福泰製藥 (VRTX) 2020 Q3 法說會逐字稿

Good evening. Welcome to the Vertex Third Quarter 2020 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2020年第三季財務業績電話會議。這是 Vertex 公司投資者關係資深副總裁 Michael Partridge。

Making prepared remarks on the call tonight, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Commercial Officer; and Charlie Wagner, Chief Financial Officer; Dr. David Altshuler, Chief Scientific Officer, will join the Q&A portion of the call following the prepared remarks.

在今晚電話會議上，Vertex 的執行長兼總裁 Reshma Kewalramani 博士、商務長 Stuart Arbuckle 和財務長 Charlie Wagner 將發表事先準備好的演講；首席科學官 David Altshuler 博士將在演講結束後參加問答環節。

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。本次電話會議正在錄音，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 our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed CF medicines, our pipeline, and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance we will review on the call this evening are non-GAAP.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受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、我們的研發管線以及 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此有重大差異。我還想指出，我們今晚電話會議上將要討論的部分財務表現和指引是非GAAP準則的。

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

現在我將把電話轉給雷什瑪·凱瓦拉瑪尼醫生。

Thanks, Michael. I'll begin tonight with a few general comments across the business and then provide details on our R&D programs before turning it over to Stuart for a review of the commercial performance.

謝謝你，麥可。今晚我將先對公司整體狀況做一些整體評價，然後詳細介紹我們的研發項目，最後將商業表現的評估交給史都華。

First, starting with CF. 2020 continues to be a remarkable year for our growing CF business. Our performance through the third quarter was driven by the strong TRIKAFTA launch in the U.S., and we are building on that progress as we launch KAFTRIO, as a triple combination is known in Europe. Based on our year-to-date performance, we are again revising upward our 2020 product revenue guidance to $6 billion to $6.2 billion.

首先，從CF開始。2020年對於我們不斷發展的CF業務來說，仍然是意義非凡的一年。第三季業績主要得益於 TRIKAFTA 在美國的強勁上市，而我們正在以此為基礎，推出 KAFTRIO（歐洲稱為三重組合）。根據我們今年迄今的業績，我們再次上調 2020 年產品收入預期至 60 億美元至 62 億美元。

There are 2 important aspects that characterize our outlook in CF and I want to be sure to provide a perspective on both. The first is growth, which has been exceptional. 2020 is poised to deliver more than 50% growth in revenue over 2019 and we see significant top and bottom line growth beyond 2020. Driven by 3 factors: expansion of the triple combination geographically, expansion of our medicines to lower age groups and additional mutations, as well as the development of a treatment for the last 10% of CF patients who cannot benefit from CFTR modulators.

CF 的前景有兩個重要方面，我想就這兩個方面都闡述我的觀點。首先是成長，而且成長非常顯著。2020 年的營收預計將比 2019 年成長 50% 以上，我們預計 2020 年以後營收和利潤將大幅成長。受以下三個因素驅動：三重療法的地域性擴展、藥物適用範圍擴大到更低年齡層和更多突變，以及為最後 10% 無法從 CFTR 調節劑中獲益的 CF 患者開發治療方法。

There's 2 ways to think about this growth. Near term, even for the CF population who are currently eligible and reimbursed for our medicines, there are many patients who have yet to begin treatment. And beyond that, there are at least 20,000 more who we anticipate will become eligible through label, geographic and reimbursement expansions. Stuart will go into more details on these growth drivers in a moment. The other aspect of our business I want to address is leadership. We have a strong leadership position in cystic fibrosis, and we believe this will last a very long time into at least the late 2030s as a base case when considering the high bar set by the significant benefit of TRIKAFTA to patients and the patent coverage for this regimen.

看待這種增長有兩種方式。短期內，即使對於目前有資格獲得我們藥物報銷的囊性纖維化患者群體來說，也有許多患者尚未開始接受治療。除此之外，我們預計至少還有 2 萬人將透過標籤、地理和報銷範圍的擴大而獲得資格。史都華稍後將詳細介紹這些成長驅動因素。我想談談我們業務的另一個方面，那就是領導力。我們在囊性纖維化領域擁有強大的領導地位，考慮到 TRIKAFTA 給患者帶來的顯著益處以及該療法的專利保護所設定的高標準，我們相信這種領導地位至少會持續到 2030 年代後期。

Turning to the pipeline. Our pipeline reflects a deliberate strategy of investing in serial innovation, both internally and externally to develop first-in-class or best-in-class treatments for serious diseases. The diseases we pursue are selected based on the understanding of causal human biology, target validation and biomarkers with high fidelity from bench to bedside. Once we begin working on a disease, we are relentless in our pursuit of a transformative therapy. Because drug development is an inherently high-risk endeavor, we strive to increase our chances of success by advancing a portfolio of drug candidates for each disease so that we can bring the very best one to market. This strategy is working exactly as expected and it is the reason for our success in CF. And this is exactly the same approach we are applying to every pipeline program. With this strategy, Vertex has advanced a broad and deep portfolio with first-in-class programs in the clinic in 5 different disease areas outside of CF.

轉向管道。我們的研發管線體現了我們深思熟慮的策略，即透過內部和外部的持續創新，開發針對嚴重疾病的首創或一流療法。我們選擇研究的疾病是基於對人類生物學成因的理解、標靶驗證以及從實驗室到臨床應用的高保真度生物標記。一旦我們開始研究某種疾病，我們就會不懈地追求變革性療法。由於藥物研發本身就是一項高風險的活動，我們努力提高成功幾率，針對每種疾病推進一系列候選藥物的研發，以便將最好的藥物推向市場。這項策略完全達到了預期效果，這也是我們在CF領域取得成功的原因。而這正是我們對每個管道項目都採用的相同方法。憑藉這一策略，Vertex 已在囊性纖維化以外的 5 個不同疾病領域推進了廣泛而深入的產品組合，其中包括處於臨床階段的同類首創項目。

The programs in sickle cell disease, beta-thalassemia, FSGS and alpha-1 antitrypsin deficiency are already in patients. And the type 1 diabetes program is projected to be in patients next year. A number of these programs have the potential to read out important proof-of-concept data between now and the end of '21. Individually, each represents a potentially transformative treatment for a serious disease. And collectively, they represent a very large opportunity.

鐮狀細胞疾病、β-地中海貧血、FSGS 和 α-1 抗胰蛋白酶缺乏症的治療方案已在患者身上實施。預計明年將開始對第 1 型糖尿病患者進行治療。從現在到 2021 年底，其中一些項目有可能讀取重要的概念驗證資料。單獨來看，每一種療法都可能對嚴重的疾病產生變革性的影響。總的來說，它們代表著一個巨大的機會。

Some compounds will inevitably fail and some programs will not fulfill their early potential. In terms of the Vertex portfolio, not all of the molecules will succeed. And not all of them have to, even if 2 or 3 of the programs succeed, and we firmly believe that they will, the return on investment for the innovations that emerge will create exceptional outcomes for patients and drive exceptional returns for our shareholders. That is our R&D and corporate strategy.

有些化合物注定會失敗，有些計畫也注定無法發揮其早期潛力。就Vertex的產品組合而言，並非所有分子都會成功。即使其中 2 或 3 個項目成功（我們堅信它們會成功），也並非所有項目都必須成功，由此產生的創新所帶來的投資回報將為患者帶來卓越的療效，並為我們的股東帶來卓越的回報。這就是我們的研發和企業策略。

Lastly, a few words about the AATD program. This program is an example of our portfolio approach at work. The recent discontinuation of VX-814 is disappointing. But it is neither unusual nor extraordinary to have a clinical program discontinued in early or mid-stage development. This is a potential for any molecule, and it is anticipated in our overall strategy. Hence, our portfolio approach. That is to say, the advancement of multiple molecules in parallel, through research and into early clinical development. Our enthusiasm for the AATD program is not diminished. And it does not change how we think about VX-864 or our follow-on molecules.

最後，簡單介紹一下AATD項目。這個項目是我們運用組合式方法的一個實例。VX-814 近期停產令人失望。但臨床項目在早期或中期發展階段中止，既不罕見也不特殊。任何分子都有這種潛力，這也是我們整體策略中所預期的。因此，我們採取了投資組合策略。也就是說，透過研究和早期臨床開發，並行推進多個分子的發展。我們對AATD項目的熱情絲毫未減。但這並不會改變我們對 VX-864 或我們後續分子的看法。

Let me now turn to reviewing some of our R&D programs in more detail and highlight some specific upcoming pipeline events. Starting with CF. We have completed the study of TRIKAFTA in patients 6 to 11 years of age and are on track for filing this quarter with a potential approval in 2021. The Phase III study in TRIKAFTA for 2- to 5-year olds is also now underway. And lastly, we continue our efforts in nucleic acid therapies to bring forward a treatment to the last 10% of CF patients who do not make any CFTR protein and hence, cannot be served by CFTR modulators. On this front, I'm pleased with our second collaboration with Moderna, and the preclinical progress using mRNA to serve the last 10% of CF patients.

現在，我將更詳細地回顧我們的一些研發項目，並重點介紹一些即將開展的具體項目。從CF開始。我們已經完成了 6 至 11 歲患者的 TRIKAFTA 研究，並預計在本季度提交申請，預計在 2021 年獲得批准。TRIKAFTA 針對 2 至 5 歲兒童的 III 期研究也正在進行中。最後，我們將繼續努力進行核酸療法研究，以期為最後 10% 的 CF 患者提供治療，這些患者不會產生任何 CFTR 蛋白，因此無法使用 CFTR 調節劑。在這方面，我對我們與 Moderna 的第二次合作以及使用 mRNA 為最後 10% 的囊性纖維化患者提供服務的臨床前進展感到滿意。

Moving to AATD. The Phase II study of VX-864 is ongoing and continues to enroll and dose patients. This Phase II study is a dose-ranging proof-of-concept study in approximately 40 people with AATD. The duration of treatment is 28 days, followed by 28 days of safety follow up. We expect to see results from this program in the first half of 2021.

轉至AATD。VX-864 的 II 期研究正在進行中，並繼續招募和給予患者。這項 II 期研究是一項劑量範圍概念驗證研究，受試者為約 40 名 AATD 患者。治療療程為 28 天，之後進行 28 天的安全追蹤。我們預計該計畫將於 2021 年上半年取得成果。

We're also advancing additional small molecule correctors through preclinical development with a goal of at least 1 new corrector entering the clinic next year.

我們也正在推進其他小分子矯正劑的臨床前開發，目標是明年至少有一種新的矯正劑進入臨床試驗階段。

Next, the CTX001 program. Our gene editing program in transfusion-dependent beta-thalassemia and sickle cell disease is gaining momentum. As you will recall, data at the EHA conference in June included the results for 2 patients in the beta-thalassemia study, which provided clinical proof-of-concept for CRISPR-Cas9 ex vivo gene editing in this disease. Results were also presented for 1 patient with sickle cell disease. Also in the summer, we updated you on enrollment and dosing progress, noting that a total of 7 patients had been treated with CTX001 and all had successfully engrafted. Since then, we have enrolled and dosed additional patients across both studies.

接下來是 CTX001 程式。我們在輸血依賴型β地中海貧血和鐮狀細胞疾病方面的基因編輯計畫正在取得進展。您可能還記得，6 月 EHA 會議上公佈的數據包括 β-地中海貧血研究中 2 名患者的結果，該研究為 CRISPR-Cas9 體外基因編輯治療該疾病提供了臨床概念驗證。此外，也公佈了 1 位鐮狀細胞疾病患者的檢測結果。今年夏天，我們也向您報告了招募和給藥進展情況，指出共有 7 名患者接受了 CTX001 治療，並且全部成功植入。此後，我們在兩項研究中招募並給予更多患者進行了給藥。

Given the progress across these trials, we look forward to reporting additional clinical data including more patients and longer durations of follow-up by the end of this year.

鑑於這些試驗的進展，我們期待在今年年底前公佈更多臨床數據，包括更多患者和更長的追蹤時間。

With regard to the APOL1-mediated FSGS program, enrollment is ongoing in our Phase II proof-of-concept study of VX-147. Evaluating the safety, pharmacokinetics and reduction in proteinuria over 13 weeks. We expect to obtain initial data from this study in '21. And with our cell therapy for type 1 diabetes, we have completed the required IND-enabling studies and manufacturing work, which were key priorities in the first half of the year and we are on track to submit an IND application to the FDA before the end of this year. We expect the first study to focus on islet cells alone and I'm optimistic about the progress we're making. This program is important in so many ways, including the number of patients who are living with this disease and the approach which holds the potential to truly transform this condition.

關於 APOL1 介導的 FSGS 項目，我們正在進行 VX-147 的 II 期概念驗證研究，目前正在招募受試者。評估 13 週內的安全性、藥物動力學和蛋白尿減少。我們預計將於 2021 年獲得這項研究的初步數據。針對 1 型糖尿病的細胞療法，我們已經完成了所需的 IND 申報研究和生產工作，這些都是今年上半年的重點工作，我們預計在今年年底前向 FDA 提交 IND 申請。我們預計第一項研究將只關注胰島細胞，我對我們的進展感到樂觀。這個計畫意義重大，體現在許多方面，包括患有這種疾病的患者人數，以及它有可能真正改變這種疾病的治療方法。

In summary, we've made strong progress across the business in Q3, and we are well positioned for continued growth in CF and continued advancement of our portfolio of small molecules, cell and genetic therapies across multiple different disease areas.

總而言之，我們在第三季度在各個業務領域都取得了強勁的進展，我們已做好充分準備，在 CF 領域繼續成長，並在多個不同的疾病領域繼續推進我們的小分子、細胞和基因療法產品組合。

And now over to Stuart.

現在把麥克風交給史都華。

Thank you, Reshma. I am pleased to review with you this evening, our continued strong commercial performance. It is amazing to think that TRIKAFTA was first approved in the U.S. just a little over a year ago. The response to the product has been incredibly positive. Payers recognize the value of the medicine and provided almost immediate access for eligible patients. The CF community enthusiastically welcomed the approval and CF centers have worked tirelessly to initiate treatment for patients even during the disruption caused by the COVID-19 pandemic. As a result, today, the vast majority of eligible patients in the U.S. are now being treated with TRIKAFTA.

謝謝你，雷什瑪。今晚我很高興與各位一起回顧我們持續強勁的商業表現。令人難以置信的是，TRIKAFTA 在美國首次獲得批准僅僅一年多一點的時間。產品反應非常正面。支付方認可這種藥物的價值，並為符合條件的患者提供了幾乎立即獲得治療的機會。囊性纖維化 (CF) 患者群體對此批准表示熱烈歡迎，即使在 COVID-19 疫情造成的干擾期間，囊性纖維化中心也一直在不懈地為患者啟動治療。因此，如今美國絕大多數符合條件的患者都在接受 TRIKAFTA 治療。

Total CF product revenues for the third quarter were $1.54 billion, reflecting this impressive uptake in the U.S. We continue to observe that patients are maintaining the relatively high levels of personal inventory that they built up at the beginning of the pandemic. Moving forward, we are focused on maintaining the high rates of patient persistence and compliance that have been important factors contributing to our revenue performance in the year-to-date.

第三季 CF 產品總營收為 15.4 億美元，反映了該產品在美國的強勁成長。我們繼續觀察到，患者保持著疫情初期累積的相對較高的個人庫存水準。展望未來，我們將專注於維持較高的患者堅持率和依從性，因為這些因素對我們今年的收入表現起到了重要作用。

In late August, we were delighted to receive an earlier-than-expected approval for KAFTRIO in Europe. We have begun to execute what is our first fully remote launch. Despite the challenges posed by COVID-19, which continues to surge in Europe, our team has enabled patients to access KAFTRIO in multiple countries.

8 月下旬，我們欣喜地得知 KAFTRIO 在歐洲的審批比預期提前了。我們已經開始執行首次完全遠端發布。儘管 COVID-19 疫情持續在歐洲肆虐，為患者帶來了許多挑戰，但我們的團隊已幫助多個國家的患者獲得了 KAFTRIO 治療。

Germany, which provides immediate access to new medicines, and other countries where we secured reimbursement for the triple combination ahead of approval, including England, Ireland, Scotland, Wales and Denmark. We are also working to secure reimbursement and access for all eligible patients in countries where we don't yet have agreements in place. As in the U.S., enthusiasm in the CF community is high. And over time, we expect the vast majority of patients will be treated.

德國可以立即獲得新藥，而其他一些國家，例如英格蘭、愛爾蘭、蘇格蘭、威爾斯和丹麥，我們在三聯療法獲得批准之前就已確保了其報銷。我們也在努力確保在尚未達成協議的國家，所有符合資格的患者都能獲得報銷和醫療服務。與美國一樣，囊性纖維化患者族群的熱情也很高。隨著時間的推移，我們預計絕大多數患者都將得到治療。

We expect the impact of the KAFTRIO launch to become a significant driver of growth starting in the fourth quarter. All of these factors and their potential impact on results for the fourth quarter and full year of 2020, are reflected in our revised revenue guidance, which Charlie will review in more detail.

我們預計 KAFTRIO 的上市將從第四季開始成為重要的成長驅動力。所有這些因素及其對 2020 年第四季和全年業績的潛在影響，都已反映在我們修訂後的收入預期中，查理將對此進行更詳細的審查。

I am pleased by the progress we've made in bringing our medicines to patients to date. Our teams are working hard to ensure that we are able to reach all eligible patients with CF as quickly as possible after regulatory approval. And we expect to see continued revenue growth in CF beyond 2020.

我對我們迄今為止在將藥物帶給患者方面取得的進展感到滿意。我們的團隊正在努力確保在獲得監管部門批准後，能夠盡快為所有符合條件的囊性纖維化患者提供服務。我們預計 CF 的營收將在 2020 年後持續成長。

Our goal remains, as it has always been, to treat the 90% of all CF patients who might benefit with our CFTR modulators. While we have made great progress towards this goal, our job is far from done. Today, there are still many patients who, although they are eligible and have reimbursement and access to our medicines have yet to start treatment. These patients are primarily in Europe and our teams are working toward treating all of these patients.

我們的目標始終如一，那就是治療所有 CF 患者中 90% 可能受益於我們 CFTR 調節劑的患者。雖然我們朝著這個目標取得了巨大進展，但我們的工作遠未完成。如今，仍有許多患者雖然符合條件，可以獲得報銷和藥物，但尚未開始治療。這些患者主要集中在歐洲，我們的團隊正在努力治療所有這些患者。

As we think about our CF business heading into 2021 and beyond, there are more than 20,000 patients who we believe will become eligible for our medicines as we achieve additional regulatory approvals and secure future reimbursement agreements. The key expected drivers for our near and long-term growth in CF include: first, reaching reimbursement agreements for KAFTRIO in additional countries in the EU; next, regulatory and reimbursement approvals for the triple combination in additional geographies, such as Australia; third, regulatory approval and reimbursement of the triple combination in children age 6 to 11; and finally, continued label expansions and reimbursement in younger age groups and additional mutations for our portfolio of CF medicines.

展望 2021 年及以後的 CF 業務，我們相信，隨著我們獲得更多監管批准和達成未來的報銷協議，將有超過 20,000 名患者符合我們藥物的用藥條件。我們預計在囊性纖維化領域實現近期和長期增長的關鍵驅動因素包括：首先，在歐盟其他國家/地區達成 KAFTRIO 的報銷協議；其次，在澳大利亞等其他地區獲得三聯療法的監管和報銷批准；第三，獲得 6 至 11 歲兒童三聯療法的監管批准和報銷；最後，繼續擴大我們囊性纖維化藥物組合的年齡範圍，在更年輕。

We remain steadfast in our belief that we will be able to treat 90% of all CF patients with our CFTR modulators in the years to come. And we look forward to continuing to update you on our progress.

我們仍然堅定地相信，在未來的幾年裡，我們將能夠用我們的 CFTR 調節劑治療 90% 的 CF 患者。我們期待繼續向您報告我們的進展。

I am very grateful to the CF teams at Vertex in both the U.S. and internationally, who have delivered tremendous results during these challenging times, all in service of our shared dedication to patients' living with this life shortening disease. It is because of this commitment to delivering for our patients that I have high confidence in our ability to reach all eligible patients with our CFTR modulators.

我非常感謝Vertex公司在美國和國際上的CF團隊，他們在這些充滿挑戰的時期取得了巨大的成果，這一切都是為了我們共同致力於幫助患有這種縮短壽命疾病的患者更好地生活。正是因為我們致力於為患者提供優質服務，我才對我們能夠讓所有符合條件的患者都能使用 CFTR 調節劑充滿信心。

Finally, I would like to thank once again the CF community for their commitment to collaborating with us to reach our shared goals.

最後，我要再次感謝 CF 社群致力於與我們合作，實現我們的共同目標。

Charlie will now review our third quarter results and financial guidance.

查理接下來將審查我們第三季的業績和財務預期。

Thanks, Stuart. In the third quarter of 2020, we continued our exceptional financial performance headlined by the strong results with TRIKAFTA in the U.S. Third quarter total product revenues were $1.54 billion, a 62% increase compared to 2019, bringing our year-to-date revenues to $4.58 billion.

謝謝你，斯圖爾特。2020 年第三季度，我們繼續保持了卓越的財務業績，其中以美國 TRIKAFTA 的強勁業績最為突出。第三季產品總收入為 15.4 億美元，比 2019 年成長了 62%，使我們今年迄今的營收達到 45.8 億美元。

Our third quarter revenues included $1.22 billion in the U.S. and $314 million in revenues outside the U.S. Revenues from outside the U.S. in the third quarter grew 31% over the prior year driven by continued uptake of our medicines following the completion of several reimbursement agreements late last year.

第三季度，我們的營收包括美國境內的 12.2 億美元和美國境外的 3.14 億美元。由於去年底完成了幾項報銷協議，我們的藥品銷售持續成長，第三季美國境外的營收比去年同期成長了 31%。

And as Stuart mentioned, KAFTRIO launched late in the third quarter so we expect to see increased contribution to international revenues in the fourth quarter and beyond.

正如 Stuart 所提到的，KAFTRIO 是在第三季末推出的，因此我們預計在第四季度及以後，它將對國際收入做出更大的貢獻。

Our third quarter 2020 combined R&D and SG&A expenses were $497 million, compared to $416 million for the third quarter of 2019, bringing our year-to-date expenses to $1.44 billion.

2020 年第三季度，我們的研發與銷售、管理及行政費用合計為 4.97 億美元，而 2019 年第三季為 4.16 億美元，使我們今年的累計費用達到 14.4 億美元。

Our expenses in 2020 reflect increased cost to support the rapid global expansion of our CF business as well as targeted investment in the expansion of our pipeline into new disease areas and the progression of several important clinical programs.

2020 年，我們的支出反映了為支持 CF 業務在全球範圍內的快速擴張而增加的成本，以及對將產品線擴展到新的疾病領域和推進幾個重要臨床項目的有針對性的投資。

The significant continued growth in revenues, combined with more moderate growth in spending, resulted in year-to-date operating margin of 57%, and year-to-date operating income of $2.6 billion, an increase of 118% compared to operating income in the first 3 quarters of 2019.

收入的持續大幅成長，加上支出成長較為溫和，使得今年迄今的營業利潤率達到 57%，營業收入達到 26 億美元，比 2019 年前三個季度的營業收入增長了 118%。

Year-to-date net income for 2020 was $2.06 billion compared to $945 million in the first 3 quarters of 2019. With our strong revenue and profitability, we finished the second quarter with $6.2 billion in cash. Consistent with our corporate strategy, our top priority for capital deployment is to reinvest in innovation, both in our internal R&D engine and an external innovation aligned with our R&D strategy to accelerate the development of transformative medicines for serious diseases.

截至 2020 年 1 月 3 日，公司淨收入為 20.6 億美元，而 2019 年前三個季度的淨收入為 9.45 億美元。憑藉強勁的收入和獲利能力，我們第二季末的現金餘額為 62 億美元。與我們的集團策略一致，我們資本部署的首要任務是再投資於創新，包括內部研發引擎和與我們的研發策略一致的外部創新，以加速開發治療嚴重疾病的變革性藥物。

In summary, Vertex's exceptional financial performance represents an attractive combination of growth, profitability and scale that is unique among large-cap biotech.

總而言之，Vertex 出色的財務表現代表了成長、盈利能力和規模的極具吸引力的組合，這在大型生物技術公司中是獨一無二的。

Now to guidance. Today, we are pleased to once again revise upward our 2020 financial guidance for total product revenues to a range of $6.0 billion to $6.2 billion, which at the midpoint reflects 52% growth over 2019. This revised guidance primarily reflects the ongoing and impressive performance of TRIKAFTA in the U.S., our current view of persistence and compliance trends and the impact of the KAFTRIO launch on fourth quarter revenue.

現在進入指導環節。今天，我們很高興再次上調 2020 年產品總收入的財務預期，目標區間為 60 億美元至 62 億美元，其中值較 2019 年增長 52%。此次修訂後的指導意見主要反映了 TRIKAFTA 在美國持續且令人印象深刻的表現、我們目前對堅持性和合規性趨勢的看法以及 KAFTRIO 的推出對第四季度收入的影響。

For non GAAP OpEx, we are maintaining our guidance of $1.95 billion to $2 billion, with the vast majority of the year-over-year increase concentrated in R&D.

對於非GAAP營運支出，我們維持19.5億美元至20億美元的預期，其中絕大部分年成長集中在研發方面。

With the expansion and progression of our pipeline in 2020, we are poised to generate important clinical data and results across our programs in coming quarters. The progress of these programs will be the primary driver of further investments in 2021 as well as investments in critical technologies and capabilities.

隨著我們在 2020 年的研發管線不斷擴展和推進，我們預計在接下來的幾個季度裡，在各個專案中產生重要的臨床數據和結果。這些項目的進展將是 2021 年進一步投資以及對關鍵技術和能力投資的主要驅動力。

For example, we expect our Vertex cell and genetic therapies efforts to remain a priority as programs enter the clinic and advance further in clinical development. This include investments in our ongoing CTX001 Phase I/II program and our type 1 diabetes program, which we expect to move into patients as we initiate a Phase I/II study next year.

例如，我們預計隨著計畫進入臨床階段並在臨床開發中取得進一步進展，我們的 Vertex 細胞和基因療法工作仍將是優先事項。這包括對我們正在進行的 CTX001 I/II 期計畫和我們的 1 型糖尿病計畫的投資，我們預計明年啟動 I/II 期研究後，該計畫將進入患者階段。

Lastly, due to changes in the utilization of certain tax assets, we are revising our 2020 full year non-GAAP tax rate guidance to a range of 20% to 21%. I would note that the benefits that lower our 2020 tax rate are not expected to repeat, so our non-GAAP tax rate is expected to remain at 21% to 22% in subsequent years.

最後，由於某些稅務資產的使用情況發生了變化，我們將 2020 年全年非 GAAP 稅率預期調整為 20% 至 21%。需要指出的是，降低我們 2020 年稅率的優惠政策預計不會重現，因此，我們預計未來幾年的非 GAAP 稅率將保持在 21% 至 22%。

Now back to Reshma for a few concluding remarks.

現在請雷什瑪做幾句總結性發言。

As we head into 2021, I'm very pleased with both, the achieved and potential growth of the CF franchise and the breadth of our pipeline. Our strategy of investing in internal and external innovation is working with more CF patients becoming eligible and receiving treatment, with CFTR modulators and our portfolio of first-in-class and best-in-class therapies advancing, providing additional confidence for our long-term growth.

展望 2021 年，我對 CF 特許經營權已取得的成就和潛在的成長以及我們產品線的廣度都非常滿意。我們投資於內部和外部創新的策略正在發揮作用，越來越多的囊性纖維化患者符合治療條件並接受治療，CFTR 調節劑和我們首創及同類最佳療法的產品組合不斷進步，這為我們的長期增長提供了更多信心。

I want to make a point of recognizing the progress of our R&D teams, especially in diseases outside of CF, with a broad pipeline of potentially transformative programs. Throughout our history, we have built this differentiated pipeline now extending to 5 diseases already in the clinic outside of CF by investing in game-changing science, research and development. With continued internal innovation in our labs as well as external innovation through business development, such as partnerships with CRISPR Therapeutics and our acquisitions of Semma and Exonics, we are on track to deliver multiple programs into the clinic and multiple proof-of-concept readouts in the coming year. This proven R&D and business development strategy of investing in transformative science and medicines internally and externally, is core to our current success. And it will continue to be so as we move forward into 2021 and beyond.

我想特別表揚一下我們研發團隊的進展，尤其是在囊性纖維化以外的疾病領域，我們擁有廣泛的、具有潛在變革意義的專案儲備。綜觀我們的發展歷程，我們透過投資顛覆性科學、研究和開發，建構瞭如今已擴展到囊性纖維化以外的 5 種疾病的差異化產品線，目前這些疾病已進入臨床階段。憑藉實驗室內部的持續創新以及透過業務發展（例如與 CRISPR Therapeutics 的合作以及對 Semma 和 Exonics 的收購）進行的外部創新，我們預計在未來一年內將多個專案推向臨床，並獲得多個概念驗證結果。這種經過驗證的研發和商業發展策略，即投資於內部和外部的變革性科學和藥物，是我們目前成功的核心。這種情況在2021年及以後仍將持續。

I look forward to updating you on the progress across the business and the multiple R&D programs in the clinic in the coming months.

我期待在接下來的幾個月向您報告公司各業務部門的進展以及臨床上的多個研發項目。

Thank you, and we'll now open the call up to questions.

謝謝，現在我們將開放提問環節。

(Operator Instructions)

（操作說明）

Our first question comes from the line of Phil Nadeau from Cowen & Company.

我們的第一個問題來自 Cowen & Company 的 Phil Nadeau。

It sounds like, based on our conversations over the last week, investors are really trying to figure out whether the issue is with 814 or mechanism-based or molecule specific. And therefore, how optimistic should we about -- be about 864? So I'm curious, how do you think about that particular question? And in particular, were there any differences in bioavailability in the healthy volunteer studies between the 2 molecules? Or anything from the preclinical studies that you can point to that would suggest 864 won't have the same issues with LFT elevations that 814 did?

根據我們過去一週的對話，投資人似乎真的在努力弄清楚問題出在 814 本身，還是出在作用機制上，或是出在特定分子上。因此，我們應該對 864 這個數字抱持多大的樂觀態度呢？所以我很好奇，你對這個問題有什麼看法？特別是，在健康志願者研究中，這兩種分子的生物利用度是否有差異？或者，您能否指出臨床前研究中的任何證據表明，864 不會像 814 那樣出現肝功能指標升高的問題？

Phil, this is Reshma. Let me start with that question, and I'm going to ask David Altshuler, who's with us, to comment further. You're asking a really important question about whether the findings with 814 should be considered molecule specific or should be considered on mechanism. And there's another question in there about how different is 864 from 814.

菲爾，這位是雷什瑪。讓我先從這個問題開始，然後請和我們在一起的大衛·阿爾特舒勒進一步評論一下。你提出了一個非常重要的問題，關於 814 的研究結果應該被認為是分子特異性的，還是應該根據機制來考慮的。裡面還有一個問題，就是 864 與 814 有多大差別。

So let me just tell you where we are and then I'll ask David to give you some color. From all of the data that we have and our understanding, I have no reason to believe that this is on mechanism. I believe that this is molecule specific idiosyncratic to VX-814. And 864 and 814 are different chemical entities. And I'm going to ask David to give you a little bit more color on the on mechanism versus 814 and then tell you specifically a few differences between these molecules, which are clearly different molecular structures. David?

那麼，我先簡單介紹一下我們現在的位置，然後我會請大衛來補充一些細節給大家。根據我們掌握的所有數據和我們的理解，我沒有理由相信這是某種機製造成的。我認為這是 VX-814 特有的分子特性。864 和 814 是不同的化學實體。接下來，我將請 David 為大家詳細介紹 on 機制與 814 機制的對比，然後具體說明這些分子之間的一些區別，它們顯然是不同的分子結構。大衛？

Thank you, Reshma. And thanks for the question, Phil. First, with regard to whether or not these are on mechanism or idiosyncratic findings in 814, although we don't know, and of course, we can't know for sure, we see no reason to conclude that the LFT findings are on mechanism. There's really 2 lines of logic there that we think are most convincing.

謝謝你，雷什瑪。謝謝你的提問，菲爾。首先，關於這些結果是否與機制有關，還是與 814 號病例的特殊發現有關，雖然我們不知道，當然我們也不能確定，但我們認為沒有理由得出 LFT 結果與機制有關的結論。我們認為最有說服力的邏輯其實有兩個。

The first is that it is very common to have LFT abnormalities as a cause of programs stopping in early development. And these are typically chemical based, not mechanism based. The second is that with regard to a specific interaction of our mechanism and hepatotoxicity, I'll just note that we have done multiple studies in mouse models that carry the human ZAAT gene, where the polymers are seen and liver histology and injury happens. And in those models, and we treat with our small molecules, not only do we see no evidence whatsoever of hepatotoxicity. We actually see improvement in liver histology.

首先，肝功能異常是導致早期發育程序停止的常見原因。而這些通常是基於化學性質的，而不是基於機制的。第二點是，關於我們機制與肝毒性的具體相互作用，我只想指出，我們已經在攜帶人類 ZAAT 基因的小鼠模型中進行了多項研究，在這些模型中觀察到了聚合物，並且發生了肝臟組織學損傷。在這些模型中，我們用小分子藥物治療，不僅沒有發現任何肝毒性的證據。我們確實看到肝臟組織學方面有所改善。

And so common things being common and the specific chemical nature of most LFT abnormalities, combined with the mouse data, makes us think that it's premature to conclude that it's mechanism based and we certainly look forward to the 864 data.

因此，常見現象的普遍性以及大多數肝功能異常的特定化學性質，結合小鼠數據，讓我們認為現在就斷定它是基於機制的還為時過早，我們當然期待 864 數據。

Finally, just to close, you asked about 864 and 814. They're chemically different molecules. They have different structures. 864 is multifold, more potent than 814 and does have different physical properties and metabolism.

最後，作為結尾，你問到了 864 和 814。它們是化學性質不同的分子。它們的結構各不相同。864 比 814 強效數倍，並且具有不同的物理特性和代謝方式。

And these really represent 2 different opportunities to treat the disease. And just to close in our CF experience, we put multiple next-gen correctors into the clinic. We saw that different molecules, even in the same class of quite different properties. And so that actually underlies our portfolio strategy.

這實際上代表了治療這種疾病的兩種不同機會。最後，為了總結我們的 CF 經驗，我們向診所投入了多台新一代矯正器。我們發現，即使是同一類分子，其性質也截然不同。而這其實構成了我們投資組合策略的基礎。

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

我們的下一個問題來自高盛的薩爾文·里希特。

On the AAT program, can you speak to your third-generation compounds and how you might be able to optimize them on the Ford? And I have a second question.

關於AAT項目，您能否談談您的第三代化合物，以及您如何在福特車上優化它們？我還有第二個問題。

Salveen, I think you were asking about the generation of compounds coming behind VX-864 for AATD. And I'm going to ask David to make some comments. The one thing I'd like to say is, as I said in my prepared remarks, once we have a disease in our sandbox, we are absolutely relentless about pursuing a transformative therapy. And in the case of AATD, but honestly, across our entire pipeline, our approach is defined by this idea of bringing multiple molecules in parallel forward up through early development. And that's exactly what's happening in AATD. David, do you have any points that you want to make about the next-generation of molecules?

Salveen，我想你是在問關於VX-864之後用於治療AATD的化合物的生成。接下來，我要請大衛發表一些看法。我想說的一點是，正如我在準備好的演講稿中所說，一旦我們發現某種疾病，我們就會毫不猶豫地尋求變革性療法。就 AATD 而言，但說實話，在我們整個研發管線中，我們的方法都是以並行推進多個分子直至早期開發為核心的。而這正是AATD正在發生的事情。大衛，關於下一代分子，你有什麼觀點想說嗎？

Just that we've been working for some time as we always do, to have multiple scaffolds to get improvements in potency in properties and all of the features you would look for and we're excited to move forward molecules that are in late preclinical development that would have a differentiated and improved features.

我們一直在努力研發多種支架，以提高藥物的效力、特性以及您所期望的所有特徵。我們很高興能夠推進處於臨床前後期開發的分子，這些分子將具有差異化和改進的特性。

And then secondly, can you just speak to your business development strategy on the Ford? And if this initial setback has changed this outlook as well as maybe commenting here on your mRNA and CRISPR-Cas9 programs and kind of where they stand in terms of moving into the clinic?

其次，您能否談談福特的業務發展策略？如果這次最初的挫折改變了您的看法，您能否也談談您的 mRNA 和 CRISPR-Cas9 項目，以及它們在進入臨床階段方面所處的進展？

Yes, sure thing. Salveen, let me take that. This is Reshma. Now we have had a long interest in business development. We have this fundamental belief in investing in innovation, be it internal or external. Last year, you know we did over $1.5 billion worth of business development activities. And that interest remains. Our desire to have business development be one and the same in terms of strategic approach with internal R&D, that remains.

好的，沒問題。薩爾文，讓我來接吧。這是雷什瑪。我們一直對業務拓展很有興趣。我們始終堅信要投資創新，無論是內部創新或外部創新。你知道，去年我們開展了價值超過15億美元的業務拓展活動。而這種興趣依然存在。我們希望業務發展與內部研發在策略方法上保持一致，這一點依然不變。

And very specifically, our 3 pillars of interest, that remains exactly the same. That is to say, we are interested in CF, particularly in technologies that could help us with the last 10%. We continue to be very interested in tools like we did deals with Affinia and Moderna and Arbor and others.

更確切地說，我們的三大關注點始終保持不變。也就是說，我們對 CF 感興趣，特別是對那些可以幫助我們完成最後 10% 的技術感興趣。我們仍然對相關工具非常感興趣，就像我們之前與 Affinia、Moderna、Arbor 等公司達成的合作一樣。

And we are very interested equally in assets that could tackle diseases that are in our Sandbox. Now the one thing that has changed, I think, pretty obviously, is our growing financial strength. And we certainly have the capacity to do more deals or bigger deals. And from that perspective, what we are really focused on is our strategy. And we're prepared to use our balance sheet for business development opportunities that fit within this very disciplined strategy that I've laid out.

我們同樣非常關注那些能夠解決我們沙盒中疾病的資產。現在，我認為最明顯的變化是我們日益增長的經濟實力。我們當然有能力達成更多交易或更大額的交易。從這個角度來看，我們真正關注的是我們的策略。我們已準備好利用我們的資產負債表，抓住符合我制定的這項嚴謹策略的業務發展機會。

The -- I'll quickly get through to our mRNA. I think you must be asking about the collaboration with Moderna. I'm pleased with the way our teams in San Diego and Moderna are working together on the CF last 10% program. And with CRISPR-Cas9, that is in partnership with CRISPR therapeutics. As you heard in the prepared remarks, since the summer and since EHA, we've enrolled more patients, we've dosed more patients.

——我會盡快聯絡我們的mRNA。我想你一定是想問與 Moderna 的合作吧。我對我們聖地牙哥團隊和 Moderna 團隊在 CF 最後 10% 計畫上的合作方式感到滿意。而CRISPR-Cas9技術則是與CRISPR Therapeutics公司合作開發的。正如你們在準備好的發言稿中聽到的那樣，自從夏季以來，自從 EHA 以來，我們已經招募了更多患者，我們給更多患者進行了給藥。

Those early results were very impressive to us, 2 patients in beta-thalassemia and 1 in sickle cell, that we presented over the summer. And for sure, those are small numbers of patients. But it is really a functional cure for those patients. And we're very much looking forward to the results that we intend to share before the end of the year with more patients being treated and longer duration of follow-up.

那些早期結果給我們留下了非常深刻的印象，我們在夏季展示了 2 例 β-地中海貧血患者和 1 例鐮狀細胞貧血患者。當然，這些患者人數確實很少。但對這些患者來說，這確實是一種有效的治療方法。我們非常期待在年底前公佈研究結果，屆時將有更多患者接受治療，且追蹤時間會更長。

Our next question comes from the line of Geoff Meacham from Bank of America.

我們的下一個問題來自美國銀行的傑夫·米查姆。

I just have a couple. One, Stuart, with COVID accelerating in Europe and countries going into full quarantine. The question is, what, if any, are there tweaks to the launch plan?

我只有幾個。第一，斯圖爾特，新冠疫情在歐洲加速蔓延，各國紛紛進入全面隔離狀態。問題是，發布計劃是否有任何調整？如果有，調整幅度是多少？

And then the second question, Reshma, I thought the stock reaction after the AAT setback was a bit overdone, but it is implying that there's not a lot of investor confidence in the portfolio behind CF. So to put an emphasis on Salveen's question. Is there urgency to move the pipeline to mid- or late-stage through a larger scale BD? The pipeline is broad. It just seems like it's early, it won't catch up in time for when CFs potentially starts to moderate growth wise?

雷什瑪，關於第二個問題，我認為AAT挫折後股票的反應有點過激，但這暗示投資者對CF背後的投資組合缺乏信心。所以，我想強調一下薩爾文提出的問題。是否迫切需要透過更大規模的業務拓展，將產品線推進中期或後期階段？管道覆蓋範圍很廣。現在看來似乎還為時過早，恐怕來不及趕上CFs增長可能開始放緩的時候？

Yes. Thanks for the question. Let me ask Stuart to go first, and then I'll come back for the second part of your question.

是的。謝謝你的提問。我先請史都華回答，然後我再回來回答你問題的第二部分。

Yes, Geoff, thanks for the question. So obviously, the reaction from the community to KAFTRIO in Europe has been high exactly as we saw here in the U.S., and we fully expect, over time, that we will treat the vast majority of eligible patients. The real question is, how quickly are we going to get to that destination and obviously, there are a number of factors that are important there. But clearly, one is the ongoing and rapidly changing pandemic.

是的，傑夫，謝謝你的提問。顯然，歐洲社會對 KAFTRIO 的反應與我們在美國看到的情況完全一樣強烈，我們完全有理由相信，隨著時間的推移，我們將治療絕大多數符合條件的患者。真正的問題是，我們能以多快的速度到達目的地？顯然，這其中有許多重要因素。但很顯然，其中一個是正在持續且快速變化的新冠疫情。

In terms of changing our launch planning, which I think was your question, it really hasn't changed our launch planning at all. We had been planning since March for a fully virtual launch and that's what we are executing right now. Obviously, that causes some uncertainty, the pandemic leads to uncertainty about how easy it will be for patients and physicians to interact. So that's why it's certainly uncertain as to how we will -- how quickly we will get to that kind of peak uptake. The early trends are, I have to say, very encouraging. Obviously, in this quarter, we were just a few short weeks into the launch, but the early trends are encouraging. And as I say, we expect to get to the vast majority of them over time. The real question is just how quickly we get there.

至於你問的關於改變我們的發布計劃的問題，實際上我們的發布計劃根本沒有改變。我們從三月就開始計劃進行完全線上發布，而我們現在正在執行的就是這個計劃。顯然，這造成了一些不確定性，疫情導致人們對患者和醫生之間互動是否容易產生不確定性。所以，我們究竟要如何──以多快的速度──才能達到那種峰值接受度，目前還存在著很大的不確定性。不得不說，目前的趨勢非常令人鼓舞。顯然，本季我們才剛開始幾週，但早期的趨勢令人鼓舞。正如我所說，我們預計隨著時間的推移，我們將解決其中絕大多數問題。真正的問題是，我們能以多快的速度到達那裡。

And about your question for the pipeline, including business development, I think if I just stand back and reflect that, I think you're really talking about how do I see growth in the coming years, the next decade. Let me parse that out into 2 parts. We have to be very careful about making sure that we don't forget about CF. So where we are in CF, as you heard Stuart talk about, we are at a place where we have TRIKAFTA, KAFTRIO, which can serve up to 90% of patients. But that is not all today. It means that there are some patients in some geographies where there's regulatory approval and reimbursement, but we haven't yet gotten to those patients.

至於你提出的關於業務拓展管道的問題，包括業務發展，我想如果我冷靜下來思考一下，我認為你實際上是在談論我如何看待未來幾年、未來十年的成長。讓我把它分成兩部分來解釋。我們必須非常小心，確保不會忘記囊性纖維化。所以，正如你聽到史都華所說，就 CF 而言，我們現在擁有 TRIKAFTA 和 KAFTRIO，可以為高達 90% 的患者提供服務。但今天還不是全部。這意味著在某些地區，一些患者已經獲得了監管部門的批准和報銷，但我們還沒有接觸到這些患者。

And then, of course, there's the 20,000-plus patients that we are going to get you to with future approvals and reimbursements. And then there is the last 10% of our CF patients. So that is multiple years of getting to more and more patients and by treating more and more CF patients, more growth for the company.

當然，未來隨著審批和報銷的進行，我們也將為超過 2 萬名患者提供服務。最後還有 10% 的囊性纖維化患者。因此，經過多年的努力，公司接觸到越來越多的患者，並透過治療越來越多的囊性纖維化患者，實現了更大的發展。

Then let's go very specifically to the non-CF pipeline. And I want to make sure I take a minute to really go through this. The non-CF pipeline today, this is not in the future, this is not 1 year from now, it's not even a few months from now, today. The pipeline is already in Phase II. So it's in proof-of-concept stage in 5 disease areas. And let me just make sure I take another minute and just underline a few important points. In the CRISPR CTX001 program, beta-thalassemia, we shared clinical proof-of-concept results in beta-thalassemia over the summer time frame. We anticipate proof-of-concept results for sickle cell disease by the end of this year when we shared the data from the patients who are currently going through their treatment. That's two. AATD and this one is really important. You'll remember that 814 and 864 were, let's say, 6 months apart, something like that. It's certainly months apart, not years apart. And while disappointing, our strategy fully contemplates that molecules and programs may not succeed. And that's why 864 was already in the clinic already in Phase II and we do expect those results in the first half of 2021.

接下來，我們具體來說談談非CF流程。我想確保花點時間認真仔細地過一遍。今天的非CF產品線，不是在未來，不是一年後，甚至不是幾個月後，而是今天。該管道項目目前已進入二期工程。目前該技術在 5 個疾病領域處於概念驗證階段。讓我再花一分鐘時間，把幾個重點劃出來。在 CRISPR CTX001 計畫中，針對 β-地中海型貧血，我們在夏季期間分享了 β-地中海型貧血的臨床概念驗證結果。我們預計在今年年底前獲得鐮狀細胞疾病的概念驗證結果，屆時我們將分享目前正在接受治療的患者的數據。那是兩個。AATD，而且這一點非常重要。你應該記得，814 和 864 這兩個數字相隔大約 6 個月。肯定是相隔幾個月，而不是幾年。雖然令人失望，但我們的策略充分考慮到了分子和程序可能不會成功。因此，864 已經進入 II 期臨床試驗階段，我們預計在 2021 年上半年就能獲得試驗結果。

Moving on then to FSGS, that's also in Phase II. And then just to go a little bit more into the pipeline, the type 1 diabetes program, that IND is going to go in by the end of this year, which means that's going to be in patients now, that means in patients, not in healthy volunteers, but in a Phase II in patients in 2021.

接下來是 FSGS，它也屬於第二階段。然後，為了更深入地了解研發管線，1 型糖尿病項目，IND 將於今年年底提交，這意味著現在就要在患者身上進行試驗了，指的是在患者身上，而不是在健康志願者身上，而是在 2021 年進入 II 期臨床試驗。

So I think when you really carefully look at the pipeline and you stand back and say, "Where are we really?" I think we're in a really good place, 5 disease areas already in the clinic with more coming through up in the pipeline and much to look forward to even in the last few months of this calendar year. And what I mean by that is the 6 to 11 in CF, that application going in, the CRISPR data coming out and the IND for type 1 diabetes. I hope that helps.

所以我覺得，當你真正仔細審視我們的研發管線，並退後一步思考「我們現在到底處於什麼位置？」時，我認為我們處境非常好，目前已有 5 個疾病領域的產品進入臨床階段，還有更多產品正在研發中，即使在今年的最後幾個月，也有很多值得期待的事情。我的意思是，CF 的 6 到 11 個病例，該申請正在提交，CRISPR 數據即將公佈，以及 1 型糖尿病的 IND 申請。希望對您有幫助。

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

我們的下一個問題來自 Stifel 的 Paul Matteis 團隊。

One AAT and one commercial, if you don't mind. On AAT, in the 814 press release, you mentioned that analysis of the PK data from the study indicated the exposure levels were low. Did -- were you implying that they were lower than seen in healthy volunteers? And if so, what would you kind of make about that? Could that have anything to do with the fact that these AAT patients may have livers that operate differently?

如果你不介意的話，請給我一輛AAT和一輛商業車。關於 AAT，在 814 新聞稿中，您提到該研究的 PK 數據分析顯示暴露程度較低。你的意思是說，他們的數值低於健康志願者的數值嗎？如果真是這樣，你對此有什麼看法？這是否與這些 AAT 患者的肝臟運作方式不同有關？

And then commercially, just one question on ex-U. S. price. I know you're not going to disclose granular details. But as you think about price of TRIKAFTA, or the triple outside of the U.S. in year 1, with the country mix you're launching in initially, how might that compare to kind of the long-term price that you're anticipating?

然後，在商業方面，只有一個關於前美國的問題。S.價格。我知道你不會透露具體細節。但是，當您考慮 TRIKAFTA 的價格，或者說第一年在美國以外地區推出的三重奏的價格，以及您最初推出的國家/地區組合時，這與您預期的長期價格相比會如何呢？

Well, let me take the first part of your question first, and then I'll ask Stuart to comment on ex-U. S. pricing. So with regard to 814, that study is obviously an incomplete study. What that means is that we don't have all of the patients in all of the dose groups, completing the full treatment period, and we're in the process of closing out that study and bringing all that data in. From the data that we did have access to, what we see is that the exposure across the dose range is lower than the target exposure that we were looking for. And the target exposure that we are looking for is the range at which we expect, let's call it, therapeutic elevations of AAT levels to have occurred. Now when we think about -- well, gosh, why is there low PK? There's a standard list of things one thinks about. And yes, you're right, that healthy volunteers are different than disease patients in the fact that one's healthy and one has the disease. But there are actually a number of other fairly obvious, but nonetheless, differences.

好的，我先回答你問題的第一部分，然後我會請史都華評論一下前美國隊的情況。S.定價。所以關於 814 號研究，顯然這是一項不完整的研究。這意味著我們還沒有所有劑量組的所有患者完成整個治療期，我們正在結束這項研究並收集所有數據。從我們所能獲得的數據來看，我們發現整個劑量範圍內的暴露量低於我們所尋找的目標暴露量。我們所尋找的目標暴露範圍，就是我們預期 AAT 水準達到治療性升高的範圍內。現在我們來思考一下——哎呀，為什麼 PK 值這麼低呢？人們通常會想到一些固定的事情。是的，你說得對，健康志工與患病患者的差別在於，一個是健康的，一個是生病的。但實際上還有許多其他相當明顯但又不可忽視的差異。

Differences in age, differences in gender, diet, concomitant medicines, formulations, et cetera. So those are the kinds of things we think about. Absolutely, as we bring in all the data, we're certainly going to evaluate all of that. I think the important point, though, is that 864 is the medicine that's in Phase II, and we're looking forward to the 864 study to give us a full view of this pathway and this mechanism.

年齡差異、性別差異、飲食差異、伴隨用藥差異、製劑差異等等。所以這些都是我們會考慮的問題。當然，當我們收集到所有數據後，一定會對所有這些數據進行評估。但我認為重點是，864 是處於 II 期臨床試驗階段的藥物，我們期待 864 研究能讓我們全面了解這一途徑和機制。

You asked a question in there, before I turn it over to Stuart, about livers. There's about 100,000 people in the U.S. who have AATD and we have no evidence that they react differently to oral medicines. So I don't have any evidence of that. Stuart, over to you for the question about pricing in Europe.

在我把問題交給史都華之前，你問了一個關於肝臟的問題。美國約有 10 萬人患有 AATD，我們沒有證據表明他們對口服藥物的反應與其他族群不同。所以我沒有這方面的證據。斯圖爾特，關於歐洲的定價問題，請問你一個問題。

Yes. So Paul, I think it's important to think about the 2 types of countries that we are able to get the medicine to immediately. So the first one is countries like Germany, which provide immediate access and there, because of the structure of the German market, you get immediate access for patients at the list price, whilst you negotiate of price over the next 12 months. Whereas in contrast, countries like the U.K., Ireland, Denmark, where we negotiated prior to the approval, the negotiated price for KAFTRIO there, we are essentially selling at our final price, as it were.

是的。所以保羅，我認為重要的是要考慮我們能夠立即將藥物送到哪兩類國家。首先是像德國這樣的國家，它們提供即時准入，而且由於德國市場的結構，患者可以立即以標價獲得藥品，同時在接下來的 12 個月內協商價格。相比之下，像英國、愛爾蘭、丹麥這樣的國家，我們在獲得批准之前就與這些國家進行了談判，KAFTRIO 在那裡的談判價格，我們基本上是以最終價格出售的。

So moving forward, we're going to be entering more and more markets where we have negotiated prices. Your question was, how will the negotiated price compare, really hard to say because we haven't finalized those negotiations. But in general, I'm expecting our negotiated prices to be as they are for our other medicines, in a pretty narrow range across Europe because we know that the products provide the same value and benefit to patients no matter what country they're in.

因此，展望未來，我們將進入越來越多的市場，並在這些市場中協商價格。您的問題是，協商後的價格會如何，這很難說，因為我們還沒有最終確定協商結果。但總的來說，我預計我們協商的價格將與我們其他藥品的價格一樣，在整個歐洲範圍內保持在一個相當窄的範圍內，因為我們知道，無論患者身處哪個國家，這些產品都能為他們提供相同的價值和益處。

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

我們的下一個問題來自坎托爾的阿萊西亞·楊家族。

And I just wanted to kind of ask another one around AAT. Just can you talk about some of the scientific work that you've done to kind of address when you were formulating these molecules, kind of the efficiency that's going to be needed to kind of clear the large amount of AAT created? I know you've been very thoughtful about that. So just wanted to get some more detail on that.

我只是想問AAT附近的其他人。您能否談談您在配製這些分子時所做的一些科學研究，以解決清除大量產生的 AAT 所需的效率問題？我知道你對此考慮得很周全。所以我想了解更多細節。

Yes. Sure. Thanks. I'm going to ask David to give you some color of how we think about this molecule. I think what you're really getting to, Alethia, is that the -- AAT as a protein is an abundant protein. And I'll ask David to give you some of our insights. Obviously, we're not going to give you the answer to this question because it's a nonobvious insight that our scientists had, but David will give you some color.

是的。當然。謝謝。我將請大衛為大家詳細介紹一下我們是如何看待這個分子的。阿萊西亞，我認為你真正想表達的是－AAT 作為一種蛋白質，是一種含量豐富的蛋白質。我會請大衛向你們分享我們的一些見解。顯然，我們不會直接告訴你這個問題的答案，因為這是我們的科學家們得出的一個非顯而易見的見解，但大衛會為你提供一些細節。

Sure. Thank you for the question. One of the reasons we've been excited and remain very excited about this program is because it's the only approach that has the potential to address both the lung disease and the liver disease in this important condition. And the key thing to the question you're asking and why the solution is so promising is because although there is a lot of AAT made, 1 molecule of the drug can refold or appropriately fold, I should say, more than 1 molecule of AAT.

當然。謝謝你的提問。我們一直對這個計畫感到非常興奮，現在仍然非常興奮的原因之一是，它是唯一有可能同時解決這種重要疾病中的肺部疾病和肝臟疾病的方法。你所提問題的關鍵以及該解決方案如此有希望的原因在於，儘管AAT的產量很大，但1個藥物分子可以重新折疊或適當折疊，應該說，可以折疊超過1個AAT分子。

So it's really not a concern that we have based on all the experiments we've done in molecules and cells and animals about whether or not 1 molecule can do. And it just underscores our commitment to beyond 814 and obviously being very excited about 864, also other molecules because this mechanism has so much problem.

所以，根據我們在分子、細胞和動物身上進行的所有實驗，我們真的不必擔心一個分子能否做到什麼。這更加凸顯了我們對 814 之後的研究的承諾，我們顯然對 864 以及其他分子感到非常興奮，因為這種機制存在許多問題。

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

我們的下一個問題來自傑富瑞集團的邁克爾葉。

Great. 2-part question around AAT. I guess you can see from some of the questioning that maybe there is a hypothesis that some of it might be mechanism-based either because it's specifically a liver-targeted drug, and you're actually trying to buy in aggregates in the liver. So I guess my question is, one, how confident are you that it's not something mechanism related there other than the preclinical model since it's a liver-targeted drug, and that's actually might be related?

偉大的。關於AAT的兩部分問題。我想從一些問題中可以看出，可能存在一種假設，即其中一些問題可能基於機制，因為它是一種專門針對肝臟的藥物，而你實際上是在試圖在肝臟中購買聚集體。所以我想問的是，第一，除了臨床前模型之外，你有多大把握認為這不是其他機制相關的問題，因為這是一種靶向肝臟的藥物，而這可能確實與此有關？

And two is, I guess, how fast did it come on in 814? And do you have some degree of confidence here, at least as the early purchase of the study for 864, to make us feel just a little bit better?

其次，我想問的是，它在 814 年發展得有多快？您是否對此有一定的信心，至少作為早期購買 864 研究的成果，能讓我們稍微安心一些？

Yes. Mike, I think that the bottom line to your question is help us understand why we think this is -- this liver finding is not going to be a recurrent finding in 864. And I'm going to ask David Altshuler to comment on this important question about why we don't think that this is on mechanism. I'll just say that, Mike, the absolute bottom line, there is no way that I can promise you or that David A can promise you that with VX-864 or any molecule in our pipeline is not going to have a safety finding. There is no way to promise that.

是的。麥克，我認為你問題的關鍵在於幫助我們理解為什麼我們認為這是——這種肝臟發現不會在 864 中再次出現。接下來，我要請大衛·阿爾特舒勒就這個重要問題發表評論，即為什麼我們認為這不是一種機制。我只想說，麥克，最根本的一點是，我和大衛A 都無法向你保證，VX-864 或我們研發管線中的任何分子都不會出現安全問題。無法保證這一點。

Obviously, that is the reason we do the Phase II studies, specifically to assess safety, PK exposure and then, of course, a sense for the primary end point. But I don't believe that this is an on mechanism finding, and I'll ask David to walk you through the multiple lines of reasoning. And I think David has done that, but I'll just ask him to go through one more time. What we've seen in our animal models because we have studied this in great detail in our mouse models because we're actually evaluating the liver. David?

顯然，這就是我們進行 II 期研究的原因，專門用於評估安全性、藥物動力學暴露，當然還有主要終點。但我認為這並非單一機制的發現，我會請大衛向你解釋其中多種推理的思路。我認為大衛已經做到了，但我還是想請他再檢查一遍。我們在動物模型中觀察到的情況，因為我們在小鼠模型中對此進行了非常詳細的研究，因為我們實際上是在評估肝臟。大衛？

Thank you. And thanks a lot for the question. I mean, I think one thing I'll say before I go through that is, we have no evidence that this is a liver-targeted drug. I just want to be clear. This is a drug that acts on a protein that's expressed in the liver. And actually, one of the things we're excited about in the approach is actually AAT is not only made in the liver, it's actually made in other cells of the body. And actually, this drug is systemic. And so it would be, I think, incorrect to say this is a drug targeted to the liver, even though it does act on the liver.

謝謝。非常感謝你的提問。我的意思是，在詳細解釋之前，我想先說明一點，我們沒有證據表明這是一種針對肝臟的藥物。我只是想把話說清楚。這是一種作用於肝臟中表現的蛋​​白質的藥物。事實上，我們對這種方法感到興奮的原因之一是，AAT 不僅在肝臟中產生，而且在身體的其他細胞中也產生。實際上，這種藥物是全身性的。因此，我認為，即使這種藥物確實作用於肝臟，但說它是針對肝臟的藥物也是不正確的。

And then I think you come back to the question, and I'll just go through again, the 3 lines of logic that make us think it's premature, certainly to conclude that this is an on mechanism or because of the disease. Even though, as Reshma said, we can't know for sure. And the 3 arguments are: Most LFT abnormalities are chemical in nature, not on mechanism. The second is, we've specifically studied in mouse models, the human ZAAT protein and being corrected by this mechanism with multiple different compounds, multiple different chronic studies, and we see not liver toxicity, but improvement. And then the third is perhaps in people's minds is that the liver of a patient with AAT just somehow can't tolerate medicines. And I think that, as we know, 100,000 people have this disease, and there's no evidence we're aware of for any sort of liver toxicity associated with having AATD. So I just don't think it's the right conclusion. But -- and nonetheless, we certainly are excited for 864 in the next molecule, and we'll look forward to telling you more data as we collect it.

然後，我認為你又回到了這個問題，我再解釋一遍，這三條邏輯讓我們認為現在就斷定這是某種機製或疾病的緣故還為時過早。正如雷什瑪所說，我們無法確定。三個論點是：大多數肝功能異常本質上是化學性的，而不是機制性的。第二點是，我們專門在小鼠模型中研究了人類 ZAAT 蛋白，並利用多種不同的化合物和多種不同的慢性研究，透過這種機制對其進行了糾正，結果發現沒有肝臟毒性，反而有所改善。第三點可能是人們認為患有 AAT 的患者的肝臟無法耐受藥物。而且我認為，正如我們所知，有 10 萬人患有這種疾病，而且我們目前還沒有發現任何證據表明 AATD 與任何形式的肝毒性有關。所以我認為這並不是正確的結論。但是——儘管如此，我們當然對下一個分子中的 864 感到興奮，我們期待在收集更多數據後告訴大家。

And just a follow-up, the comment on 864 and how far you've gone and enough to feel better versus 814?

還有一個後續問題，關於 864 的評論，以及你走了多遠，感覺比 814 好多少？

Yes. Yes. Sorry about that, Mike. It's very early days. We are just in the early parts of that study. So I don't have more details for you. It's obviously a study that is going to take some time to complete, given that we expect our results in the first half of '21.

是的。是的。抱歉啊，麥克。現在還為時過早。我們目前還處於這項研究的早期階段。所以我沒有更多細節可以提供給你。顯然，這項研究需要一些時間才能完成，因為我們預計要到 2021 年上半年才能得到結果。

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

我們的下一個問題來自摩根大通的科里·卡西莫夫。

This is Turner on for Cory. So just trying to understand the ultimate opportunity for TRIKAFTA, where do you see pockets of patients that are more difficult to get on label or bring in for treatment beyond just the 10% that aren't amenable to CFTR modulators? And how do you just quantify that in the context of the estimated 68,000 CF patients eligible for TRIKAFTA? And then I have one quick follow-up.

這裡是特納為科里主持節目。所以，我只是想了解 TRIKAFTA 的最終機會，除了 10% 不適合使用 CFTR 調節劑的患者之外，您認為還有哪些患者群體更難獲得適應症或接受治療？那麼，在估計有 68,000 名囊性纖維化患者符合 TRIKAFTA 資格的情況下，如何量化這一點？最後我還有一個簡短的後續問題。

Yes. This is Reshma. I'm going to ask Stuart to comment, but I just want to make sure that we set the frame correctly. The number that we use is 75,000 total patients. I just want to make sure that we get that one clear. The 68,000 represents 90% for whom a medicine like TRIKAFTA could offer potential. The last 10% being those who need a nucleic acid approach. And the opportunity, I'm going to turn over to Stuart.

是的。這是雷什瑪。我打算請史都華發表意見，但我只想確保我們正確地設定了框架。我們使用的數字是總共75,000名患者。我只是想確保我們把這一點弄清楚。這 68,000 人佔總人口的 90%，像 TRIKAFTA 這樣的藥物可能對他們有益。最後 10% 的人需要使用核酸檢測方法。而這個機會，我將交給史都華。

Yes, Turner, thanks for the question. Based on our experience here in the U.S., which is now just over a year, and we have the vast, vast majority of patients across all eligible types, those who were naive to therapy, not even eligible for a CFTR modulator, those who were already being treated with ORKAMBI and SYMKEVI, those who had discontinued across all of those groups, we have seen very, very strong uptake. And so I really can't identify you -- for you a group of patients that we have to date found that it is more difficult to be initiated on TRIKAFTA.

是的，特納，謝謝你的提問。根據我們在美國一年多的經驗，我們擁有絕大多數符合條件的患者，包括那些從未接受過治療、甚至不符合 CFTR 調節劑治療條件的患者，以及那些已經接受 ORKAMBI 和 SYMKEVI 治療的患者，還有所有這些群體中已經停止治療的患者，我們都看到了非常非常強勁的接受度。因此，我真的無法確定你——對於我們迄今為止發現的一組患者來說，開始使用 TRIKAFTA 更加困難。

In terms of future growth, we address some of that in my prepared remarks, obviously, with the approval of KAFTRIO, we're now hoping to replicate what we've done with TRIKAFTA here in the U.S. with KAFTRIO in the EU. We are encouraged by the early trends in Germany and the U.K. and Ireland, where we already have access for patients. And that is clearly important, we need to secure similar reimbursement agreements across the rest of Europe to be able to access those patients. So that is obviously a first step to getting access for those patients we don't have reimbursement for today. And then as we said, in total, if you count those patients and additional patients who we can get to through expanding the KAFTRIO label to other countries like Australia, to going to younger age groups with TRIKAFTA and KAFTRIO, such as the 6- to 11-year olds, and then further expanding our entire CF portfolio to younger patients and also to other mutations like the rare mutations. In aggregate, in addition to what we've already been able to deliver, we think there's over 20,000 more patients that we will be able to benefit. And so we continue to feel good about where we are but we know the job is not done, and we have a long way to go to make sure that 90% of patients that are going to be eligible for CFTR modulators have the ability to try one. And then, as Reshma said, in addition to that, we're continuing to work hard to develop new medicines and new interventions for the 10% who won't benefit from the CFTR modulator.

關於未來的發展，我在準備好的演講稿中已經談到了一些，顯然，在 KAFTRIO 的批准下，我們現在希望將我們在美國透過 TRIKAFTA 取得的成就複製到歐盟的 KAFTRIO 上。德國、英國和愛爾蘭的早期趨勢令我們感到鼓舞，我們已經在這些地區為患者提供了治療機會。這點顯然很重要，我們需要在歐洲其他地區達成類似的報銷協議，才能接觸到這些患者。所以這顯然是讓那些目前無法獲得報銷的患者獲得醫療服務的第一步。正如我們所說，總的來說，如果你把這些患者以及我們通過將 KAFTRIO 標籤擴展到其他國家（如澳大利亞）而能夠接觸到的其他患者，再把 TRIKAFTA 和 KAFTRIO 推廣到更年輕的年齡組（如 6 至 11 歲兒童），然後進一步將我們的整個 CF 產品組合擴展到更年輕的患者以及其他突變（如多突變），那麼我們接觸到更多的患者。總的來說，除了我們已經能夠提供的服務之外，我們認為還將有超過 20,000 名患者從中受益。因此，我們對目前的狀況感到滿意，但我們知道這項工作還沒有完成，我們還有很長的路要走，才能確保 90% 符合 CFTR 調節劑使用條件的患者有機會嘗試這種藥物。此外，正如雷什瑪所說，我們還在繼續努力為那 10% 無法從 CFTR 調節劑中受益的患者開發新藥和新療法。

That's helpful. And then just understanding that you're bringing in the remaining 814 data. Is there a potential chance that we get a glimpse at the data prior to seeing 864 results as we're just trying to benchmark 864 for ourselves? If so, to what extent of the data could we potentially see? Or alternatively, do you plan on publishing preclinical 814 data?

那很有幫助。然後，你只需要明白你正在匯入剩餘的 814 個資料。我們能否在看到 864 的結果之前先了解一下數據，因為我們只是想自己對 864 進行基準測試？如果屬實，我們可能看到的資料範圍有多廣？或者，您是否計劃發表 814 項臨床前數據？

Yes. Yes. All really great questions. Obviously, we're going to bring all the data in from the VX-814 program as we close that out. Again, the key finding there is that we have low exposure, and we didn't achieve the target range. So I don't have high expectations that the data is going to be informative. I think the key thing to look forward to is VX-864, and those results. And we certainly are working expeditiously to get that trial enrolled and to be able to see those results. And as I said before, that should be available in the first half of '21.

是的。是的。這些問題都非常好。顯然，在結束 VX-814 專案時，我們會把該專案的所有資料都匯入進來。再次強調，關鍵發現是我們曝光度低，沒有達到目標範圍。所以我並不指望這些數據能提供什麼有用的資訊。我認為最值得期待的是 VX-864 以及它的結果。我們當然正在加緊努力，爭取盡快完成試驗招募，並能看到試驗結果。正如我之前所說，這應該會在 2021 年上半年推出。

Our next question comes from the line of Mohit Bansal from Citigroup.

我們的下一個問題來自花旗集團的莫希特·班薩爾。

And maybe switching a little bit to FSGS. So given that it is a small trial and relatively short, is it possible that we could see that data even before the AAT data? I mean, this trial did not stop because of COVID. And the follow-up question is, APOL1 mutation is implicated in many kidney diseases. So if this first compound were to be successful, do you have any plans to go into those broader indications like lupus nephropathy and other indications?

或許可以稍微轉向FSGS。鑑於這是一項規模較小且時間相對較短的試驗，我們是否有可能在 AAT 數據之前看到該試驗數據？我的意思是，這場審判並沒有因為新冠疫情而停止。後續問題是，APOL1 突變與許多腎臟疾病有關。如果第一個化合物獲得成功，您是否有計劃將其應用於更廣泛的適應症，例如狼瘡性腎臟疾病和其他適應症？

Yes. Mohit, thanks so much for the question about FSGS. So with regard to the trial, you're right, it's a reasonably efficient trial, a dozen or so patients. It is a longer duration trial than the AATD program. It's a 12-week trial. So there's a difference there. And it's a little bit early to call for both the 864 program and the VX-147 program, when exactly the results will be available. They're both studies that are active, enrolling and we're dosing patients, but it's just a little bit too early to call.

是的。莫希特，非常感謝你提出關於FSGS的問題。所以關於試驗，你說得對，這是一項相當有效的試驗，大約有十幾名患者。這項試驗的持續時間比 AATD 項目更長。這是一項為期 12 週的試驗。所以這兩者之間是有差別的。現在就對 864 計劃和 VX-147 計劃下結論還為時過早，具體結果何時公佈還有待觀察。這兩項研究都在積極進行中，正在招募患者並進行給藥，但現在下結論還為時過早。

I'll just point out on that one, the FSGS program, the endpoint there is proteinuria and as you know, there have been multiple discussions between the community and regulatory agencies. And that does seem to be a very acceptable endpoint to the agency. So I'm particularly eager to look at those results.

關於 FSGS 項目，我只想指出一點，該項目的終點是蛋白尿，正如您所知，社區和監管機構之間已經進行了多次討論。而且，這似乎也是該機構可以接受的最終結果。所以我特別想看看這些結果。

I'm going to ask David Altshuler to tell you a little bit more about APOL1-mediated kidney disease. Although I am the nephrologist here, some people tease that this is one of David's most favorite program. So I'll let him tell you about a couple more APOL1-mediated kidney disease that we are looking at. David, do you want to just quickly talk about that?

我將請大衛‧阿爾特舒勒（David Altshuler）為大家詳細介紹一下APOL1介導的腎臟疾病。雖然我是這裡的腎臟科醫生，但有些人開玩笑說這是大衛最喜歡的節目之一。那麼，就讓他來跟大家介紹一下我們正在研究的另外幾種由 APOL1 介導的腎臟疾病吧。大衛，你想簡單談談這件事嗎？

Absolutely. APOL1 strikes us as a really compelling target for the strategy of using human genetics and genetically validated targets to go over after major unmet needs. And you've got the strategy right because the idea is to first go into FSGS, which is a severe disease, very strongly driven in certain populations by APOL1 genotype. But in addition, there are many, many patients with nondiabetic kidney disease with other forms of proteinuric kidney for which APOL1 is a driver. And so certainly, we first need to get proof-of-concept for the mechanism and figure it out, but it would be our expectation if that succeeds that we would be able to go into a variety of other indications. And it's really one of the most unusual and compelling common genetic risk factors with a major effect on a disease -- proteinuric kidney disease for which there is great unmet need.

絕對地。APOL1 對我們來說是一個非常有吸引力的目標，可以採用人類遺傳學和基因驗證標靶的策略來滿足重大未滿足的需求。你的策略是對的，因為我們的想法是先研究 FSGS，這是一種嚴重的疾病，在某些人群中，APOL1 基因型對其影響很大。此外，還有許多患有非糖尿病腎病變和其他類型蛋白尿腎病變的患者，APOL1 是這些疾病的驅動因素。因此，我們首先需要驗證該機制的概念並弄清楚它，但如果成功的話，我們期望能夠進一步研究其他各種適應症。而且，這確實是最不尋常、最引人注目的常見遺傳風險因素之一，對一種疾病——蛋白尿腎病變——有重大影響，而這種疾病目前存在巨大的未滿足需求。

Our next question comes from the line of Gena Wang from Barclays.

我們的下一個問題來自巴克萊銀行的王嘉娜。

And I'm sorry, I also have to ask one more question about AATD. So David, you did mention there are 3 possible reasons. One being as a small molecule, but 864 also small molecule, could you help us understand a little bit regarding what you see between healthy volunteers? Anything differences in terms of exposure and the drug dose that will make you feel more confident that 864 will show better clinical profile?

抱歉，我還要再問一個關於AATD的問題。大衛，你確實提到有 3 個可能的原因。其中一種是小分子，但 864 也是小分子，您能否幫助我們了解您在健康志願者之間觀察到的情況？在藥物暴露量和劑量方面是否有任何差異，能夠讓您更有信心認為 864 會展現出更好的臨床療效？

And my second question is regarding the beta-thalassemia sickle cell program. And so should we expect the lay break abstract at ASH? And also, will we see the data beyond 7 patients that announced? And also, what would be the plan for the registration path from here?

我的第二個問題是關於β-地中海貧血鐮狀細胞疾病治療方案的。那麼，我們是否應該期待ASH會議上出現非專業人士參與的摘要呢？另外，我們是否會看到除已公佈的7名患者之外的其他數據？另外，接下來的註冊流程規劃是什麼？

Gena, I think you managed to get 3 questions in there. I know we're coming up on the hour. Let me quickly tackle the CTX001 question, and I'll ask David to -- I think you're really asking about differences between 814 and 864. And I'll ask David to give you a quick comment on that.

吉娜，我覺得你成功地問了三個問題。我知道我們快到整點了。讓我快速回答一下 CTX001 的問題，我會請 David 來回答——我認為你真正想問的是 814 和 864 之間的差異。我會請大衛就此簡單談談他的看法。

So you should expect to see more data from the CTX001 program. You should expect to see data in more patients and longer duration of follow-up in both beta-thalassemia and sickle cell disease. And we'll just have to be a little bit more patient with regard to the exact venue of those data.

因此，您應該會看到來自 CTX001 專案的更多資料。預計在β地中海貧血和鐮狀細胞疾病方面，將有更多患者的數據和更長的追蹤時間。至於這些數據的具體發布地點，我們還需要多一些耐心。

David, do you have a quick question on 814, 864 that you haven't already commented on?

David，關於 814、864 這幾個問題，你還有什麼尚未評論過的問題嗎？

All I would say is we were saying about the idea of LFT abnormalities being chemical specific, we meant specific to the particular molecule. And 864 being structurally different than 814, we would not necessarily expect to see the same kind of problems again.

我只想說，我們之前討論的肝功能異常具有化學特異性，指的是對特定分子具有特異性。864 的結構與 814 不同，因此我們不一定會再看到相同的問題。

Our next question comes from the line of Robyn Karnauskas from Truist.

我們的下一個問題來自 Truist 的 Robyn Karnauskas。

This is Kripa on for Robyn. I had a question about your diabetes program, whereas when you talked about 2 different types of opportunities. Can you tell us where you are in terms of time lines for the device? How much work is left before you can think of moving into patients and does the IND that you expect to file cover both of those opportunities? Are you looking at them as independent programs? Or do you believe that they have to be done in sequence?

這裡是Kripa為Robyn報道。我有一個關於你們糖尿病計畫的問題，當時你們談到了兩種不同的機會。能告訴我們一下該設備目前的研發進度嗎？在考慮進入臨床階段之前，還有多少工作要做？您預計提交的IND申請是否涵蓋了這兩個機會？你們是把它們當作獨立的項目來看待嗎？或者你認為它們必須按順序進行？

Yes. Yes, sure. I really appreciate the question and the opportunity to talk a little bit more about the type 1 diabetes program. I think you've characterized it correctly. I see this opportunity as 2 shots on goal. The first and the one we're starting with is, let's call it, naked cells. That's the IND that's going in by the end of this year. And that's the program I anticipate will be in the clinic in 2021. The kinds of patients that the naked cells could serve as an example, there are a few thousand people who have what are called SHEs or severe hypoglycemic episodes. Now while diabetes certainly has the morbidity when you have hyperglycemia that are nephropathy, neuropathy and retinopathy, that takes years to develop. These SHEs can kill you because you become severely hypoglycemic with lack of awareness. So that's one group of patients this could serve.

是的。當然可以。我非常感謝您的提問，也感謝您給我這個機會，讓我能更詳細地談談第 1 型糖尿病計畫。我認為你的描述很準確。我認為這是兩次射門機會。首先，也是我們開始討論的，是裸露的細胞。這是今年底前要推出的IND。我預計該方案將於 2021 年在診所實施。裸露細胞可以作為這類患者的一個例子，有數千人患有所謂的 SHE 或嚴重低血糖發作。雖然糖尿病在高血糖時確實會導致腎臟病、神經病變和視網膜病變等疾病，但這些疾病需要數年才會發展。這些SHE（嚴重低血糖症）會致命，因為你會在缺乏意識的情況下出現嚴重的低血糖症。所以，這便是這項技術可以服務的患者群之一。

And the second group of patients, obviously, are people, for example, who are type 1 diabetics who are post kidney transplant who are already on immunosuppressive medicine. So that is the naked cell alone program. But clearly, the high fruit and the biggest population we could serve is the population that could have the cells encapsulated in the device. And that's the second program that we're going to bring forward in.

第二組患者顯然是指例如第 1 型糖尿病患者，他們已經接受了腎臟移植手術，並且正在服用免疫抑制藥物。這就是裸細胞單獨運作的程序。但很顯然，我們能夠獲得的最高收益和最大受益人群是那些細胞能夠被封裝在設備中的人群。這是我們即將推出的第二個項目。

I look forward to telling you more about it as the months go by. But the one to look out for now is the IND for the naked cell program.

隨著時間的推移，我期待著向你詳細介紹這件事。但現在最值得關注的是裸細胞計畫的IND申請。

Operator, we're coming right up on the hour, so we'll take 2 more quick questions.

接線員，馬上就要到整點了，我們再快速回答兩個問題。

Then our next question comes from the line of Geoffrey Porges, Leerink.

那麼，我們的下一個問題來自 Geoffrey Porges 的 Leerink 系列。

Reshma, so you have $6.2 billion in cash on the balance sheet. You're generating about close to $1.25 billion in free cash flow it seems, or you will be by the end of the year. So hypothetically, let's say that you could have $12 billion in cash on your balance sheet in the middle of next year. Could you give us an idea how you plan to deploy that capital? You've had questions on the call about business development activity, but that's a huge amount of cash, and you have no debt. So what are you thinking of doing?

Reshma，所以你的資產負債表上有 62 億美元的現金。看來你們的自由現金流已經接近 12.5 億美元，或者到年底就會達到這個數字。假設到明年年中，你的資產負債表上將擁有 120 億美元的現金。您能否簡要說明一下您計劃如何運用這筆資金？在電話會議中，有人問到了業務拓展活動的問題，但那是一大筆現金，而且你沒有任何債務。所以你打算怎麼做？

Yes. Jeff, thanks for the question. And as you point out, this is -- you're asking a question that's broader than business development and about capital allocation. Let me make a high level statement, and then I'm going to ask Charlie to also chime in.

是的。傑夫，謝謝你的提問。正如你所指出的，你提出的問題比業務發展和資本配置的範圍更廣。我先做一個概括性的陳述，然後我會請查理也補充幾句。

We are very pleased with the way the business is progressing. We are very pleased with the strength of our balance sheet. And we recognize that this is a really favorable position to be in. We believe at our core, that the best deployment of our capital is in innovation.

我們對公司目前的業務發展狀況非常滿意。我們對公司穩健的資產負債表非常滿意。我們意識到，我們處於非常有利的地位。我們堅信，資本的最佳運用方式是創新。

And I'm going to turn it over to Charlie to give you a sense of how we specifically think about that. Charlie?

接下來我將把麥克風交給查理，讓他來具體談談我們是如何看待這個問題的。查理？

Yes. Thanks, Reshma. Jeff, I appreciate the question. Really, the strength of the business, of course, with the growth and the profitability, we do generate a lot of cash flow, as you point out. And so naturally, we are very focused on capital allocation. As Reshma highlights, we clearly believe that the best use of capital is to invest in innovation. And you've seen us be very active over the last 2 years in BD, gaining access to important platform technologies and capabilities as well as assets that have really helped us broaden and deepen the pipeline, importantly, with Semma and Exonics. So looking ahead, you can expect that we'll continue to be active. The BD team is very active. And we have, as you point out, the balance sheet capacity and flexibility to do more and potentially do bigger deals. But importantly, we do intend to stay very close to our corporate and our research strategy because we feel that for BD specifically, that is the best opportunity for us to add value, and drive ROI over the long term.

是的。謝謝你，雷什瑪。傑夫，感謝你的提問。當然，正如您所指出的，業務實力強勁，成長迅速，獲利能力強，確實能產生大量現金流。因此，我們自然非常關注資本配置。正如雷什瑪所強調的，我們堅信，資本的最佳用途是投資於創新。在過去的兩年裡，您已經看到我們在業務拓展方面非常活躍，獲得了重要的平台技術和能力以及資產，這確實幫助我們拓寬和深化了產品線，尤其是在與 Semma 和 Exonics 的合作中。展望未來，您可以期待我們將繼續保持活躍。業務拓展團隊非常活躍。正如您所指出的，我們擁有足夠的資產負債表能力和靈活性，可以做更多的事情，並有可能進行更大的交易。但重要的是，我們打算與公司和研究策略保持緊密聯繫，因為我們認為，對於 BD 而言，這是我們增加價值並在長期內推動投資回報率的最佳機會。

And our final question for today comes from the line of Evan Seigerman from Crédit Suisse.

我們今天的最後一個問題來自瑞士信貸的 Evan Seigerman。

I'll be quick. So in KOL calls, I've gotten very positive feedback on curative approaches to sickle cell disease and beta-thalassemia. Do you have any color as to what you might need to show at a pivotal or registration-directed trial in terms of efficacy or a follow-up, just to give us a sense as to when that could potentially be part of the Vertex commercial story?

我會盡快。因此，在與 KOL 的通話中，我收到了關於鐮狀細胞疾病和β地中海貧血症治療方法的非常積極的回饋。您能否透露一下，在關鍵性試驗或註冊試驗中，您可能需要在療效或後續研究方面證明哪些內容？這樣我們就能了解這何時可能成為 Vertex 商業故事的一部分。

I didn't catch the tail end of the question, but I think you're really asking about CTX001 in beta-thalassemia and sickle cell disease and how we see the registrational approach. It's a little bit too early to call exactly the number of patients, the duration of follow-up and the -- what exactly the regulators will require.

我沒聽清問題的後半部分，但我認為你真正想問的是 CTX001 在 β-地中海貧血和鐮狀細胞病中的應用，以及我們如何看待註冊方法。現在要準確預測患者人數、追蹤時間以及監管機構的具體要求還為時過早。

That being said, clearly, the results that we've shared from the summer are exceptional. And while very small in number, 2 people in beta-thal, 1 in sickle cell, they do represent, in essence, a functional cure for those patients. We also have secured multiple regulatory designations like Prime and RMAT, Fast Track, et cetera, that give us the opportunity to have conversations with regulators. And that is, of course, very helpful. So I think that the studies that we're doing are exactly the right ones, in the right patients. So for example, in beta-thalassemia, what I mean specifically is patients who are both beta 0, beta 0 and nonbeta 0 for the beta-thalassemia side. And for the sickle cell side, patients who are severe sickle cell patients with multiple VOCs over 1- to 2-year period. And I'm really very much looking forward to those regulatory interactions. In a little bit more time, we will be able to come back to you and let you know specifically what those packages look like after we have the opportunity to work through that with regulators.

也就是說，很顯然，我們夏季公佈的成果非常出色。雖然人數很少（2 名 β 地中海貧血患者，1 名 鐮狀細胞貧血患者），但從本質上講，它們確實代表了對這些患者的一種功能性治癒。我們還獲得了多個監管資格認證，如 Prime 和 RMAT、Fast Track 等，這使我們有機會與監管機構進行對話。這當然非常有幫助。所以我認為我們正在進行的研究非常正確，研究對像也完全正確。例如，在β-地中海貧血中，我具體指的是β-地中海貧血側同時存在β0、β0和非β0的患者。對於鐮狀細胞疾病患者，指的是 1 至 2 年內多次發生 VOC 的重度鐮狀細胞疾病患者。我非常期待與監管機構進行這些互動。再過一段時間，我們將有機會與監管機構協商解決相關事宜，屆時我們將能夠回覆您，並具體告知您這些方案的具體內容。

Okay. Thank you, everybody, for joining us on the call tonight and on the webcast. We appreciate it. The Investor Relations team, if you have additional questions, is available tonight. Please reach out to us. We'd be happy to help.

好的。感謝各位今晚參加電話會議及網路直播。我們很感激。如有其他疑問，投資者關係團隊今晚隨時為您解答。請與我們聯絡。我們很樂意提供協助。

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

感謝各位女士、先生參加今天的會議。節目到此結束。您現在可以斷開連線了。再會。