福泰製藥 (VRTX) 2022 Q2 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals Second Quarter 2022 Earnings Call. (Operator Instructions) Please note this event is being recorded.

大家好，歡迎參加Vertex Pharmaceuticals 2022年第二季財報電話會議。 （操作說明）請注意，本次會議正在錄音。

I would now like to turn the conference over to Charlie Wagner, Chief Financial Officer. Please go ahead.

現在我將會議交給財務長查理·瓦格納先生。請開始吧。

Good evening. This is Charlie Wagner, Vertex' Chief Financial Officer. Welcome to our second quarter 2022 financial results conference Call.

晚安.我是Vertex公司的財務長查理·瓦格納。歡迎參加我們2022年第二季財務業績電話會議。

On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating Officer; and myself. We recommend that you access the webcast slides as you listen to this call. Also, the call is being recorded, and a replay will be available on our website.

在今晚的電話會議上，Vertex公司執行長兼總裁Reshma Kewalramani博士、營運長Stuart Arbuckle以及我本人將分別發表演說。我們建議您在收聽本次電話會議的同時查看網路直播投影片。此外，本次電話會議將進行錄音，錄音回放將在我們的網站上提供。

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. These statements including, without limitation, those regarding Vertex's marketed CF medicines, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance we will review on the call this evening are non-GAAP.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受制於今天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。這些聲明，包括但不限於有關Vertex已上市的囊性纖維化藥物、我們的研發管線以及Vertex未來財務表現的聲明，均基於管理層目前的假設。實際結果和事件可能與這些假設有重大差異。此外，我還要指出，我們今晚將在電話會議上討論的部分財務表現和指引為非GAAP財務數據。

I will now turn the call over to Dr. Reshma Kewalramani.

現在我將把電話轉給雷什瑪·凱瓦拉瑪尼醫生。

Thanks, Charlie, and good evening all.

謝謝你，查理，大家晚上好。

Vertex continues to make strong progress towards our goal of reaching all CF patients eligible for our medicines. Based on the continued uptake of TRIKAFTA in the U.S. as well as in the international region, our Q2 CF product revenues grew 22% year-on-year to $2.2 billion. And based on this uptake as well as the new reimbursements recently secured, we are updating revenue guidance from $8.4 billion to $8.6 billion, to $8.6 billion to $8.8 billion.

Vertex在實現讓所有符合條件的囊性纖維化（CF）患者都能用上我們藥物的目標方面持續取得顯著進展。基於TRIKAFTA在美國和國際市場的持續成長，我們第二季的CF產品營收年增22%，達到22億美元。鑑於這一成長動能以及近期獲得的新醫保報銷，我們將營收預期從84億至86億美元上調至86億至88億美元。

We're also making rapid progress in advancing our R&D portfolio with programs in 5 disease areas now entering or progressing through late-stage clinical development, and the next wave of innovation getting ready to enter the clinic. Our expanding leadership in CF, coupled with the broad, deep and advanced research and clinical stage pipeline brings Vertex to this new inflection point highlighted last quarter. This inflection point is rooted in our differentiated R&D strategy, which is designed to increase the odds of success in drug discovery and development.

我們在推動研發項目組合方面也取得了快速進展，目前已有5個疾病領域的多個項目進入或推進至後期臨床開發階段，而下一批創新成果也即將進入臨床試驗。我們在囊性纖維化領域不斷擴大的領先地位，以及廣泛、深入且先進的研發和臨床階段產品線，使Vertex公司達到了上季度強調的這一全新轉折點。這一轉折點源於我們差異化的研發策略，旨在提高藥物發現和開發的成功率。

This strategy is working. First in CF and more recently, we have seen it deliver potentially transformative, if not curative therapies in multiple disease areas, including sickle cell disease, beta thalassemia, APOL1-mediated kidney disease, acute pain and type 1 diabetes, programs that are all now past the proof-of-concept stage. Each of these programs individually represents a multibillion-dollar market opportunity. And taken together, they represent enormous potential for patients and for Vertex.

這項策略正在奏效。首先是在囊性纖維化領域，最近，我們看到它在多種疾病領域帶來了可能具有變革性甚至治癒性的療法，包括鐮狀細胞病、β地中海貧血、APOL1介導的腎病、急性疼痛和1型糖尿病，所有這些項目目前都已超越概念驗證階段。每個項目都代表著數十億美元的市場機會。而綜合來看，它們為患者和Vertex公司都帶來了巨大的潛力。

In addition, we continue to use our strong balance sheet to pursue external innovation that complements or accelerates our internal efforts. The Viacyte acquisition, for example, has the potential to accelerate development of our type 1 diabetes programs. The early stage assets from Catalyst and the Verve collaboration complement our internal efforts in sandbox diseases. With our strong revenue growth and rapidly advancing pipeline, we are continuing to invest in internal and external innovation, as you see us do today with the increase in OpEx guidance to $3 billion to $3.1 billion, and the multiple business development deals we've announced this quarter.

此外，我們將繼續利用穩健的資產負債表，尋求能夠補充或加速內部研發工作的外部創新。例如，收購Viacyte有望加速我們第一型糖尿病計畫的開發。來自Catalyst的早期資產以及與Verve的合作，都與我們在沙盒疾病領域的內部研發工作相輔相成。憑藉強勁的營收成長和快速推進的研發管線，我們將繼續增加對內部和外部創新的投入，正如您今天所看到的，我們將營運支出預期上調至30億至31億美元，並在本季度宣布了多項業務拓展協議。

Let me now turn to the pipeline and review some of our recent R&D progress. Starting with CF. For patients who can benefit from CFTR modulators, TRIKAFTA has set a very high bar. But if it is possible to develop more effective medicines, we are determined to be the ones who do so. Our next-in-class triple combination, VX-121/tezacaftor/VX-561, is now in Phase III development enrolling patients 12 years and older, and we remain on track to complete enrollment by the end of this year or early next. With the progress in the SKYLINE 1 and SKYLINE 2 trials, we've also recently initiated pivotal development of VX-121/tez/VX-561 in patients 6 to 11 years old.

現在，我想談談我們的研發管線，並回顧我們近期的研發進展。首先是囊性纖維化（CF）領域。對於能夠從CFTR調節劑中獲益的患者而言，TRIKAFTA已經樹立了很高的標竿。但如果有可能開發出更有效的藥物，我們決心成為第一個做到這一點的人。我們下一代三重療法VX-121/tezacaftor/VX-561目前正處於III期臨床試驗階段，招募12歲及以上的患者，我們預計今年底或明年初即可完成招募。隨著SKYLINE 1和SKYLINE 2試驗的進展，我們近期也啟動了VX-121/tez/VX-561在6至11歲患者的關鍵性臨床試驗。

Lastly, for patients who do not make any CFTR protein and cannot benefit from a CFTR modulator, we're developing an mRNA therapy with our partners at Moderna. We are on track to file the IND for the mRNA program in the second half of this year.

最後，對於不產生任何CFTR蛋白且無法從CFTR調節劑中獲益的患者，我們正在與Moderna的合作夥伴共同開發一種mRNA療法。我們計劃在今年下半年提交該mRNA計畫的研究性新藥申請（IND）。

Moving to CTX001. Our most advanced pipeline program outside of CF is our exa-cel, or CTX001 gene editing program in severe sickle cell disease and beta thalassemia. In June, we presented data for more patients treated with exa-cel and with longer follow-up at the Annual Meeting of the European Hematology Association. These data, which included 75 patients with up to 37 months of follow-up continue to demonstrate that exa-cel holds the potential to be a durable, onetime functional cure for these patients and the safety data continue to be consistent with myeloablative conditioning and autologous bone marrow transplant.

接下來是CTX001。除囊性纖維化領域外，我們最先進的研發管線計畫是針對重型鐮狀細胞疾病和β地中海貧血的exa-cel（即CTX001）基因編輯計畫。今年6月，我們在歐洲血液學協會年會上發表了更多接受exa-cel治療且追蹤時間更長的患者數據。這些數據包括75例患者，追蹤時間長達37個月，持續顯示exa-cel有望為這些患者提供持久的一次性功能性治愈，且其安全性數據與清髓性預處理和自體骨髓移植方案一致。

In terms of next steps, we have recently concluded our discussions on the filing package with EMA and MHRA and have reached agreement on the filing package. We remain on track to submit the MAAs in both sickle cell disease and beta thalassemia in the EU and the U.K. in Q4 of this year. We expect to wrap up our conversations with the FDA regarding the filing package, in particular, the number of patients and duration of follow-up, in the coming weeks, and we look forward to updating you after that.

關於後續步驟，我們近期已與歐洲藥品管理局 (EMA) 和英國藥品和保健產品監管署 (MHRA) 就申報材料包進行了磋商並達成協議。我們仍按計畫於今年第四季向歐盟和英國提交鐮狀細胞貧血症和β地中海貧血的上市許可申請 (MAA)。我們預計在未來幾週內完成與美國食品藥物管理局 (FDA) 就申報資料包的磋商，特別是關於患者數量和追蹤時間等問題，屆時我們將及時向您匯報最新進展。

Turning now to inaxaplin, or VX-147 in APOL1-mediated kidney disease, or AMKD. Inaxaplin is a small molecule inhibitor of APOL1 that targets the underlying cause of AMKD. Based on the unprecedented Phase II proof-of-concept results, which showed a 47.6% reduction in proteinuria, inaxaplin received Breakthrough Therapy designation in the U.S. and Priority Medicines, or PRIME designation in the EU. The pivotal trial is a single adaptive Phase II/III randomized, placebo-controlled trial, and the primary endpoint is the reduction in the rate of decline of kidney function in patients who have been treated for approximately 2 years. Importantly, the study is designed to have a preplanned interim analysis at 48 weeks of treatment. If the interim analysis is positive, it will serve as the basis for us to seek accelerated approval in the U.S.

現在我們來談談伊那沙普林（inaxaplin），或稱VX-147，用於治療APOL1介導的腎臟病（AMKD）。伊那沙普林是一種APOL1小分子抑制劑，針對治療AMKD的根本病因。基於前所未有的II期概念驗證結果（顯示蛋白尿減少47.6%），伊那沙普林獲得了美國突破性療法認定和歐盟優先藥物認定（PRIME）。這項關鍵性試驗是一項適應性II/III期隨機、安慰劑對照試驗，主要終點是治療約2年後患者腎功能下降速度的降低。重要的是，該研究設計在治療48週時進行預先計劃的中期分析。如果中期分析結果為陽性，這將作為我們在美國尋求加速批准的依據。

We initiated the inaxaplin pivotal trial in late March, site activation, patient screening and enrollment are all ongoing.

我們在 3 月下旬啟動了 inaxaplin 的關鍵性試驗，目前試驗中心已啟動，患者篩選和招募工作正在進行中。

Moving to pain. And VX-548, a novel first-in-class NaV1.8 inhibitor. We have high expectations from this program because NaV1.8 is both a genetically and pharmacologically validated target across acute, neuropathic and musculoskeletal pain. And VX-548 demonstrated a very desirable benefit/risk ratio profile in Phase II. Additionally, the VX-548 program represents a near-term commercial opportunity.

接下來我們來談談疼痛治療。 VX-548 是一種新型的首創 NaV1.8 抑制劑。我們對該計畫寄予厚望，因為 NaV1.8 是一個經過基因和藥理學驗證的靶點，可有效治療急性疼痛、神經性疼痛和肌肉骨骼疼痛。 VX-548 在 II 期臨床試驗中展現出非常理想的效益/風險比。此外，VX-548 專案也代表著近期商業化的機會。

To recap, earlier this year, we shared positive proof-of-concept results from VX-548, which demonstrated statistically significant and clinically meaningful relief of pain in 2 Phase II studies of acute pain, one in the post-bunionectomy setting and one in the post-abdominoplasty setting. Based on these results, the VX-548 has received Breakthrough Therapy designation, highlighting the significant need for highly efficacious and well-tolerated non-opioid pain medicines.

回顧一下，今年早些時候，我們分享了VX-548的積極概念驗證結果，該藥物在兩項II期急性疼痛研究中均顯示出具有統計學意義和臨床意義的鎮痛效果，一項針對拇外翻切除術後患者，另一項針對腹部整形術後患者。基於這些結果，VX-548獲得了突破性療法認定，凸顯了市場對高效且耐受性良好的非鴉片類鎮痛藥物的迫切需求。

We are very pleased to have completed our end of Phase II meeting with the FDA and reach agreement on the VX-548 pivotal program in acute pain. The Phase III program will include 2 randomized placebo-controlled trials that will evaluate VX-548 post-bunionectomy and abdominoplasty. The exact same postsurgical acute pain settings we explored in Phase II.

我們非常高興地宣布，已與FDA完成了二期臨床試驗的總結會議，並就VX-548在急性疼痛治療​​中的關鍵性研究項目達成一致。第三期臨床試驗項目將包括兩個隨機、安慰劑對照試驗，分別評估VX-548在拇外翻切除術和腹部整形術後的療效。這些試驗將涵蓋我們在二期臨床試驗中探索的完全相同的術後急性疼痛情況。

These trials are shortened duration, approximately 2 days of treatment followed by 14 days of safety follow-up. Both of these Phase III studies will also include an opioid treatment arm. A third single-arm study will evaluate the safety and effectiveness of dosing with VX-548 for up to 14 days across multiple other types of moderate to severe acute pain. We remain on track to initiate the pivotal development program by the end of this year. In addition, we have completed our preclinical studies to support initiating a Phase II dose-ranging proof-of-concept study of VX-548 in neuropathic pain towards the end of this year.

這些試驗的療程較短，大約為期2天的治療，隨後進行14天的安全追蹤。這兩項III期研究都將包含一個鴉片類藥物治療組。第三項單臂研究將評估VX-548在多種其他類型的中度至重度急性疼痛中，療程長達14天的安全性和有效性。我們仍按計劃於今年底啟動關鍵性開發案。此外，我們已完成臨床前研究，以支持在今年年底啟動VX-548治療神經性疼痛的II期劑量範圍概念驗證研究。

Turning now to type 1 diabetes. In June, our VX-880 clinical data were featured in an oral presentation at the ADA Scientific Sessions. We've previously shared that we achieved proof-of-concept with the results from the first 2 patients who were treated in Part A with half the targeted dose. Both achieved glucose-responsive insulin secretion, improvements in hemoglobin A1C with concurrent reductions in or, as in the case of the first patient, elimination of exogenous insulin.

現在我們來談談第一型糖尿病。今年6月，我們在ADA科學年會上以口頭報告的形式展示了VX-880的臨床數據。先前我們曾分享過，在A部分研究中，我們透過前兩名接受目標劑量一半治療的患者的結果，驗證了該療法的概念。這兩名患者均實現了葡萄糖反應性胰島素分泌，糖化血紅蛋白A1c水平有所改善，同時外源性胰島素用量減少，其中一名患者甚至完全停止了外源性胰島素的使用。

The new data that we presented at ADA included glucose time and range measurements. Time and range is important because it gives much more granular and comprehensive data than hemoglobin A1C alone and is correlated with the risk of developing micro and macrovascular complications. Patient 1 achieved a glucose timing range of 99.9% at day 270 versus 40.1% at baseline and remained insulin-independent. Patient 2 showed a glucose timing range of 51.9% at day 150 versus 35.9% at baseline with a 30% reduction in exogenous insulin. The trial, which has remained open in Canada and resumed enrollment in the United States last month, continues to screen and enroll patients in Part B.

我們在ADA年會上公佈的新數據包括血糖時間和範圍測量值。血糖時間和範圍非常重要，因為它比單獨的糖化血紅蛋白A1c提供更精細、更全面的數據，並且與發生微血管和大血管併發症的風險有關。患者1在第270天時血糖時間範圍達到99.9%，而基線時為40.1%，並且維持了胰島素非依賴性。患者2在第150天時血糖時間範圍達到51.9%，而基線時為35.9%，且外源性胰島素用量減少了30%。該試驗在加拿大仍在進行，並於上個月在美國恢復了患者招募，目前仍在B部分進行患者篩選和招募。

To close, a word on the next wave of innovative therapies. These are programs in late preclinical development that are rapidly approaching the clinic. For the CFTR mRNA program, our cells and device program in type 1 diabetes and our next-generation AATD molecules, we expect to file INDs this year. Lastly, our gene editing program in DMD is in IND-enabling studies, and we plan to file the IND for this asset in 2023.

最後，我想談談下一波創新療法。這些項目正處於臨床前開發的後期階段，即將進入臨床試驗階段。我們預計今年將提交CFTR mRNA計畫、1型糖尿病的細胞和器械計畫以及下一代AATD分子藥物的IND申請。此外，我們用於治療DMD的基因編輯計畫目前正處於IND申報前的準備階段，我們計劃於2023年提交該計畫的IND申請。

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

接下來，我將把這個任務交給斯圖爾特，讓他做個商業概述。

Thanks, Reshma. I'm pleased to review tonight our continued strong performance in CF, the path towards future growth and the commercial opportunity and plans for some of the most advanced disease areas in our pipeline.

謝謝，雷什瑪。今晚我很高興能回顧我們在囊性纖維化領域持續強勁的表現，展望未來的成長之路，以及我們研發管線中一些最先進疾病領域的商業機會和計劃。

I'll start with CF. Our CF business continued its rapid pace of growth this quarter, with impressive performance in both the U.S. and internationally. In the U.S., we continue to add new TRIKAFTA patients, with most of them being younger patients in the 6 to 11 age group, and persistence and compliance remain very high across all patient groups. Outside the U.S., we have seen rapid uptake of KAFTRIO across multiple European countries where we recently reached reimbursement agreements, notably France, Spain and Italy. We've now turned our focus in Europe to the launch of KAFTRIO in children ages 6 to 11. Additionally, the launches of TRIKAFTA in Canada and Australia are both off to a strong start.

我先來說說囊性纖維化（CF）業務。本季度，我們的CF業務持續保持快速成長，在美國和國際市場均取得了令人矚目的成績。在美國，我們持續新增TRIKAFTA患者，其中大部分是6至11歲的低齡患者，所有患者群體的用藥堅持率和依從性均保持在非常高水平。在美國以外，我們在近期達成健保報銷協議的多個歐洲國家，特別是法國、西班牙和義大利，KAFTRIO的市場接受度迅速提升。目前，我們已將歐洲市場的重點轉向KAFTRIO在6至11歲兒童的上市。此外，TRIKAFTA在加拿大和澳洲的上市也取得了良好的開端。

We began the year with more than 25,000 patients in North America, Europe and Australia who could benefit from a CFTR modulator but were not yet on therapy. These patients fell primarily into 1 of 3 categories. One, patients who had not yet initiated therapy, largely in countries where we are recently reimbursed and therefore, early in the launch curve. Two, patients in geographies where we are not yet reimbursed and three, younger age groups who will be addressed through ongoing label expansions.

年初，北美、歐洲和澳洲有超過25,000名患者可能受益於CFTR調節劑，但尚未接受治療。這些患者主要分為三類：第一類是尚未開始治療的患者，他們大多來自我們近期獲得醫保報銷的國家，因此處於市場推廣的早期階段；第二類是來自我們尚未獲得醫保報銷地區的患者；第三類是年齡較小的患者群體，我們將透過持續的適應症擴展來惠及他們。

We are confident in our ability to reach the vast majority of these patients over time. We have made good headway securing new reimbursements and launching our medicines in the first half of 2022.

我們有信心隨著時間的推移，能夠惠及絕大多數患者。我們在爭取新的健保報銷和於2022年上半年推出新藥方面取得了良好進展。

Additionally, we continue to make important progress in expanding access to younger patients. For instance, we completed the study of TRIKAFTA in patients 2 to 5 years old with positive efficacy results on the endpoints of lung clearance index and sweat chloride and no new safety signals. We expect to present these data at a medical meeting later this year and are on track to submit global regulatory filings by the end of the year. Additionally, we submitted regulatory filings in the U.S. and Europe for ORKAMBI in patients 12 months to less than 24 months of age. The PDUFA date for this filing is September 4.

此外，我們在擴大低齡患者的用藥範圍方面持續取得重要進展。例如，我們已完成針對2至5歲患者的TRIKAFTA研究，在肺部清除指數和汗液氯化物終點指標上取得了正面的療效結果，且未發現新的安全性訊號。我們預計將於今年稍晚在醫學會議上公佈這些數據，並預計在年底前提交全球監管申請。此外，我們已向美國和歐洲提交了針對12個月至24個月以下患者的ORKAMBI的監管申請。該申請的PDUFA日期為9月4日。

We were pleased to present compelling long-term and real-world data on TRIKAFTA at the European Cystic Fibrosis Society's conference in June. These data underscore the outcomes with TRIKAFTA, specifically improved lung function, a 77% reduced risk of pulmonary exacerbations, an 87% lower risk of lung transplant and a 74% lower risk of death for patients with CF.

我們很高興在六月舉行的歐洲囊性纖維化協會會議上展示了關於TRIKAFTA的令人信服的長期真實世界數據。這些數據突顯了TRIKAFTA的療效，特別是改善肺功能、降低77%的肺部急性惡化風險、降低87%的肺移植風險以及降低74%的囊性纖維化患者死亡風險。

Finally, in CF, as Reshma mentioned, we are developing a CFTR mRNA therapy to treat patients who do not make any CFTR protein and thus cannot benefit from a CFTR modulator. We estimate there are approximately 5,000 of these patients in North America, Europe and Australia. Outside of CF, we have made impressive strides with our clinical stage pipeline over the past 12 months. Today, I'd like to highlight the market potential for 3 of our late-stage clinical programs, exa-cel, inaxaplin and VX-548, and some of our pre-commercial activities. Each of these programs serves a very high unmet need and is a first-in-class or best-in-class approach, and each represents a multibillion-dollar opportunity.

最後，如Reshma所提到的，在囊性纖維化（CF）領域，我們正在開發一種CFTR mRNA療法，用於治療那些自身不產生CFTR蛋白、因而無法從CFTR調節劑中獲益的患者。我們估計，北美、歐洲和澳洲大約有5,000名這樣的患者。除了CF領域，過去12個月裡，我們在臨床階段的研發管線也取得了令人矚目的進展。今天，我想重點介紹我們三個後期臨床項目——exa-cel、inaxaplin和VX-548——以及一些商業化前活動的市場潛力。這些項目都滿足了極高的未滿足醫療需求，屬於同類首創或同類最佳療法，每個項目都蘊藏著數十億美元的市場機會。

Beginning with our most advanced pipeline program, exa-cel.

首先介紹我們最先進的管道項目 exa-cel。

On our last few quarterly calls, we provided details on our launch preparation activities. So I'll briefly recap how we are thinking about the market size and our approach. There are approximately 32,000 patients who have severe sickle cell disease, or transfusion-dependent beta thalassemia in the U.S. and EU. Our initial launch will focus on these 32,000 patients with severe disease, of whom 25,000 are patients with severe sickle cell disease with the vast majority of them living in the U.S. A small number of centers of excellence in the U.S. and Europe will treat the vast majority of these patients. Our research suggests that about 90% of U.S. patients reside in 24 states, and more than 75% of patients in Europe reside in 4 countries. We have identified the potential treatment centers and their referral networks in all of these countries.

在最近幾次季度電話會議上，我們詳細介紹了產品上市準備。因此，我將簡要回顧我們對市場規模的評估以及我們的策略。美國和歐盟約有32,000名患有重型鐮狀細胞疾病或輸血依賴型β地中海貧血的患者。我們的初期產品上市將聚焦在這32,000名重症患者，其中25,000名是重型鐮狀細胞疾病患者，絕大多數居住在美國。美國和歐洲的少數幾家卓越醫療中心將為這些患者提供治療。我們的研究表明，約90%的美國患者居住在24個州，超過75%的歐洲患者居住在4個國家。我們已經確定了所有這些國家的潛在治療中心及其轉診網絡。

We are confident that we'll be ready to launch exa-cel following approval. We have hired the launch teams, including medical science liaisons, medical affairs and access and reimbursement teams, and they are already active in the field. And finally, we are developing robust patient service programs to support patients throughout the treatment journey.

我們有信心在獲得批准後立即推出exa-cel。我們已組建了上市團隊，包括醫學聯絡官、醫學事務人員以及市場准入和報銷團隊，他們已在一線積極開展工作。最後，我們正在製定完善的患者服務計劃，為患者提供全程治療支援。

Moving on to inaxaplin, or VX-147, which is in pivotal development for patients with AMKD. We've previously talked about a number of AMKD patients, which we estimate to be approximately 100,000 in the U.S. and Europe, with over 80% of them living in the U.S.

接下來是inaxaplin，也稱為VX-147，它正處於治療AMKD患者的關鍵性研發階段。我們之前討論過一些AMKD患者，據估計，美國和歐洲約有10萬名AMKD患者，其中超過80%居住在美國。

Here, I'll touch on the work we are undertaking to raise awareness of AMKD. Awareness, diagnosis and genotyping of patients with AMKD are all low within the medical and patient communities, which is not surprising, given this is a newly defined disease without existing targeted therapies. To increase awareness of AMKD and of genetic testing options, we are working with the kidney disease community and with minority health organizations to support sponsored education campaigns and scientific workshops and seminars.

在此，我將簡要介紹我們為提高大眾對AMKD的認知所做的工作。鑑於AMKD是一種新近確診的疾病，目前尚無針對性療法，因此，醫療界和患者群體對AMKD的認知度、診斷率和基因分型率均較低，這並不令人意外。為了提高大眾對AMKD及其基因檢測方案的認知度，我們正與腎臟病群體和少數族裔健康組織合作，支持教育宣傳活動、科學研討會和講座。

Some examples of this work include: Sponsoring the American Kidney Funds APOL1 education campaign, which will launch this year to provide educational materials and digital engagement tools for patients and providers. And we are also educating people about AMKD at Black Health Matters Health Fairs and Summits, and through NephCure's Health Equity Initiative.

這項工作的一些例子包括：贊助美國腎臟基金會的APOL1教育活動，該活動將於今年啟動，旨在為患者和醫療服務提供者提供教育材料和數位互動工具。此外，我們也在「黑人健康至關重要」健康博覽會和高峰會上，以及透過NephCure的健康公平倡議，向大眾普及AMKD的相關知識。

In addition to these disease awareness and education efforts, we and others are also working on important policy initiatives to support AMKD diagnosis. Specifically, we are advocating for federal legislation introduced in the spring entitled the New Era of Preventing End-Stage Kidney Disease Act that would establish a rare kidney disease research center at NIH, investigate the role of genetic screening in improving kidney disease outcomes and address kidney health disparities in communities of color. And we're also advocating alongside the National Kidney Foundation as well as other stakeholders to increase kidney disease screening. You may have seen in the news recently that the U.S. preventive services task force has added chronic kidney disease screening to the list of services they have under active consideration. If recommended, patients would have access to screening at no cost, which would make a huge difference in improving availability and access to screening for AMKD patients. Additionally, we are exploring pathways with diagnostic testing companies to make genetic testing more accessible to patients.

除了這些疾病認知和教育工作之外，我們和其他機構也積極推動重要的政策舉措，以支持AMKD的診斷。具體而言，我們正在倡導一項於今年春季提出的聯邦法案——《預防終末期腎病新時代法案》，該法案旨在美國國立衛生研究院（NIH）設立一個罕見腎病研究中心，研究基因篩檢在改善腎病預後方面的作用，並解決有色人種社區的腎臟健康差異問題。此外，我們也與美國國家腎臟基金會及其他利益相關者攜手合作，倡導提高腎病篩檢率。您可能最近在新聞中看到，美國預防服務工作小組已將慢性腎臟病篩檢列入其正在積極考慮的服務清單。如果該篩檢獲得批准，患者將可以免費接受篩檢，這將大大提高AMKD患者獲得篩檢的機會和便利性。此外，我們正在與診斷檢測公司探討各種途徑，以使患者更容易獲得基因檢測服務。

Finally, VX-548 in pain. Given we recently announced agreement with FDA on the pivotal development program for acute pain, I'd like to give you a summary of the market opportunity. There is a real need for effective, safe and well-tolerated pain medicines as there have been no novel pain medicines introduced in the past 20 years. We see utility for our NaV1.8 inhibitors in different types of pain, including acute, neuropathic and musculoskeletal.

最後，我們來談談VX-548在疼痛治療領域的應用。鑑於我們近期已宣布與FDA就急性疼痛的關鍵性研發項目達成協議，我想向大家簡要概述一下市場機會。由於過去20年沒有推出任何新型止痛藥，因此市場對有效、安全且耐受性良好的止痛藥有著迫切的需求。我們認為我們的NaV1.8抑制劑可用於治療不同類型的疼痛，包括急性疼痛、神經性疼痛和肌肉骨骼疼痛。

Today, I'm going to focus on acute pain.

今天，我將重點討論急性疼痛。

In the U.S., there are approximately 1.5 billion treatment days for acute pain each year, and approximately 2/3 or 1 billion of those are driven by hospital prescribing. This includes treatment for inpatient and outpatient visits and the patient's related pain management following discharge. Consistent with our business strategy, a small specialty commercial organization will allow us to reach a large proportion of this market, given the concentration of pain treatment driven by hospital prescribing.

在美國，每年約有15億個急性疼痛治療​​日，其中約三分之二（即10億個）是由醫院處方驅動的。這包括住院和門診治療，以及患者出院後的疼痛管理。鑑於疼痛治療主要由醫院處方驅動，根據我們的商業策略，成立小型專業商業機構將使我們能夠涵蓋該市場的大部分份額。

Today, oral treatment of acute pain is roughly a $4 billion market, even though over 90% of prescriptions are generic. Considering the price of a typical branded pain medicine is roughly $10 per day, a safe and effective new pain medication without addictive potential that captures even a partial share of that market represents a multibillion-dollar opportunity. Importantly, given the magnitude and severity of the ongoing opioid crisis in the U.S., the initiation of the Phase III studies for VX-548 later this year, and the relatively short duration of the trials, we will be working with urgency to build out our teams and go-to-market plans to bring this novel nonopioid pain medicine to patients.

如今，口服治療急性疼痛的市場規模約為40億美元，儘管超過90%的處方藥都是仿製藥。考慮到典型的品牌止痛藥每天的價格約為10美元，一種安全有效且無成癮性的新型止痛藥，即使只佔據部分市場份額，也蘊藏著數十億美元的商機。尤其值得注意的是，鑑於美國當前阿片類藥物危機的嚴重程度，以及VX-548將於今年稍後啟動的III期臨床試驗，再加上試驗週期相對較短，我們將爭分奪秒地組建團隊並製定上市計劃，盡快將這種新型非阿片類止痛藥帶給患者。

In closing, I'm excited about bringing TRIKAFTA to even more patients around the globe, and also commercializing multiple potentially transformative therapies outside of CF in the future.

最後，我很高興能將 TRIKAFTA 帶給全球更多患者，並期待未來在囊性纖維化以外的領域實現多種具有變革意義的療法的商業化。

Now, I'll turn it over to Charlie.

現在，我把麥克風交給查理。

Thanks, Stuart.

謝謝你，斯圖爾特。

In the second quarter of 2022, Vertex continued to deliver strong financial performance. Second quarter product revenues were $2.2 billion, an increase of 22% compared to the second quarter of 2021. Our growth was again driven by an increased number of patients on therapy compared to the prior year, resulting from several approvals and reimbursements for TRIKAFTA/KAFTRIO over the last year as well as continued strong execution with market launches.

2022年第二季度，Vertex持續保持強勁的財務表現。第二季產品營收達22億美元，較2021年第二季成長22%。與去年同期相比，接受治療的患者人數增加再次推動了我們的成長，這得益於過去一年TRIKAFTA/KAFTRIO獲得多項批准和醫保報銷，以及市場推廣工作的持續高效執行。

Movements in foreign exchange had only a small impact on reported growth, primarily because of our active hedging program, which helps offset impact from currency movements.

外匯波動對報告的成長影響甚微，這主要是因為我們積極的避險計畫有助於抵銷匯率波動的影響。

Our second quarter combined non-GAAP SG&A, R&D and acquired IPR&D expenses were $750 million compared to $1.5 billion in the second quarter of 2021. The year-over-year decline was primarily related to the $900 million payment in the second quarter of 2021 for the amended collaboration agreement with CRISPR Therapeutics. This effect was partially offset by higher expenses resulting from our advancing pipeline, especially in CF, pain and type 1 diabetes as well as expenses for CF launches and pre-commercial activities for exa-cel.

我們第二季的非GAAP合併銷售、管理及行政費用、研發費用以及收購智慧財產權開發費用為7.5億美元，而2021年第二季為15億美元。年比下降的主要原因是2021年第二季支付了9億美元，用於與CRISPR Therapeutics公司修訂合作協議。這項影響部分被我們不斷推進的研發管線（尤其是在囊性纖維化、疼痛和1型糖尿病領域）帶來的更高費用以及exa-cel在囊性纖維化領域的上市和商業化前活動費用所抵消。

Our continued strong revenue growth, combined with our efficient operating model resulted in a Q2 non-GAAP operating margin of 54% and non-GAAP operating income of $1.19 billion compared to $71 million in the second quarter of 2021. This increase was primarily driven by strong product revenue growth and the year-over-year comparison to the second quarter of 2021, which included the $900 million payment to CRISPR. Our non-GAAP effective tax rate for the second quarter of 2022 was 22%. We ended the quarter with $9.3 billion in cash and investments, and our balance sheet profile remains very strong.

我們持續強勁的營收成長，加上高效率的營運模式，使得2022年第二季非GAAP營業利潤率達到54%，非GAAP營業收入達到11.9億美元，而2021年第二季為7,100萬美元。這一成長主要得益於強勁的產品營收成長以及與2021年第二季相比的年成長，後者包含了向CRISPR支付的9億美元。 2022年第二季的非GAAP實際稅率為22%。季度末，我們持有現金及投資93億美元，資產負債表狀況依然非常穩健。

As Reshma highlighted, on the external innovation front, we've recently announced multiple business development deals including the acquisition of Viacyte for $320 million in cash with closing subject to certain conditions, including the expiration of the Hart-Scott-Rodino waiting period. This transaction will bring us tools, technologies and assets that will accelerate our goal of bringing curative therapy to millions of people with type 1 diabetes.

正如雷什瑪所強調的，在外部創新方面，我們近期宣布了多項業務拓展交易，包括以3.2億美元現金收購Viacyte公司，該交易的完成需滿足特定條件，例如哈特-斯科特-羅迪諾反壟斷法案規定的等待期屆滿。這項交易將為我們帶來工具、技術和資產，從而加速我們為數百萬1型糖尿病患者提供治癒性療法的目標。

Now to guidance. We are raising our 2022 product revenue guidance to a range of $8.6 billion to $8.8 billion based on current exchange rates. The increase reflects the rapid uptake we have seen with new launches in geographies where we recently secured reimbursement for TRIKAFTA/KAFTRIO as well as continued performance in the U.S. Year-over-year, our updated guidance represents product revenue growth of approximately 15% at the midpoint.

現在來說說業績展望。根據目前匯率，我們將2022年產品收入預期上調至86億美元至88億美元。此次上調反映了我們在近期獲得TRIKAFTA/KAFTRIO醫保報銷的地區推出新產品後，市場反應迅速，以及產品在美國市場的持續良好表現。與前一年相比，我們更新後的預期中位數約為15%。

Now to OpEx. Our R&D strategy was designed to deliver disproportionate success and we are seeing that strategy play out with multiple programs now in mid- and late-stage development, each of which could drive significant future growth. With our strong financial profile, we expect to continue investing in both internal innovation with our rapidly advancing pipeline as well as external innovation that fits with our R&D strategy and complements our existing portfolio. As a result, non-GAAP operating expenses for the year are now projected to be in a range of $3 billion to $3.1 billion, an increase from our previous guidance of $2.82 billion to $2.92 billion. The increase is primarily due to incremental expenses resulting from the advancement of our pipeline programs into late-stage clinical trials, particularly in pain and AMKD as well as additional upfront and milestone payments.

接下來談談營運支出。我們的研發策略旨在取得超乎尋常的成功，目前我們看到該策略正在逐步實現，多個專案已進入中後期研發階段，每個專案都有望推動未來顯著成長。憑藉我們穩健的財務狀況，我們將繼續投資於內部創新（包括我們快速推進的研發管線）以及符合我們研發策略並能補充我們現有產品組合的外部創新。因此，我們預計本年度非GAAP營運支出將在30億美元至31億美元之間，高於先前28.2億美元至29.2億美元的預期。成長的主要原因是，我們的研發管線計畫（尤其是在疼痛和AMKD領域）進入後期臨床試驗階段，以及新增的預付款和里程碑付款。

Finally, we continue to project a non-GAAP effective tax rate in the range of 21% to 22%. As we consider the second half of 2022 and into early 2023, we look forward to a number of important milestones to mark our continued progress, several of which are outlined on this slide.

最後，我們繼續預期非GAAP有效稅率在21%至22%之間。展望2022年下半年和2023年初，我們期待一系列重要的里程碑事件，這些事件將標誌著我們持續取得進展，其中一些已在本幻燈片中概述。

As Reshma discussed earlier in the call, Vertex is at a new inflection point. We're in our eighth consecutive year of double-digit revenue growth, and we've built a remarkably durable business with long-term leadership in CF delivering strong cash flow for years to come. We're also well on our way to diversifying the business and adding to our long-term growth potential with 5 disease areas now in late-stage development and multiple new medicines set to enter the clinic. We are developing these programs with the intent of creating transformative, high-value medicines, each of which represents a multibillion-dollar opportunity.

正如Reshma在先前的電話會議中提到的，Vertex正處於一個新的轉折點。我們已連續八年實現兩位數的營收成長，並打造了一個極具韌性的業務，在囊性纖維化領域保持著長期領先地位，能夠為未來數年帶來強勁的現金流。同時，我們也穩步推動業務多元化，並不斷提升長期成長潛力。目前，已有5個疾病領域的藥物研發進入後期階段，多個新藥即將進入臨床試驗。我們開發這些計畫的目標是打造具有變革意義的高價值藥物，每個藥物都蘊藏著數十億美元的商機。

Fueled by our success in CF, we can continue to invest in our advancing pipeline while also delivering exceptional profitability and cash flow. As always, we look forward to updating you on our further progress throughout the balance of the year.

憑藉我們在CF領域的成功，我們可以繼續投資於正在推進的專案研發，同時實現卓越的獲利能力和現金流。我們將一如既往地在今年餘下的時間裡向您報告我們的進一步進展。

Let's now open the call to questions.

現在開始接受提問。

(Operator Instructions)

（操作說明）

And the first question will come from Salveen Richter with Goldman Sachs.

第一個問題將來自高盛的薩爾文·里希特。

Nice quarter here. Just a pipeline question with regard to your program for beta cell and sickle cell, what does the FDA want with regard to number of patients? And what duration here, are they looking at a proportion out to 2 years similar to what we saw with bluebird? Just curious where you stand there.

本季業績不錯。關於你們的β細胞和鐮狀細胞貧血症項目，我有個關於研發管線的問題：FDA對病人數量有什麼要求？研發週期是多久？他們是否希望達到兩年左右，就像我們之前看到的Bluebird計畫一樣？我只是好奇你們目前的進展。

Yes. Salveen, this is Reshma. With regard to the exa-cel program and what the FDA is looking for, it is down to these 2 areas for us to reach conclusion on the number of patients in the file and the duration of follow-up. We are -- we have been having conversations, very productive conversations with them over the last many months, and we are done in our -- in terms of the conversations for the preclinical package, CMC and manufacturing and all of the other modules. It is about these 2 areas. And we are expecting to wrap up these conversations in the coming weeks. So we don't have to speculate. We'll be able to update you after that. But it is really down to just those 2 points; number of patients they'd like to see in the file and the duration of follow-up.

是的，Salveen，我是Reshma。關於Exa-Cel計畫以及FDA的核准要求，我們需要在兩個方面做出最終決定：一是納入研究的患者數量，二是追蹤時間。過去幾個月，我們一直在與他們進行富有成效的溝通，目前我們已經完成了臨床前研究、CMC（化學、製造和控制）、生產以及其他所有模組的討論。現在的問題就集中在這兩個方面。我們預計將在未來幾週內完成這些討論，所以無需猜測。之後我們會及時更新進展。但關鍵在於這兩點：他們希望納入研究的患者數量以及追蹤時間。

I will just reiterate that we've -- these are similar topics that we've been talking to the EMA and MHRA on, and we have come to conclusion on that.

我只想重申一下，這些是我們一直在與歐洲藥品管理局 (EMA) 和英國藥品和保健產品監管署 (MHRA) 討論的類似話題，我們已經就此達成了結論。

The next question will come from Michael Yee with Jefferies.

下一個問題將來自傑富瑞集團的邁克爾葉。

A question on, I guess, inaxaplin. You are enrolling the Phase II portion, and then it rolls into a Phase III. Could you comment on how the Phase II portion is going in terms of pace of enrollment, and whether you've data to talk about at the end of the year? I think that would give a good insight into how you would think about the Phase III because I know it is a challenging population to necessarily enroll. So maybe talk a little bit about that. And then, I guess, a follow-up to Salveen's question on exa-cel. If it is a 2-year requirement, how long does that push things out? Does that push the timing out by a year? Or just help us out with that dynamic?

我想問一個關於inaxaplin的問題。你們正在進行二期臨床試驗，之後會進入第三期臨床試驗。能否談談二期臨床試驗的進展情況，例如入組速度如何？年底是否有相關數據可以分享？我認為這將有助於我們了解你們對三期臨床試驗的規劃，因為我知道三期臨床試驗的入組人群比較困難。所以能否談談這方面的情況？另外，我想就Salveen關於exa-cel的問題來補充一下。如果exa-cel需要兩年時間，那麼整個流程會因此延遲多久？是會延長一年嗎？還是說只是對這方面的進展有幫助？

Yes. Michael, there were 2 questions in there. One about AMKD and one about exa-cel. Let me just close out on exa-cel first.

是的，邁克爾，裡面有兩個問題。一個是關於AMKD的，一個是關於exa-cel的。我先來說說exa-cel吧。

As we were just discussing, we are going to have our meetings with the FDA to wrap up these discussions in the coming weeks. And so we're not going to need to speculate. We'll be able to update you on the specifics and give you a timeline in the near future.

正如我們剛才討論的，我們將在未來幾週內與FDA舉行會議，以結束這些討論。因此，我們無需進行任何猜測。我們將在不久的將來向您提供具體細節和時間表。

With regard to AMKD, the point that you make about the difficulty enrollment based on the patient population is a really good point. While the AMKD population shares many similarities with CF, genetically driven disease, about 100,000 patients, and our approach to treating CF is by targeting the CFTR protein, the underlying cause of disease. It's the same thing with AMKD. We're targeting the APOL1 protein. Where the big difference comes in is in diagnosis, disease awareness and genotyping. But recognizing this, we've inserted 3 initiatives into this Phase II/III program. The first is we're opening over 150 sites globally so that we have sites to close to where the patients are, and simply many of them. Second, we have an observational study ongoing. That's a genotyping study. People who genotype in with 2 APOL1 alleles are then eligible and could be enrolled in the randomized controlled trial. And lastly, as you heard Stuart discuss, we're working with patient groups and physician groups and the community as a whole to raise awareness.

關於AMKD，您提到的基於病患群體招募困難的問題確實非常重要。雖然AMKD患者群體與CF（一種由基因驅動的疾病，約有10萬名患者）有很多相似之處，而我們治療CF的方法是靶向CFTR蛋白，即該疾病的根本原因，AMKD也是如此。我們標靶的是APOL1蛋白。兩者最大的差別在於診斷、疾病認知和基因分型。有鑑於此，我們在二/三期臨床試驗計畫中加入了三項措施。首先，我們正在全球開設超過150個研究中心，以便盡可能靠近患者，並涵蓋更多患者。其次，我們正在進行一項觀察性研究，這是一項基因分型研究。基因分型結果顯示攜帶兩個APOL1等位基因的人符合條件，可以參與隨機對照試驗。最後，正如你聽到史都華所說，我們正在與病人團體、醫生團體以及整個社區合作，以提高人們的意識。

I will point out, Michael, that the beauty of the Phase II/III study is we do everything upfront. That is to say that the phase -- the trial sites that will be the Phase III trial sites, they're all being opened up right now as part of the Phase II/III study.

邁克爾，我要指出的是，二/三期臨床試驗的優勢在於我們所有工作都提前完成。也就是說，作為二/三期臨床試驗的一部分，所有試驗中心——也就是未來三期臨床試驗的中心——現在都已在二/三期臨床試驗階段開放。

So you're committed to giving data on the Phase II? Will you say anything, or just move forward?

所以你們承諾會公佈二期臨床試驗的數據嗎？你們會透露一些訊息，還是就此作罷？

Yes. Sorry about -- you had a question on the data. When we are at the point of having selected our dose on the Phase II part, you should expect to hear from us.

是的。抱歉，您之前問了關於數據的問題。當我們確定二期臨床試驗的劑量後，我們會與您聯繫。

The next question will come from Phil Nadeau with Cowen.

下一個問題將來自 Cowen 公司的 Phil Nadeau。

This is (inaudible) on for Phil. Congrats on the progress. Maybe just on 147. Potentially, could you give us an update on how you're thinking about potential baseline characteristics for the patients enrolled in the Phase II/III study now that it's targeting the broader AMKD population. Just curious how you're thinking about the potential differences in proteinuria and eGFR looking across the clinical sector of APOL1 (inaudible).

這是給菲爾的（聽不清楚）。祝賀你的進展。也許只是關於147號。鑑於目前II/III期研究的目標族群已擴大到更廣泛的AMKD族群，你能否更新一下你對入組患者基線特徵的考慮？我只是好奇你如何看待APOL1（聽不清楚）臨床領域中蛋白尿和eGFR的潛在差異。

Yes. I think the question is how are we thinking about the patients who would enroll and what do we think their baseline characteristics would be in this AMKD population?

是的。我認為問題在於，我們如何考慮入組患者，以及我們認為AMKD患者群體的基線特徵是什麼？

To reground the unifying entry criteria for the Phase II/III study are really threefold in terms of the key criteria. The first is 2 APOL1 alleles. The second is a reduced renal function. And the third is proteinuria that's greater than 0.7 grams. So all patients in this study will have those key criteria. Now of course, as you point out, there's going to be a spectrum of disease, and we fully expect patients to have diversity in terms of the range of proteinuria as well as the renal function. But the really important point is that this is a rather homogeneous population of 2 APOL1 alleles, proteinuria and reduced kidney function.

為了明確二/三期研究的統一入組標準，關鍵標準主要有三點：第一是攜帶兩個APOL1等位基因；第二是腎功能減退；第三是尿蛋白定量大於0.7克。所有入組患者均需符合這些關鍵標準。當然，正如您所指出的，疾病譜系會很廣，我們完全預料到患者在尿蛋白定量和腎功能方面會存在差異。但真正重要的是，這是一群相對同質的患者，他們均攜帶兩個APOL1等位基因，存在尿蛋白定量和腎功能減退。

Great. That's very helpful. And if I may, is there any chance that you'll release data from the observational study that you mentioned that you're enrolling? Just to get the genotyping data, et cetera?

太好了，這很有幫助。如果可以的話，請問您能否公佈您提到的正在招募參與者的觀察性研究的數據？我想取得基因分型數據等等。

Yes, it's a great question. I'm sure the teams are planning to share that data. That study because it is a very simple observational study that is genotyping people is already well into the hundreds of patients that we have screened and enrolled. I'm sure the IR team can give you specifics offline.

是的，這是一個很好的問題。我相信各團隊正在計劃分享這些數據。這項研究是一項非常簡單的觀察性研究，主要對受試者進行基因分型，目前我們已經篩選並招募了數百名患者。我相信介入放射學團隊可以私下提供更詳細的資訊。

The next question will come from Liisa Bayko with Evercore ISI.

下一個問題將來自 Evercore ISI 的 Liisa Bayko。

I was wondering if you could give us any sense of what you're looking for in the SKYLINE 102 and 103 study specifically, to be able to follow on that. What are the benchmarks and clinical meaningfulness that you're looking for?

我想請您具體說明您在SKYLINE 102和103研究中希望獲得哪些結果，以便我們能夠跟進。您希望達到的基準和臨床意義是什麼？

Yes. Sure thing, Liisa.

好的，當然可以，莉莎。

So SKYLINE -- the 2 SKYLINE studies and now the [RIDGELINE] study, which is the study of 121/561 tezacaftor in the 6- to 11-year-olds, which is also ongoing. Here's what we're looking for based on every piece of data that we have, including our HBE assays, which you know is not only qualitatively but quantitatively predictive of what we see in the clinic. We expect to see greater sweat chloride than even TRIKAFTA. Based on the Phase II studies where we looked at sweat chloride and we looked at ppFEV1, we expect 121/561 tez has the potential to be even greater than TRIKAFTA. And at the end of the day, what we are really looking for here is ppFEV1, sweat chloride levels and, of course, the safety profile.

所以，SKYLINE——包括兩項SKYLINE研究，以及目前正在進行的RIDGELINE研究（一項針對6至11歲兒童的121/561 tezacaftor研究）。基於我們掌握的所有數據，包括我們的HBE檢測（您知道，HBE檢測不僅能定性預測，還能定量預測我們在臨床上觀察到的結果），我們正在尋找以下資訊：我們預計121/561 tezacaftor的汗液氯化物水平甚至高於TRIKAFTA。基於我們先前在II期研究中對汗液氯化物和ppFEV1的觀察，我們預期121/561 tezacaftor的潛力甚至可能超過TRIKAFTA。最終，我們真正關注的是ppFEV1、汗液氯化物水平以及安全性。

From what we see preclinically and clinically in those Phase II studies that I described, I expect that 121/561 tez has the real potential to be superior to TRIKAFTA. And remember, when we talk about that, the best readout of the function of CFTR modulators is on sweat chloride. That's the most direct readout, the PD readout, if you will. And that has been consistently superior in HBEs, Phase I and our Phase II studies.

從我之前提到的那些II期臨床前和臨床研究結果來看，我預期121/561 tez確實有潛力優於TRIKAFTA。請記住，當我們討論這個問題時，CFTR調節劑功能的最佳指標是汗液氯化物。這是最直接的指標，或者說是藥效學指標。在人體試驗、I期和II期研究中，汗液氯化物水平始終優於TRIKAFTA。

The next question will come from Geoff Meacham with Bank of America.

下一個問題將來自美國銀行的傑夫·米查姆。

Congrats on the good quarter. I wanted to ask on 548. When you consider the market opportunity and what could be a pretty broad program, I just wanted to get your perspective on what success looks like kind of at a high level. And then I wasn't sure if you've had pre-Phase III meetings with FDA, but how you're thinking about the size and scope of the pivotal that you'll start the second half of the year?

恭喜你們季度業績出色。我想問一下關於548號專案的問題。考慮到市場機會以及可能相當廣泛的專案規模，我想了解你們對成功的高層次理解。另外，我不確定你們是否已經與FDA進行過III期臨床試驗前的會談，但你們是如何考慮下半年啟動的關鍵性試驗的規模和範圍的呢？

Geoff, sure thing. This is Reshma. Let me start, and then I'll turn it over to Stuart to talk about the market opportunity.

傑夫，當然可以。我是雷什瑪。我先開始，然後我把麥克風交給史都華，讓他談談市場機會。

This is one of the programs that I have very high enthusiasm for it, and we are -- we have high expectations for it. And the reason for that is, I've already talked about the genetic and pharmacologic validation, but the other reason for this is it really has potential across acute pain, neuroplastic pain and, let's call it, musculoskeletal pain, although the focus right now in terms of where the program is most advanced is in acute pain.

這是我非常看好並寄予厚望的項目之一。原因在於，我之前已經談到了基因和藥理學驗證，但另一個原因是它在急性疼痛、神經可塑性疼痛以及我們姑且稱之為肌肉骨骼疼痛方面都具有巨大潛力，儘管目前該項目進展最快的地方在於急性疼痛。

The last reason I have such excitement for this program is the market opportunity is near term. Let me describe the pivotal program. And yes, we have completed our end of Phase II meeting with the FDA, and we have reached agreement on this program.

我對這個項目如此興奮的最後一個原因是，它即將迎來市場機會。讓我來詳細介紹一下這個關鍵項目。是的，我們已經完成了與FDA的二期臨床試驗結束會議，並就該計畫達成了一致。

So here's the program. It's about 2,000-or-so patients in 2 randomized controlled trials that look exactly like the Phase II trial, one in abdominoplasty, and one in bunionectomy and a third single-arm study that takes all pain types, procedure-related as well as, for example, a fracture or a sprain or soft tissue injury. And the program is so designed so that we have a broad acute pain indication for the treatment of moderate-to-severe pain. That's really the beauty of this program.

這就是這個項目。它包含大約2000名患者，分為兩項隨機對照試驗，與二期臨床試驗完全相同，一項針對腹部整形術，另一項針對拇外翻切除術；此外還有一項單組研究，涵蓋所有類型的疼痛，包括手術相關疼痛以及例如骨折、扭傷或軟組織損傷等引起的疼痛。該計畫的設計旨在獲得廣泛的急性疼痛適應症，用於治療中度至重度疼痛。這正是該專案的優勢所在。

Stuart, I'm going to turn it over to you for market potential.

斯圖爾特，我打算把它交給你來評估市場潛力。

Yes, Geoff. And so why we're so excited about our agreement with the FDA and the broad indication it could lead to if the studies are positive, which we have a high level of confidence, they will be is because the moderate-to-severe acute pain market is incredibly large. So as I said in my prepared remarks, it's over 1.5 billion with the B treatment days a year in the U.S. alone. And 2/3 of those are about 1 billion treatment days a year are either initiated in hospital or influenced by hospital as a result of patients being discharged after either their inpatient or outpatient visit where they were given treatment for pain.

是的，傑夫。我們之所以對與FDA達成的協議以及如果研究結果積極（我們對此非常有信心）可能帶來的廣泛適應症感到如此興奮，是因為中重度急性疼痛市場規模巨大。正如我在準備好的演講稿中所說，光是在美國，每年就有超過15億個B類治療日。其中約三分之二，也就是每年約10億個治療日，要么是在醫院開始的，要么是受醫院影響的，因為患者在住院或門診接受疼痛治療後出院。

So 1.5 billion treatment days, as you know, the vast majority of that market is currently genericized. But even so, it's a $4 billion market in the U.S. alone today. And so we know that if we bring to market a highly effective pain med that also has a great safety and tolerability profile, we should expect to be able to get a decent share of that market and then a branded oral pain medicine at price of around $10 a day. That is a very significant multibillion-dollar opportunity. And so that's why both Reshma and I have a high level of enthusiasm for this program.

如您所知，15億個治療日，目前絕大部分市場份額已被仿製藥佔據。即便如此，光是在美國，如今的市場規模也高達40億美元。因此，我們知道，如果我們能推出一種高效、安全性高且耐受性好的止痛藥，就能佔據相當可觀的市場份額，並推出價格在每天10美元左右的品牌口服止痛藥。這是一個價值數十億美元的巨大商機。正因如此，我和雷什瑪都對這個計畫充滿熱情。

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

下一個問題將來自 BMO 資本市場的 Evan Seigerman。

Congrats on the quarter. Kind of following up to Geoff's question on pain. I'd love to take a step back and really get some color on how you envision 548 fitting within the acute pain management paradigm? And I assume the goal would be to use 548 ahead of opioid therapy but still kind of have the option for opioid therapy if there's breakthrough pain. And with that, would you need to show a safety kind of perspective using both together? Maybe provide us color as to how you think about this fitting in.

恭喜你本季取得佳績。我想就Geoff關於疼痛的問題做個補充。我想深入了解你對548在急性疼痛管理模式中的應用願景。我猜你的目標是在阿片類藥物治療之前使用548，但如果出現突破性疼痛，仍然可以選擇阿片類藥物治療。那麼，你是否需要從安全性的角度來闡述這兩種藥物合併使用的情況呢？能否詳細解釋一下你對這種療法如何融入現有治療方案的看法？

Yes. Evan, it's Stuart here. I'll take that one.

是的。埃文，我是史都華。我來接這個任務。

So the way acute pain is currently managed, obviously, if it were very, very mild, people might be taking kind of over-the-counter pain meds, then people would go to transition to kind of sort of nonsteroidal, then go through to opioids and then maybe something else. So what we're imagining here with VX-548 is essentially sort of a step therapy approach where we would be sort of inserting ourselves between those initial prescription NSAs and opioids. And we believe that's a realistic proposition based on the clinical profile that we've seen to date and our discussions with physicians, that's where they would see this kind of medicine fitting in. So that's how we would see it fitting into the treatment paradigm based on the sort of efficacy profile and safety and tolerability profile that we've seen.

所以，目前急性疼痛的治療方法顯然是這樣的：如果疼痛非常輕微，人們可能會先服用非處方止痛藥，然後過渡到非類固醇類抗發炎藥，再到鴉片類藥物，最後可能還會嘗試其他藥物。因此，我們所設想的VX-548療法本質上是一種階梯式治療方法，在最初的處方非類固醇類抗發炎藥物和鴉片類藥物之間插入一種治療方案。根據我們目前觀察到的臨床數據以及與醫生的討論，我們認為這是一個切實可行的方案，醫生也認為這種藥物適合在這個階段使用。因此，根據我們觀察到的療效、安全性和耐受性數據，我們認為VX-548應該融入現有的治療模式中。

Evan, this is Reshma.

艾文，這位是雷什瑪。

To add to what Stuart said, there is a raging opioid epidemic in this country. And it is a public health crisis. So I think the most recent CDC report indicated 75,000 deaths in this last year, which is a 35% increase over the past year. So this is not a historic issue. It's a current day crisis. And I think that this approach that Stuart described where there is a step from over-the-counter pain medicines and then to a drug like VX-548, which because it only works in the periphery, there are no central receptors. There is no addictive potential here, I think, has enormous potential. And from physicians and community groups and health care officials that we've spoken with, there is huge enthusiasm for this kind of mechanism.

正如史都華所說，美國正面臨一場肆虐的鴉片類藥物濫用危機，這是一場公共衛生危機。根據疾管中心最新的報告，去年有7.5萬人死於鴉片類藥物濫用，比前一年增加了35%。這並非歷史遺留問題，而是當下的危機。我認為史都華描述的這種方法——先使用非處方止痛藥，然後過渡到像VX-548這樣的藥物——具有巨大的潛力。 VX-548只作用於週邊神經系統，沒有中樞受體，因此不存在成癮性。我們與醫生、社區團體和衛生官員交流後發現，他們對這種治療機制充滿熱情。

The next question will come from Colin Bristow with UBS.

下一個問題將來自瑞銀集團的柯林布里斯托。

Congrats on the quarter. So on the Viacyte acquisition, the VX-880 program. Could you just walk us through just -- obviously, there's areas of program overlap. Just how should we think about prioritization here? And maybe just flesh out a little bit more about just some of the -- and how it augments the program for you overall? And then on VX-548, so it sounds like trial initiation before year-end and acknowledging that it's large population size, but it is a short primary endpoint. When do you think you'd be in a position to (inaudible) out topline for those trials?

恭喜本季業績。關於Viacyte的收購以及VX-880項目，您能否簡要介紹一下——顯然，這兩個項目在某些方面存在重疊。我們應該如何考慮優先排序？能否再詳細闡述一下，它如何增強您整體的專案？另外，關於VX-548，聽起來試驗將在年底前啟動，雖然樣本量很大，但主要終點指標較短。您預計何時能夠公佈這些試驗的主要結果？

Yes. Colin, let me just tackle the 548 question first, and then I'll get to Viacyte and the type 1 diabetes programs. The 548 programs are the pivotal program. It's really quite an efficient development program. These studies are quite short in duration. We know exactly how to do them. We've done them with VX-150. We did it again with VX-548. And the RCTs, the 2 randomized clinical trials, are very well understood surgical procedures, bunionectomy and abdominoplasty. I expect that these programs will progress quickly.

是的。科林，我先回答548的問題，然後再談Viacyte和第1型糖尿病計畫。 548項目是關鍵項目，也是非常有效率的研發項目。這些研究週期很短，我們非常清楚如何進行。我們已經用VX-150做過類似的研究，也用VX-548做過。另外兩個隨機對照試驗（RCT）針對的是非常成熟的外科手術－拇趾外翻切除術和腹部整形術。我預計這些項目會進展迅速。

With regard to the Viacyte acquisition. The real goal here for us in the type 1 diabetes program is to transform, if not cure, this disease. That is certainly what we are aiming for. And we have 3 programs internally aimed at exactly that goal, VX-880, let's call it the naked cell program. The next program, which is the same cells as VX-880 in a device to evade the immune system. And the third program is those same cells that we edit and we call them hypoimmune cells. We are well on our way to achieving this goal of transforming type 1 diabetes, which you can see from the first 2 patients dosed at half dose with VX-880. What we're doing and the value of the Viacyte acquisition is accelerating our ability to get there. Specifically, Viacyte brings us tools and technologies, IP capabilities in manufacturing in particular and talent that's going to accelerate our ability to get to this cure.

關於收購Viacyte，我們1型糖尿病計畫的真正目標是改變甚至治癒這種疾病。這當然是我們努力的方向。我們內部有三個項目正是為了實現這一目標：VX-880，我們暫且稱之為裸細胞項目；第二個項目是將與VX-880相同的細胞植入一種能夠逃避免疫系統的裝置中；第三個項目則是對這些細胞進行基因編輯，我們稱之為低免疫細胞。我們正朝著改變第1型糖尿病目標穩步前進，正如前兩位接受半劑量VX-880治療的患者所展現的那樣。我們正在做的事情以及收購Viacyte的價值在於加速我們實現這一目標。具體而言，Viacyte為我們帶來了工具和技術，尤其是在生產製造方面的智慧財產權和人才，這些都將加速我們找到治癒方法的進程。

If I double-click on that, what I'm really talking about are GMP cell lines, GMP manufacturing, access to a clinical-stage program with hypoimmune cells via the Viacyte CRISPR collaboration. And as we did with CF, our goal here -- and what we expect to do is move multiple programs in parallel and then choose the best one or ones to take the late-stage development and commercialization.

如果我雙擊那個鏈接，我真正指的是符合GMP標準的細胞系、符合GMP標準的生產流程，以及透過與Viacyte的CRISPR合作，獲得一個處於臨床階段的低免疫細胞項目。就像我們在囊性纖維化（CF）領域所做的那樣，我們的目標——也是我們計劃要實現的——是並行推進多個項目，然後選擇最佳項目進入後期開發和商業化階段。

The next question will come from David Risinger with SVB Securities.

下一個問題將來自SVB證券的David Risinger。

So I have a couple of questions about the AMKD interim that you have spoken to. Could you discuss your expectations for the control arm's eGFR rate of decline at 48 weeks. That's a short period of time and the control arm patients, I think, will be well taken care of on the standard of care, which is not always the case in the real world. So it would be helpful to understand what you're expecting for the control arm's decline. And then assuming that you do succeed in handing on the interim, has the FDA suggested that it would be supportive of an early filing on just the positive interim data?

關於您提到的AMKD中期研究，我有幾個問題。您能否談談您對對照組在48週時eGFR下降率的預期？ 48週時間很短，我認為對照組患者會得到很好的標準治療，但這在現實世界中並非總是如此。因此，了解您對對照組eGFR下降率的預期將很有幫助。另外，假設您成功提交了中期研究結果，FDA是否表示會支持僅憑積極的中期數據就提前提交申請？

Yes. Sure thing.

好的，沒問題。

With regard to the question around the interim analysis, and is the agency supported of an accelerated approval based on the interim analysis. Unambiguously, yes. This is one of the points of agreement that we reached at our end of Phase II meeting, which is one of the very important points that we were driving to ensure we had conclusion on. The reason for that is the following: APOL1-mediated FSGS or APOL1-mediated kidney disease as a whole is a different ball of wax than non-APOL1-mediated kidney disease. In other words, those who have 2 APOL1 alleles have very aggressive disease. We're talking about rate of declines annually north of 5 CCs per year. That is a very significant reduction in kidney function.

關於中期分析的問題，以及監管機構是否支持基於中期分析結果加速批准，答案是肯定的。這是我們在二期臨床試驗結束會議上達成的共識之一，也是我們力求達成一致的重要議題之一。原因如下：APOL1 介導的局部節段性腎絲球硬化症（FSGS）或 APOL1 介導的腎臟疾病與非 APOL1 介導的腎臟疾病截然不同。換句話說，攜帶兩個 APOL1 等位基因的患者病情進展非常迅速。我們指的是每年腎小球濾過率下降超過 5 毫升。這代表著腎功能的顯著下降。

Unfortunately, there are no specific treatments for AMKD, and they certainly are no targeted treatments. So even though patients are often on standard of care medicines, this decline that I talked about is continuing. So with regard to our program, we have designed it to have this interim analysis after 48 weeks of treatment, where we will be able to assess the proteinuria difference between those treated with VX-147 versus the standard of care as well as the decline in renal function. And because these patients are so fit and the progression is so fast, it offers the opportunity to make this assessment at 1 year, which is not always the case in non-APOL1-mediated kidney disease. That's why it usually takes longer because the rate of decline is just playing slower. Very, very different in AMKD.

可惜的是，目前尚無針對AMKD的特效療法，更沒有標靶治療。因此，即使患者通常接受標準治療藥物，我之前提到的病情惡化仍在持續。就我們的計畫而言，我們設計了在治療48週後進行中期分析，以便評估VX-147治療組與標準治療組在蛋白尿差異以及腎功能下降方面的差異。由於這些患者身體狀況良好，病情進展迅速，因此我們有機會在1年時進行評估，這在非APOL1介導的腎臟病中並不常見。通常情況下，由於腎功能下降速度較慢，評估時間會更長。而AMKD的情況則截然不同。

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

下一個問題將來自富國銀行的莫希特·班薩爾。

Congrats on the quarter. I have a question and a clarification for Charlie. So the clarification is, are we including $300 million of Viacyte acquisition in IPR&D at this point for your guidance? Number one. And the question is for R&D and SG&A combined, it looks like -- I mean you're in a good situation of having so many programs which are entering into pivotal phase. Keeping that in mind, how sustainable is this a mid-50% operating margin profile going forward for the next couple of years, given that you are investing heavily in R&D.

恭喜你本季業績出色。我有一個問題想請教查理。首先，我想問的是，你目前的業績指引是否已將Viacyte收購的3億美元計入研發投入？這是第一個問題。其次，關於研發和銷售、管理及行政費用（SG&A）的合併情況，你目前的情況看起來不錯——有很多項目都進入了關鍵階段。考慮到這一點，鑑於你在研發方面投入龐大，未來幾年能否維持50%左右的營業利潤率？

Sure. Good question. As we mentioned, the success that we've had in the pipeline recently really is unprecedented. And so not surprisingly, with the great data and several multibillion-dollar opportunities, we are investing behind the success of these programs, and that really is what drives the OpEx increase in recent quarters and in our guidance. Specifically in the guidance I would highlight the success in pain and AMKD as the biggest drivers of the change in the OpEx guidance. And importantly, all of the increase, 90-plus percent of the increase is in R&D. So it's certainly very, very good news from our perspective, and we'll continue to invest.

當然。問得好。正如我們之前提到的，我們近期在研發管線方面取得的成功確實是前所未有的。因此，毫不奇怪，憑藉著出色的數據和幾個價值數十億美元的項目，我們正在加大對這些項目的投資，而這正是近幾個季度營運支出成長以及我們業績指引的主要驅動因素。具體來說，在績效指引方面，我想強調疼痛治療和AMKD領域的成功是推動營運支出指引變化的最大因素。而且重要的是，所有成長，超過90%的成長都用於研發。所以從我們的角度來看，這無疑是個非常好的消息，我們將繼續增加投資。

In terms of the ability to sustain margins, we have a fantastic model. When you develop transformative medicines for serious diseases, there's tremendous value unlocked there, which allows us to consistently reinvest in innovation. And so we believe that with this model, we can sustain very, very attractive operating margins for the foreseeable future.

就維持利潤率而言，我們擁有一個絕佳的模式。當我們研發出治療嚴重疾病的變革性藥物時，就能釋放出巨大的價值，這使我們能夠持續地對創新進行再投資。因此，我們相信，憑藉這一模式，我們可以在可預見的未來保持極具吸引力的營運利潤率。

Your specific question around Viacyte. That is not in the guidance yet as we are in the Hart-Scott-Rodino waiting period and can't accurately forecast a close date for the transaction. That is not included in the guidance. And when we know the transaction close date, we'll update accordingly.

關於您提出的Viacyte的具體問題，目前尚未納入指導意見中，因為我們正處於《哈特-斯科特-羅迪諾反壟斷改進法案》的等待期內，無法準確預測交易完成日期。因此，該資訊暫未包含在指導意見中。一旦確定交易完成日期，我們將及時更新指導意見。

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

下一個問題將來自 Cantor Fitzgerald 公司的 Olivia Brayer。

Congrats on the great quarter. I wanted to follow up on CTX001. I know you're still in conversations with FDA, but are there any metrics beyond number of patients and duration of follow-up that could be different between the agreed upon EMA and MHRA submission packages versus what you might have to file in the U.S. And then just a quick clarification question on the filings. It looks like in the press release, you guys mentioned you're on track to file in Europe and the U.K. by year-end but it doesn't specifically call out the U.S. So I just wanted to clarify to see if there's any change to your assumptions there.

恭喜貴公司本季業績斐然。我想跟進一下關於CTX001的情況。我知道貴公司仍在與FDA進行溝通，但除了患者數量和追蹤時間之外，EMA和MHRA的備案資料與貴公司可能需要在美國提交的資料之間，還有哪些指標可能存在差異？另外，關於備案事宜，我還有一個疑問。在新聞稿中，貴公司提到計劃在年底前向歐洲和英國提交申請，但沒有明確提及美國。所以我想確認一下，貴公司在這方面的預期是否有改變。

Yes. Sure thing.

好的，沒問題。

We have been having conversations, and we're really fortunate because we have every designation offered by regulators on this side of the pond and the other that allow us to have frequent conversations with them. And so we've been having these conversations with MHRA, EMA and FDA for many months. The topic of conversations have evolved because over time, we've settled out the preclinical package. We've settled out on CMC and manufacturing and all of the other modules. The conversation with EMA and MHRA towards the end as we were concluding those discussions, we're on the same point as with FDA. And that was around number of patients in the filing and duration of follow-up. We have come to conclusion. We have reached agreement. And therefore, I can say that we are on track, and we fully expect to get our filing in towards the end of this year.

我們一直在進行溝通，非常幸運的是，我們獲得了大西洋兩岸監管機構授予的所有資格，這使我們能夠與他們頻繁交流。因此，我們與英國藥品和保健產品監管署 (MHRA)、歐洲藥品管理局 (EMA) 和美國食品藥物管理局 (FDA) 的溝通已經持續了數月。隨著我們逐步完善臨床前研究方案、CMC（化學、製造和控制）、生產以及所有其他模組，溝通的內容也在不斷變化。在與 EMA 和 MHRA 的討論接近尾聲時，我們與 FDA 的立場一致，即申報的患者數量和追蹤持續時間。我們已經達成一致，並達成了共識。因此，我可以肯定地說，我們一切進展順利，完全有信心在今年年底前提交申請。

With regard to the FDA, we simply haven't hit that milestone yet that we have with MHRA and EMA. We simply haven't concluded our discussions on the number of patients and the duration of follow-up. I do expect we will do so in the coming few weeks, and I look forward to updating you after that.

關於FDA，我們還沒有達到與MHRA和EMA那樣的里程碑式進展。我們尚未完成關於患者數量和追蹤時間的討論。我預計我們將在未來幾週內完成討論，屆時我將及時向您報告最新情況。

The next question will come from Hartaj Singh with Oppenheimer.

下一個問題將來自奧本海默公司的哈塔吉·辛格。

A really nice quarter. Not to -- Reshma, to talk about a little bit of about memory from a year or 2 years ago, but AATD looks like you're going to be bringing a couple more molecules into the clinic this year. And previously, you had mentioned that you're trying to increase the potency of these molecules and get them at higher concentrations to do the tissue of interest. So how are you thinking about that with the approach for these molecules in the clinic this year? And then assuming you get them in the clinic this year, when could we see a readout going forward?

這是一個非常棒的季度。雷什瑪，我不想再提一兩年前的記憶問題了，但AATD方面，你們今年似乎會將幾個新分子推進臨床試驗。之前您提到過，你們正在努力提高這些分子的效力，使其濃度更高，以便作用於目標組織。那麼，您是如何考慮今年這些分子的臨床試驗計畫的呢？假設今年它們能夠順利進入臨床試驗，我們什麼時候才能看到後續的試驗結果？

With regard to the AATD program, AATD remains a disease of high interest, and one that fits the Vertex strategy like a glove. I'm excited that the next wave of molecules are about to enter the clinic, and I do expect the IND for at least 1 to go in this year, but there are many molecules, more than 1 in this next wave. We have been able to dial up the potency. The doses are low. I expect that we're going to fully explore the dose range. And I expect that we'll have results that we can talk about by next year.

關於AATD項目，AATD仍然是一種備受關注的疾病，與Vertex的策略完美契合。我很高興下一批分子即將進入臨床試驗，我預計今年至少會有一個分子提交IND申請，但下一批分子不只一個。我們已經成功提高了藥物的效力。目前劑量較低。我預計我們將全面探索劑量範圍。我預計明年我們將獲得可以公佈的結果。

So the programs are progressing and the opportunity here, Hartaj, just to remind others, is to tackle both the lung and liver manifestations of this disease. That's why the small molecule approach is so inviting to us, and why we're so eager to pursue it. All the other approaches out there simply don't tackle both manifestations of disease. And in my mind, therefore, are not transformative. So that's really what we're looking for. And next year, we should have results that we can all look at and evaluate.

所以，這些項目正在推進中。哈塔傑，我再提醒大家一下，我們面臨的機會在於同時攻克這種疾病的肺部和肝臟病變。這就是為什麼小分子療法如此吸引我們，也是為什麼我們如此渴望推進它的原因。其他所有療法都無法同時解決疾病的這兩種病變。因此，在我看來，它們並不具有變革性。所以，這才是我們真正追求的目標。明年，我們應該就能看到結果，供大家查看和評估。

We have time for one more question, and that will come from Brian Abrahams with RBC Capital Markets.

我們還有時間回答最後一個問題，這個問題將由加拿大皇家銀行資本市場的布萊恩亞伯拉罕提出。

As you approach the filings, I'm curious where you stand with respect to CTX001 manufacturing and supply? I know you recently posted a bridging study. I'm curious how that might help you ultimately expand manufacturing and scale up? And then relatedly, where do you see the field with respect to next-generation or conditioning regimens? And how much would that be potentially helpful for expanding that long-term opportunity?

在您即將提交申請之際，我很好奇您在CTX001的生產和供應方面進展如何？我知道您最近發布了一項過渡性研究。我想知道這項研究最終將如何幫助您擴大生產規模？另外，您如何看待下一代療法或預處理方案的發展前景？這些療法對拓展長期發展機會又有多大的潛在幫助？

Yes. I'm going to ask Stuart to comment on the opportunity, the near-term opportunity with busulfan in the long term, and I'll come back and tell you a little bit about manufacturing.

是的。我會請史都華談談白消安的短期和長期發展機遇，之後我會回來簡單介紹一下生產製造方面的情況。

Yes. So Brian, thanks for the question. So across the U.S. and the EU, across sickle cell and TDT, we think there's approximately 150,000 patients who have sickle cell disease or beta thalassemia. Our initial launch is going to focus on those that have more severe disease, similar to the patients that are being included in the clinical trial, those that are likely to consider going through this treatment given the current busulfan conditioning regimen. We think that population is probably around 32,000 patients, about 25,000 of those are sickle cell disease patients and the majority of those are in the United States. So that's the initial launch population.

是的。布萊恩，謝謝你的提問。在美國和歐盟，包括鐮狀細胞疾病和TDT患者在內，我們估計約有15萬名患者患有鐮狀細胞疾病或β地中海貧血。我們最初的推廣將重點放在病情較重的患者，類似於臨床試驗中的患者，以及那些鑑於目前布蘇凡預處理方案而可能考慮接受這種治療的患者。我們估計這部分族群約有3.2萬人，其中約2.5萬人是鐮狀細胞疾病患者，而且大部分都在美國。這就是我們最初的推廣人群。

In terms of what the opportunity could look like if we can get to a truly gentler conditioning regimen, which may turn this kind of much more towards an outpatient procedure. Reshma will comment on it technically. But in terms of opportunity, we think that would significantly expand it beyond the 32,000 well into the 150,000 population. Maybe not all the way there, but certainly expand it significantly. It would become a procedure that a significantly higher number of people would consider having.

如果能找到一種真正溫和的治療方案，使這種手術更傾向於門診進行，那麼它的發展前景將非常廣闊。 Reshma 會就此技術層面進行評論。但就發展前景而言，我們認為這將使手術的適用人群從目前的 32,000 人大幅增加到 150,000 人。或許無法達到 15 萬人，但肯定會顯著擴大適用範圍。這將使更多人考慮接受這種手術。

And with regard to the manufacturing, in the grand scheme of things, this is an easier manufacturing challenge than other diseases that are being tackled with CRISPR-Cas9, for example. And I say that because this is ex vivo gene editing. And in essence, what we're talking about is a guide RNA and Cas9.

就生產製造而言，從整體來看，這比其他一些利用 CRISPR-Cas9 技術治療的疾病要容易一些。我說這話是因為這是體外基因編輯。本質上，我們討論的是引導 RNA 和 Cas9 蛋白。

The second point to make here is that -- and credit to our partners at CRISPR, we've thought about the commercial manufacturing of this therapy from the get-go. I mean that in terms of the process development. I also mean that in terms of the actual manufacturing sites. It's fundamentally the same process that we are using in the clinical trial space, that is what we will be using in the commercial space. And it's actually the exact same manufacturing sites as well. So we feel really good about where we are with the commercial manufacturing of CTX001. And as I said, in the grand scheme of things, it's an easier challenge because it's ex vivo gene editing, and it is Cas9 and guide RNA, and that's it.

第二點是──這要感謝我們在CRISPR的合作夥伴──我們從一開始就考慮到了這種療法的商業化生產。我指的是製程開發方面，也包括實際的生產基地。從根本上來說，我們在臨床試驗中使用的製程與商業化生產的製程相同，而且生產基地也完全相同。因此，我們對CTX001的商業化生產進展非常有信心。正如我所說，從整體來看，這相對來說挑戰較小，因為它是體外基因編輯，只需要Cas9和引導RNA。

Yes, I was just going to say thank you, to everyone, for tuning into the Q2 call tonight. If you have additional questions, please reach out to the Investor Relations team who are available in the office this evening. Good night.

是的，我只是想感謝大家今晚收聽第二季財報電話會議。如果您還有其他問題，請聯絡今晚在辦公室的投資者關係團隊。晚安。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議已結束。感謝您參加今天的報告。您可以斷開連線了。