFTA, KAFTRIO, the next-generation CFTR modulator or NG 1.0. ALYFTREK is NG 2.0. The NG 3.0 regimen consists of VX-828, a CFTR corrector; VX-118, a CFTR potentiator; and tezacaftor. This NG 3.0 triple combo regimen has shown even greater efficacy. In other words, even greater improvement in CFTR-dependent chloride transport than ALYFTREK in our CF human bronchial epithelial cell assays, which have been shown to be highly predictive of clinical outcomes.

我們將 TRIKAFTA、KAFTRIO 稱為下一代 CFTR 調節劑或 NG 1.0。 ALYFTREK 是 NG 2.0。 NG 3.0 方案包括 CFTR 校正劑 VX-828； VX-118，一種 CFTR 增效劑；和 tezacaftor。該NG 3.0三重療法已顯示出更高的療效。換句話說，在我們的 CF 人類支氣管上皮細胞測定中，CFTR 依賴性氯化物轉運比 ALYFTREK 有更大的改善，這已被證明可以高度預測臨床結果。

We expect this regimen to be in the clinic in a study of CF patients this year. We also continue to enroll and dose the MAD portion of the Phase 1/2 study of VX-522 for the 5,000-plus patients who cannot benefit from our CFTR modulators. Results from the MAD portion of the study are expected later this year.

我們預計該方案將在今年的 CF 患者臨床研究中得到應用。我們也繼續為超過 5,000 名無法從我們的 CFTR 調節劑中受益的患者招募 VX-522 1/2 期研究的 MAD 部分並為其給藥。該研究的 MAD 部分結果預計將於今年稍後公佈。

Moving on now to what I see as a real renaissance in renal therapeutic drug development. We are focused on advancing potential therapeutics that hold the promise to treat the underlying cause of disease in three different severe renal conditions. First, inaxiplin for APOL1-mediated kidney disease or AMKD. As mentioned, we're working towards our goal of completing enrollment of the interim analysis cohort of the pivotal amplitude study this year. Amplitude is a study of primary AMKD.

現在讓我們來談談我所看到的腎臟治療藥物開發的真正復興。我們致力於推動有希望治療三種不同嚴重腎臟疾病的根本病因的潛在治療方法。首先，inaxiplin 治療 APOL1 介導的腎臟疾病或 AMKD。如上所述，我們正在努力實現今年完成關鍵振幅研究中期分析隊列招募的目標。振幅是對原發性 AMKD 的研究。

That is to say patients with two APOL-1 alleles and no additional renal comorbidities. After completing enrollment, when this cohort reaches 48 weeks of treatment, we'll conduct the interim analysis. If positive, we will be able to file for potential accelerated approval in the US.

也就是說，患者有兩個 APOL-1 等位基因，且沒有其他腎臟合併症。完成招募後，當該隊列達到 48 週的治療時，我們將進行中期分析。如果結果是肯定的，我們將能夠在美國申請潛在的加速批准。

In addition, I am pleased to announce that last month, we initiated a new study amplified which is a Phase 2 proof-of-concept study of inaxiplin in patients with AMKD and other comorbidities, including type 2 diabetes; second, povetacicept, a dual antagonist of the APRIL and BAFF cytokines, which play key roles in the pathogenesis of B cell-mediated autoimmune diseases. This tool inhibition mechanism of action, the preclinical and clinical data to date plus pove's once-monthly dosing frequency and small volume subcutaneous administration give us high confidence in its promise as a transformative medicine for patients with IgAN and other B-cell-mediated diseases.

此外，我很高興地宣布，上個月我們啟動了一項新的研究，這是一項針對 AMKD 和其他合併症（包括 2 型糖尿病）患者的 inaxiplin 的 2 期概念驗證研究；第二，povetacicept，APRIL 和 BAFF 細胞因子的雙重拮抗劑，在 B 細胞介導的自體免疫疾病的發病機制中起關鍵作用。這種工具抑製作用機制、迄今為止的臨床前和臨床數據加上 pove 每月一次的給藥頻率和小容量皮下給藥使我們對其作為 IgAN 和其他 B 細胞介導疾病患者的轉化藥物的前景充滿信心。

As mentioned in January, we expect to complete enrollment of the interim analysis cohort of the pove study in IgAN this year. To this end, I am pleased to report that we have now opened more than 100 clinical trial sites in more than 20 countries, including in the US, Europe, and Asia, and enrollment in dosing are well underway. Once this cohort has 36 weeks of follow-up, we'll conduct the interim analysis. And if positive, it would support filing for a potential accelerated approval in the US. And third, an earlier stage renal program that represents an additional significant opportunity.

正如一月所提到的，我們預計今年將完成 IgAN pove 研究中期分析隊列的招募。為此，我很高興地報告，我們現在已經在美國、歐洲和亞洲等 20 多個國家開設了 100 多個臨床試驗點，給藥招募工作正在順利進行中。一旦對該群體進行了 36 週的跟踪，我們將進行中期分析。如果結果為陽性，它將支持在美國申請潛在的加速批准。第三，早期腎臟病計畫代表額外的重要機會。

VX-407 in autosomal dominant polycystic kidney disease, or ADPKD, where we are nearing completion of the Phase 1 trial ADPKD is the most common severe monogenic disease amongst Caucasians and the most common inherited cause of end-stage renal disease in the US and globally, an estimated 300,000 people in the US and Europe are living with ADPKD, yet there are no treatments that address the underlying cause of disease. It is a life-shortening disease that is characterized by the growth of numerous cysts that impair kidney function and can ultimately lead to kidney failure.

VX-407 用於治療常染色體顯性多囊性腎病變（ADPKD），我們即將完成該疾病的 1 期試驗。這是一種縮短壽命的疾病，其特徵是大量囊腫的生長，損害腎功能並最終導致腎衰竭。

Around half of patients with ADPKD experienced kidney failure by the age of 60. The majority of ADPKD cases are caused by variants in the PKD1 gene, which encodes the polycystin 1 or PC1 protein. These inherited variants lead to the loss of PC1 function that leads to the proliferation of kidney epithelial cells, increased fluid secretion and the formation and expansion of fluid-filled sits. The progressive cyst formation causes an increase in kidney size and decline in kidney function.

大約一半的 ADPKD 患者在 60 歲前會出現腎衰竭。大多數 ADPKD 病例是由 PKD1 基因變異引起的，該基因編碼多囊蛋白 1 或 PC1 蛋白。這些遺傳變異導致 PC1 功能喪失，從而引起腎臟上皮細胞增生、液體分泌增加以及充滿液體的囊泡形成和擴張。逐漸的囊腫形成導致腎臟增大，腎功能下降。

VX-407 is a first-in-class small molecule protein folding corrected that is designed to target the underlying cause of ADPKD by correcting PC1 folding to restore function, this has the potential to arrest assist growth. By way of its mechanism of action, VX-407 has potential in a subset of patients with protein-folding mutations of PKD1 estimated at up to 30,000 patients or about 10% of the overall ADPKD population.

VX-407 是一流的小分子蛋白質折疊矯正藥，旨在透過矯正 PC1 折疊來恢復功能，針對 ADPKD 的根本原因，有可能阻止輔助生長。根據其作用機制，VX-407 對 PKD1 蛋白質折疊突變患者亞群具有治療潛力，估計該類患者多達 30,000 名，或占 ADPKD 總體人口的約 10%。

As we're doing in CF, we seek to serially innovate and over time, reach the full 300,000 patients with ADPKD. For VX-407, we expect to complete our Phase 1 study soon. And if the results are supportive advance to Phase 2 later this year.

正如我們在 CF 領域所做的那樣，我們尋求持續創新，並隨著時間的推移，惠及 30 萬名 ADPKD 患者。對於 VX-407，我們預計很快就會完成第一階段的研究。如果結果支持的話，將在今年稍後進入第二階段。

With that review, I'll turn it over to Stuart for a commercial update.

經過該審查後，我將把它交給斯圖爾特進行商業更新。

Thank you very much, Reshma. While I admit to having very mixed emotions at retiring from Vertex in July, I know that the timing is right from both professional and personal standpoint.

非常感謝，Reshma。儘管我承認七月從 Vertex 退休時心情很複雜，但我知道從職業和個人角度來看，時機都是正確的。

It's been an amazing journey at Vertex over the last 13 years as we've executed on our unique and differentiated strategy to develop and commercialize transformative medicines for patients with CF, sickle cell disease, beta thalassemia, and pain. And I'm very confident we will successfully develop many more transformative medicines, such as in diabetes, renal and autoimmune diseases from our broad late-stage clinical pipeline. The business has never been in a better position scientifically and commercially than we are today.

過去 13 年對 Vertex 來說，是一段奇妙的旅程，我們執行了獨特的差異化策略，為 CF、鐮狀細胞疾病、β 地中海貧血和疼痛患者開發和商業化變革性藥物。我非常有信心，我們將從廣泛的後期臨床管線中成功開發出更多變革性藥物，例如用於治療糖尿病、腎臟病和自體免疫疾病的藥物。無論從科學或商業角度而言，我們的業務都處於前所未有的良好地位。

I'm also highly confident that we have developed the right talent to maximize these significant opportunities. I'm thrilled to transition leadership of our outstanding commercial organization to Duncan as the new CCO. I've known Duncan for decades and recruited him to Vertex. He brings a rare combination of outstanding strategic thinking, results focused operational excellence and people management skills, and I have every confidence he will help lead the company to even greater heights.

我也非常有信心，我們已經培養出合適的人才來最大限度地利用這些重要機會。我很高興將我們傑出的商業組織的領導權移交給新商務長鄧肯。我認識鄧肯幾十年了，並招募他加入 Vertex。他將出色的策略思維、注重成果的卓越營運和人員管理技能融為一體，這在同行中十分罕見，我完全有信心他將帶領公司走向更高的高度。

Although I will see many of you between now and July, I'd like to take this opportunity to thank all our shareholders and analysts for your support and engagement over the years, and I look forward to helping you get to know Duncan over the coming months.

雖然從現在到七月我還會見到你們中的許多人，但我還是想藉此機會感謝我們所有的股東和分析師多年來的支持和參與，並期待在接下來的幾個月裡幫助你們了解鄧肯。

With that, I will focus my comments tonight on our three recent launches, including the early US launch of ALYFTREK, the continuing global launch of CASGEVY building on the foundation we established in 2024 and the initial launch of JOURNAVX in acute pain, starting with CF.

因此，今晚我將重點談論我們最近推出的三款產品，包括 ALYFTREK 在美國的早期推出、CASGEVY 在我們 2024 年建立的基礎上繼續在全球推出以及 JOURNAVX 在急性疼痛領域的首次推出，首先是 CF。

Once again, we delivered strong CF results for the quarter and the full year as we further grew the number of eligible patients taking our CFTR modulators. We made rapid regulatory and reimbursement progress in 2024, and enabling us to expand to younger patients, patients with rare mutations, and patients in new geographies.

隨著服用我們 CFTR 調節劑的合格患者數量進一步增加，我們在本季度和全年再次取得了強勁的 CF 業績。我們在 2024 年取得了快速的監管和報銷進展，並使我們能夠擴展到年輕患者、具有罕見突變的患者以及新地區的患者。

ALYFTREK is now our fifth CFTR modulator approved to treat the underlying cause of CF. We were pleased with the early approval of ALYFTREK which in clinical trials has demonstrated noninferiority on function to TRIKAFTA, the current standard of care for eligible patients with CF.

ALYFTREK 是我們目前第五種獲準用於治療 CF 根本病因的 CFTR 調節劑。我們很高興看到 ALYFTREK 獲得早期批准，臨床試驗證明，其功能不劣於 TRIKAFTA，而 TRIKAFTA 是目前適合 CF 患者的標準治療方法。

ALYFTREK clinical trials also demonstrated further improvements in CFTR function as measured by sweat chloride. We believe this profile, along with the convenience of once-daily dosing sets the stage for ALYFTREK, potentially become the new standard of care in CF.

ALYFTREK 臨床試驗也證明，透過汗液氯化物測量，CFTR 功能進一步改善。我們相信，這種特性加上每日一次給藥的便利性為 ALYFTREK 奠定了基礎，有可能成為 CF 治療的新標準。

ALYFTREK is also approved for an additional 31 mutations that are not covered by the TRIKAFTA label. And finally, ALYFTREK carries a meaningfully lower royalty burden for Vertex and extends our composition of matter patent protection from 2037 for TRIKAFTA into 2039 for ALYFTREK.

ALYFTREK 也被批准用於治療 TRIKAFTA 標籤未涵蓋的另外 31 種突變。最後，ALYFTREK 為 Vertex 帶來了顯著較低的專利使用費負擔，並將我們的物質成分專利保護從 TRIKAFTA 的 2037 年延長至 ALYFTREK 的 2039 年。

We have received positive feedback from physicians and patients for ALYFTREK. Early insights show enthusiasm for a new option that offers the convenience of once-daily dosing to simplify treatment and expanded eligibility for many patients who are today not being treated with a CFTR modulator, including those who have 1 of the 31 rare mutations that are not responsive to our other CFTR modulators. In these early days of the launch, centers are familiarizing themselves with the data and the liver monitoring requirements to frame conversations about initiation with naive, discontinued and potential SWIFT patients.

我們收到了醫生和患者對 ALYFTREK 的正面回饋。早期見解表明，人們對這種新選擇充滿熱情，它提供了每日一次給藥的便利，以簡化治療並擴大許多目前未接受 CFTR 調節劑治療的患者（包括那些攜帶 31 種對我們的其他 CFTR 調節劑沒有反應的罕見突變中的 1 種的患者）的治療資格。在啟動初期，各中心正在熟悉數據和肝臟監測要求，以便與初治、已停藥和潛在的 SWIFT 患者開展關於開始治療的對話。

We have seen interest in ALYFTREK from all of these groups of eligible patients, and I'm pleased to report that the first patients have already initiated treatment with ALYFTREK. As we think about the uptake of ALYFTREK, we are confident that CF patients will seek the best medicine for them. And we believe that for the majority of patients, that is a lift track.

我們看到所有符合條件的患者群體對 ALYFTREK 表現出興趣，我很高興地報告，第一批患者已經開始接受 ALYFTREK 治療。當我們考慮 ALYFTREK 的採用時，我們相信 CF 患者會尋求最適合他們的藥物。我們相信，對大多數患者來說，這就是一條升降軌道。

We expect that the short-term liver monitoring requirements to initiate a lift trick will be considered in the context of the potential for a lifetime of improved CFTR function and the benefits of once-daily dosing. Outside the US, regulatory reviews are underway for ALYFTREK, including in the United Kingdom, European Union, Canada, Switzerland, Australia, and New Zealand. We look forward to the potential approvals of this best-in-class medicine in these markets in 2025.

我們期望，啟動舉重技巧的短期肝臟監測要求將在終生改善 CFTR 功能的可能性和每日一次給藥的好處的背景下考慮。在美國以外，英國、歐盟、加拿大、瑞士、澳洲和紐西蘭等國正在進行對 ALYFTREK 的監管審查。我們期待這種一流的藥物能在 2025 年在這些市場獲得批准。

Now turning to CASGEVY, our transformative onetime treatment for patients with sickle cell disease and beta thalassemia. It is just over a year since the historic approval of CASGEVY, which has been enthusiastically received by patients, physicians, payers and policymakers and the launch is gathering momentum across all regions.

現在來談談 CASGEVY，這是我們針對鐮狀細胞疾病和β地中海貧血患者的變革性一次性治療方法。CASGEVY 歷史性獲批至今僅一年多時間，受到了患者、醫生、付款人和政策制定者的熱烈歡迎，並在各地區獲得大力支持。

Two important markers of our launch progress are ATC activations and patient cell collections. As we reported in January, we exited 2024 with more than 50 authorized treatment centers, well on our way to our goal to activate approximately 75 total ATCs globally. Approximately 50 patients across all regions have their first cell collections in 2024.

我們啟動進展的兩個重要標誌是 ATC 活化和患者細胞收集。正如我們在一月份報告的那樣，到 2024 年，我們將擁有超過 50 個授權治療中心，並且正在朝著在全球範圍內啟動約 75 個 ATC 的目標邁進。2024 年，各地區約有 50 名患者將首次接受細胞採集。

And patient infusions of CASGEVY-edited cells have already occurred in both the Middle East and the US. We continue to make exciting progress in the Middle East. In November of 2023 and January of 2024, we secured regulatory approvals in Bahrain and Kasei, respectively. And on December 31, 2024, we secured regulatory approval in the United Arab Emirates. We are working to expand further in the region with anticipated filings in Kuwait and Qatar later this year.

中東和美國都已向患者輸入 CASGEVY 編輯的細胞。我們在中東持續取得令人振奮的進展。2023 年 11 月和 2024 年 1 月，我們分別獲得了巴林和 Kasei 的監管批准。2024 年 12 月 31 日，我們獲得了阿拉伯聯合大公國監管部門的批准。我們正在努力進一步拓展該地區的業務，預計今年稍後將在科威特和卡達提交申請。

In this region, we now have national reimbursement in Bahrain, hospital-based coverage in Saudi Arabia and are working towards coverage in the United Emirates. Continuing with the payer landscape, we recently reached a reimbursement agreement with NHS England for the treatment of patients with sickle cell disease. This means that eligible sickle cell disease and beta-thalassemia patients now have access to CASGEVY in England. In the US, both SCD and TDT patients have access either through private insurance, where over 250 million lives are covered or through single case agreements.

在該地區，我們目前已在巴林實現國家報銷，在沙烏地阿拉伯實現醫院覆蓋，並正在努力實現在阿聯酋的覆蓋範圍。繼續討論付款人情況，我們最近與 NHS England 達成了治療鐮狀細胞疾病患者的報銷協議。這意味著符合條件的鐮狀細胞疾病和β地中海貧血患者現在可以在英國接受 CASGEVY 治療。在美國，SCD 和 TDT 患者都可以透過私人保險獲得治療，目前有超過 2.5 億人受到保險保障，或透過單例協議獲得治療。

And in the Medicaid segment, as of last month, states may now begin to apply to participate in the CMMI cell and gene therapy access model, which we believe will further expand access for eligible patients as states may then subsequently opt in to the CMS negotiated agreements. We are focused on leveraging the foundation we established for CASGEVY in 2024 to build momentum in 2025 and beyond for this multibillion-dollar opportunity. as we work to get this transformative therapy to more and more patients around the world.

在醫療補助領域，截至上個月，各州現在可以開始申請參與 CMMI 細胞和基因治療獲取模式，我們相信這將進一步擴大符合條件的患者獲取治療的機會，因為各州隨後可能會選擇加入 CMS 談判協議。我們專注於利用 2024 年為 CASGEVY 奠定的基礎，為 2025 年及以後這個價值數十億美元的機會積蓄力量。我們致力於讓這種變革性的療法惠及世界各地越來越多的患者。

Shifting now to JOURNAVX in acute pain as we are currently 10 days post the milestone approval of this first selective oral non-opioid pain signal inhibitor. The approval is so critical because JOURNAVX represents the first new class of pain medicine in over 20 years. It combines effective pain relief with a favorable safety profile. And based on its MoA, it does not have addiction potential. It is indicated for use across all types of moderate to severe acute pain.

現在我們轉向使用 JOURNAVX 治療急性疼痛，因為目前距離首個選擇性口服非阿片類疼痛訊號抑制劑獲得里程碑式批准已過去 10 天。這項批准至關重要，因為 JOURNAVX 代表了 20 多年來第一類新型止痛藥。它結合了有效的止痛效果和良好的安全性。並且根據其 MoA，它不具有成癮性。它適用於治療所有類型的中度至重度急性疼痛。

For example, post surgery, broken bones, sports injuries and has the potential to establish a new standard of care for the 80 million patients who seek a prescription therapy treat moderate to severe acute pain each year in the US. Half of those seeking out for their acute pain or approximately 40 million Americans each year are prescribed opioids, which although effective, have significant safety and tolerability concerns and addictive potential. In fact, tragically an estimated 85,000 people each year will develop opioid use disorder within the first year of being prescribed an opioid for acute pain.

例如，術後、骨折、運動傷害，並有可能為美國每年 8,000 萬名尋求處方治療中度至重度急性疼痛的患者建立新的護理標準。每年有一半的急性疼痛患者（即約 4000 萬美國人）被處方阿片類藥物，儘管這種藥物有效，但卻存在嚴重的安全性和耐受性問題，並且容易上癮。事實上，不幸的是，每年約有 85,000 人在因急性疼痛被開立阿片類藥物後的第一年內會出現阿片類藥物使用障礙。

We believe we now have the opportunity to transform how acute pain is treated in the US and to build another multibillion-dollar franchise for Vertex.

我們相信，我們現在有機會改變美國治療急性疼痛的方式，並為 Vertex 建立另一個價值數十億美元的特許經營權。

We were launch ready for the PDUFA date and have now begun commercialization of generics. Our focus for 2025 is to engage with healthcare professionals, formulary decision makers and payers to establish the conditions for rapid patient access that will deliver long-term commercial success for our pain franchise.

我們已為 PDUFA 上市日期做好了準備，現已開始仿製藥的商業化。我們 2025 年的重點是與醫療保健專業人士、處方決策者和付款人合作，為患者快速獲得治療創造條件，從而為我們的疼痛治療特許經營帶來長期的商業成功。

To that end, while still just a few days into the launch, we believe that the incredibly broad positive media coverage JOURNAVX has received since approval is one measure of the high unmet need and an indication of the societal importance of providing both physicians and patients with a new non-opioid option for the treatment of acute pain. We've already seen tremendous interest and requests for information from both doctors and patients and we look forward to being able to serve them.

為此，儘管距離上市僅過去幾天，我們相信，JOURNAVX 自獲批以來就獲得了極為廣泛的正面媒體報道，這是衡量未滿足需求程度高的一個指標，也表明了為醫生和患者提供治療急性疼痛的新型非阿片類藥物選擇具有社會重要性。我們已經看到醫生和患者的極大興趣和資訊請求，我們期待能夠為他們提供服務。

Our 150-person sales force is actively engaging with healthcare providers and physicians on the compelling efficacy and safety data of generics and its role in all types of moderate to severe acute pain. In the institutional setting, we are engaging with roughly 2,000 high-volume hospitals and approximately 150 related health systems. We have line of sight to accelerate the typical P&T committee processes in many networks to support the use of generics in this setting.

我們擁有 150 名銷售人員，積極與醫療保健提供者和醫生交流仿製藥的令人信服的功效和安全性數據，以及其在所有類型的中度至重度急性疼痛中的作用。在機構設置方面，我們與大約 2,000 家大型醫院和大約 150 個相關衛生系統合作。我們有理由加速許多網路中典型的 P&T 委員會流程，以支持在這種情況下使用通用藥物。

We are advancing our discussions with national and regional payers and group purchasing organizations to provide access to generics, building on our work preapproval to accelerate formula reviews and limit inappropriate utilization management controls. And lastly, with retail pharmacies, we are working to secure broad stocking agreements at national retail pharmacies and regional chains to ensure availability of generics for patients across the country.

我們正在推進與國家和地區付款人以及團體採購組織的討論，以提供仿製藥，並在我們工作預批准的基礎上加快配方審查並限制不適當的利用管理控制。最後，我們正在與零售藥局合作，與全國零售藥局和地區連鎖店達成廣泛的備貨協議，以確保全國各地的患者都能獲得仿製藥。

We have also now begun our nonpersonal promotional initiatives to physicians and patients to promote broad awareness of the first oral non-opioid pain signal inhibitor for moderate to severe acute pain, such as embedded content in relevant websites like Medscape for physicians and WebMD for consumers, along with point-of-care marketing.

我們現在也開始針對醫生和患者進行非個人化的宣傳活動，以提高人們對第一種用於治療中度至重度急性疼痛的口服非阿片類疼痛信號抑製劑的廣泛認識，例如在針對醫生的 Medscape 和針對消費者的 WebMD 等相關網站中嵌入內容，以及即時診斷營銷。

Furthermore, we continue to see momentum and interest by policymakers both on the federal and the state level in providing equal access to non-opioid options for pain relief. The NOPAIN Act launched on January 1 and provides a Medicare add-on payment for non-opioids used in the hospital outpatient or ambulatory surgery center settings. We expect JOURNAVX to be added near term to the list of medicines approved for this add-on payment. The alternatives to Paymac had 78 co-sponsors from both parties last year and is expected to be reintroduced in the new Congress with similar and growing support.

此外，我們繼續看到聯邦和州兩級政策制定者在提供平等獲得非阿片類止痛藥物選擇方面的動力和興趣。《NOPAIN 法案》於 1 月 1 日推出，為醫院門診或門診手術中心使用的非鴉片類藥物提供醫療保險附加支付。我們預計 JOURNAVX 將在近期被添加到此項附加付款批准的藥品名單中。去年，Paymac 的替代方案獲得了來自兩黨 78 位共同提案人的支持，預計將在新國會中再次提出，並獲得類似且日益增多的支持。

Additional federal and state initiatives also continued to progress. For example, just six weeks into 2025, 17 states have already introduced legislation to support the use of non-opioid options, adding to the seven states that enacted legislation for Medicaid and state-regulated plans in 2024. We expect more states to join this movement.

聯邦和州的其他措施也繼續取得進展。例如，2025 年剛過六週，已有 17 個州出台立法支持使用非阿片類藥物，而 2024 年又有 7 個州出台了醫療補助和州監管計劃的立法。我們期待更多國家加入這項運動。

On the pricing front, we have priced JOURNAVX at $15.50 per pill or $31 per day at list price. We believe this price strikes a balance between ensuring broad access with the benefits it brings to patients and society, including the cost offsets that JOURNAVX may provide. It also recognizes our 20-plus year investment in pain. And significantly, we feel that this pricing enables us to continue to invest so that we can be the leader in serving patients with acute and chronic pain for decades to come.

在定價方面，我們將 JOURNAVX 的定價定為每粒 15.50 美元或每天 31 美元。我們相信，這個價格在確保廣泛可及性和為患者和社會帶來的利益（包括 JOURNAVX 可能提供的成本補償）之間取得了平衡。這也對我們在疼痛領域20多年的投入表示認可。重要的是，我們認為這個定價使我們能夠繼續投資，以便我們能夠在未來幾十年內成為服務急性和慢性疼痛患者的領導者。

As previously discussed, in the early months of the launch, we are strategically investing in initiatives, including financial assistance programs for eligible patients that enable smooth, rapid access for patients prescribed genomics which is critical given the acute nature of the condition. And lastly, we expect to start shipping genomics to wholesalers by the end of this month with retail availability a few days later.

正如前面所討論的，在推出的最初幾個月，我們正在策略性地投資於一些舉措，包括為符合條件的患者提供財務援助計劃，使患者能夠順利、快速地獲得處方基因組學治療，這對於病情的急性性質來說至關重要。最後，我們預計將在本月底開始向批發商運送基因組學產品，並在幾天後提供給零售商。

To conclude, we had a very strong commercial execution throughout 2024 and are already executing on the multiple launches and growth opportunities ahead of us in 2025. We are in a new and exciting era of commercial diversification with the ongoing global launch of CASGEVY, the launch of ALYFTREK in CF and JOURNAVX in moderate to severe acute pain in the US.

總而言之，我們在整個 2024 年都擁有非常強大的商業執行力，並且已經在執行 2025 年面臨的多項發布和成長機會。隨著 CASGEVY 的全球上市、ALYFTREK 在 CF 中的上市以及 JOURNAVX 在美上市，我們正處於商業多元化的激動人心的新時代，JOURNAVX 在美國用於治療中度至重度急性疼痛。

I'll now turn the call over to Charlie to review the financials.

我現在將電話轉給查理審查財務狀況。

Thanks, Stuart. Vertex's excellent results in the fourth quarter of 2024 demonstrate once again our consistent strong performance and attractive growth profile.

謝謝，斯圖爾特。Vertex 在 2024 年第四季的出色業績再次證明了我們持續強勁的業績和誘人的成長前景。

Fourth-quarter 2024 total product revenue increased 16% year over year to $2.91 billion, including revenue growth of 17% in the US and 14% outside the US. The exceptional US CF revenue growth in the quarter resulted from continued strong patient demand and the effect of the January 2024 price increase as well as a favorable gross to net dynamic. Ex-US revenue growth was driven by strong CF performance in many established markets as well as in newer markets where we have recently transitioned to long-term reimbursement agreements.

2024 年第四季總產品營收年增 16% 至 29.1 億美元，其中美國地區營收成長 17%，美國以外地區營收成長 14%。本季美國 CF 收入的優異成長得益於患者需求持續強勁、2024 年 1 月價格上漲的影響以及有利的毛利與淨利動態。美國以外地區的收入成長得益於許多成熟市場以及我們最近已轉向長期報銷協議的新興市場的強勁 CF 表現。

Revenue in the quarter also benefited from certain non-recurring items. Full-year revenue of $11.02 billion represents 12% growth versus 2023, our tenth consecutive year of double-digit growth.

本季的收入也受惠於某些非經常性項目。全年營收為 110.2 億美元，較 2023 年成長 12%，這是我們連續第十年實現兩位數成長。

Fourth quarter 2024 combined non-GAAP R&D acquired IP R&D and SG&A expenses were $1.3 billion, an increase of 29% compared to $1 billion in the fourth quarter of 2023. The most significant areas of increased investment versus prior year included the pivotal studies for type 1 diabetes, IgAN, AMKD, and DPN, as well as the build-out of capabilities for both our expanding pipeline and ongoing commercial launches.

2024 年第四季非 GAAP 研發收購 IP 研發和銷售、一般及行政費用總計為 13 億美元，較 2023 年第四季的 10 億美元成長 29%。與前一年相比，投資增加的最重要領域包括針對 1 型糖尿病、IgAN、AMKD 和 DPN 的關鍵研究，以及不斷擴大的產品線和正在進行的商業發布的能力建設。

Also included in Q4 2024 results are $88 million of acquired IPR&D expenses, including for the Orna collaboration to develop next-generation in vivo therapeutics for sickle cell disease and beta thalassemia. This compares to $18 million of such charges in the fourth quarter of 2023. Full-year 2024 combined non-GAAP R&D acquired IPR&D and SG&A expenses were $8.82 billion compared to $4.24 billion in 2023.

2024 年第四季的業績還包括 8,800 萬美元的收購智慧財產權與開發費用，其中包括與 Orna 合作開發針對鐮狀細胞疾病和β地中海貧血的下一代體內療法。相比之下，2023 年第四季此類費用為 1,800 萬美元。2024 年全年非 GAAP 研發獲得的智慧財產權、開發及銷售、一般及行政費用合計為 88.2 億美元，而 2023 年為 42.4 億美元。

Included in full-year 2024 results are $4.63 billion of acquired IPR&D charges with the vast majority resulting from the Alpine Immune Sciences acquisition. Acquired IP R&D charges were $527 million for the full-year 2023. The year-over-year increase in R&D expenses were driven by continued investment in our pipeline, including four ongoing pivotal studies. The year-over-year increase in SG&A costs was primarily driven by investments in our commercial organization to support the launches of JOURNAVX and CASGEVY.

2024 年全年業績包括 46.3 億美元的收購 IPR&D 費用，其中絕大部分來自對 Alpine Immune Sciences 的收購。2023 年全年收購的 IP 研發費用為 5.27 億美元。研發費用的年增率得益於我們對產品線的持續投資，包括四項正在進行的關鍵研究。銷售、一般及行政費用的同比增長主要是由於我們對商業組織的投資，用於支持 JOURNAVX 和 CASGEVY 的推出。

Fourth-quarter 2024 non-GAAP operating income was $1.2 billion compared to $1.15 billion in non-GAAP operating income in the fourth quarter of 2023. Full-year 2024 non-GAAP operating income was $696 million compared to $4.37 billion in 2023. Recall that full-year 2024 non-GAAP operating income reflects a $4.4 billion charge for acquired IPR&D from the acquisition of Alpine.

2024 年第四季非 GAAP 營業收入為 12 億美元，而 2023 年第四季非 GAAP 營業收入為 11.5 億美元。2024 年全年非 GAAP 營業收入為 6.96 億美元，而 2023 年為 43.7 億美元。回想一下，2024 年全年非 GAAP 營業收入反映了收購 Alpine 所產生的 44 億美元 IPR&D 費用。

Fourth-quarter 2024 non-GAAP effective tax rate of 21.3% was in line with our expectations, while our 16.3% tax rate in Q4 '23 benefited from higher US R&D tax credits. Our full-year 2024 effective tax rate of 91% reflects the non-deductibility of the Alpine acquired IPR&D charge. Our non-GAAP effective tax rate in 2023 was 19.4%.

2024 年第四季非 GAAP 有效稅率為 21.3%，符合我們的預期，而 2023 年第四季 16.3% 的稅率受益於美國更高的研發稅收抵免。我們 2024 年全年有效稅率為 91%，反映了阿爾派所獲得的 IPR&D 費用的不可扣除性。我們 2023 年的非 GAAP 有效稅率為 19.4%。

Fourth-quarter 2024 non-GAAP earnings per share were $3.98 compared to $4.20 in the fourth quarter of 2023, largely as a result of lower interest income and the tax rate differential previously noted. Full-year 2024 non-GAAP earnings per share were $0.42 compared to $15.23 in 2023. For reference, the Alpine AIP R&D charge equates to roughly $17 on a per share basis. We ended the quarter with $11.2 billion in cash and investments.

2024 年第四季非 GAAP 每股盈餘為 3.98 美元，而 2023 年第四季為 4.20 美元，主要是由於利息收入減少和先前提到的稅率差異所致。2024 年全年非 GAAP 每股收益為 0.42 美元，而 2023 年為 15.23 美元。作為參考，Alpine AIP 研發費用約為每股 17 美元。截至本季末，我們的現金和投資總額為 112 億美元。

Our priorities for cash deployment remain unchanged as we continue to prioritize investment in innovation, including external innovation by business development. We also continued our share repurchase program and deployed approximately $1.2 billion to repurchase 2.7 million shares over the course of 2024, including 961,000 shares in the fourth quarter.

我們的現金部署重點保持不變，因為我們繼續優先投資創新，包括透過業務發展進行外部創新。我們也繼續執行股票回購計劃，並於 2024 年間投入約 12 億美元回購 270 萬股，其中包括第四季的 961,000 股。

Now switching to guidance. For 2025, we expect total revenue in a range of $11.75 billion to $12 billion, representing growth of approximately 8% at the midpoint at current exchange rates with the US as the main driver of total revenue growth. This outlook reflects our expectation for continued growth from our portfolio of CF medicines, including the US launch of ALYFTREK.

現在轉到指導。預計 2025 年總營收將在 117.5 億美元至 120 億美元之間，以當前匯率計算中間值成長約 8%，美國是總營收成長的主要推動力。這一前景反映了我們對 CF 藥物組合持續成長的預期，包括在美國推出的 ALYFTREK。

Note that ex-US CF revenue growth will be impacted by a reduction of revenue in one country outside our core markets where certain intellectual property rights are being violated. This impact will be most pronounced in Q1 as the increases in international channel inventory that occurred in Q1 of 2024 will not repeat in Q1 2025.

請注意，美國以外的 CF 收入成長將受到我們核心市場以外的某個國家/地區收入減少的影響，因為這些國家的某些智慧財產權受到侵犯。這種影響將在第一季最為明顯，因為 2024 年第一季出現的國際通路庫存增加不會在 2025 年第一季重現。

Guidance also includes a continued ramp-up in CASGEVY revenue as we treat more patients in approved geographies. Given the very recent approval of JOURNAVX, guidance also reflects a contribution from this launch in the US, primarily in the back half of the year.

該指引還包括，隨著我們在核准地區治療更多的患者，CASGEVY 收入將繼續增加。鑑於 JOURNAVX 最近獲得批准，該指引也反映了在美國推出的貢獻，主要是在今年下半年。

We expect JOURNAVX volumes to ramp up ahead of revenue as a result of financial assistance programs that are designed to provide eligible patients with immediate access while we work to secure broad sustainable payer coverage. To give you context on the launch progress of JOURNAVX, we will provide metrics on total covered lives and prescription data over the course of 2025. Also note that the expected benefit to gross margin in 2025 from the lower royalty rate on ALYFTREK will largely be offset by the higher cost of goods on our other new product launches as they scale towards their long-term margins.

我們預計，由於財政援助計劃旨在為符合條件的患者提供即時治療，同時我們努力確保廣泛而可持續的付款人覆蓋，JOURNAVX 的交易量將超過收入。為了讓您了解 JOURNAVX 的發布進度，我們將提供 2025 年期間的總覆蓋率和處方資料指標。另請注意，隨著 ALYFTREK 特許權使用費率降低，2025 年預計的毛利率收益將在很大程度上被我們其他新產品推出時更高的商品成本所抵消，因為它們正向長期利潤率邁進。

For combined non-GAAP R&D, acquired IPR&D expenses, and SG&A, we project a range of $4.9 billion to $5 billion for the full-year 2025. This guidance includes approximately $100 million in currently anticipated IPR&D charges. We will continue to invest a majority of our operating expenses into R&D given the momentum in our multiple mid- and late-stage clinical development programs.

對於非公認會計準則研發費用、獲得的智慧財產權與開發費用以及銷售、一般和行政費用的總額，我們預計 2025 年全年的範圍將在 49 億美元至 50 億美元之間。該指引包括目前預計的約 1 億美元的 IPR&D 費用。鑑於我們多個中後期臨床開發項目的勢頭，我們將繼續將大部分營運費用投入研發。

The cost for four Phase 3 studies were a driver of increased investment in Q4 '24, and this trend will continue over the course of 2025 with the four Phase 3 studies continuing and multiple Phase 2's ongoing as well. The increase in commercial costs in 2025 supports our increasingly diversified commercial portfolio and reflects a full year of investments to support the launch of JOURNAVX as well as targeted spending on commercial capabilities for future potential multi-billion dollar opportunities in renal therapies and zimislecel, for example.

四項 3 期研究的成本是 2024 年第四季投資增加的驅動力，這一趨勢將持續到 2025 年，四項 3 期研究將繼續進行，多項 2 期研究也將持續進行。2025 年商業成本的增加支持了我們日益多樣化的商業組合，並反映了全年的投資，以支持 JOURNAVX 的推出，以及針對未來腎臟治療和 zimislecel 等潛在數十億美元機會的商業能力的定向支出。

Given our differentiated business model and focus on specialty markets, we can make these targeted investments while maintaining attractive profitability and cash flow. Our full-year 2025 non-GAAP effective tax rate is expected to be in the range of 20.5% to 21.5%.

鑑於我們差異化的商業模式和對專業市場的關注，我們可以進行這些有針對性的投資，同時保持有吸引力的獲利能力和現金流。我們預計 2025 年全年非 GAAP 有效稅率在 20.5% 至 21.5% 之間。

In closing, Vertex delivered excellent results yet again in 2024, achieving strong revenue growth, advancing our CASGEVY launch, and gaining important regulatory approvals that position us for commercial launches, all while continuing to make significant pipeline progress across the portfolio. We are now launching two new products in the US, driving the CASGEVY global launch and enrolling four Phase 3 studies with three of them expected to reach significant enrollment milestones this year. These and other anticipated milestones of continued progress in multiple disease areas are detailed on slide 16.

最後，Vertex 在 2024 年再次取得了優異的成績，實現了強勁的收入成長，推進了我們的 CASGEVY 上市，並獲得了重要的監管批准，為商業上市奠定了基礎，同時繼續在整個產品組合中取得重大進展。我們目前正在美國推出兩款新產品，推動 CASGEVY 的全球發布，並招募四項 3 期研究，其中三項預計將在今年達到重要的招募里程碑。投影片 16 詳細介紹了這些以及其他預期在多個疾病領域持續取得進展的里程碑。

We look forward to updating you on our progress on future calls, and I'll now ask Susie to begin the Q&A period.

我們期待在未來的電話會議上向您通報我們的進展情況，現在我將請蘇西開始問答環節。

(Operator Instructions) Salveen Richter, Goldman Sachs.

（操作員指示） Salveen Richter，高盛。

On JOURNAVX -- and actually, Stuart, we really are going to miss you and Duncan welcome here. Maybe just going back to my question on JOURNAVX, can you further elaborate on pre-launch efforts in the retail pharmacies and the P&T committee review processes and how you can work to accelerate these aspects?

在 JOURNAVX 上——實際上，斯圖爾特，我們真的會想念你，歡迎鄧肯來到這裡。也許只是回到我關於 JOURNAVX 的問題，您能否進一步詳細說明零售藥局的上市前工作和 P&T 委員會審查流程，以及您如何努力加速這些方面？

And then secondly, on your mRNA program in cystic fibrosis, maybe frame for us how you think of success here.

其次，關於您在囊性纖維化中的 mRNA 計劃，也許可以為我們闡述您對這項計劃的成功的看法。

Yeah. Salveen, let me turn it over to Stuart first, and then I'll come back to the mRNA question. Stuart?

是的。薩爾文，讓我先把它交給斯圖爾特，然後我再回到 mRNA 問題上。史都華？

Yeah, Salveen, thanks for the kind words. Yeah, so in terms of our work with retail, we've been working with the largest national retail chains and also regional chains to ensure that we get broad availability of JOURNAVX across the US.

是的，Salveen，謝謝你們的好意。是的，就我們與零售業的合作而言，我們一直與最大的全國零售連鎖店和地區連鎖店合作，以確保 JOURNAVX 能夠在美國各地廣泛供應。

And it's very important, obviously, to have broad availability because we want the product to be there when a patient in acute pain turns up with their prescription because they obviously can't wait. And as I said in my prepared remarks, we are expecting to have the product with wholesalers by the end of this month and in retail shortly thereafter.

顯然，廣泛的可用性非常重要，因為我們希望當急性疼痛的患者拿著處方出現時，產品就在他們身邊，因為他們顯然等不及了。正如我在準備好的演講中所說，我們預計本月底該產品將交付給批發商，隨後不久將在零售店銷售。

And I am expecting that we will have broad availability across the entire U.S. In terms of our work with both payers on their approval processes and also institutions on their pre-approval. We are working on them compliantly to provide them with information that they need, such as the full clinical profile of the medicine.

我希望我們將在全美範圍內廣泛提供服務，包括我們與付款人合作的審批流程以及與機構合作的預先批准。我們正在按照規定為他們提供所需的信息，例如該藥品的完整臨床概況。

Obviously, now, we also have the established price, which is an important component for them as well. And we do have indications that people are looking to move quickly to provide access to genetics given the benefit risk profile, and we'll keep you updated on our progress with that over the next few weeks and months.

顯然，現在我們也已經確定了價格，這對他們來說也是一個重要組成部分。而且我們確實有跡象表明，考慮到利益風險狀況，人們正在尋求迅速採取行動來提供獲取遺傳基因的途徑，我們將在接下來的幾週和幾個月內向您通報我們的進展。

And Salveen, on your question with regard to mRNA. So these are the last 5,000 or so patients, they have no options available to them. And so if I think about the approved medicines ORKAMBI on the one hand with about a 3% improvement in ppFEV1 and then TRIKAFTA and ALYFTREK on the other side with about a 14% improvement on ppFEV1, and because the mRNA, VX-522, is an inhaled therapeutic, we're not expecting any movement on sweat chloride. So this would be a readout on ppFEV1.

Salveen，關於您關於 mRNA 的問題。所以，這些最後的 5,000 名左右的患者，他們沒有其他選擇。因此，如果我考慮已批准的藥物 ORKAMBI，一方面其 ppFEV1 改善了約 3%，而另一方面 TRIKAFTA 和 ALYFTREK 其 ppFEV1 改善了約 14%，而且由於 mRNA VX-522 是一種吸入治療劑，我們預計汗液氯化物不會有任何變化。所以這將是 ppFEV1 的讀數。

And any number between 3% and 14% would be just fine. And of course, if it's more than that, that would be acceptable as well. But based on the approved medicines, I think you could look at a range from 3% to 14% as what would be important. If you translate the 3%, let's say, that's what ORKAMBI had into long-term outcomes. Remember that the 3% in acute improvement in ppFEV1 translated to a 50%-plus improvement or reduction in pulmonary exacerbations.

3% 到 14% 之間的任何數字都可以。當然，如果更多的話，也是可以接受的。但根據批准的藥物，我認為你可以將 3% 到 14% 之間的範圍視為重要的範圍。如果你將 3% 轉化為 ORKAMBI 的長期成果。請記住，ppFEV1 急性改善 3% 意味著肺部症狀惡化改善或減少 50% 以上。

Evan Seigerman, BMO Capital Markets.

埃文·塞格曼 (Evan Seigerman)，BMO 資本市場。

Congrats on a strong '24 and a great start to 2025. Also Stuart, congrats on your retirement. It's been an honor to watch you really transform this company.

恭喜 2024 年取得強勁進展並迎來 2025 年良好開端。另外，斯圖爾特，恭喜你退休。我很榮幸能夠看到您真正改變了這家公司。

So I want to touch on JOURNAVX. Talk to me a little bit about how your early discussions with payers have been progressing. How many covered lives do you expect to have access to therapy when it is a retail channel? And how is that going to change over the course of the year?

所以我想談談 JOURNAVX。請跟我簡單談談您與付款人的早期討論進度如何。當採用零售通路時，您預計有多少受保人可以獲得治療？今年這情況將如何改變？

Evan, again, thanks for the kind words. I appreciate it. And let me just reassure everybody, I'm going to be here until July 1 and 100% focused on driving the JOURNAVX launch and CASGEVY and ALYFTREK as well.

埃文，再次感謝你的善意。我很感激。我只想向大家保證，我會在這裡待到 7 月 1 日，全心投入推動 JOURNAVX 的發布以及 CASGEVY 和 ALYFTREK 的工作。

In terms of our pay discussions, we were having payer discussions prior to the approval. And obviously, we've continued to have them post approval, Evan. They've gone really well. I think it's no surprise. Everybody is acutely aware unmet need to have better treatment options and opioids and everybody is excited about the fact that this is the first non-opioid for decades.

就我們的薪酬討論而言，我們在批准之前就進行了付款人討論。顯然，在獲得批准後我們會繼續擁有它們，埃文。他們一切進展順利。我認為這並不奇怪。每個人都敏銳地意識到尚未滿足的治療需求需要更好的治療選擇和阿片類藥物，每個人都對這是幾十年來第一個非阿片類藥物感到興奮。

I am expecting that we will get broad access over time, and I expect it to grow over time. We're not giving specific expectations or guidance on exactly how many covered lives we expect at what point through the year. But obviously, we are expecting it to grow throughout the year as more payers choose to put generics on their formulary.

我期望隨著時間的推移，我們將獲得廣泛的訪問權，並且我期望它會隨著時間的推移而增長。我們並沒有給出具體的期望或指導，說明今年的哪個時間點預計會涵蓋多少人。但顯然，隨著越來越多的付款人選擇將仿製藥納入處方表，我們預計該數字全年都會成長。

Jessica Fye, JPMorgan.

摩根大通的傑西卡·菲伊 (Jessica Fye)。

Thinking about the 2025 top-line guidance, it seems like that's largely driven by CF. I was wondering if you could talk about how we should think about the US versus ex-US contribution to that growth rate in the CF business? And kind of what's driving those respective growth rates in the US and outside the US.

想想 2025 年的營收預期，這似乎主要是由 CF 推動的。我想知道您是否可以談談我們應該如何看待美國和美國以外地區對 CF 業務成長率的貢獻？以及推動美國國內和美國以外地區各自成長率的因素是什麼。

Charlie?

查理？

Yes, Jess, thanks for the question. Our guidance range of $11.75 billion to $12 billion, as we highlighted in the prepared remarks, represents 8% at the midpoint. We did call out in the prepared remarks sort of the differential between the US and ex-US. If you think about what's going on, I think about 2024, obviously, we continue to see very strong growth in the CF business around the world.

是的，傑西，謝謝你的提問。正如我們在準備好的評論中所強調的，我們的指導範圍是 117.5 億美元至 120 億美元，中間值為 8%。我們確實在準備好的評論中指出了美國和美國以外地區的差異。如果你思考現在發生的事情，我想到 2024 年，顯然，我們將繼續看到全球 CF 業務的強勁成長。

We expect that to continue into 2025. The US has the benefit of the electric launch as well as the JOURNAVX launch in addition to ramping CASGEVY and the ongoing growth in CF. If you think about international, we'll see strong growth in CF. In most markets, we did call out that there is one country where our IP is not being respected.

我們預計這種情況將持續到 2025 年。除了 CASGEVY 的推進和 CF 的持續成長之外，美國還受益於電力發射和 JOURNAVX 的發射。如果你考慮國際，我們會看到 CF 出現強勁成長。在大多數市場，我們確實指出有一個國家不尊重我們的智慧財產權。

That has an impact on the ex-US growth rate that will be most pronounced and visible in the first quarter, so we thought we would call that out for you. And then obviously, the CASGEVY launch continues to ramp ex-US as well. So with those dynamics, there is a little bit of a difference between the US and ex-US in 2025. But overall, a very healthy growth rate on the top line for us.

這對美國以外地區的成長率產生了影響，這種影響在第一季將最為明顯，因此我們想向您指出這一點。顯然，CASGEVY 的推出也將繼續推動美國以外的發展。因此，從這些動態來看，到 2025 年，美國和美國以外地區將會有一點差異。但總體而言，我們的營收成長率非常健康。

Great. And can I just throw on a follow-up. I think you also mentioned the 4Q revenue benefited from some nonrecurring items. Possible to quantify that at all?

偉大的。我能否繼續後續問題？我記得您還提到第四季度的收入受益於一些非經常性項目。有可能量化嗎？

Yes. I'm not going to get into that. I'll just qualitatively, I'll tell you, the fourth quarter was very strong. Growth in the US was driven by strong volume in CF as well as the benefit from the price increase that we took earlier in the year.

是的。我不想談論這個。我只是從品質上告訴你，第四季的表現非常強勁。美國市場的成長主要得益於CF的強勁銷售以及今年稍早價格上漲的好處。

In addition, we saw a very favorable gross to net dynamic in the US. Gross to net fluctuates, honestly from quarter to quarter. Typically, it's a little more negative in the first quarter. But we did see a meaningful benefit in the fourth quarter. Outside the US, again, strong volume growth in CF.

此外，我們發現美國的毛利率與淨利率呈現非常良好的關係。老實說，毛利與淨利每季都有波動。通常情況下，第一季的情況會稍微負面一些。但我們確實在第四季度看到了顯著的好處。在美國以外，CF 的銷售再次出現強勁成長。

We did also have the benefit of some one-time items, things like VAT rebates and some other settlements that we worked out in different markets, those don't reoccur necessarily every quarter.

我們確實也受益於一些一次性項目，例如增值稅退稅和我們在不同市場達成的一些其他協議，這些並不一定每季都會重複發生。

Geoffrey Meacham, Citibank.

花旗銀行的傑弗瑞‧米查姆。

Greater also want to offer up and graphs to Stuart as well as Charlie and Duncan just on all the announcements today. So just on JOURNAVX and LSR. I know you guys have taken a deep dive into the Phase 2 and maybe you've gotten some KOL feedback. Are there any more considerations you're thinking about for Phase 3 design? I know you're still awaiting regulatory feedback, but I want to get your perspective on that.

Greater 還想向 Stuart 以及 Charlie 和 Duncan 提供有關今天所有公告的圖表。因此僅關注 JOURNAVX 和 LSR。我知道你們已經深入研究了第二階段，也許已經收到了一些 KOL 回饋。您對第三階段的設計還有其他考量嗎？我知道您仍在等待監管部門的回饋，但我想聽聽您對此的看法。

And then second question is on ALYFTREK. I want to get maybe any early anecdotes from you guys on new patients coming into care either just qualitative or quantitative feedback on those that are perhaps not on TRIKAFTA or unmet need populations.

第二個問題是關於 ALYFTREK 的。我希望從你們那裡獲得一些關於新病人的早期軼事，無論是定性還是定量的回饋，這些回饋可能不屬於 TRIKAFTA 或未滿足需求的人群。

Sure thing. just I'll take the LSR question, and then I'll ask Stuart to comment on ALYFTREK. So you actually have it exactly right. The big thing that we're waiting for is our end of Phase 2 meeting with the regulators. Where we are with our analysis is our teams are very deep into their analysis of everything we can possibly glean from the Phase 2.

當然可以。我只回答 LSR 問題，然後我會請 Stuart 對 ALYFTREK 發表評論。所以事實上你是完全正確的。我們正在等待的大事是與監管機構的第二階段會議結束。我們的分析是，我們的團隊對我們可能從第二階段收集到的所有資訊進行了深入的分析。

We are out talking to not only key opinion leaders, but PIs and those who are very involved in doing LSR studies, and we are preparing ourselves for our regulatory meetings I'll have more to share with you this summer, but I don't have an update. I'd rather collect all of this and present it to you all at once and summer after we've gone through our regulatory interactions.

我們不僅與關鍵意見領袖進行了交談，還與 PI 以及那些積極參與 LSR 研究的人員進行了交談，我們正在為監管會議做準備，今年夏天我會與大家分享更多信息，但我還沒有最新消息。我寧願把所有這些收集起來，一次呈現給你們，然後在我們完成監管互動之後的夏天呈現給大家。

And obviously, the really big thing that we are looking to understand is what the FDA would like to see what are the packages, what they we need to include in the package for this broad PNP indication that we seek. Stuart?

顯然，我們真正想要了解的是 FDA 希望看到的方案是什麼，對於我們尋求的這種廣泛的 PNP 適應症，我們需要在方案中包含什麼。史都華？

Yes. On ALYFTREK, Geoff, we've seen strong interest from patients who are either kind of naive have never been on a CFTR modulator and in particular, those who are now eligible for a CFTR modulator, ALYFTREK is approved, which, as you know, has additional mutations over and above even TRIKAFTA. So we've seen strong interest there, as you might expect.

是的。Geoff，關於 ALYFTREK，我們看到了來自患者的強烈興趣，這些患者要么是從未使用過 CFTR 調節劑的患者，要么是現在有資格使用 CFTR 調節劑的患者，ALYFTREK 已獲批准，如您所知，它比 TRIKAFTA 還具有額外的突變。因此，正如您所料，我們看到了人們濃厚的興趣。

But we've also seen interest in transition patients, either those who are on something like TRIKAFTA, but also those who previously discontinued. So we've seen interest across all three of the population that we were expecting. And I'm pleased to say that the first patients have already received their first prescriptions and already received their first packs of ALYFTREK, which is great to see.

但我們也看到了對過渡期患者的興趣，無論是正在服用 TRIKAFTA 之類的藥物的患者，還是之前已停藥的患者。因此，我們看到了預期的三類人群對此表現出的興趣。我很高興地說，第一批患者已經收到了他們的第一張處方，並收到了第一包 ALYFTREK，這真是令人高興。

Michael Yee, Jefferies.

傑富瑞 (Jefferies) 的邁克爾楊 (Michael Yee)。

Stuart, hopefully, you're not making me nervous going into the acute pain launch. But thinking about reimbursement, which is I know something you're working on with JOURNAVX, can you just comment about your thoughts around public payer coverage as it relates to Medicare, Medicaid and the understanding that. Presumably, the administration know that, that's an important thing in the opioid as well as the commercial side where you would think that bad headline coverage of not paying for that is probably not a good thing.

斯圖爾特，希望你沒有讓我在進入急性疼痛發作階段時感到緊張。但考慮到報銷，我知道您正在與 JOURNAVX 合作處理一些事情，您能否就與醫療保險、醫療補助相關的公共付款人保險以及對此的理解發表一下看法。據推測，政府知道，這對阿片類藥物以及商業方面都是一件重要的事情，你可能會認為，有關不支付這筆費用的負面頭條報道可能不是一件好事。

And so given those two things, are you fairly confident that reimbursement is something that should not be an issue on the launch of JOURNAVX.

那麼考慮到這兩點，您是否有信心在推出 JOURNAVX 時報銷不會成為問題？

Yes. Well, Mike, let me first address your first comment. I've never been more excited to be at Vertex. I have never been more confident about the future of this company. It is firing on all cylinders, both scientifically and commercially.

是的。好吧，麥克，讓我先回答一下你的第一條評論。我從來沒有像現在這樣興奮地加入 Vertex。我從未對這家公司的未來如此有信心。無論從科學角度或商業角度，它都全速發展。

And so I wouldn't want you to have any doubts about my confidence in either the launch of JOURNAVX or the launch of any other things that we have ongoing right now. It is a purely personal decision that the time is right for me to move on to the next chapter of my life. In terms of payer coverage, I am expecting us to get broad coverage for generics over time across all segments. For the reasons that you described, Mike, to be perfectly honest with you. Everybody is aware of the enormous unmet need.

因此，我不希望你們對我對 JOURNAVX 的推出或我們目前正在進行的任何其他項目的推出的信心產生任何懷疑。這純粹是個人決定，現在是時候讓我開啟人生的下一個篇章了。在付款人覆蓋方面，我希望我們能夠隨著時間的推移在所有領域獲得對仿製藥的廣泛覆蓋。麥克，坦白告訴你，原因正如你所描述的。每個人都意識到了巨大的未滿足的需求。

Everybody has been waiting for a truly effective non-opioid pain reliever that did not have the adverse events, including indicative potential of opioids. And so I'm expecting us to get broad access over time. In addition to individual discussions we've been having, I think we've talked a number of times about the many both federal and state policy moves, which are already in flight to create, if I can put it this way, so to the availability of JOURNAVX. So I mean, credit excited. We're obviously only seven days, seven business days into the launch, but the feedback has been absolutely tremendous and I'm sure JOURNAVX is going to be a huge success.

每個人都在等待一種真正有效的非鴉片類止痛藥，這種止痛藥沒有不良事件，包括鴉片類藥物的指標性潛力。因此我希望我們能夠隨著時間的推移獲得廣泛的應用。除了我們進行過的個人討論之外，我想我們已經多次談論過聯邦和州的許多政策舉措，這些政策舉措已經在實施中，如果我可以這樣說的話，它們正在為 JOURNAVX 的可用性創造條件。所以我的意思是，信用令人興奮。顯然，我們只發布了七天，七個工作日，但反饋非常熱烈，我相信 JOURNAVX 將取得巨大成功。

William Pickering, Bernstein.

威廉‧皮克林，伯恩斯坦。

Congrats on all the progress, and Stuart, congrats on your retirement. I had a question about the DPN Phase 3 what placebo effect? Did you assume in designing that study? And how does that compare to the 2 points placebo effect we saw in LSR is 1.5 points placebo effect to reasonable ballpark? And what delta versus placebo would be clinically meaningful versus hetrogene?

恭喜你所有的進步，斯圖爾特，恭喜你退休。我對 DPN 第 3 階段的安慰劑效應有疑問？在設計這項研究時您是否有假設？那麼，與我們在 LSR 中看到的 2 分安慰劑效應相比，1.5 分安慰劑效應是否合理？與異質性相比，與安慰劑相比，哪種差異具有臨床意義？

Yes. Well, first, I did read your note from earlier in the week and I appreciate that you were doing primary research, while going through your own surgical procedure. On DPN Phase 3, I will share the specifics with you, Will. But what I will tell you is that in the DPN area, there are many Phase 2 studies and many Phase 3 studies and there are several medicines that have been approved. And we have taken full advantage of that rich data set to appropriately size our Phase 3 trial, and you will note that the Phase 3 trial has not only a placebo group, but also has a gabapentin group in addition to the JOURNAVX group.

是的。嗯，首先，我確實閱讀了您本週早些時候的記錄，並且我很感激您在進行自己的手術時也做了初步研究。關於 DPN 第三階段，我將與您分享具體細節，威爾。但我要告訴你的是，在DPN領域，有許多2期研究和3期研究，並且有幾種藥物已經獲得批准。我們充分利用了豐富的資料集來適當調整我們第 3 階段試驗的規模，您會注意到第 3 階段試驗不僅有安慰劑組，而且除了 JOURNAVX 組外，還有加巴噴丁組。

And we've taken all that into account as we think about the outcomes there. So while I won't share with you the specifics, please note that we have taken full advantage of all that's available out there. the general ranges that you have suggested are indeed what the literature tells you. And the study that we've designed, including the sample size, well takes care of that level of a placebo effect. Yes, you bet.

當我們思考其結果時，我們已經將所有這些都考慮在內了。因此，雖然我不會與您分享具體細節，但請注意，我們已經充分利用了所有可用的資源。您建議的一般範圍確實是文獻所告訴您的。我們設計的研究，包括樣本量，很好地解決了安慰劑效應的程度。是的，確實如此。

Liisa Bayko, Evercore ISI.

Liisa Bayko，Evercore ISI。

I'll just get in line and offer my congratulations to both to everybody involved actually. It's a great transition and have fun. We'll be living vicariously for you. So I wanted to ask about the pain program. Just a couple of questions.

我只是排隊向兩位以及所有參與的人表示祝賀。這是一個偉大的轉變並且很有趣。我們將為你活得充實。所以我想問疼痛計劃。僅有幾個問題。

Can you maybe describe sort of any like stocking? It seems like you are trying to get products available in the different channels. So just wanted some commentary there. And also, how are you thinking about who is the right patient? We did a pain call earlier this week and a big topic was onset of action and kind of like where it falls in line in the ambulatory care setting if the onset of action is a little bit longer.

您能描述一下類似長襪的東西嗎？看起來您正在嘗試透過不同的管道提供產品。所以只是想得到一些評論。而且，您如何考慮誰是合適的患者？本週早些時候，我們進行了一次疼痛電話諮詢，其中一個重要主題是起效時間，以及如果起效時間稍長一些，它在門診護理環境中的位置如何。

So where are you thinking of how it is positioned in terms of first, second or third line? And what is the right patient for this hetrogene.

那麼，您認為它應該定位在第一行、第二行還是第三行呢？那麼對於這種異質基因來說，什麼樣的患者才是適當的呢？

Liisa, I'm going to turn it over to Stuart to give you some color, but I just want to say upfront, our goal here is for JOURNAVX to be the first line prescribed pain medicine for moderate to severe acute pain. Stuart?

Liisa，我將把話題交給 Stuart 來給你講解一下，但我只想先說一下，我們的目標是讓 JOURNAVX 成為治療中度至重度急性疼痛的一線處方止痛藥。史都華？

Yeah. So Liisa, just to address your first question on stocking. Yes, we are looking to get the product broadly stocked in retail across the country in addition to in hospital pharmacies as well. So yes, we are striving to do that, and I feel very confident that, that will happen as I said, our product we would be the wholesalers by the end of this month and then in the channel shortly thereafter.

是的。那麼 Liisa，我只想回答你關於長襪的第一個問題。是的，我們希望除了醫院藥局外，還能在全國各地的零售店廣泛銷售該產品。是的，我們正在努力做到這一點，我非常有信心，正如我所說的，我們的產品將在本月底成為批發商，然後不久後進入通路。

As Reshma said, the great thing about JOURNAVX is we got a broad label for the treatment of moderate to severe acute pain. And we've heard people from across the spectrum of different physicians talking about how they think they're going to be using it in many, many different populations. I do think some of the early ones might be procedures where after a procedure somebody feels like they often need to prescribe a product for a week or two weeks afterwards. And in those situations where they are most concerned about prescribing opioids in the discharge setting there.

正如 Reshma 所說，JOURNAVX 的優點在於我們獲得了治療中度至重度急性疼痛的廣泛標籤。我們聽到了來自不同領域的醫生談論他們認為如何在不同人群中使用它。我確實認為，早期的一些治療方法可能是，在治療後，有人感覺他們經常需要在治療後一周或兩週內開一些產品。在這些情況下，他們最擔心的是在出院時開立鴉片類藥物。

So I think that will certainly be an area where there will be patients treated relatively early on. But as Reshma said, our goal and I think how people are seeing JOURNAVX is that it is for the treatment of mono severe acute pain regardless about etiology. And so I expect it's going to be used broadly across the spectrum.

所以我認為這肯定會成為一個相對較早對患者進行治療的領域。但正如 Reshma 所說，我們的目標以及我認為人們對 JOURNAVX 的看法是，它用於治療單發性重度急性疼痛，無論病因如何。因此我預計它將被廣泛應用於各個領域。

Liisa, we have just one more comment from Charlie on your question.

Liisa，對於你的問題，Charlie 也提出了一則評論。

What I would add to Stuart's comment, we'll absolutely see stocking in the first half of the year, which is why we commented that you'll see volumes increasing ahead of revenues. The reason for that is the impact of our patient assistance programs while we work to secure broad access. And so while there will be stocking in the channel in the first half of the year, the revenue contribution will really be more loaded to the second half of the year.

我想補充一下斯圖爾特的評論，我們絕對會在上半年看到庫存，這就是為什麼我們評論說你會看到銷售在收入之前增加。原因在於我們在努力確保廣泛獲得醫療服務的同時，病患援助計畫也扮演了重要角色。因此，雖然上半年通路會有庫存，但收入貢獻實際上會更集中在下半年。

Philip Nadeau, TD Cowen.

菲利普·納多（Philip Nadeau），TD Cowen 公司。

Stuart, Charlie, and Duncan, congratulations on today's announcements and your transitions. In terms of our questions, a couple on JOURNAVX and one on ALYFTREK. On JOURNAVX, can you give us some sense of will the prescription data that we see from third-party sources be accurate? And what are Vertex's expectations for the average duration of a script?

史都華、查理和鄧肯，恭喜你們今天的公告和轉變。就我們的問題而言，有幾個是關於 JOURNAVX 的，還有一個是關於 ALYFTREK 的。在 JOURNAVX 上，您能否告訴我們從第三方來源看到的處方資料是否準確？Vertex 對於腳本的平均長度有何期望？

Now on ALYFTREK, there is a dispute going on between you and royalty pharma as to exactly what royalty is owed. Can you give us some sense of the milestones in that dispute. When could we hear something? And what are the procedures to getting that resolved?

現在在 ALYFTREK 上，您和 Royalty Pharma 之間就究竟應支付多少特許權使用費存在爭議。您能否向我們介紹這場爭端的里程碑事件？我們什麼時候可以聽到一些消息？解決這個問題的程序是什麼？

So let me take your second question first, and then I'll turn it over to Stuart to talk about JOURNAVX. On ALYFTREK, this is really not a matter of opinion. We have a contractual agreement with the CF Foundation and the contract very clearly spells out what our responsibilities are. And so I don't see any room for interpretation or opinion on that. Stuart, on JOURNAVX, a few questions on that.

所以，讓我先回答你的第二個問題，然後我會把它交給史都華來談談 JOURNAVX。在 ALYFTREK 上，這確實不是一個意見問題。我們與 CF 基金會簽訂了合約協議，合約非常清楚地規定了我們的責任。因此，我認為對此沒有任何解釋或意見的餘地。斯圖爾特，在 JOURNAVX 上，我有幾個問題想問一下。

Yes. JOURNAVX, on lens of therapy, Phil, so the first thing I would say is that the label is for moderate to severe acute pain. It does not have a time limitation or a days of therapy limitation contained within the label although acute pain is considered to be paying asking for less than 90 days.

是的。JOURNAVX，關於治療的鏡頭，菲爾，所以我要說的第一件事是，該標籤適用於中度至重度急性疼痛。雖然急性疼痛被認為是要求支付少於 90 天的費用，但標籤中沒有時間限製或治療天數限制。

In terms of -- obviously, in the inpatient setting, it's very short length of therapy there in the discharge or outpatient setting for non-steroids. You see length of therapy at around about 14 days.

就——顯然，在住院環境中，出院或門診使用非類固醇的治療時間非常短。治療時間約14天。

For opioids, it's markedly less somewhere in the seven- to eight-day range for all the reasons that we probably expect I would expect generics is going to be more like the nonsteroids because it doesn't have the sort of baggage that the opioids have, which is what leads people to want to give out as little data therapy as they possibly can.

對於鴉片類藥物，由於各種原因，它在七到八天的範圍內明顯較少，我們可能預料到我會預期仿製藥會更像非類固醇，因為它沒有阿片類藥物那樣的負擔，這導致人們希望盡可能少地進行數據治療。

And sure, there's a quick question in there about will the prescription data be accurate, maybe split them out into the retail and what happens in the inpatient.

當然，這裡有一個簡單的問題，關於處方數據是否準確，也許可以將它們分成零售和住院部分。

Yeah. So it depends a little bit on what prescription data you buy, Phil. So it's a little bit hard to comment on exactly what how good it will be. But prescription data overall in the retail setting is very robust in the hospital setting. It's more volume-related data that's available.

是的。所以這有點取決於你購買的處方數據，菲爾。因此很難評論它到底有多好。但零售環境中的處方數據總體而言在醫院環境中非常可靠。有更多與數量相關的數據可用。

We will be providing, as Charlie said in his prepared remarks, information on prescriptions as one of the markers of our success in ongoing calls for 2025. We'll also be providing updates on the number of covered lives as well as two of the most important markers of our early-launch success.

正如查理在其準備好的演講中所說，我們將提供有關處方的信息，作為我們在 2025 年持續呼籲中取得成功的標誌之一。我們還將提供有關受保人數的最新信息，以及我們早期發布成功的兩個最重要的標誌。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

You mentioned with ALYFTREK, you've seen starts from all the different patient segments. Can you give any color on the new sets that are coming from the patients who had previously been on a CFTR modulator but no longer were and what their rationale had been for discontinuing other CFTR modulators but coming back to ALYFTREK? And basically, taking a step back, I guess, what drives your confidence that you can recapture this segment of 6,000 patients globally?

您提到，透過 ALYFTREK，您已經看到了來自不同患者群體的開始。您能否介紹一下先前使用過但不再使用 CFTR 調節劑的患者的新情況，以及他們停止使用其他 CFTR 調節劑而重新使用 ALYFTREK 的理由是什麼？那麼基本上，退一步來說，我想，是什麼讓您有信心能夠重新贏得全球這 6,000 名患者的青睞呢？

Yeah. So I mean, the first thing that drives our confidence that we have a good shot at getting those patients back is the clinical profile of ALYFTREK itself. Obviously, it has terrific efficacy and it's once a day as well. So it really is the profile and the fact that we know that all CF patients want to be on the best CFTR modulator. They certainly want to be on a CFO modulator if they can.

是的。所以我的意思是，讓我們有信心讓這些患者康復的第一件事就是 ALYFTREK 本身的臨床特徵。顯然，它的功效非常好，而且每天只需使用一次。所以，這確實是事實，我們知道所有 CF 患者都希望使用最好的 CFTR 調節劑。如果可以的話，他們當然希望成為 CFO 調節器上的成員。

And these patients unfortunately have not been able to stay on a CFTR modulator for a whole range of reasons. So that's what gives us the confidence that a lot of those people are going to come back and be initiated on ALYFTREK. I can't give you any granularity on the patients to date. It's a relatively small number of patients in the grand scheme of things, and I don't have the granularity to know exactly what those individual patients were thinking when they came back on to ALYFTREK or even why they discontinued at this stage.

不幸的是，由於各種原因，這些患者無法繼續使用 CFTR 調節劑。所以，我們有信心，很多人都會回來並加入 ALYFTREK。我無法向您提供迄今為止患者的具體情況。從整體來看，這只是相對較少的患者數量，而且我無法詳細了解這些患者再次使用 ALYFTREK 時到底在想什麼，甚至無法了解他們為什麼在這個階段停止使用。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

One on CF. So for this year, just to clarify, are you expecting to see cannibalization of TRIKAFTA from ALYFTREK? And if so, how should we be thinking about that rate of switching? And then from your pipeline, I just wanted to get a sense of expectations for the type 1 diabetes data that you're set to show and how we should be thinking about the opportunity there.

CF 上有一個。所以就今年而言，只需澄清一下，您是否預計 TRIKAFTA 會被 ALYFTREK 蠶食？如果是這樣，我們應該怎麼考慮這種轉換率？然後從您的管道中，我只是想了解您將要展示的 1 型糖尿病數據的期望，以及我們應該如何考慮那裡的機會。

All right. Let me turn it over to Stuart.

好的。讓我把它交給史都華。

Yeah. So on ALYFTREK, yes, we are expecting patients to transition from TRIKAFTA and even patients who may be on one of our older CFTR modulators to ALYFTREK given the benefit risk profile it has and the benefit it has of being once a day. We haven't set expectations or given any guidance on what we think the rate of switching will be.

是的。因此對於 ALYFTREK，是的，我們預計患者將從 TRIKAFTA 過渡，甚至可能正在使用我們較舊的 CFTR 調節劑之一的患者過渡到 ALYFTREK，因為它具有益處風險狀況以及每天一次的優勢。我們沒有設定預期，也沒有就轉換率給予任何指引。

On the T1D question, maybe the best way to summarize it is this. The lead program is the VX-880 program, let's call it the naked cell program. that's now in the Phase 2 portion of the development. That's the trial that we talked about is going to have enrollment complete this year, and we'll be in a position to file when that group of patients has one year of follow-up being insulin free. We are estimating that opportunity, maybe something like 60,000 people or so.

關於 T1D 問題，也許最好的總結是這樣的。領頭的項目是VX-880項目，我們稱之為裸細胞項目。目前正處於開發的第二階段。我們所談論的這項試驗將在今年完成招募，當該組患者經過一年的無胰島素追蹤後，我們將能夠提交申請。我們估計這個機會可能有 6 萬人左右。

And the reason we say that is that it's maybe 45,000 people or so who are brittle diabetics, very high, highs in terms of their sugars and load loads and maybe 15,000, something like that patients who have already been transplanted with a kidney transplant because of their type 1 diabetes and are therefore already on immunosuppressive.

我們這麼說的原因是，大概有 45,000 人左右是脆弱型糖尿病患者，他們的血糖和負荷都非常高，大約有 15,000 人，因為患有 1 型糖尿病而已經接受腎移植，因此正在接受免疫抑制治療。

And then the next program, which is in Phase 1/2, that's the same cells encapsulated with the device no immunosuppression required there. And of course, with that program, we aim to get to all of the type 1 diabetic patients. And we have programs in research that aim to make the same VX-880 cell hyporemute with certain gene edits, and we're also working on alternative immunosuppressions. All of those latter programs, our goal would be to get them to all patients.

下一個項目目前處於第 1/2 階段，將相同的細胞封裝在設備中，無需免疫抑制。當然，透過該計劃，我們的目標是惠及所有第 1 型糖尿病患者。我們正在進行的研究計畫旨在透過某些基因編輯使相同的 VX-880 細胞減數分裂，同時我們也正在研究替代性免疫抑制劑。對於所有這些後期項目，我們的目標是讓它們惠及所有患者。

We'll take two more questions, please.

我們將再回答兩個問題。

David Risinger, Leerink Partners.

Leerink Partners 的 David Risinger。

So I wanted to add my congrats to Stuart, Charlie and Duncan as well. And I have two questions. So first, with respect to the plans to secure broad formulary access, I'm hoping that you can discuss that in a little bit more detail. So if a drug is on formulary, but there are hassles for the physicians. It just won't be prescribed all.

因此我也想向史都華、查理和鄧肯表示祝賀。我有兩個問題。首先，關於確保廣泛處方權的計劃，我希望您能更詳細地討論一下。因此，如果某種藥物在處方表上，但醫生會遇到麻煩。它只是不會被全部規定出來。

Surgeons don't have time to go through step edits and other challenges. So do you expect to be able to pay the rebates that are necessary to get broad unfettered access to suzetrigine? And then second, with respect to the country that is violating Vertex, what are the company's plans to take action to prevent other countries from doing the same as that single country?

外科醫生沒有時間進行步驟編輯和應對其他挑戰。那麼，您是否希望能夠支付廣泛、不受限制地使用 Suzetrigine 所需的回扣？第二，針對違反 Vertex 規定的國家，公司計劃採取什麼行動來阻止其他國家採取與該國相同的行動？

David, let me ask Stuart to go first and then Charlie will comment.

大衛，讓我先請史都華發言，然後查理會發表評論。

Yes, Dave. Okay. So you're right, getting broad access if you have significant utilization management controls is really not getting broad access if you're putting lots of hurdles in the way of prescribers to actually use your medicine, 100% agree with you. And so our goal is not just broad access, but it's broad access in both commercial and government channels, but with minimal utilization management controls, and that's certainly been the nature of the discussions that we've been having with them preapproval and since the approval because I absolutely agree with your broad access on its own is insufficient.

是的，戴夫。好的。所以您說得對，如果您有嚴格的利用管理控制，那麼獲得廣泛的使用權實際上並不意味著獲得廣泛的使用權，如果您在開處方者實際使用您的藥物的道路上設置了許多障礙，我 100% 同意您的看法。因此，我們的目標不僅是廣泛的訪問，而且是在商業和政府管道的廣泛訪問，但要盡量減少利用管理控制，這當然是我們與他們進行預批准和批准後的討論的性質，因為我完全同意你們的廣泛訪問本身是不夠的。

And so that is a key part of what we are talking to payers, as I say, in both the government and indeed the commercial area. And it's actually what you see in some of the policy initiative that's been introduced as well.

正如我所說，這是我們與政府和商業領域的付款人談判的關鍵部分。事實上，這也是您從已經出台的一些政策舉措中看到的。

So for instance, the alternatives to pay and act, which was actually reintroduced to Congress just last week. One of the things that it includes is there for Medicare Part D patients, it's two things. One, no utilization management controls and also no equal co-pays for a branded non-opioid with generic opioids to the point that you are making.

例如，付款和行動的替代方案實際上是上週才重新提交給國會的。它所包含的內容之一是針對 Medicare Part D 患者，總共有兩件事。第一，沒有利用管理控制，也沒有對品牌非鴉片類藥物和仿製鴉片類藥物進行同等的共付費用。

Charlie, a quick word.

查理，說幾句話。

Yes, Dave, we have an incredibly strong and robust IP portfolio around CF, and you know that it goes out to the late 2030s. We've been very successful in defending and enforcing our IP in every market. The one country in question is Russia, where they have made a decision to disregard the IP and allow an unauthorized copy.

是的，戴夫，我們圍繞 CF 擁有非常強大和穩健的 IP 產品組合，你知道它的使用壽命可以達到 2030 年代末。我們在每個市場都非常成功地捍衛和執行我們的智慧財產權。有問題的一個國家是俄羅斯，他們決定忽視智慧財產權並允許未經授權的複製。

We are taking every measure possible to enforce our rights. But that is a sort of, let's say, a unique market for that reason. I feel that this issue is very isolated.

我們正在採取一切可能的措施來維護我們的權利。但由於這個原因，可以說這是一個獨特的市場。我覺得這個問題很孤立。

Olivia Brayer, Cantor Fitzgerald.

奧莉維亞·布雷爾，費茲傑拉領唱者。

Do you know yet whether there will be quantity limits or any other utilization management parameters put in place for JOURNAVX? Maybe just any feedback you're getting so far from those payer conversations? And do you have a sense yet around how long it will take before P&T committees actually officially retimed formulary coverage? Or maybe just asked another way, what would you consider to be an expedited process?

您是否知道 JOURNAVX 是否會設定數量限製或任何其他使用管理參數？也許您只是從這些付款人對話中得到了任何回饋？您是否知道 P&T 委員會實際上需要多長時間才能正式重新安排處方集覆蓋時間？或者也許只是換個方式問，您認為什麼是加快流程？

Yes, Olivia. I'll kind of repeat a little bit of what I said in my answer to Dave, just a second ago. We certainly are very aware of the fact that utilization management controls can get in the way of physicians wanting to prescribe and patients getting access to a new medicine and certainly our discussions with payers, as I said, on the government and on the commercial side, have involved discussions about minimizing those utilization management controls and certainly not considering things like step edits through generic opioids, which I think would be medically and ethically inappropriate. So that is a discussion that we've been having prior to launch, and we are continuing to have.

是的，奧莉維亞。我將重複剛才回答戴夫時說過的內容。我們當然非常清楚，使用管理控制可能會妨礙醫生開處方和患者獲得新藥，而且正如我所說，我們與政府和商業方面的付款人的討論已經涉及到盡量減少這些使用管理控制，當然不會考慮通過仿製阿片類藥物進行分步編輯之類的事情，我認為這在醫學和倫理上都是不合適的。這是我們在發布之前就一直在進行的討論，我們還將繼續進行。

In terms of the P&T formulary committees, particularly in the institutional setting, again, one of the things that we were doing in the run-up to the approval in a compliant way as making sure we understood those processes, we were providing the institutions with everything that we could compliantly prior to the approval to allow them to think about how quickly they wanted to review generics when it was approved.

就 P&T 處方委員會而言，特別是在機構環境中，我們在批准之前所做的事情之一就是以合規的方式確保我們了解這些流程，我們在批准前向機構提供一切我們可以合規提供的資料，讓他們考慮在仿製藥獲得批准後他們希望以多快的速度進行審查。

We've obviously reengaged with those institutions post approval. I do believe a number of them will accelerate their processes faster than they typically do. They can certainly take up to 12 to 18 months in some cases. for some new products, and we are looking to significantly accelerate that everywhere that we can.

顯然，我們在獲得批准後就重新與這些機構進行了接觸。我確實相信，他們中的許多人會比通常更快地加快他們的進程。在某些情況下，這可能需要長達 12 至 18 個月的時間。對於一些新產品，我們希望盡一切可能大大加快這一進程。

That'll do it. If you could wrap us up, please?

就這樣就可以了。請您幫我們包紮一下好嗎？

Yes, ma'am. This will conclude our question-and-answer session as well as our conference call for today. Thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 1-877-344-7529 or 1-412-317-0088 using replay access code 10187033.

是的，女士。我們的問答環節以及今天的電話會議到此結束。感謝您參加今天的演講。通話結束後不久即可撥打 1-877-344-7529 或 1-412-317-0088（重播接入碼 10187033）收聽今天活動的重播。

Thank you for your participation today. You may now disconnect.

感謝您今天的參與。您現在可以斷開連線。