福泰製藥 (VRTX) 2019 Q2 法說會逐字稿

Welcome. This is Michael Partridge, Senior Vice President of Investor Relations. Tonight, we will review with you Vertex's business progress and provide our second quarter financial results.

歡迎。這是投資者關係高級副總裁邁克爾·帕特里奇。今晚，我們將與各位一起回顧Vertex的業務進展，並提供我們第二季的財務表現。

Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Dr. Reshma Kewalramani, Chief Medical Officer; and Charlie Wagner, Vertex's Chief Financial Officer. Stuart Arbuckle, Chief Commercial Officer, will join us for Q&A. We recommend that you access the webcast slides on our website as you listen to the call. This conference call is being recorded and a replay will be on our website.

今晚在電話會議上發表準備好的演講的有：董事長兼首席執行官 Jeff Leiden 博士；首席醫療官 Reshma Kewalramani 博士；以及 Vertex 首席財務官 Charlie Wagner。首席商務官史都華·阿巴克爾將參加問答環節。我們建議您在收聽電話會議的同時，請造訪我們網站上的網路直播投影片。本次電話會議正在錄音，錄音回放將在我們的網站上發布。

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 our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed CF medicines, the ongoing development and potential commercialization of our triple combination regimens for cystic fibrosis, Vertex's other programs and Vertex's 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，這些聲明受到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的影響。這些聲明，包括但不限於有關 Vertex 已上市的 CF 藥物、我們用於治療囊性纖維化的三聯療法的持續開發和潛在商業化、Vertex 的其他項目以及 Vertex 未來的財務業績的聲明，均基於管理層目前的假設。實際結果和事件可能與此有重大差異。

I will now turn the call over to Dr. Jeff Leiden.

現在我將把電話交給傑夫·萊頓博士。

Thanks, Michael. Good evening, everyone. It's with great pride and appreciation for all that our employees and leadership team are achieving, that I'd like to take a few moments to talk about our progress and to affirm our strategy going forward.

謝謝你，麥可。各位晚上好。我懷著無比的自豪和感激之情，感謝我們的員工和領導團隊所取得的成就，我想花幾分鐘時間談談我們取得的進展，並重申我們未來的策略。

I'm pleased to say that our business is outperforming on multiple fronts. As we enter the second half of the year, we are on track to achieve or exceed our 2019 goals, and we're well positioned for continued innovation and growth in the future.

我很高興地告訴大家，我們的業務在多個方面都表現出色。隨著我們進入下半年，我們有望實現或超越 2019 年的目標，並且我們已做好充分準備，在未來繼續創新和發展。

We're treating more people with CF than ever before with our approved medicines, which continues to drive significant revenue growth to support investment and to creating future medicines. We have rapidly grown our pipeline beyond CF, and we now have ongoing development programs evaluating 7 different potentially transformative medicines spanning 5 specialty diseases.

我們使用核准藥物治療的囊性纖維化患者比以往任何時候都多，這持續推動了顯著的收入成長，以支持投資和開發未來的藥物。我們的研發管線已迅速擴展到囊性纖維化以外的領域，目前我們正在進行研發項目，評估 7 種不同的、具有潛在變革意義的藥物，涵蓋 5 種專科疾病。

We have also established multiple new collaborations and acquisitions over the past year, aimed at complementing our productive internal research engine. First is CF. Our progress in CF has been extraordinary. In 2019 alone, we have received 9 new regulatory approvals or label expansions for our CF medicines globally, reached new reimbursement agreements in 10 countries outside the U.S. and completed the Phase III program for our triple combination regimens involving nearly 1,000 patients.

過去一年，我們也建立了多項新的合作關係和收購，旨在補充我們高效的內部研發引擎。首先是CF。我們在囊性纖維化治療方面取得了非凡的進展。僅在 2019 年，我們的 CF 藥物就獲得了全球 9 項新的監管批准或標籤擴展，在美國以外的 10 個國家/地區達成了新的報銷協議，並完成了涉及近 1000 名患者的三聯療法 III 期項目。

And just last week, we announced the submission of the New Drug Application for the triple combination of VX-445 tezacaftor and ivacaftor to the U.S. FDA, marking the most significant milestones to date in our efforts to create new CF medicines over the past 2 decades. The Phase III data we announced in May for the VX-445 triple combination regimen were unprecedented showing improvements in lung function and other measures of the disease that were among the highest magnitude ever seen in any of our CF studies.

就在上週，我們宣布向美國 FDA 提交了 VX-445 tezacaftor 和 ivacaftor 三聯療法的新藥申請，這標誌著我們在過去 20 年中為研發新的 CF 藥物所取得的最重要里程碑。我們在 5 月公佈的 VX-445 三重療法的 III 期數據是前所未有的，顯示肺功能和其他疾病指標的改善程度在我們所有 CF 研究中都是最高的。

CF is a progressive and debilitating disease. We share the urgency of patients who are waiting for a new medicine to treat the underlying cause of their CF, and we therefore moved quickly to complete our NDA for the VX-445 triple combination within just weeks of receiving the final data.

囊性纖維化是一種進行性加重且使人衰弱的疾病。我們和等待新藥治療囊性纖維化根本病因的患者一樣迫切需要這種藥物，因此，我們在收到最終數據後的短短幾週內就迅速完成了 VX-445 三聯療法的 NDA。

Outside the U.S., we are focused on reaching new reimbursement agreements for our current CF medicines. And wherever possible, we are seeking portfolio agreements that will also provide patients with access to future CF innovations from Vertex. Beyond CF, our pipeline is expanding and advancing rapidly. We have 7 potentially transformative new medicines in clinical development across 5 serious specialty disease areas, including alpha-1 antitrypsin deficiency, APOL1-mediated kidney diseases, pain, sickle cell disease, and beta-thalassemia.

在美國以外，我們正致力於為我們現有的囊性纖維化藥物達成新的報銷協議。我們盡可能尋求投資組合協議，以便讓患者獲得 Vertex 未來在囊性纖維化治療的創新成果。除了CF之外，我們的產品線正在快速擴展和推進。我們在 5 個嚴重專科疾病領域有 7 種具有潛在變革意義的新藥正在進行臨床開發，包括 α-1 抗胰蛋白酶缺乏症、APOL1 介導的腎臟疾病、疼痛、鐮狀細胞疾病和 β-地中海貧血。

We are also increasing our external investment to build a tool kit to develop future breakthrough medicines in specific diseases we're interested in. Most recent example of these efforts are the recently completed acquisition of Exonics Therapeutics, and our expanded collaboration with CRISPR Therapeutics, and the development of new genetic therapies for DMD and DM1.

我們也在增加外部投資，以建立一套工具包，用於開發我們感興趣的特定疾病的未來突破性藥物。這些努力的最新例證是最近完成的對 Exonics Therapeutics 的收購，以及我們與 CRISPR Therapeutics 擴大合作，並開髮用於治療 DMD 和 DM1 的新基因療法。

These agreements provide us with development candidates that have shown promising preclinical results and also enable us to integrate cutting-edge scientific technology and expertise in diseases that are highly aligned with our business strategy. We plan to execute more of these types of fields as we further expand our pipeline of transformative medicines over the coming months and years.

這些協議為我們提供了已顯示出有希望的臨床前結果的候選藥物，也使我們能夠整合尖端科學技術和專業知識，以應對與我們業務戰略高度契合的疾病。在未來幾個月和幾年裡，我們將進一步拓展變革性藥物的研發管線，並計劃進行更多此類領域的研究。

Our strategy to create medicines by investing in serial scientific innovation is working as demonstrated by our continued strong performance in the first half of 2019. Importantly, our commercial success allows us to invest both internally in our own pipeline and externally through new collaborations to fuel our future growth. The results of our substantial and highly directed investments in R&D are evident in the significant progression of our pipeline, and we have the potential to achieve a risk-lowering clinical data in several programs in 2020.

我們透過投資連續科學創新來研發藥物的策略正在奏效，2019 年上半年我們持續強勁的業績證明了這一點。重要的是，我們的商業成功使我們能夠既投資於內部產品線，又透過新的合作進行外部投資，從而推動我們未來的成長。我們在研發方面投入了大量資源，並進行了有針對性的投入，其成果已在研發管線的顯著進展中得到體現。我們預計在 2020 年在多個項目中取得降低風險的臨床數據。

Before I end my prepared remarks, I'd like to say a few words about the leadership transition that will happen 8 months from now, where I will become Executive Chairman and Reshma will become Vertex's new President and CEO.

在我結束準備好的發言之前，我想就8個月後即將發生的領導層過渡發表幾句看法，屆時我將擔任執行董事長，而Reshma將成為Vertex的新任總裁兼首席執行官。

First, let me say that it's been a tremendous pleasure and honor to lead this company since 2012. I'm very proud of what the team has accomplished during that time. Vertex has never been stronger. Our business is growing rapidly, and we'll continue to grow for the next decade as we bring elexacaftor to the vast majority of CF patients worldwide, and then deliver on our clinical stage pipeline in multiple other serious diseases.

首先，我想說，自 2012 年以來，領導這家公司對我來說是莫大的榮幸和樂趣。我為團隊在那段時間所取得的成就感到非常自豪。Vertex從未如此強大。我們的業務正在快速成長，未來十年我們將繼續成長，我們將把 elexacaftor 帶給全球絕大多數 CF 患者，然後實現我們在多種其他嚴重疾病領域的臨床階段研發管線。

Based upon our success in CF, we now have the financial strength to invest in both internal and external innovation to deliver even more transformative medicines to more patients with serious diseases.

基於我們在囊性纖維化領域的成功，我們現在擁有足夠的財力投資於內部和外部創新，為更多患有嚴重疾病的患者提供更具變革性的藥物。

Finally, we have an outstanding senior leadership team with a proven track record of executing against our strategy. Together, these factors differentiate us and position us for long-term success. I've been working closely with Reshma for the last several years, I know that she is the perfect choice to succeed me as CEO and is fully prepared to lead Vertex into the future.

最後，我們擁有一支傑出的高階領導團隊，他們在執行我們的策略方面有著良好的業績記錄。這些因素共同使我們脫穎而出，並為我們的長期成功奠定了基礎。過去幾年我一直與雷什瑪密切合作，我知道她是接替我擔任執行長的最佳人選，並且已經做好充分準備帶領Vertex走向未來。

As a physician scientist, she has a deep commitment to our strategy of serial innovation as well as our inclusive culture of outstanding science. She's an excellent communicator and a strong collaborative leader with a proven ability to execute against our strategy and deliver results. Importantly, she has a track record of putting patients first in driving innovation to have a transformative impact on patients' lives.

作為一名醫學科學家，她對我們持續創新的策略以及我們包容性的卓越科學文化有著深刻的認同。她是一位優秀的溝通者和優秀的協作型領導者，擁有執行我們策略並取得成果的成熟能力。重要的是，她一直以來都以患者為先，推動創新，從而對患者的生活產生變革性的影響。

Of course, you all aren't getting rid of me quite yet. As you probably know, smooth, non-disruptive succession has historically been one of the biggest challenges for biotech companies. Recognizing this, the Board and I worked for several years on a succession plan that would ensure both strategic and operational continuity.

當然，你們現在還甩不掉我。您可能知道，平穩、不造成乾擾的繼任計畫歷來是生技公司面臨的最大挑戰之一。認識到這一點，董事會和我花了數年時間制定繼任計劃，以確保策略和營運的連續性。

As part of this plan, I'm looking forward to playing a continued active role in the company as Executive Chairman, supporting Reshma and our team through a smooth transition through Q1 2023. Specifically, Reshma and I have agreed that I will maintain an active role in 4 areas of the company: business development, helping to get deals done and secure our access to external innovation in products; building our new Boston research site dedicated to genetic therapies; Investor Relations; and public affairs and government relations, where I've established important relationships with the state, federal and international levels over the last 7 years.

作為該計劃的一部分，我期待繼續以執行主席的身份在公司中發揮積極作用，支持 Reshma 和我們的團隊順利過渡到 2023 年第一季。具體來說，我和雷什瑪已達成一致，我將在公司的四個領域繼續發揮積極作用：業務發展，幫助達成交易並確保我們獲得外部產品創新；建設我們位於波士頓的新研究基地，致力於基因療法；投資者關係；以及公共事務和政府關係，在過去的 7 年裡，我已與州、聯邦和國際層面建立了重要的關係。

I look forward to continuing to engage with you as the company progresses. I'll now turn the call over to Reshma.

我期待著隨著公司的發展繼續與您保持合作。現在我將把電話交給雷什瑪。

Thank you, Jeff. I'm honored to become Vertex's next CEO. Over the last 8 years, your strategic vision and relentless dedication to science and serial innovation has transformed the company, revolutionized the treatment of CF, and produced a pipeline of breakthrough medicines for other serious diseases. The success of our serial innovation strategy has also resulted in unprecedented financial strength.

謝謝你，傑夫。我很榮幸能成為Vertex的下一任執行長。在過去的 8 年裡，您的策略遠見和對科學及持續創新的不懈奉獻改變了公司，徹底改變了囊性纖維化的治療方法，並為其他嚴重疾病研發出了一系列突破性藥物。我們持續創新策略的成功也帶來了前所未有的財務實力。

I believe strongly in our differentiated strategy and I have no plans to change it. Our commitment to finish the journey in CF and to create multiple transformative medicines for other serious diseases has never been stronger. I look forward to continuing to work alongside Jeff and our outstanding senior leadership team at a time of such great opportunity for the company. And to deliver on our promises to bring more transformative medicines to patients with serious diseases who are waiting for them.

我堅信我們差異化的策略，並且沒有改變這項策略的計畫。我們致力於完成囊性纖維化治療的旅程，並為其他嚴重疾病研發多種變革性藥物，這項決心從未如此堅定。我期待在這個公司面臨巨大機會的時刻，繼續與傑夫和我們傑出的高階領導團隊並肩工作。並履行我們的承諾，為等待治療的重症患者帶來更多變革性藥物。

Now turning to key updates on our medicines in clinical development. 2019 has been a year of important clinical and regulatory milestones for our CF medicines and our pipeline beyond CF. In CF, we recently submitted our NDA for the VX-445 triple combination regimen and remain on track to complete our application in Europe in the fourth quarter of this year. Our NDA included a request for priority review, which if granted, would provide a PDUFA date sometime late in the first quarter of next year.

接下來，我們將介紹一些處於臨床開發階段的藥物的關鍵最新進展。2019 年對於我們的 CF 藥物以及 CF 以外的研發管線而言，都是具有重要臨床和監管里程碑的一年。在 CF 領域，我們最近提交了 VX-445 三聯療法的 NDA，並預計在今年第四季完成在歐洲的申請。我們的保密協議中包含優先審查請求，如果獲得批准，PDUFA 日期將在明年第一季末確定。

If approved, this regimen would not only be the first medicine to treat the cause of CF for the FMF population, the largest remaining group of people with CF without a medicine for the underlying cause of their disease, but it would also be a significant enhancement for the SF population. The VX-445 triple combination regimen represents a significant advance over currently available medicines and may be able to treat up to 90% of people with CF in the future. We want to bring this medicine to as many patients as quickly as possible, and we've already begun our efforts towards gaining approval for this regimen in younger patients through an ongoing Phase III study in children ages 6 to 11.

如果獲得批准，該療法不僅將成為首個針對 FMF 人群（目前最大的尚未有針對其疾病根本原因的藥物的 CF 患者群體）的 CF 病因進行治療的藥物，而且還將顯著改善 SF 人群的狀況。VX-445 三合一療法代表著對現有藥物的重大進步，未來或許能夠治療高達 90% 的囊性纖維化患者。我們希望盡快讓盡可能多的患者使用這種藥物，我們已經開始努力爭取通過一項針對 6 至 11 歲兒童的 III 期研究，獲得該療法在年輕患者中的批准。

Outside of CF, we have clinical development efforts ongoing across 5 different diseases and expect important clinical data readouts from multiple programs in 2020. In our AAT program, we have completed evaluation of single and multiple ascending doses of our first small molecule corrector, VX-814, in healthy volunteers. Based on the safety tolerability and pharmacokinetic data from this study, we have decided to advance VX-814 into a Phase II dose-ranging study in AATD patients who have 2 Z mutations.

除了 CF 之外，我們還在 5 種不同的疾病領域進行臨床開發工作，並預計在 2020 年獲得多個計畫的重要臨床數據結果。在我們的 AAT 專案中，我們已經完成了對健康志願者使用我們第一個小分子矯正劑 VX-814 的單次和多次遞增劑量的評估。根據這項研究的安全性耐受性和藥物動力學數據，我們決定將 VX-814 推進到針對具有 2 個 Z 突變的 AATD 患者的 II 期劑量範圍研究。

We expect to obtain clinical data from our AAT program in people with 2 Z mutations in 2020. And consistent with our approach of developing a portfolio of multiple potential medicines in each of our programs, we have also recently advanced a second AAT corrector, VX-864 into Phase I development, both VX-814 and VX-864 have received Fast Track designation from the FDA.

我們預計將於 2020 年獲得 AAT 計畫在攜帶 2 個 Z 突變的人群中的臨床數據。秉承我們每個項目都開發多種潛在藥物組合的方針，我們最近還將第二種 AAT 矯正劑 VX-864 推進到 I 期開發階段，VX-814 和 VX-864 都獲得了 FDA 的快速通道資格。

In pain, we have established proof-of-concept for NaV1.8 inhibition in multiple Phase II studies in acute, neuropathic and musculoskeletal pain conditions. We have identified a number of selective NaV1.8 inhibitors, and our plan is to obtain clinical data from multiple compounds in order to choose the best molecule or molecules to advance into late-stage development. We announced today that we are initiating a Phase I study of a novel NaV1.8 inhibitor, VX-961.

在疼痛治療方面，我們已在多項 II 期研究中證實了 NaV1.8 抑制劑在治療急性疼痛、神經性疼痛和肌肉骨骼疼痛的有效性。我們已經確定了一些選擇性 NaV1.8 抑制劑，我們的計劃是從多種化合物中獲取臨床數據，以便選擇最佳分子或分子群進入後期開發階段。我們今天宣布，我們將啟動一項新型 NaV1.8 抑制劑 VX-961 的 I 期研究。

In sickle cell disease and beta-thalassemia, we've now dosed 2 patients in our hemoglobinopathies program with our partner, CRISPR Therapeutics, using the novel gene editing therapy, CTX001. The first sickle cell patient was dosed in the middle of this year, which follows the first patient with beta-thalassemia who was dosed in the first quarter of the year.

在鐮狀細胞疾病和β地中海貧血症方面，我們現在已經與合作夥伴 CRISPR Therapeutics 一起，使用新型基因編輯療法 CTX001 為我們的血紅蛋白疾病計畫中的 2 名患者進行了治療。今年年中，首例鐮狀細胞貧血症患者接受了治療；此前，今年第一季度，首例β-地中海貧血症患者也接受了治療。

Before I turn the call over to Charlie, I'd like to spend a few minutes talking about a new area for Vertex, APOL1-mediated kidney diseases, which includes FSGS or focal segmental glomerulosclerosis. There have been few to no medicines developed and approved specifically to address the underlying cause of kidney diseases. So as a nephrologist who has treated these patients, I find this program exciting both scientifically and personally. Our approach to the treatment of APOL1-mediated kidney diseases will initially focus on the inhibition of APOL1 function in patients with FSGS. We estimate that there are approximately 10,000 people with FSGS in the U.S. who are homozygous for APOL1 mutations. These patients exhibit high levels of protein in the urine, known as proteinuria, and typically progress to reduced kidney function and/or kidney failure.

在將電話轉給查理之前，我想花幾分鐘時間談談 Vertex 的一個新領域，即 APOL1 介導的腎臟疾病，其中包括 FSGS 或局部節段性腎小球硬化症。目前幾乎沒有專門針對腎臟疾病根本原因而研發和批准的藥物。因此，作為一名治療過這些患者的腎臟科醫生，我發現這個計畫無論從科學角度還是個人角度來看都令人興奮。我們治療 APOL1 介導的腎臟疾病的方法最初將專注於抑制 FSGS 患者的 APOL1 功能。我們估計美國約有 1 萬名患有 FSGS 的 APOL1 突變純合子。這些患者尿液中蛋白質含量很高，稱為蛋白尿，通常會發展為腎功能下降和/或腎衰竭。

We have developed proprietary cell and animal models to evaluate our compounds in FSGS and based on our preclinical data, we believe that inhibiting APOL1 protein function will reduce proteinuria and also the course of this progressive disease.

我們已開發出專有的細胞和動物模型來評估我們的化合物在 FSGS 中的療效，並且根據我們的臨床前數據，我們相信抑制 APOL1 蛋白功能將減少蛋白尿，並延緩這種進行性疾病的進展。

I am pleased to report that we recently began dosing healthy volunteers in a Phase I study of our first oral, small molecule inhibitor of APOL1 function. This molecule, known as VX-147, is the first of multiple potential medicines for APOL1-mediated kidney diseases that we are advancing in late-stage research. If we are successful in Phase I, our plan is to initiate a Phase II proof-of-concept study in 2020 where we would evaluate the ability of VX-147 to reduce protein levels in the urine. A demonstrated reduction in proteinuria in FSGS would represent an important biological proof-of-concept for this program.

我很高興地報告，我們最近開始對健康志願者進行 I 期研究，測試我們首個口服小分子 APOL1 功能抑制劑。這種名為 VX-147 的分子是我們正在推進後期研究的多種治療 APOL1 介導的腎臟疾病的潛在藥物中的第一種。如果我們在第一階段取得成功，我們的計劃是在 2020 年啟動第二階段概念驗證研究，屆時我們將評估 VX-147 降低尿液中蛋白質水平的能力。如果 FSGS 患者的蛋白尿得到證實減少，這將為該計畫提供重要的生物學概念驗證。

In summary, we've made outstanding progress in CF and in multiple other disease areas in 2019 and are positioned to obtain important clinical data from multiple diseases in our pipeline in 2020.

總而言之，我們在 2019 年在 CF 和其他多個疾病領域取得了傑出的進展，並有望在 2020 年從我們研發管線中的多種疾病中獲得重要的臨床數據。

I'll now turn the call over to Charlie.

現在我將把電話交給查理。

Thanks, Reshma. I'm pleased to review with you our second quarter financial results, which showed both strong commercial performance as a result of treating more CF patients globally and disciplined investment focused on internal and external innovation to create future medicines. All of the results and guidance I will discuss tonight are non-GAAP.

謝謝你，雷什瑪。我很高興與大家一起回顧我們第二季度的財務業績，業績顯示，由於在全球範圍內治療了更多囊性纖維化患者，公司實現了強勁的商業表現；同時，公司也進行了嚴謹的投資，專注於內部和外部創新，以創造未來的藥物。我今晚將要討論的所有結果和指導意見均不符合GAAP準則。

Our second quarter total product revenues were $940 million, a 25% increase compared to the second quarter of 2018. This increase was driven primarily by the uptake of SYMDEKO in the U.S. and the recent launch of SYMKEVI in Germany. SYMDEKO and SYMKEVI revenues for the second quarter were $362 million, the strong SYMKEVI launch in Germany represented the majority of the $46 million of SYMDEKO and SYMKEVI revenues from outside the U.S.

我們第二季產品總營收為 9.4 億美元，比 2018 年第二季成長了 25%。這一增長主要得益於 SYMDEKO 在美國的普及以及 SYMKEVI 最近在德國的推出。SYMDEKO 和 SYMKEVI 第二季度的收入為 3.62 億美元，SYMKEVI 在德國的強勁上市為 SYMDEKO 和 SYMKEVI 在美國以外地區貢獻了 4600 萬美元的收入。

As a result of new reimbursement agreements and new regulatory approvals for young children, we also continue to see new patients initiating treatment with KALYDECO and ORKAMBI. Our second quarter 2019 combined R&D and SG&A expenses were $394 million, similar to the $388 million seen in the second quarter of 2018. The significant growth in revenues and disciplined spending in the second quarter resulted in operating income of $413 million, a 59% increase compared to the second quarter of 2018.

由於新的報銷協議和針對幼兒的新監管批准，我們也繼續看到新的患者開始使用 KALYDECO 和 ORKAMBI 進行治療。2019 年第二季度，我們的研發與銷售、管理及行政費用合計為 3.94 億美元，與 2018 年第二季的 3.88 億美元相近。第二季營收大幅成長，加上支出控制得當，營業收入達到 4.13 億美元，比 2018 年第二季成長了 59%。

Net income for the second quarter of 2019 was $327 million compared to $244 million in the second quarter of 2018. We also continue to strengthen our balance sheet, ending the second quarter with approximately $4 billion in cash and marketable securities compared to $3.2 billion at the end of 2018.

2019 年第二季淨收入為 3.27 億美元，而 2018 年第二季淨收入為 2.44 億美元。我們也持續加強資產負債表，截至第二季末，我們的現金和有價證券約為 40 億美元，而 2018 年底為 32 億美元。

We expect to continue to generate significant cash flow throughout 2019 and beyond as more patients are treated with our medicines, and we have a clear strategy of reinvesting in both internal R&D and external innovation to support our long-term growth. The results of our commitment to reinvest in R&D are clear, as evidenced by the progression of our internal pipeline into multiple new diseases and also by our increased use of capital to establish new collaborations and acquisitions aimed at the creation of future medicines.

我們預計，隨著越來越多的患者接受我們的藥物治療，我們將在 2019 年及以後繼續產生可觀的現金流，並且我們制定了明確的策略，將資金再投資於內部研發和外部創新，以支持我們的長期成長。我們致力於研發再投資的成果顯而易見，這體現在我們內部研發管線在多種新疾病領域的進展，以及我們加大資本投入，建立新的合作關係和收購，旨在創造未來的藥物。

Over the past 12 months, we have invested more than $600 million in cash to establish multiple new collaborations and acquisitions that provide us with access to new external scientific technologies, programs and expertise in multiple diseases to complement our internal research engine. These activities and the significant expansion of our internal team dedicated to finding and securing new scientific opportunities underscore our commitment to investing in external innovation to support our future growth. Importantly, with our growing free cash flow, we have even more flexibility to enter into additional deals.

在過去的 12 個月裡，我們投入了超過 6 億美元的現金，建立了多項新的合作關係和收購，使我們能夠獲得新的外部科學技術、專案和多種疾病的專業知識，以補充我們的內部研究引擎。這些活動以及我們致力於尋找和獲取新的科學研究機會的內部團隊的大幅擴充，凸顯了我們致力於投資外部創新以支持未來發展的決心。重要的是，隨著自由現金流的成長，我們有了更大的彈性來進行更多交易。

Now on to guidance. As a result of our strong commercial performance seen in the first half of 2019, we are increasing our total CF product revenue guidance to $3.6 billion to $3.7 billion from the prior range of $3.45 billion to $3.55 billion. Our revenue guidance reflects anticipated revenues from countries where our medicines are currently reimbursed. Our financial guidance for both combined R&D and SG&A expenses, and our anticipated effective tax rate is unchanged.

接下來是指導部分。由於我們在 2019 年上半年取得了強勁的商業業績，我們將 CF 產品總收入預期從先前的 34.5 億美元至 35.5 億美元上調至 36 億美元至 37 億美元。我們的收入預期反映了我們藥品目前已納入醫保報銷範圍的國家的預期收入。我們對研發及銷售、管理及行政費用的財務預期及預期實際稅率均維持不變。

We remain on the trajectory of significant revenue growth, which is driving expansion of operating margin and increases in net income. Importantly, our increasing revenues are allowing for significant reinvestment in internal and external programs to fuel our future growth with new medicines.

我們繼續保持著顯著的收入成長勢頭，這推動了營業利潤率的擴大和淨收入的成長。重要的是，我們不斷增長的收入使我們能夠對內部和外部項目進行大量再投資，以透過新藥的研發推動我們未來的成長。

Echoing Jeff's comments from the start of the call, Vertex has never been stronger and is well positioned to continue executing on its strategy to drive value and growth through investment in serial innovation.

正如傑夫在電話會議開始時所說，Vertex 目前實力空前強大，並已做好充分準備，繼續執行其策略，透過對連續創新的投資來推動價值和成長。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) Our first question or comment comes from the line of Phil Nadeau from Cowen and Company.

（操作說明）我們的第一個問題或評論來自 Cowen and Company 的 Phil Nadeau。

Congratulations on the progress. Just 2 for me. First on the financials for the quarter. There was a big step up quarter-over-quarter in the double up revenue, the ORKAMBI, SYMKEVI, SYMDEKO revenue and still not clear to me what exactly drove that uptick in Q2 versus Q1. Would you be willing to delineate what factors drove that uptick?

恭喜你取得進展。我只要2個。首先來看本季的財務數據。與第一季相比，第二季雙倍營收大幅成長，ORKAMBI、SYMKEVI、SYMDEKO 的營收也大幅成長，但我仍然不清楚究竟是什麼因素推動了第二季與第一季度相比的成長。您能否詳細說明一下導致這一增長的因素？

And then second, on VX-814. Curious if you'd be willing to say anything more about the Phase I profile you saw or the Phase II trial design you're about to start.

其次，在 VX-814 上。我很想知道您是否願意詳細介紹您看到的 I 期臨床試驗方案或即將開始的 II 期臨床試驗設計。

Yes. I'll take the first question, Phil, on the step-up in revenues. It's actually -- this was driven by a number of things. It was the ongoing launches of SYMDEKO here in the U.S. and SYMKEVI outside the U.S., most notably in Germany, where the team there has driven fantastic performance. So that's led to the growth of SYMDEKO, SYMKEVI.

是的。菲爾，我先回答第一個問題，關於收入成長的問題。實際上，這是由多種因素造成的。SYMDEKO 在美國持續推出，SYMKEVI 在美國以外地區（尤其是德國）持續推出，當地團隊取得了令人矚目的成績。因此，這促成了 SYMDEKO 和 SYMKEVI 的發展。

And while that had cannibalized some of our ORKAMBI revenues, we've actually received a number of new approvals for lower age ranges for ORKAMBI and KALYDECO over the last few quarters. And as those launches are being executed, that's adding new patients in for KALYDECO and ORKAMBI as well. So it really is a combination of expanded labeled indications for our older medicines, ORKAMBI and KALYDECO, and then the successful launch of SYMDEKO around the world.

雖然這蠶食了我們 ORKAMBI 的部分收入，但在過去幾個季度裡，我們實際上已經獲得了 ORKAMBI 和 KALYDECO 針對更低年齡層的多項新批准。隨著這些產品的上市，KALYDECO 和 ORKAMBI 也獲得了新的病患。所以，這其實是我們舊藥 ORKAMBI 和 KALYDECO 擴大適應症範圍，以及 SYMDEKO 在全球範圍內成功上市的結合。

Phil, this is Reshma. With regard to your question about VX-814, that's the first small molecule corrector we've taken into AAT. We have completed the Phase I study, which is the SAD, a single-ascending dose; and then MAD, a multiple ascending dose. And what we saw there was a profile that looked really good from a safety and tolerability point of view. That was, of course, the primary endpoint. But also, importantly, around the PK.

菲爾，這位是雷什瑪。關於您提出的 VX-814 的問題，這是我們引入 AAT 的第一個小分子校正劑。我們已經完成了 I 期研究，即 SAD（單次遞增劑量）和 MAD（多次遞增劑量）。我們看到的是一個從安全性和耐受性角度來看非常好的產品概況。當然，那是主要終點。但更重要的是，這與PK有關。

With regard to what we're going to do in Phase II, obviously, we need to have our discussions with the regulators, but what I can tell you is that I expect the study to be of a very reasonable size, and of a very reasonable duration, not dissimilar to what you've seen us do with CF. And I say that because what we're going to be measuring is AAT levels and activity.

關於我們將在 II 期開展的工作，顯然，我們需要與監管機構進行討論，但我可以告訴你們的是，我預計這項研究的規模和持續時間將非常合理，與我們之前在 CF 方面所做的工作不會有太大差別。我這麼說是因為我們要測量的是 AAT 水平和活性。

Our next question or comment comes from the line of Salveen Richter from Goldman Sachs.

我們下一個問題或評論來自高盛的薩爾文·里希特。

So regarding the AAT program, you talked about looking at the endpoint of AAT levels. Do you think that liver histology would be required? And then, how do you see the asset sitting into the treatment paradigm in light of different approaches that are in development? And I have a follow-up.

關於 AAT 計劃，您談到要關注 AAT 水平的終點。您認為需要進行肝臟組織學檢查嗎？那麼，鑑於目前正在開發的不同方法，您認為該資產在治療模式中處於什麼位置？我還有一個後續問題。

Sure. Sure. So Salveen, you know that the data point that's available to us right now, pertains to the infusion therapies and what they used in their Phase III programs and what their approvals were based on, even the AAT levels. And that's a data point and that's what's available to us. What I foresee here in terms of our AAT program are a few points I just want to make sure I highlight. One, this is a small molecule oral corrector. So that's important. This is oral. The second is that, certainly, for the lung, liver -- sorry, for the lung, AAT levels and activity will be important. And for the liver, I do expect that we're going to evaluate liver biopsies in Phase II and that we will need to have discussions with regulators with regard to how that fits into the label and what that program looks like. Let me ask Jeff to make a comment as well.

當然。當然。所以 Salveen，你知道我們現在掌握的數據點與輸液療法以及他們在 III 期計畫中使用的療法和他們的批准依據有關，甚至包括 AAT 水平。這是一個數據點，也是我們目前能夠獲得的數據。就我們的 AAT 專案而言，我預見到以下幾點，我只想強調一下。第一，這是一種小分子口服矯正劑。所以這一點很重要。這是口頭的。第二點是，對於肺、肝臟——抱歉，是對於肺部而言，AAT 水平和活性肯定很重要。至於肝臟方面，我預計我們將在 II 期臨床試驗中評估肝臟活檢，並且我們需要與監管機構討論如何將其納入標籤以及該計畫的具體內容。我也想請傑夫發表一下意見。

Yes. I think the second part of your question, Salveen, which is related to first, is how does this compare to other approaches?

是的。Salveen，我認為你的問題的第二部分與第一部分相關，那就是這種方法與其他方法相比如何？

And maybe just to remind you that AAT, as Reshma said, is both a lung disease and a liver disease. The mutant protein is misfolded and accumulated to the liver, and therefore causes significant liver disease in up to 30% of patients. And obviously, it doesn't get into the serum in an active form. And so it doesn't protect the lung against autodigestion by protease. So there's 2 different organs that are involved.

或許也要提醒大家，正如雷什瑪所說，AAT既是一種肺部疾病，也是一種肝臟疾病。突變蛋白錯誤折疊並積聚在肝臟中，因此導致高達 30% 的患者出現嚴重的肝臟疾病。顯然，它不會以活性形式進入血清中。因此，它不能保護肺部免受蛋白酶的自身消化。所以這裡牽涉到兩個不同的器官。

And really successful treatment of the disease will require treatment of both liver and lung. This approach, as Reshma said, is a small molecule which has the distinct and sort of differentiated advantage of treating both by refolding the protein in the liver and clearing the liver. Now we believe it will have a positive effect on the liver disease, and of course by refolding the protein to an active form in serum, we expect it to have a positive effect in the lung.

要真正成功治療這種疾病，需要同時治療肝臟和肺部。正如雷什瑪所說，這種方法使用的小分子具有獨特且差異化的優勢，既能透過在肝臟中重新折疊蛋白質來治療，又能透過清除肝臟中的蛋白質來治療。現在我們相信它將對肝臟疾病產生積極影響，當然，透過將蛋白質在血清中重新折疊成活性形式，我們期望它對肺部產生積極影響。

And I think you can see why we're enthusiastic about that. If you look at our slides, this time -- we've shown you 814 in the past. This time, we showed you 864, which is the next molecule for a longer period of time for 12 weeks now. And what you see in that slide, in a mouse model, that's actually expressing the human mutant protein is 2 important things. One, we're able to drive functional levels of AAT in the serum well into the carrier range quickly, and that effect is sustained over 12 weeks. But if anything, it increases as we go through the 12 weeks.

我想你應該能明白我們為什麼對此充滿熱情了。如果你看一下我們的投影片，這次——我們之前已經向你展示了 814 張。這次，我們向大家展示了 864 號分子，它將在接下來的 12 週內持續進行更長的研究。你在幻燈片中看到的，在小鼠模型中，實際上表達了人類突變蛋白，這其中有兩件重要的事情。第一，我們能夠迅速將血清中 AAT 的功能水準提升到載體範圍，而這種效果可以持續 12 週。但隨著 12 週的進行，這種情況反而會加劇。

And 2, with 12 weeks of therapy, we're really able to see remarkable clearing of the liver, both the non-aggregated forms of the blush and the aggregated forms, which are the [protease] forms. And so those are exactly the things -- the reason we're excited, exactly the things that we want to look for in the human.

2，經過 12 週的治療，我們確實能夠看到肝臟中明顯的清除效果，包括非聚集形式的淤血和聚集形式的淤血，即蛋白酶形式。所以，這些正是我們感到興奮的原因，也是我們想要在人身上尋找的特質。

Most of the other approaches out there as you know either treat the lung, so for instance, the replacement therapy or they treat the liver, for instance, in antisense or knockdown therapies that are out there. But they don't treat both, and so the reason we're so excited about this is it's a small-molecule approach that treats both, at least in our mouse model, and that's what we'll be looking for as Reshma described in the Phase II studies, which can be a fairly small number of patients for a fairly short period of time.

如你所知，目前大多數其他方法要么治療肺部，例如替代療法，要么治療肝臟，例如反義療法或基因敲除療法。但它們並不能同時治療這兩種疾病，因此我們對此感到非常興奮，因為它是一種小分子療法，可以同時治療這兩種疾病，至少在我們的鼠模型中是這樣，而這正是我們將在 II 期研究中尋找的，正如 Reshma 在 II 期研究中所描述的那樣，II 期研究的患者數量可能相當短，持續時間也可能相當短。

Great. And then on the call, you did discuss a couple of times today using capital for external opportunities. And are you thinking about smaller transactions like the one you just did with Exonics? And in the context of that, when you think of building a genetic center, do you see yourself sticking just to gene-editing? Or would you expand into other modalities?

偉大的。在今天的電話會議上，您確實幾次討論了利用資金抓住外部機會的問題。您是否考慮過像您剛才與 Exonics 進行的那種小額交易？在這種背景下，當您考慮建立基因中心時，您是否認為自己只會專注於基因編輯？或是您會拓展到其他治療方式嗎？

And then further, would it be these smaller transactions? Or could there be a larger transaction in your future?

那麼，更進一步來說，是不是指這些較小的交易呢？或者，您未來是否會有更大規模的交易？

Sure. First of all, I don't want to call Exonics a smaller transaction. They might be insulted by that. We found it to be an important, significant transaction. But I know of course what you mean.

當然。首先，我並不認為Exonics是一筆小額交易。他們可能會因此感到受辱。我們認為這是一筆重要的交易。但我當然明白你的意思。

As we said before, first of all, we are accumulating significant financial firepower capital on our balance sheet, and so you should expect to see us do more deals and potentially larger deals. But the strategy will remain the same as it's been for the last 4 years. And as you know, we focused on 3 areas. Anything in CF that could be complementary or were additive to what we're doing now, the triple. Obviously, we're not seeing many of those because the triple has set such a high bar, but we continue to look at everything out there.

正如我們之前所說，首先，我們的資產負債表上累積了大量的財務實力資本，因此你們應該會看到我們進行更多交易，而且可能會進行更大規模的交易。但該戰略將與過去4年一樣保持不變。如您所知，我們重點關注了三個領域。CF 中任何可以與我們現在正在做的三重奏互補或相加的東西。顯然，由於三分球的門檻太高，我們很少看到這樣的情況，但我們會繼續關注所有可能出現的情況。

The second one is, technologies or technology platforms that would allow us to better treat the kinds of diseases, which as you've heard about today, either alone or potentially in combination with small molecules. And you've seen us do the CRISPR deal, the Moderna deal, the Arbor deal, the X-Chem deal, all of those fall into that category.

第二點是，能夠讓我們更好地治療各種疾病的技術或技術平台，正如你們今天所聽到的，這些疾病可以單獨治療，也可以與小分子藥物聯合治療。你們也看到了我們達成的 CRISPR 交易、Moderna 交易、Arbor 交易、X-Chem 交易，所有這些都屬於這一類。

And then the third area is looking for assets, mostly preclinical and early clinical assets that would complement our pipeline in the diseases we're interested in. In a way, Exonics was a part of that because DMD and DM1 are 2 diseases we're interested in, and we continue to look for those assets. So I think you can expect to see more of that. With respect to the size of the transactions, we do have more firepower, and so you could potentially see larger deals. But what I think you will not see is us doing large deals to buy on-market products or late-stage products to grow revenue or to buy revenue growth. We really don't need that given the revenue growth we're projecting out well into the 2020 from both the CF franchise and then the pipeline.

第三個方面是尋找資產，主要是臨床前和早期臨床資產，以補充我們在感興趣的疾病領域的研發管線。從某種意義上說，Exonics 是其中的一部分，因為 DMD 和 DM1 是我們感興趣的兩種疾病，我們將繼續尋找這些資產。所以我覺得以後會看到更多這樣的狀況。就交易規模而言，我們的確擁有更強大的實力，因此您可能會看到規模更大的交易。但我認為你們不會看到我們進行大規模交易來購買已上市產品或後期產品，以增加收入或透過購買產品來增加收入。鑑於我們預計 CF 系列產品和後續產品在 2020 年都能實現收入成長，我們真的不需要那麼做。

Does that give you better sense of what we're looking for?

這樣您是不是更清楚我們想要的是什麼了？

Yes. That's helpful.

是的。那很有幫助。

Our next question or comment comes from the line of Michael Yee from Jefferies.

下一個問題或評論來自 Jefferies 的 Michael Yee。

On AAT, I just wanted to go back to that and ask Reshma if you have had a lot of confidence in the assays that you guys have used and how relatable or translatable that is to CF, specifically as it relates to what level you could get in the human? And then how long that would take for that to show up and what, specifically, (inaudible) indication?

關於 AAT，我想回到之前的問題，問問 Reshma，你們對所使用的檢測方法有多大信心，以及這些方法與 CF 的相關性或可轉化性如何，特別是與在人體中能達到的水平有關？那麼，這種情況需要多久才能顯現出來？具體來說，會有什麼（聽不清楚的）跡象？

Yes. Thanks for that. So maybe let me talk about AAT and our level of confidence with regard to the assay and our approach. So with regard to the assays, that was pretty simple. The assay 4 levels is...

是的。謝謝。那麼，或許我可以談談 AAT 以及我們對此檢測方法和我們研究方法的信心程度。所以就檢測方面而言，那非常簡單。檢測4個水平是…

It might be -- we may be getting a lot of background noise. Maybe you could go on mute?

有可能——我們可能聽到了很多背景噪音。或許你可以把靜音模式調成靜音？

I'll try and speak over the noise. The assay, with regard to AAT levels, that was pretty simple. That's a commercially available, readily accessible assay 4 levels. With regard to activity, that one is also well worked through. It's an ELISA. And that is not something that we think is going to be particularly complicated.

我會盡量蓋過噪音說話。偵測AAT水平的方法非常簡單。這是一個市面上可買到的、容易取得的 4 個等級的檢測方法。至於活動方面，那一項也已經安排妥當。這是酵素連結免疫吸附試驗（ELISA）。我們認為這不會是一件特別複雜的事。

With regard to confidence, obviously, unlike CF, which has already gone through our preclinical assays and through the clinic, so we can look back and make those correlations, with AAT, we have yet to go into patients.

就信心而言，顯然，與 CF 不同，CF 已經完成了我們的臨床前試驗和臨床試驗，所以我們可以回顧並建立這些關聯，而對於 AAT，我們還沒有進入患者體內。

That being said, the reason we have confidence and the reason I'm very excited about taking this forward to Phase II is the animal models we have remember has the human gene inserted into it. And whether we look at levels or activity in the mouse or we look at the liver, and particularly as we look at the liver over time, it just continues to impress us and raise our levels of confidence.

也就是說，我們有信心推進到 II 期臨床試驗的原因，也是我非常興奮的原因，是我們擁有的動物模型中已經插入了人類基因。無論我們觀察小鼠體內的水平或活性，或是觀察肝臟，特別是隨著時間的推移觀察肝臟，它不斷給我們留下深刻印象，並提高我們的信心。

And then, Mike, the other thing as you know, is that we know from sort of experiments of nature that carriers, meaning the parents of these patients, are asymptomatic, and they have reduced levels anywhere from sort of 11 to 17 micromolar. Certainly, by the time we get to 17 micromolar, there's a lot of evidence that's highly protected. So we know the level that we're looking for in advance. And as Reshma said, simply by measuring levels of active AAT in these Phase II patients, we had a pretty good idea of where we are with respect to treatment efficacy and carrier levels.

還有一點，麥克，你也知道，我們從自然界的實驗中得知，帶因者，也就是這些患者的父母，是無症狀的，他們的病毒量降低到 11 到 17 微摩爾左右。當然，當濃度達到 17 微摩爾時，有許多證據都受到了高度保護。所以我們事先就知道我們要達到的水準。正如雷什瑪所說，僅僅透過測量這些 II 期患者體內活性 AAT 的水平，我們就能很好地了解我們在治療效果和攜帶者水平方面所處的位置。

Our next question or comment comes from the line of Alethia Young from Cantor Fitzgerald.

我們接下來的問題或評論來自坎托·菲茨杰拉德的阿萊西亞·楊的一句話。

Congrats on a very good quarter and progress from the pipeline. I just wanted to kind of maybe take a step back and ask a strategic question around the pain program. I noticed it’s under differentiating molecules. So can you just spend some time, maybe, discussing how you think pain and the certain indications associated with it might fit with for your business? And are you planning on partnering some of them? Or keeping some to yourself? That would be very appreciated.

恭喜你們本季業績出色，專案進展順利。我只是想退後一步，就疼痛管理方案提出一個策略性的問題。我注意到它在區分分子的範疇內。所以，您能否花點時間，討論一下您認為疼痛以及與之相關的某些症狀，對您的業務有何意義？你打算和其中一些人建立合作關係嗎？或自己留一些？非常感謝。

Alethia, let me start, this is Reshma, and let me just bring everyone up to speed on where we are, and then I'll turn it over to Jeff to make some comments about strategically where it fits into the business, partnering and all of that.

Alethia，讓我先開始吧，這位是Reshma，讓我先向大家介紹一下我們目前的情況，然後我會把發言權交給Jeff，讓他就它在戰略上如何融入業務、合作等等方面發表一些評論。

So with regard to the pain program, you know that we have advanced VX-150 through Phase IIb dose ranging, and we've had positive results in neuropathic pain, osteoarthritis, as well as acute pain. The safety profile look good. The tolerability look good. And that's 1/2 of the equation. The other half of the equation goes back to our approach to CF as well as the AAT, and that has to do with bringing forward a portfolio of molecules. And that part as it pertains to the new news for today, we're advancing VX-961, our next NaV1.8 inhibitor into the clinic. So we're going to wait for the results from that one, and then pick the best molecule or molecules to advance into late-stage development.

所以關於疼痛治療方案，您知道我們已經推進了 VX-150 的 IIb 期劑量範圍研究，並且在神經性疼痛、骨關節炎以及急性疼痛方面取得了積極的成果。安全性能看起來不錯。耐受性看起來不錯。這只是問題的一半。等式的另一半要追溯到我們對 CF 和 AAT 的方法，這與推出一系列分子有關。至於今天要公佈的新聞，我們將把我們的下一個 NaV1.8 抑制劑 VX-961 推進到臨床試驗階段。所以我們將等待那項研究的結果，然後選擇最好的分子或分子進入後期開發階段。

If I try to maybe simplify it and raise the altitudes, we always talk about cracking the biology and then pouring out the chemistry. In the pain program, the part of it that we're at is pouring on the chemistry. And what we're doing now is bringing our molecules forward, and we're going to pick the very best one or ones to take to late-stage development. Jeff?

如果我嘗試簡化它並提高它的層次，我們總是談論破解生物學，然後再傾瀉化學。在疼痛治療方案中，我們目前正在進行的是化學製劑的添加。我們現在正在做的是推進我們的分子研究，我們將挑選出最好的一個或多個分子進入後期開發階段。傑夫？

So Alethia, with respect to how we think about pain sort of strategically and commercially, which I think is your question. We said in the past, we really view it as multiple indications, even, potentially, multiple causes. But we see it as acute pain, which is the kind of pain that you have when you have a surgery or a tooth extraction or an injury. That pain is treated mostly -- not entirely, but mostly, in hospitals, pain centers, Dental offices, et cetera, and you can reach most of those patients with a specialty sales force.

所以，阿萊西亞，關於我們如何從策略和商業角度看待疼痛，我想這就是你的問題。我們過去曾說過，我們認為這確實有多種跡象，甚至可能有許多原因。但我們認為這是急性疼痛，就像你做手術、拔牙或受傷時所感受到的疼痛一樣。這種疼痛大部分（雖然不是全部，但大部分）是在醫院、疼痛中心、牙科診所等地治療的，而且你可以透過專業的銷售團隊接觸到大多數這類患者。

So we view acute pain, which is the multibillion-dollar opportunity, as something that's certainly consistent with our Vertex strategy of making transformative drug in the specialty area. And obviously, the other driver in acute pain is that we're sitting in the middle of a horrible opioid crisis, and the majority of the pain treatments for acute pain are opioids.

因此，我們認為急性疼痛（這是一個價值數十億美元的市場）與我們 Vertex 在該專業領域研發變革性藥物的策略完全一致。顯然，導致急性疼痛的另一個原因是，我們正處於一場可怕的鴉片類藥物危機之中，而大多數用於治療急性疼痛的藥物都是鴉片類藥物。

So we think having a molecule, like 150 or 961, that would have opioid-like efficacy without any of the addictive potential or side effects would be very powerful transformative advance in the treatment of acute pain. That one we would develop and commercialize ourselves.

因此，我們認為，如果能有一種分子，例如 150 或 961，具有類似阿片類藥物的療效，而沒有任何成癮性或副作用，那麼在治療急性疼痛方面將是一項非常強大的變革性進步。那款產品我們將自行研發並商業化。

If you move on to neuropathic pain, which is the second type of pain, very, very different. There's a diabetic and nondiabetic component there. It's also a specialty market, it requires slightly more -- slightly larger sales force, but certainly one we could muster. And the key there is going to be to demonstrate that one of our molecules is superior to the molecules out there, like Virica, Pregabalin et cetera, which as you know, are going generic. And so we're doing those studies as part of our Phase II program. And then we'll be able to decide what the commercial strategy is there.

如果再進一步討論神經性疼痛，這是第二種類型的疼痛，那就非常非常不一樣了。這其中包含糖尿病患者和非糖尿病患者兩部分。這也是一個專業市場，需要稍微多一點——稍微大一點的銷售團隊，但我們肯定能夠組建一支。關鍵在於證明我們的一種分子優於市面上的分子，例如 Virica、Pregabalin 等，而眾所周知，這些分子正在逐漸被仿製藥取代。因此，我們正在進行這些研究，作為我們第二階段計劃的一部分。然後我們就可以決定那裡的商業策略了。

And then the third area is what we call musculoskeletal pain. It's what you would think of as low back pain, sciatica. It's a huge market, as you know, a multibillion-dollar market. That's a community market, for the most part, and that's a market that we would not enter ourselves. We are looking -- we have positive results in that market, but that's one where we would look to partner with a company that had a community sales force that we would not intend to build.

第三個面向就是我們所說的肌肉骨骼疼痛。這就是我們通常所說的腰痛，坐骨神經痛。如你所知，這是一個巨大的市場，一個價值數十億美元的市場。那基本上就是一個社區市場，我們自己不會進入那個市場。我們正在尋求——我們在該市場取得了積極的成果，但在這個市場，我們希望與一家擁有社區銷售團隊的公司合作，因為我們不打算自己組建銷售團隊。

We still think we can monetize this with them, but we wouldn't -- we certainly wouldn't do it ourselves. So maybe that gives you a little clarity about how you think about these 3 different components of the market.

我們仍然認為我們可以利用這一點來獲利，但我們不會——我們肯定不會自己做。所以，這或許能讓你更清楚地了解你是如何看待市場的這三個不同組成部分的。

Our next question or comment comes from the line of Cory Kasimov from JPMorgan.

我們下一個問題或評論來自摩根大通的 Cory Kasimov。

Congrats to both Jeff and Reshma on the news. So 2 for you. First on AAT, I know this is standard strategy for Vertex, but can you describe the key differences between the 2 AAT molecules you have? Now is there anything that really stands out there?

恭喜傑夫和雷什瑪！所以給你2個。首先是關於 AAT，我知道這是 Vertex 的標準策略，但是您能否描述一下您擁有的 2 個 AAT 分子之間的主要差異？那麼，有沒有什麼特別突出的地方呢？

And then, secondly, I just wanted to ask about the triple and the potential of a future once daily. Did the selection of 445 over 659, did that -- was the decision made to any extent based off of like early work in combination with your other next-gen correctors that you're working on? Or with VX-651 for use in that once-daily combination? How important do you think a once-daily option is at this point?

其次，我想問關於三倍收益以及未來每天一次的潛力。選擇 445 而不是 659，這個決定是否在某種程度上是基於早期工作以及您正在研究的其他下一代校正器？或與 VX-651 一起用於每日一次的組合療法？您認為目前每日一次的服用方式有多重要？

Okay. Two very different questions. Maybe let me tackle the CF one first, and I'll go backwards and do AAT. With regard to triple combination, let me take the first half of that, and I'm going to ask Stuart to comment on the importance of once daily.

好的。兩個截然不同的問題。或許我應該先攻克 CF 的難題，然後再反過來攻克 AAT 的難題。關於三聯療法，我先說前半部分，然後請史都華談談每天一次的重要性。

So no. The decision to select 445 versus 659 really had nothing to do with our ability to combine it with some of our other molecules. I think you're thinking about VX-561, our deuterated ivacaftor compound that it is, itself, in Phase II.

所以不。選擇 445 而不是 659 的決定，實際上與我們能否將其與其他一些分子結合無關。我想你指的是 VX-561，我們氘代伊伐卡托化合物，它本身目前處於 II 期臨床試驗階段。

The VX-561 corrector could be combined with VX-121, which is what it is combined with currently, and it is in Phase II, but we could have easily paired it with 445 or 659. Stuart, do you want to talk through once daily?

VX-561 校正器可以與 VX-121 組合使用，目前它就是與 VX-121 組合使用的，並且處於第二階段，但我們本來可以輕鬆地將其與 445 或 659 配對使用。斯圖爾特，你想每天聊一次嗎？

Yes. Cory, once daily is an advance for sure, and we certainly want to try and make things as easy as possible for patients to take our medicines, but much more important is the efficacy and safety of the triple-combination regimen. So it's definitely an advantage. It's something we want to do to try and make things as easy as possible for our patients. But going from twice a day to once a day is nowhere near as important as the levels of efficacy that we are delivering with the triple-combination regimens. And then, AAT, I'll hand it back to Reshma.

是的。科里，每天一次肯定是一個進步，我們當然希望盡可能方便患者服用我們的藥物，但更重要的是三聯療法的療效和安全性。所以這絕對是個優勢。我們希望盡一切努力讓患者感到方便。但是，從一天兩次減少到一天一次，遠沒有三聯療法所帶來的療效水準重要。然後，AAT，我會把它還給雷什瑪。

Okay. So with regard to AAT, VX-814 and VX-864, preclinically, they both look very good, and obviously, we look at parameters pertaining to efficacy as well as safety, but there are also additional parameters that we pay careful attention to preclinically. Those include things like formulation, DDI, PK, and both VX-814 and VX-864 look really very good. The reason we're taking multiple molecules into the clinic is what we've learned, honestly, from CF. And what we've learned is once you crack the biology, it really is about pouring on the chemistry. And it serves as risk mitigation as we progress forward. So both 864 and 814 look very good, and we're going to be moving those as quickly as possible.

好的。因此，就 AAT、VX-814 和 VX-864 而言，從臨床前研究來看，它們都非常好。顯然，我們會關注與療效和安全性相關的參數，但除此之外，在臨床前研究中，我們也會密切注意其他一些參數。其中包括配方、藥物交互作用、藥物動力學等方面，VX-814 和 VX-864 看起來都非常好。坦白說，我們之所以將多種分子帶入臨床，是因為我們從囊性纖維化中學到的東西。我們發現，一旦你攻克了生物學難題，接下來就真的要著手研究化學了。它能幫助我們降低前進過程中的風險。所以 864 和 814 這兩個版本看起來都非常好，我們會盡快推進它們。

Our next question or comment comes from the line of Matthew Harrison from Morgan Stanley.

下一個問題或評論來自摩根士丹利的馬修·哈里森。

Two for me. One, Jeff or Reshma, could you just give us an update on the current status of your negotiations with various EU countries about reimbursement for your CF medicine? And then, second, on FSGS, can you just talk broadly, is proteinuria a potential regulatory endpoint in that disease? Or how should we think about that as a biomarker that could be used from a regulatory standpoint?

我兩個。傑夫或雷什瑪，能否向我們介紹一下你們與歐盟各國就囊性纖維化藥物報銷問題進行的談判的最新進展？其次，關於 FSGS，您能否大致談談，蛋白尿是否是疾病的潛在調節終點？或者我們應該如何從監管角度將其視為一種生物標記？

So Matt, it's Stuart here. I'll take the question on reimbursement, and then Reshma will take the question on FSGS and proteinuria.

嗨，馬特，我是史都華。我來回答有關報銷的問題，然後 Reshma 將回答有關 FSGS 和蛋白尿的問題。

So as Jeff said in our prepared remarks, we have made some important progress in the first half of this year in securing new pricing and reimbursement agreements in various countries around the world, either for SYMDEKO, SYMKEVI or for our expanded indications for ORKAMBI and KALYDECO. There's a number of countries where we are yet to establish access, and that is a very, very high priority for us as a company. We're in active discussions with all of the governments where we don't currently have access and our commitment to securing access for our current and indeed future medicines is as strong as it's ever been. Unfortunately, it's impossible to comment on exactly when we'll be able to bring those discussions to a successful conclusion, but it absolutely remains a top priority for us, and we remain committed to getting access as soon as we possibly can. Reshma, FSGS?

正如傑夫在我們準備好的發言稿中所說，今年上半年，我們在世界各地多個國家/地區就 SYMDEKO、SYMKEVI 或 ORKAMBI 和 KALYDECO 的擴展適應症達成了新的定價和報銷協議，取得了一些重要的進展。我們還有一些國家尚未建立市場准入，這對我們公司來說是一個非常非常重要的優先事項。我們正在與所有目前我們無法獲得藥品供應的國家的政府進行積極磋商，我們確保現有藥品以及未來藥品供應的承諾一如既往地堅定。遺憾的是，我們無法確切說明何時才能成功完成這些討論，但這絕對是我們的首要任務，我們將繼續致力於盡快獲得存取權限。Reshma，FSGS？

All right. FSGS. So with regard to what could the regulatory endpoint be, and could it be proteinuria? I guess there are a few important points to raise. The first is that, not all proteinuria is created equal. And what I mean by that is regulators around the globe have actually thought about this issue and have handled workshops, and this is something that is often discussed in the renal community. And really, where we are is that there are certain homogeneous real diseases that lead to heavy proteinuria. And in those sorts of conditions, proteinuria may well be an endpoint that is the one that is important in the long run.

好的。FSGS。那麼，監管終點可能是什麼？會不會是蛋白尿？我想有幾點需要提出來。首先，並非所有蛋白尿都是一樣的。我的意思是，全球各地的監管機構實際上都考慮過這個問題，並舉辦過研討會，這也是腎臟病界經常討論的話題。實際上，我們所處的現狀是，存在一些同質性的真實疾病會導致大量蛋白尿。在這種情況下，蛋白尿很可能是重要的長期終點指標。

Now there are many other diseases that are far more heterogeneous with levels of proteinuria that are smaller, and that's a different kettle of fish. We have to go through our regulatory interactions. We have to have these discussions, and we're not there yet. But what I will say is that not all proteinuria is created equal. And in my mind, when you're looking at a homogeneous disease, a disease like APOL1-mediated FSGS, which is a genetically defined condition, it is a very described patient population, and the proteinuria that we're talking about is heavy with the consequence invariably being progression of the kidney dysfunction or progression to end-stage renal disease, which really means dialysis or transplantation, that there's a lot of conversation to be had around proteinuria being the endpoint. I hope that helps.

現在還有許多其他疾病的異質性更大，其蛋白尿水平也更低，那是另一回事了。我們必須履行監管義務。我們必須進行這些討論，但我們還沒有達到那個階段。但我要說的是，並非所有的蛋白尿都是一樣的。在我看來，當你觀察一種同質性疾病時，例如 APOL1 介導的 FSGS，這是一種基因定義的疾病，患者群體特徵非常明確，而且我們討論的蛋白尿後果嚴重，必然會導致腎功能障礙加重或發展為終末期腎病，這意味著需要透析或腎移植，因此圍繞蛋白尿是否是終點有很多值得探討的地方。希望對您有幫助。

Our next question or comment comes from the line of Brian Abrahams from RBC Capital Markets.

下一個問題或評論來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

Congrats on the quarter. My congrats to Jeff and Reshma as well. A question on AAT, and then a question on the kidney program. On AAT, any reason why 864 was tested for longer periods in the assays that you presented versus 814? And then on the kidney program, some recent data suggested that APOL1 RNA variance might have a more direct impact on podocyte damage that leads to proteinuria. So I'm just curious what drives your confidence that targeting the protein will reverse the path of physiology?

恭喜你本季取得佳績。我也要恭喜傑夫和雷什瑪。先問了一個關於AAT的問題，然後問了一個關於腎臟疾病治療計畫的問題。關於 AAT，在您提供的檢測中，864 的檢測時間比 814 更長，這是為什麼？而在腎臟疾病方面，最近的一些數據表明，APOL1 RNA 變異可能對導致蛋白尿的足細胞損傷產生更直接的影響。所以我很好奇，是什麼讓你如此確信靶向該蛋白質就能逆轉生理過程？

Yes. Maybe I'll take those both. First of all, with respect to 864 and 814, no, there was no real reason that we had different time frames. In fact, we've looked at shorter time frames for 864 and longer time frames for 814. I think what you should take away from that is, we've seen very, very consistent results for both of these molecules, which is one of the reasons why we're so encouraged and excited about taking them into the clinic. So I think that's pretty simple. Second question was about -- oh, the RNA merits, yes, on APOL1. So yes, let's touch on this real quickly. Actually, Reshma maybe talk about APOL1 and what we know about the mechanism, and why we're excited about what we've got there.

是的。或許我會兩個都拿。首先，關於 864 和 814，不，我們並沒有不同的時間框架，這並非真正的原因。事實上，我們已經研究了 864 的較短時間框架和 814 的較長時間框架。我認為你應該從中得到的結論是，我們已經看到這兩種分子都取得了非常非常一致的結果，這也是我們如此鼓舞人心並興奮地將它們帶入臨床試驗的原因之一。所以我覺得很簡單。第二個問題是關於——哦，RNA 的優點，是的，關於 APOL1。是的，我們快速地談談這個問題。實際上，Reshma 可能會談論 APOL1 以及我們對機制的了解，以及我們為什麼對我們目前的成果感到興奮。

Yes. Sure. Sure. So let me try to break down APOL1-mediated kidney disease. It's a genetic disease. It follows an autosomal recessive pattern, so you need homozygosity to get the disease. And maybe this thing that is the most important to note is, amongst African-Americans who have FSGS, 70-plus percent of these patients have APOL1-mediated disease. So that's why this is so important. And in the U.S., there's about 10,000 people who have this.

是的。當然。當然。那麼，讓我來試著解釋一下APOL1介導的腎臟疾病。這是一種遺傳性疾病。它遵循體染色體隱性遺傳模式，因此只有純合子才會患病。或許最值得注意的是，在患有 FSGS 的非裔美國人中，超過 70% 的患者患有 APOL1 介導的疾病。所以這件事才如此重要。在美國，大約有10000人患有這種疾病。

What we -- we understand the mechanism of APOL1-mediated disease very well, and we also understand the mechanism of our molecule, VX-147 very well. We have developed a host of in vitro cell-based assays, and we also have a mouse model with the human gene that we've inserted. And we really have a very, very good understanding of what happens with the protein, the next steps, how we are interdicting on this resulting in decreased proteinuria. And the 75% that you see is a very big number. And the bottom line of all of this is the way you end the progression of kidney disease, the way you stop this is you need to do 2 things. One, you need to target the underlying biology; and two, you actually need to decrease proteinuria because proteinuria itself further damages the kidney.

我們－我們非常了解 APOL1 介導疾病的機制，我們也非常了解我們的分子 VX-147 的機制。我們已經開發出一系列基於體外細胞的檢測方法，我們也建立了一個插入了我們人類基因的小鼠模型。我們對蛋白質的後續反應、下一步步驟以及我們如何干預以減少蛋白尿都有非常非常深入的了解。你看到的75%是一個非常大的數字。而這一切的根本原因在於，要阻止腎臟疾病的進展，要停止這種疾病，你需要做兩件事。第一，你需要針對其潛在的生物機制；第二，你實際上需要減少蛋白尿，因為蛋白尿本身會進一步損害腎臟。

And so that's sort of where we are, and that's why we feel very good about our program. Jeff, I don't know if you have any other comments you want to make?

這就是我們目前的狀況，也是我們對我們的專案感到非常滿意的原因。傑夫，你還有什麼要補充的嗎？

I think, if I heard you correctly, Brian, you were asking, specifically, do we believe this is an RNA variance issue? And the answer to that is no. We believe it has very strong evidence, both pharmacologically, and genetically, and biochemically that this is a protein defect within the mutant APOL1 protein.

布萊恩，如果我沒聽錯的話，你具體是想問，我們是否認為這是 RNA 變異問題？答案是否定的。我們相信，從藥理學、遺傳學和生物化學角度來看，都有非常強大的證據表明，這是突變 APOL1 蛋白中的蛋白質缺陷。

Our next question or comment comes from the line of Paul Matteis from Stifel.

我們下一個問題或評論來自 Stifel 的 Paul Matteis。

To continue the trend, I'm going to ask 2 on AAT. One, on the mouse data. Can you talk about how early you're treating in the lifespan of mice, where you're seeing this level of clearance in the liver? How much protein accumulation has already occurred?

為了延續這一趨勢，我打算在 AAT 上問 2 個問題。第一，關於滑鼠數據。您能否談談您在小鼠生命週期的哪個早期階段就開始進行治療，並觀察到肝臟中達到這種清除水平？目前已經累積了多少蛋白質？

And second, we had found a posting on the A-1AT Foundation for a study for VX-814 going on at the Covance research unit in Dallas looking at ZZ mutant patients that was -- it looked like it was recruiting. Can you clarify, is that study ongoing? And is that something that could produce some data, potentially, on the sooner side?

其次，我們在 A-1AT 基金會上發現了一則關於達拉斯 Covance 研究部門正在進行的 VX-814 研究的帖子，該研究針對 ZZ 突變患者，而且看起來正在招募患者。請問這項研究還在進行嗎？這樣做是否有可能更快產生一些數據？

And maybe I'll take the first one, and Reshma will take the second part of that. This is Jeff. So we started treating these mice at about 1 month of age. We treated them, and this particular experiment showed you they'd explored for 12 weeks. And in answering your question, there's already protein accumulation, very significantly, yes. You can see that, actually, in the slide there, and you see that protein accumulation occurring early and getting worse and worse over time in the control animals, and essentially clearing or mostly clearing in the treated animals.

也許我會做第一部分，而雷什瑪會做第二部分。這是傑夫。所以我們開始對這些大約1個月大的小鼠進行治療。我們對它們進行了治療，而這項特殊的實驗表明，它們已經探索了 12 週。至於你的問題，是的，蛋白質已經大量累積了。實際上，你可以從幻燈片中看到，在對照組動物中，蛋白質累積出現得較早，隨著時間的推移越來越嚴重，而在治療組動物中，蛋白質累積基本上被清除或大部分被清除。

I think your second question was around VX-814 and some clinical trial postings and such. What you can expect to see from us is the same level of urgency that we worked on CF with AAT. And so you're right, we are starting to really mobilize our clinical trial efforts. And you may well see some postings for patient recruitment. I would anticipate that the data event with regard to when can we see some data from people with ZZ -- the ZZ mutation, I would say that that's likely to be a 2020 event.

我認為你的第二個問題是關於 VX-814 以及一些臨床試驗資訊之類的。您可以期待我們以與 AAT 合作開發 CF 時同樣的緊迫感來對待這項工作。所以你說得對，我們正在真正開始調動臨床試驗力量。您很可能會看到一些招募患者的招募資訊。關於何時能看到一些來自 ZZ 基因突變患者的數據，我預計這很可能是 2020 年發生的事情。

Our next question or comment comes from the line of Geoffrey Porges from SVB Leerink.

我們下一個問題或評論來自 SVB Leerink 的 Geoffrey Porges。

Stuart, just a couple on the core business. Could you just give us an update on where you are with the success of SYMDEKO in the penetration of the adult population carrying F508del allele? Just help us with benchmarking.

斯圖爾特，就核心業務而言，就幾點。能否請您介紹一下SYMDEKO在攜帶F508del等位基因的成年人群體中的滲透情況？請協助我們進行基準測試。

And then, related to that, would you anticipate the vast majority of those patients switching pretty quickly to the triple? And should we anticipate that there is incremental patient volume available to the triple, or is it primarily going to be the cannibalization of existing volume? And that's in the adult market in the U.S., obviously, the individual geographies around the world will play out over time.

那麼，與此相關的是，您是否預期絕大多數患者會很快轉而接受三重療法？我們是否應該預期三聯診療模式會有新增患者量，還是主要會蠶食現有患者量？顯然，這是在美國成人市場的情況，世界各地的具體情況將隨著時間的推移而逐漸明朗。

Yes, Jeff. So SYMDEKO here in the U.S., in the 12-plus population, we are about 18 months into that launch now. That launch has gone spectacularly well. The vast, vast majority of F508del homozygous patients are now being treated with either SYMDEKO or ORKAMBI because there are a large number of patients who have chosen to remain on ORKAMBI.

是的，傑夫。所以，SYMDEKO 在美國，在 12 歲及以上的人群中，我們已經進行了大約 18 個月的推廣。那次發表會進行得非常成功。絕大多數 F508del 純合子患者現在都接受 SYMDEKO 或 ORKAMBI 治療，因為有許多患者選擇繼續使用 ORKAMBI。

So that launch is going to vary kind of long in its life cycle, and as you know the life cycle of our launches in CF is pretty short. The uptake tends to be fairly vertical. And obviously we're earlier in the launch in ex U.S. markets. But as Charlie said in his prepared remarks, the launch, for instance, in Germany is going tremendously well. And there, we are now over 80% of F508 homozygous patients are being treated with a CFTR modulator, either ORKAMBI or increasingly, SYMKEVI.

所以這次發表會持續相當長的時間，而你也知道，我們在 CF 中的發布週期通常都很短。吸收率往往呈現垂直上升趨勢。顯然，我們在美國以外的市場推出得更早。但正如查理在事先準備好的演講稿中所說，例如，在德國的發布會進展得非常順利。目前，超過 80% 的 F508 純合子患者正在接受 CFTR 調節劑治療，要么是 ORKAMBI，要么越來越多地使用 SYMKEVI。

So the launch is in the 12-plus population, going very well, and that's largely what's driven the strong revenue growth this quarter. In terms of the number of patients who might transition, hard to predict until we get out there in the real world, but certainly, given the strength of the clinical data that we have in terms of the additional clinical benefit patients see from adding in a third product, our second corrected to SYMDEKO, I think the demand is likely to be really, really strong. Those levels of efficacy are truly, truly incredible. And certainly, the feedback we've had from the physician and patient community, both directly and also through research, would suggest that we're going to see very high levels of uptake. In fact if anything, it's likely going to be most constrained by the actual capacity of the CF centers to be able to make that transition, rather than physician and patient interest in getting on to the triple.

因此，該產品在 12 歲以上人群中的推廣非常成功，這在很大程度上推動了本季強勁的營收成長。至於有多少患者可能會進行轉換，這很難預測，直到我們真正進入現實世界，但可以肯定的是，鑑於我們擁有的臨床數據，患者從添加第三種產品（我們的第二種產品更正為 SYMDEKO）中獲得的額外臨床益處，我認為需求可能會非常非常強勁。這些療效水平真是令人難以置信。當然，我們從醫生和患者群體直接或透過研究獲得的回饋表明，我們將看到非常高的接受度。事實上，如果說有什麼限制的話，那很可能是囊性纖維化中心實際上有能力進行這種轉變，而不是醫生和病人對接受三合一療法的興趣。

Our next question or comment comes from the line of Mohit Bansal from Citi.

下一個問題或評論來自花旗銀行的 Mohit Bansal。

Congrats to both Jeff and Reshma. Maybe -- I would love to get your thought on the recent mRNA data we have seen retranslate. Do you think the delivery -- what do you think of the delivery here? And what is the challenging part of delivering a micro RNA -- mRNA therapy, in lung? And I would love to get your comments on your own efforts to modernize that.

恭喜傑夫和雷什瑪。或許——我很想聽聽您對我們最近看到的mRNA數據進行重新翻譯的看法。你覺得這裡的配送怎麼樣？在肺部進行微RNA（mRNA）療法治療的困難是什麼？我很想聽聽您對您在現代化改造方面所做的努力的看法。

Sure. Thanks for the question, Mohit. This is Jeff. Obviously, it's a little too early, I think, to really make much of any comments about the data we saw today. Very early data, one part of the trial, single doses in very small numbers of patients. I honestly can't really give you much of a comment, and we usually don't comment on competitors anyway.

當然。謝謝你的提問，莫希特。這是傑夫。顯然，我認為現在對我們今天看到的數據發表任何評論都為時過早。非常早期的數據，試驗的一部分，在極少數患者中進行了單劑量給藥。說實話，我沒什麼好說的，而且我們通常也不會對競爭對手發表評論。

I certainly can comment on what we think about nucleic assay therapy or mRNA therapies, which as you know, we're working on as well. We do believe that, ultimately, they may play a role in the treatment of CF, but we also believe it's a very long journey. And the reason for that, as you just pointed out is, the delivery issue. It is very difficult to deliver to the entire lung, to the rights cells, which we'll come back to in a minute. And in the case of mRNA, to do that repetitively which will certainly be needed. And while we're working out and many others are as well, it's a difficult problem.

我當然可以就核酸檢測療法或mRNA療法發表一些看法，正如您所知，我們也正在研究這些療法。我們相信，最終它們可能會在囊性纖維化的治療中發揮作用，但我們也認為這是一條非常漫長的道路。正如你剛才指出的，原因在於配送問題。要將藥物輸送到整個肺部，輸送到正確的細胞是非常困難的，我們稍後會再討論這個問題。而對於 mRNA 來說，則需要重複進行這種操作，這肯定是必要的。雖然我們正在努力，而且許多其他人也在努力，但這仍然是一個難題。

And the problem isn't expressing CFTR. That is a relatively easy problem. The problem is how do you deliver it to a football field of surface area and a lung that's inflamed full of nucleates and other immune cells, get it into the right cells, and then do it over and over again in the case of RNA. That's a really tough problem, and we said we think that's 10 or 15 years away before we crack that problem -- or others crack that problem.

問題不在於表達 CFTR。這是一個相對簡單的問題。問題在於如何將RNA輸送到足球場大小的表面積和充滿細胞核和其他免疫細胞的發炎肺部，使其進入正確的細胞，然後在RNA的情況下反覆進行。那真是一個棘手的問題，我們認為還需要 10 到 15 年的時間才能解決這個問題——或者其他人才能解決這個問題。

Now the other issue that's worth keeping in mind is CF is not a lung disease. CF is a systemic disease that affects many different organs, including the pancreas, the liver, the GI tract, et cetera. While the obvious advantage of the small molecule CFTR correctors like a triple approach is they treat all the organs, which is very important and very beneficial for these patients. Even when we work out the inhalation therapy, or someone works out the inhalation therapy for the lung, if it's possible that will only, obviously, treat the lung. And so I think as a standalone therapy, these will be quite challenging.

還有一點值得注意，那就是囊性纖維化不是一種肺部疾病。囊性纖維化是一種全身性疾病，會影響許多不同的器官，包括胰臟、肝臟、胃腸道等等。小分子 CFTR 矯正劑（如三聯療法）的明顯優勢在於它們可以治療所有器官，這對這些患者來說非常重要且非常有益。即使我們制定了吸入療法，或者有人制定了肺部吸入療法（如果可能的話），顯然也只能治療肺部。因此，我認為作為一項獨立的療法，這些療法將相當具有挑戰性。

And then, the final thing I would say is, there are 2 different fundamental approaches here. One is some sort of gene therapy or gene-editing approach, where you get into a stem cell, which can repopulate the airway continuously, and the other one is you deliver it to the bronchial epithelial cells, but unfortunately, as you know, those turn over every few weeks.

最後我想說的是，這裡有兩種不同的基本方法。一種方法是基因療法或基因編輯，即進入幹細胞，使其能夠不斷地再生氣道；另一種方法是將其輸送到支氣管上皮細胞，但不幸的是，正如你所知，這些細胞每隔幾週就會更新一次。

And so if you're going to deliver mRNA to the bronchial epithelial cells, that will require continuous retreatment, which it has all sorts of immune and other inflammatory challenges itself.

因此，如果要將 mRNA 輸送到支氣管上皮細胞，就需要不斷重複治療，而這本身就面臨各種免疫和其他發炎方面的挑戰。

So we're very interested in this. We think it's a very hard problem. We and others are working on it. I think it is a 10- or 15-year journey, and unfortunately, these inhalation therapy probably won't treat the entire disease, but just treat the lung.

所以我們對此非常感興趣。我們認為這是一個非常棘手的問題。我們和其他人正在努力解決這個問題。我認為這將是一個長達 10 到 15 年的過程，不幸的是，這些吸入療法可能無法治癒整個疾病，而只能治療肺部。

Our next question or comment comes from the line of Brian Skorney from Baird.

我們下一個問題或評論來自 Baird 公司的 Brian Skorney。

Just maybe if I can ask a question on the APOL1 program. Is there still activity for this molecule for the different variance? And would you expect this to be equally effective for G1 or G2? And that the ultimate goal here for complete knockdown of APOL1? And are there any infectious risks that we should be thinking about for full inhibition of APOL1? And would you expect to see reductions of wild-type APOL1 in the healthy volunteer study?

或許我可以問一個關於 APOL1 專案的問題。對於不同的變異情況，該分子是否仍具有活性？你認為這種方法對 G1 或 G2 也同樣有效嗎？而徹底摧毀 APOL1 的最終目標就是這樣嗎？完全抑制 APOL1 是否有任何感染風險是我們應該考慮的？那麼，您是否預期在健康志願者研究中看到野生型 APOL1 的減少？

Yes. This is Reshma. I think you're asking a few different questions about what do we understand about APOL1 in our models? And what do we understand about how VX-147 works?

是的。這是雷什瑪。我認為你問了一些關於我們在模型中對 APOL1 的理解的不同問題？我們對VX-147的作用機轉了解多少？

And so in general, we feel quite good, and we have data in our models with both G1 and G2. So I do expect that when we go to the clinic and treat patients with APOL1-mediated FSGS that it would be all comers of APOL1-mediated disease.

所以總的來說，我們感覺相當不錯，我們的模型中同時包含了 G1 和 G2 的數據。因此，我預計當我們去診所治療 APOL1 介導的 FSGS 患者時，將會遇到所有 APOL1 介導的疾病患者。

With regard to what do we expect to see in -- with our inhibition? We haven't taken this to humans yet so it's difficult to say. But what I can tell you is that in our animal models, we have seen good preclinical safety, good PK, and the data we've shown you on this slide, very good reductions in protein levels.

至於我們預期在抑制狀態下會看到什麼？我們還沒有進行人體試驗，所以很難說結果如何。但我可以告訴你們的是，在我們的動物模型中，我們已經看到了良好的臨床前安全性、良好的藥物動力學，以及我們在這張投影片上展示的數據，蛋白質水平的降低非常顯著。

And would we -- just in the healthy volunteers, would we be looking at a biomarker in terms of wild type of APOL1?

那麼，我們——僅在健康志願者中——是否會以野生型 APOL1 為生物標記呢？

As you know, the Phase I SAD/MAD study, the primary endpoint for that is going to be safety and tolerability. The key secondary endpoint is going to be PK. And when we get to our dose-ranging study is when we're really going to start to see the impact on proteinuria.

如您所知，I 期 SAD/MAD 研究的主要終點是安全性和耐受性。關鍵的次要終點將是PK。當我們進行劑量範圍研究時，我們才能真正開始看到對蛋白尿的影響。

Our next question or comment comes from the line of Whitney Ijem from Guggenheim.

我們下一個問題或評論來自古根漢美術館的惠特尼·伊傑姆。

Reshma, my congrats as well. I wanted to follow up on an earlier question around gene editing versus gene therapy and some of the investments you guys are making, specifically with the research center and bringing John Gray on to the team. So as we think about Vertex investing in viral vector capability, specifically, is that more around delivery in gene editing or even RNA as we think about that? Or does that signal an interest in broader gene therapy applications going forward?

雷什瑪，我也要祝賀你。我想就之前提出的關於基因編輯與基因療法的問題以及你們正在進行的一些投資，特別是對研究中心的投資以及邀請約翰·格雷加入團隊的投資，進行後續討論。所以，當我們考慮 Vertex 投資病毒載體能力時，具體來說，這是否與基因編輯或 RNA 的遞送有關？這是否預示著未來對更廣泛的基因療法應用感興趣？

Yes. This is Jeff. So maybe just to remind those who aren't familiar as you are with what we have announced. So we are very interested in both gene editing and gene therapy. Not as pure therapeutic modalities. We're not going to become a gene editing company. But because the diseases that we're interested in, many of them, are very amenable to gene editing or gene therapy approaches or combinations of gene editing, gene therapy with small molecules.

是的。這是傑夫。所以，或許只是想提醒一下那些不太了解我們已宣佈內容的人。所以我們對基因編輯和基因治療都非常感興趣。並非純粹的治療手段。我們不會成為一家基因編輯公司。但是，因為我們感興趣的許多疾病都非常適合基因編輯或基因治療方法，或基因編輯、基因治療與小分子藥物結合的方法。

And so we're really building a toolbox, a broad toolbox, of mRNA, gene editing, of potentially gene therapy approaches that we can use to address those diseases. We're actually also very interested in learning how we can combine those with small molecule approaches.

因此，我們正在建立一個工具箱，一個廣泛的工具箱，其中包含 mRNA、基因編輯以及潛在的基因療法，我們可以使用這些方法來應對這些疾病。我們其實也很有興趣了解如何將這些方法與小分子方法結合。

As part of that effort, we recently announced, simultaneously, 3 things. One was the expansion of the collaboration with CRISPR Therapeutics into DMD and DM1. Simultaneously, the acquisition of Exonics, which gives us great scientific expertise with Eric Olson, very important guy at IP, very impressive preclinical data in the dog model, and really accelerates our DMD and DM1 programs.

作為這項工作的一部分，我們最近同時宣布了 3 件事。其中一項是將與 CRISPR Therapeutics 的合作擴展到 DMD 和 DM1 領域。同時，我們收購了 Exonics，為我們帶來了強大的科學專業知識，包括與 IP 的重要人物 Eric Olson 的合作，以及在犬類模型中令人印象深刻的臨床前數據，這確實加速了我們的 DMD 和 DM1 項目。

And the third was, you mentioned, was hiring John Gray, who's really one of the world's experts in making and manufacturing AV vectors because AV vectors are obviously going to be very important in both gene editing and gene therapy approaches.

第三點，正如你所提到的，是聘請了約翰·格雷，他是世界上製造和生產AV載體的專家之一，因為AV載體顯然在基因編輯和基因治療方法中都將非常重要。

We plan to combine all of those into a new research site here in Boston, which we call Vertex Genetic Therapies. It'll have 150 to 200 scientists or so, and it will have both the project teams around these diseases like DMD and DM1, but also a preclinical and clinical manufacturing facility that will allow John to do vector work, vector formulation, bioanalytics and preclinical and clinical vector manufacturing.

我們計劃將所有這些整合到位於波士頓的一個新的研究基地，我們稱之為 Vertex 基因療法。它將擁有大約 150 到 200 名科學家，不僅有針對 DMD 和 DM1 等疾病的專案團隊，還有一個臨床前和臨床生產設施，這將使約翰能夠進行載體研究、載體配製、生物分析以及臨床前和臨床載體生產。

Our final question comes from the line of Evan Seigerman from Credit Suisse.

最後一個問題來自瑞士信貸的埃文·塞格曼。

Congrats on the strong quarter, and my congrats as well to Reshma on your upcoming promotion. So one on the drug pricing front. Do you see any risk to Vertex's U.S. businesses with the recent proposal by the administration to allow for importation of drugs from Canada?

恭喜公司本季業績出色，也恭喜雷什瑪即將晉升。這是關於藥品定價方面的一個問題。您認為政府最近提出的允許從加拿大進口藥品的提案，會對Vertex在美國的業務造成任何風險嗎？

And while Vertex has not been a focus of recent discussion on drug pricing, how are you managing the potential risk of increased drug pricing pressures in the U.S., as this discussion is unlikely to go away anytime soon?

雖然 Vertex 並非近期藥品定價討論的焦點，但鑑於美國藥品定價壓力可能持續存在，您如何應對這一潛在風險？

Yes. Thank you for the question. It's really a 2-part question. First, with respect to drug importation, and I would also include in that, by the way, price importation because those are really both the same things.

是的。謝謝你的提問。這其實是一個包含兩個部分的問題。首先，關於藥品進口，順便說一句，價格進口也包含在內，因為這兩者實際上是一回事。

We believe very strongly in policies that do 2 things: policies that encourage innovation to make more breakthrough transformative drugs; and policies that then make sure that all eligible patients can have access to those breakthrough drugs, which is equally important for us.

我們堅信，政策應該做到兩點：一是鼓勵創新，研發出更多具有突破性變革意義的藥物；二是確保所有符合資格的患者都能獲得這些突破性藥物，這對我們來說同樣重要。

When we look at the drug importation or price importation proposals that have been made, they don't meet either of those objectives. And in fact, we would argue that they're counter to both of them. From an access standpoint, imported drugs from Canada doesn't solve the problem because there's not nearly enough supply to supply access to the patients who need them in the U.S.

當我們檢視已提出的藥品進口或價格進口方案時，會發現它們都未能實現這兩個目標。事實上，我們認為它們與這兩者的觀點都相悖。從取得途徑的角度來看，從加拿大進口藥品並不能解決問題，因為供應量遠遠不足以滿足美國需要這些藥品的患者的需求。

Second, we feel that the potential very significant safety issue of allowing drugs to flow across the boarder in an unregulated fashion.

其次，我們認為允許藥品以不受監管的方式跨境流通可能會造成非常嚴重的安全問題。

And third, we're very certain that these kinds of policies will stifle the innovation that's led the industry here in the U.S. to be the leading innovator to make new breakthrough drugs. And so we feel that, that type of legislation is completely inconsistent with our principles.

第三，我們非常肯定，這類政策將會扼殺創新，而正是創新使美國製藥業成為研發突破性新藥的領先創新者。因此，我們認為，這類立法與我們的原則完全不符。

With respect to what are we doing for the future? I think the biggest thing we're doing for the future is to make sure that we're making transformational drugs because at the end of the day, these are the kind of drugs that patients and payers want to pay for and they want us to invest them and the best evidence of that is our CF programs here in the U.S. where we've seen very rapid reimbursement from all forms of payer, including government payers, Medicaid, Medicare, as well as the promotional players. And the reason for that is simple, they understand the value of those medicines to patients, and these are the kind of medicines that they actually want to pay for.

關於我們未來要做什麼？我認為我們為未來所做的最重要的事情是確保我們研發出具有變革意義的藥物，因為歸根結底，這些才是患者和支付者願意付費並希望我們投資的藥物。最好的證明就是我們在美國的囊性纖維化項目，我們已經看到來自各種支付方的快速報銷，包括政府支付方、醫療補助、醫療保險以及推廣機構。原因很簡單，他們了解這些藥物對病人的價值，而這些正是他們願意付費購買的藥物。

I think when you look at our pipeline, as Reshma described it, what you see is exactly the same kinds of medicines for serious diseases like sickle cell disease, pain, AAT, APOL1. That's the most important thing. Obviously, we talk with politicians and lawmakers to explain the value of innovation, and we have active programs to do that. But the most important thing we do is to actually do innovation and invest in it because I think that's how we protect the value for patients and shareholders.

我認為，正如雷什瑪所描述的那樣，當你審視我們的研發管線時，你會發現，我們研發的藥物都是針對鐮狀細胞疾病、疼痛、AAT、APOL1等嚴重疾病的同類型藥物。這是最重要的事。顯然，我們會與政治家和立法者交談，解釋創新的價值，我們有積極的計劃來實現這一目標。但我們最重要的工作是真正進行創新並對其進行投資，因為我認為這才是我們保護病患和股東價值的方式。

That concludes the Q&A period for today. I'd like to turn the conference back over to Mr. Partridge for any closing remarks.

今天的問答環節到此結束。我謹將會議交還給帕特里奇先生，請他作總結發言。

Thank you, operator. Thanks for tuning in to our call. If you have additional questions, the Investor Relations team is available for follow-up in the office tonight. Have a good evening.

謝謝接線生。感謝您收聽我們的電話會議。如果您還有其他疑問，投資者關係團隊今晚會在辦公室為您提供後續諮詢。祝你晚上愉快。

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You can now disconnect. Everyone, have a wonderful day.

女士們、先生們，感謝各位參加今天的會議。節目到此結束。您現在可以斷開連線了。祝大家今天過得愉快。