福泰製藥 (VRTX) 2024 Q1 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals First Quarter 2024 Earnings Conference Call. (Operator Instructions) I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

美好的一天，歡迎參加 Vertex Pharmaceuticals 2024 年第一季財報電話會議。 （操作員指示）我現在將會議轉交給 Susie Lisa 女士。請繼續。

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 first quarter 2024 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.

大家晚上好。我叫蘇西‧麗莎，擔任投資人關係資深副總裁。我很高興歡迎您參加我們的 2024 年第一季財務業績電話會議。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, Vertex' anticipated acquisition of Alpine Immune Sciences and Vertex' future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

這些陳述，包括但不限於有關Vertex 銷售的囊性纖維化、鐮狀細胞病和β 地中海貧血藥物、我們的產品線、Vertex 預期收購Alpine Immune Sciences 以及Vertex 未來財務業績的陳述，均基於管理層當前的假設。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. Continuing our strong momentum from 2023, we've kicked off '24 with another quarter of excellent performance across the board.

謝謝，蘇西。大家晚上好，感謝您今天加入我們的電話會議。延續 2023 年以來的強勁勢頭，我們以另一個季度的全面出色表現拉開了 24 年的序幕。

Vertex continued to reach more CF patients, delivering $2.7 billion in revenue in Q1, representing 13% growth versus the prior year period. We also began our journey of revenue diversification with the launch of CASGEVY in both sickle cell disease and beta thalassemia in multiple regions.

Vertex 持續覆蓋更多 CF 患者，第一季營收達 27 億美元，較去年同期成長 13%。我們也開始了收入多元化之旅，在多個地區推出了用於治療鐮狀細胞疾病和β地中海貧血的 CASGEVY。

In our late stage pipeline, we continue to drive programs into Phase III and towards regulatory approval, creating multiple opportunities for both revenue growth and diversification, including: one, completing our regulatory submissions for the vanzacaftor triple in patients with cystic fibrosis 6 years and older in both the U.S. and the EU; initiating the rolling NDA submission for VX-548 or suzetrigine in moderate-to-severe acute pain; three, advancing inaxaplin into the Phase III portion of its pivotal trial in APOL1-mediated kidney disease and expanding the eligible patient population down to age 10; and four, following the successful completion of the end of Phase II regulatory meeting with the FDA, we are on track to initiate the Phase III trials of suzetrigine in painful diabetic peripheral neuropathy in the second half of this year.

在我們的後期管道中，我們繼續推動項目進入III 期並爭取監管批准，為收入增長和多元化創造多種機會，包括：一、完成針對6 歲及以上囊性纖維化患者的vanzacaftor 三聯療法的監管提交在美國和歐盟；啟動 VX-548 或 Suzetrigine 治療中度至重度急性疼痛的滾動 NDA 提交；第三，將 inaxaplin 推進到 APOL1 介導的腎臟疾病關鍵試驗的 III 期部分，並將符合條件的患者群體擴大到 10 歲；第四，在與 FDA 成功完成 II 期監管會議後，我們預計在今年下半年啟動 Suzetrigine 治療疼痛性糖尿病週邊神經病變的 III 期試驗。

And milestones in our early and mid-stage pipeline matched this pace of progress as we resumed the VX-880 trial in type 1 diabetes; initiated clinical development of VX-407 in polycystic kidney disease; and three, achieve regulatory clearances in multiple regions, including the U.S., and initiated the Phase I/II clinical trial of VX-670 in patients with myotonic dystrophy type 1.

隨著我們恢復第 1 型糖尿病 VX-880 試驗，我們早期和中期研發管線中的里程碑與此進展速度相符；啟動VX-407治療多囊腎的臨床開發；第三是獲得包括美國在內的多個地區的監管許可，並啟動了 VX-670 針對 1 型強直性肌肉營養不良患者的 I/II 期臨床試驗。

And of course, we are very excited to expand the Vertex portfolio and team with our definitive agreement to acquire Alpine Immune Sciences announced on April 10. Alpine's lead asset, povetacicept or pove, is a potential best-in-class Phase III-ready molecule for IgA nephropathy or IgAN, a disease with high unmet need. Pove is also a molecule that holds a pipeline in a product potential in a number of other serious autoimmune renal diseases and cytopenias in Phase II development.

當然，我們非常高興能夠擴大 Vertex 產品組合和團隊，並於 4 月 10 日宣布達成收購 Alpine Immune Sciences 的最終協議。或IgAN，這是一種需求未被滿足的疾病。 Pove 也是一種分子，在 II 期開發中擁有治療許多其他嚴重自體免疫腎病變和血球減少症的產品潛力。

We see the acquisition as just the right fit with just the right assets at just the right phase of development, where Vertex' capabilities can accelerate pove's development in IgAN and other indications. And lastly, Alpine will add protein engineering and immunotherapy expertise to Vertex' capabilities, with particular relevance for our development programs in gentler conditioning for CASGEVY and immune evasion for type 1 diabetes cell therapies. We are excited to begin working with the Alpine team and together, advance pove into Phase III in IgAN later this year.

我們認為這項收購恰到好處地適合在正確的開發階段使用正確的資產，Vertex 的能力可以加速 pove 在 IgAN 和其他適應症方面的開發。最後，Alpine 將為 Vertex 的能力增添蛋白質工程和免疫療法專業知識，特別與我們在 CASGEVY 溫和調理和 1 型糖尿病細胞療法免疫逃脫方面的開發項目相關。我們很高興開始與 Alpine 團隊合作，並在今年稍後共同將 pove 推進到 IgAN 的第三階段。

With that overview, let me now turn to a more detailed pipeline review. This quarter, I'll limit my comments to the programs with the most significant recent updates: cystic fibrosis, pain, type 1 diabetes and the pending Alpine acquisition. Starting with CF. We are very pleased with the Phase III results of the vanza triple we announced in early February as we continue to advance towards our ultimate goal of bringing all eligible patients to carrier levels of sweat chloride.

有了這個概述，現在讓我轉向更詳細的管道審查。本季度，我將僅限於對近期最重要更新的項目進行評論：囊性纖維化、疼痛、1 型糖尿病和即將進行的 Alpine 收購。從CF開始。我們對二月初宣布的 vanza 三聯療法的 III 期結果感到非常滿意，因為我們將繼續朝著使所有符合條件的患者達到汗液氯化物載體水平的最終目標前進。

Results from the vanza pivotal program met our high expectations, and were an important milestone in our progress towards this aspiration. Results from the 2 randomized studies in patients 12 and above demonstrated vanza was non-inferior to TRIKAFTA on lung function and superior to TRIKAFTA on sweat chloride, including as measured by the proportion of patients achieving sweat chloride levels below the diagnostic threshold of 60 millimoles per liter and below the carrier level or normal levels of sweat chloride of less than 30 millimoles per liter.

Vanza 關鍵計劃的結果滿足了我們的高期望，並且是我們實現這一願望的重要里程碑。對12 名及以上患者進行的2 項隨機研究的結果表明，vanza 在肺功能方面不劣於TRIKAFTA，在汗液氯化物方面優於TRIKAFTA，包括通過達到汗液氯化物水平低於診斷閾值60 毫摩爾/分的患者比例來衡量。

Included in the pivotal program was the RIDGELINE study in patients 6 to 11 years of age. To underscore the potential impact of vanzacaftor, consider 95% of patients age 6 to 11 in this study achieved sweat chloride levels below the level of diagnosis for cystic fibrosis, and more than half reached sweat chloride levels considered to be in the normal or carrier level range of sweat chloride. We believe these results indicate that vanza could set a new standard in the treatment of CF.

關鍵項目包括針對 6 至 11 歲患者的 RIDGELINE 研究。為了強調 vanzacaftor 的潛在影響，考慮到本研究中 95% 的 6 至 11 歲患者的汗液氯化物水平低於囊性纖維化的診斷水平，超過一半的汗液氯化物水平被認為處於正常或攜帶者水平汗液氯化物範圍。我們相信這些結果表明 vanza 可以為 CF 的治療樹立新的標準。

To round out the profile of the vanzacaftor triple, it's important to note that the therapy also offers the convenience of once-daily dosing and a substantially lower royalty burden. With these results in hand, we've been working rapidly to compile the regulatory marketing applications, and I am pleased to share that we have completed submissions in the U.S. and EU for patients ages 6 years and older ahead of our midyear goal.

為了完善 vanzacaftor 三重療法的概況，值得注意的是，該療法還提供每日一次給藥的便利性和大幅降低的特許權使用費負擔。有了這些結果，我們一直在快速編制監管行銷申請，我很高興地告訴大家，我們已經在年中目標之前完成了針對 6 歲及以上患者的美國和歐盟提交申請。

In the U.S., we use one of our priority review vouchers, which, if the filing is accepted, provides an expedited 6-month review versus the standard 10-month review time line. We're also on track to complete submission in the U.K., Canada, Australia, New Zealand and Switzerland by midyear.

在美國，我們使用優先審查憑證之一，如果申請被接受，將提供 6 個月的加急審查，而標準審查時間為 10 個月。我們還有望在年中之前完成在英國、加拿大、澳洲、紐西蘭和瑞士的提交。

I'll close on CF with VX-522, our CFTR mRNA therapy in development with our partners at Moderna for the treatment of the more than 5,000 people with CF who do not make any CFTR protein, and therefore cannot benefit from CFTR modulators. We continue to enroll in the multiple ascending dose portion of the study and expect data late in 2024 or early 2025.

我將用 VX-522 來結束 CF，這是我們與 Moderna 的合作夥伴正在開發的 CFTR mRNA 療法，用於治療 5,000 多名不產生任何 CFTR 蛋白、因此無法從 CFTR 調節劑中受益的 CF 患者。我們繼續參與研究的多次劑量遞增部分，預計數據將在 2024 年末或 2025 年初獲得。

Moving to the pain program and suzetrigine, our novel, highly selective NaV1.8 pain signal inhibitor. Suzetrigine offers the compelling combination of both strong safety and strong efficacy with the potential to treat moderate to severe pain across multiple settings of care. In acute pain, suzetrigine has secured Fast Track and Breakthrough Therapy designations, and we were very pleased that the FDA granted us a rolling NDA submission. I'm also pleased to share that multiple modules have already been submitted and we are on track to complete the submission this quarter.

轉向疼痛計劃和 Suzetrigine，我們的新型高選擇性 NaV1.8 疼痛訊號抑制劑。 Suzetrigine 提供了強大的安全性和強大的功效的令人信服的結合，並有可能在多種護理環境中治療中度至重度疼痛。在急性疼痛方面，suzetrigine 已獲得快速通道和突破性治療指定，我們非常高興 FDA 批准我們滾動 NDA 提交。我還很高興地告訴大家，多個模組已經提交，我們預計在本季完成提交。

Consistent with our serial innovation strategy, the next asset in our acute pain pipeline is VX-993. We recently received IND clearance for the intravenous formulation of VX-993 and have already started the Phase I trial. We're also planning a VX-993 oral formulation Phase II study in acute pain, which we expect to initiate later this year. Beyond suzetrigine and VX-993, we continue to innovate in the NaV1.8 space and are also making strong progress preclinically with our NaV1.7 pain signal inhibition program that may be used alone or in combination with suzetrigine or other NaV1.8 inhibitors.

與我們的系列創新策略一致，我們急性疼痛產品線中的下一個資產是 VX-993。我們最近獲得了 VX-993 靜脈製劑的 IND 批准，並已開始 I 期試驗。我們也計劃進行 VX-993 口服製劑治療急性疼痛的 II 期研究，預計今年稍後啟動。除了Suzetrigine 和VX-993 之外，我們還在NaV1.8 領域繼續創新，並且我們的NaV1.7 疼痛信號抑制計劃在臨床前也取得了巨大進展，該計劃可單獨使用或與Suzetrigine 或其他NaV1. 8 抑制劑聯合使用。

In peripheral neuropathic pain or PNP, we are very pleased with the outcomes from the recently completed end of Phase II meeting with the FDA and are excited to begin the pivotal program for suzetrigine in painful diabetic peripheral neuropathy or DPN in the second half of this year. The program will consist of 2 randomized sister studies of approximately 1,000 patients each, with 3 arms in each study: a suzetrigine 70-milligram arm once daily, a placebo arm and a pregabalin or Lyrica arm.

在周邊神經病理性疼痛或 PNP 方面，我們對最近與 FDA 完成的 II 期會議的結果感到非常滿意，並很高興在今年下半年開始 Suzetrigine 治療疼痛性糖尿病週邊神經病變或 DPN 的關鍵項目。該計畫將包括兩項隨機姊妹研究，每項研究約 1,000 名患者，每項研究分為 3 個組別：每日一次 70 毫克的 Suzetrigine 組、安慰劑組以及普瑞巴林或 Lyrica 組。

The efficacy endpoints are based on the change from baseline to week 12. The primary endpoint is the comparison of suzetrigine versus placebo in the weekly average of the daily pain intensity score or NPRS. The first key secondary endpoint will test for non-inferiority of suzetrigine to pregabalin on the same NPRS pain score, and if successful, we will test for superiority.

療效終點是根據基線到第 12 週的變化。第一個關鍵次要終點將在相同的 NPRS 疼痛評分上測試蘇三嗪與普瑞巴林的非劣效性，如果成功，我們將測試其優越性。

And finally, the second key secondary is quality of life measures versus placebo. In order to evaluate the long-term safety and effectiveness of suzetrigine, a subset of patients completing the 12-week study will have the opportunity to roll into a 52-week open-label extension study. Our goal continues to be a broad peripheral neuropathic pain label.

最後，第二個關鍵的次要因素是生活品質指標與安慰劑的比較。為了評估 Suzetrigine 的長期安全性和有效性，完成 12 週研究的部分患者將有機會進入為期 52 週的開放標籤擴展研究。我們的目標仍然是廣泛的周邊神經病理性疼痛標籤。

And in support of this goal, we're also studying suzetrigine in lumbosacral radiculopathy or LSR, a PNP condition for which there are no specifically indicated or approved treatments. LSR accounts for approximately 40% of all PNP patients, and together with DPN, make up more than 60% of the PNP segment. We are continuing to enroll and dose our Phase II study of suzetrigine in LSR, and I'm pleased to share that the study is on track to complete enrollment by the end of this year.

為了支持這一目標，我們也正在研究 Suzetrigine 在腰薦神經根病變或 LSR 中的應用，腰骶神經根病變是一種 PNP 疾病，目前還沒有專門的適應症或批准的治療方法。 LSR 約佔所有 PNP 患者的 40%，與 DPN 一起構成 PNP 部分的 60% 以上。我們正在繼續招募和劑量我們的 LSR 中的 Suzetrigine II 期研究，我很高興地告訴大家，該研究預計將在今年年底完成招募。

Just as we've transformed the treatment of CF, we believe we have the potential to transform the treatment of pain, both acute and neuropathic, and look forward to helping address the unmet need of the tens of millions of Americans suffering with these conditions.

正如我們改變了囊性纖維化的治療方法一樣，我們相信我們有潛力改變急性疼痛和神經性疼痛的治療方法，並期待幫助解決數千萬患有這些疾病的美國人未得到滿足的需求。

Turning now to type 1 diabetes. VX-880 is our stem cell-derived, fully differentiated islet cell therapy for patients with T1D and impaired hypoglycemic awareness who suffer from severe hypoglycemic events. I'm pleased to share that after data review by the independent data monitoring committee, the VX-880 study has resumed. Parts A, B and C of the global 17 patient study are fully enrolled, and we expect to complete dosing soon. We look forward to sharing updated data this June at the American Diabetes Association annual meeting.

現在轉向第 1 型糖尿病。 VX-880 是我們的幹細胞衍生、完全分化的胰島細胞療法，適用於患有嚴重低血糖事件且低血糖意識受損的第 1 型糖尿病患者。我很高興地告訴大家，經過獨立資料監測委員會的資料審查後，VX-880 研究已經恢復。全球 17 名患者研究的 A、B 和 C 部分已全部入組，我們預計很快就能完成給藥。我們期待在今年六月的美國糖尿病協會年會上分享最新數據。

VX-264, the next asset in our T1D program, is our cells plus device program. Using the same VX-880 cells, which have already demonstrated efficacy, VX-264 is designed to eliminate the need for immunosuppression by shielding the cells from the immune system in the proprietary device. This Phase I/II study has completed Part A and Part B is underway. Lastly, our hypoimmune program, which aims to evade the immune system by introducing certain edits into the same VX-880 cells, is yet another approach to avoiding the use of immunosuppresses. This program continues to advance in preclinical development.

VX-264 是我們 T1D 計劃中的下一個資產，是我們的細胞加設備計劃。 VX-264 使用已證明功效的相同 VX-880 細胞，旨在透過在專有設備中保護細胞免受免疫系統的影響，從而消除免疫抑制的需要。此 I/II 期研究已完成 A 部分，B 部分正在進行中。最後，我們的低免疫計畫旨在透過在相同的 VX-880 細胞中引入某些編輯來逃避免疫系統，這是避免使用免疫抑制劑的另一種方法。該計劃在臨床前開發方面繼續取得進展。

I'll conclude with a few comments on povetacicept, the lead asset from our pending acquisition of Alpine Immune Sciences. We are excited about the potential of povetacicept across multiple dimensions, including preclinically, with its high affinity and potency against both APRIL and BAFF pathways in preclinical assays as well as high efficacy in cell and animal models of B cell-driven diseases; clinically, with patient data in IgAN through Phase II that look potentially best-in-class; in proteinuria; in hematuria; GFR; and clinical remission; better drug-like properties with direct patient benefit, including once every 4-week dosing, subcutaneously, with low injection volume; a good safety and tolerability profile; the broadest development plan in the field; and a robust IP portfolio.

最後，我將對 povetacicept 進行一些評論，povetacicept 是我們即將收購的 Alpine Immune Sciences 的主要資產。我們對 povetacicept 在多個方面的潛力感到興奮，包括臨床前，其在臨床前檢測中對 APRIL 和 BAFF 通路的高親和力和效力，以及在 B 細胞驅動疾病的細胞和動物模型中的高功效；臨床上，IgAN 至 II 期的患者數據看起來可能是同類最佳的；蛋白尿；血尿；腎小球濾過率；和臨床緩解；更好的藥物特性，可直接使患者受益，包括每 4 週一次、皮下注射、低注射量給藥；良好的安全性和耐受性；該領域最廣泛的發展計劃；以及強大的智慧財產權組合。

Important upcoming pove milestones in the second half of this year include initiation of the Phase III study in IgAN, and readouts from the ongoing RUBY-3 and RUBY-4 basket studies in autoimmune renal diseases and cytopenias, respectively.

今年下半年即將到來的重要 POVE 里程碑包括啟動 IgAN III 期研究，以及正在進行的自體免疫性腎病變和血球減少症的 RUBY-3 和 RUBY-4 籃子研究的結果。

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

這樣，我會將其交給斯圖爾特進行商業概述。

Thanks, Reshma. I'll first discuss CF, and then as we're entering a new era of commercial diversification, provide some highlights of the ongoing CASGEVY launch and the outlook for suzetrigine in acute pain. As Reshma noted, we once again delivered strong results in CF as we continue to grow the number of eligible patients receiving our CFTR modulators.

謝謝，瑞詩瑪。我將首先討論 CF，然後在我們進入商業多元化的新時代時，提供正在進行的 CASGEVY 上市的一些亮點以及 Suzetrigine 在急性疼痛方面的前景。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 CF 方面再次取得了強勁的成果。

First quarter year-over-year U.S. growth was driven by continued strong performance of TRIKAFTA, including in patients ages 2 to 5 years old following the approval in this patient population in April of last year. Outside the U.S., we also saw growth this quarter, driven by the rollout of KAFTRIO in the EU in patients ages 2 to 5 following approval in this age group in November 2023, and we will continue to drive access and uptake in more EU countries over the course of the year.

美國第一季的同比增長是由 TRIKAFTA 持續強勁的表現推動的，其中包括去年 4 月在該患者群體中獲得批准後的 2 至 5 歲患者。在美國以外，本季度我們也看到了增長，這是由於 KAFTRIO 於 2023 年 11 月在歐盟批准用於 2 至 5 歲年齡組的患者，之後我們將繼續推動更多歐盟國家的使用和採用這一年的歷程。

Our outlook in CF is bright in the short, medium and long term. We will drive growth in the near term by reaching more eligible patients, including younger age groups and additional geographies. For example, we recently received EU approval of KALYDECO in patients between the ages of 1 month up to 4 months old. We also expect regulatory approvals for additional rare genotypes for KAFTRIO in the EU and TRIKAFTA in the U.S. and Canada later this year.

從短期、中期和長期來看，我們對 CF 的前景都是光明的。我們將透過接觸更多符合資格的患者（包括年輕族群和其他地區）來推動近期成長。例如，我們最近獲得了歐盟批准 KALYDECO 用於 1 個月至 4 個月大的患者。我們也預計今年稍後歐盟的 KAFTRIO 以及美國和加拿大的 TRIKAFTA 的其他稀有基因型將獲得監管機構的批准。

And Brazil is a good example of a new geography. Up to now, some patients in Brazil have been able to benefit from our CFTR modulators through named patient sales. We recently secured government reimbursement for TRIKAFTA in ages 6 plus and are in the process of launching TRIKAFTA for all eligible patients there. We will then look to drive further CF growth over the medium term with the vanzacaftor triple combination launch, as many existing TRIKAFTA patients may seek to achieve even greater levels of CFTR function with the added convenience of once-daily dosing. And there are also more than 6,000 patients who have discontinued one of our current CFTR modulators, who may be interested in a new treatment option.

巴西是新地理的一個很好的例子。到目前為止，巴西的一些患者已經能夠透過指定患者銷售從我們的 CFTR 調節劑中受益。我們最近獲得了政府對 6 歲以上 TRIKAFTA 的報銷，並且正在為所有符合條件的患者推出 TRIKAFTA。然後，我們將尋求在中期內透過 vanzacaftor 三聯組合的推出推動 CF 的進一步增長，因為許多現有的 TRIKAFTA 患者可能會尋求透過每日一次給藥的便利性來實現更高水平的 CFTR 功能。還有超過 6,000 名患者已停用我們目前的一種 CFTR 調節劑，他們可能對新的治療選擇感興趣。

Furthermore, there are 31 additional rare mutations not previously responsive to our other CFTR modulators that are responsive to the vanzacaftor triple. Our launch preparations are well underway, including pre-approval information exchange with payers, and we are both encouraged by our interactions to date and excited by the opportunity to launch our fifth medicine in CF. Longer term, we expect continued growth in CF from our mRNA program, VX-522, for the more than 5,000 people with CF who do not respond to CFTR modulators.

此外，還有 31 個額外的罕見突變，以前對我們的其他 CFTR 調節劑沒有反應，但對 vanzacaftor 三聯反應。我們的上市準備工作正在順利進行，包括與付款人交換預先批准信息，我們對迄今為止的互動感到鼓舞，並對有機會在 CF 中推出我們的第五種藥物感到興奮。從長遠來看，我們預計我們的 mRNA 計畫 VX-522 將使 5,000 多名對 CFTR 調節劑沒有反應的 CF 患者繼續成長。

Now turning to CASGEVY and our launches in sickle cell disease and beta thalassemia. We are making strong progress with ATC activation, physician and patient engagement and payer conversations. Enthusiasm from stakeholders is high in all regions, and our teams are working to translate this historic scientific achievement into meaningful patient benefit in the real world.

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。我們在 ATC 啟動、醫生和患者參與以及付款人對話方面取得了巨大進展。所有地區的利害關係人熱情高漲，我們的團隊正在努力將這一歷史性的科學成就轉化為現實世界中有意義的病患利益。

Let me provide some insights on the launch with 2 key metrics we are sharing externally as important markers of our early launch progress: the number of activated authorized treatment centers or ATCs, and patient cell collections. Recall that Vertex will recognize revenue for CASGEVY near the end of the patient journey at infusion. Starting with ATC activation. You may recall we are prioritizing approximately 75 ATCs globally and already had 9 ATCs activated at launch, even ahead of knowing the final label or pricing for CASGEVY.

讓我提供一些關於此次啟動的見解，我們正在對外分享兩個關鍵指標，作為我們早期啟動進度的重要標誌：激活的授權治療中心或 ATC 的數量，以及患者細胞收集。回想一下，Vertex 將在患者輸液旅程即將結束時確認 CASGEVY 的收入。從 ATC 啟動開始。您可能還記得，我們​​正在全球範圍內優先考慮大約 75 個 ATC，並且在發佈時已經啟動了 9 個 ATC，甚至在知道 CASGEVY 的最終標籤或定價之前也是如此。

We are pleased with our progress as we now have more than 25 activated centers, including centers in all regions where CASGEVY is approved. Even more important than the number of ATCs activated is patient initiations and cell collections. Many patients have begun the treatment journey, and as of mid-April, 5 patients already had cells collected. This is excellent progress given the short time frame since approval and the complexity and length of the patient journey. These cells collections have occurred across all regions where CASGEVY is approved: the U.S., Europe and the Middle East.

我們對我們的進展感到滿意，因為我們現在擁有超過 25 個已啟動的中心，包括 CASGEVY 獲得批准的所有地區的中心。比活化的 ATC 數量更重要的是患者啟動和細胞收集。許多患者已經開始了治療之旅，截至4月中旬，已有5名患者接受了細胞採集。考慮到批准以來的時間很短以及患者旅程的複雜性和長度，這是一個非常好的進展。這些細胞採集發生在 CASGEVY 核准的所有地區：美國、歐洲和中東。

We also continue to make great progress with payers, who recognize the transformative clinical benefits of CASGEVY and are moving quickly to provide rapid and equitable access. In the U.S. commercial market, we have contracts and/or published policies in place for over 200 million lives or nearly 65% of total lives. In the government Medicaid sector, we have policies in place or active contract negotiations ongoing with 18 states. And in the meantime, all states have confirmed their intent to provide case-by-case coverage.

我們也繼續與付款人取得巨大進展，他們認識到 CASGEVY 的變革性臨床效益，並正在迅速採取行動，提供快速、公平的使用機會。在美國商業市場，我們為超過 2 億人或近 65% 的人制定了合約和/或發布了保單。在政府醫療補助部門，我們已製定政策或正在與 18 個州進行積極的合約談判。同時，所有州都已確認有意提供個案承保。

Outside the U.S., we are also making progress with reimbursement and access, either through formal reimbursement agreements or early access programs. In Europe, we see strong traction in France, with a reimbursed early access program in TDT. We're particularly pleased with our progress in the Middle East, which is a new region for Vertex and especially important for CASGEVY given the high prevalence of sickle cell disease in particular, and the government's clear focus on elevating the health of their citizens.

在美國以外，我們也在透過正式報銷協議或早期訪問計劃在報銷和訪問方面取得進展。在歐洲，我們在法國看到了強大的吸引力，在 TDT 中推出了可報銷的早期訪問計劃。我們對我們在中東的進展感到特別滿意，該地區對於Vertex 來說是一個新地區，對於CASGEVY 來說尤其重要，因為鐮狀細胞病的患病率特別高，而且政府明確致力於提高公民的健康。

Since receiving regulatory approvals from KSA and Bahrain, we have worked with local health care authorities and refined our epidemiology estimates for the region. Our work indicates that the eligible 12-plus sickle cell disease and beta thalassemia population in KSA and Bahrain that we could serve is in excess of 23,000 patients, a potentially larger opportunity than even the U.S. These regions have the infrastructure to administer medicines like CASGEVY, given the prevalence of the diseases and relatively high volume of allogeneic stem cell transplants performed annually.

自從獲得沙烏地阿拉伯和巴林的監管批准以來，我們一直與當地衛生保健當局合作，並完善了對該地區的流行病學估計。我們的工作表明，我們可以為沙烏地阿拉伯和巴林超過23,000 名符合條件的鐮狀細胞疾病和β 地中海貧血患者提供服務，這可能比美國有更大的機會。 ，鑑於這些疾病的流行以及每年進行的同種異體幹細胞移植的數量相對較多。

And importantly, we have already secured reimbursement agreements in KSA and Bahrain, allowing certain eligible patients to access CASGEVY for both sickle cell disease and transfusion-dependent thalassemia. In addition to having activated ATCs and collected cells from our first patients in the Middle East, we continue to work with local health care professionals to increase the number of ATCs and expand patient access in the region.

重要的是，我們已經在沙烏地阿拉伯和巴林達成了報銷協議，允許某些符合條件的患者獲得 CASGEVY 治療鐮狀細胞疾病和輸血依賴性地中海貧血。除了啟動 ATC 並從中東第一批患者身上收集細胞外，我們還繼續與當地醫療保健專業人員合作，增加 ATC 的數量並擴大該地區的患者就診範圍。

Shifting now to suzetrigine. We believe this highly selective NaV1.8 pain signal inhibitor has the potential to provide a transformative treatment option for the millions of patients suffering from acute and peripheral neuropathic pain. This quarter, I'm going to limit my commercial comments to the opportunity in acute pain. Throughout its clinical trials to date, suzetrigine has shown a compelling combination of efficacy and safety, with strong potential to be used across a range of moderate to severe acute pain conditions, both surgical and nonsurgical, and across a range of settings. This profile will ideally address the clear unmet need among both patients and physicians: effective pain relief with a favorable safety and tolerability profile.

現在轉向suzetrigine。我們相信這種高度選擇性的 NaV1.8 疼痛訊號抑制劑有潛力為數百萬患有急性和周邊神經性疼痛的患者提供變革性的治療選擇。本季度，我將把我的商業評論僅限於急性疼痛中的機會。在迄今為止的整個臨床試驗中，suzetrigine 已顯示出令人信服的療效和安全性組合，具有強大的潛力，可用於治療各種中度至重度急性疼痛（包括手術和非手術）以及各種環境。該概況將理想地解決患者和醫生之間明顯未滿足的需求：有效緩解疼痛，並具有良好的安全性和耐受性。

On prior investor webcasts, we provided details on this opportunity, including the magnitude: approximately 80 million patients are prescribed a medicine for moderate-to-severe acute pain each year in the U.S.; and the high concentration, with approximately 2/3 of patients being treated in the institutional setting. There is further concentration within that setting in approximately 2,000 institutions that roll up to around 150 IDNs. Accordingly, they can be served with a specialty commercial infrastructure.

在先前的投資者網路廣播中，我們提供了有關此機會的詳細信息，包括其規模：在美國，每年約有 8000 萬患者接受治療中度至重度急性疼痛的藥物；集中度高，約 2/3 的患者在機構環境中接受治療。該環境進一步集中於約 2,000 家機構，總計約 150 個 IDN。因此，可以為他們提供專業的商業基礎設施。

We have also detailed the mix of settings for their over 1 billion calendar days of acute pain treatment: 15% are prescribed and dispensed in an institutional setting, 35% are prescribed at discharge and 50% are prescribed in physicians' offices. This quarter, I'll provide you with some insights on our go-to-market strategy and an update on the legislative and payer landscape. We are focused on the institutional setting, given these approximately 2,000 institutions account for 50% of acute pain prescriptions.

我們還詳細介紹了他們超過 10 億日曆日的急性疼痛治療​​的設定組合：15% 在機構環境中開處方和分發，35% 在出院時開處方，50% 在醫生辦公室開處方。本季度，我將為您提供有關我們的市場進入策略的一些見解以及有關立法和付款人情況的最新資訊。我們專注於機構環境，因為這大約 2,000 個機構佔急性疼痛處方的 50%。

Extensive market research has also helped us identify an initial set of specific acute pain conditions and procedure types with high clinical fit, such as high-volume surgical procedures, pain conditions that typically require prescription pain medicines at discharge, or where we can seek to replace or significantly reduce opioid utilization. And the related physician specialties that are likely to adopt and champion suzetrigine. The key health care professionals we will be targeting include orthopedic, general and plastic surgeons, emergency department physicians, anesthesiologists and pain medicine specialists.

廣泛的市場研究也幫助我們確定了一組初步的特定急性疼痛狀況和具有高度臨床適應性的手術類型，例如大容量外科手術、出院時通常需要處方止痛藥的疼痛狀況，或者我們可以尋求替代的地方或顯著減少阿片類藥物的使用。以及可能採用及支持蘇三嗪的相關醫師專業。我們針對的主要醫療保健專業人員包括骨科醫生、一般外科醫生和整形外科醫生、急診科醫生、麻醉師和疼痛醫學專家。

Given the dynamics for new medicines to be approved for use in institutions, we expect the earliest uptake of suzetrigine will occur at discharge. Recall this discharge segment represents roughly 35% of the approximately 1.1 billion calendar days of acute pain treatment in the U.S. each year. The average prescription length in this setting is approximately 2 weeks. Treatment in this setting commonly includes opioids, where prescription length is shorter, 4 to 5 days, due to side effect profile, addiction concerns and prescribing limits at the state and IDN and hospital level.

鑑於批准在機構中使用的新藥的動態，我們預計最早服用舒三嗪將發生在出院時。回想一下，這一出院部分約占美國每年約 11 億個日曆日的急性疼痛治療​​時間的 35%。這種情況下的平均處方長度約為 2 週。這種情況下的治療通常包括鴉片類藥物，由於副作用、成癮問題以及州、IDN 和醫院層面的處方限制，處方長度較短，為 4 至 5 天。

We are already engaging with key decision-makers across the formulary and access landscape, including pharmacists, PBMs, payers, IDNs and GPOs. We expect these stakeholders to make formulary and coverage decisions throughout the first year of the launch, and thus plan to engage in contracting discussions in the second half of this year ahead of launch to support the potential for accelerated formulary adoption.

我們已經與處方和准入領域的關鍵決策者進行了接觸，包括藥劑師、PBM、付款人、IDN 和 GPO。我們希望這些利害關係人在推出的第一年做出處方和覆蓋範圍決定，因此計劃在今年下半年推出之前進行合約討論，以支持加速處方採用的潛力。

We've also made great progress in the build-out of our commercial team. Our field leadership team are now on board and fully trained, and having [gated] the hiring of the field force until after the Phase III data, we are now finalizing the hiring of 150 new customer-facing colleagues.

我們在商務團隊的建立方面也取得了巨大進展。我們的現場領導團隊現已入職並接受了全面培訓，並且在第三階段數據發布之前[限制]了現場人員的招聘，我們現在正在最終確定 150 名面向客戶的新同事的招聘。

Finally, we know the significance of policy in the world of pain treatment, with important legislation like the NOPAIN Act already on track for implementation in 2025 and bills like the Alternatives to PAIN Act recently introduced. Our long-standing efforts continue to help shape state and federal policy initiatives to: one, encourage consideration and use of non-opioid alternatives; and two, remove financial barriers to choosing a branded non-opioid. Overall, we plan for a high science, digitally-enabled commercialization approach with a strong focus on population health decision makers. In addition, both patient advocacy and public policy efforts complement and supplement our commercial activities.

最後，我們知道政策在疼痛治療領域的重要性，《NOPAIN 法案》等重要立法已有望於 2025 年實施，而《PAIN 替代法案》等法案最近推出。我們的長期努力繼續幫助制定州和聯邦政策舉措，以：第一，鼓勵考慮和使用非阿片類藥物替代品；第二，消除選擇品牌非鴉片類藥物的經濟障礙。總體而言，我們計劃採用高度科學、數位化的商業化方法，並專注於人口健康決策者。此外，病患倡議和公共政策努力都補充和補充了我們的商業活動。

In conclusion, it's an exciting time to be at Vertex. We continue to treat more CF patients around the world and are well advanced in planning for the launch of the vanzacaftor triple combination. We are entering a new era of commercial diversification with the launch of CASGEVY in the U.S., Europe and the Middle East, and our launch preparations for suzetrigine in acute pain are well underway as we seek to fundamentally redefine the treatment of pain and drive further diversified revenue growth.

總之，在 Vertex 是一個激動人心的時刻。我們繼續在世界各地治療更多的囊性纖維化患者，並在計劃推出 vanzacaftor 三重療法方面取得了進展。隨著CASGEVY 在美國、歐洲和中東的上市，我們正在進入商業多元化的新時代，而用於急性疼痛的舒三嗪的上市準備工作也在順利進行，我們力求從根本上重新定義疼痛治療並推動進一步多元化收入成長。

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 start to the year demonstrates once again our consistent strong performance and attractive growth profile. First quarter 2024 revenue increased 13% year-over-year to $2.7 billion, with solid growth of 8% in the U.S. and 21% outside the U.S. The drivers of this strong start were in line with our expectations, with some outperformance due to channel inventory phasing in select international markets.

謝謝，斯圖爾特。祥峰今年的出色開局再次證明了我們一貫的強勁業績和有吸引力的成長前景。 2024 年第一季營收年增13%，達到27 億美元，其中美國地區穩定成長8%，美國以外地區成長21%。通路選定國際市場的庫存分階段。

First quarter U.S. growth was driven by continued strong performance of TRIKAFTA, including in patients ages 2 to 5 following the approval in this patient population in April of last year, partially offset by the typical pattern of seasonally higher gross to net in the first quarter. Outside the U.S., growth was also driven by KAFTRIO 2 to 5 launch, and a benefit from channel inventory phasing is expected to reverse in subsequent quarters, similar to the dynamics we saw in the first half of 2023.

美國第一季的成長是由TRIKAFTA 的持續強勁表現推動的，其中包括去年4 月批准該患者群體後的2 至5 歲患者，但部分被第一季毛額與淨額季節性較高的典型模式所抵消。在美國以外，KAFTRIO 2 至 5 的推出也推動了成長，通路庫存分階段帶來的好處預計將在隨後的幾個季度逆轉，類似於我們在 2023 年上半年看到的動態。

First quarter 2024 combined non-GAAP R&D, acquired IPR&D and SG&A expenses were $1 billion compared to $1.2 billion in the first quarter of 2023. Included in Q1 '24 results are $77 million of acquired IPR&D charges compared to $347 million of such charges in the first quarter of 2023.

2024 年第一季度，非GAAP 研發、收購的IPR&D 和SG&A 費用合計為10 億美元，而2023 年第一季為12 億美元。 2023 年第一季此類費用為3.47 億美元。

Non-GAAP R&D expenses in Q1 '24 were relatively flat year-over-year and reflect growing investment in the advancement of our broad earlier-stage R&D portfolio offset by reduced costs from the recent successful completion of multiple late-stage clinical trials for CASGEVY, vanzacaftor and suzetrigine as well as the associated transition of certain costs from R&D to COGS and inventory.

24 年第一季的非公認會計準則研發費用同比相對持平，反映了對我們廣泛的早期研發組合的推進的投資不斷增加，但最近成功完成CASGEVY 的多項後期臨床試驗所帶來的成本降低所抵銷、vanzacaftor 和 suzetrigine 以及某些成本從研發到銷貨成本和庫存的相關轉變。

The increase in non-GAAP SG&A costs versus Q1 '23 includes investment in the commercial organization and launch activities for CASGEVY and acute pain. We anticipate the quarterly non-GAAP R&D and SG&A expenses will increase over the remainder of 2024 as we advance inaxaplin into Phase III development in AMKD, initiate the suzetrigine Phase III program in painful diabetic peripheral neuropathy and continue to invest in preparation for upcoming potential new commercial launches, including the further build-out of our suzetrigine team.

與 23 年第一季相比，非 GAAP SG&A 成本的增加包括對商業組織的投資以及 CASGEVY 和急性疼痛的啟動活動。我們預計，隨著我們將inaxaplin 推進到AMKD 的III 期開發、啟動用於治療疼痛性糖尿病周圍神經病變的Suzetrigine III 期項目，並繼續投資為即將推出的潛在新產品做準備，我們預計2024 年剩餘時間內的季度非GAAP 研發和SG&A 費用將增加。

First quarter 2024 non-GAAP operating income was $1.3 billion, a 48% increase compared to $902 million in non-GAAP operating income in the first quarter of 2023. First quarter 2024 non-GAAP effective tax rate of 17.4% compares to 21.3% in Q1 '23 and includes a benefit from a discrete adjustment to Vertex' income tax reserves. First quarter 2024 non-GAAP earnings per share were $4.76, including benefits from revenue and expense phasing as well as a lower tax rate, compared to $3.05 in the first quarter of 2023.

2024 年第一季非GAAP 營業收入為13 億美元，較2023 年第一季非GAAP 營業收入9.02 億美元成長48%。非GAAP 有效稅率為21.3%。 2024 年第一季非公認會計原則每股收益為 4.76 美元，包括分階段收入和支出以及較低稅率帶來的收益，而 2023 年第一季為 3.05 美元。

We ended the quarter with $14.6 billion in cash and investments. We will use a portion of this cash on hand to fund the $4.9 billion acquisition of Alpine Immune Sciences, which is expected to close this quarter, subject to certain customary conditions. Alpine is a prime example of our priority for capital deployment: to invest in innovation, including external innovation via business development.

本季結束時，我們擁有 146 億美元的現金和投資。我們將使用手頭現金的一部分來資助以 49 億美元收購 Alpine Immune Sciences，該收購預計將於本季度完成，但須符合某些慣例條件。阿爾派是我們資本部署優先事項的典型例子：投資於創新，包括透過業務發展進行外部創新。

We see multibillion-dollar potential for Phase III-ready povetacicept given its transformative and best-in-class potential in IgAN, a disease area with high unmet need. We also look forward to exploring pove's full potential in other serious diseases. Additionally, we deployed over $140 million of cash in the first quarter to repurchase 336,000 shares.

鑑於 Povetacicept 在 IgAN（需求未滿足的疾病領域）的變革性和同類最佳潛力，我們認為處於 III 期階段的 povetacicept 具有數十億美元的潛力。我們也期待探索 pove 在其他嚴重疾病的全部潛力。此外，我們在第一季部署了超過 1.4 億美元現金，回購了 336,000 股股票。

Now switching to guidance. There is no change to our 2024 total product revenue guidance range of $10.55 billion to $10.75 billion, representing revenue growth of 8% at the midpoint at current exchange rates. We have high visibility into this revenue outlook. We expect continued growth in CF as we continue to reach more patients, including younger ones in core markets and select other countries as well as contribution in the second half of the year from the commercial launch of CASGEVY in approved indications and geographies.

現在切換到指導。我們的 2024 年產品總收入指引範圍維持不變，為 105.5 億美元至 107.5 億美元，以目前匯率中位數計算，營收成長 8%。我們對這項收入前景有很高的了解。我們預計，隨著我們繼續涵蓋更多患者，包括核心市場和其他選定國家的年輕患者，以及下半年 CASGEVY 在已批准的適應症和地區的商業推出，CF 業務將持續成長。

For total Vertex operating expenses, we continue to project $4.3 billion to $4.4 billion in full year 2024 combined non-GAAP SG&A, R&D and acquired IPR&D. This operating expense range continues to include approximately $125 million in currently anticipated IPR&D charges.

對於 Vertex 總營運支出，我們繼續預期 2024 年全年的非 GAAP SG&A、研發和收購的 IPR&D 總計為 43 億至 44 億美元。該營運費用範圍繼續包括目前預計的約 1.25 億美元的智慧財產權與開發費用。

Upon the close of the Alpine acquisition, we expect Alpine's projected non-GAAP operating expenses for the remainder of 2024 to be absorbed within this guidance range, but note the potential impacts of transaction accounting, including any potential acquired IPR&D charges, will be determined at the time of closing. There's also no change to our full year 2024 non-GAAP effective tax rate guidance range of 20% to 21%.

阿爾派收購結束後，我們預計阿爾派2024 年剩餘時間的預計非GAAP 營運費用將吸收在此指導範圍內，但請注意，交易會計的潛在影響，包括任何潛在收購的知識產權與開發費用，將在以下時間確定：關閉的時間。我們 2024 年全年非 GAAP 有效稅率指引範圍 20% 至 21% 也沒有變動。

In closing, Vertex posted excellent results yet again to start off the year as we delivered strong revenue growth, regulatory approvals and commercial launches. We also strengthened our capabilities in preparation for additional near-term launches, progressed our mid- and earlier-stage pipeline and entered the clinic in our 10th disease area of ADPKD.

最後，福泰 (Vertex) 在年初再次取得了優異的業績，我們實現了強勁的收入成長、監管批准和商業發布。我們也加強了為近期其他上市做準備的能力，推進了我們的中早期管道，並進入了 ADPKD 第 10 個疾病領域的臨床。

Importantly, we also announced the anticipated acquisition of Alpine Immune Sciences, a compelling fit with Vertex' strategy. Post close, we aim to leverage Vertex' clinical, regulatory and commercial capabilities to accelerate development and commercialization of pove. We are targeting approval in IgAN in 2027 and contribution to Vertex' revenue growth and diversification beginning in 2028, leveraging a specialty market approach with attractive margins.

重要的是，我們也宣布了預期收購 Alpine Immune Sciences，這與 Vertex 的策略非常契合。交易完成後，我們的目標是利用 Vertex 的臨床、監管和商業能力來加速 pove 的開發和商業化。我們的目標是在 2027 年獲得 IgAN 的批准，並從 2028 年開始利用具有有吸引力利潤的專業市場方法為 Vertex 的收入成長和多元化做出貢獻。

As we move through 2024, we anticipate further important milestones as detailed on Slide 18 to mark our continued progress in multiple disease areas. Please note that this pipeline slide will not reflect programs from Alpine Immune Sciences until post transaction close.

隨著 2024 年的到來，我們預計將出現更多重要的里程碑，如幻燈片 18 所示，以標誌著我們在多個疾病領域的持續進展。請注意，在交易結束之前，此管道幻燈片不會反映 Alpine Immune Sciences 的項目。

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

我們期待向您通報未來通話的最新進展，我現在請 Susie 開始問答環節。

(Operator Instructions) And the first question will come from Geoff Meacham with Bank of America.

（操作員說明）第一個問題將由美國銀行的 Geoff Meacham 提出。

I had a few on the filings. So the first question is for vanza. Do you think you guys will get a claim for the sweat chloride benefit? It seems like, obviously, you'll have the Phase III data on the label. I'm just curious what you can do from a regulatory perspective to kind of elevate the sweat chloride benefit. So that's the first question.

我在檔案上有一些。所以第一個問題是針對vanza的。您認為你們會獲得汗液氯化物益處的索賠嗎？顯然，你會在標籤上看到第三階段的數據。我只是好奇從監管角度來看你可以做些什麼來提高汗液氯化物的益處。這是第一個問題。

The second one, kind of the same question for 548 in acute pain. Do you think that -- are you guys going to push to make a claim for -- as an option to opioids or to Lyrica? I wondered if the regulatory climate can drive that.

第二個問題與 548 的急性疼痛問題類似。你們是否認為——你們會推動提出主張——作為阿片類藥物或 Lyrica 的選擇？我想知道監管環境是否可以推動這一點。

Yes. Geoff, this is Reshma. Let me take those questions. On the vanzacaftor triple, if you go back and look at all of the CFTR modulated labels, you'll see that we always have sweat chloride in the labels, and they are reflected because it is indeed a pharmacodynamic or PD marker. So I fully expect that the sweat chloride data from the vanza triple studies will be reflected in the label. Obviously, we are just at the point of having submitted the filing, so we're not at the point of label negotiations yet. But if history serves as a guide, I expect the sweat chloride will absolutely be in the label.

是的。傑夫，這是瑞詩瑪。讓我回答這些問題。在 vanzacaftor 三元組上，如果您返回並查看所有 CFTR 調製標籤，您會發現標籤中始終含有汗液氯化物，並且它們會反映，因為它確實是藥效學或 PD 標記物。因此，我完全希望 Vanza 三重研究的汗液氯化物數據能夠反映在標籤中。顯然，我們剛剛提交申請，所以我們還沒有到標籤談判的階段。但如果以史為鑑，我預期汗水氯化物絕對會出現在標籤上。

On VX-548, Geoff, I think your question was about the DPN, diabetic peripheral neuropathy, study, but let me broaden the question about 548 and acute pain because that's the filing that we have already initiated the rolling submission. We've already submitted a few of the modules, and we expect, as I said in my prepared remarks, to complete the filing this quarter. We are submitting all of the data that we generated in acute pain, and the same will be true when it comes to the diabetic peripheral neuropathy data.

關於 VX-548，Geoff，我認為您的問題是關於 DPN（糖尿病周圍神經病變）研究，但讓我擴大關於 548 和急性疼痛的問題，因為這是我們已經啟動滾動提交的文件。我們已經提交了一些模組，正如我在準備好的演講中所說，我們預計將在本季度完成提交。我們正在提交我們在急性疼痛中產生的所有數據，對於糖尿病週邊神經病變數據也是如此。

And insofar as the acute pain Phase III results are versus placebo as the primary end point but there are data that have the opioid arm in there, I expect that it will be a discussion with the regulators about how exactly they want to display it. We are not at the point for the acute pain studies to have label negotiations and quite a bit far away from it for the DPN studies, which are just starting Phase III. But I will say that the reason we have a pregabalin arm in the Phase III DPN study is exactly for that reason, for us to be able to share the data with prescribers.

就急性疼痛 III 期結果與安慰劑相比作為主要終點而言，但有數據包含阿片類藥物，我預計這將與監管機構討論他們想要如何準確地顯示它。對於急性疼痛研究來說，我們還沒有到進行標籤談判的階段，對於剛開始 III 期的 DPN 研究來說，距離它還很遠。但我要說的是，我們在 III 期 DPN 研究中使用普瑞巴林組的原因正是出於這個原因，以便我們能夠與處方醫生分享數據。

Reshma, just a quick follow-up to that. Just on the alternative to opioids. I mean, obviously, you don't know yet when it comes to the label, but do you think you'll need that to help with Medicare kind of reimbursement?

Reshma，只是對此的快速跟進。只是阿片類藥物的替代品。我的意思是，顯然，您還不知道該標籤是什麼時候，但您認為您需要它來幫助獲得醫療保險類型的報銷嗎？

Yes. So on the acute pain side, Geoff, I think that the most important data are going to be the primary endpoint data, and I'll ask Stuart to comment on that in a minute. And with regard to securing reimbursement and ensuring that there are no barriers to prescribing a non-opioid, we see that as a very important place for policy. Stuart?

是的。因此，在急性疼痛方面，傑夫，我認為最重要的數據將是主要終點數據，我將請史都華立即對此發表評論。關於確保報銷並確保開出非阿片類藥物沒有障礙，我們認為這是一個非常重要的政策。史都華？

Yes. Thanks, Reshma. So first thing I would say, Geoff, is remember, we are seeking a broad moderate to severe acute pain label so that the product could be used, if the physician decides and the patient wants to, for any type of acute pain, and so we're not really looking for a label that's looking to niches or pre-position us relative to other agents that are out there. We want physicians to have the broadest possible ability to use the product in the patients they see fit.

是的。謝謝，瑞詩瑪。所以，傑夫，我要說的第一件事是記住，我們正在尋求一個廣泛的中度至重度急性疼痛標籤，以便如果醫生決定並且患者願意，該產品可以用於任何類型的急性疼痛，等等我們並不是真的在尋找一個尋找利基市場或相對於其他代理商預先定位我們的品牌。我們希望醫生擁有盡可能廣泛的能力，在他們認為合適的患者身上使用該產品。

As Reshma said, the primary endpoint, which talks to the really strong efficacy we see in moderate-to-severe acute pain, is clearly very important as is all the additional safety and tolerability data that we have to support VX-548 in combination with the fact that given its mechanism, it doesn't have addictive potential. So we're really looking at the full range of efficacy and safety, which I think is going to be the most important thing that's going to allow physicians to decide who they want to prescribe the product for.

正如 Reshma 所說，主要終點，即我們在中度至重度急性疼痛中看到的真正強大的療效，顯然非常重要，我們必須支持 VX-548 與事實上，鑑於其機制，它不具有成癮潛力。因此，我們真正關注的是全方位的功效和安全性，我認為這將是最重要的事情，可以讓醫生決定為誰開設該產品。

Your next question will come from Jessica Fye with JPMorgan.

您的下一個問題將來自摩根大通的傑西卡·菲伊。

I'm curious. For your various NaV1.8 and 1.7 programs, would you consider advancing maybe another molecule for musculoskeletal pain, perhaps engaging a commercial partner to the extent it's not a Vertexian sales detail? Just curious if you kind of have any thoughts about that, so as to like not leave potential value on the table.

我很好奇。對於您的各種 NaV1.8 和 1.7 項目，您是否會考慮推進另一種治療肌肉骨骼疼痛的分子，也許在不涉及 Vertexian 銷售細節的情況下與商業合作夥伴合作？只是好奇您是否對此有任何想法，以免留下潛在的價值。

Yes. Thanks for that question, Jess. So just to set the stage, we see 3 distinct areas in pain: acute pain, neuropathic pain and then everything else. And in everything else, I would add, musculoskeletal pain. It's the kind of osteoarthritis kind of pain. We fully intend to serve all patients, and I fully do expect that our NaV1.8, and when the time is right, the NaV1.7 or the NaV1.7, 1.8 combinations, our pain assets, will serve patients with musculoskeletal pain.

是的。謝謝你提出這個問題，傑西。因此，為了做好準備，我們看到了 3 個不同的疼痛領域：急性疼痛、神經性疼痛以及其他所有疼痛。在其他方面，我想補充一點，肌肉骨骼疼痛。這是一種骨關節炎的疼痛。我們完全打算為所有患者提供服務，並且我完全期望我們的 NaV1.8，以及在時機成熟時，NaV1.7 或 NaV1.7、1.8 組合（我們的疼痛資產）將為肌肉骨骼疼痛患者提供服務。

And I say that because, as you know, the predecessor molecule to VX-548, VX-150, already demonstrated that potential. But we want to go one step at a time here. So first, we're going to do acute and neuropathic pain, and we see the research development and commercialization is completely Vertexian. And then for the musculoskeletal pain, whether that's with VX-548, the next-in-class medicine, VX-993, or the ones that come after that, again, either NaV1.8 or NaV1.7 alone or in combination, any of those for musculoskeletal pain.

我這麼說是因為，如你所知，VX-548 的前身 VX-150 已經證明了這種潛力。但我們想在這裡一步一步地走下去。首先，我們將研究急性和神經性疼痛，我們看到研究開發和商業化完全是 Vertexian 的。然後對於肌肉骨骼疼痛，無論是使用 VX-548、下一代藥物 VX-993，還是之後的藥物，單獨或組合使用 NaV1.8 或 NaV1.7，任何藥物那些用於肌肉骨骼疼痛的藥物。

We will get them to patients, but we will not be commercializing that ourselves because it is a primary care sell. But we do absolutely see value there, and we see a need to help those patients. But one step at a time. First, neuropathic and acute pain, and that, we will do ourselves.

我們會將它們提供給患者，但我們自己不會將其商業化，因為這是初級保健銷售。但我們確實看到了那裡的價值，並且我們看到了幫助這些患者的必要性。但一步一步來。首先，神經性疼痛和急性疼痛，我們會自己解決。

Your next question will come from Salveen Richter with Goldman Sachs.

您的下一個問題將來自高盛的 Salveen Richter。

Two part here on the acute pain program. With regard to engaging with key decision makers, can you help us to understand the importance of the hospital administrators who are taking into account the legislative tailwinds versus the physician treaters here in the specific verticals that you cited and how they might make -- or work together here to make a decision?

這裡有兩個部分是關於急性疼痛計劃的。關於與關鍵決策者的互動，您能否幫助我們了解在您引用的特定垂直領域中考慮立法順風的醫院管理人員與醫生治療人員的重要性以及他們可能如何工作或工作一起在這裡做出決定？

And my second question is what hospitals really need to make an argument for using it in lieu of opioids, and whether outcomes data is required, be it reduction in recovery room time or lower usage of opioids or rates of addictions being reported?

我的第二個問題是，醫院真正需要提出什麼論點來使用它來代替阿片類藥物，以及是否需要結果數據，是減少恢復室時間還是減少阿片類藥物的使用或報告的成癮率？

Sure, Salveen. Let me ask Stuart to comment.

當然，薩爾文。讓我請斯圖爾特發表評論。

Yes. So Salveen, all of the stakeholders that you described are going to be important in making decisions on the use of a new medicine in the institutional setting. So administrators are certainly going to be important, but as are our physician advocates who are going to advocate based on the efficacy and safety of the medicine.

是的。 Salveen，您所描述的所有利害關係人對於在機構環境中使用新藥的決策都將發揮重要作用。因此，管理者當然很重要，但我們的醫生倡導者也很重要，他們將根據藥物的功效和安全性進行倡導。

And the process is a relatively standardized process. It's not going to be created newly for suzetrigine. This is a standard process that hospitals go through to decide whether they're going to put it on their formulary, and typically go through some sort of P&T committee process where all of the various stakeholders, be it physicians, be it the pharmacy team, be it the administrators, are all going to be making that decision collectively.

而且流程是一個比較標準化的流程。它不會為 Suzetrigine 新創建。這是醫院決定是否將其納入處方集的標準流程，通常會經過某種 P&T 委員會流程，所有利益相關者，無論是醫生還是藥房團隊，無論是管理者，都將集體做出決定。

They're particularly interested in the use, obviously, within the institutional setting. Use in the discharge setting is typically something which is a little bit more straightforward, and that's why I suggested in my prepared remarks that we see that as the likely setting where there is going to be the earliest uptake of a medicine like suzetrigine.

顯然，他們對在機構環境中的使用特別感興趣。在出院環境中使用通常更簡單一些，這就是為什麼我在準備好的評論中建議我們將其視為最早使用舒三嗪等藥物的可能環境。

In terms of some of the outcomes data that you were referring to, I think the clearest way of describing is every patient that is treated with suzetrigine when the other choice would have been an opioid is essentially providing opioid-sparing for that patient.

就您提到的一些結果數據而言，我認為最清晰的描述方式是每一位接受舒三嗪治療的患者，而另一種選擇是阿片類藥物，本質上是為該患者提供阿片類藥物的備用。

So that data, in many ways, is kind of already sort of readily available just from the data that we've already shared, and I think that data in addition to all the other efficacy and safety data we've got is going to be pretty impactful and compelling to the various stakeholders we've described.

因此，從許多方面來說，這些數據已經可以從我們已經共享的數據中輕鬆獲得，我認為除了我們獲得的所有其他功效和安全性數據之外，這些數據也將是對於我們所描述的各個利益相關者來說非常有影響力和吸引力。

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。

Love to know if you to provide any additional color on how many patients in the United States have gotten their cells collected, and maybe how we should think about the growth of cell collections in the U.S. going forward. I'm just trying to understand what the trajectory of this could be like this year and next year.

我很想知道您是否能提供任何關於美國有多少患者已經收集了細胞的信息，以及我們應該如何考慮美國未來細胞收集的增長。我只是想了解今年和明年的發展軌跡。

Yes. Evan, just to set expectations, we're not going to comment very specifically on patients and exactly where they are in the cell collection process in each region, but I will ask Stuart to give you a little bit of color commentary on what we're seeing.

是的。埃文，只是為了設定期望，我們不會對患者以及他們在每個地區的細胞收集過程中所處的具體位置發表非常具體的評論，但我會請斯圖爾特對我們的內容進行一些彩色評論重新看到。

And if I was stealing Stuart's thunder, if you really think about when CASGEVY was approved, which is December and January, I am so very pleased that the number of ATCs that are activated around the globe and the number of patients who have already started cell collection. Stuart, is there anything you want to add?

如果我搶了史都華的風頭，如果你真的考慮到 CASGEVY 被批准的時間，即 12 月和 1 月，我非常高興看到全球範圍內激活的 ATC 數量以及已經開始使用細胞療法的患者數量收藏。斯圖爾特，你還有什麼要補充的嗎？

Only that we are expecting the momentum to build based on all of the feedback that we've got and the trends that we're seeing in activations and cell collections, as Reshma said. We're delighted to have had 5 cell collections already.

正如 Reshma 所說，只是我們期望根據我們收到的所有回饋以及我們在活化和細胞收集中看到的趨勢來建立勢頭。我們很高興已經收集了 5 個細胞。

As she also mentioned, that represents patients in every region in which we are operating, including obviously, the United States, and we expect those trends to continue to ramp up during the course of 2024, which we've always said was going to be a foundational year for CASGEVY.

正如她還提到的，這代表了我們開展業務的每個地區的患者，顯然包括美國，我們預計這些趨勢將在 2024 年期間繼續上升，我們一直說這將是CASGEVY 的基礎年。

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。

Maybe first on the pain pipeline. I see you're advancing 993 to Phase 2. Could you just give us any sort of color or detail on how you expect this to be differentiated? And does this advancement mean you won't be taking 973 forward, which I think also recently completed Phase I? And then if I may, a quick housekeeping one. Any inventory moves in the quarter that we should be aware of?

也許首先是在疼痛管道上。我看到您正在將 993 推進到第 2 階段。這項進步是否意味著你們不會繼續推進 973，我認為 973 也最近完成了第一階段？然後，如果可以的話，我會做一次快速的家事工作。本季有哪些我們應該注意的庫存變動？

Colin, let me break that up into 2 questions. One on inventory, which I will ask Charlie to comment on first, and then I'll come back on 993 and 973.

科林，讓我把它分成兩個問題。一個是關於庫存的，我會先請查理評論一下，然後我會回來評論 993 和 973。

Colin, in my prepared remarks, I mentioned that we saw some benefit in the first quarter from phasing of international channel inventory, so I assume that's what you're talking about. That benefit was on the order of $75 million to $100 million in the quarter, and I expect that to begin to reverse in the second quarter.

科林，在我準備好的發言中，我提到我們在第一季看到了國際通路庫存分階段的一些好處，所以我認為這就是您所說的。本季的收益約為 7,500 萬至 1 億美元，我預計這種情況將在第二季開始逆轉。

On 993, 973, Colin, this is all part of serial innovation. 993 is a little bit further ahead than 973 in terms of the preclinical package, the manufacturing and all of the things we need to do to get our medicines ready to go into Phase II. That's why that one is ready to go. 973 is just a little bit further behind.

993、973，科林，這都是系列創新的一部分。 993 在臨床前包裝、生產以及我們為進入 II 期藥物做好準備所需要做的所有事情方面都比 973 稍微領先一些。這就是為什麼那個人準備好了。 973 稍微落後一點。

What are we looking for in terms of differentiation? There's really 2 major elements other than our overarching serial innovation strategy. But very specifically, one, we are looking for molecules that can be both oral and IV, VX-548 is oral only, because our goal here is to own the waterfront on pain management, including for those patients who may be just coming out of surgery or for other reasons, not able to take by mouth.

我們在差異化方面尋求什麼？除了我們的整體系列創新策略之外，實際上還有兩個主要要素。但非常具體的是，第一，我們正在尋找既可以口服又可以靜脈注射的分子，VX-548 只能口服，因為我們的目標是在疼痛管理方面佔據領先地位，包括那些可能剛從疼痛管理中出來的患者。

The second big goal here is to ensure that we have medicines with the right drug-like properties that can be therefore combined with the NaV1.7, which is also making good progress in preclinical development. So that's what we're really looking for. And why 993 next? It's because it's a little bit further ahead. And 973, we're going to be working on just as soon as all of the data already there.

第二個大目標是確保我們擁有具有正確類藥特性的藥物，從而可以與 NaV1.7 結合，NaV1.7 在臨床前開發方面也取得了良好進展。這就是我們真正要尋找的。接下來為什麼是 993？因為距離還遠一點。 973，一旦所有資料都已存在，我們將立即處理。

Your next question will come from Terence Flynn with Morgan Stanley.

您的下一個問題將由摩根士丹利的特倫斯弗林提出。

Great. Maybe a two-part for me as well. I was just wondering if you can give us any insight on a potential presentation venue for the 548 Phase III data. And then the second question relates to CASGEVY. I was just wondering, any directional insight on pricing and reimbursement in the Middle East?

偉大的。也許對我來說也是兩個部分。我只是想知道您是否能為我們提供有關 548 III 期數據的潛在展示地點的任何見解。第二個問題與CASGEVY有關。我只是想知道，對中東的定價和報銷有什麼方向性的見解嗎？

Yes, on VX-548, fall meetings, shall we say. You should expect more data on 548 with those Phase III results. certainly not only in Congress form but in publications. So I'd say fall meetings. And let me ask Stuart to comment on CASGEVY in the Middle East. It is a really exciting opportunity for us.

是的，我們可以說，在 VX-548 上，秋季會議。您應該期待更多關於 548 的數據以及這些 III 期結果。當然不僅以國會的形式，而且以出版物的形式。所以我想說的是秋季會議。讓我請史都華對中東的卡斯吉維發表評論。這對我們來說是一個非常令人興奮的機會。

Yes, super exciting opportunity for us, Terence, which is why we provide a little bit more color on it. Specifically to answer your question, we don't provide pricing data at an individual country level, but suffice to say, the price we are receiving in the existing reimbursement agreements that we've signed there reflect the transformative value of the product and the lifetime benefits that patients can accrue from it. And that's going to be the same kind of philosophy we're going to have everywhere around the world where we're commercializing CASGEVY.

是的，這對我們來說是超級令人興奮的機會，特倫斯，這就是為什麼我們在上面提供了更多的色彩。具體來說，為了回答您的問題，我們不提供單一國家/地區的定價數據，但足以說明的是，我們在當地簽署的現有報銷協議中收到的價格反映了產品和生命週期的變革價值患者可以從中獲得的好處。這將是我們在世界各地將 CASGEVY 商業化的地方所秉持的理念。

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。

Two from us. So first on the suzetrigine formulary and access discussions. Stuart, I think you made an interesting comment that you thought enabling reimbursement ahead of opioids in the acute pain setting will be something that government programs could help incentivize it or something to that effect.

我們兩個。首先對 Suzetrigine 處方和取得進行討論。斯圖爾特，我認為你做了一個有趣的評論，你認為在急性疼痛環境中在阿片類藥物之前實現報銷將是政府計劃可以幫助激勵它或達到這種效果的東西。

Could you speak a bit more about that? And in particular, are your formulary and access discussions suggesting that in the absence of legislative initiatives, it's likely that 548 will be reimbursed after opioids in the acute pain setting?

您能多說一點嗎？特別是，您的處方和可及性討論是否表明，在缺乏立法舉措的情況下，在急性疼痛情況下使用阿片類藥物後，548 可能會得到報銷？

And then second, small commercial question. Can you give us some sense of how big Brazil could be for the CF franchise?

然後是第二個小商業問題。您能為我們介紹一下巴西對 CF 特許經營權的影響有多大嗎？

Yes. Phil, I will ask Stuart to comment on both CF in Brazil. You know that we have regulatory approval and reimbursement there as well as formulary discussions on suzetrigine. But just to make sure we are on the same page, the formulary discussions are separate from our discussions with policymakers.

是的。菲爾，我會請史都華對巴西的兩場比賽發表評論。你知道我們在那裡有監管部門的批准和報銷以及關於蘇三嗪的處方討論。但為了確保我們意見一致，規定的討論與我們與政策制定者的討論是分開的。

The common theme is that both of those stakeholders, and frankly, all of the stakeholders are very aware of the opioid crisis. They have high awareness of suzetrigine, and there is enthusiasm to using non-opioids. But those discussions are separate. Over to you, Stuart.

共同的主題是，坦白說，所有利益相關者都非常清楚阿片類藥物危機。他們對蘇三三嗪的認知度較高，對使用非鴉片類藥物有熱情。但這些討論是分開的。交給你了，史都華。

Yes. So just to add to that, Reshma, what I would say, Phil, is that the policy initiatives that we've seen so far are really looking at trying to reduce financial disincentives for patients and indeed for institutions to selecting a branded non-opioid in a market which is obviously currently dominated by generic opioids. And so that's why things like NOPAIN, which is providing an additional payment above the DRG in the outpatient and ambulatory surgical center setting, is important there.

是的。因此，補充一點，雷什瑪，菲爾，我想說的是，我們迄今為止看到的政策舉措實際上是在努力減少對患者以及機構選擇品牌非阿片類藥物的經濟抑制因素目前市場顯然由非專利阿片類藥物主導。這就是為什麼像 NOPAIN 這樣的計畫在這裡很重要，它在門診和門診手術中心環境中提供高於 DRG 的額外付款。

And then on the patient side, the Alternatives to PAIN Act is looking at in Medicare Part D, ensuring that there are no co-pay disadvantages to a patient for using a branded non-opioid in a market where there are already generic opioids. So I'd say that's the kind of the policy landscape.

然後在患者方面，醫療保險 D 部分正在考慮《疼痛替代法》，確保在已經有仿製藥阿片類藥物的市場上使用品牌非阿片類藥物的患者不會在自付費用上受到不利影響。所以我想說這就是政策環境。

Those are kind of slightly different discussions that we're having with the institutions and the stakeholders there, which were much more clinically based on whether this is the right medicine to be using in the patients who are being prescribed and dispensed medicines in the institutional setting. So that's how I would describe the difference between the conversations. They're obviously linked in some ways, but they are -- they have a different focus from the policy side to the institutional side.

這些是我們與那裡的機構和利益相關者進行的略有不同的討論，這些討論更多地基於臨床，基於這是否是在機構環境中開處方和配藥的患者使用的正確藥物。這就是我如何描述對話之間的差異。它們顯然在某些方面存在聯繫，但從政策方面到製度方面，它們的重點不同。

Maybe just a follow-up. The basis for our question is we recently did a survey, and 75% of physicians thought that patients would have to step through a generic opioid. Is that Vertex' expectation as well?

也許只是後續行動。我們問題的基礎是我們最近做了一項調查，75% 的醫生認為病人必須使用非專利鴉片類藥物。這也是Vertex的期望嗎？

I can't really speculate on exactly what's going to happen with, for instance, 2,000 institutions. But my hope would be that, that's not what's happening. I don't think it's very reasonable to expect a patient to have to step through a therapy which has significant side effect liability, including addictive potential, when there is a product available, which has very good efficacy from a pain control perspective and has an excellent safety and tolerability profile, including lack of addictive potential. So I don't think that would be something that we would -- certainly wouldn't be advocating and I don't think would be particularly medically reasonable.

例如，我無法準確推測 2,000 家機構將會發生什麼事。但我希望，事實並非如此。我認為，當有一種產品可用時，期望患者必須接受具有顯著副作用（包括成癮潛力）的治療是非常合理的，該產品從疼痛控制的角度來看具有非常好的功效，並且具有出色的安全性和耐受性，包括沒有成癮潛力。所以我認為這不會是我們會——當然不會提倡的事情，而且我認為這在醫學上也不是特別合理。

I didn't answer the second part of your question, which was around Brazil. We estimate there's around 1,500 patients who are eligible for TRIKAFTA. That's 6 and over in Brazil. As I mentioned in my prepared remarks, a number of those patients did already have access to TRIKAFTA through named patient sales, but we now have a reimbursement agreement with the national government there, which is going to allow us to launch the medicine and make it available for all of those patients now.

我沒有回答你問題的第二部分，那是關於巴西的。我們估計大約有 1,500 名患者符合 TRIKAFTA 的資格。在巴西，這個數字是 6 歲以上。正如我在準備好的發言中提到的，其中一些患者確實已經通過指定患者銷售獲得了 TRIKAFTA，但我們現在與那裡的國家政府達成了報銷協議，這將使我們能夠推出該藥物並製造它現在可供所有這些患者使用。

The next question will come from Olivia Brayer with Cantor Fitzgerald.

下一個問題將由奧利維亞·布雷耶和坎托·菲茨杰拉德提出。

What's your level of confidence that you'll get priority review in acute pain? And Stuart, I know you've talked about the commercial build-out, but what's your base case for when you'll start to actually see revenue recognition from that program? And just a quick clarification on CASGEVY. Just wanted to clarify that I heard 5 patients have already finished collection versus just having initiated the cell collection process.

您對自己在急性疼痛方面獲得優先審查的信心有多大？斯圖爾特，我知道您已經談到了商業擴建，但是當您開始真正看到該計劃的收入確認時，您的基本情況是什麼？對 CASGEVY 進行快速澄清。只是想澄清一下，我聽說 5 名患者已經完成了細胞收集，而不是剛開始細胞收集過程。

Olivia, this is Reshma. Let me take 1 and 3, and then I'll ask Stuart to take the question on where are we exactly with paying commercialization. On number 3, again, just to set expectations on CASGEVY. We're thrilled with the number of ATCs, 25 since approval, which has been in just the last few months, and we commented on the cell collection, but we're not going to comment any further on exactly where each one patient is in their journey.

奧莉薇亞，這是瑞詩瑪。讓我回答 1 和 3，然後我會請 Stuart 回答我們在付費商業化方面到底處於什麼階段的問題。再次提到第三點，只是為了設定對 CASGEVY 的期望。我們對 ATC 的數量感到非常興奮，自批准以來已有 25 個，這只是在過去的幾個月裡，我們對細胞收集進行了評論，但我們不會進一步評論每名患者的確切位置他們的旅程。

On VX-548 and acute pain, 3 things to say. Maybe the most important thing is we'll know whether or not we've received priority review in about -- after we complete the submission, and then it takes some 60 days or so for the FDA to tell us what the final review time lines will be. However, the leading indicators of whether or not we will get priority review are all quite favorable. We have Fast Track status, we have Breakthrough Designation and our conversations with the FDA have shown me that they have high enthusiasm for a medicine that has high efficacy and does not have addictive potential.

關於 VX-548 和急性疼痛，有 3 件事要說。也許最重要的是，在我們完成提交後，我們會知道我們是否收到了優先審查，然後 FDA 需要大約 60 天左右的時間才能告訴我們最終的審查時間表將。不過，我們是否獲得優先審查的先行指標都是相當有利的。我們擁有快速通道資格，我們擁有突破性指定，並且我們與 FDA 的對話向我表明，他們對一種高效且不具有成癮潛力的藥物抱有很高的熱情。

I'll turn it over to Stuart for the question about where are we with the acute pain launch, and when we're going to be out there.

我將把它交給斯圖爾特，詢問我們在哪裡進行急性疼痛發射，以及我們什麼時候去那裡。

Yes. So the recruitment of our teams is going very well. Obviously, we are in the middle of our rolling submission here. Obviously, once we've completed that, we'll get an indication from the regulators on when we could expect our PDUFA date to be, and we are going to be launch ready.

是的。所以我們團隊的招募工作進展順利。顯然，我們正在滾動提交。顯然，一旦我們完成了這項工作，我們就會從監管機構那裡得到關於我們預計 PDUFA 日期的指示，並且我們將做好發布準備。

In terms of the question around revenue recognition, this is unlike CASGEVY, I would say, which has an extended treatment process where revenue recognition is at infusion. This is a small molecule, and therefore, we're going to be kind of selling and distributing it in the normal way. And so there really isn't going to be that kind of lag, I would suggest, around revenue recognition that people are aware of with CASGEVY.

就收入確認問題而言，我想說，這與 CASGEVY 不同，後者有一個擴展的處理流程，其中收入確認是在註入時進行的。這是一種小分子，因此，我們將以正常方式銷售和分銷它。因此，我認為，人們在 CASGEVY 中所了解的收入確認方面，確實不會出現這種滯後。

Next question will come from Debjit Chattopadhyay with Guggenheim Securities.

下一個問題將由古根漢證券公司的 Debjit Chattopadhyay 提出。

I got a couple. First on IgAN, when Vertex is ready to launch in IgAN, it's likely Otsuka will have GFR data. How are you thinking about navigating this commercially?

我有一對。首先是 IgAN，當 Vertex 準備在 IgAN 中推出時，大塚很可能會擁有 GFR 數據。您如何考慮將其商業化？

And then on DM1, with the IND cleared and the Phase I/II underway, do you think myotonia is an approvable endpoint? Or is the agency going to ask for [splicing] correction with strength or force measurements?

然後在 DM1 上，隨著 IND 的批准和 I/II 期的進行，您認為肌強直是一個可批准的終點嗎？或者該機構是否會要求透過強度或力測量進行[拼接]校正？

Debjit, let me take both of those. On DM1 or myotonic dystrophy type 1, we actually haven't had a chance to talk about it extensively. But this is a program that is in Phase I/II in patients. So we are going to have the opportunity in this study to not only assess safety, but to assess efficacy as well. With regard to what the agency might want to see for the endpoint for approval, the real answer is I don't know yet because we haven't gotten to that phase in the clinical trial.

Debjit，讓我把這兩樣都拿走。關於 DM1 或強直性肌肉營養不良症 1 型，我們實際上還沒有機會廣泛討論。但這是一項處於患者 I/II 期的項目。因此，我們將有機會在這項研究中不僅評估安全性，而且還評估療效。至於該機構可能希望看到什麼終點獲得批准，真正的答案是我還不知道，因為我們還沒有進入臨床試驗的那個階段。

But your point around, is myotonia possible? Insofar as this is a disease that is a rare disease, a serious disease and one that doesn't have any therapies that target the underlying cause of the disease or very specifically works on the genetic defect, I think that opportunity is there. And I've seen -- and we've seen a lot of openness for accelerated end points in these kinds of rare serious diseases.

但你的觀點是，肌強直可能嗎？就這種疾病而言，它是一種罕見疾病、一種嚴重疾病，並且沒有任何針對疾病根本原因或非常具體地針對遺傳缺陷的治療方法，我認為機會就在那裡。我已經看到——我們已經看到對這些罕見的嚴重疾病的加速終點有很大的開放性。

On IgA nephropathy, so the most important thing to know about IgA nephropathy is that it's a serious chronic disease, and this is a disease that over time leads to decline in GFR and end-stage renal disease, death or transplantation. The most important thing that I would be looking at as a nephrologist is efficacy. Because proteinuria is known to translate to GFR and therefore, the decline in renal function, so if we have a medicine that has high reductions in proteinuria, and as I said in my prepared remarks, everything that we've seen from pove, preclinically and clinically through Phase II, is best-in-class across many dimensions, but certainly including efficacy. I think that's the drug that physicians will choose.

關於IgA腎病，所以關於IgA腎病最重要的是要了解它是一種嚴重的慢性疾病，而且這種疾病隨著時間的推移會導致GFR下降和終末期腎病、死亡或移植。身為腎臟病專家，我最重視的是療效。因為眾所周知，蛋白尿會轉化為GFR，從而導致腎功能下降，所以如果我們有一種藥物可以大幅降低蛋白尿，正如我在準備好的發言中所說，我們從臨床前和臨床前所看到的一切在臨床上通過第二階段，在許多方面都是同類最佳，但當然包括功效。我認為這是醫生會選擇的藥物。

One last quick question, please, Chuck.

最後一個快速問題，查克。

That will come from Ms. Liisa Bayko with Evercore ISI.

這將來自 Evercore ISI 的 Liisa Bayko 女士。

So just 2 from me. Just a follow-up on IgA nephropathy. Have you thought any more about how you might highlight having [BAFF]? Because in addition to APRIL, I think that's one kind of key differentiator of this program. And just wondering how you're thinking about how you could differentiate on that point. I don't know if there's biopsies or some kind of different points that you could really highlight the potential benefits of BAFF.

所以我只有 2 個。只是 IgA 腎病的後續行動。你有沒有想過如何強調擁有[BAFF]？因為除了 APRIL 之外，我認為這是該計劃的關鍵差異化因素。只是想知道您是如何考慮如何在這一點上實現差異化的。我不知道是否有活檢或某種不同的點可以真正強調 BAFF 的潛在好處。

And then just for the -- for CF and TRIKAFTA for the quarter, I noticed you had your price increase yet sales looked slightly down quarter-over-quarter. Can you kind of just describe in the U.S. what's going on? Was there some higher gross to net inventory changes, whatnot? Maybe -- great for some color there.

然後，就本季的 CF 和 TRIKAFTA 而言，我注意到你們的價格有所上漲，但銷售額環比略有下降。您能簡單描述一下美國正在發生的事情嗎？總庫存與淨庫存變動是否增加，等等？也許——非常適合那裡的一些顏色。

Let me take the IgAN question first, and then I'll ask Charlie to comment on CF. On IgAN, you are correct in pointing out that it's a dual inhibitor. It's an inhibitor of BAFF as well as APRIL. And this is one of the most attractive features of povetacicept is this dual inhibition. Yes, preclinically, we can certainly share when we have information, and you'll certainly see all of this with the fullness of time, the inhibition of BAFF and the measurement of that, and how we can show that preclinically. We can also do that with APRIL.

讓我先回答 IgAN 問題，然後我會請 Charlie 對 CF 發表評論。關於 IgAN，您指出它是雙重抑制劑是正確的。它是 BAFF 和 APRIL 的抑制劑。而povetacicept最吸引人的特點之一就是這種雙重抑制。是的，在臨床前，當我們掌握資訊時，我們當然可以分享，隨著時間的推移，您一定會看到所有這些，BAFF 的抑制和測量，以及我們如何在臨床前證明這一點。我們也可以透過 APRIL 做到這一點。

However, I think the data that's more interesting is the clinical data which is already available, and that is with this dual APRIL, BAFF inhibitor on proteinuria, but I'd encourage you to look at the poster from the WCN meeting that Alpine showed. It has proteinuria results, it has hematuria results, it has GFR results, and it has a composite of remission. And I find those data very, very interesting, particularly the hematuria results clinically, because as you know, hematuria is a hallmark of this disease along with proteinuria.

然而，我認為更有趣的數據是已經可用的臨床數據，即這種雙重 APRIL、BAFF 抑制劑對蛋白尿的影響，但我鼓勵您查看 Alpine 展示的 WCN 會議的海報。它有蛋白尿結果、血尿結果、GFR 結果，還有緩解的複合結果。我發現這些數據非常非常有趣，特別是臨床上的血尿結果，因為如你所知，血尿和蛋白尿一樣是這種疾病的標誌。

Let me turn it over to Charlie on the question about CF and U.S.

讓我把關於 CF 和 U.S. 的問題交給 Charlie。

Yes, Liisa. On the quarter, I wouldn't read too much into sequential quarter fluctuations. We saw strong volume growth in the U.S. year-over-year. As we normally do, we see some seasonal gross to net in the first quarter, and the benefit of the price increase really isn't fully reflected in the quarter that comes throughout the balance of the year. So all of those factors affect the comparison. But overall, very, very strong year-over-year growth in the U.S. and outside the U.S.

是的，莉莎。就本季而言，我不會過度解讀連續季度的波動。我們看到美國的銷量較去年同期強勁成長。正如我們通常所做的那樣，我們在第一季看到了一些季節性總收入，而價格上漲的好處實際上並沒有完全反映在全年剩餘的季度中。所以所有這些因素都會影響比較。但總體而言，美國和美國以外地區的年成長非常非常強勁。

Thanks. Chuck?

謝謝。查克？

This concludes 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 10186968. Thank you for your time today. You may now disconnect.

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