福泰製藥 (VRTX) 2023 Q4 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals Fourth Quarter 2023 Earnings Call. (Operator Instructions) Please note this event is being recorded.

美好的一天，歡迎參加 Vertex Pharmaceuticals 2023 年第四季財報電話會議。 （操作員說明）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.

現在我想把會議交給蘇西·麗莎女士。請繼續，女士。

Good evening, everyone. 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 and full year 2023 financial results conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex' CEO and President; Stuart Arbuckle, Chief Operating Officer; and Charlie Wagner, Chief Financial Officer.

各位晚上好。我叫 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 2023 年第四季和全年財務業績電話會議。在今晚的電話會議上，福泰 (Vertex) 執行長兼總裁 Reshma Kewalramani 博士發表了事先準備好的演講。 Stuart Arbuckle，營運長；和財務長查理·瓦格納。

We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission.

我們建議您在收聽本次電話會議時存取網路廣播投影片。通話正在錄音，我們的網站上將提供重播。我們將在本次電話會議上發表前瞻性聲明，這些聲明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。

These statements, including without limitation, those regarding Vertex' marketed medicines for cystic fibrosis, sickle cell disease and beta thalassemia; our pipeline; and Vertex' future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

這些聲明，包括但不限於有關 Vertex 銷售的囊性纖維化、鐮狀細胞疾病和 β 地中海貧血藥物的聲明；我們的管道；祥峰未來的財務表現是基於管理層目前的假設。實際結果和事件可能存在重大差異。

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. In addition, the impact of foreign exchange is presented inclusive of our foreign exchange risk management program.

我還想指出，我們將在今晚的電話會議上審查的部分財務表現和指導是在非公認會計原則的基礎上提出的。此外，外匯的影響也包含在我們的外匯風險管理計畫中。

I will now turn the call over to Reshma.

我現在將把電話轉給雷什瑪。

Thanks, Susie. Good evening all, and thank you for joining us on the call today. We've delivered another excellent quarter to finish 2023, established a strong foundation for continued growth and started off 2024 with tremendous momentum, with additional approvals for CASGEVY, positive Phase III results for VX-548 in acute pain last week and positive results for the vanzacaftor triple program in CF this afternoon.

謝謝，蘇西。大家晚上好，感謝您今天加入我們的電話會議。我們在2023 年完成了又一個出色的季度，為持續成長奠定了堅實的基礎，並以巨大的勢頭開始了2024 年，CASGEVY 獲得了更多批准，上週VX-548 在急性疼痛方面的III 期試驗取得了積極成果，以及vanzacaftor 今天下午在 CF 進行三重節目。

In 2023, Vertex continued to reach more CF patients and achieved full year CF product revenues of $9.87 billion, representing 11% growth versus 2022. Following the historic approvals of CASGEVY, the first-ever CRISPR/Cas9-based therapy, our launch is off and running globally as we are now approved in both sickle cell disease and beta thalassemia in the U.S., Great Britain, the Kingdom of Saudi Arabia and Bahrain.

2023 年，福泰(Vertex) 繼續涵蓋更多CF 患者，全年CF 產品收入達到98.7 億美元，較2022 年增長11%。繼第一個基於CRISPR/Cas9 的療法CASGEVY 獲得歷史性批准後，我們的上市工作已啟動並在全球範圍內開展業務，因為我們現在在美國、英國、沙烏地阿拉伯王國和巴林獲得了鐮狀細胞疾病和β地中海貧血的批准。

CASGEVY is a onetime precise, durable CRISPR/Cas9 gene-edited therapy that is generating strong enthusiasm from physicians and patients and excellent support from payers. We're also working toward multiple additional near-term commercial opportunities driving toward our 5 launches in 5 years ago.

CASGEVY 是一種一次性精確、持久的 CRISPR/Cas9 基因編輯療法，引起了醫生和患者的強烈熱情以及付款人的大力支持。我們也正在努力爭取多個額外的近期商業機會，以推動我們在 5 年前推出 5 次產品。

The recent approvals for CASGEVY in both sickle cell disease and beta thalassemia deliver the first 2. Now with the positive Phase III results from VX-548 in acute pain and from the vanzacaftor triple therapy in CF, these are potentially the next 2. And with a strong clinical stage pipeline with first-in-class or best-in-class assets, we are well on our way to our goal of 5 launches by 2028.

最近批准的 CASGEVY 治療鐮狀細胞疾病和 β 地中海貧血是前 2 項。現在，隨著 VX-548 治療急性疼痛的 III 期試驗和 vanzacaftor 三聯療法治療 CF 的積極結果，這些可能是下 2 項。憑藉強大的臨床階段管道和一流或一流的資產，我們正在順利實現到2028 年推出5 項產品的目標。

In addition to the rapidly advancing clinical stage pipeline, the next wave of innovation also continues to make progress. And as we announced last month, we are pleased to be advancing 2 new disease areas into the clinic. First, myotonic dystrophy type 1 or DM1, a serious disease with high unmet need and no approved therapies.

除了快速推進的臨床階段管線外，下一波創新也持續取得進展。正如我們上個月宣布的那樣，我們很高興將 2 個新的疾病領域推進到臨床。首先，強直性肌肉營養不良症 1 型或 DM1，這是一種嚴重的疾病，需求未被滿足，並且沒有批准的治療方法。

This disease affects approximately 110,000 patients in North America and Europe. Our DM1 program represents our ninth disease area to advance into the clinic. We already initiated a Phase I/II study in patients, that is to say a study that will be able to assess both safety and efficacy, late last year.

這種疾病影響北美和歐洲約 11 萬名患者。我們的 DM1 計畫代表了我們進入臨床的第九個疾病領域。去年年底，我們已經在患者中啟動了一項 I/II 期研究，也就是說，這項研究將能夠評估安全性和有效性。

And second, we expect to advance into our tenth disease area in autosomal dominant polycystic kidney disease or ADPKD, the most common genetic kidney disease that affects approximately 250,000 patients in the U.S. and EU alone, into the clinic, with a healthy volunteer study in the first half of this year.

其次，我們希望透過一項健康志願者研究，將常染色體顯性多囊性腎病變（ADPKD）進入臨床，這是最常見的遺傳性腎病，僅在美國和歐盟就影響了約 25 萬名患者。今年上半年。

With that overview, let me now turn to a more deep pipeline review. This quarter, I'll limit my comments to the programs with significant recent updates: cystic fibrosis, sickle cell disease, beta thalassemia and pain, so as to leave time for your questions.

有了這個概述，現在讓我轉向更深入的管道審查。本季度，我將把我的評論限制在最近有重大更新的項目上：囊性纖維化、鐮狀細胞病、β地中海貧血和疼痛，以便為您的提問留出時間。

Starting with cystic fibrosis and our next-in-class vanzacaftor triple combination therapy. This afternoon, we reported positive results from the Phase III program, including the SKYLINE 102 and 103 studies in patients 12 years and above and the RIDGELINE study in patients ages 6 to 11. We are very pleased with these results and the arc of progress in treating patients with CF as we continue to advance our ultimate goal of bringing all eligible patients to carrier levels of sweat chloride.

從囊性纖維化和我們的下一代 vanzacaftor 三合一療法開始。今天下午，我們報告了 III 期計畫的正面結果，包括針對 12 歲及以上患者的 SKYLINE 102 和 103 研究以及針對 6 至 11 歲患者的 RIDGELINE 研究。我們對這些結果和進展感到非常滿意治療CF 患者，同時我們繼續推進我們的最終目標，即使所有符合條件的患者達到汗液氯化物攜帶者水平。

Treatment with the vanza triple met all primary and secondary endpoints in the 3 Phase III studies, and once again, our proprietary HBE assays were both qualitatively and quantitatively predictive. In the SKYLINE 102 and 103 trials, the vanzacaftor triple combination met its primary endpoint of non-inferiority versus TRIKAFTA on ppFEV1, consistent with our expectations. The difference in ppFEV1 in the TRI and vanza treated groups was negligible.

Vanza 三合療法在 3 項 III 期研究中達到了所有主要和次要終點，而我們專有的 HBE 檢測再次具有定性和定量預測性。在 SKYLINE 102 和 103 試驗中，vanzacaftor 三聯療法達到了 ppFEV1 與 TRIKAFTA 相比的非劣效性主要終點，與我們的預期一致。 TRI 和 vanza 治療組中 ppFEV1 的差異可以忽略不計。

In SKYLINE 102, the LS mean difference was 0.2, numerically favoring vanza and meeting non-inferiority with a p-value of less than 0.0001. And in the SKYLINE 103 study, again, the difference in ppFEV1 in the TRI and vanza treated groups was negligible and numerically favored vanzacaftor, with LS mean difference of 0.2, meeting non-inferiority with a p-value of less than 0.0001.

在 SKYLINE 102 中，LS 平均差為 0.2，在數值上有利於 vanza，且滿足非劣效性，p 值小於 0.0001。在 SKYLINE 103 研究中，TRI 和 vanza 治療組的 ppFEV1 差異可以忽略不計，在數值上 Vanzacaftor 更受青睞，LS 平均差異為 0.2，符合非劣效性，p 值小於 0.0001。

Recall the improvement in ppFEV1 in treatment-naive patients in the original TRI Phase III program was approximately 14%. In addition, all key secondary endpoints were met across SKYLINE 102 and 103 and showed a statistically significant and clinically meaningful reduction in sweat chloride.

回想一下，在最初的 TRI III 期計畫中，初治患者的 ppFEV1 改善約為 14%。此外，SKYLINE 102 和 103 均達到了所有關鍵的次要終點，並顯示出汗液氯化物具有統計意義和臨床意義的減少。

The sweat chloride results were measured in 3 key secondary endpoints. First, the overall achieved sweat chloride levels in the 2 RCTs were lower in the vanza-treated group versus the TRIKAFTA-treated group. The LS mean difference was minus 8.4 with a p-value of less than 0.0001 in SKYLINE 102. The LS mean difference was minus 2.8 with a p-value of 0.0034 in SKYLINE 103.

汗液氯化物結果透過 3 個關鍵次要終點進行測量。首先，在 2 個隨機對照試驗中，vanza 治療組的整體汗液氯化物水準低於 TRIKAFTA 治療組。 SKYLINE 102 的 LS 平均差為 -8.4，p 值小於 0.0001。SKYLINE 103 中的 LS 平均差為 -2.8，p 值為 0.0034。

The key difference of course in SKYLINE 102 and 103 was the genotype studied. SKYLINE 102 included F/MF patients who have more severe disease and therefore higher sweat chloride levels at baseline, and SKYLINE 103 included F/F and other responsive mutations with lower baseline sweat chloride levels.

SKYLINE 102 和 103 的主要差異在於所研究的基因型。 SKYLINE 102 包括患有更嚴重疾病、因此基線汗液氯化物水平較高的 F/MF 患者，SKYLINE 103 包括基線汗液氯化物水平較低的 F/F 和其他反應性突變。

Next, the second key secondary endpoint, a proportion of sweat chloride less than 60 millimoles pooled across 2 studies. 86% of patients in the vanza-treated groups and 77% of patients in the TRIKAFTA-treated groups achieved sweat chloride levels below 60 millimoles, leading to an odds ratio of 2.21 and a p-value of 0.0001. This means about 2x greater likelihood in the odds of achieving sweat chloride less than 60 with vanza versus TRIKAFTA.

接下來是第二個關鍵的次要終點，即兩項研究中汗液氯化物含量低於 60 毫摩爾的比例。 Vanza 治療組中 86% 的患者和 TRIKAFTA 治療組中 77% 的患者的汗液氯化物水平低於 60 毫摩爾，比值比為 2.21，p 值為 0.0001。這意味著使用 vanza 使汗液氯化物低於 60 的可能性比 TRIKAFTA 高出約 2 倍。

Last, the third key secondary endpoint, a proportion of sweat chloride less than 30 millimoles pooled across the 2 studies. 31% of patients in the vanza-treated groups versus 23% of patients in the TRIKAFTA-treated groups achieved sweat chloride levels below 30 millimolars, leading to an odds ratio of 2.87 and a p-value of 0.0001. This means about 3x greater likelihood in the odds of achieving sweat chloride less than 30 with vanzacaftor versus TRIKAFTA.

最後，第三個關鍵次要終點，即兩項研究中汗液氯化物含量低於 30 毫摩爾的比例。 Vanza 治療組中有 31% 的患者汗液氯化物低於 30 毫摩爾，而 TRIKAFTA 治療組中有 23% 的患者達到低於 30 毫摩爾的水平，比值比為 2.87，p 值為 0.0001。這意味著使用 vanzacaftor 使汗液氯化物低於 30 的可能性比 TRIKAFTA 高出約 3 倍。

The results were even more pronounced in the RIDGELINE study evaluating children ages 6 to 11. The primary endpoint in this single-arm study was safety, which I will come to in a minute. On efficacy, 95% of patients achieved sweat chloride below 60 millimole, the diagnostic threshold for cystic fibrosis, and more than half reached sweat chloride levels below the carrier level threshold of 30 millimoles. These sweat chloride results with the vanza triple are both impressive and important.

在評估 6 至 11 歲兒童的 RIDGELINE 研究中，結果更加明顯。這項單臂研究的主要終點是安全性，我稍後會談到這一點。就療效而言，95% 的患者汗液氯化物水平低於囊性纖維化的診斷閾值 60 毫摩爾，超過一半的患者汗液氯化物水平低於載體水平閾值 30 毫摩爾。 vanza 三元組的這些汗液氯化物結果既令人印象深刻又重要。

Let me take a step back to frame the significance of these results. While CF is a systemic multi-organ disease, historically, the focus has been primarily on lung function as measured by ppFEV1, given it is the most visible symptom and typically the cause of death in CF patients. ppFEV1 is also the regulatory enabling endpoint.

讓我退後一步來闡述這些結果的重要性。雖然 CF 是一種全身性多器官疾病，但從歷史上看，重點主要放在 ppFEV1 測量的肺功能上，因為它是 CF 患者最明顯的症狀，通常也是死亡原因。 ppFEV1 也是監理啟用端點。

Given the strides we have made with TRIKAFTA, we believe we may have reached the maximum potential benefit in lung function from CFTR modulators. Thus, our objective with vanzacaftor moves beyond the focus on lung function to a broader, more ambitious goal to improve CFTR protein function as measured by lower sweat chloride levels and deliver even greater systemic benefit than TRIKAFTA.

鑑於我們在 TRIKAFTA 方面取得的進步，我們相信我們可能已經從 CFTR 調節劑中獲得了肺功能的最大潛在益處。因此，我們對vanzacaftor 的目標超越了對肺功能的關注，轉向了更廣泛、更雄心勃勃的目標，即改善CFTR 蛋白功能（透過降低汗液氯化物水平來衡量），並提供比TRIKAFTA 更大的全身益處。

To be clear, the goal with the vanza pivotal development program was to show the lung function benefit was non-inferior to TRIKAFTA, and over and above that, to deliver additional benefit on sweat chloride, the direct marker of CFTR protein function. A note on CFTR protein. CFTR protein dysfunction is the underlying pathophysiology in CF. And while CF is often diagnosed by a genetic test at birth, it is confirmed via a sweat chloride test because it is the direct measure of CFTR protein dysfunction.

需要明確的是，vanza 關鍵開發計畫的目標是證明對肺功能的益處不遜色於 TRIKAFTA，除此之外，還對汗液氯化物（CFTR 蛋白功能的直接標記）產生額外的益處。關於 CFTR 蛋白的註釋。 CFTR 蛋白功能障礙是 CF 的潛在病理生理學。雖然 CF 通常是透過出生時的基因測試來診斷的，但它是透過汗液氯化物測試來確認的，因為它是 CFTR 蛋白功能障礙的直接測量方法。

Simply put, higher levels of sweat chloride associated with more severe disease. Therefore, the ultimate goal is to restore CFTR protein function, as measured by sweat chloride, back to normal or as close to normal as possible so that there is no manifestation of disease. And more specifically, sweat chloride values below 60 millimoles are associated with improved outcomes such as better and more stable lung function, fewer pulmonary exacerbations, better quality of life and improved survival.

簡而言之，汗液氯化物含量越高，疾病就越嚴重。因此，最終目標是使 CFTR 蛋白功能（透過汗液氯化物測量）恢復正常或盡可能接近正常，從而不再出現疾病表現。更具體地說，汗液氯化物值低於 60 毫摩爾與改善的結果相關，例如更好和更穩定的肺功能、更少的肺部惡化、更好的生活品質和提高的生存率。

Vertex' ultimate treatment goal is to restore sweat chloride levels to below 30, which is considered normal and are typical of CF carriers who do not have the disease, for instance, the parents of children with CF. Thus, our goal in designing the vanzacaftor triple therapy studies was to test if even more patients treated with vanza could achieve those sweat chloride thresholds of less than 60 and less than 30 than those treated with TRIKAFTA.

Vertex 的最終治療目標是將汗液氯化物水平恢復到 30 以下，這被認為是正常的，並且是未患有該疾病的 CF 攜帶者的典型情況，例如患有 CF 的兒童的父母。因此，我們設計 vanzacaftor 三聯療法研究的目標是測試是否有更多接受 vanza 治療的患者能夠比接受 TRIKAFTA 治療的患者達到低於 60 和低於 30 的汗液氯化物閾值。

Switching to safety. The vanza triple was generally safe and well tolerated in all studies. The adverse events seen in the vanza triple pivotal development program are consistent with the underlying disease, and with the incidence and nature of adverse events we have seen with previous CFTR modulators. As a reminder and to round out the profile of the vanzacaftor triple, this therapy offers the convenience of once-daily dosing for patients and a substantially lower royalty burden.

轉向安全。在所有研究中，vanza 三聯藥物總體上是安全的且耐受性良好。 vanza 三重關鍵開發計劃中觀察到的不良事件與基礎疾病一致，並且與我們在先前的 CFTR 調節劑中觀察到的不良事件的發生率和性質一致。作為提醒並完善 vanzacaftor 三聯療法的概況，該療法為患者提供了每日一次給藥的便利，並大大降低了特許權使用費負擔。

In summary, we set a goal to establish a new and higher bar in the treatment of CF with CFTR modulators, and with these Phase III vanza triple results, we have the first evidence that we have done so. And with these results, we now know that the vanza triple has indeed surpassed the very high bar set by TRIKAFTA in people with CF ages 6 and older. And by treating patients early with the vanza triple, we have the potential to possibly prevent systemic manifestations of CF in more people.

總之，我們設定了一個目標，在CFTR 調節劑治療CF 方面建立一個新的、更高的標準，並且透過這些III 期vanza 三重結果，我們有了第一個證據表明我們已經做到了這一點。透過這些結果，我們現在知道，vanza 三聯療法確實超過了 TRIKAFTA 對 6 歲及以上 CF 患者設定的非常高的標準。透過早期使用 vanza 三重療法治療患者，我們有可能預防更多人出現 CF 的全身症狀。

These results also reaffirm our conviction that continued investment in scientific and serial innovation will allow us to complete our journey to transform CF by bringing all eligible CF patients down to carrier levels of sweat chloride where there are no manifestations of disease. I want to acknowledge the CF patients in our clinical trials who put their trust in us as well as the Vertex San Diego team and the CF R&D teams, some of whom have worked on CF for more than 20 years to deliver yet another potentially transformative medicine.

這些結果也重申了我們的信念，對科學和系列創新的持續投資將使我們能夠透過將所有符合條件的囊性纖維化患者的汗液氯化物降至無疾病表現的載體水平來完成改造囊性纖維化的旅程。我要感謝參與我們臨床試驗的 CF 患者以及 Vertex 聖地牙哥團隊和 CF 研發團隊的信任，其中一些已經在 CF 領域工作了 20 多年，以提供另一種潛在的變革性藥物。

We are working rapidly to compile the regulatory submissions and anticipate filing in both the U.S. and Europe for patients ages 6 and older by the middle of 2024. We will be using one of our priority review vouchers entitling us to designate the vanza NDA for priority review, which provides an expedited 6-month review versus a standard 10-month review time line.

我們正在快速編制監管提交文件，並預計到 2024 年中期在美國和歐洲針對 6 歲及以上患者進行提交。我們將使用我們的優先審查憑證之一，使我們有權指定 vanza NDA 進行優先審查，它提供6 個月的加急審查，而不是10 個月的標準審查時間表。

I'll close on CF with VX-522, our CFTR mRNA therapy in development with our partners at Moderna for the more than 5,000 CF patients who do not make any CFTR protein and therefore cannot benefit from CFTR modulators. Late last year, we completed enrollment in dosing in the single ascending dose portion of our study for VX-522 and initiated the multiple ascending dose portion of the study. This study continues to screen and roll in dose patients, and we expect data late this year or early next.

我將以VX-522 結束CF，這是我們與Moderna 的合作夥伴共同開發的CFTR mRNA 療法，用於治療超過5,000 名CF 患者，這些患者不產生任何CFTR 蛋白，因此無法從CFTR 調節劑中受益。去年年底，我們完成了 VX-522 研究的單劑量遞增部分的劑量入組，並啟動了該研究的多劑量遞增部分。這項研究將繼續篩選和滾動接受劑量的患者，我們預計將在今年年底或明年初獲得數據。

Turning now to CASGEVY, our precise durable CRISPR/Cas9 gene-edited therapy that delivers a potential onetime functional cure for patients with sickle cell disease and transfusion-dependent beta thalassemia. CASGEVY represents an enormous advancement for the estimated 35,000 people living with severe sickle cell disease and transfusion-dependent beta thalassemia across the U.S. and Europe, as well as thousands of patients in other regions, such as the Kingdom of Saudi Arabia and Bahrain.

現在轉向 CASGEVY，我們精確耐用的 CRISPR/Cas9 基因編輯療法可為鐮狀細胞疾病和輸血依賴性β地中海貧血患者提供潛在的一次性功能性治癒。 CASGEVY 對美國和歐洲約 35,000 名患有嚴重鐮狀細胞病和輸血依賴性β地中海貧血的患者以及沙烏地阿拉伯王國和巴林等其他地區的數千名患者來說代表著巨大的進步。

CASGEVY represents a significant commercial opportunity as well, and Stuart will discuss the strong start to the launch following the rapid approvals in multiple countries. While these launches are underway, we are awaiting approval in the EU, where CASGEVY has received CHMP positive opinion for both sickle cell disease and beta thalassemia. CASGEVY is also under review in Switzerland, and we anticipate filing in Canada this quarter.

CASGEVY 也代表著一個重要的商業機會，史都華將討論在多個國家迅速獲得批准後啟動的良好開端。在這些產品上市的同時，我們正在等待歐盟的批准，CASGEVY 已收到 CHMP 對鐮狀細胞疾病和 β 地中海貧血的積極意見。 CASGEVY 也在瑞士接受審查，我們預計本季在加拿大提交申請。

Lastly on CASGEVY, recognizing the importance of treating patients with sickle cell disease and beta thalassemia early in life to minimize organ damage and other complications of the disease, we are conducting studies in both sickle cell disease and beta thalassemia to expand the label to younger age groups. To that end, we recently completed enrollment in our 2 global Phase III studies in patients 5 to 11 years of age, and dosing in these studies is underway.

最後，關於CASGEVY，認識到在生命早期治療鐮狀細胞病和β 地中海貧血患者以盡量減少器官損傷和其他疾病並發症的重要性，我們正在對鐮狀細胞病和β 地中海貧血進行研究，以將標籤擴展到更年輕的年齡層。為此，我們最近完成了兩項針對 5 至 11 歲患者的全球 III 期研究的入組，這些研究的給藥劑量正在進行中。

Moving to the pain program and VX-548, our novel, highly selective NaV1.8 pain signal inhibitor. With VX-548, we finally have the possibility of a medicine that has the compelling combination of both strong efficacy and strong safety that can be used for multiple moderate to severe pain types across multiple settings of care.

轉向疼痛項目和 VX-548，我們的新型高選擇性 NaV1.8 疼痛訊號抑制劑。借助 VX-548，我們終於有可能開發出一種藥物，它具有強大的功效和強大的安全性，可用於多種護理環境中的多種中度至重度疼痛類型。

Last week, we detailed the positive results from the 3 Phase III trials that comprise our pivotal program for VX-548 in acute pain, including randomized, placebo-controlled trials in 2 different pain models: abdominoplasty, a soft tissue pain model; and bunionectomy, a hard tissue pain model, and a single-arm safety and effectiveness trial in a broad range of surgical and nonsurgical pain conditions. Both the abdominoplasty and bunionectomy RCTs met the primary endpoint with statistically significant improvement in pain compared to placebo on the primary endpoint of SPID48.

上週，我們詳細介紹了3 項III 期試驗的積極結果，這些試驗構成了我們VX-548 治療急性疼痛的關鍵計劃，包括針對2 種不同疼痛模型的隨機、安慰劑對照試驗：腹部成形術，一種軟組織疼痛模型；拇囊炎切除術、硬組織疼痛模型以及針對各種手術和非手術疼痛情況的單臂安全性和有效性試驗。腹部成形術和拇囊炎切除術隨機對照試驗均達到了主要終點，在 SPID48 的主要終點上，與安慰劑相比，疼痛有統計學上的顯著改善。

The SPID48 is derived from a change in the numeric pain rating scale or NPRS. Practicing physicians tell us that in addition to SPID48, they focus on this reduction in the NPRS from baseline, and this change in baseline in NPRS score is also how clinical meaningfulness is assessed in the field. In acute post-operative pain studies, clinical meaningfulness is defined by at least a 2-point change in NPRS from baseline or at least a 30% reduction in NPRS from baseline.

SPID48 源自於數字疼痛評分量表 (NPRS) 的變化。執業醫師告訴我們，除了 SPID48 之外，他們還關注 NPRS 相對於基線的降低，而 NPRS 評分基線的這種變化也是該領域評估臨床意義的方式。在術後急性疼痛研究中，臨床意義的定義是 NPRS 相對於基線至少有 2 點變化，或 NPRS 相對於基線至少降低 30%。

In that context, both RCTs demonstrated that treatment with VX-548 led to rapid clinically meaningful reductions on the NPRS, with more than 3 points of pain reduction or roughly a 50% reduction from baseline in the VX-548 arms. The single arm safety and effectiveness trial was conducted in a broad range of surgical and nonsurgical pain conditions and supported longer-term safety and effectiveness. VX-548 was safe and well tolerated across all 3 studies, including multiple acute pain types and settings.

在這種情況下，兩項隨機對照試驗都表明，VX-548 治療可導致 NPRS 快速降低，具有臨床意義，VX-548 組疼痛減輕超過 3 個點，或較基線降低約 50%。單臂安全性和有效性試驗在廣泛的手術和非手術疼痛條件下進行，並支持長期安全性和有效性。在所有 3 項研究中，包括多種急性疼痛類型和環境，VX-548 都是安全且耐受性良好的。

Of importance, with respect to safety, in the 2 RCTs, the incidence of adverse events in the VX-548 arms was lower than placebo, an uncommon and noteworthy finding. We believe the results of this comprehensive Phase III program support a broad, moderate-to-severe acute pain label, and if approved, should enable prescribing and usage across multiple care settings. VX-548 has already secured Fast Track and Breakthrough designations, and we are working with urgency to file the NDA by mid-2024.

重要的是，就安全性而言，在 2 項隨機對照試驗中，VX-548 組的不良事件發生率低於安慰劑，這是一個不常見且值得注意的發現。我們相信，這項綜合性第三階段計畫的結果支持廣泛的中度至重度急性疼痛標籤，如果獲得批准，應該能夠在多個護理機構中進行處方和使用。 VX-548 已獲得快速通道和突破性指定，我們正在緊急工作，以便在 2024 年中期之前提交 NDA。

Moving now to neuropathic pain. Two months ago, we also reported positive results from our Phase II study of VX-548 in diabetic peripheral neuropathy, one type of peripheral neuropathic pain and another area of high unmet need. We look forward to our end of Phase II meeting with the FDA towards the end of this quarter and starting our Phase III program thereafter. We also continue to enroll and dose our second Phase II neuropathic pain study of VX-548 in lumbosacral radiculopathy or LSR.

現在轉向神經性疼痛。兩個月前，我們也報告了 VX-548 治療糖尿病週邊神經病變的 II 期研究的正面結果，糖尿病週邊神經病變是一種週邊神經性疼痛，也是另一個需求未滿足的領域。我們期待在本季末結束與 FDA 的第二階段會議，並隨後開始我們的第三階段計劃。我們也繼續招募 VX-548 治療腰骶神經根病變或 LSR 的第二項 II 期神經病理性疼痛研究並進行劑量研究。

Ultimately, we seek a broad neuropathic pain label and believe by studying 2 of the largest pain segments, DPN and LSR, which together represent more than 60% of all peripheral neuropathic pain, we have a pathway to that broad indication. Just as we transform the treatment of CF, we believe we have the potential to transform the treatment of pain, both acute and neuropathic, based on the compelling and consistent results we have seen with VX-548.

最終，我們尋求一個廣泛的神經病理性疼痛標籤，並相信透過研究兩個最大的疼痛部分DPN 和LSR（它們合計佔所有周邊神經病理性疼痛的60% 以上），我們有一條通往該廣泛適應症的途徑。正如我們改變 CF 的治療方法一樣，我們相信，基於我們在 VX-548 上看到的令人信服且一致的結果，我們有潛力改變急性疼痛和神經性疼痛的治療。

We now have results in hand from the Phase III program in acute pain as well as the Phase II results in DPN. We are underway with the Phase II study in LSR, and we are continuing to execute our portfolio approach of serial innovation. We are well on our way to helping address the unmet need of 90 million patients suffering with pain.

我們現在手邊有急性疼痛 III 期計畫的結果以及 DPN II 期計畫的結果。我們正在進行 LSR 的二期研究，並繼續執行我們的系列創新組合方法。我們正在努力協助解決 9,000 萬名疼痛患者未被滿足的需求。

With that, I'll now turn it over to Stuart.

這樣，我現在就把它交給史都華。

Thanks, Reshma. With the recent approvals of CASGEVY in sickle cell disease and transfusion-dependent thalassemia in multiple countries and the recent positive results in our pivotal trials for VX-548 in acute pain and for the vanzacaftor triple combination in CF, we are well and truly entering a new era of commercial diversification.

謝謝，瑞詩瑪。隨著CASGEVY 最近在多個國家獲得批准用於治療鐮狀細胞病和輸血依賴性地中海貧血，以及最近在VX-548 用於治療急性疼痛和vanzacaftor 三聯療法用於治療CF 的關鍵試驗中取得積極結果，我們正在真正進入一個新的階段。商業多元化新時代。

As Reshma noted, we delivered strong fourth quarter and full year commercial results in CF as we continue to grow the number of eligible patients receiving our CFTR modulators. Fourth quarter U.S. growth was driven by continued strong performance of TRIKAFTA, including in patients ages 2 to 5 years old following the approval for these patients in April. Outside the U.S., we saw continued growth from both label expansions and new reimbursement agreements.

正如 Reshma 指出的那樣，隨著我們繼續增加接受 CFTR 調節劑的合格患者數量，我們在第四季度和全年的 CF 領域取得了強勁的商業業績。美國第四季度的成長是由 TRIKAFTA 持續強勁的表現推動的，其中包括 4 月批准用於 2 至 5 歲患者的患者。在美國以外，我們看到標籤擴張和新報銷協議帶來的持續成長。

In the near term, we will continue to focus on reaching more eligible patients, including younger age groups, which will provide revenue growth, and then we expect to drive further growth with the vanzacaftor triple combination. Given the positive Phase III data we released today that demonstrates a strong benefit risk profile and the ability to deliver greater restoration of CFTR function than even TRIKAFTA, we believe the vanzacaftor triple combination will be widely welcomed by the CF community, both as a new treatment option for the greater than 6,000 patients who have discontinued one of our current CFTR modulators, and as an opportunity for TRIKAFTA patients to achieve even greater levels of CFTR function.

短期內，我們將繼續專注於涵蓋更多符合條件的患者，包括年輕年齡組，這將帶來收入成長，然後我們預計將透過 vanzacaftor 三聯療法推動進一步成長。鑑於我們今天發布的積極的III 期數據顯示了強大的獲益風險狀況以及比TRIKAFTA 更好地恢復CFTR 功能的能力，我們相信vanzacaftor 三聯組合將受到CF 社區的廣泛歡迎，兩者都作為一種新的治療方法為超過 6,000 名已停用我們現有 CFTR 調節劑之一的患者提供選擇，並為 TRIKAFTA 患者提供更高水平 CFTR 功能的機會。

Longer term, we see additional growth from our mRNA program, VX-522, that we are developing in partnership with Moderna for the more than 5,000 CF patients with mutations that do not respond to CFTR modulators. In addition, we recently updated our estimate of the number of people living with CF in North America, Europe and Australia to 92,000 from the previous estimate of 88,000. This increase is in large part due to patients living longer as a result of improvements in CF care, including the advent of CFTR modulators. We expect this trend to continue based on the real-world evidence we have generated on the clinical benefits of CFTR modulators, and this will also drive long-term growth.

從長遠來看，我們看到我們的 mRNA 項目 VX-522 取得了額外的增長，我們正在與 Moderna 合作開發該項目，用於治療 5,000 多名攜帶對 CFTR 調節劑沒有反應的突變的 CF 患者。此外，我們最近將北美、歐洲和澳洲 CF 患者人數的估計值從先前的 88,000 人更新為 92,000 人。這一增長在很大程度上是由於 CF 護理的改進（包括 CFTR 調節劑的出現）導致患者壽命延長。根據我們就 CFTR 調節劑的臨床益處產生的現實證據，我們預計這一趨勢將持續下去，這也將推動長期成長。

Now turning to CASGEVY and our launches in sickle cell disease and beta thalassemia. Enthusiasm from patients, physicians and payers is very high around the globe, and we are focused on translating the scientific and medical innovation that CASGEVY represents into transformative patient benefit in the real world. In countries where CASGEVY has been approved, our sales, reimbursement and access teams as well as patient engagement teams have hit the ground running. Let me provide some insights on the early days of the launch.

現在轉向 CASGEVY 以及我們在鐮狀細胞疾病和β地中海貧血方面的推出。全球患者、醫生和付款人的熱情非常高，我們致力於將 CASGEVY 所代表的科學和醫療創新轉化為現實世界中變革性的患者利益。在 CASGEVY 獲得批准的國家/地區，我們的銷售、報銷和訪問團隊以及患者參與團隊已開始運作。讓我提供一些關於發布初期的見解。

Starting with physicians. There is tremendous interest in CASGEVY and what it can do for their patients, and we see the impact of that in the rapid activation of authorized treatment centers. Less than 2 months post approval, we already have 12 ATCs in the U.S., 3 in the EU and 1 in the Kingdom of Saudi Arabia, all ready to receive patients.

從醫生開始。人們對 CASGEVY 及其能為患者做的事情產生了極大的興趣，我們看到了授權治療中心快速啟動的影響。在獲得批准後不到 2 個月，我們已在美國擁有 12 個 ATC，在歐盟擁有 3 個，在沙烏地阿拉伯王國擁有 1 個，並已準備好接收患者。

Reaction from payers has also been very positive. In the U.S., across commercial and government payers, all eligible CASGEVY patients have case-by-case coverage through single case agreements. We continue to see excellent progress from payers on the development of their formal medical policies and reimbursement pathways. We have a contract in place with Synergie for up to 100 million lives and are actively engaged with other commercial payers to finalize medical policies, which would bring the total percentage of covered lives to over 80%.

付款人的反應也非常正面。在美國，所有商業和政府付款人都透過單一案例協議獲得符合條件的 CASGEVY 患者的個案承保。我們繼續看到付款人在製定正式醫療政策和報銷途徑方面取得了巨大進展。我們與 Synergie 簽訂了覆蓋多達 1 億人生命的合同，並積極與其他商業付款人合作敲定醫療政策，這將使受保生命的總比例達到 80% 以上。

In the government sector, Medicaid state agencies representing over 60% of sickle cell disease lives have established reimbursement pathways for CASGEVY, with an additional 25% of Medicaid sickle cell disease lives in states actively progressing their reimbursement methodologies. In addition, we were pleased to have received the January approval in the U.S. for CASGEVY for transfusion-dependent thalassemia patients 2.5 months early and are working to achieve a similarly fast trajectory for gaining reimbursement and access for patients.

在政府部門，代表超過 60% 的鐮狀細胞疾病患者的醫療補助州機構已經建立了 CASGEVY 的報銷途徑，另外 25% 的鐮狀細胞疾病患者的醫療補助州機構正在積極推進其報銷方法。此外，我們很高興提前 2.5 個月在美國獲得了 CASGEVY 的批准，用於治療輸血依賴性地中海貧血患者，並正在努力實現類似的快速軌跡，為患者獲得報銷和使用。

Last week, there was an important update by the Biden administration on the CMMI Cell and Gene Therapy Access Demonstration Model that was originally announced in February of 2023 and was recently accelerated for implementation from 2026 to 2025. We believe the CMMI CGT Access Model could be an important additional path to access, and we now have greater clarity on the scope and process to be employed in the model. The model is intended to provide a comprehensive strategy to address barriers to equitable access to cell and gene therapies for Medicaid beneficiaries as well as the long-standing inequities of care in the sickle cell disease community.

上週，拜登政府對CMMI 細胞和基因療法准入示範模型進行了重要更新，該模型最初於2023 年2 月宣布，最近加速實施，將於2026 年至2025 年實施。我們相信CMMI CGT 准入模型可以這是一個重要的額外存取途徑，我們現在對該模型中採用的範圍和流程有了更清晰的了解。該模型旨在提供全面的策略，以解決醫療補助受益人公平獲得細胞和基因療法的障礙，以及鐮狀細胞疾病社區長期存在的護理不平等問題。

Last week's update also confirmed additional federal funding to support access and included a defined scope of manufacturer-provided fertility support in the model in recognition that for patients choosing to embark on the treatment journey, the costs of fertility preservation are a barrier to access. In the meantime, we continue to actively engage with state Medicaid agencies to finalize medical policies for CASGEVY even in advance of the CGT Access Model to ensure patient access without delay.

上週的更新還確認了額外的聯邦資金來支持獲取，並在模型中納入了製造商提供的生育支持的明確範圍，因為認識到對於選擇開始治療旅程的患者來說，生育力保存的成本是獲取的障礙。同時，我們繼續積極與州醫療補助機構合作，甚至在 CGT 訪問模式之前最終確定 CASGEVY 的醫療政策，以確保患者立即獲得服務。

Outside the U.S., we are pleased that the French National Authority for Health has approved our request for the implementation of an early access program or EAP for TDT patients ages 12 to 35 years. We are delighted to have secured a path to access and payment in France ahead of a national reimbursement agreement and are also in an EAP review process for sickle cell disease patients. In the U.K., CASGEVY will be reviewed by the highly specialized technology committee in February, and we are advancing our reimbursement discussions in other European countries as well.

在美國以外，我們很高興法國國家衛生局批准了我們為 12 至 35 歲 TDT 患者實施早期訪視計畫或 EAP 的請求。我們很高興在國家報銷協議達成之前在法國找到了獲取和付款的途徑，並且還在針對鐮狀細胞病患者進行 EAP 審查過程。在英國，CASGEVY 將於 2 月接受高度專業化的技術委員會的審查，我們也在其他歐洲國家推進報銷討論。

We also see strong progress in the Middle East, which is especially important for CASGEVY, given the high prevalence of these diseases in the region and the government's clear focus on elevating the health of their citizens. We are working with local health care authorities in the Kingdom of Saudi Arabia and Bahrain to refine our estimates of the exact number of eligible patients, but there are thousands of patients we could serve, and we are focused on securing access and reimbursement for them. We have established a local presence in the region, have already activated our first ATC and are working with local health care professionals to expand the number of ATCs and establish the required infrastructure to meet patient demand.

我們也看到中東地區取得了巨大進展，這對 CASGEVY 來說尤其重要，因為該地區這些疾病的盛行率很高，而且政府明確致力於提高公民的健康。我們正在與沙烏地阿拉伯王國和巴林的當地醫療保健當局合作，以完善我們對符合條件的患者的確切數量的估計，但我們可以服務數千名患者，我們的重點是確保他們獲得服務和報銷。我們已經在該地區建立了當地辦事處，已經啟動了我們的第一個 ATC，並正在與當地醫療保健專業人員合作，擴大 ATC 的數量並建立必要的基礎設施，以滿足患者的需求。

As we have previously outlined, the CASGEVY patient journey can be broken down into 3 key phases, each of which can take several months: pretreatment; cell collection and manufacturing; and then infusion of the edited cells. We are pleased with the early days of what will be a foundational year for CASGEVY as we work to deliver transformative patient outcomes with the possibility of a lifetime of benefit. We look forward to updating you on the CASGEVY launch over the course of this year.

如同我們先前所概述的，CASGEVY 患者治療歷程可分為 3 個關鍵階段，每個階段可能需要幾個月的時間：預處理；細胞採集和製造；然後輸注編輯過的細胞。我們對 CASGEVY 基礎年的早期階段感到高興，因為我們致力於提供變革性的患者治療結果，並有可能使患者終生受益。我們期待向您通報今年 CASGEVY 發布的最新情況。

To help track our progress, our expectation is to provide quarterly updates on the number of activated ATCs as well as the number of patients in the cell collection phase. ATCs have begun assessing their patients for the ability to be treated with CASGEVY, and we expect that the first commercial patients will start the journey in the coming weeks.

為了幫助追蹤我們的進展，我們的期望是每季提供活化的 ATC 數量以及細胞收集階段患者數量的最新資訊。 ATC 已開始評估患者接受 CASGEVY 治療的能力，我們預計第一批商業患者將在未來幾週內開始這趟旅程。

Shifting now to VX-548. We are very excited about the potential for this highly selective NaV1.8 inhibitor to provide a transformative treatment option for the millions of patients suffering from acute and peripheral neuropathic pain. This quarter, I'll limit my comments to acute pain. As we discussed last week, when we shared the results from the pivotal program, we are very excited about VX-548's compelling combination of efficacy and safety and the demonstration that it can be used for moderate to severe pain across a range of pain conditions, both surgical and nonsurgical and across a range of settings.

現在轉向 VX-548。我們對這種高選擇性 NaV1.8 抑制劑為數百萬患有急性和周邊神經性疼痛的患者提供變革性治療選擇的潛力感到非常興奮。本季度，我的評論僅限於急性疼痛。正如我們上週討論的那樣，當我們分享關鍵計劃的結果時，我們對VX-548 令人信服的功效和安全性結合感到非常興奮，並證明它可以用於治療一系列疼痛狀況的中度至重度疼痛，手術和非手術以及各種環境。

If approved, VX-548 will be the first of a new class of medicines that inhibit the pain signal and represent the first new class of medicines for acute pain in over 20 years. The reason we're so excited about the potential for VX-548 to positively impact patient care is because we estimate approximately 80 million patients are prescribed a medicine for moderate to severe acute pain every year in the U.S., representing over 1 billion calendar days of treatment.

如果獲得批准，VX-548將成為第一種抑制疼痛訊號的新型藥物，也是20多年來第一種治療急性疼痛的新型藥物。我們對 VX-548 對患者護理產生積極影響的潛力感到如此興奮，因為我們估計美國每年約有 8000 萬患者接受中度至重度急性疼痛藥物治療，這意味著超過 10 億日曆天的時間。治療。

Given this massive patient population, acute pain is a multibillion dollar market today despite the fact that essentially all prescriptions are generic. We also see upside to this market opportunity, given the significant unmet need that stems from the suboptimal benefit risk profiles of existing agents such as the limited efficacy but acceptable side effects of NSAIDs or the adverse effects and addiction potential of opioids, all of which leads to suboptimal pain management.

考慮到如此龐大的患者群體，儘管基本上所有處方藥都是通用的，但今天的急性疼痛市場已達到數十億美元。我們也看到了這個市場機會的上行空間，因為現有藥物的效益風險狀況不佳，例如非類固醇抗發炎藥的功效有限但可以接受的副作用或阿片類藥物的不良反應和成癮潛力，這些都導致了顯著的未滿足需求。疼痛管理不理想。

What physicians and patients seek is a medicine that combines effective relief of moderate to severe pain with a clear safety and tolerability profile, and VX-548 delivers on that profile. We've previously shared our go-to-market strategy, and we are now actively recruiting our field force in anticipation of our regulatory filing and approval. The commercial team will focus on the roughly 2,000 hospitals and institutions where a majority of acute pain patients are seen and prescriptions are written. We continue to see a multibillion dollar opportunity for VX-548 in acute pain alone.

醫生和患者尋求的是一種既能有效緩解中度至重度疼痛，又具有明確的安全性和耐受性的藥物，而 VX-548 就滿足了這項要求。我們之前已經分享了我們的進入市場策略，現在我們正在積極招募我們的現場人員，以等待我們的監管備案和批准。商業團隊將重點關注約 2,000 家醫院和機構，大多數急性疼痛患者都在這些醫院和機構就診並開出處方。我們仍然認為 VX-548 僅在急性疼痛方面就有數十億美元的機會。

The well-known risk of opioids have led to widespread restrictions and limitations on their use over the years. Increasingly, we are seeing a paradigm shift in policy initiatives across various stakeholders to encourage consideration and use of non-opioid alternatives and to remove financial barriers to choosing a branded non-opioid. As an example, late last month, Congress introduced the bipartisan alternatives to Prevent Addiction in the Nation Act or the alternatives to pain act.

阿片類藥物的眾所周知的風險導致多年來對其使用進行廣泛的限制和限制。我們越來越常看到各個利害關係人的政策舉措發生範式轉變，以鼓勵考慮和使用非阿片類藥物替代品，並消除選擇品牌非阿片類藥物的財務障礙。例如，上個月末，國會提出了兩黨的《國家預防成癮法》或《疼痛替代法》的替代方案。

If enacted, Medicare Part D plans would be required to set co-pays for non-opioids like VX-548 in line with co-pays for generic opioids, which are typically between $0 and $15. The bill would also prohibit Medicare Part D plans from requiring seniors to step through opioids first or requiring prior authorization for non-opioids. In addition, the NOPAIN Act or Non-Opioids Prevent Addiction in the Nation Act, which was enacted in late 2022, provides for an add-on payment for non-opioids in the outpatient and ambulatory surgery center settings and remains on track to go into effect in 2025.

如果頒布，醫療保險 D 部分計劃將需要為 VX-548 等非阿片類藥物設定自付費用，與非阿片類藥物的自付費用一致，一般為 0 至 15 美元。該法案還禁止 Medicare D 部分計劃要求老年人首先使用阿片類藥物或要求非阿片類藥物事先授權。此外，2022 年底頒布的《NOPAIN 法案》或《國家非阿片類藥物預防成癮法案》規定，在門診和門診手術中心設置非阿片類藥物時需支付附加費用，並且仍有望進入2025年生效。

And just recently, 7 states: Maine, Massachusetts, Missouri, Oklahoma, Tennessee, Washington and West Virginia, have pending legislation that would require education on non-opioid options and would remove financial barriers to patient access within state-based health insurance programs like Medicaid. We expect additional states to introduce similar legislation later this year. We believe that these advances in federal and state legislation represent further momentum in Congress and across the U.S. to encourage adoption of and remove any financial barriers to using non-opioid therapies like VX-548.

就在最近，緬因州、麻薩諸塞州、密蘇裡州、俄克拉荷馬州、田納西州、華盛頓州和西維吉尼亞州等7 個州正在懸而未決的立法，要求對非鴉片類藥物選擇進行教育，並消除患者獲得基於州的健康保險計劃的財務障礙，例如醫療補助。我們預計更多州將在今年稍後推出類似的立法。我們相信，聯邦和州立法的這些進步代表了國會和整個美國鼓勵採用和消除使用 VX-548 等非阿片類藥物療法的任何財務障礙的進一步動力。

In conclusion, it's an incredibly exciting time at Vertex. We continue to treat more CF patients around the world, and with the vanza triple, now have visibility to provide an option for the patients who have discontinued CFTR modulators as well as the possibility to bring even more patients below diagnostic levels and even to carrier levels of sweat chloride.

總之，這是 Vertex 令人難以置信的激動人心的時刻。我們繼續在世界各地治療更多的 CF 患者，透過 vanza 三聯，現在可以為已停用 CFTR 調節劑的患者提供一種選擇，並有可能使更多患者低於診斷水平，甚至達到攜帶者水平汗液氯化物。

We're entering a new era of commercial diversification with the launch of CASGEVY, the first ever gene-edited therapy that brings a potential functional cure to patients with sickle cell disease and beta thalassemia across multiple regions, and we are preparing for additional near-term launches with significant market potential, including VX-548 in acute pain.

隨著CASGEVY 的推出，我們正在進入商業多元化的新時代，這是第一個基因編輯療法，為多個地區的鐮狀細胞病和β 地中海貧血患者帶來了潛在的功能性治愈，我們正在為更多的近期治療做好準備。具有巨大市場潛力的定期上市，包括治療急性疼痛的 VX-548。

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

我現在將電話轉給查理檢查財務狀況。

Thanks, Stuart. Vertex' excellent results in the fourth quarter of 2023 demonstrate once again our consistent strong performance and attractive growth profile. Fourth quarter 2023 revenue increased 9% year-over-year to $2.52 billion and was nicely balanced with revenue growth of 8% in the U.S and 12% outside the U.S. Full year revenue of $9.87 billion represents 11% growth versus 2022, our ninth consecutive year of at least double-digit growth. Overall, the primary drivers of revenue growth in 2023 were in line with our expectations.

謝謝，斯圖爾特。 Vertex 在 2023 年第四季的優異業績再次證明了我們一貫的強勁業績和有吸引力的成長前景。 2023 年第四季營收年增9%，達到25.2 億美元，與美國地區營收成長8% 和美國以外地區營收成長12% 實現良好平衡。全年營收為98.7 億美元，與2022 年相比成長11 %，這是我們連續第九個季度的營收成長年至少達到兩位數成長。整體而言，2023年營收成長的主要驅動力符合我們的預期。

Fourth quarter 2023 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $1 billion compared to $872 million in the fourth quarter of 2022. Included in Q4 '23 results are $18 million of acquired IP R&D charges compared to $23 million of such charges in the fourth quarter of 2022. Note that with the approval of CASGEVY in the fourth quarter, cost for manufacturing capacity for CASGEVY are now being recorded in cost of goods sold rather than in R&D. Full year 2023 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $4.24 billion compared to $3.07 billion in 2022.

2023 年第四季的非GAAP 研發、收購的IP 研發及銷售及管理費用合計為10 億美元，而2022 年第四季為8.72 億美元。23 年第4 季的業績中包括1,800 萬美元的收購IP 研發費用，而此類費用為2,300 萬美元2022 年第四季度。請注意，隨著 CASGEVY 在第四季度的批准，CASGEVY 的製造能力成本現在記錄在銷售成本中，而不是記錄在研發中。 2023 年全年非 GAAP 研發、收購的智慧財產權研發和銷售、一般管理費用合計為 42.4 億美元，而 2022 年為 30.7 億美元。

Fourth quarter and full year operating expense growth was driven as expected by continued investment in research and our pipeline as we have now advanced assets into the clinic in 9 different disease areas. In the fourth quarter and throughout 2023, the most significant areas of increased investment versus prior year included the pivotal studies for VX-548 in acute pain and the vanzacaftor triple in CF, the Phase I/II study for type 1 diabetes as well as the build-out of capabilities for both our expanding pipeline and our anticipated near-term commercial launches.

第四季和全年營運費用的成長正如預期的那樣受到對研究和管道的持續投資的推動，因為我們現在已將資產推進到 9 個不同疾病領域的診所。在第四季度和整個 2023 年，與去年相比，投資增加的最重要領域包括 VX-548 治療急性疼痛的關鍵研究和 vanzacaftor 三聯治療 CF 的關鍵研究、1 型糖尿病的 I/II 期研究以及為我們不斷擴大的產品線和預期的近期商業發布增強能力。

In addition, approximately $400 million of the year-over-year increase in operating expenses was the result of increased AIP R&D costs from new business development. Fourth quarter 2023 non-GAAP operating income was $1.15 billion consistent with $1.15 billion in non-GAAP operating income in the fourth quarter of 2022. Full year 2023 non-GAAP operating income was $4.37 billion compared to $4.79 billion in 2022. Fourth quarter 2023 effective tax rate of 16.3% reflects an increase in our 2023 U.S. R&D tax credits. This benefit lowered the Q4 rate and brought the full year 2023 effective tax rate to 19.4%, slightly below our guidance range of 20% to 21%.

此外，營運費用年增約4億美元是由於新業務開發導致AIP研發成本增加的結果。 2023 年第四季非GAAP 營業收入為11.5 億美元，2022 年第四季非GAAP 營業收入為11.5 億美元。2023 年全年非GAAP 營業收入為43.7 億美元，2022 年為47.9 億美元。2023 年第四季生效16.3% 的稅率反映了我們 2023 年美國研發稅收抵免的增加。這項好處降低了第四季的稅率，並使 2023 年全年有效稅率達到 19.4%，略低於我們 20% 至 21% 的指導範圍。

Fourth quarter 2023 non-GAAP earnings per share were $4.20, representing 12% growth compared to $3.76 in the fourth quarter of 2022. Full year 2023 non-GAAP earnings per share were $15.23 compared to $14.88 in 2022. We ended the quarter with $13.7 billion in cash and investments. Our priorities for cash deployment remain unchanged as we continue to prioritize investment in innovation, including external innovation via business development. During 2023, we completed 10 transactions and recognized over $500 million of AIP R&D. We also deployed over $400 million to repurchase 1.3 million shares over the course of 2023.

2023 年第四季非GAAP 每股盈餘為4.20 美元，與2022 年第四季的3.76 美元相比成長12%。2023 年全年非GAAP 每股盈餘為15.23 美元，而2022 年為14.88 美元。本季度末，我們的淨利潤為137 億美元現金和投資。我們的現金部署優先事項保持不變，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。 2023 年，我們完成了 10 筆交易，並確認了超過 5 億美元的 AIP 研發。我們也斥資 4 億多美元在 2023 年回購 130 萬股股票。

Now switching to guidance. For 2024, we expect total product revenue in a range of $10.55 billion to $10.75 billion, representing revenue growth of 8% at the midpoint at current exchange rates. Included in this outlook is our expectation for continued growth in CF as we continue to reach more patients, including younger ones, in core markets and select other countries. Guidance also includes contribution from the commercial launch of CASGEVY in approved indications and geographies.

現在切換到指導。到 2024 年，我們預計產品總收入在 105.5 億美元至 107.5 億美元之間，以當前匯率中位數計算，營收成長 8%。這項展望中包括我們對 CF 持續成長的預期，因為我們將繼續在核心市場和選定的其他國家接觸到更多患者，包括年輕患者。指南還包括 CASGEVY 在批准的適應症和地區的商業推出的貢獻。

We continue to expect a foundational year for CASGEVY in 2024 as we ramp up patient initiations and build toward a multibillion dollar market opportunity over time. We are providing total product revenue guidance rather than specifics by disease area or product given the inherent uncertainty of new launches as well as the significant disparity and size of our established CF business relative to other revenues.

我們繼續預計 2024 年是 CASGEVY 的基礎年，因為我們將加強患者啟動力度，並隨著時間的推移爭取數十億美元的市場機會。考慮到新產品上市的固有不確定性以及我們已建立的 CF 業務相對於其他收入的巨大差異和規模，我們提供的是總產品收入指導，而不是疾病領域或產品的具體情況。

As a reminder, on the accounting for CASGEVY and the CRISPR profit share arrangement, Vertex will book 100% of revenues for CASGEVY. The profit share with CRISPR calculated after product and commercial costs will be recorded in cost of goods sold. Any ongoing research and development costs will be recorded in operating expenses net of CRISPR's share.

需要提醒的是，就 CASGEVY 的會計處理和 CRISPR 利潤分享安排而言，Vertex 將為 CASGEVY 記入 100% 的收入。在產品和商業成本之後計算的 CRISPR 利潤分成將記錄在銷售成本中。任何持續的研發成本都將計入扣除 CRISPR 份額後的營運費用。

For total Vertex operating expenses, we project $4.3 billion to $4.4 billion in full year 2024 combined non-GAAP SG&A, R&D and acquired IP R&D. This operating expense range includes approximately $125 million in currently anticipated IP R&D charges. We 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 Vertex 總營運支出，我們預計 2024 年全年的非 GAAP SG&A、研發和收購的 IP 研發合計為 43 億至 44 億美元。該營運費用範圍包括目前預計的約 1.25 億美元的 IP 研發費用。鑑於我們多個中後期臨床開發項目的勢頭，我們繼續將大部分營運費用投入研發。

Note that the costs for multiple Phase III studies have been a significant driver of our growth in our total operating expenses in recent years. Given that a number of Phase III studies were completed as we entered 2024, we were able to fund new additional Phase III studies without the same rate of growth in operating expenses.

請注意，多項 III 期研究的成本是近年來我們總營運費用成長的重要動力。鑑於進入 2024 年時已經完成了許多 III 期研究，我們能夠為新的額外 III 期研究提供資金，而無需以相同的營運費用成長率。

While we have substantially completed our commercial investments for CASGEVY, we're also funding the expansion of our commercial capabilities in anticipation of other multibillion dollar opportunities represented by our programs with near-term launch potential while continuing to leverage an attractive business model afforded by our focus in specialty markets. With a more normalized impact from U.S. R&D tax credits in 2024, our full year 2024 non-GAAP effective tax rate is expected to be in the range of 20% to 21%.

雖然我們已經基本完成了對CASGEVY 的商業投資，但我們也正在為擴展我們的商業能力提供資金，以期我們具有近期啟動潛力的項目所代表的其他數十億美元的機會，同時繼續利用我們提供的有吸引力的商業模式專注於專業市場。隨著 2024 年美國研發稅收抵免的影響更加正常化，我們 2024 年全年非 GAAP 有效稅率預計將在 20% 至 21% 範圍內。

In closing, Vertex delivered excellent results yet again in 2023, achieving strong revenue growth, important regulatory approvals and commercial launches and positive pivotal trial results that will enable additional near-term launches. We also made progress in our earlier stage pipeline, with proof of concept for VX-548 in neuropathic pain and anticipated advancement of 2 additional disease areas into the clinic. We also made substantial investments behind our programs and commercial capabilities for near-term launches.

最後，Vertex 在 2023 年再次取得了優異的業績，實現了強勁的收入成長、重要的監管批准和商業發布以及積極的關鍵試驗結果，這將使得更多的近期發布成為可能。我們的早期研發管線也取得了進展，VX-548 治療神經性疼痛的概念得到驗證，預計另外 2 個疾病領域將進入臨床。我們也為近期發布的項目和商業能力進行了大量投資。

As we head into 2024, we anticipate further important milestones as highlighted on Slide 20, to mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

進入 2024 年，我們預計將出現幻燈片 20 中強調的更多重要里程碑，以標誌著我們在多個疾病領域的持續進展。我們期待在未來的通話中向您通報我們的最新進展，我將請 Susie 開始問答環節。

Thanks, Charlie. Just to note, given the multiple positive updates this quarter and thus the longer duration of our prepared remarks, we'll plan to go to about 5:40 this evening, so as to allow 30 minutes for your questions. Chuck, please go ahead and assemble the queue.

謝謝，查理。請注意，鑑於本季度出現了多項積極更新，因此我們準備好的發言時間較長，我們計劃在今晚 5:40 左右進行，以便為您提供 30 分鐘的提問時間。 Chuck，請繼續排隊。

(Operator Instructions) The first question will come from Ms. Salveen Richter with Goldman Sachs.

（操作員說明） 第一個問題將由高盛的 Salveen Richter 女士提出。

Congratulations on the data. Two questions for me. One is, with regard to the initial patient you'll be targeting with the next-generation CF program, could you just elaborate whether it's switch patients or patients who have discontinued, naive patients here and where you anticipate the most demand?

恭喜數據。有兩個問題問我。一是，關於您將針對下一代 CF 計劃的初始​​患者，您能否詳細說明一下是轉換患者還是已經停藥的患者、這裡的初始患者以及您預計需求最大的患者？

And then secondly, on the CASGEVY launch, in light of the Innovation Cell and Gene Therapy Access Demonstration Model, how do you work that into the launch at this point? And is there an overhang as you have to determine how these outcome-based agreements may play out?

其次，關於 CASGEVY 的發布，根據創新細胞和基因療法獲取演示模型，您目前如何將其融入發布中？當您必須確定這些基於結果的協議如何發揮作用時，是否存在懸而未決的問題？

Sure thing, Salveen. Let me turn it over to Stuart for both the question on vanza commercialization and on the CASGEVY launch with the focus on the CMMI question.

當然可以，薩爾文。讓我將有關 vanza 商業化和 CASGEVY 發布的問題交給 Stuart，重點關注 CMMI 問題。

Yes, Salveen. So in answer to your first question on vanzacaftor, the answer is both. I think vanzacaftor is going to be an attractive treatment option, both for patients who are currently being treated who might want superior control of their CFTR function, because both patients and physicians know that CFTR function and dysfunction is the underlying cause of CF, and so if you can further improve CFTR function, you're going to get better clinical outcomes down the line.

是的，薩爾文。因此，在回答您關於 vanzacaftor 的第一個問題時，答案是兩者兼而有之。我認為vanzacaftor 將是一個有吸引力的治療選擇，無論是對於目前正在接受治療的、可能希望更好地控制其CFTR 功能的患者來說，因為患者和醫生都知道CFTR 功能和功能障礙是CF 的根本原因，因此如果您可以進一步改善 CFTR 功能，您將獲得更好的臨床結果。

So I think we're going to see interest from those who are currently being treated, but I also think we're going to see a lot of interest from patients who previously discontinued one of our CFTR modulators, given the profile that we've demonstrated today. And then on CASGEVY, a couple of comments, really. The first one I would make is we're very excited about the demo and the opportunity to work with CMS for those states who are interested in working with CMS and are interested in outcomes-based agreements. I don't particularly see that being a delay for a couple of reasons.

因此，我認為我們會看到那些目前正在接受治療的患者的興趣，但我也認為我們會看到之前停止使用我們的一種 CFTR 調節劑的患者的許多興趣，因為我們已經今天展示了。然後關於 CASGEVY，真的有一些評論。我要說的第一句話是，我們對演示感到非常興奮，對於有興趣與 CMS 合作並對基於結果的協議感興趣的州來說，有機會與 CMS 合作。由於幾個原因，我並不特別認為這是一個延遲。

One, we're already working with many state Medicaid agencies. We're not waiting for the demo before we secure access for patients who are covered by Medicaid. And then secondly, in terms of do I think it's going to be complex and be a delay to negotiate outcomes-based agreements? I don't, really.

第一，我們已經與許多州醫療補助機構合作。在確保醫療補助覆蓋的患者能夠訪問之前，我們不會等待演示。其次，我認為談判基於結果的協議是否會很複雜並且會被推遲？我不，真的。

If you look at the profile of CASGEVY, it is so incredibly strong that really we're talking about an outcomes-based agreement, which is looking at whether a very, very small number of patients may not respond. And so I don't think it's an outcomes-based agreement where there's lots of uncertainty and difficulty with the outcomes and metrics and endpoints. And so I don't expect that to be particularly challenging.

如果你看一下 CASGEVY 的概況，它是如此令人難以置信的強大，以至於我們實際上正在談論一個基於結果的協議，該協議正在考慮是否有非常非常少的患者可能不會做出反應。因此，我不認為這是一個基於結果的協議，其中結果、指標和​​終點存在許多不確定性和困難。因此，我認為這不會特別具有挑戰性。

Next question will come from Geoff Meacham with Bank of America.

下一個問題將由美國銀行的 Geoff Meacham 提出。

Congrats on the data. On vanza, I just have a couple of questions. Can you follow SKYLINE or RIDGELINE in an extension? I'm just trying to think if you can pick up more differentiation versus TRIKAFTA just in terms of maybe exacerbations or measuring pancreatic sufficiency over a longer period. I guess ultimately, where I'm going is that sweat chloride isn't readily used in the clinic for treatment decisions, so I'm trying to see rationale for maybe switching a patient away from TRIKAFTA if they're stable.

恭喜數據。關於萬扎，我有幾個問題。您可以在分機中跟隨 SKYLINE 或 RIDGELINE 嗎？我只是想知道，與 TRIKAFTA 相比，您是否可以在病情加重或在較長時間內測量胰腺充足性方面獲得更多差異。我想最終，我要去的地方是，氯化汗液在臨床上不容易用於治療決策，所以我試著找出如果病人病情穩定，可能會從 TRIKAFTA 換掉的理由。

Yes. Thanks, Geoff. This is Reshma. Let me take that one. When we think about the patients who were enrolled in both the SKYLINE trial, so the 12-year olds and above, and the RIDGELINE patients, 6 to 11, there are already extension studies. So those patients have the opportunity to roll over into open-label extended studies just like we did with TRIKAFTA.

是的。謝謝，傑夫。這是瑞詩瑪。讓我拿走那個。當我們想到參加 SKYLINE 試驗的患者（12 歲及以上）和 RIDGELINE 患者（6 至 11 歲）時，已經有擴展研究。因此，這些患者有機會轉入開放標籤擴展研究，就像我們對 TRIKAFTA 所做的那樣。

And I do suspect you're right about the ability to evaluate and document the overall improvements in patients with CF lives over time. And just to give you a sense for what I'm looking at and why I say that, if you look in the safety tables that were one of the slides, unsurprisingly, the most common or one of the most common AEs in this patient population is pulmonary exacerbation.

我確實懷疑您關於評估和記錄 CF 患者生活隨時間的整體改善的能力是正確的。只是為了讓您了解我正在查看的內容以及我為什麼這麼說，如果您查看其中一張幻燈片的安全表，毫不奇怪，這是該患者群體中最常見或最常見的 AE 之一是肺部病情加重。

And if you look, there are less pulmonary exacerbations numerically in those safety tables in the patients on vanza than on the patients who are on TRIKAFTA. And TRIKAFTA is an amazing drug that has already documented improvements in pulmonary exacerbation and other longer-term outcomes.

如果你看一下，在安全表中，使用 Vanza 的患者的肺部病情惡化數量比使用 TRIKAFTA 的患者要少。 TRIKAFTA 是一種令人驚訝的藥物，已經記錄了對肺部病情惡化和其他長期結果的改善。

So I do think you're very correct that we'll be able to pick up these long-term outcomes as these patients are followed in the open-label extension studies and then as they are followed in registries, and we are very fortunate in CF that the registries already exists and the vast majority of patients with cystic fibrosis are followed in registries.

所以我確實認為你是非常正確的，我們將能夠獲得這些長期結果，因為這些患者在開放標籤擴展研究中被跟踪，然後在註冊中被跟踪，我們非常幸運CF 登記處已經存在，並且絕大多數囊性纖維化患者都在登記處進行追蹤。

The next question will come from Mohit Bansal with Wells Fargo.

下一個問題將由富國銀行的 Mohit Bansal 提出。

Just following up on Geoff's question. So how commonly doctors check sweat chloride levels as part of -- I know it is for diagnostic purposes, but do they check it for -- do they test it for prescribing as well? Or it is something that you will have to educate these adopters on that?

只是跟進傑夫的問題。那麼，醫生檢查汗液氯化物水平的情況有多普遍——我知道這是為了診斷目的，但他們是否檢查它——他們是否也測試它以用於處方？或者您必須對這些採用者進行相關教育？

And then my follow-up is actually on the COGS for Charlie, cost of goods sold. As you think about 2024, what happened in 2023 fourth quarter was a onetime movement from R&D to COGS which drove it? Or is this something that we to continue more going forward?

然後我的後續行動實際上是查理的 COGS，即銷售商品成本。當你想到 2024 年時，2023 年第四季發生的事情是從研發到銷貨成本的轉變，推動了這個趨勢？或者說，這是我們未來應該繼續前進的事情嗎？

Let me ask Charlie to tackle the COGS question first, and I'll come back and tell you about sweat chloride in clinical practice.

讓我先請查理解決 COGS 問題，然後我會回來告訴您臨床實踐中的汗液氯化物。

Yes, Mohit. In the fourth quarter, because CASGEVY was approved in the U.S., we started treating it as a commercial product, and therefore we took some of the manufacturing costs that previously had been recorded in R&D and moved them up to cost of goods sold. Those manufacturing costs will remain in cost of goods sold going forward.

是的，莫希特。第四季度，由於CASGEVY在美國獲得批准，我們開始將其視為商業產品，因此我們將先前記錄在研發中的一些製造成本轉移到銷售成本中。這些製造成本將繼續計入銷售成本。

Mohit, with regard to sweat chloride measurement in clinical practice, you're very correct. In terms of diagnosis, patients in the Western world are diagnosed by a gene test, a genetic test, when -- oftentimes when patients are born or when people are born, and then that's confirmed with the sweat chloride test. If the number is above 60, that diagnosis of CF, if it's between 30 and 60 millimoles for sweat chloride, that's indeterminate and if it's less than 30, that is not diagnosed as CF.

莫希特，關於臨床實務中汗液氯化物的測量，你是非常正確的。在診斷方面，西方世界的患者會透過基因測試進行診斷，通常是在患者出生或人們出生時進行基因測試，然後透過汗液氯化物測試來確認。如果數字高於 60，則診斷為 CF；如果汗液氯化物在 30 至 60 毫摩爾之間，則為不確定；如果低於 30，則不診斷為 CF。

This is not a metric. Sweat chloride is not a measure that's followed routinely in clinical practice. But what physicians understand very well, especially pulmonologists who are CF experts, is that the underlying cause of disease in CF is dysfunction of the CFTR protein. That's very well understood. And further, that a direct readout of that CFTR protein function is sweat chloride. So I think the concepts are very well understood, but sweat chloride other than the diagnosis is not a commonly used test in the clinic.

這不是一個指標。汗液氯化物不是臨床上常規遵循的測量方法。但醫生，尤其是 CF 專家的肺科醫生非常清楚，CF 疾病的根本原因是 CFTR 蛋白的功能障礙。這很好理解。此外，CFTR 蛋白功能的直接讀數是汗液氯化物。所以我認為這些概念很好理解，但是汗液氯化物除了診斷之外並不是臨床上常用的測試。

The next question will come from Phil Nadeau with TD Cowen.

下一個問題將由 Phil Nadeau 和 TD Cowen 提出。

Let us add our congratulations on another positive pivotal program. One on sweat chloride, then one actually on the pain data that you released last week. First, on the sweat chloride, it does look like TRIKAFTA gets a decent proportion of patients to below 60 millimole per liter and below 30 millimole per liter.

讓我們對另一個積極的關鍵計劃表示祝賀。一項是關於汗液氯化物，另一項是關於您上週發布的疼痛數據。首先，就汗液氯化物而言，TRIKAFTA 確實使相當一部分患者的氯化物水平低於每公升 60 毫摩爾和低於每公升 30 毫摩爾。

Do you have data following the patients who've been on TRIKAFTA for a long time to show better outcomes for those TRIKAFTA patients who got to low levels of sweat chloride, which then presumably you could extrapolate to the vanza triple and show a higher proportion of patients would have good outcomes? That's the first question.

您是否有追蹤長期使用 TRIKAFTA 的患者的數據，以顯示那些汗液氯化物水平較低的 TRIKAFTA 患者有更好的結果，然後您大概可以推斷出 vanza 三重並顯示更高比例的汗液氯化物患者會有好的結果嗎？這是第一個問題。

And then the second question on the pain data released last week. It does seem like the bunionectomy Phase III trial underperformed the Phase IIs that you had previously released as well as the abdominoplasty Phase III released last week. Was there anything different about that trial which would have caused 548 to act less potently there than it had in the prior studies?

然後是關於上週發布的疼痛數據的第二個問題。拇囊炎切除術 III 期試驗似乎確實不如您之前發布的 II 期試驗以及上週發布的腹部成形術 III 期試驗。該試驗是否存在任何不同之處，導致 548 的作用不如先前的研究有效？

Yes. Phil, let me take bunionectomy, abdominoplasty, VX-548 first, and then we'll come back to sweat chloride. You know what I actually find remarkable, Phil, is the -- how consistently 548 has performed. That, to me, is more striking than the smaller differences in bunionectomy readout Phase II to Phase III or across from bunionectomy to abdominoplasty.

是的。 Phil，讓我先進行拇囊炎切除術、腹部成形術、VX-548，然後我們再回來進行汗氯化物治療。 Phil，你知道我真正發現的非凡之處是 548 的表現有多穩定。對我來說，這比第二階段到第三階段或從拇囊炎切除術到腹部成形術的拇囊炎切除術讀數的較小差異更引人注目。

So if I look at the totality of the VX-548 evidence, and it's easy enough to do because the structure of the study design was very similar in Phase II as Phase III and we have the same dose, the high dose from Phase II, you'll see that bunionectomy and abdominoplasty performed virtually identically. Like the SPID48 was something like 40 points or something like that. I think that was the actual number.

因此，如果我查看 VX-548 證據的整體情況，這很容易做到，因為 II 期研究設計的結構與 III 期非常相似，而且我們的劑量相同，II 期的高劑量，您會發現拇囊炎切除術和腹部成形術的效果幾乎相同。就像 SPID48 是 40 點之類的東西。我認為這就是實際數字。

And then when you move to Phase III, again, positive studies against placebo. In the grand scheme of things, this is remarkable because as you know, the conduct of clinical trials in the pain field is notoriously difficult. Placebo effects move around significantly. The effect of any comparator group moves around significantly.

然後當你進入第三階段時，再次進行針對安慰劑的積極研究。從總體上看，這是值得注意的，因為如您所知，在疼痛領域進行臨床試驗是出了名的困難。安慰劑效應顯著變化。任何比較組的效果都會顯著改變。

So when I look at the totality of the data, and for me, that means looking at the data from Phase II to Phase III, and it also means looking at the SPID48, let's focus on bunionectomy, in bunionectomy, and connecting that with the NPRS. Remember, the NPRS is the actual score that feeds the SPID48, which is an integration of NPRS over time.

因此，當我查看全部數據時，對我來說，這意味著查看從II 期到III 期的數據，也意味著查看SPID48，讓我們重點關注拇囊炎切除術，並將其與拇囊炎切除術 連結起來。NPRS。請記住，NPRS 是提供給 SPID48 的實際分數，SPID48 是 NPRS 隨著時間的推移的積分。

So if you look at the NPRS data, it's -- the decrease in the NPRS is 3.4 points in bunionectomy, it's 3.4 points in abdominoplasty start to hour 48. And it's about a 50% decrease in terms of the relative decrease. And when you look at that in comparison to Norco, the opioid we used in the trial, that number is 3.2 in abdominoplasty, 3.6 in bunionectomy and it's approximately a 50% reduction in terms of the relative change. So I put that all together, and I see quite a bit of consistency and very good therapeutic effectiveness and efficacy.

因此，如果您查看NPRS 數據，您會發現，拇囊炎切除術中NPRS 下降了3.4 個點，腹部成形術從第48 小時開始下降了3.4 個點。就相對下降而言，大約下降了50% 。與我們在試驗中使用的鴉片類藥物 Norco 相比，腹部成形術中的數字為 3.2，拇囊炎切除術中的數字為 3.6，相對變化大約減少了 50%。所以我把所有這些放在一起，我看到了相當多的一致性和非常好的治療效果和功效。

On sweat chloride. So it's a really, really great question. And in order to sort of really understand this, you have to triangulate a couple of different data points. One data point is around just the natural history and the genetics of this disease. So take, for example, patients who are F/MF versus those who are F/RF, F/MF patients have very high sweat chlorides and have more severe disease. F/RF patients, the residual function patients, have relatively better sweat chloride levels and relatively less severe disease. That's one set of data.

對汗液氯化物。所以這是一個非常非常好的問題。為了真正理解這一點，您必須對幾個不同的數據點進行三角測量。一個數據點僅涉及這種疾病的自然史和遺傳學。例如，F/MF 患者與 F/RF 患者相比，F/MF 患者的汗液氯化物非常高，且病情更嚴重。 F/RF患者，即殘餘功能患者，汗液氯化物水平相對較好，病情相對較輕。這是一組數據。

And then to your point, if you look at interventional data, the data that we have, the greatest reduction in ppFEV1, sweat chloride and long-term evidence is TRIKAFTA. And if you compare that to KALYDECO, for example, you can see where TRIKAFTA does even better than KALYDECO. And the best example I can give you is on rate of decline. The TRIKAFTA real-world data on rate of decline shows there is no decline.

然後就你的觀點而言，如果你看一下介入數據，我們擁有的數據、ppFEV1、汗液氯化物和長期證據的最大減少是 TRIKAFTA。例如，如果將其與 KALYDECO 進行比較，您會發現 TRIKAFTA 比 KALYDECO 做得更好。我能給你的最好的例子就是下降率。 TRIKAFTA 真實世界的下降率數據顯示沒有下降。

And until we got to TRIKAFTA, what we could show is we slowed the rate of decline. And so I have every reason in the world to believe as the vanzacaftor triple is used over a longer time point and we get CFTR protein function to higher levels, and the Vanza triple has given us the best, highest achieved CFTR protein levels, I do think we're going to see long-term benefit. And yes, you can do all of that math and triangulation from the available data.

在我們達成 TRIKAFTA 之前，我們可以表明我們減緩了下降速度。因此，我完全有理由相信，隨著vanzacaftor 三元組的使用時間更長，我們將CFTR 蛋白功能提升到更高的水平，而Vanza 三元組為我們提供了最佳、最高的CFTR 蛋白水平，我相信我認為我們將會看到長期利益。是的，您可以根據可用數據進行所有數學計算和三角測量。

Next question will come from Robyn Karnauskas with Truist.

下一個問題將由 Robyn Karnauskas 和 Truist 提出。

So commercialization, I know it's really hard switching from one drug to the next. Can you walk me through switching from TRIKAFTA to the next drug. And like given that people are stable, their lung functions are great, how would you think about what motivates commercial Europe as well as U.S. to allow people to stay on drug and like move to a next-generation drug?

所以商業化，我知道從一種藥物轉向另一種藥物真的很困難。您能指導我從 TRIKAFTA 切換到下一種藥物嗎？鑑於人們情況穩定，肺功能良好，您如何看待歐洲和美國商業允許人們繼續服用藥物並轉向下一代藥物的動機？

And I think -- I'm coming from the point of like I remember from a long time ago, the people had a hard time switching from one drug to the other. And I want to understand like more like how you actually help people, help commercial organizations switch from one to the next.

我認為，我的觀點是，我記得很久以前，人們很難從一種藥物轉向另一種藥物。我想更多地了解你如何實際幫助人們，幫助商業組織從一種組織轉變到另一種組織。

Stuart?

史都華？

Yes, Robyn, thanks. So I must confess our experience is a little bit different to that. We've seen very rapid transitions from our medicines as we've serially innovated and delivered better and better medicines. And even, for instance, when we introduced TRIKAFTA and patients who had been on KALYDECO, for instance, for a very long time, and obviously, KALYDECO had set a very, very high bar for efficacy. We did see rapid adoption with TRIKAFTA, even in those patients, given that it had a clear benefit/risk profile.

是的，羅賓，謝謝。所以我必須承認我們的經驗與此有點不同。隨著我們不斷創新並提供越來越好的藥物，我們看到了藥物的快速轉變。甚至，例如，當我們引入 TRIKAFTA 和使用 KALYDECO 很長時間的患者時，很明顯，KALYDECO 為療效設定了非常非常高的標準。我們確實看到 TRIKAFTA 得到了迅速採用，即使在這些患者中，因為它具有明確的益處/風險特徵。

So I think we've seen relatively rapid transitions for our medicines as we've serially innovated. And interestingly, the design of the study actually gives a proof for the fact that patients can effectively transition from TRIKAFTA to vanzacaftor because, as Reshma mentioned in her remarks, the design of the study was to have people stable on 4 weeks of TRIKAFTA therapy to establish a baseline, and they were then randomized to either continue on TRIKAFTA or transition to vanzacaftor. So we have, within the study, real-world evidence of people being able to transition.

因此，我認為隨著我們的不斷創新，我們的藥物已經發生了相對快速的轉變。有趣的是，該研究的設計實際上證明了患者可以有效地從TRIKAFTA 過渡到vanzacaftor，因為正如Reshma 在她的演講中提到的那樣，該研究的設計是讓人們在4 週的TRIKAFTA 治療中保持穩定建立基線，然後他們被隨機分配繼續使用 TRIKAFTA 或過渡到 vanzacaftor。因此，在研究中，我們有現實世界的證據顯示人們能夠轉變。

And then you'll ask me what do I think is going to motivate people to want to consider the vanzacaftor triple combination? I think it's the benefit/risk profile that we've been able to demonstrate here. We're achieving higher levels of sweat chloride reduction than with any of our previous medicines, including now TRIKAFTA, and the fact that this is a once-a-day therapy. So as I've said a number times, I think with this profile, we're going to see a lot of enthusiasm from the CF community.

然後您會問我，我認為什麼會促使人們考慮 vanzacaftor 三重組合？我認為這是我們在這裡展示的收益/風險概況。與我們以前的任何藥物（包括現在的 TRIKAFTA）相比，我們實現了更高水平的汗液氯化物減少，而且這是一種每天一次的療法。正如我多次說過的，我認為透過這個簡介，我們將看到 CF 社群的極大熱情。

So follow-up question for you is what about the payers and the governments in Europe? Do they believe -- and like you've had very stable levels of lung function with TRIKAFTA, do you think that people will focus on like that? Or do they need more data moving forward?

那麼接下來的問題是歐洲的付款人和政府怎麼辦？他們是否相信——就像你透過 TRIKAFTA 獲得了非常穩定的肺功能水平一樣，你認為人們會關注這樣的事情嗎？或者他們需要更多數據來推進？

Well, I mean, I think we've had a long track of working with payers on cystic fibrosis for again of well over a decade now. So I think there's a significant amount of understanding about the disease. Obviously, we'll be presenting the data to vanzacaftor to payers in a compliant manner at the right time.

嗯，我的意思是，我認為我們與付款人在囊性纖維化方面的合作已經有十多年了。所以我認為人們對這種疾病有了很多了解。顯然，我們將在適當的時間以合規的方式向 vanzacaftor 向付款人提供數據。

The one other thing would I note about the vanzacaftor triple combination is it's likely to be indicated for a very similar population of patients to TRIKAFTA, which I do think is going to make this launch, from a payer perspective, a bit different to previous launches, as you will recall, because you've been on this journey with us for a while.

關於 vanzacaftor 三聯療法，我要注意的另一件事是，它可能適用於與 TRIKAFTA 非常相似的患者群體，我確實認為，從付款人的角度來看，這次推出與之前的推出略有不同，正如您所記得的，因為您已經和我們一起踏上這段旅程一段時間了。

When we launched ORKAMBI, we were moving from kind of single-digit numbers of eligible patients to a medicine that could potentially treat up to 50% of CF patients. When we then brought TRIKAFTA forward, we were moving it towards being able to treat 90% of patients. Vanza is going to likely have a very similar label to TRIKAFTA, and so it's not likely to be as scary, I would suggest to payers, in terms of a big budget impact hit.

當我們推出 ORKAMBI 時，我們正在從符合條件的患者數量轉向一種可以治療多達 50% 的 CF 患者的藥物。當我們推進 TRIKAFTA 時，我們正朝著能夠治療 90% 的患者的目標邁進。 Vanza 可能會有與 TRIKAFTA 非常相似的標籤，因此我建議付款人就預算影響大而言，它不太可能那麼可怕。

Next question will come from Jessica Fye with JPMorgan.

下一個問題將由摩根大通的 Jessica Fye 提出。

Great. Can you set expectations around how you see the cadence of patients initiating the CASGEVY journey for us?

偉大的。您能否對患者為我們啟動 CASGEVY 旅程的節奏設定預期？

Sure thing. Stuart?

當然可以。史都華？

Yes, Jess. So I think we've described the patient journey for CASGEVY. It has kind of these multiple phases from patients being evaluated by their physician and deciding with their physician that this is the journey that they want to go on. You then have to go through the cell collection and manufacturing process and then the cells are infused. Each of those steps can take a number of months. And as you know, we've said that we'll be recognizing revenue at the point of infusion.

是的，傑西。所以我想我們已經描述了 CASGEVY 的病患歷程。它有多個階段，從患者接受醫生評估並與醫生決定這是他們想要繼續的旅程。然後你必須經歷細胞收集和製造過程，然後將細胞注入。其中每一步都可能需要數月的時間。如您所知，我們說過我們將在輸注時確認收入。

So in contrast to our cystic fibrosis launches, which have really seen incredibly rapid uptake, we have said that we are expecting this launch to be more like a traditional biopharma launch, but we are expecting this, and we have said we are expecting this, to be a foundational year for us as we build momentum around CASGEVY. Having said that, in terms of the destination, we continue to believe that the destination for CASGEVY is going to be used in thousands of patients and represents a multibillion dollar opportunity.

因此，與我們的囊性纖維化產品的上市相比，我們已經說過，我們預計這次上市更像是傳統的生物製藥上市，但我們期待這一點，我們已經說過我們期待這一點，對我們來說，這是基礎性的一年，因為我們圍繞 CASGEVY 建立了動力。話雖如此，就目的地而言，我們仍然相信 CASGEVY 的目的地將用於數千名患者，並代表著數十億美元的機會。

The next question will come from Evan Seigerman with BMO Capital.

下一個問題將由 BMO Capital 的 Evan Seigerman 提出。

I know there's a lot on the vanza triple, but kind of -- can you maybe walk us through some of the clinical considerations as you would get to maybe have a physician switch patient? And then thinking about kind of potential TRIKAFTA quitters returning on drug, what does that conversation look like? And I guess, maybe more specifically, why would a patient discontinue TRIKAFTA and why would they want to reinitiate with the vanza triple?

我知道 vanza 三人組有很多內容，但是，您能否向我們介紹一些臨床注意事項，因為您可能會要求醫生更換患者？然後考慮一下潛在的 TRIKAFTA 戒菸者重新使用藥物的情況，對話是什麼樣的？我想，也許更具體地說，為什麼患者會停止 TRIKAFTA 以及為什麼他們想要重新開始使用 vanza 三重療法？

Sure thing, Evan. I think Stuart has talked about this, and maybe I'll shorthand it by saying we have the approximately 6,000 patients who are in the system. They are known to have CF. They are seen by a CF provider. They used to be on TRIKAFTA. So they're not lost, they simply have discontinued it either because of an adverse event or perhaps because of compliance. TRIKAFTA (inaudible). Vanza is, of course, once a day.

當然可以，埃文。我想史都華已經談到了這一點，也許我會簡略地說，我們系統中有大約 6,000 名患者。眾所周知，他們患有CF。它們被 CF 提供者看到。他們曾經在 TRIKAFTA 上。所以他們並沒有迷失，他們只是因為不良事件或可能因為合規而停止了它。 TRIKAFTA（聽不清楚）。 Vanza 當然是每天一次。

So we see those 6,000 patients potentially coming back, and the short version of the conversation would be they're coming to see their doctor, usually CF patients are seen by their doctor once a quarter, so when they return, the conversation might be something like, if and when vanza is approved, there's a new drug. It has this safety. It has this efficacy. Do you want to try it? You had tried a medicine before. This is a new one. And the doctor and patient would have a communication about that.

因此，我們看到這 6,000 名患者可能會回來，對話的簡短版本是他們要去看醫生，通常 CF 患者每季度見一次醫生，所以當他們回來時，對話可能是這樣的就像，如果萬扎獲得批准，就會有一種新藥。它有這個安全性。有這個功效。你想嘗試嗎？您之前曾嘗試過一種藥物。這是一個新的。醫生和病人會就此溝通。

So the patients who are already on TRIKAFTA and are doing well, I suspect it's going to be just like it was from SYMDEKO and ORKAMBI to TRIKAFTA or from KALYDECO to TRIKAFTA. Our CF patients are very educated patients. They know what clinical trials are going on. They know what potential medicines might be coming down the pipe, and they are interested in being treated with the most effective medicine, the medicine with the best benefit/risk.

因此，已經使用 TRIKAFTA 且狀況良好的患者，我懷疑情況會像從 SYMDEKO 和 ORKAMBI 到 TRIKAFTA 或從 KALYDECO 到 TRIKAFTA 一樣。我們的囊性纖維化患者都是受過良好教育的患者。他們知道正在進行哪些臨床試驗。他們知道可能會出現哪些潛在藥物，並且有興趣接受最有效的藥物治療，即具有最佳效益/風險的藥物。

And they do this because it is a disease that starts at birth and is with them their entire life. Now with the life expectancy, based on modeled data, being in the 80s, I do think the idea is that we can get patients to as close to normal as possible, at least we're on that journey with vanza is an attractive option for physicians and patients. And I suspect that's what that conversation is going to be about.

他們這樣做是因為這是一種從出生就開始的疾病，並伴隨他們一生。現在，根據建模數據，預期壽命為80 多歲，我確實認為我們的想法是，我們可以讓患者盡可能接近正常，至少我們正在走上這段旅程，而vanza 對於以下患者來說是一個有吸引力的選擇醫生和病人。我懷疑這就是這次談話的主題。

The next question will come from Chris Raymond with Piper Sandler.

下一個問題將由克里斯·雷蒙德和派珀·桑德勒提出。

Congrats from us as well on the data. Just 2 questions, if possible. First maybe on CASGEVY. We've gotten some physician feedback that, of course, access is a barrier to uptake. But maybe a surprise that we got from some of the questions we've asked is that transplant center capacity and prioritization of non-oncology patients is also sort of a consideration.

我們也對數據表示祝賀。如果可能的話，只有兩個問題。首先可能是CASGEVY。我們收到了一些醫生的回饋，當然，獲取途徑是採用的障礙。但也許我們從我們提出的一些問題中得到的驚喜是，移植中心的能力和非腫瘤患者的優先順序也是一個考慮因素。

Just curious, as you activate these ATCs, maybe talk about transplant capacity. Does this factor into the discussions as you're activating these sites? And then maybe on vanzacaftor, I know you guys have described the royalty differential. I think TRIKAFTA is in the low double digits, and you've described vanzacaftor as down in the single digits. But are there plans to put some guardrails around this leverage improvement as you get closer to launch of the vanza triple?

只是好奇，當你啟動這些 ATC 時，也許會談論移植能力。當您啟動這些網站時，這會影響討論嗎？然後也許在 vanzacaftor 上，我知道你們已經描述了版稅差異。我認為 TRIKAFTA 的銷售額處於低兩位數，而您將 vanzacaftor 描述為低個位數。但是，隨著 Vanza 三重車的推出，是否有計劃圍繞槓桿改進設置一些護欄？

I'm sorry, Chris, I didn't follow the question on the vanza triple. I got you on CASGEVY. Is it about the royalties?

對不起，克里斯，我沒有聽懂萬扎三人組的問題。我在《CASGEVY》上找到你了。與版稅有關嗎？

Yes, sorry. On -- yes, just on the leverage and the royalty differential. I think you guys described the difference, but are there plans to put guardrails around that leverage as people model that?

是的，抱歉。是的，只是槓桿和特許權使用費差異。我想你們描述了這種差異，但是當人們建模時，是否有計劃在這種槓桿周圍設置護欄？

Yes. Yes. Sure thing. Let me take CASGEVY quickly, turn it over to Stuart and then we'll just do one minute real quick with Charlie, and he'll tell you about the royalty structure for vanza.

是的。是的。當然可以。讓我快速了解 CASGEVY，將其交給 Stuart，然後我們將與 Charlie 快速交流一分鐘，他會告訴您 vanza 的版稅結構。

Real quickly on CASGEVY, we have not heard of there being a center capacity issue. And honestly, we have not heard about challenges for reimbursement. We've actually had very positive reception from payers. But I'll turn it over to Stuart to make a quick comment on activation and his perspective.

很快，在 CASGEVY 上，我們還沒有聽說有中心容量問題。老實說，我們還沒有聽說過報銷方面的挑戰。事實上，我們得到了付款人非常積極的歡迎。但我會將其轉交給斯圖爾特，以便對激活和他的觀點做出快速評論。

Yes. And we're making great progress, Chris, I would say, activating authorized treatment centers just here in the U.S. We're now up to 12, and I don't think those centers would be going through the effort of becoming an activated treatment center if they weren't fully intending to treat patients with CASGEVY. And then as Reshma said, the reaction we've had from payers has been really positive.

是的。克里斯，我想說，我們正在取得巨大進展，正在激活美國的授權治療中心。我們現在已達到 12 個，我認為這些中心不會努力成為激活的治療中心中心，如果他們不完全打算治療CASGEVY 患者。正如雷什瑪所說，我們從付款人那裡得到的反應非常積極。

I think they're incredibly impressed with the clinical data. They are well aware of the unmet need in sickle cell disease and indeed transfusion-dependent thalassemia and the burden that places on patients and indeed the health care system. They like the label that we've got, and they like our value-based price. And so I've been very encouraged by the conversations we've been having with payers, and I'm fully expecting us to be able to secure great access for sickle cell disease and TDT patients.

我認為他們對臨床數據印象深刻。他們清楚地意識到鐮狀細胞疾病和輸血依賴性地中海貧血的需求未被滿足，以及對患者和醫療保健系統造成的負擔。他們喜歡我們的標籤，也喜歡我們基於價值的價格。因此，我們與付款人的對話讓我深受鼓舞，我完全期待我們能夠為鐮狀細胞疾病和 TDT 患者提供良好的服務。

Charlie, a word on royalties.

查理，談版稅。

Yes, just briefly on the royalties bit, Chris. The blended royalty rate on our current CF portfolio is just under 10%. And so high single digit, call it. And we expect with the vanza triple, that royalty burden will be meaningfully lower in the single digits. No additional color to add today. And then, of course, if you want to model the impact of that, you have to factor in the rate of switching from TRI and other medicines again. So as we get closer to commercialization, we'll have more to say.

是的，克里斯，簡單介紹一下版稅。我們目前 CF 投資組合的混合特許權使用費率略低於 10%。如此高的個位數，稱之為。我們預計，隨著 Vanza Triple 的推出，特許權使用費負擔將大幅降低個位數。今天無需添加其他顏色。當然，如果你想對其影響進行建模，你必須再次考慮從 TRI 和其他藥物的轉換率。因此，當我們越來越接近商業化時，我們會有更多話要說。

The next question will come from Colin Bristow with UBS.

下一個問題將由瑞銀集團 (UBS) 的 Colin Bristow 提出。

Congrats on all the data. Maybe first on the vanza triplet. Can you say if there are any cases of AST or ALT elevations greater than 3 or 5x the upper limit of normal? And then secondly, I see that you've now got 3 follow-on pain assets in clinic: 993, 973 and 708. Could you just give us more color on how you expect them to be differentiated and just elaborate a bit more on the strategy from here?

恭喜獲得所有數據。也許首先是萬扎三胞胎。您能說一下是否有 AST 或 ALT 升高超過正常上限 3 或 5 倍的情況嗎？其次，我看到您現在在臨床上有 3 個後續疼痛資產：993、973 和 708。您能否給我們更多關於您期望如何區分它們的信息，並詳細說明一下策略從這裡開始？

Yes. Sure thing, Colin. Quickly on LFT elevations with the vanzacaftor triple. As with all of the CFTR modulators, there are some elevations in LFTs. They're approximately the same with the vanzacaftor triple as with TRIKAFTA.

是的。當然可以，科林。使用 vanzacaftor 三人車快速到達 LFT 高地。與所有 CFTR 調製器一樣，LFT 也有一些升高。 vanzacaftor 三元組與 TRIKAFTA 的作用大致相同。

On the pain program, Colin, this is exactly what you saw us do in CF and frankly, what you should expect from us across the portfolio. And that is to say a portfolio approach to every disease in our sandbox. If there is a way to improve on our assets, we aim to be the ones who do so.

關於疼痛計劃，Colin，這正是您在 CF 中看到的我們所做的，坦白說，您應該對我們整個產品組合抱有期望。也就是說，針對我們沙箱中的每種疾病採取組合方法。如果有辦法改善我們的資產，我們的目標就是成為這樣做的人。

So a couple of examples of what we're doing with 993, for example. 993 is a medicine that may be able to be dosed both oral and IV, and we're pursuing both. We believe that there is a real opportunity here for a patient to come into hospital and have 993 or one of our NaV1.8 inhibitors be the medicine that they get for pain relief, let's say, intraoperatively. And then when they can take by mouth, then they can switch to 548, 993, as an example.

舉幾個我們對 993 所做的事情的例子。 993 是一種既可以口服也可以靜脈注射的藥物，我們正在研究這兩種給藥方式。我們相信，患者有一個真正的機會進入醫院並使用 993 或我們的一種 NaV1.8 抑制劑作為他們在手術中緩解疼痛的藥物。然後當他們可以透過口取的時候，他們可以切換到548、993，例如。

Another example that we're working on, you know that we also have a pipeline of NaV1.7 inhibitors. Those are still in preclinical development, but they are making good progress. So one of the other elements we're working on is formulations in terms of drug-drug interactions and the possibility to combine. So NaV1.7 could be a molecule as a single agent therapy or it could also be a therapy in combination with the NaV1.8. That's kind of a sense for what we're doing with our follow-on approach.

我們正在研究的另一個例子，你知道我們還有 NaV1.7 抑制劑的管道。這些仍處於臨床前開發階段，但取得了良好進展。因此，我們正在研究的其他要素之一是藥物間相互作用和組合可能性方面的配方。因此，NaV1.7 可以是一種分子作為單一藥物療法，也可以是與 NaV1.8 組合的療法。這就是我們對後續方法所做的事情的一種感覺。

Our last question for the evening will come from Myles Minter with William Blair.

今晚我們的最後一個問題將由邁爾斯·明特和威廉·布萊爾提出。

You just mentioned the first commercial patients on CASGEVY are expected to start the journey in the coming weeks. Can you clarify what geographies they are in? And do you have a sense of how many patients you've screened out at those ATCs to identify those first patients?

您剛剛提到 CASGEVY 的第一批商業患者預計將在未來幾週內開始旅程。您能澄清一下他們位於哪些地區嗎？您是否知道您在這些 ATC 中篩選出了多少患者以識別出第一批患者？

Sure thing. Myles, we're not going to comment in detail on the first patients, but as Stuart said in his prepared remarks, we're expecting our first patient shortly.

當然可以。邁爾斯，我們不會詳細評論第一批患者，但正如斯圖爾特在他準備好的演講中所說，我們很快就會迎來第一位患者。

This concludes our question-and-answer session as well as our conference call for today. I want to thank everyone 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 10178829. Thank you, and have a great day.

我們今天的問答環節和電話會議到此結束。我要感謝大家參加今天的演講。通話結束後不久即可重播今天的活動，請撥打 1 (877) 344-7529 或 1 (412) 317-0088 使用重播訪問代碼 10178829。謝謝，祝您有美好的一天。