福泰製藥 (VRTX) 2021 Q1 法說會逐字稿

Good evening. Welcome to the Vertex First Quarter 2021 Financial Results Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex.

晚安.歡迎參加Vertex公司2021財年第一季財務業績電話會議。我是Vertex公司投資者關係資深副總裁麥可‧帕特里奇。

Making prepared remarks on the call tonight, we have Dr. Reshma Kewalramani, Vertex' CEO and President; Stuart Arbuckle, Chief Commercial and Operations Officer; and Charlie Wagner, Chief Financial Officer.

今晚在電話會議上發表準備好的演講的有：Vertex 執行長兼總裁 Reshma Kewalramani 博士；首席商務和營運長 Stuart Arbuckle；以及財務長 Charlie Wagner。

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

我們建議您在收聽本次電話會議的同時，請造訪我們網站上的網路直播投影片。本次電話會議將被錄音，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' marketed CF medicines, our pipeline; the expectations regarding the closing of the CRISPR transaction, which is subject to antitrust clearance; and Vertex' future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially.

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，包括但不限於關於Vertex已上市的囊性纖維化藥物、我們的研發管線、關於CRISPR交易完成的預期（該交易尚需獲得反壟斷機構的批准）以及Vertex未來財務業績的聲明，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。

I would also note that we will review select non-GAAP financial results and guidance this evening.

我還想指出，我們今晚將審查部分非GAAP財務表現和指引。

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。

Thank you, Michael. Our goal is to continue to transform cystic fibrosis and other serious diseases and, in so doing, reach more patients and drive future growth. One quarter into 2021, I'm very pleased with the progress we're making across the board in support of this goal. We are treating more patients with our CFTR modulators than ever before. And our clinical pipeline, spanning 7 disease areas and 3 modalities, has advanced significantly. In addition, we continue to execute on our strategy to use external innovation to complement our internal innovation efforts, including 2 new deals announced already this year.

謝謝您，邁克爾。我們的目標是繼續改變囊性纖維化和其他嚴重疾病的治療現狀，從而惠及更多患者，並推動未來的成長。 2021年已經過去一個季度，我對我們在實現這一目標方面取得的全面進展感到非常滿意。我們使用CFTR調節劑治療的患者人數比以往任何時候都多。我們的臨床研發管線涵蓋7個疾病領域和3種治療方式，並且取得了顯著進展。此外，我們繼續執行利用外部創新來補充內部創新工作的策略，包括今年已經宣布的兩項新交易。

I'll start with CF. Vertex has built an exceptionally strong and durable franchise and earned a leadership position in cystic fibrosis. Our CF medicines have transformed the treatment of this disease, and we continue to significantly increase the number of patients we're treating. Our first quarter revenues totaled more than $1.7 billion, which represents a 14% year-over-year growth and reflects the high level of treatment penetration of TRIKAFTA in the U.S. and strong KAFTRIO launch in international markets. We are poised for continued significant growth in the coming years as we achieve additional approvals and reimbursement agreements for our medicines globally and as we bring our medicines to younger patients.

我先來說說囊性纖維化（CF）領域。 Vertex 已建立起極其強大且持久的業務基礎，並在囊性纖維化領域佔據領先地位。我們的 CF 藥物徹底改變了這種疾病的治療方式，而且我們正在持續顯著增加接受治療的患者數量。我們第一季的總收入超過 17 億美元，年增 14%，這反映了 TRIKAFTA 在美國的高治療滲透率以及 KAFTRIO 在國際市場的強勁上市。隨著我們在全球範圍內獲得更多藥物批准和醫保報銷協議，以及我們將藥物推廣至更年輕的患者群體，我們預計在未來幾年繼續保持顯著增長。

The clinical benefit that the triple combination delivers is remarkable. And with this medicine, we believe we can treat 90% of all people with CF. But we are not stopping there. We're investing to bring new and potentially better regimens, such as the VX-121, 561, tezacaftor combination to patients. This new combination is a once-a-day regimen with potential for enhanced patient benefit as well as enhanced economics with the reduced royalty obligation. Finally, we remain committed to and are making progress in developing genetic therapies for the remaining 10% of CF patients.

三聯療法的臨床療效顯著。我們相信，憑藉這種藥物，我們可以治療90%的囊性纖維化患者。但我們並未止步於此。我們正在投資研發新的、可能更有效的治療方案，例如VX-121、561和tezacaftor的組合療法。這種新的組合療法只需每日服用一次，有望提高患者的獲益，並因降低專利使用費而帶來更佳的經濟效益。最後，我們始終致力於為剩餘10%的囊性纖維化患者開發基因療法，並且正在取得進展。

In summary, consistent with our strategy to bring transformative medicines to all patients with CF, the combination of label expansion, additional approvals and reimbursement agreements and the next generation of products will continue to provide significant top and bottom line growth in the coming years.

總而言之，為了實現我們為所有囊性纖維化患者帶來變革性藥物的策略目標，標籤擴展、額外批准和報銷協議以及下一代產品的推出，將在未來幾年繼續為公司帶來顯著的收入和利潤成長。

Let me turn to our clinical pipeline, which includes programs in 7 disease areas and spans small molecules, cell and genetic therapies. We have made substantial progress across the breadth of the pipeline and are poised for multiple data readouts in the next 6 to 12 months. First, CTX001. CTX001 is our most advanced program beyond CF. In the last year, we've generated remarkable clinical data that demonstrates the potential of this therapy to be a onetime functional cure for patients suffering from sickle cell disease and beta thalassemia. CTX001 has been granted RMAT, Fast Track and Rare Pediatric Disease designations from the FDA for both sickle cell disease and beta thalassemia; as well as PRIME designation from the EMA for both diseases.

接下來，我想介紹我們的臨床研發管線，涵蓋7個疾病領域的多個項目，包括小分子藥物、細胞療法和基因療法。我們在整個研發管線中都取得了顯著進展，並預計在未來6到12個月內公佈多項數據。首先是CTX001。 CTX001是我們除囊性纖維化（CF）之外進展最快的項目。在過去一年中，我們獲得了令人矚目的臨床數據，這些數據表明該療法有望成為鐮狀細胞貧血症和β地中海貧血患者的一次性功能性治癒方案。 CTX001已獲得美國食品藥物管理局（FDA）授予的鐮狀細胞貧血症和β地中海貧血症的RMAT（研究藥物優先治療）資格、快速通道資格和罕見兒科疾病資格；同時，它也獲得了歐洲藥品管理局（EMA）授予的這兩種疾病的PRIME（優先治療）資格。

With the compelling clinical profile and rapid progress of CTX001 towards registration and commercialization, now is the ideal time for Vertex to take the lead for this program and bring the full breadth of our development, regulatory, manufacturing and commercialization expertise, so that we can reach all eligible patients who may benefit from CTX001 as quickly as possible. As Stuart will discuss in a moment, there are nearly 170,000 patients with sickle cell disease and beta thalassemia in the U.S. and Europe, of whom 32,000 patients have severe disease and we believe will be eligible for CTX001 therapy with the current conditioning regimen. This number could extend significantly once gentler conditioning regimens are available.

鑑於 CTX001 具有令人信服的臨床療效，且在註冊和商業化方面進展迅速，現在正是 Vertex 主導該項目並充分發揮我們在研發、監管、生產和商業化方面的專長，從而盡快惠及所有可能受益於 CTX001 的合格患者的最佳時機。正如 Stuart 稍後將要提到的，美國和歐洲約有 17 萬名鐮狀細胞貧血症和 β 地中海貧血患者，其中 3.2 萬名患者病情嚴重，我們相信他們符合目前預處理方案下接受 CTX001 治療的條件。一旦更溫和的預處理方案問世，這一數字可能會顯著增加。

To date, more than 30 patients have been dosed with CTX001, and we anticipate sharing updated data from the ongoing sickle cell and transfusion-dependent thalassemia studies with more patients and longer duration of follow-up at upcoming medical meetings this year. We also expect to complete enrollment in both of these studies this year.

迄今為止，已有超過30名患者接受了CTX001治療。我們預計將在今年即將召開的醫學會議上分享正在進行的鐮狀細胞貧血症和輸血依賴型地中海貧血研究的最新數據，這些數據將涵蓋更多患者並延長追蹤時間。我們也預計將在今年完成這兩項研究的患者招募。

Lastly, while we've initiated, we have not yet completed our discussions with regulators regarding filing expectations. Based on conversations to date, we believe regulatory submissions for approval of CTX001 may be possible in the next 18 to 24 months. We'll provide further details as we conclude our discussions.

最後，雖然我們已經與監管機構就申報預期展開討論，但尚未完成。根據目前的溝通情況，我們認為CTX001的監理核准申報可能在未來18至24個月內完成。待討論結束後，我們將提供更多詳情。

Moving on to the AATD program. Our approach targets the underlying cause of this disease by using a small molecule corrector to appropriately fold the misfolded Z-AAT protein. We believe this is the optimal approach for treating AATD, and it is the only approach that addresses both the lung and liver manifestations of the disease. VX-864 is our most advanced molecule in the program. We have completed enrollment. And recently, we also completed dosing in the Phase II proof-of-concept study of VX-864. Patients are now in the process of completing the 28-day safety follow-up period. We are on track for a data readout later this quarter.

接下來談談AATD項目。我們的治療方案旨在透過小分子矯正劑來糾正錯誤折疊的Z-AAT蛋白，從而從根本上解決該疾病。我們相信這是治療AATD的最佳方法，也是唯一能夠同時解決疾病肺部和肝臟表現的方法。 VX-864是我們這個計畫中進展最快的分子。我們已經完成了病患招募。最近，我們也完成了VX-864 II期概念驗證研究的給藥。目前，患者正在進行為期28天的安全追蹤。我們預計將在本季稍後公佈數據。

Turning to APOL1-mediated kidney disease. APOL1-mediated kidney disease is a particularly aggressive form of renal disease characterized by proteinuria, declining renal function and progression to ESRD. Our lead molecule in this program, VX-147, is being studied in a Phase II proof-of-concept study in APOL1-mediated FSGS, evaluating safety, pharmacokinetics and reduction of proteinuria in patients over the course of 13 weeks. We expect to have the results from this study in the second half of 2021.

接下來我們來談談APOL1介導的腎臟疾病。 APOL1介導的腎臟疾病是一種侵襲性極強的腎臟疾病，其特徵是蛋白尿、腎功能下降並最終進展至末期腎病變（ESRD）。我們此計畫的主要候選藥物VX-147正在進行一項針對APOL1介導的局部節段性腎小球硬化症（FSGS）的II期概念驗證研究，該研究旨在評估VX-147在13週內對患者的安全性、藥物動力學以及降低蛋白尿的效果。我們預計將於2021年下半年獲得該研究的結果。

Next, turning to our pain program. Earlier this week, we announced that we plan to advance VX-548, the next lead molecule in our pain program, into Phase II development. In VX-150, we were the first to validate the NaV1.8 target with 3 positive Phase II proof-of-concept trials in 3 different pain indications. The recent decision to move VX-548 to Phase II was based on supportive Phase I data in healthy volunteers, including safety, tolerability and pharmacokinetics. In these studies, the molecule exhibited a favorable profile at doses considerably lower than those required with our previous NaV1.8 inhibitors. The Phase II studies will evaluate the safety and efficacy of VX-548 in the treatment of acute pain following bunionectomy and also in abdominoplasty. These are well-characterized settings for the evaluation of 2 broad categories of acute pain, visceral and nonvisceral, and we expect the studies to start in the second half of this year.

接下來，我們來談談疼痛治療項目。本週早些時候，我們宣布計劃將疼痛治療計畫中的下一個先導化合物VX-548推進至II期臨床試驗。在VX-150項目中，我們率先透過三項針對三種不同疼痛適應症的II期概念驗證試驗，驗證了NaV1.8標靶的有效性。此次將VX-548推進至II期臨床試驗的決定，是基於健康志願者中I期臨床試驗的支持性數據，包括安全性、耐受性和藥物動力學數據。在這些研究中，該分子在遠低於我們先前NaV1.8抑制劑所需劑量的情況下，展現出良好的療效特徵。 Ⅱ期臨床試驗將評估VX-548在拇外翻切除術後急性疼痛以及腹部整形術後急性疼痛治療​​的安全性和有效性。這些適應症是評估內臟疼痛和非內臟疼痛兩大類急性疼痛的典型適應症，我們預計試驗將於今年下半年啟動。

Finally, in our type 1 diabetes program, we received FDA Fast Track Designation for the cells alone study and initiated the Phase I/II study in patients with difficult-to-treat type 1 diabetes in Q1. Screening is now open, and we look forward to providing updates on our progress this year.

最後，在我們的1型糖尿病計畫中，我們獲得了FDA針對單細胞療法研究的快速通道資格認定，並於第一季度啟動了針對難治性1型糖尿病患者的I/II期研究。目前篩選工作已經開始，我們期待今年向大家報告研究進度。

With those comments, I'll hand it off to Stuart.

有了這些發言，我就把麥克風交給史都華了。

Thank you, Reshma. Today, I am pleased to review with you our Q1 commercial performance and our excitement about the prospects for CTX001. One year into the pandemic, our CF revenues continue to grow. Our Q1 global revenues were $1.7 billion driven by continued strong execution in both the U.S. and the EU.

謝謝Reshma。今天，我很高興與您一起回顧我們第一季的商業業績，並分享我們對CTX001前景的樂觀態度。疫情爆發一年後，我們的CF收入持續成長。第一季全球營收達17億美元，主要得益於我們在美國和歐盟市場持續強勁的業績表現。

Our performance in the U.S. continues to be impressive. To date, nearly all eligible CF patients in the U.S. have initiated treatment with TRIKAFTA. Based on the original approval in patients 12 years and older with at least 1 F508del mutation. And persistence and compliance remain high among these patients. In December 2020, TRIKAFTA's approval was expanded in the U.S. to include patients 12 years and older with rare mutations. Many of these patients have now initiated treatment as well, and we are pleased by the uptake we have seen in this newly eligible group.

我們在美國的表現持續令人矚目。迄今為止，美國幾乎所有符合條件的囊性纖維化（CF）患者都已開始接受TRIKAFTA治療。最初，TRIKAFTA獲準用於治療12歲及以上且至少攜帶一個F508del突變的患者。這些患者的治療堅持率和依從性仍然很高。 2020年12月，TRIKAFTA在美國的適應症範圍擴大至12歲以上且帶有罕見突變的患者。許多這類患者也已開始接受治療，我們對這新增適應症族群的接受度感到欣慰。

Outside of the U.S., in markets where patients have access, the adoption of KAFTRIO is just as impressive as in the U.S. We have seen rapid uptake, particularly in the U.K. and Germany. And persistence and compliance are similarly strong, reflecting the very favorable risk/benefit profile of KAFTRIO. Our ex-U.S. revenues in Q1 were $470 million, 43% higher than the same period last year, primarily due to the successful launch of KAFTRIO.

在美國以外的市場，在患者能夠獲得治療的地區，KAFTRIO 的普及程度與美國一樣令人矚目。我們看到了快速成長，尤其是在英國和德國。患者的持續用藥率和依從性同樣出色，這反映了 KAFTRIO 極佳的風險/獲益比。我們第一季在美國以外的營收為 4.7 億美元，比去年同期成長 43%，這主要歸功於 KAFTRIO 的成功上市。

Earlier this year, we shared our updated estimate that there are approximately 83,000 people living with CF in the U.S., Europe, Canada and Australia. Today, we are treating about half of all patients, leaving an additional 30,000 patients who could benefit from our medicines but who are not yet treated. Going forward, we are very confident that we will be able to reach these patients.

今年早些時候，我們公佈了最新的估計數據，即美國、歐洲、加拿大和澳洲約有83,000名囊性纖維化患者。目前，我們正在治療大約一半的患者，這意味著還有30,000名患者可以從我們的藥物中獲益，但尚未接受治療。展望未來，我們非常有信心能夠幫助這些患者。

Approximately 2/3 of the untreated patients are 12 and older, and we expect we will be able to treat these patients through the ongoing launch, uptake and reimbursement of KAFTRIO outside the U.S. In countries where we have regulatory approval and reimbursement, our teams are working hard to reach all eligible patients who could benefit from KAFTRIO. In countries such as France, Spain and Australia where we have regulatory approval but have not yet secured reimbursement, our teams continue to make progress to ensure access, and we are confident that we will be able to secure reimbursement in the remaining large markets.

約三分之二的未接受治療的患者年齡在12歲及以上，我們預計透過KAFTRIO在美國以外地區的持續上市、推廣和醫療保險報銷，我們將能夠為這些患者提供治療。在已獲得監管部門批准並實現醫療保險報銷的國家，我們的團隊正努力讓所有符合資格的患者都能受益於KAFTRIO。在法國、西班牙和澳洲等已獲得監管部門批准但尚未實現健保報銷的國家，我們的團隊也持續努力確保病患能夠獲得治療，我們有信心在其餘主要市場實現健保報銷。

For example, TRIKAFTA was recently approved in Australia, and we are committed to continuing to work collaboratively with the Pharmaceutical Benefits Advisory Committee there to ensure all 2,200 patients who can benefit from treatment have government-funded access to TRIKAFTA as quickly as possible.

例如，TRIKAFTA 最近在澳洲獲得批准，我們致力於繼續與當地的藥物福利諮詢委員會合作，以確保所有 2,200 名可以從治療中受益的患者都能盡快獲得政府資助的 TRIKAFTA。

Lastly, in Canada, we are still awaiting regulatory approval, and we expect approval there in the second half of this year.

最後，在加拿大，我們仍在等待監管部門的批准，預計今年下半年獲得批准。

The majority of the remaining approximately 10,000 patients are younger than 12. Our work to secure approvals for these younger patient populations is ongoing, and we are making good progress here. We anticipate approval of TRIKAFTA in 6- to 11-year-olds in the U.S. in mid-2021 and have filed the regulatory submission for this population in Europe as well.

剩餘的約1萬名患者中，絕大多數年齡在12歲以下。我們正在努力爭取為這些低齡患者群體獲得批准，並且進展順利。我們預計TRIKAFTA將於2021年中期在美國獲準用於6至11歲的兒童，並且已在歐洲提交了針對該族群的監管申請。

In summary, our continued progress in achieving label expansion, new approvals and reimbursements and development of new products will drive continued growth in the years to come. In all of this, we are grateful for the tireless work and continued support of the global CF community.

總之，我們在擴大適應症範圍、獲得新藥批准和報銷以及開發新產品方面取得的持續進展，將推動未來幾年的持續成長。在此，我們衷心感謝全球囊性纖維化社群的不懈努力和持續支持。

Let's now turn to CTX001, which is our next medicine that is rapidly advancing toward regulatory submissions and commercialization. Given the tremendous progress of CTX001 that we and our partners at CRISPR have made, as well as Vertex' established expertise in development, manufacturing, regulatory and commercialization in serious diseases, both companies believe that having Vertex lead all aspects of the CTX001 program going forward would provide for the most efficient and expeditious path to bring this medicine to patients. By doing this, we aim to ensure a coordinated global launch, which will maximize the potential of this program for both patients and our shareholders.

現在讓我們來看看CTX001，這是我們正在快速推進的下一個藥物項目，目前正朝著監管申報和商業化方向發展。鑑於我們和CRISPR的合作夥伴在CTX001項目上取得的巨大進展，以及Vertex在嚴重疾病的研發、生產、監管和商業化方面積累的豐富經驗，兩家公司都認為，由Vertex主導CTX001項目的所有環節，將為患者提供最高效、最快捷的藥物上市途徑。透過這種方式，我們旨在確保全球同步上市，從而最大限度地發揮該計畫對患者和股東的益處。

CTX001 is a groundbreaking therapy that has demonstrated great momentum with the potential to be the first approved genetic therapy for patients with sickle cell disease. Sickle cell disease and beta thalassemia represent a multibillion-dollar commercial opportunity. Today, there are approximately 32,000 patients in the U.S. and Europe who would likely be eligible for gene editing therapy based on the severity of their disease and the current busulfan-based conditioning regimen. Vertex, CRISPR and a number of other companies are actively pursuing gentler conditioning regimens. Such regimens would potentially expand the eligible patient population to approximately 170,000 total patients in the U.S. and Europe.

CTX001 是一種突破性療法，發展勢頭強勁，有望成為首個獲準用於治療鐮狀細胞貧血的基因療法。鐮狀細胞貧血症和β地中海貧血症蘊藏著數十億美元的商業潛力。目前，美國和歐洲約有32,000名患者，根據其疾病嚴重程度和現有的基於白消安的預處理方案，他們可能符合基因編輯療法的治療條件。 Vertex、CRISPR 和其他一些公司正在積極研發更溫和的預處理方案。此類方案可望將符合治療條件的患者群體擴大到美國和歐洲約17萬人。

The commercial opportunity in sickle cell disease and beta thalassemia fits well within Vertex' strategic focus on specialty markets. Patients are primarily cared for by hematologists, and the treatment will be focused at transplant centers in the U.S. and Europe, which can be covered by a specialist infrastructure. By taking a leadership role on CTX001, we will be able to leverage our proven expertise in product launches, reimbursement and access to bring the curative potential of this treatment to more patients more quickly around the world.

鐮狀細胞疾病和β地中海貧血的商業機會與Vertex專注於專科市場的策略方向高度契合。患者主要由血液科醫師診治，治療將主要在美國和歐洲的移植中心進行，這些中心擁有完善的專科醫療體系。透過在CTX001計畫中發揮領導作用，我們將能夠利用我們在產品上市、醫保報銷和市場准入方面的豐富經驗，更快地將這種療法的治癒潛力帶給全球更多患者。

Given we believe that regulatory submissions could happen in the next 18 to 24 months, our precommercial work is underway. CTX001 is breaking new grounds in many respects, and I'm very much looking forward to providing more details on this exciting work on future calls.

鑑於我們預計監管審批流程將在未來18至24個月內完成，我們的商業化前期工作正在進行中。 CTX001在許多方面都具有開創性意義，我非常期待在未來的電話會議上分享更多關於這項令人興奮的工作的細節。

And now I'll hand it over to Charlie.

現在我把它交給查理。

Thanks, Stuart. In the first quarter of 2021, Vertex continued its record of exceptional financial performance. First quarter total product revenues were $1.7 billion, a 14% increase compared to the first quarter of 2020. And these results included $1.25 billion of revenue in the U.S. and $470 million from outside the U.S. The ex-U.S. results represent growth of 43% over the prior year driven largely by the rapid uptake of KAFTRIO in countries where we have secured reimbursement, particularly England and Germany.

謝謝，斯圖爾特。 2021年第一季度，Vertex繼續保持了其卓越的財務表現。第一季產品總營收達17億美元，較2020年第一季成長14%。其中，美國市場收入為12.5億美元，美國以外市場收入為4.7億美元。美國以外市場的收入較上年同期成長43%，這主要得益於KAFTRIO在已獲得健保報銷的國家（尤其是英國和德國）的快速普及。

Our first quarter non-GAAP combined R&D and SG&A expenses were $530 million compared to $477 million for the first quarter of 2020. Expenses in Q1 were primarily driven by investment in innovation, and we expect our R&D investments will continue to be substantial as we drive toward proof-of-concept data and further clinical and regulatory progress across our broad pipeline.

我們第一季的非GAAP研發及銷售、管理及行政費用合計為5.3億美元，2020年第一季為4.77億美元。第一季的費用主要由創新投資驅動，我們預計隨著我們努力獲得概念驗證數據以及在廣泛的產品線中取得進一步的臨床和監管進展，我們的研發投資將繼續保持強勁勢頭。

Our continued growth in revenues, combined with carefully managed growth in spending, translates to a first quarter non-GAAP operating margin of 58%. With our strong revenue and profitability, we ended the first quarter with $6.9 billion in cash. Consistent with our corporate and R&D strategy, we're investing more in innovation than ever before, including external innovation. This was most recently exemplified by both our amended collaboration agreement with CRISPR and our new discovery collaboration with Obsidian Therapeutics.

我們持續成長的營收，加上謹慎控制的支出成長，使得第一季非GAAP營業利潤率達到58%。憑藉強勁的營收和獲利能力，我們第一季末現金儲備達69億美元。秉承公司及研發策略，我們加大了對創新的投入，包括外部創新。近期，我們與CRISPR公司修訂了合作協議，並與Obsidian Therapeutics公司進行了新的研發合作，這就是最新例證。

Now on to guidance. We are maintaining our previously issued 2021 guidance for total product revenues in the range of $6.7 billion to $6.9 billion. Our Q1 revenues were very strong, but they also include an approximately $50 million benefit from channel inventory fluctuations that are not directly reflective of underlying patient demand. As a reminder, our 2021 guidance reflects our expectations for currently approved products in regions where we are reimbursed, plus an expectation of TRIKAFTA approval for the 6- to 11-year-old population in the U.S. in mid-2021. It does not include any additional reimbursements that we might obtain this year.

接下來談談業績展望。我們維持先前發布的2021年產品總收入預期，預計在67億美元至69億美元之間。我們第一季的營收表現非常強勁，但其中包含約5,000萬美元的通路庫存波動收益，這部分收益並不能直接反映患者的實際需求。需要提醒的是，我們2021年的業績展望反映了我們對目前已獲批產品在醫保覆蓋地區的預期，以及我們對TRIKAFTA（一種用於6至11歲兒童的藥物）於2021年中期在美國獲得批准的預期。該預期不包括我們今年可能獲得的任何其他醫療覆蓋範圍。

For non-GAAP OpEx, we are reiterating our guidance range of $2.25 billion to $2.3 billion. We expect to continue allocating greater than 70% of OpEx to R&D as we further advance our pipeline programs. We are poised to generate important clinical data from a number of programs over the course of the year, and these data sets will drive decisions on further investment.

對於非GAAP營運支出，我們重申先前22.5億美元至23億美元的預期範圍。隨著我們進一步推進在研項目，我們預計將繼續把超過70%的營運支出用於研發。我們預計在今年內從多個項目中獲得重要的臨床數據，這些數據將指導我們後續的投資決策。

For our non-GAAP tax rate, we are guiding to a range of 21% to 22% this year.

今年，我們的非GAAP稅率預計在21%至22%之間。

In summary, I'm very pleased with our performance in the first quarter of 2021 and look forward to updating you on our continued progress over the course of this year.

總而言之，我對我們2021年第一季的表現非常滿意，並期待今年內向您報告我們持續取得的進展。

Now back to Reshma for closing remarks.

現在請雷什瑪作總結發言。

Thanks, Charlie. In sum, we have made significant progress across the business. We have confidence in and continue to execute on our innovation-based growth strategy. Our strategy is working. And our investments, both internal and external, are driving discovery and development of game-changing new medicines. Vertex is delivering exceptional financial performance. Our CF business is poised to continue to grow, and our broad pipeline continues to advance.

謝謝查理。總而言之，我們在各個業務領域都取得了顯著進展。我們對以創新為導向的成長策略充滿信心，並將繼續執行。我們的策略行之有效。我們內部和外部的投資正在推動突破性新藥的發現和發展。 Vertex 的財務表現表現卓越。我們的囊性纖維化業務預計將繼續成長，我們廣泛的研發管線也在持續進行中。

Thanks, and we'll now open the call to questions.

謝謝，現在開始接受提問。

(Operator Instructions) And our first question comes from Michael Yee from Jefferies.

（操作說明）我們的第一個問題來自傑富瑞集團的麥可伊。

And our next question comes from Phil Nadeau from Cowen and Company.

下一個問題來自 Cowen and Company 的 Phil Nadeau。

I think the most common question we've been getting from investors recently is on AAT program, and it's what would serve as proof-of-concept in the upcoming data that you're seeing? Can you maybe give us your most recent thoughts on what levels are necessary, what proportion of patients need to be responders and whatnot? And then a second -- Part B to that question. In the past, you've been guiding to moving another AAT molecule into the clinic this year. It didn't seem like from your prepared remarks that's still the case. Can you confirm whether there has actually been a change there and maybe give us a reason why if it -- if the guidance has changed?

我認為最近投資人最常問的問題是關於AAT計畫的，他們想知道即將公佈的數據中哪些可以作為概念驗證？您能否談談您最近對所需劑量水平、需要多少比例的患者有反應等方面的看法？第二個問題──也就是上述問題的第二部分。過去，您曾表示今年會將另一種AAT分子推進臨床試驗。但從您準備的發言稿來看，似乎並非如此。您能否確認一下這方面是否真的改變了？如果確實發生了變化，能否解釋一下原因？

Thanks, Phil, this is Reshma. Let me take that for you. I think the questions really are, where are we with the 864 program, what are we expecting, what would be success and a little bit about the portfolio approach and other molecules. So let me take that in pieces.

謝謝菲爾，我是雷什瑪。讓我來回答你。我認為真正的問題是，864專案進度如何？我們預期會取得什麼成果？怎樣才算成功？以及關於投資組合策略和其他分子的一些問題。讓我分步驟來回答。

So you know this, but to review for others on the call, we are taking small molecule correctors to refold the misfolded Z-AAT protein. That's our approach to this disease. And the reason it's important to understand that is that, fundamentally, this is the only approach that holds the potential to treat both liver and lung, hence, our enthusiasm for this approach.

你們都知道這一點，但為了讓其他參與者再次了解，我們正在使用小分子矯正劑來重新折疊錯誤折疊的Z-AAT蛋白。這就是我們治療這種疾病的方法。之所以要理解這一點，是因為從根本上講，這是唯一有可能同時治療肝臟和肺部疾病的方法，因此我們對這種方法充滿熱情。

VX-864 is in the clinic. You heard me in the prepared remarks talk about the fact that we've hit some really important milestones. We are done with enrollment. Our patients have completed the dosing period, and they are now in the 28-day safety follow-up period.

VX-864 正在進行臨床試驗。正如我在事先準備好的演講稿中所提到的，我們已經取得了一些非常重要的里程碑式進展。我們已經完成了病患招募。我們的患者已經完成了給藥期，現在正處於 28 天的安全追蹤期。

Here's what I'm looking for from the study and what I would consider success, really 3 things. The first, safety. This is the first time we've had VX-864 in patients with AATD, so that's obviously front and center. Second, a dose exposure or dose response relationship; and third, elevation in functional AAT levels. That's really what I'm looking for and what I would be very excited to see.

以下是我對這項研究的期望，也是我認為研究成功的標準，其實有三點。首先是安全性。這是我們首次在AATD患者中使用VX-864，所以安全性顯然是首要任務。其次是劑量暴露或劑量反應關係；第三是功能性AAT水準的升高。這正是我所期待的，也是我非常希望看到的。

In terms of the portfolio and molecule beyond VX-864, as with all of the programs in the pipeline, so we have a whole portfolio of molecules. And that continues to be true for AATD as well.

就VX-864之後的藥物組合和分子而言，就像所有在研項目一樣，我們擁有完整的分子組合。 AATD項目也同樣如此。

And our next question comes from Geoff Meacham from Bank of America.

下一個問題來自美國銀行的傑夫‧米查姆。

I just have 2 quick ones. On the updated economics with CRISPR on 001, was the decision based on ongoing data? Or was there some regulatory feedback or maybe commercial analysis? I know it's always better to lead a program when you can, but I wasn't sure what the ultimate catalyst was for the deal. And then just a follow-up on AAT. Just assuming that there is a clean safety profile, Reshma, do you view the corrector approach as kind of the only approach for Vertex? Or is there a thought that you're committed to AAT and may have other mechanisms of action even more beyond what you have in the pipeline today?

我還有兩個問題想問。關於001號晶片上CRISPR技術的最新經濟效益分析，這個決定是基於持續的數據嗎？還是受到了監理機關的回饋，或是進行了商業分析？我知道如果可以的話，主導一個專案總是更好的，但我不太確定促成這筆交易的最終催化劑是什麼。另外，關於AAT技術，我想再問一個後續問題。 Reshma，假設AAT技術的安全性良好，你是否認為這種校正方法就是Vertex公司唯一的選擇？或者你認為，你們致力於AAT技術，也可能還有其他作用機制，甚至比你們目前正在研發的方案更有潛力？

Yes. Sure. Let me start with the question around the amended agreement with CRISPR. Geoff, it's a number of catalysts that happened over the course of the last, let's say, 6 to 8 months that led us to amending the agreement. If you go back to last year, between last year and now, we have delivered proof-of-concept results from both sickle cell and beta thalassemia. Not only that, but we have data that we've shown from 10 patients, and the data are really nothing short of remarkable. We're also at a point now where we've dosed more than 30 people in this program. And we are looking to complete enrollment in both beta thal and sickle cell disease this year.

是的，當然。首先我想談談關於與CRISPR公司修訂協議的問題。 Geoff，過去六到八個月發生的一系列事件促使我們修訂了協議。回顧去年，從去年到現在，我們已經獲得了鐮狀細胞貧血症和β地中海貧血症的概念驗證結果。不僅如此，我們還展示了來自10名患者的數據，這些數據確實非常出色。目前，我們已經為該計畫中的30多名患者進行了給藥。我們計劃今年完成β地中海貧血症和鐮狀細胞貧血的受試者招募工作。

The program has a lot of momentum behind it, and it is progressing overall even faster than we expected. You put that all together, and this is really just the perfect time for Vertex to take the leadership role and bring the full weight of our experience and infrastructure and expertise to get to as many patients as possible, as quickly as possible.

該專案勢頭強勁，整體進展速度甚至超過了我們的預期。綜上所述，現在正是Vertex發揮領導作用，充分發揮我們豐富的經驗、完善的基礎設施和專業技術，盡快惠及盡可能多的患者的最佳時機。

With regard to your question on AATD, the answer to your question around how committed are we, how do we think about this disease, this disease fits our strategy like a glove, and we are exceptionally committed to AATD.

關於您提出的 AATD 問題，關於我們對這種疾病的投入程度，以及我們如何看待這種疾病，答案是這種疾病與我們的策略完美契合，我們對 AATD 的投入非常巨大。

With regard to the approach, there is no better approach to AATD than small molecule correction of the misfolded protein, right? The Z-AAT protein that is misfolded in the disease, that is the underlying cause of the disease. And with the small molecule approach, you have the opportunity to target that underlying cause of disease and, in so doing, treat both the liver and lung manifestations. So we are absolutely committed to AATD and to the small molecule correctors.

就治療方法而言，對於AATD來說，沒有比小分子藥物糾正錯誤折疊蛋白更好的方法了，對吧？這種疾病的根本原因在於Z-AAT蛋白的錯誤折疊。而小分子藥物療法則能夠針對這個根本病因，從而同時治療肝臟和肺部的病變。因此，我們堅定地致力於AATD的治療以及小分子藥物的研發。

And our next question comes from Michael Yee from Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

Can you hear me now?

現在能聽到我說話嗎？

Yes, Mike. Thanks.

是的，麥克。謝謝。

Okay. Great. I actually have a question about diabetes. I know, Reshma actually talked about this, but actually, there's data later this year. Can you maybe just comment about what proof-of-concept is? Would it be surprising to see changes in HB A1C, et cetera? Maybe just talk about the value of what we'd see there, realizing it's the naked cells.

好的，太好了。我其實有個關於糖尿病的問題。我知道雷什瑪之前也談過，但實際上，今年稍後會有相關數據公佈。能否簡單解釋一下什麼是概念驗證？如果糖化血紅素（HbA1c）等指標發生變化，您會感到驚訝嗎？或許您可以談談，考慮到這是裸露的細胞，我們觀察到的結果有什麼價值。

Yes. Yes. Michael, I think you're asking about the type 1 diabetes program. And just to understand a little bit about the background and maybe a little bit about where we are, and I certainly heard your question about when we can expect to see some data. Okay, so the type 1 diabetes program is a cell-based program that comes really in 2 flavors. One, let's call it the naked cell approach, that's the one that had the IND cleared earlier in the year. That's the one that's in patients -- the study in patients is ongoing right now, the Phase I/II study. And that program is in the Phase I/II stage. The second one is the cell plus device program.

是的，是的。邁克爾，我想你是在問關於第​​一型糖尿病計畫的問題。為了更了解專案背景和目前進展，我先簡單介紹一下。當然，我也聽到你問什麼時候可以看到一些數據了。好的，1型糖尿病項目是一個以細胞為基礎的治療項目，主要有兩種方案。第一種，我們稱之為裸細胞療法，也就是今年稍早獲得IND批准的方案。目前正在進行臨床試驗—這項臨床試驗正在進行中，是I/II期臨床試驗。該項目目前處於I/II期階段。第二種方案是細胞聯合器械療法。

Now let me just step back and explain 2 more things here. There is very little biological risk in terms of the approach that we're taking to type 1 diabetes, right? Because we understand very clearly what the cause of disease is, it's autoimmune destruction of pancreatic islet cells. Maybe more importantly, we have known for many years that islet cell transplants lead to great outcomes in patients with type 1 diabetes. That is already known. Islet cell transplants have been done for years. The issue has been the quality and quantity of cells. And that's exactly the solution that Semma and now Vertex are bringing forward. So with the naked cell program, this would be about, let's say, 60,000 patients. These are patients with severe diabetes that I think could benefit from this program, which would include chronic immunosuppression.

現在讓我先退一步，再解釋兩點。就我們目前治療第1型糖尿病的方法而言，生物學風險非常低，對吧？因為我們非常清楚這種疾病的病因，即自體免疫性胰島細胞破壞。或許更重要的是，我們多年來都知道，胰島細胞移植能為第一型糖尿病患者帶來顯著的療效。這一點早已是公認的。胰島細胞移植已經開展多年。問題在於細胞的品質和數量。而這正是Semma和Vertex公司正在提出的解決方案。假設使用裸細胞，那麼大約會有6萬名患者。這些患者都是重症糖尿病患者，我認為他們可以從這個計畫中獲益，因為他們需要長期服用免疫抑制劑。

If we go then to the cell and device program, there are over 1 million people just in the U.S. and an equivalent number in the EU with type 1 diabetes that could benefit from the cell and device program. That, of course, would not require any immunosuppression.

如果我們再來看細胞和設備移植項目，光在美國就有超過100萬1型糖尿病患者，歐盟也有相當數量的患者可以從中受益。當然，這不需要任何免疫抑制治療。

And with regard to timing, so the naked program is cleared to IND. It's in the Phase I/II now. You recall that we're starting at a lower dose, and then just like with CTX001, we would then get to the target dose. And I would say that just like the CTX001 program, you should think of it as a efficient program, and a reasonable number of patients will give us a good sensitive profile. And I would say that you should have a mindset towards 2022 for data readout from that program.

關於時間安排，裸藥計畫已獲批准IND申請，目前處於I/II期臨床試驗階段。您可能還記得，我們​​是從較低劑量開始的，然後就像CTX001一樣，逐步達到目標劑量。我認為，就像CTX001項目一樣，您應該將其視為一個高效的項目，只要納入足夠數量的患者，就能獲得良好的敏感性分析結果。我建議您預計該專案的數據將在2022年公佈。

And our next question comes from Cory Kasimov from JPMorgan.

下一個問題來自摩根大通的科里·卡西莫夫。

On the strategic front, on the heels of the expanded deal with CRISPR as well as the smaller Obsidian collaboration, just curious if we should be thinking about business development or M&A any differently going forward. I know there are some recent expectation of larger deals to come. Is that still the plan? Or are we kind of looking at the smaller, earlier stage ones where you can add more of your expertise?

在策略層面，繼與 CRISPR 擴大合作以及與 Obsidian 的小規模合作之後，我很好奇我們是否應該以不同的方式考慮未來的業務拓展或併購策略。我知道最近有一些關於未來達成更大規模交易的預期。這仍然是我們的計劃嗎？或者我們應該更專注於規模較小、處於早期階段的交易，以便您能發揮更多專業優勢？

Yes. So this is Reshma again. Let me take that one for you. Our business development or external innovation strategy is exactly the same as it has been over the last several years. And what I mean by that is we're looking for assets in CF that complement our internal pipeline. We're looking for tools to expand our toolkit, and we're looking for assets that fit our disease areas of interest. And when I say that, I mean assets that we, Vertex, could add value: research, development, regulatory, et cetera. I've been really pleased with the deals that we've done. You could look at Semma or Exonics as examples, but you can also just look back in the last couple of weeks with the amended agreement with CRISPR Therapeutics and the collaboration agreement with Obsidian. That's what you should think about when you think about our external innovation approach, and you should expect to see more of the same.

是的，我是Reshma。讓我來為您解答。我們的業務拓展或外部創新策略與過去幾年完全相同。我的意思是，我們正在尋找能夠補充我們內部研發管線的囊性纖維化（CF）相關資產。我們正在尋找能夠擴展我們工具箱的工具，以及符合我們關注疾病領域的資產。我所說的“符合我們關注的疾病領域”，是指我們Vertex能夠為其增值的資產，包括研發、監管等方面。我對我們達成的交易非常滿意。您可以看看Semma或Exonics的例子，也可以回顧一下最近幾週與CRISPR Therapeutics的修訂協議以及與Obsidian的合作協議。這就是您在考慮我們的外部創新策略時應該想到的，而且您應該會看到更多類似的舉措。

And our next question comes from Salveen Richter from Goldman Sachs.

下一個問題來自高盛的薩爾文·里希特。

On the 11 micromolar threshold for AAT CRM levels, how are you thinking about that in context of dose response and what you're trying to ascertain with the upcoming Phase II data? And then just a second question, if you could just remind us where you stand on the in vivo CRISPR/CAS9 work on Duchenne and DM1.

關於AAT CRM水平11微摩爾的閾值，您如何看待劑量反應以及您希望透過即將公佈的II期數據確定的內容？另外，能否請您簡單介紹一下您在杜氏肌肉營養不良症和DM1的體內CRISPR/Cas9研究方面的進展？

Sure. Salveen, this is Reshma. I could answer those questions for you. Let me tackle DMD and DM1 first, and then I'll come back to AATD. So we're making good progress on the DMD and DM1 programs that are both in late preclinical development. Obviously, you've seen what's been going on in the field with regard to real setbacks that others have experienced. And what we're doing is being very deliberate and very careful about process development, analytical development dosing, and we are making progress in those regards. And I'm eager to share with you when those programs will come into the clinic, but that's for another day.

當然可以。薩爾文，我是雷什瑪。我可以回答你的問題。我先來談談杜氏肌肉營養不良症（DMD）和1型肌肉失養症（DM1），然後再談α1-抗胰蛋白酶缺乏症（AATD）。我們在DMD和DM1專案上都取得了不錯的進展，這兩個專案目前都處於臨床前開發的後期階段。顯然，你也看到了其他研究者在這個領域遇到的挫折。我們正在做的，是謹慎地推進製程開發、分析方法開發和劑量測定，並且在這方面取得了進展。我很想告訴你這些項目何時能進入臨床試驗階段，但那是之後的事了。

With regard to the AATD question, there's no magic number here. What we're looking for from this proof-of-concept study is the totality of the evidence. And as I mentioned, that is safety. That's dose responsiveness, dose exposure. And what I mean specifically by that is that there is an association with higher dose to greater exposure or greater response and certainly, elevations in functional AAT levels. I'm eager to talk to you about the data and the next steps. And we're very close now. I fully expect that the data readout will be later this quarter.

關於AATD的問題，這裡並沒有什麼神奇的數字。我們希望從這項概念驗證研究中獲得全面的證據。正如我之前提到的，這包括安全性、劑量反應性和劑量暴露。具體來說，我的意思是，更高的劑量是否與更大的暴露量或更顯著的反應有關，當然也與功能性AAT水平的升高有關。我非常期待與您討論數據和下一步計劃。我們現在已經非常接近目標了。我完全預計數據將在本季稍後公佈。

And our next question comes from Mohit Bansal from Citigroup.

下一個問題來自花旗集團的莫希特·班薩爾。

Congrats on all the progress. Maybe a question -- again, one other question with AAT. Our checks suggest that AAT levels do fluctuate naturally in human body depending on if you're in an acute case or not. And to that end, let's just say, if we see some elevation in functional AAT levels of VX-864 trial, is there any reason to believe it could be just due to a chance alone, especially at these patients, rather than being an effect of the drug?

恭喜所有的進展。或許還有一個問題──關於AAT，我們還有一個疑問。我們的研究表明，人體內AAT水平會根據病情輕重而自然波動。因此，假設我們在VX-864試驗中觀察到功能性AAT水平升高，是否有任何理由認為這只是偶然現象，尤其是在這些患者中，而不是藥物的作用？

Yes. Mohit, this is Reshma. I really do understand your question. And what we're talking about when I say I want to see elevation in functional AAT level is real elevation. And when I say we're looking for dose responsiveness, that's part of what we're looking for, right? We are looking to see that exposure increases with dose. And that responsiveness, the actual functional AAT levels, vary with dose. Those are all elements of what we're looking for. So when I say functional AAT levels go up, that's what we're looking for. I mean real elevation in functional AAT levels.

是的，莫希特，我是雷什瑪。我完全理解你的問題。我說我想看到功能性AAT水平升高，指的是真正的升高。我說我們在尋找劑量反應性，這也是我們尋找的內容之一，對吧？我們想看到藥物暴露量隨劑量增加而增加。而這種反應性，也就是實際的功能性AAT水平，會隨劑量而改變。這些都是我們尋找的內容。所以，當我說功能性AAT水平升高時，這就是我們所尋找的。我指的是功能性AAT水平的真正升高。

And our next question comes from Liisa Bayko from Evercore ISI.

下一個問題來自 Evercore ISI 的 Liisa Bayko。

I want to ask a little bit about the pain program. You started to talk about it a little bit more, VX-548. Can you maybe talk about how it's different from VX-150, which actually made it quite far into the clinic? And then in terms of your kind of intentions clinically, I know you're setting some acute indications. Are you going to be eventually [serving] chronic as well? Or is this more muted for chronic? Those are my questions.

我想問一些關於疼痛治療方案的問題。您剛才稍微提到了VX-548。您能否談談它與VX-150的區別？ VX-150其實已經進入臨床應用相當深入的階段了。另外，就您的臨床應用目標而言，我知道您正在針對急性疼痛制定一些適應症。您最終也會將其用於治療慢性疼痛嗎？還是說目前針對慢性疼痛的治療效果並不突出？以上就是我的問題。

Yes. Yes. Sure, Liisa. Let me break this up into 2 parts, and I'm going to take the first. And I'm going to ask Stuart to comment on the second. I'm going to tackle the things that you need to know from an R&D perspective, and I'm going to ask Stuart to comment on the commercial prospects here.

是的，好的，莉莎。我把它分成兩部分，我先講第一部分，然後請史都華談談第二部分。我會從研發的角度談談你需要了解的內容，然後請史都華談談這方面的商業前景。

Three things, Liisa, to know from the R&D perspective. First, the target. The target here is NaV1.8. And that's important to know because NaV1.8 is a genetically validated target, but it's also a pharmacologically validated target. And exactly right, it was VX-150 that had positive Phase II proof-of-concept readouts across 3 different pain indications: acute, neuropathic and, let's call it, musculoskeletal pain.

莉薩，從研發角度來看，有三件事你需要了解。首先是靶點。這裡的靶點是NaV1.8。這一點很重要，因為NaV1.8不僅是經過基因驗證的靶點，也是經過藥理驗證的標靶。沒錯，VX-150在針對三種不同疼痛適應症（急性疼痛、神經性疼痛以及我們暫時且稱之為肌肉骨骼疼痛）的II期概念驗證試驗中均取得了積極結果。

The second thing to know is our approach with VX-548. So VX-548, as it's emerged from its Phase I trial, it really has all of the properties that we're looking for, not only in terms of safety and tolerability but also PK and exposures and at doses that are considerably lower than what we saw with our previous NaV1.8 inhibitors, including 150. And that obviously has significant benefits in a multitude of ways but including in formulation and manufacturability.

第二點要了解的是我們對VX-548的研究方法。 VX-548從I期臨床試驗中脫穎而出，它確實具備我們所尋找的所有特性，不僅在安全性和耐受性方面，而且在藥物動力學和暴露量方面也表現出色，並且其劑量遠低於我們之前使用的NaV1.8抑製劑，包括150毫克。這顯然在許多方面都具有顯著優勢，包括製劑和生產流程。

And the last thing I'll say on the R&D side is we're starting with acute pain. Bunionectomy will be first and then abdominoplasty. We're doing that because the pathway to registration is a visceral and nonvisceral indication. Acute pain, as the name implies, it's a very short duration of treatment. It's a couple of days. And we've done a bunionectomy studies before. We know how to do it. So that's kind of how I'm viewing that.

最後，關於研發方面，我想說的是，我們先著手於急性疼痛。拇外翻切除術將是首選，然後是腹部整形。我們這樣做是因為註冊途徑涵蓋內臟和非內臟適應症。顧名思義，急性疼痛的治療週期非常短，通常只有幾天。而且我們之前做過拇趾外翻切除術的研究，我們知道該怎麼做。這就是我對研發的看法。

I'm going to turn it over to Stuart to tell you a little bit more about the market size and the opportunity there.

接下來我將把麥克風交給斯圖爾特，讓他再詳細介紹市場規模和其中的機會。

Yes, Liisa. So in the acute and neuropathic segments of the pain market, they're both currently multibillion-dollar segments of the market, both largely dominated by generics currently and both in need of significant innovation. And so we're looking to bring forward an agent, which is both superior in terms of efficacy and tolerability. And as a result of that, we believe it will be used in a great deal of patients in both of those segments.

是的，莉薩。在急性疼痛和神經性疼痛這兩個市場領域，目前都是數十億美元的市場，都主要由仿製藥主導，而且都亟需重大創新。因此，我們正在努力研發一種在療效和耐受性方面都更勝一籌的藥物。我們相信，憑藉這種藥物，它將在這兩個領域中廣泛應用。

And because we're targeting that superior profile, we think we'll be able to compete in a really, really strong way with generic opioids and also generic pregabalins in the neuropathic segment of the market. Both of those as well are markets which are served by a relatively concentrated group of prescribers. And so we feel that those segments in particular play into our overall corporate strategy of focusing on specialty markets.

正因為我們瞄準的是這種卓越的產品特性，我們相信我們能夠在神經性疼痛市場領域與仿製阿片類藥物和仿製普瑞巴林展開強有力的競爭。這兩個市場都由相對集中的處方醫生群體服務。因此，我們認為這些細分市場尤其符合我們專注於專科市場的整體企業策略。

And our next question comes from Gena Wang from Barclays.

下一個問題來自巴克萊銀行的王吉娜。

I will also ask one question on AAT. Reshma, you mentioned that dose responses are also one very important criteria. Can you share with us like how did you choose doses in the Phase II study? And do you also anticipate further dose escalation? If Phase II data showing still have some room or either not reaching optimal or the safety looks good, were you planning to dose further up?

我還有一個關於AAT的問題。 Reshma，你提到劑量反應也是一個很重要的標準。可以和我們分享一下，在II期研究中你們是如何選擇劑量的嗎？你們是否也計劃進一步增加劑量？如果II期數據顯示劑量還有提升空間，或尚未達到最佳劑量，或安全性良好，你們是否計劃進一步增加劑量？

Sure. Gena, the way we choose our doses for AATD are really the same as we do for all of our programs. You know our programs in CF very well, and maybe that's a good example to talk through. What we're really looking at is our in vitro data and translating what we see in our models into the clinic and into patients. And obviously, we have a track record of doing that quite well in CF, and that is exactly the same methodology that we use here in AATD.

當然。吉娜，我們選擇AATD治療方案的劑量方法，實際上與我們所有其他治療方案都一樣。你很了解我們在囊性纖維化（CF）的治療方案，或許我們可以就此舉個例子。我們主要關注的是體外實驗數據，並將模型中的觀察結果轉化到臨床和患者身上。顯然，我們在CF治療方面已經取得了相當不錯的成績，而這正是我們在AATD治療中採用的方法。

If I just elevate a little bit, Gena, what I think your question behind your question might be is, gosh, how confident are you that you're going to be able to bring forward a medicine for this disease? How confident are you in this mechanism? And, in general, how do we view this? And let me be very clear about that. We are committed to this disease. This disease fits our strategy like a glove. We have been working on this mechanism for many years, and we feel high confidence that we have the right approach. And I'm looking forward to sharing with you the data. As I said, that's going to be coming out very soon in this quarter.

吉娜，如果我稍微深入一點，我想你真正想問的是，你對研發出治療這種疾病的藥物有多大信心？你對這種機制有多大信心？總的來說，我們是如何看待這個問題的？讓我明確一點：我們致力於攻克這種疾病。這種疾病與我們的策略完美契合。我們多年來一直在研究這種機制，我們非常有信心我們找到了正確的方法。我期待與你分享數據。正如我所說，數據將在本季很快公佈。

And our next question comes from Robyn Karnauskas from Truist.

下一個問題來自 Truist 的 Robyn Karnauskas。

Very good. Well done. So 2 really quick questions. Let's start with the triple, the triple-combo 121. I know you haven't talked a lot about it. But what sort of control arm would you need? What is the angle with advancing that program? What kind of expectations would you have for that program? On pain, I think my direct question would be, you've always said, if you get it to Phase II, you'd want to like partner first to go into Phase III. So is that still the case? Do you think a partner would want to partner in maybe a big deal for you to go into chronic pain and be a catalyst for you as well? Is that still the plan for pain? And then going back to 121, educate us on what your plan is for that.

非常好，做得很好。那我有兩個非常簡短的問題。我們先從三聯療法，也就是三聯療法121開始。我知道您很少談到它。但是您需要什麼樣的對照組呢？推進這個專案的角度是什麼？您對這個專案有什麼期望？關於疼痛，我想直接問的是，您一直說，如果專案進入二期，您希望先找到合作夥伴進入三期。現在情況仍然如此嗎？您認為合作夥伴是否願意與您合作，共同推動慢性疼痛領域的研究，並成為您研究的催化劑？疼痛治療方面，您仍有這樣的計畫嗎？然後回到121療法，請您介紹您的計劃。

Sure. Robyn, it's Reshma. Let me do pain first. We are focused on acute pain and neuropathic pain. And those are both pain conditions, as you heard Stuart say, that we believe to be Vertex-ing and to be managed in the specialty market manner in which we feel very comfortable. So that's what we are focused on: acute pain first and then neuropathic is what we're looking at.

當然。羅賓，我是雷什瑪。我先來說說疼痛方面的問題。我們主要關注急性疼痛和神經性疼痛。正如你剛才聽到的史都華所說，我們認為這兩種疼痛都屬於Vertex的範疇，並且我們覺得在專科市場進行管理會更加得心應手。所以，這就是我們關注的重點：首先是急性疼痛，然後是神經性疼痛。

What you've heard us say in the past is when we get to considerations in musculoskeletal pain, for example, that is not something that we would commercialize. But what we're talking about here is acute pain and neuropathic pain.

我們之前說過，例如在考慮肌肉骨骼疼痛這類問題時，我們不會將其商業化。但我們現在討論的是急性疼痛和神經性疼痛。

Going to CF, the next wave of combination of potentiators and correctors is, indeed, the combination of VX-121, VX-561 and tezacaftor. And really, what we're looking at here is a combination that has the potential to have superior efficacy for patients, once-a-day dosing and also improved economics. And what I mean by that is going from royalties that are in the low double digits to low single digits. We are wrapping up our conversations with regulators on that program, and we are readying that program to go to Phase III, which I expect will happen later this year.

就囊性纖維化（CF）而言，下一代增強劑和矯正劑的組合療法，實際上是VX-121、VX-561和tezacaftor的組合。我們關注的這種組合療法，有望為患者帶來更優的療效，實現每日一次給藥，並改善經濟效益。我的意思是，其專利使用費將從兩位數的低點降至個位數的低點。我們正在與監管機構就該計畫進行最後的磋商，並準備啟動該計畫的III期臨床試驗，預計今年稍後啟動。

Reshma, how do you get there? That would be a great, enticing opportunity for your Vertex shareholders. How do you get -- convert people to that drug? Do you have a sense of how you would go that direction?

雷什瑪，你打算怎麼達成這個目標？這對你的Vertex股東來說將是一個絕佳的、極具吸引力的機會。你打算如何讓人們接受這種藥物？你有沒有想過該如何著手？

Yes. Yes. Robyn, when we bring molecules forward into late-stage development like the 121, tezacaftor, 561 combination, we are doing so because we have full expectation that we are going to be able to do something that is better for patients. We are all about first-in-class and best-in-class, and we aim to out-innovate ourselves. And so bringing this forward to patients is about having better efficacy, once-a-day dosing for them. There is, of course, going to be a control arm, and I fully expect the control arm to be the triple combination. And triple combination is a fantastic medicine. It has the potential to treat up to 90% of patients. And what we see in the real world in terms of efficacy has been what we saw in the clinical trials. So yes, indeed, this is a very high bar, but that is what we're aiming for.

是的，是的。 Robyn，當我們把像121、tezacaftor和561組合這樣的分子推進到後期研發階段時，我們這樣做是因為我們完全相信我們能夠為患者帶來更好的療效。我們致力於打造同類首創、同類最佳的藥物，並力求超越自我創新。因此，將這些藥物推向市場是為了為患者帶來更好的療效，以及每日一次的給藥方案。當然，我們會設定一個對照組，我完全預期對照組會是三重療法。三聯療法是一種非常有效的藥物，它有潛力治療高達90%的患者。我們在實際應用中觀察到的療效與臨床試驗的結果一致。所以，是的，這確實是一個非常高的標準，但這正是我們努力的目標。

And our next question comes from Matthew Harrison from Morgan Stanley.

下一個問題來自摩根士丹利的馬修·哈里森。

Stuart, I was wondering if I could just get you to comment in a little bit more detail on uptake across the European countries where you do have reimbursement and then maybe give us some sense for the time line of what you're thinking about in terms of the countries where you don't yet.

斯圖爾特，我想請你更詳細地評論一下在你們已經實行報銷的歐洲國家，報銷的普及情況，然後再給我們一些關於你們在尚未實行報銷的國家中，計劃採取哪些措施的時間表。

Yes. Matt, thanks for the question. Yes, the uptake in the countries outside the U.S. where we do have reimbursement has been very, very strong. Indeed, almost superimposable on what we saw here in the U.S., both in terms of uptake but also in terms of the levels of persistence and compliance that we've seen. And that's what's really driven the strong growth of our ex-U.S. revenues in Q1 versus the same period last year. And so we've seen the 43% growth over the same quarter last year. So that's very, very impressive as they are driven by uptake in those markets where we already have reimbursement.

是的，馬特，謝謝你的提問。是的，在美國以外我們已經提供健保報銷的國家，健保的普及率非常非常高。事實上，無論是在普及率，還是在病人的堅持率和依從性方面，這些國家的醫保普及率幾乎與我們在美國本土的情況完全一致。這正是我們第一季美國以外地區營收較去年同期強勁成長的真正原因。因此，我們看到了與去年同期相比43%的成長。考慮到這些成長主要來自我們已經提供健保報銷的市場，這樣的成績非常令人矚目。

We're continuing to make good progress in getting reimbursement in new countries. Indeed, during the first few months of this year, we have added new reimbursement agreements in places like Finland and Israel and Switzerland. And we're continuing to work with countries where we have regulatory approval but don't yet have reimbursement. And in Europe, that would be countries like France and Italy and Spain. Obviously, we recently received regulatory approval in Australia. We're working with the P back there. And obviously, we're still waiting for regulatory approval in Canada.

我們在拓展新國家的健保報銷方面持續取得良好進展。事實上，今年前幾個月，我們就與芬蘭、以色列和瑞士等國新增了健保報銷協議。我們也持續與那些已獲得監管部門批准但尚未獲得健保報銷的國家合作。在歐洲，這些國家包括法國、義大利和西班牙。顯然，我們最近獲得了澳洲的監管部門批准，目前正在與澳洲的藥品監管機構合作。當然，我們仍在等待加拿大的監管部門批准。

What I can tell you is that we continue to feel very, very confident that we are going to get both regulatory approvals and reimbursement agreements in those countries. And that's why we continue to believe that we have very strong growth in our CF franchise in the years to come.

我可以告訴大家的是，我們仍然非常有信心能夠獲得這些國家的監管部門批准和醫療保險報銷協議。正因如此，我們仍然相信，未來幾年我們的囊性纖維化業務將保持強勁成長。

Our next question comes from Brian Abrahams from RBC Capital.

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

Just a couple of quick ones on AAT. From your ongoing work, do you have a sense for how long it might take to reach steady state levels of functional AAT in the serum? I guess I'm just wondering if we should look at the 28-day data as a snapshot in time or reflecting the full potential of the agent. And then how functional would the corrected AAT detected by your assay be relative to wild type?

關於AAT，我有幾個問題想快速問一下。根據您目前的研究，您認為血清中功能性AAT達到穩態水平需要多長時間？我想知道，我們應該把這28天的數據看作是某個時間點的快照，還是能反映出該藥物的全部潛力？另外，您偵測出的校正後AAT的功能與野生型相比如何？

Yes. This is Reshma. I can take both of those for you. From all of the work that we've done preclinically and in our modeling work, 28 days is going to be sufficient for us to reach steady state. And I think that data that we get from this Phase II proof-of-concept study is going to be very helpful.

是的，我是雷什瑪。我可以幫您解答這兩個問題。根據我們先前在臨床前研究和模型建構所做的工作，28天足以讓我們達到穩態。我認為我們從這項二期概念驗證研究中獲得的數據將非常有幫助。

With regard to whether or not the AAT -- the corrected AAT is functional or not, the -- we are, indeed, going to be measuring antigenic AAT levels, but we're also going to be measuring functional AAT levels, and those assays are reasonably straightforward. So I don't think that that's going to pose any challenge.

至於校正後的AAT是否具有功能，我們確實會檢測抗原性AAT的水平，但也會檢測功能性AAT的水平，這些檢測方法都相當簡單。所以我認為這不會構成任何挑戰。

And just to complete the thought, Brian, in all these comments that we've done, the corrected protein we -- corrected protein that we produce with the small molecule approach is the same as wild type.

最後補充一點，布萊恩，在我們所做的所有這些評論中，我們用小分子方法生產的校正蛋白與野生型相同。

And our next question comes from Alethia Young from Cantor Fitzgerald.

下一個問題來自 Cantor Fitzgerald 公司的 Alethia Young。

Congrats on the quarter. I guess I just wanted to talk a little bit about kind of when you think we might start to see some novel conditioning regimens for CTX001. And do you think that's something that possibly could happen relatively soon after potential commercial launch? Or do you think wait a couple of years before kind of getting to a more kind of tolerable conditioning regimen?

恭喜你本季取得佳績。我想稍微聊聊你認為我們大概什麼時候才能看到CTX001的一些新型預處理方案。你覺得這會在潛在的商業上市後不久出現嗎？還是說需要再等幾年才能找到更容易接受的預處理方案？

Yes. Yes. This is Reshma, let me address that one for you. So the conditioning regimen, as we talked about earlier, is really important in opening up this opportunity for the patients beyond that original 32,000 that we discussed that I think are severe enough that they would be amenable to busulfan-based therapy, right? And so I do think that the initial launch will be with current conditioning regimen. That being said, I do also believe it's a matter of when, not if, gentler conditioning regimens will be here. And the reason I say that is we at Vertex are working on gentler regimen, CRISPR Therapeutics is working on gentler regimen as are a number of other companies.

是的，是的。我是雷什瑪，讓我來回答這個問題。正如我們之前討論過的，預處理方案對於讓更多患者有機會接受治療至關重要，這不僅包括我們之前提到的那32000名病情嚴重的患者，也包括其他一些適合接受白消安療法的患者，對吧？所以我認為，最初的上市將採用目前的預處理方案。話雖如此，我也相信更溫和的預處理方案的出現只是時間問題。我這麼說的原因是，我們Vertex公司正在研發更溫和的方案，CRISPR Therapeutics公司也在研發，其他一些公司也在進行類似的研究。

There are targets that we already know about. There are self-surface markers on hematopoietic stem cells that are the specific cells that we wanted to target. Those are already known, CD117, for example. And the payloads are already known as well. And remember, this gentler conditioning regimen has potential use for both oncology indications as well as what we would be looking at in terms of sickle cell and beta cell.

我們已經知道一些靶點。造血幹細胞表面存在一些自身標記物，這些標記物正是我們想要標靶的特定細胞。例如，CD117 就是已知的標靶。有效載荷也已經確定。請記住，這種較溫和的預處理方案不僅在腫瘤治療方面具有潛在應用價值，而且在鐮狀細胞貧血和β細胞貧血方面也具有應用價值。

So net sum, there's a lot of work in this area. I do think it's a matter of when and not if. And I think that this is something that is in the near future.

總而言之，這個領域還有很多工作要做。我認為這只是時間問題，而不是會不會發生的問題。而且我認為這在不久的將來就會實現。

And our next question comes from Paul Matteis from Stifel.

下一個問題來自 Stifel 公司的 Paul Matteis。

I wanted to ask one more question on business development. It might be my mistake, but I've kind of gotten a sense over a couple of prior quarters that you've been more open to doing larger transactions. And then when we look at the balance sheet this year, you made and closed it -- close to $10 billion in cash. What's your thought here on deal size? And I guess, you had said, Reshma, more of the same. So does that mean we shouldn't really expect a deal that's, say, bigger than $1 billion or so and maybe more likely a number of kind of smaller strategic transactions?

我想再問一個關於業務拓展的問題。也許是我理解有誤，但我感覺過去幾季你們似乎更願意進行規模較大的交易。而且，從今年的資產負債表來看，你們完成了近100億美元的現金交易。您對此有何看法？我想，您之前說過，Reshma，情況會和以前一樣。那麼，這是否意味著我們不應該預期出現超過10億美元的大單，而更有可能出現一些規模較小的策略性交易？

Paul, it's all about our strategy, and I laid out our business development strategy a few minutes ago. It's not about deal size. And I'm not going to add to the speculation, but you should feel high confidence that the strategy is exactly the same.

保羅，一切都取決於我們的策略，幾分鐘前我已經闡述了我們的業務拓展策略。這與交易規模無關。我不想再做任何猜測，但你應該完全相信，我們的策略絲毫未變。

And our next question comes from Brian Skorney from Baird.

下一個問題來自 Baird 公司的 Brian Skorney。

I was hoping -- I want to kind of get some of your insights on the gene editing approach for DMD and how to kind of think about the various mutations that occur in dystrophin and how do you correct. We're all sort of used to the various mutations based on the exon skipping (inaudible) groups. But even within those areas, there seem to be many unique mutations. So I guess, when you think of gene editing, would you have to tackle each one of these mutations in a separate product? Or is there something out of the box in terms of an edit that can be done to sort of tackle the whole disease landscape with 1 product?

我希望——我想了解您對杜氏肌肉營養不良症（DMD）基因編輯方法的一些見解，以及如何看待肌肉營養不良蛋白中發生的各種突變並進行糾正。我們都比較熟悉基於外顯子跳躍（聽不清楚）的各種突變。但即使在這些領域內，似乎也存在著許多獨特的突變。所以我想，當您考慮基因編輯時，是否需要針對每種突變開發單獨的產品？或者是否有一種突破常規的編輯方法，可以用一種產品來解決整個疾病問題？

Yes. Yes. So when you talk about DMD, right, there are 2 fundamentally different approaches to this. One is with microdystrophins, which many others are doing, not us. And our approach, which is based in CRISPR gene editing, to reframe the reading of the codon, so that we can produce full length or near-full length protein, right? So when you think about the advantages and disadvantages of each, and there are, the potential advantage to a microdystrophin approach is that it's a singular approach for multiple exons. The great disadvantage, of course, is that it's not anywhere close to a full-length protein.

是的。是的。所以，說到杜氏肌肉營養不良症（DMD），對吧？目前有兩種截然不同的治療方法。一種是使用微型肌肉營養不良蛋白，很多其他研究者都在採用這種方法，但我們沒有。另一種方法是基於CRISPR基因編輯，透過重新排列密碼子來改變密碼子的讀取方式，從而產生全長或接近全長的蛋白質，對吧？所以，當你考慮到每種方法的優缺點時（它們確實都有），微型肌肉營養不良蛋白方法的潛在優點在於，它可以針對多個外顯子進行單一的治療。當然，它最大的缺點是，它產生的蛋白質遠非全長。

Our approach is the full-length protein, which has the great benefit of being what is exactly the protein that is what we are trying to target. So having full-length protein is critically important. What we see as the approach here is to come forward with the first exon and then to have an approach and an agreement with regulators that once we have that first exon, that the second, third, fourth would be far more efficient. And obviously, our intent is to bring those forward on shorter time lines because the bulk of the work will have been done with the first exon.

我們採用的是全長蛋白，其最大的優點在於它正是我們想要標靶的蛋白。因此，獲得全長蛋白至關重要。我們認為，目前的策略是先獲得第一個外顯子，然後與監管機構達成協議，一旦獲得第一個外顯子，後續第二個、第三個甚至第四個外顯子的定序效率將大大提高。顯然，我們的目標是縮短後續定序的時間，因為大部分工作都將在第一個外顯子定序階段完成。

Got it. So then just to clarify, would the approach to the added be to like effectively edit out the entire exon 51, in the case of an exon 51, amenable mutation?

明白了。那麼為了確認一下，對於新增的基因，處理方法是像刪除整個外顯子51那樣，在存在可編輯突變的情況下，直接刪除整個外顯子51嗎？

Maybe I could explain it this way. What we're really talking about to get to all of the mutations in DMD is we would need a few vectors, just a few different guides, and then we could get to all of the amenable mutations. And remember, the big picture item here really is a bigger difference than whether we need to have 1 vector or not. It will take a few vectors and a few guides. But the more important issue is the microdystrophins are a very short form of the protein that are not expected to provide the benefit of the full-length protein.

或許我可以這樣解釋。我們真正要討論的是，為了研究杜氏肌肉營養不良症（DMD）的所有突變，我們需要一些載體，也就是一些不同的引導序列，這樣我們就能研究所有合適的突變。記住，這裡的關鍵遠不止於是否需要一個載體。我們需要一些載體和一些引導序列。但更重要的問題是，微型肌肉營養不良蛋白是蛋白質的極短形式，預計無法提供全長蛋白所具有的益處。

And you know that in January of this year, there was the first readout of a randomized controlled trial using microdystrophin, and it was not a positive trial. That's why the bigger picture item to keep in mind here is that our approach is a near-full length or full-length dystrophin.

您也知道，今年一月，一項使用微型肌肉營養不良蛋白的隨機對照試驗的首個結果公佈，結果並不理想。因此，我們需要記住的關鍵一點是，我們的研究方法是使用接近全長或全長的肌肉營養不良蛋白。

And now I would now like to turn the call back over to Michael Partridge for closing remarks.

現在，我想把電話交還給麥可·帕特里奇，請他作總結發言。

Thanks, operator. Thank you all for tuning into our first quarter conference call. The investor relations team is available tonight if you have additional questions. Have a good night, and you can now disconnect.

謝謝接線生。感謝各位收聽我們第一季財報電話會議。如果您還有其他問題，投資者關係團隊今晚隨時為您解答。祝您晚安，現在可以掛斷電話了。

This concludes today's conference call. Thank you for participating, and you may now disconnect. Thank you, and have a great day.

今天的電話會議到此結束。感謝您的參與，您可以斷開連接了。謝謝，祝您今天愉快。