福泰製藥 (VRTX) 2018 Q3 法說會逐字稿

Welcome to the Vertex Third Quarter 2018 Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Tonight, we will review our financial results, our continued progress to develop new medicines for all people with cystic fibrosis and recent advances in our research and development pipeline. Dr. Jeff Leiden, Chairman and CEO; and Ian Smith, Chief Operating Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer; and Dr. Reshma Kewalramani, Chief Medical Officer, will join us for Q&A. We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded. A replay will be available on our website.

歡迎參加 Vertex 2018 年第三季電話會議。這是 Vertex 公司投資者關係資深副總裁 Michael Partridge。今晚，我們將回顧我們的財務表現、為所有囊性纖維化患者開發新藥的持續進展以及我們研發管線的最新進展。董事長兼執行長傑夫萊頓博士和營運長伊恩史密斯將於今晚發表準備好的演講。首席商務官斯圖爾特·阿巴克爾和首席醫療官雷什瑪·凱瓦拉馬尼博士將參加問答環節。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。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, 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. I'm pleased to say that we have made tremendous progress across our business in 2018 and are well on track to achieve the key goals that we outlined to start this year. In CF, approximately half of all patients are now eligible for a Vertex CF medicine, and we're progressing rapidly toward the development of a single medicine to treat any CF patient with one or more F508del mutations, approximately 90% of all people with the disease.

謝謝你，麥可。各位晚上好。我很高興地宣布，2018 年我們的業務取得了巨大的進步，並且正朝著我們年初制定的關鍵目標穩步前進。目前，大約一半的 CF 患者符合 Vertex CF 藥物的使用條件，我們正在快速開發一種單一藥物，用於治療任何攜帶一個或多個 F508del 突變的 CF 患者，約佔所有 CF 患者的 90%。

In our development pipeline, we have initiated the first clinical study of CTX001 in beta-thalassemia with our partner CRISPR Therapeutics and are progressing VX-150 for the treatment of pain. And in research, we're preparing to advance the first of our potential medicines for alpha-1 antitrypsin deficiency into clinical development by year-end and to move other molecules into development in 2019.

在我們的研發管線中，我們已與合作夥伴 CRISPR Therapeutics 啟動了 CTX001 在 β-地中海型貧血的首個臨床研究，並且正在推進 VX-150 用於治療疼痛的研發。在研究方面，我們正準備在年底前將我們首個用於治療α-1抗胰蛋白酶缺乏症的潛在藥物推進到臨床開發階段，並在2019年將其他分子推進到開發階段。

First, to our recent progress in cystic fibrosis. CF is a progressive multi-organ disease that is present from birth and a key part of our strategy is to treat patients as early as possible to slow or prevent the progression of disease. To that end, we gained important approvals throughout 2018 that now allow us to treat eligible children as young as 1 year of age with KALYDECO and as young as 2 years of age with ORKAMBI.

首先，談談我們最近在囊性纖維化方面的進展。囊性纖維化是一種先天性多重器官進行性疾病，我們治療策略的關鍵在於儘早治療患者，以減緩或阻止疾病的進展。為此，我們在 2018 年獲得了重要的批准，現在我們可以使用 KALYDECO 治療 1 歲及以上的符合條件的兒童，使用 ORKAMBI 治療 2 歲及以上的符合條件的兒童。

With SYMDEKO, demand continues to be strong following the U.S. approval in February. The launch of this medicine in the U.S. has been a significant driver of revenue growth in 2018 as new patients initiate treatment. And we also plan to submit a supplemental New Drug Application to the FDA later this year to gain approval in eligible patients as young as 6 years of age.

自 2 月獲得美國批准以來，SYMDEKO 的需求依然強勁。該藥物在美國的上市是 2018 年收入成長的重要驅動力，因為許多新患者開始接受治療。我們還計劃在今年稍後向 FDA 提交補充新藥申請，以獲得批准用於年僅 6 歲的合格患者。

In Europe, we anticipate approval of this medicine before the end of this year, which will further increase the number of patients eligible to be treated with the medicine for the underlying cause of their disease.

在歐洲，我們預計該藥物將在今年年底前獲得批准，這將進一步增加符合條件使用該藥物治療其疾病根本原因的患者人數。

We've also reached multiple important reimbursement agreements across the world to provide access to ORKAMBI, enabling patients in many countries to treat the underlying cause of the disease for the first time. Many of these agreements, including those recently signed in Denmark and Australia also provide a pathway to access and rapid reimbursement for certain future CF medicines. Importantly, these portfolio agreements provide certainty to patients that they will have immediate access to future innovations in CF from Vertex. We remain in discussions regarding this type of agreement in other countries that have yet to reimburse ORKAMBI.

我們也與世界各地達成了多項重要的報銷協議，使許多國家的患者能夠首次獲得 ORKAMBI 治療，從而治療該疾病的根本原因。這些協議中有很多，包括最近在丹麥和澳洲簽署的協議，也為未來某些囊性纖維化藥物的取得和快速報銷提供了途徑。重要的是，這些投資組合協議為患者提供了確定性，即他們將立即獲得 Vertex 公司在囊性纖維化治療方面的未來創新成果。我們仍在與其他尚未向 ORKAMBI 支付補償的國家就此類協議進行磋商。

We're also rapidly progressing our 2 Phase III programs, evaluating 2 different triple combination regimens that include a next-generation corrector, either VX-659 or VX-445. In September, we completed the enrollment of the 2 Phase III studies for the VX-659 triple combination regimen and expect data from these studies in late 2018. We expect to complete enrollment for the VX-445 Phase III studies this quarter and to report data from these studies in the first quarter of 2019.

我們也在快速推進我們的 2 個 III 期項目，評估 2 種不同的三聯療法，其中包括下一代矯正劑 VX-659 或 VX-445。9 月，我們完成了 VX-659 三聯療法的 2 項 III 期研究的入組工作，預計將於 2018 年底獲得這些研究的數據。我們預計將在本季完成 VX-445 III 期研究的入組工作，並於 2019 年第一季公佈這些研究的數據。

We will evaluate data from both programs with the goal of choosing the best regimen to submit for regulatory approval. We remain on track to submit a New Drug Application for a triple combination regimen no later than mid-2019. In parallel, we've also recently initiated studies with both of our triple combination regimens in patients ages 6 to 11 years of age with the goal of gaining approval for this group of children as quickly as possible.

我們將評估這兩個項目的數據，以期選擇最佳方案提交監管部門批准。我們仍按計畫推進，最遲將於 2019 年年中提交三聯療法的新藥申請。同時，我們最近也針對 6 至 11 歲的患者啟動了兩種三重療法的研究，目標是盡快獲得該年齡層兒童的批准。

We also continue to innovate in CF to develop even better regimens for the future, including potential once daily triple combination regimens with our potentiator, VX-561, in regimens that contain other next-generation correctors that may have enhanced profiles. We expect to advance one or more of these novel, next-generation correctors into early clinical development in the coming months.

我們也在 CF 領域不斷創新，以開發更好的未來治療方案，包括潛在的每日一次的三重療法，其中包含我們的增效劑 VX-561，以及其他可能具有增強療效的下一代矯正劑。我們預計在未來幾個月內，將一種或多種新型的下一代矯正器推進到早期臨床開發階段。

Beyond CF, our research strategy is well-defined and focused on the development of transformational medicines for serious specialty diseases with large unmet medical need. And we're advancing a portfolio of such potential new medicines into the clinic. The diseases we are targeting all have well understood biology where we can use or create early clinical markers that support the potential for transformative benefit and rapid development time lines.

除了囊性纖維化之外，我們的研究策略也十分明確，專注於開發針對嚴重專科疾病的變革性藥物，這些疾病存在巨大的未滿足醫療需求。我們正在推進一系列此類潛在新藥進入臨床試驗階段。我們所針對的疾病的生物學特性都已得到充分研究，我們可以利用或創建早期臨床標誌物，以支持變革性療效和快速研發進程。

We are establishing proprietary, scientific insights into a number of these diseases, just as we did in CF and CFTR. And we are bringing significant resources to bear to both advance our development-stage assets and also to bring other potential new medicines from research into early clinical studies.

我們正在針對其中許多疾病建立專有的科學見解，就像我們在 CF 和 CFTR 中所做的那樣。我們正在投入大量資源，既推進我們處於研發階段的資產，也推動其他潛在的新藥從研究階段進入早期臨床研究階段。

With our partner CRISPR Therapeutics, we're advancing CTX001 as the first gene editing treatment for both sickle cell disease and beta-thalassemia using the CRISPR-Cas9 technology. This is a cutting-edge, transformational technology that holds great promise in the treatment of many diseases, and we're pleased with the rapid progress we are making together with CRISPR toward dosing the first patient with a CRISPR-Cas9 gene editing therapy.

我們與合作夥伴 CRISPR Therapeutics 一起，正在推進 CTX001 的研發，使其成為首個利用 CRISPR-Cas9 技術治療鐮狀細胞疾病和 β 地中海貧血的基因編輯療法。這是一項尖端、變革性的技術，在治療許多疾病方面具有巨大的潛力，我們很高興與 CRISPR 一起在為第一位患者使用 CRISPR-Cas9 基因編輯療法方面取得快速進展。

Our pain program is another example of Vertex's innovative science translating to the clinic, where Phase II data generated to date for VX-150 provided the first clinical validation for the sodium channel 1.8 mechanism in the treatment of acute and chronic pain. We expect to have Phase II results for VX-150 in the third type of pain, neuropathic pain, in early 2019.

我們的疼痛治療方案是 Vertex 創新科學轉化為臨床應用的又一例證，迄今為止 VX-150 的 II 期數據首次驗證了鈉通道 1.8 機制在治療急性和慢性疼痛方面的臨床應用。我們預計將於 2019 年初獲得 VX-150 治療第三種疼痛類型（神經性疼痛）的 II 期臨床試驗結果。

We now also plan to initiate a Phase IIb dose-ranging study of VX-150 in acute pain following bunionectomy surgery that has the potential to support future pivotal development of this medicine in acute pain. Acute pain represents a multibillion-dollar opportunity where many of the conditions that lead to acute pain are treated by physicians that can be reached with a specialty sales force.

我們現在還計劃啟動一項 IIb 期劑量範圍研究，研究 VX-150 在拇外翻切除術後急性疼痛中的療效，這有可能支持該藥物未來在急性疼痛治療​​方面的關鍵性開發。急性疼痛是一個價值數十億美元的市場，許多導致急性疼痛的疾病都可以由醫生治療，而專業的銷售團隊可以接觸到這些醫生。

Given the significant need for highly efficacious pain medicines that do not have the addiction, tolerability and abuse issues associated with opioids, acute pain is an opportunity that is well-suited to inhibitors of the NaV1.8 sodium channel, and we're also continuing to invest in the discovery of other potential pain molecules, including additional NaV1.8 inhibitors as well as medicines targeting other new mechanisms.

鑑於目前對高效止痛藥的巨大需求，以及這些藥物不具有阿片類藥物相關的成癮性、耐受性和濫用問題，急性疼痛是一個非常適合使用 NaV1.8 鈉通道抑製劑的機會，我們也將繼續投資於其他潛在止痛分子的發現，包括其他 NaV1.8 抑製劑以及針對其他新機制的藥物。

We're also advancing a portfolio of small molecule correctors for the treatment of alpha-1 antitrypsin deficiency or AAT. And I'm pleased to report that we expect to move the first of these compounds into clinical development later this year. There are many similarities between AAT and CF, both in the biology of the disease and how we may target its cause and in the potential to establish early clinical proof of concept and rapid development pathways for new AAT medicines.

我們也正在推進一系列用於治療α-1抗胰蛋白酶缺乏症（AAT）的小分子矯正劑的研發。我很高興地宣布，我們預計將於今年稍後將其中第一種化合物推進臨床開發。AAT 和 CF 之間有許多相似之處，無論是疾病的生物學特性，還是我們如何針對其病因進行治療，以及建立早期臨床概念驗證和快速開發新 AAT 藥物的途徑的潛力。

Like CF, AAT is a protein folding disorder caused by mutations in a single gene where more than 90% of patients have one common mutation that results in life-shortening, systemic complications primarily in the lung, but also in the liver. We believe our scientific expertise with CFTR protein folding, coupled with our development experience, position us well to rapidly advance our novel small molecule approach to the treatment of AAT.

與 CF 類似，AAT 是一種蛋白質折疊障礙，由單一基因的突變引起，其中 90% 以上的患者都存在一種常見的突變，導致壽命縮短，並出現全身性併發症，主要影響肺部，但也可能影響肝臟。我們相信，我們在 CFTR 蛋白折疊方面的科學專長，加上我們的研發經驗，使我們能夠快速推進我們治療 AAT 的新型小分子方法。

I look forward to updating you on this program as we enter development later this year and to providing additional insight into our research programs, including those in focal segmental glomerulosclerosis and others as they progress in 2019.

我期待在今年晚些時候，隨著我們進入開發階段，向您匯報該項目的最新進展，並向您提供更多關於我們研究項目的見解，包括局灶節段性腎小球硬化症和其他研究項目在 2019 年的進展情況。

As we move our internal R&D pipeline forward, we're also continuously evaluating external opportunities where our research and business development strategies are fully aligned. With our strong financial profile, we have increased ability to in-license or acquire assets or establish scientific collaborations that provide access to unique product opportunities and technology platforms.

在推動內部研發專案的同時，我們也不斷評估外部機會，以確保我們的研發和業務發展策略完全契合。憑藉我們雄厚的財務實力，我們有能力引進或收購資產，或建立科學合作，從而獲得獨特的產品機會和技術平台。

We've completed a number of such transactions in recent years, and we've expanded our internal team devoted to finding and evaluating potential opportunities for scientific innovation with the goal of further broadening our pipeline and scientific expertise in the future.

近年來，我們完成了許多此類交易，並擴大了致力於尋找和評估潛在科學創新機會的內部團隊，目標是在未來進一步拓寬我們的產品線和科學專業知識。

We believe that it is a combination of our R&D strategy with our business model that truly differentiates Vertex as a biotechnology company with the potential for highly profitable, long-term growth based on a portfolio of transformative medicines for multiple serious diseases. This year has been marked by significant progress across research and development and in our efforts to bring our CF medicines to more patients globally, which has led to significant growth in our revenues and earnings, which Ian will now discuss in more detail.

我們相信，正是我們的研發策略與商業模式的結合，才真正使 Vertex 成為一家具有高利潤、長期成長潛力的生物技術公司，這得益於我們針對多種嚴重疾病的變革性藥物組合。今年，我們在研發方面取得了顯著進展，並努力將我們的 CF 藥物帶給全球更多患者，這帶來了收入和利潤的顯著增長，Ian 接下來將對此進行更詳細的討論。

Thanks, Jeff, and good evening to everyone. I'm pleased to review with you our third quarter 2018 financial results and to discuss our outlook for future financial growth as we approach 2019.

謝謝你，傑夫，大家晚上好。我很高興與各位一起回顧我們 2018 年第三季的財務業績，並探討我們在 2019 年到來之際對未來財務成長的展望。

Revenues first. Total CF product revenues of $783 million in the third quarter of 2018 represent a 42% increase compared to the $550 million we recorded in the third quarter of 2017. We continue to see significant revenue growth as we increase the number of patients treated with our medicines globally.

收入優先。2018 年第三季 CF 產品總營收為 7.83 億美元，比 2017 年第三季的 5.5 億美元成長了 42%。隨著全球範圍內使用我們藥物治療的患者人數不斷增加，我們的收入也持續顯著增長。

The third quarter included $255 million in revenues from the launch of SYMDEKO in the U.S., which is the primary driver of the rapid growth in our total CF revenues. Demand for SYMDEKO remains strong, and we continue to receive positive feedback from patients and physicians and strong coverage for SYMDEKO across both public and private payers.

第三季營收為 2.55 億美元，這主要得益於 SYMDEKO 在美國的上市，也是我們 CF 總營收快速成長的主要動力。SYMDEKO 的需求仍然強勁，我們不斷收到患者和醫生的正面回饋，SYMDEKO 在公共和私人支付方中也獲得了強有力的覆蓋。

Similar to prior quarters, demand for SYMDEKO has come from all groups of eligible patients: F508del homozygous patients initiating treatment for the first time, patients who discontinued ORKAMBI coming back to initiate therapy with SYMDEKO and also patients switching from ORKAMBI to SYMDEKO.

與前幾季類似，SYMDEKO 的需求來自所有符合條件的患者群體：首次接受治療的 F508del 純合子患者、停止使用 ORKAMBI 後重新開始使用 SYMDEKO 治療的患者，以及從 ORKAMBI 轉用 SYMDEKO 的患者。

Our third quarter 2018 non-GAAP combined R&D and SG&A expenses were $379 million compared to $334 million in the third quarter 2017. This increase was primarily due to the advancement of our portfolio of triple combination regimens for CF and the investment to support the treatment of patients with our medicines globally.

2018 年第三季非 GAAP 合併研發及銷售、管理及行政費用為 3.79 億美元，而 2017 年第三季為 3.34 億美元。這一增長主要歸功於我們針對囊性纖維化的三聯療法產品組合的推進，以及為支持全球患者使用我們的藥物進行治療而進行的投資。

Non-GAAP net income for the third quarter of 2018 was $282 million with an earnings per share of $1.09, compared to non-GAAP net income of $136 million with an earnings per share of $0.53 for the third quarter 2017. Our non-GAAP net income and EPS has more than doubled compared to last year largely driven by strong growth in the total CF product revenues.

2018 年第三季非 GAAP 淨收入為 2.82 億美元，每股收益為 1.09 美元，而 2017 年第三季非 GAAP 淨收入為 1.36 億美元，每股收益為 0.53 美元。與去年相比，我們的非GAAP淨收入和每股盈餘翻了一番以上，這主要得益於CF產品總收入的強勁成長。

We ended the quarter with approximately $3.1 billion in cash, cash equivalents and marketable securities compared to $2.1 billion at the beginning of this year.

本季末，我們持有約 31 億美元的現金、現金等價物和有價證券，而今年年初這一數字為 21 億美元。

Today, we also reiterated our guidance for total CF product revenues of $2.9 billion to $3 billion and for combined non-GAAP R&D and SG&A expenses of $1.5 billion to $1.55 billion.

今天，我們也重申了對CF產品總收入29億美元至30億美元以及非GAAP研發和銷售、管理及行政費用15億美元至15.5億美元的預期。

I will close with a few comments on our expectations for future financial growth and how we anticipate providing revenue guidance next year as well as how we may start to record noncash tax charges. We have already created a strong financial profile for our business, and we anticipate that our revenues will continue to grow next year.

最後，我想就我們對未來財務成長的預期以及我們預計明年如何提供收入指引以及我們可能如何開始記錄非現金稅項支出發表一些看法。我們已經為公司建立了強勁的財務狀況，預計明年的收入將繼續成長。

In 2019, revenue growth will be based largely on the impact of SYMDEKO and SYMKEVI launches, the impact of label expansions across our CF portfolio and the recent completion of multiple reimbursement agreements. The timing of further revenue growth from countries where we do not currently have reimbursement for ORKAMBI is unpredictable. Therefore, when we provide 2019 guidance for total CF revenues early next year, it will be based only on the geographies where we have established reimbursement agreements at that date. If we gain additional reimbursement agreements in 2019, we will update you on our guidance as appropriate.

2019 年的收入成長將主要取決於 SYMDEKO 和 SYMKEVI 的上市影響、囊性纖維化產品組合標籤擴展的影響以及近期完成的多項報銷協議的影響。目前我們尚未獲得 ORKAMBI 報銷的國家/地區的進一步收入成長時間尚無法預測。因此，當我們明年年初提供 2019 年 CF 總收入指引時，指引將僅基於我們屆時已建立報銷協議的地區。如果我們在 2019 年獲得更多報銷協議，我們將視情況向您更新我們的指導意見。

This is consistent with how we provided guidance at the beginning of 2018. Beyond 2019, continued revenue growth will be driven largely by the potential approval and launch of a triple combination medicine for the large group of patients with one minimal function mutation and one F508del mutation who are not eligible for our currently approved medicines.

這與我們2018年初提供的指導意見一致。2019 年以後，持續的收入成長將主要得益於針對大量攜帶一個最小功能突變和一個 F508del 突變、目前不符合我們已批准藥物條件的患者群體，可能批准並推出三重藥物。

Now to taxes. I would note that in 2019, we may begin recording a noncash tax provision at an effective tax rate in the low to mid-20s as a result of the improving profitability of our business and our future strong financial outlook. The vast majority of our tax provision would be a noncash expense until we fully utilize our net operating losses. This will be further discussed in our 10-Q filing.

接下來談談稅收。我想指出的是，由於我們業務盈利能力的提高以及未來強勁的財務前景，我們可能會在 2019 年開始確認一項非現金稅收準備，實際稅率在 20% 到 25% 之間。在我們充分利用淨營業虧損之前，絕大部分稅收準備金將以非現金支出的形式產生。我們將在10-Q文件中對此進行更詳細的討論。

The financial profile of our business is strong, and the current year will be important period to define our future growth as we obtain Phase III data from our triple combination regimens for CF, provide access to each of our CF medicines to more patients globally, progress multiple new medicines in development and also to advance new approaches for the treatment of serious diseases from research into development. I look forward to updating you on our progress.

我們公司的財務狀況良好，今年將是決定我們未來成長的重要時期，因為我們將獲得 CF 三聯療法的 III 期數據，讓全球更多患者能夠獲得我們的每一種 CF 藥物，推進多種新藥的研發，並將治療嚴重疾病的新方法從研究推進到開發階段。我期待著向您報告我們的進展。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) And our first question is from Phil Nadeau from Cowen and Company.

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

Two questions for me, one on competition and one on kind of the financial guidance or financial comments that you just made. Ian, in your comments, you talked about 2019 sources of revenue growth. Can you specifically talk about the revenue growth outside the U.S., which I know you said was unpredictable, which countries could be drivers of growth where you recently got expansions, which ones are possible for next year and which ones are total wildcards?

我有兩個問題，一個是關於競爭的，另一個是關於您剛才給出的財務指導或財務評論的。伊恩，你在評論中談到了 2019 年的營收成長來源。能否具體談談美國以外的營收成長情況？我知道您說過這部分收入難以預測。您能否具體談談最近擴張的哪些國家可能是成長的驅動力？明年有哪些可能？哪些國家完全是未知數？

Yes. Thanks for the question Phil, and thanks for the comment on the good quarter. I do want to kind of replay some of the comments I just made, which is when we think about 2019, first of all, we see 2019 as being the continued growth year for our revenues. When we looked over the previous years and we look over future years, I think what we're seeing here is, we're treating more patients. We're treating more patients globally. And therefore, that's driving our revenue line year-on-year and into the future. And so it's a really nice profile. As we think about more proximally in time and we think about going from 2018 to 2019, we should continue to see growth even without reimbursement outside the U.S. And that growth would be driven by the continued launch of SYMDEKO in the U.S. and getting a full year's contribution for patients that are on drug. But then also outside of the U.S., SYMDEKO, which is known as SYMKEVI outside the U.S., is also launching in certain markets where it is already reimbursed. So we see baseline growth from already approved geographies. More specifically to your question of where are the geographies that we could anticipate will possibly attain reimbursement approval, to have an impact in terms of growth on our revenues, it would have to be in those larger markets. And principally, those would be either the U.K., France or Canada. I do want to replay though, this is unpredictable in terms of timing. And in particular, in the U.K., it is the second-largest CF market. If we are to obtain reimbursement over there, then we are launching the drug from anew. So we're in a launch curve in the U.K. It's not that we're just switching on a large bolus of revenue. We have to launch the drugs in the U.K. We continue to make good progress with discussions with all 3 of those countries. However, resolution, whether it is in 2019 or whether it's in 2020, we'll update you as we progress.

是的。謝謝你的提問，菲爾，也謝謝你對本季業績的肯定。我想重申我剛才的一些評論，那就是當我們展望 2019 年時，首先，我們認為 2019 年是我們收入持續成長的一年。當我們回顧過去幾年並展望未來幾年時，我認為我們看到的是，我們正在治療更多的患者。我們正在為全球越來越多的患者提供治療。因此，這將推動我們的收入逐年成長，並持續到未來。所以，這是一個非常好的個人資料。如果我們把時間線拉近一些，從 2018 年到 2019 年，即使在美國以外沒有報銷，我們也應該繼續看到成長。而這種增長將由 SYMDEKO 在美國的持續推出以及為服用該藥物的患者提供一整年的補貼來推動。但同時，在美國以外，SYMDEKO（在美國以外被稱為 SYMKEVI）也在某些市場推出，這些市場已經對其進行報銷。因此，我們看到的是已獲批准地區的基準成長。更具體地回答您的問題，即我們預計哪些地區的醫保報銷會對我們的收入成長產生影響，那麼這些地區必須是較大的市場。而主要來說，這些國家不是英國，就是法國，就是加拿大。不過我確實想重玩一遍，因為比賽時間難以預測。尤其是在英國，它是第二大CF市場。如果我們想在那邊獲得報銷，那麼我們就需要重新推出這種藥物。所以，我們目前在英國正處於啟動階段。這並不是說我們要一下子就獲得巨額收入。我們必須在英國推出這些藥物。我們與這三個國家的討論持續取得良好進展。然而，無論是在 2019 年還是 2020 年，我們都會隨著進展向您通報解決方案。

That's really helpful. And then second on competition. After the close today, Galapagos and AbbVie had a couple of announcements, some new data as well as a change to the collaboration. And Proteostasis recently announced some data for their programs. I'm curious to get the team's updated thoughts on competition from those 2 parties, how real is it? What do you see as the strengths and weaknesses?

這真的很有幫助。其次是競爭。今天收盤後，Galapagos 和 AbbVie 發布了一些公告，公佈了一些新數據，並宣布了合作方式的改變。Proteostasis公司最近公佈了其專案的一些數據。我很想知道團隊對這兩方競爭的最新看法，這種競爭到底有多真實？你認為它的優點和缺點分別是什麼？

Yes. So this is Jeff. Thanks for the question. As you know, we don't typically comment on individual competitor data. I think actually the data sort of speaks for itself. But what I would like to comment on is sort of how we view our competitive position and our data and sort of where we are in the process. I think we've learned a lot over the last year. In fact, I think our competitive position has improved over the last year significantly. One of the things we've learned is that, it's going to be a world of triples. And it's going to be a world of triples pretty quickly. And the reason for that is that in order to really get to all patients, particularly the het/min patients who are so difficult to treat and to maximize benefit for the homozygous patients, it's pretty clear now that you need a triple. Any company needs a triple. And that doesn't only mean you have 3 components. It means you have 3 medicines that can be combined, co-formulated, that have the right PK, that can provide really superior efficacy. And I think the bar in efficacy has gone up very significantly, we'll talk about that in a minute. And also importantly is that they're tolerable and safe. These are medicines that kids are going to take for the rest of their lives. And we've learned a lot about our regimens in that regard in the last year. We know that we have 2 different triple regimens that have now been in hundreds of patients. They are co-formulatable. They do have the right PK. They raise the bar in efficacy very significantly into the double digits for the het/min patients and into the mid-double digits for the homozygous patients. That's going to be the bar, I think, for the future. And most importantly to us, we're well into our Phase III trials, which are enrolling ahead of schedule to the point where we're very confident we'll be able to file one of those regimens no later than mid next year, which would allow us to launch those drugs and get patients on them pretty quickly in the coming years. And so I think from our perspective, we like where we are. We have multiple options. And most importantly, we have clinical data both on efficacy and on safety with these drugs, which is a high bar, frankly.

是的。這位是傑夫。謝謝你的提問。如您所知，我們通常不會對個別競爭對手的數據發表評論。我覺得數據本身就能說明問題。但我想要談談的是我們如何看待自身的競爭地位、我們的數據以及我們目前所處的階段。我認為過去一年我們學到了很多。事實上，我認為過去一年來我們的競爭地位有了顯著提升。我們學到的其中一件事是，這將是一個充滿三元組的世界。很快，三連勝的世界就會到來。原因在於，為了真正惠及所有患者，特別是那些難以治療的雜合子/隱性基因型患者，並最大限度地提高純合子患者的獲益，現在很明顯，你需要三聯療法。任何公司都需要三重保障。但這不僅僅意味著你有三個組成部分。這意味著你有 3 種藥物可以組合、共同配製，具有合適的藥物動力學，可以提供真正卓越的療效。我認為療效標準已經顯著提高了，我們稍後會討論這個問題。而且更重要的是，它們是可以耐受的，也是安全的。這些藥物孩子需要終生服用。過去一年，我們在這方面對我們的治療方案有了很多了解。我們知道目前有兩種不同的三重療法，已經用於數百名患者。它們可以共同配製。他們的確擁有合適的PK。對於雜合子/單倍體患者，療效顯著提高到兩位數；對於純合子患者，療效提高到兩位數中段。我認為，這將成為未來的標竿。對我們來說最重要的是，我們的 III 期試驗進展順利，招募工作提前完成，我們非常有信心最遲在明年年中就能提交其中一項方案的申請，這將使我們能夠在未來幾年內推出這些藥物並讓患者很快開始使用。所以我覺得從我們的角度來看，我們對現狀很滿意。我們有多種選擇。最重要的是，我們擁有這些藥物的療效和安全性方面的臨床數據，坦白說，這是一個很高的標準。

Our next question is from Geoff Meacham from Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

Just have a couple. The first one is on the triple selection process just for the NDA. When you guys think about it, you likely won't have much in the way of mature data on exacerbations or BMI when you pick the regimen. And that may matter actually over the long term. So is it just about safety, tolerability and FEV1? Or are there other parts of the profile that you think will be impactful that you're looking for?

就吃幾個吧。第一個問題是針對保密協議的三重篩選過程。你們仔細想想，在選擇治療方案時，你們可能沒有太多關於病情加重或 BMI 的成熟數據。從長遠來看，這可能確實很重要。所以，這僅僅是關於安全性、耐受性和 FEV1 嗎？或者，您認為個人資料中還有哪些部分會扮演重要角色？

Yes, Geoff, this is Jeff Leiden. You're right. I mean, I think at the point we can pick these triples, the primary data that we'll base that on is FEV1 data and safety and tolerability data as well as the whole profile of these drugs. Remember, we have a lot of preclinical and early clinical data as well. I think the good news is there hasn't been enormous disparity between many of those long-term outcomes and short-term outcomes. And what I mean by that is that, at least in our experience so far, drugs that have a very positive, acute effect on FEV1 and a lowering of sweat chloride that's significant acutely have also turned out to have these very profound long-term effects. And in fact, as you should know, one of the interesting things is that KALYDECO and say, ORKAMBI, which have a bit different acute profiles, ORKAMBI being less potent acutely, actually have very similar long term profiles, which suggest that if you can really hit CFTR effectively in these patients, you will get the long-term benefit. So I think the risk of a disconnect between an acute effect and a long-term effect is rather small. Now obviously, we will have the long-term effects of both of these drugs within a relatively short period of time. But you're right, probably not by the time we decide which one to file.

是的，傑夫，我是傑夫‧萊頓。你說得對。我的意思是，我認為當我們能夠選擇這些三聯療法時，我們主要依據的數據是 FEV1 數據、安全性和耐受性數據以及這些藥物的整體特性。請記住，我們還有很多臨床前和早期臨床數據。我認為好消息是，許多長期結果和短期結果之間並沒有巨大的差距。我的意思是，至少根據我們目前的經驗，那些對 FEV1 有非常積極的急性作用，並且能顯著降低汗液氯化物水平的藥物，也已被證明具有非常深遠的長期影響。事實上，你應該知道，有趣的是，KALYDECO 和 ORKAMBI 的急性作用略有不同（ORKAMBI 的急性作用較弱），但它們的長期作用卻非常相似，這表明，如果你能真正有效地作用於這些患者的 CFTR，你就能獲得長期的益處。所以我認為急性效應和長期效應之間出現脫節的風險相當小。很顯然，這兩種藥物的長期影響將在相對較短的時間內顯現出來。但你說得對，可能等我們決定要提交哪份申請的時候，已經來不及了。

Okay. Just a follow-up for Ian, and I know you haven't given a 2019 outlook, but when you plan for OpEx spend, you'll have the triple launch pending the data obviously and then a bunch of new programs in R&D. So how are you guys thinking about that in the context of also showing some operating leverage?

好的。我只是想跟伊恩提個醒，我知道你還沒有給出 2019 年的展望，但是當你計劃運營支出時，顯然會有三重產品發布（取決於數據），然後還有許多新的研發項目。那麼，在考慮如何展現一些經營槓桿效應的情況下，你們是如何看待這個問題的呢？

Geoff, thanks for the question. I really appreciate you pointing out that we've got this continued investment and commitment to CF. I just want to cover that because we do sometimes get asked the question whether when we deliver on these Phase III trials, are we declining our investments in CF? And I actually want to maintain the position that we're not. We continue to invest in CF. In fact, those patients that were in our Phase III studies roll over to open-label studies. Those open-label studies we had found to be incredibly important because we got the longitudinal data to show the benefit of these medicines longer term. We're also doing studies in the younger patients, and so we're able to treat these children at much younger ages of their lives. And so our commitment and investment to CF and these medicines we believe will be hugely beneficial to that is maintained. So you could think about that as a kind of a steady-state part of our R&D investment. And then as we think about advancing our pipeline in other disease areas beyond cystic fibrosis, we are happy to be letting you -- we'll bring you more up-to-date with how we're advancing new medicines into the clinic in these new disease areas that Jeff just referred to earlier. The investments in these disease areas is smaller in magnitude. It's earlier stage, but it is additional investments. And therefore, when you compare a 2018 operating expense profile to a 2019 operating expense profile, you should see a relatively small increase compared to the increase we anticipate on the revenue line. So yes, we do anticipate operating to increase. And then one last thing I would say is that, you have to remember, we're also launching medicines globally, not just where it's been in the U.S. And therefore, there are launch costs that are being incurred outside of the U.S., not significant because of the nature of the disease and how we can reach these patients with our medicines, but there is investments there as well. So you should expect to see operating expense margin increase in 2019 compared to 2018, but the key will be the revenue growth, which will allow us to continue to generate more cash flow.

傑夫，謝謝你的提問。我非常感謝您指出我們對CF的持續投資和承諾。我只是想談談這個問題，因為我們有時會被問到，當我們完成這些 III 期試驗時，我們是否會減少對 CF 的投資？而我其實想堅持我們並非如此的立場。我們將繼續投資CF。事實上，那些參與我們 III 期研究的患者會轉入開放標籤研究。我們發現這些開放標籤研究非常重要，因為我們獲得了縱向數據，可以證明這些藥物的長期益處。我們也在對年齡較小的患者進行研究，因此我們能夠在這些孩子更小的年紀就對他們進行治療。因此，我們對囊性纖維化及其相關藥物的承諾和投入，我們相信將對該疾病帶來巨大的益處，並將繼續保持。所以你可以把它看作是我們研發投資中一種穩定狀態的一部分。然後，當我們考慮在囊性纖維化以外的其他疾病領域推進我們的研發管線時，我們很高興能夠讓您——我們將向您帶來更多關於我們如何將新藥推進到這些新疾病領域的臨床研究的最新信息，正如傑夫剛才提到的那樣。對這些疾病領域的投資規模較小。雖然還處於早期階段，但這屬於追加投資。因此，當您將 2018 年的營運費用狀況與 2019 年的營運費用進行比較時，您會發現，與我們預期的收入成長相比，營運費用的成長相對較小。所以，是的，我們預計營運規模將會增加。最後我想說的是，你們必須記住，我們不僅在美國，還在全球推出藥物。因此，在美國以外地區也會產生一些上市成本，雖然由於疾病的性質以及我們如何用藥物惠及這些患者，這些成本並不高，但確實存在投資。因此，預計 2019 年的營運費用率將比 2018 年有所提高，但關鍵在於收入成長，這將使我們能夠繼續產生更多現金流。

Our next question is from Michael Yee from Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

On the once daily, you made a comment that you've had some positive feedback and are moving that forward. Can you just, I guess, clarify the process going forward and why you're choosing gating mutations as sort of the first move forward and not maybe a broader population. How should we think about that? And then the second question was more of a modeling finance question, which is that, obviously, the triples are advancing forward like you said, but ORKAMBI and SYMDEKO are pretty big franchises. Over some period of time, is that expected conceptually to have those doublet drugs go away and the triple is basically, is the single line item? How do you think about that? Are there patients that actually would stay on doubles?

在每日例行報告中，你提到你收到了一些正面的回饋，並且正在推進這項工作。能否請您解釋一下接下來的流程，以及為什麼您選擇以突變為切入點作為第一步，而不是擴大樣本範圍？我們該如何看待這個問題？第二個問題更像是關於金融建模的問題，那就是，顯然，正如你所說，三重奏正在向前發展，但 ORKAMBI 和 SYMDEKO 都是相當大的系列。從某種意義上說，隨著時間的推移，雙聯藥物是否會消失，而三聯藥物基本上就只剩下一個單項藥物了？你對此有何看法？真的有病人願意長期服用雙份藥物嗎？

This is Reshma. Let me start by taking the first part of the question with regard to VX-561. As you know, and we've talked about this on previous calls. The FDA had asked us to do additional dose ranging before proceeding to Phase III. And part of that request was to study VX-561 across these dose ranges in gating patients. And we've had productive discussions with the agency and we're now at the point where we've designed our study, we selected our doses, and I expect that the study will get started next year probably in the first half or so. Stuart?

這是雷什瑪。首先，讓我回答關於 VX-561 的問題的第一部分。如您所知，我們也曾在先前的電話會議中討論過這個問題。FDA要求我們在進行III期臨床試驗之前進行額外的劑量範圍研究。該請求的一部分是研究 VX-561 在這些劑量範圍內對分階段患者的影響。我們已經與該機構進行了富有成效的討論，現在我們已經設計了研究方案，選擇了劑量，我預計這項研究將於明年上半年左右開始。史都華？

Yes, Michael, on the question of what do we think the triple combinations might do to the doublets. Certainly, if we see the sort of results in Phase III that we saw in Phase II in the homozygous population where, as you know, we saw the triple combinations deliver very, very substantial increases in clinical benefit over and above a baseline of tezacaftor and ivacaftor. If those results hold true, then our expectation would be that the vast majority of patients would be transferred to a triple combination rather than staying on a doublet just given that the significant benefit-risk improvement that we saw in those Phase II studies.

是的，邁克爾，關於我們認為三重組合會對雙重組合產生什麼影響這個問題。當然，如果我們能在 III 期臨床試驗中看到與 II 期臨床試驗中在純合子人群中看到的結果類似的結果，正如您所知，我們看到三聯療法在 tezacaftor 和 ivacaftor 的基線基礎上帶來了非常非常顯著的臨床獲益。如果這些結果屬實，那麼我們預期絕大多數患者將轉為三重療法，而不是繼續使用雙聯療法，因為我們在 II 期研究中看到了顯著的獲益風險改善。

Okay. And just to clarify on 561, you have to test it in gating patients first, but the full plan certainly is to move it to a broader population after that. Is that fair?

好的。關於 561 號藥物，需要澄清的是，必須先在部分患者中進行測試，但完整的計劃肯定是之後將其推廣到更廣泛的人群。這樣公平嗎？

You got that right.

你說得對。

Our next question is from Robyn Karnauskas from Citi.

下一個問題來自花旗銀行的 Robyn Karnauskas。

So I guess let me ask about VX-150. So you mentioned that you're doing a dose-ranging study. You've already done some trials in acute. I was curious if this is to get a drug that may be superior to Vicodin since the other doses were shown to be equivalent. And then another question on that is that you talked about the acute market. And some checks we've done suggest that reimbursement might be challenging there because doctors may just give a cheap generic drug. What has your market research told you what has to happen for a more expensive, nonaddictive drug will have uptake in that setting?

那我問一下關於VX-150的問題吧。你提到你正在進行劑量範圍研究。你們已經進行了一些急性試驗。我很好奇這樣做是否是為了找到一種可能比維可丁更好的藥物，因為其他劑量已被證明是等效的。關於這一點，還有一個問題，您談到了急性市場。我們進行的一些調查表明，那裡的報銷可能會遇到困難，因為醫生可能只會開廉價的仿製藥。你的市場調查告訴你，在那種環境下，一種價格更高但無成癮性的藥物需要滿足哪些條件才能被接受？

Yes. Thanks for the questions, Robyn, both good questions. Let me start with maybe your second one. I'll come back to the dose-ranging study which is pretty straightforward. With respect to reimbursement, you're correct, a large part of the acute market has been genericized. And as you know, a large part of that market is actually opioids for acute postsurgical pain, post-dental pain, et cetera. Obviously, we're sitting in the middle of an opioid epidemic and the #1 objective that, I think, patients, physicians and the government has is to find medicines that have essentially equivalent efficacy to opioids without the abuse potential and the side effects of opioids. We believe that VX-150 based on the data we have so far has the potential to hit that profile. You saw that in the comparator trial that we did. If that's true, we feel that VX-150 is a very, very competitive drug to a generic opioid. And with reasonable pricing, that market is a multibillion-dollar opportunity even if you only capture a portion of it. In the U.S. last year, there were over 200 million opioid prescriptions written, which is a truly astounding number. Obviously, not all of them for acute pain, but a lot of them. So does that answer the question in terms of reimbursement?

是的。謝謝你的提問，Robyn，兩個問題都很好。或許我可以先回答你的第二個問題。我稍後會再談到劑量範圍研究，這部分內容相當簡單明了。關於報銷方面，您說得對，急性病市場的大部分藥品已經通用化了。如您所知，該市場很大一部分實際上是用於治療急性術後疼痛、牙科術後疼痛等的鴉片類藥物。顯然，我們正處於阿片類藥物氾濫的時期，我認為，患者、醫生和政府的首要目標是找到與阿片類藥物療效基本相當，但沒有阿片類藥物濫用風險和副作用的藥物。根據我們目前掌握的數據，我們認為 VX-150 有潛力達到這一目標。你在我們進行的對照試驗中已經看到了這一點。如果情況屬實，我們認為 VX-150 是一種非常有競爭力的鴉片類藥物。即使你只佔領其中的部分市場，只要定價合理，這個市場就是一個價值數十億美元的機會。去年美國開出了超過 2 億張鴉片類藥物處方，這是一個非常驚人的數字。顯然，並非所有藥物都用於治療急性疼痛，但許多藥物確實如此。那麼，這是否回答了有關報銷的問題？

Yes, that's very helpful.

是的，這很有幫助。

Okay. Then in terms of VX-150. I'm sorry, go ahead. Did you have another question?

好的。然後就VX-150而言。抱歉，請繼續。您還有其他問題嗎？

No, go ahead. I'm just asking about the dose ranging, if your dose is higher if you maybe show a superior profile in the acute setting, this may make reimbursement even easier.

不，你繼續。我只是想問劑量範圍的問題，如果你的劑量較高，但在急性情況下表現出更優異的療效，這可能會讓報銷變得更加容易。

Yes, yes. So you may remember the study that we did in acute bunionectomy is essentially, I would call it a proof-of-mechanism study because it was the first time anybody had shown that a 1.8 inhibitor could work in acute pain. And so we actually used a fairly high dose there just to make sure that we were getting up to a reasonable exposure. We also know that before you can move into Phase III, regulators will require you to do a dose-ranging study, really to understand 2 things. One, what is the PK/PD profile of the drug. And frankly, two, what is the lowest effective dose because you always want to give the lowest fully effective dose. And so think of this as just the standard part of the Phase II regulatory process where we need to identify the PK/PD profile or the lowest effective dose. And that would then enable us to go to the agency with a plan for a pivotal trial, again, assuming that it's successful.

是的，是的。所以你可能還記得，我們​​之前在急性拇外翻切除術中所做的研究，本質上，我稱之為機制驗證研究，因為這是第一次有人證明 1.8 抑制劑可以用於治療急性疼痛。因此，我們實際上使用了相當高的劑量，以確保達到合理的暴露量。我們也知道，在進入 III 期臨床試驗之前，監管機構會要求你進行劑量範圍研究，實際上是為了了解兩件事。第一，該藥物的藥物動力學/藥效學特徵是什麼？坦白說，第二點是，最低有效劑量是多少？因為你總是想給予最低的完全有效劑量。因此，請將此視為 II 期監管流程的標準部分，我們需要確定 PK/PD 特徵或最低有效劑量。這樣一來，我們就可以帶著關鍵性試驗計畫去見相關機構了，當然，前提是試驗成功。

Got it. And second question on alpha antitrypsin. So you mentioned the sweat chloride, there is more sweat chloride that you see per mil, so efficacy. But I do have flashbacks from sweat chloride with ORKAMBI, I think, not correlating with FEV1. In this indication, is it more straightforward that if you see a reduction, you're going to see an improvement in efficacy? Help us understand a little bit the disease.

知道了。第二個問題是關於α1-抗胰蛋白酶的。所以你提到了汗液氯化物，每毫升汗液中氯化物含量比你看到的多，所以功效也更高。但我確實會想起服用 ORKAMBI 後出現的汗液氯化物症狀，我認為這與 FEV1 無關。在這種情況下，是否更直接認為，如果看到減少，療效就會提高？請幫助我們更了解這種疾病。

Sure. Sure. Yes, let me maybe give you a little context on the disease, if you don't mind my taking a minute. One of the remarkable things about AAT is how similar. It sort of smells and looks a lot like CF in many, many different ways. It's a genetic disease. It affects somewhere between 60,000 and 100,000 people in the U.S. and probably about another 50,000 to 60,000 outside the U.S. It's caused by one major mutation in more than 90% of people. And it's a protein folding disorder as it turns out, just like CF is with sort of remarkable similarity. In this case, the normal protein AAT is made in the liver and is normally secreted into the blood where it travels to the lung. And it protects the lung against autodigestion essentially by endogenous enzymes. So in the disease, the mutant protein has 2 problems. One, it doesn't fold correctly, it accumulates in the liver, and so it causes significant liver disease actually in up to 30% of all the patients. And two, obviously, it's not secreted into the blood so it's unable to go to the lung and protect the lung. And so the lung gets autodigested and these patients suffer from early-onset emphysema. So that's the disease. The challenge is for us was to, could we make a corrector, a small molecule corrector of AAT, just as we have for CFTR, that would essentially refold the protein in the liver, so be secreted from the liver and therefore presumably help treat the liver disease. And more importantly, that would secrete functionally into the blood where it would go to the lung and protect the lung. That was the challenge. It's a very high problem, I can tell you biological problem. I think we've cracked that problem now. We've made a series of small molecule correctors that clearly do both of those things. They refold the protein so it's secreted, and it's secreted in a functional form so that it could protect the lung.

當然。當然。是的，如果您不介意我佔用您一分鐘時間，我想向您簡單介紹一下這種疾病。AAT最顯著的特徵之一就是它的相似性。它在很多方面聞起來、看起來都和 CF 非常相似。這是一種遺傳性疾病。它影響著美國大約 6 萬到 10 萬人，以及美國以外大約 5 萬到 6 萬人。超過 90% 的患者是由一種主要基因突變引起的。事實證明，它是一種蛋白質折疊紊亂，與囊性纖維化有著驚人的相似之處。在這種情況下，正常的蛋白質AAT會在肝臟中產生，並正常分泌到血液中，然後到達肺部。它主要透過內源性酵素來保護肺部免受自身消化。所以，在這種疾病中，突變蛋白有兩個問題。第一，它不能正確折疊，會在肝臟中積聚，因此實際上會導致高達 30% 的患者患有嚴重的肝臟疾病。其次，很顯然，它不會分泌到血液中，因此無法到達肺部以保護肺部。因此，肺部會發生自體消化，這些患者會罹患早發性肺氣腫。這就是這種疾病。我們面臨的挑戰是，我們能否製造出一種 AAT 的小分子校正劑，就像我們為 CFTR 製造的那樣，這種校正劑能夠使肝臟中的蛋白質重新折疊，從而從肝臟分泌出來，進而幫助治療肝臟疾病。更重要的是，它能分泌到血液中，到達肺部並保護肺部。這就是挑戰所在。這是一個非常嚴重的問題，我可以告訴你，這是一個生物學問題。我認為我們現在已經解決了這個問題。我們開發了一系列小分子校正劑，它們顯然可以同時實現這兩個目標。它們將蛋白質重新折疊，使其能夠分泌出去，並以功能性形式分泌出去，從而保護肺部。

One of the really nice things of this disease is there is both a cell or several cell models and there's also in this case an animal model, which we didn't have in CF in which the human mutation is then engineered into the animal. And so we've been able to test these molecules both in the cells and in the animals, and they do what we thought they would do. They refold the protein, secrete it from the cells. In the animals, they secreted AAT at levels that would be sufficient to essentially be preventative or curative in the disease.

這種疾病的一大優點是，它既有細胞模型，也有多種細胞模型，而且在這種情況下，它還有動物模型，而我們在囊性纖維化（CF）中是沒有的，在囊性纖維化中，人類的突變是被植入動物體內的。因此，我們已經能夠在細胞和動物體內測試這些分子，它們確實發揮了我們預期的作用。它們將蛋白質重新折疊，然後將其分泌出細胞。在動物體內，它們分泌的 AAT 水平足以對該疾病起到預防或治療作用。

And then the other thing that's very similar to CF is that it's a nice biomarker, which is simply the circulating levels of AAT in the serum. You can treat the patients for several weeks and just measure both levels and function of the AAT in the serum. And we know from human -- experiments of nature essentially that if you have a certain level of AAT in the serum, you don't get the disease. And so we know exactly what we're shooting for here. And we can measure it very easily. And so the plan is to take this into normal healthies by the end of this year, the first of these molecules, and we have a whole series of them, just like we did with CFTR correctors. And then if they are safe and more tolerable, once we understand the PK, take them into patients. And again, with relatively small numbers of patients treated for relatively short periods of time, you simply measure AAT in the serum and you know exactly where you are.

還有一點與 CF 非常相似，那就是它是一個很好的生物標記物，即血清中 AAT 的循環水平。您可以對患者進行數週的治療，然後測量血清中 AAT 的水平和功能。我們從人體實驗中得知，本質上來說，如果血清中AAT的含量達到一定水平，就不會患上這種疾病。所以我們現在很清楚我們的目標是什麼。而且我們可以很容易地測量它。因此，我們的計劃是在今年年底前將這種分子引入普通健康人群，這是第一個此類分子，我們還有一系列這樣的分子，就像我們之前對 CFTR 矯正劑所做的那樣。然後，如果它們安全且耐受性更好，一旦我們了解了它們的藥物動力學，就將它們應用於患者。再次強調，對於相對較少的患者，治療時間也相對較短，你只需測量血清中的 AAT 即可準確了解病情。

Our next question is from Geoffrey Porges from Leerink.

我們的下一個問題來自 Leerink 公司的 Geoffrey Porges。

First, Jeff, you mentioned a mid-teens FEV1 improvement now being the hurdle for triples for competition. Could you give us your sense of what the bar is for sweat chloride relative and absolute for homozygous and het/min so we can know how to appraise all these competitors coming along? And then just wondering, Stuart, if you could give us a sense of where you are in the eligible Delta F508 penetration in the U.S. between SYMDEKO and ORKAMBI. You've sort of mentioned that you had quite a few discontinuations in patients who never started on ORKAMBI. And have you called all those patients up yet or are you still substantially below the penetration you've achieved with KALYDECO in the eligible paying population spectrum?

首先，傑夫，你提到現在FEV1提高到十幾分是參加三場比賽的門檻。您能否告訴我們，對於純合子和雜合子/min，汗液氯化物相對值和絕對值的標準是多少？這樣我們才能知道如何評估所有這些競爭者。Stuart，我還想問一下，您能否介紹一下，在符合條件的 Delta F508 飛機在美國的市場滲透率方面，SYMDEKO 和 ORKAMBI 之間，您處於什麼位置？您之前提到過，有不少從未開始服用 ORKAMBI 的患者後來停止了治療。您是否已經聯繫了所有患者？或者您在符合付費條件的患者群體中，KALYDECO 的滲透率仍然遠低於您的滲透率？

Yes, Geoff, thanks, I'll answer the first part and Stuart then, of course, will answer the second part. And first of all, I do want to just correct what may have been a misimpression of what I said or maybe I said the wrong thing, but I want to be very clear. I don't think mid-teens is the bar, for instance, for het/min patients. I think the bar that we've set, as you know, from the data is somewhere between 9.8% and 13.8% in our Phase II data for het/mins. And for homozygous patients who already have an effect from doubles that we estimate is around 4%. We show an additional 9.6% or 10% improvement, which is how I get to that mid-teens. So just want to be clear that I'm not suggesting that 15% is the bar that you need for het/mins to get to be successful. With respect to sweat chloride, I think these are approximate numbers, but I think when you reach sweat chloride that approaches carrier levels, which is our sort of goal, let's say, 40 to 50, that's probably the goal that you know you're there with the triple. And so I think those are the 2 numbers we look at. In most cases, but not in all cases, they correlate pretty well. And at the end of the day, as you know, the regulatory endpoint is going to be, I think, the one.

是的，傑夫，謝謝，我會回答第一部分，然後史都華當然會回答第二部分。首先，我想糾正我之前所說的話可能造成的誤解，或者我可能說錯了話，但我希望把話說清楚。例如，我認為青少年中期並不是異質性/單核細胞增多症患者的標準。如您所知，根據我們第二階段的數據，我們設定的標準是 het/mins 的 9.8% 到 13.8% 之間。對於純合子患者，由於雙倍體的影響，我們估計其影響約為 4%。我們又提高了 9.6% 或 10%，這就是我達到十幾分水準的原因。所以我想澄清一下，我並不是說 15% 是你每分鐘達到成功所需的最低標準。關於汗液氯化物，我認為這些是近似值，但我認為當汗液氯化物達到接近載體水平時（這是我們的目標，比如說 40 到 50），這可能就是你達到三重目標的標誌。所以我認為，這就是我們要關注的兩個數字。大多數情況下（但並非所有情況），它們的相關性都相當好。歸根結底，正如你所知，監管的最終目標，我認為，就是那一個。

Geoff, it's Stuart here. Just commenting on the SYMDEKO launch in the U.S. So as you suggested, one of the most important things for us for SYMDEKO is the ability to get patients who were not being treated by ORKAMBI onto a CFTR modulator, and that was really 2 populations. One was those who were completely naïve, have never been exposed to ORKAMBI. And we've seen good uptake in that population. And the second population was those who had discontinued ORKAMBI often because of the respiratory adverse events. And we've also seen good uptake in that patient population as well. We've also seen a number of patients switch from ORKAMBI to SYMDEKO. So we've seen strong uptake in all those patient populations. We're certainly not done with the launch. Whilst we've seen good uptake, Geoff, we're certainly not done. We haven't flattened out on SYMDEKO uptake in the U.S. yet. So we still have some ways to go, but we're certainly pleased with how the launch has gone so far.

傑夫，我是史都華。我只是想就 SYMDEKO 在美國的上市發表一些看法。正如您所建議的，對於我們來說，SYMDEKO 最重要的意義之一在於能夠讓那些沒有接受 ORKAMBI 治療的患者使用 CFTR 調節劑，而這實際上涉及兩類人群。其中一類是完全天真的人，從未接觸過 ORKAMBI。我們看到該族群的接受度很高。第二類族群是因呼吸不良反應而停止服用 ORKAMBI 的人。而且我們也看到該產品在該患者群體中獲得了良好的接受度。我們也看到一些患者從 ORKAMBI 改用 SYMDEKO。因此，我們看到所有這些患者群體都表現出了強烈的接受度。我們的發表會當然還沒結束。傑夫，雖然我們看到市場反應不錯，但這絕對不是我們的目標。SYMDEKO 在美國的普及率尚未達到飽和。所以我們還有一些路要走，但我們對目前的發布感到非常滿意。

And Geoff, maybe just to add one thing that I know you're aware of is. You talked about the efficacy side of these triples, but clearly tolerability and safety is the other side of the equation, and long-term tolerability and safety, not 1 week or 2 weeks. And so I think that's going to be an important thing that we all look at as well as these trials progress.

傑夫，或許我還要補充一點，我知道你也知道這一點。你談到了這些三聯療法的療效，但顯然耐受性和安全性是等式的另一面，而且是長期耐受性和安全性，而不是 1 週或 2 週。所以我認為，隨著這些試驗的進展，這將是我們所有人都要關注的重要事項。

Our next question is from Terence Flynn from Goldman Sachs.

下一個問題來自高盛的 Terence Flynn。

I was just wondering first, you might not comment on this yet at this point, but just with respect to the triple combo. Can you maybe just give us an update on the different inputs you're thinking about with respect to pricing? And then I would just love your latest thoughts on capital allocation here. I know Jeff you made some comments in your opening remarks. But you have $3 billion on the balance sheet that might be the most you guys have ever had. So just curious how you're thinking about that as that continues to grow here into next year.

我只是想先問問，您可能現在還不會對此發表評論，但就三連擊而言。您能否簡要介紹一下您在定價方面考慮的各種因素？然後，我很想聽聽您對這裡資本配置的最新看法。我知道傑夫在開場白中發表了一些評論。但你們的資產負債表上有 30 億美元，這可能是你們有史以來擁有的最高金額。所以，我很好奇你對明年這種情況的持續發展有何看法。

Yes, Terence, Stuart here. On pricing for the triple, obviously, much too early to make any specific comment, but we'll be taking into account the same factors that we always do. That will be the magnitude of the clinical benefit that we're able to deliver for patients. It will be the label that we get approved for and that obviously leads into what's the eligible patient population. So those are really going to be the inputs that we take into consideration. And obviously, we'll get more information on those in the coming months.

是的，特倫斯，我是史都華。關於三重奏的定價，顯然現在發表任何具體評論都為時過早，但我們會考慮我們一直以來所考慮的相同因素。這將是我們能夠為患者帶來的臨床益處的程度。我們將獲得批准的標籤，這顯然會引出符合條件的患者群體。所以，這些就是我們真正需要考慮的因素。顯然，在接下來的幾個月裡，我們會獲得更多相關資訊。

And as far as capital allocation is concerned, it's really interesting. I can tell you that being in the company has invested mainly and have been about capital preservation for a long period of time and then in the last 3 years, we're now a cash accumulator and creator. And it's about capital allocation. It is an interesting philosophical change for the company, but I'd like to start by saying the revenue line is the main source of cash because after that, we then allocate inside the company on our internal programs. It's often not told about because of capital allocation, but the main source of capital is our revenue line and then we allocate that internally. And as you can see in terms of the questions asked on operating expense earlier, we still allocate a good amount of capital towards cystic fibrosis medicines, but also now we're starting to allocate capital to diseases that are beyond cystic fibrosis, and we're really happy about that. Some of those opportunities that are beyond cystic fibrosis are our next order of priority, which is we're allocating capital outside the company towards collaborations and towards medicines that we can accelerate into development. And some of the opportunities we have with beta-thalassemia and also sickle cell have been a product of a very successful and nice collaboration with CRISPR Therapeutics. And we're really excited to be going into the clinic very shortly with these medicines for sickle cell and beta-thal. And we anticipate that there will be others to follow. The medicine for FSGS, for example, was something that we in-licensed from a very early stage a couple of years ago. And what it's allows us to do is to really reignite a research just in that area is now providing the opportunity to go into the clinic in a very short period of time for a very important medicine. So it's a high order priority for us to allocate capital outside the company to do collaborations to give us opportunity with more modalities and more medicines for diseases that we would be interested in. And I would say, there is also a consideration for how we may also limit the increase of our share count. Our outstanding shares does increase year by year based on the issuance and exercise of options and restricted stock. And so we like to think of ways that we may limit that creep in outstanding shares. And we've been doing that throughout this year. We did announce earlier this year that we entered in a $500 million share buyback program. And we have been buying shares back throughout this year. And that's been very successful for us as well. And therefore has limited the creep in the outstanding shares, which obviously helps us with the small amount on the dilution. And so that's how we think about capital allocation. It's very important, very close to us. And we're happy that we have the opportunity to prioritize it in this way.

至於資本配置方面，這真的很有趣。我可以告訴你，這家公司過去主要以投資和保本為目標，但在過去的3年裡，我們已經轉型為現金累積和創造者。這關乎資本配置。對於公司而言，這是一個有趣的理念轉變，但我想首先說明的是，收入是主要的現金來源，因為之後我們會將資金分配到公司內部的專案中。由於資金分配的原因，這通常不會被提及，但主要的資金來源是我們的收入，然後我們在內部進行分配。正如你從先前關於營運費用的問題中看到的那樣，我們仍然將相當多的資金分配給囊性纖維化藥物，但現在我們也開始將資金分配給囊性纖維化以外的疾病，我們對此感到非常高興。除了囊性纖維化之外，我們接下來的優先事項是尋求其他領域的機遇，也就是將公司外部的資金用於合作以及我們可以加速開發的藥物。我們在β-地中海貧血和鐮狀細胞貧血方面取得的一些成就，得益於與 CRISPR Therapeutics 非常成功和良好的合作。我們非常興奮，很快就能帶著這些治療鐮狀細胞貧血症和β-地中海貧血的藥物進入臨床試驗。我們預計還會有其他類似案例出現。例如，治療 FSGS 的藥物是我們幾年前很早就引進的。它使我們能夠真正重新點燃該領域的研究，現在有機會在很短的時間內將一種非常重要的藥物投入臨床應用。因此，對我們來說，將資金投入公司外部進行合作，為我們帶來更多治療方式和更多針對我們感興趣的疾病的藥物，是當務之急。而且我認為，我們也需要考慮如何限制股份數量的成長。根據選擇權和限制性股票的發行和行使，我們的流通股數量逐年增加。因此，我們一直在思考如何限制流通股數量的這種緩慢增長。今年我們一直在做這件事。今年早些時候，我們宣布啟動一項 5 億美元的股票回購計畫。今年以來，我們一直在回購股票。這對我們來說也非常成功。因此限制了流通股數量的成長，這顯然有助於我們減少稀釋的損失。這就是我們對資本配置的思考方式。這非常重要，與我們息息相關。我們很高興有機會以這種方式優先考慮這件事。

Our next question is from Alethia Young from Cantor Fitzgerald.

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

This is Eliana for Alethia. Just on the earlier side of things on the R&D side, you recently did a deal with Genomics. So could you talk a little bit more about this and sort of how having this particular discovery engine will sort of enhance your R&D efforts.

這是艾莉安娜送給阿萊西亞的禮物。就研發方面的早期進展而言，你們最近與 Genomics 達成了一項協議。那麼，您能否再詳細談談這方面，以及擁有這種特定的發現引擎將如何增強您的研發工作？

Yes. Thanks for the question. We were actually quite excited about that collaboration. As you know, one of the principles of our research effort is to really work on what we call highly validated targets. There's really 2 major ways we validate targets. One is pharmacologically with medicines. That's actually the minority by the way. And the second is human genetics, where mutations, either gain of function or loss of function would tell you a lot about the role of specific targets. A beautiful example of that is NaV1.7 and NaV1.8, which we validated by human genetics, obviously, CFTR, et cetera. The collaboration with Genomics, who we believe is the leading small company in the world working on this kind of high throughput human genetics, will allow us to screen for new targets on the one hand through large scale data analysis of human genetic databases. But also it will allow us to ask questions for instance about the potential side effects of hitting a specific target because you can screen the human population for mutations on that target, a loss of function, for example, and ask other people normal or not, do they suffer from any mechanisms or side effects. That's a very important thing to know as we begin to pick targets and develop small molecules. So think about it as a way of tapping into the human genetic data resource that both help pick targets and help screen for safety. And that collaboration is off to a very nice start in a number of different diseases.

是的。謝謝你的提問。我們當時對那次合作感到非常興奮。如您所知，我們研究工作的原則之一是真正致力於我們所說的高度驗證的目標。我們驗證目標的方法主要有兩種。一種方法是使用藥物進行藥理治療。順便說一句，這其實是少數。第二點是人類遺傳學，其中突變，無論是功能獲得還是功能喪失，都能告訴你很多關於特定靶點的作用的資訊。NaV1.7 和 NaV1.8 就是一個很好的例子，我們已經透過人類遺傳學驗證了它們，例如 CFTR 等。我們相信，與 Genomics 的合作是世界上從事此類高通量人類遺傳學研究的領先小型公司，這將使我們能夠一方面透過對人類遺傳資料庫進行大規模數據分析來篩選新的靶點。但它也能讓我們提出一些問題，例如，針對特定目標的潛在副作用，因為你可以篩檢人類群體中該目標的突變、功能喪失等，並詢問其他人（無論正常與否）是否遭受任何機製或副作用的影響。當我們開始選擇標靶和開發小分子時，了解這一點非常重要。所以，可以把它看作是利用人類基因資料資源的一種方式，既可以幫助選擇目標，也可以幫助安全篩檢。這種合作在多種疾病領域都取得了非常好的開始。

Got you. And then just another one in terms of early-stage development. Can you just tell us a little bit more about the preclinical models for AAT? I mean, obviously with CF, you guys are very successful in optimizing these preclinical models. But could you tell us a little bit sort of about your thoughts on what you think the best preclinical model for AAT is and also sort of your thoughts on how predictive these models might be?

抓到你了。然後還有另一個處於早期開發階段的專案。可以再詳細介紹一下AAT的臨床前模型嗎？我的意思是，很明顯，在 CF 方面，你們在優化這些臨床前模型方面非常成功。您能否稍微談談您認為AAT的最佳臨床前模型是什麼，以及您認為這些模型的預測能力如何？

Yes. Thanks for the question. There's 2 kinds of models that are generally used. These are not, by the way, necessarily proprietary to us. One is a set of cell-based models in which either directs from patients are derived from engineered cells with the human Z mutation in them, which is the major AAT mutation. And in those cells, the mutant protein is made, it's misfolded, it's not secreted. And so one can test molecules on those cells as to the help refold the protein, secrete it as a functional, et cetera. The other one is that there's a transgenic mouse which actually expresses the human mutant protein. Again, that protein is not secreted well. It accumulates in the liver of those mice. And once we dose those mice with medicine, you'll have these protein secreted, it's a function of what levels do you reach, et cetera. So 2 very nice models which we feel actually will be highly predictive because they do actually study the human mutation, not by mouse-driven mutation.

是的。謝謝你的提問。一般常用的模型有兩種。順便說一句，這些不一定是我們獨有的。其中之一是一組基於細胞的模型，這些模型要么直接來自患者，要么源自含有人類 Z 突變的工程細胞，而 Z 突變是主要的 AAT 突變。在這些細胞中，突變蛋白被製造出來，但錯誤折疊，無法分泌。因此，人們可以測試這些細胞上的分子，看看它們是否能幫助蛋白質重新折疊，將其分泌為功能性蛋白質等等。另一種情況是，有一種基因轉殖小鼠能夠表現人類突變蛋白。同樣，這種蛋白質的分泌效果也不好。它會在這些小鼠的肝臟中累積。一旦我們給這些小鼠服用藥物，就會分泌這些蛋白質，這取決於你達到的水平等等。所以，我們找到了兩個非常好的模型，我們認為它們實際上會具有很高的預測性，因為它們確實研究的是人類突變，而不是透過老鼠驅動的突變。

Our next question is from Ying Huang from Bank of America Merrill Lynch.

下一個問題來自美國銀行美林證券的黃穎。

First one, maybe on again competition. We have seen some data from Proteostasis. I was wondering if you guys have done any work in the lab about the role of amplifier. Do you have a view on that or not? And then secondly maybe for Stu. Can you tell us by when you might see SYMDEKO pretty much reaching a full penetration in the U.S. market given where you're seeing the market today?

首先，或許會再次展開競爭。我們已經看到了一些來自蛋白質穩態的數據。我想知道你們實驗室有沒有做過關於放大器作用的研究。你對此有何看法？其次，或許對Stu來說也是。鑑於您目前對美國市場的觀察，您認為SYMDEKO大概什麼時候才能在美國市場實現全面滲透？

Yes, this is Jeff. I'll take the first one in terms of the amplifier. Again, we really don't comment on other people's specific molecules. One of the things that we like about our triple and our correctors are, we know that they're quite specific for the CFTR protein, which is I think one of the reasons, quite selective, if you will. They don't hit other proteins. One of the reasons why they've been so tolerated. And so I think as we look at -- as you look at other molecules, that issue of specificity imposed is an important thing to look at.

是的，這是傑夫。就擴大機而言，我選第一個。再次聲明，我們不對其他人的具體分子發表評論。我們喜歡我們的三聯療法和矯正劑的原因之一是，我們知道它們對 CFTR 蛋白具有很強的特異性，我認為這是其中一個原因，它們具有很強的選擇性。它們不會與其他蛋白質發生反應。這也是他們一直被容忍的原因之一。所以我認為，當我們觀察到──當你觀察其他分子時，所施加的特異性問題是一個值得關注的重要議題。

And then in terms of the SYMDEKO uptake. Obviously, we're very pleased with how it's gone to-date. Predicting exactly where it's going to reach full penetration is hard to do, but you can rest assured that when we get to the point of giving '19 guidance, we'll be including our expectations in that for how SYMDEKO is going to perform in the U.S. and then also hopefully by then, we'll have the approval of SYMKEVI in Europe as well and we'll incorporate all that into our '19 guidance.

然後是 SYMDEKO 的普及情況。顯然，我們對目前為止的進展非常滿意。要準確預測它將在哪些地區達到全面滲透是很難的，但您可以放心，當我們發布 2019 年業績指引時，我們會將 SYMDEKO 在美國的業績預期納入其中，並且希望到那時 SYMKEVI 也能在歐洲獲得批准，我們會將所有這些因素都納入我們的 2019 年業績指引中。

Our next question is from Brian Abrahams from RBC Capital Markets.

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

In the NACF data, we saw more specifics on the rate of cough with the triple combo. I know these weren't classified as bronchoconstriction. I was wondering if you can give us any more details in the quality, severity and duration. Remind us, should we think about this as related to the initial mucus clearance and how it might compare to ORKAMBI? And then just a follow-up on the pain program. Obviously, some really interesting Phase II data. Wondering if there are ways you might be able to further improve upon the bioavailability and potency of VX-150. And should we assume 128 is no longer being pursued?

在 NACF 數據中，我們看到了更多三聯療法咳嗽發生率的具體資訊。我知道這些症狀不屬於支氣管收縮的範疇。我想請您提供更多關於品質、嚴重程度和持續時間方面的資訊。請提醒我們，我們是否應該將此與初始黏液清除聯繫起來，以及它與 ORKAMBI 相比如何？然後是對疼痛治療方案的後續後續。顯然，這是一些非常有趣的二期臨床試驗數據。想知道是否有辦法進一步提高 VX-150 的生物利用度和效力。我們是否可以認為第 128 號案件不再追究？

Yes. Maybe I'll take both of those real quickly. I think the question you're trying to get at for the triple, but correct me if I'm wrong is, are we seeing bronchoconstriction as we saw with ORKAMBI? And the answer is no. And we've actually measured that specifically not only in terms of cough or anything else. So we do not see bronchoconstriction with the triple, and we did not see it with tez/iva as you remember. But I think the more important point, right, Brian, is just looking at the total tolerability and safety profile of these drugs now in a couple of hundred patients. What we're seeing is they're quite clean. They look a lot like the earlier drug, ORKAMBI accepted. They don't have the bronchoconstriction means that they've been very well tolerated and very safe so far. Did that answer your question? I just want to make sure that was the question you're asking.

是的。或許我會很快把這兩樣都拿走。我認為您想透過三聯徵提出的問題（如果我錯了請糾正我）是，我們是否看到了像 ORKAMBI 那樣的支氣管收縮？答案是否定的。我們實際上已經專門測量過這一點，不僅僅是咳嗽或其他方面。所以，三聯療法沒有引起支氣管收縮，正如你記得的那樣，使用特茲/伊瓦療法也沒有引起支氣管收縮。但我認為更重要的一點，對吧，布萊恩，現在要看看這些藥物在幾百名患者身上的整體耐受性和安全性。我們看到的是，它們都很乾淨。它們看起來很像早期的藥物，ORKAMBI 接受了這個說法。它們沒有引起支氣管收縮，這意味著到目前為止，它們的耐受性非常好，安全性也很高。這樣回答了你的問題嗎？我只是想確認一下，你問的是不是這個問題。

That's very helpful. Yes. Just wanted to contextualize that, yes.

那很有幫助。是的。是的，我只是想解釋一下背景。

Yes. And then the other question was about 150 and 128?

是的。然後另一個問題是關於 150 和 128 的？

Yes.

是的。

Yes. So maybe just again, let me take a step back and remind you that the approach that we're taking in pain, actually not unlike the approach we've taken in CF and the approach we're taking in AAT, is to create a portfolio of molecules, not one, not single rifle shots, but multiple molecules that have different properties, both with respect to things like potency, but also with respect to things like PK, biodistribution, drug-drug interactions, et cetera. And then take those molecules forward into early-stage clinical development to understand their profiles more fully. Obviously, 150, we have the most data on. We know that it's well tolerated. We know that it has efficacy, at least at these higher doses in acute pain and in osteoarthritis. And we'll get a readout on the third kind of pain, neuropathic pain, early next year. 128 was a follow-on molecule, if you will, with some different properties than 150. We discontinued the development of 128 in Phase I in healthy volunteers because it didn't have the PK profile, the tolerability improvement that we were hoping to see over 150. We have multiple additional 1.8 inhibitors coming behind that. And so you should expect to see us bring other inhibitors into early clinical development, the same way trying to optimize these molecules. Remember, in acute pain, you're going to need molecules that are highly efficacious and also highly safe and highly tolerable. We don't want to create molecules that have liabilities like opioids.

是的。所以，或許我再退一步，提醒大家一下，我們在疼痛治療方面採取的方法，實際上與我們在 CF 和 AAT 方面採取的方法並無太大區別，那就是創建一個分子組合，而不是單一的、一次性的藥物，而是多個具有不同特性的分子，這些特性不僅體現在效力等方面，還體現在藥代動力學、生物分佈、藥物相互作用等方面。然後將這些分子推進到早期臨床開發階段，以更全面地了解它們的特性。顯然，我們掌握的數據最多的是150這個數字。我們知道它耐受性良好。我們知道它具有療效，至少在高劑量下，對急性疼痛和骨關節炎有效。我們將在明年初獲得第三種疼痛——神經性疼痛——的讀數。128 可以說是後續分子，它與 150 有一些不同的性質。我們停止了 128 在健康志願者中進行的 I 期臨床試驗，因為它沒有達到我們希望在 150 中看到的藥物動力學特徵和耐受性改善。之後我們還有多個 1.8 抑制劑即將推出。因此，你們應該會看到我們以同樣的方式，將其他抑制劑引入早期臨床開發，以嘗試優化這些分子。記住，在急性疼痛的情況下，你需要高效、安全且耐受性良好的分子。我們不想製造出像鴉片類藥物那樣具有危害性的分子。

Our next question is from Paul Matteis from Stifel.

我們的下一個問題來自 Stifel 公司的 Paul Matteis。

This is Ben Burnett on for Paul. I wanted to ask another question about VX-150. I wonder if you can provide a little bit more color on the Phase IIb study in acute pain, like specifically what are you looking for and what is the efficacy hurdle that you need to advance this to a pivotal program. And then the second question just sort of more at a high level. I guess across these different pain indications, the acute and the neuropathy is ongoing as well as osteoarthritis-related pain, you have some data there. What are some of the ultimate vision for this program? And I guess under what scenarios would you want to commercialize this yourselves? And is there a scenario where a partner might be involved in that aspect of it?

這裡是本·伯內特，為您報道保羅。我想問一個關於VX-150的問題。我想請您詳細介紹 IIb 期急性疼痛研究，例如，您具體在尋找什麼，以及要將此研究推進到關鍵性項目，需要達到的療效門檻是什麼。第二個問題則更偏向宏觀層面。我想，對於這些不同的疼痛症狀，包括急性疼痛、持續性神經病變疼痛以及骨關節炎相關疼痛，你們有一些數據。這個專案的最終願景是什麼？那麼，我想問一下，在什麼情況下你們會想要自己將這項技術商業化呢？是否存在伴侶可能參與其中的情況？

Yes, Ben, thank you. I'll take the second part actually first, then gets a little more strategic, maybe we'll give you some context and then Reshma will take the first part, which is about the VX-150 Phase IIb trial. I said this before, but maybe just to give you some context. We think about pain both from a commercial standpoint and from a scientific standpoint not as one disease, but is actually multiple diseases. So an easy way to divide this, for instance, is acute pain. That's the kind of postsurgical pain, the dental pain when you have an acute injury. That's one segment. The second segment is chronic inflammatory pain, things like osteoarthritis, lower back pain. A third segment is neuropathic pain. That's pain like diabetic neuropathy. They have different commercial channels obviously, but they also potentially have different pain mechanisms. And so it's important to study them separately because some drugs will work in one and some drugs will work in 2, and frankly some drugs might work in all 3. So that's the approach that we've taken with our portfolio. We've done separate trials in acute pain using bunionectomy as the model. We've done separate trials in chronic inflammatory pain using OA as the model, osteoarthritis. And we're doing a third set of trials in neuropathic pain using small fiber neuropathy as the model. And as you know, what we've seen so far just to remind you is, a high level of efficacy in acute pain, a high level of efficacy in osteoarthritis chronic pain, and we're still waiting to see the data from the neuropathic trial, which is due early next year. So that's where things sort of stand from a scientific standpoint. Now again if I take a step back, remember that there is a very large need for a new class of pain medicines. There really hasn't been a new class for over 50 years. And the reason is that we have opioids on the one hand which have high efficacy, but are burdened with all of the addictive and other side effects. And then we have drugs like aspirin, Tylenol, NSAIDs, which have lower efficacy and also by the way, have some of their own side effects which are not trivial. And so the target for us is really can we find a new mechanism of pain that approaches opioid-like efficacy without the liabilities, addictive and other liabilities of opioids. And so far, there's been Phase II data, what we're seeing is VX 1.8 looks like such a target. Sorry, NaV1.8 looks like such a target. VX-150 is the first medicine that does look like it hits in both of those 2 pain indications. And the third one we're waiting to see. And the final part of your question is, what about commercializing that. It turns out, acute pain, as I said, is a multibillion-dollar opportunity and at least many, not all necessarily, but many of the channels in the acute pain market can be addressed by a specialty sales force. That's something that we would develop and commercialize ourselves. Contrast that with, say, OA pain or low back pain, that's clearly not a specialty disease. That's a community disease or requires a primary care sales force. And while we may take the science and Phase II trials forward, we will certainly not develop our own primary care sales force and commercialize that. That would be done with a partner. Nevertheless, we think, if we have such a molecule, it's a very valuable asset for us to partner. And the neuropathic pain lies somewhere in between. It can be covered by a rather large specialty sales force, meaning 100 to 150 reps probably in this country. So it is mostly by specialist. And it really depends on the quality of the data that we're going to see there in the first part of the year in terms of deciding what we would do with respect to further development and commercialization. Does that give you sort of a lay of the land of how we're thinking about it?

是的，本，謝謝你。實際上，我先講第二部分，然後會稍微深入一些，也許我們會給你一些背景信息，然後 Reshma 會講第一部分，也就是關於 VX-150 IIb 期試驗的內容。我之前說過，但或許只是為了提供你一些背景資訊。我們從商業角度和科學角度看待疼痛，並不將其視為一種疾病，而實際上是多種疾病的組合。例如，一種簡單的分割方法是將其分為急性疼痛。那是術後疼痛，就像急性牙傷引起的牙痛一樣。這是其中一部分。第二部分是慢性發炎性疼痛，例如骨關節炎、腰痛等。第三類是神經性疼痛。那是類似糖尿病神經病變引起的疼痛。它們的商業管道顯然不同，但它們的疼痛機制也可能不同。因此，分別研究它們非常重要，因為有些藥物對一種疾病有效，有些藥物對另一種疾病有效，坦白說，有些藥物可能對所有三種疾病都有效。這就是我們對產品組合所採取的方法。我們以拇趾外翻切除術為模型，對急性疼痛進行了單獨的試驗。我們以骨關節炎（OA）為模型，對慢性發炎性疼痛進行了單獨的試驗。我們正在進行第三組神經性疼痛試驗，以小纖維神經病變為模型。如您所知，我們目前所看到的，該藥物在急性疼痛方面療效顯著，在骨關節炎慢性疼痛方面療效顯著，我們仍在等待神經性疼痛試驗的數據，該試驗預計將於明年初進行。所以從科學角度來看，事情大概就是這樣。現在，如果我退後一步來看，請記住，目前非常需要一類新的止痛藥。已經超過50年沒有開設新班級了。原因在於，一方面我們有療效顯著的鴉片類藥物，但另一方面卻有成癮性和其他副作用。然後還有像阿斯匹靈、泰諾、非類固醇抗發炎藥物這樣的藥物，它們的療效較低，而且順便說一句，它們本身也有一些不容忽視的副作用。因此，我們的目標是找到一種新的止痛機制，使其療效接近鴉片類藥物，但又沒有鴉片類藥物的成癮性和其他副作用。到目前為止，根據第二階段的數據，我們看到 VX 1.8 看起來就是這樣一個目標。抱歉，NaV1.8 看起來就是這樣一個目標。VX-150 是第一種似乎能夠同時緩解這兩種疼痛症狀的藥物。第三個我們還在等待結果。你問題的最後一部分是，如何將其商業化。正如我所說，事實證明，急性疼痛是一個價值數十億美元的市場，而且急性疼痛市場中至少有很多管道（不一定是全部管道）可以由專業的銷售團隊來開拓。這是我們自己開發並商業化的產品。相較之下，例如骨關節炎疼痛或下背痛，顯然不是一種專科疾病。那是一種社區疾病，或是需要一支基層醫療銷售團隊。雖然我們可能會推進科學研究和第二期臨床試驗，但我們肯定不會建立自己的基層醫療銷售團隊並將其商業化。那就需要和夥伴一起完成。不過，我們認為，如果我們擁有這樣的分子，那麼它對我們來說將是一個非常寶貴的合作夥伴。而神經性疼痛則介於兩者之間。這可能需要一支規模相當大的專業銷售團隊來負責，在這個國家可能有 100 到 150 名銷售代表。所以這主要由專家負責。這實際上取決於我們在今年上半年看到的數據的質量，以便決定我們將如何進行進一步的開發和商業化。這樣是否能讓你大致了解我們的想法？

Makes sense. Appreciate it.

有道理。謝謝。

Okay. Reshma?

好的。雷什瑪？

This is Reshma. With regard to the VX-150 Phase II study that we are going to be initiating shortly, it's a fairly standard Phase II dose-ranging study. This is going to be the bunionectomy acute pain model. And in essence, it's going to be several doses that we study to get a full dose exposure range. You'll remember that the bunionectomy study that had the positive results from early in the year was a high-dose study because we were really testing proof of mechanism in that one. The endpoint is going to be SPID24, SPID48. This is a pretty standard endpoint for the bunionectomy model. And with regard to the treatment effect, we were very pleased with the treatment effect we saw in the bunionectomy study. And now we need to explore the full dose range and exposure to see what the lowest effective dose is going to be. And that's really what we're studying here.

這是雷什瑪。關於我們即將啟動的 VX-150 II 期研究，這是一項相當標準的 II 期劑量範圍研究。這將是拇外翻切除術後急性疼痛模型。從本質上講，我們將研究多個劑量，以獲得完整的劑量暴露範圍。您應該還記得，今年年初那項取得積極成果的拇外翻切除術研究是一項高劑量研究，因為我們當時確實在測試其作用機制的證據。終點將是 SPID24、SPID48。這是拇趾外翻切除術模型中相當標準的終點。至於治療效果，我們對拇外翻切除術研究中觀察到的治療效果非常滿意。現在我們需要探索完整的劑量範圍和暴露情況，以確定最低有效劑量是多少。而這正是我們在這裡真正研究的內容。

Our next question is from 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。

Two for me as well. In your prepared remarks, you mentioned you'll have some enhanced next-gen correctors moving into the clinic in the coming months. I'm wondering if there's any additional information you can provide about these in terms of how they might be further differentiated from what you already have. And then my second question is with regard to the clinical hold for CTX001 in sickle cell now being lifted and initial trials slated to begin. How much data do you ideally want to accumulate before you're potentially comfortable providing an update? And will this be something that's your responsibility or your partners?

我也是兩個。您在事先準備好的演講稿中提到，未來幾個月內，一些性能更優的新一代矯正器將陸續進入臨床應用。我想知道您是否可以提供一些關於這些產品的其他信息，以便說明它們與您已有的產品有何不同。我的第二個問題是關於 CTX001 在鐮狀細胞疾病的臨床試驗暫停現已解除，初步試驗計畫開始。理想情況下，您希望累積多少數據才會覺得可以提供更新？這件事是你的責任還是你合作夥伴的責任？

Yes, Cory, this is Jeff. Maybe I'll take Part 1 and Ian will talk about disclosure and Part 2 of the question. With respect to the enhanced next-gen correctors, I would say what we're looking for here is 2 things. One, I think we've shown you the chart before that as we've gone through the last 4 years, it's really remarkable to see how we've been able to improve the potency and efficacy of these next-gen correctors. With the current molecules, 659 and 445, we're close to getting all patients to carrier levels, but not quite there. And so the goal would be to find a next-gen corrector that could get all patients, meaning het/min in particular as well as homozygous patients to carrier levels of chloride transport because we believe if you can get there, particularly in young patients, you'll either prevent or greatly, greatly lessen the severity of the disease. The other goal of that program is to continue to diversify the chemotypes. We always like to have multiple chemotypes of any medicine that we're making. And so we've been able to explore alternative chemotypes, and we're working on those as well. So those are the 2 kinds of molecules that you can expect to see entering the clinic. We already have examples of both. And so the first one to go, I do expect one in the clinic early next year. And you can probably see some more as the year goes along as well. Does that answer your question about the enhanced next-gen correctors?

是的，科里，這是傑夫。也許我會講第一部分，而伊恩會講解資訊揭露和問題的第二部分。關於增強型下一代校正器，我認為我們在這裡尋找的是兩件事。第一，我想我們之前已經向你們展示過這張圖表了，在過去的 4 年裡，我們能夠提高這些新一代矯正器的效力和功效，這真是令人矚目。使用目前的分子 659 和 445，我們已經接近讓所有患者達到攜帶者水平，但還沒有完全達到。因此，我們的目標是找到一種下一代矯正劑，能夠使所有患者（特別是雜合子/基因型患者以及純合子患者）的氯離子轉運達到攜帶者水平，因為我們相信，如果能夠達到這個水平，尤其是在年輕患者中，就能預防或大大減輕疾病的嚴重程度。該計劃的另一個目標是繼續使化學類型多樣化。我們總是希望我們生產的任何藥物都有多種化學類型。因此，我們得以探索其他化學類型，我們也正在研究這些類型。所以，這兩種分子是預期會進入臨床應用的。我們已經有了這兩種例子。因此，第一個接受治療的，我預計明年年初會在診所進行。而且隨著時間的推移，你可能還會看到更多。這樣回答了您關於增強型下一代校正器的問題嗎？

Yes. Perfect.

是的。完美的。

Okay. And Cory, as to your disclosure question. Well, we just started recruiting patients for these studies. And I think the next disclosure we'll provide you with would be kind of an update of where we are on the recruitment. We'd anticipate dosing first patient probably towards the end of this year, early next year. And then once we have a number of patients in the study, we'd anticipate a disclosure of data from the study later on next year, but that would probably be timed with multiple patients in both studies and being on therapy or let's say, have had the procedure for a certain duration of time.

好的。科里，關於你提出的資訊揭露問題。我們剛開始招募患者參與這些研究。我認為我們接下來要向大家透露的信息，應該是關於招聘工作的最新進展。我們預計最快可能在今年底或明年年初給第一位患者用藥。然後，一旦研究中有足夠多的患者，我們預計明年稍後會公佈研究數據，但這可能要等到兩項研究中都有多名患者接受治療或手術一段時間後才會進行。

Well, that will conclude the call. The Investor Relations team is in the office tonight to answer any further follow-up questions. Thank you very much for joining the call and have a good evening.

通話到此結束。投資者關係團隊今晚在辦公室，可以回答任何後續問題。非常感謝您參加此通話，祝您晚安。

Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may now disconnect.

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。