福泰製藥 (VRTX) 2021 Q4 法說會逐字稿

Good evening. This is Michael Partridge. Welcome to the Vertex Fourth Quarter and Full Year 2021 Financial Results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating Officer; and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides as you listen to this call. This call is being recorded, and a replay will be available on our website.

晚安.我是邁克爾·帕特里奇。歡迎參加Vertex公司2021財年第四季及全年財務業績電話會議。今晚，Vertex公司首席執行官兼總裁雷什瑪·凱瓦拉馬尼博士、首席營運官斯圖爾特·阿巴克爾以及首席財務官查理·瓦格納將發表事先準備好的演講。我們建議您在收聽本次電話會議的同時查看網路直播投影片。本次電話會議將進行錄音，錄音回放將在我們的網站上提供。

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed CF medicines, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance we will review on the call this evening are non-GAAP.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受制於今天新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性。這些聲明，包括但不限於有關Vertex已上市的囊性纖維化藥物、我們的研發管線以及Vertex未來財務業績的聲明，均基於管理層當前的假設。實際結果和事件可能與這些假設有重大差異。此外，我還要指出，我們今晚將在電話會議上討論的部分財務表現和指引為非GAAP財務數據。

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

現在我將把電話轉給雷什瑪·凱瓦拉瑪尼醫生。

Thanks, Michael.

謝謝你，麥可。

I'm pleased to discuss our performance and progress in 2021 and to share our vision for where Vertex is headed. 2021 was a very important year for the company, during which we expanded our leadership position in CF, significantly advanced the mid- and late-stage pipeline and further strengthened our financial position, and one which sets us up for high-value milestones in 2022 and a very bright future for years to come.

我很高興與大家探討我們在2021年的業績和進展，並分享我們對Vertex未來發展的願景。 2021年對公司而言是至關重要的一年，我們鞏固了在囊性纖維化領域的領先地位，顯著推進了中後期研發管線，並進一步增強了財務實力。這一年為我們在2022年實現高價值里程碑奠定了基礎，也為未來幾年的美好前景創造了條件。

Our revenue and earnings continue to reflect the significant growth of our global CF franchise. And based on our success in treating more CF patients, we again delivered exceptional financial results, generating nearly $7.6 billion in product revenues, representing 22% growth year-on-year and 27% growth over Q4 2020.

我們的營收和獲利持續反映出我們全球囊性纖維化業務的顯著成長。基於我們在治療更多囊性纖維化患者方面取得的成功，我們再次取得了卓越的財務業績，產品收入近76億美元，同比增長22%，較2020年第四季度增長27%。

Also in 2021, we initiated 2 global Phase III studies with our next-in-class CF regimen VX-121/tezacaftor/VX-561; completed enrollment in the pivotal studies of CTX001; delivered proof-of-concept with VX-147 in a type of APOL1-mediated kidney disease known as FSGS; delivered early but very promising results with VX-880 in type 1 diabetes; and advanced VX-548 into 2 proof-of-concept studies in acute pain, the results of which are expected this quarter. These advancements span small molecules, gene editing and cell therapies and 6 disease areas, including CF.

同樣在2021年，我們啟動了兩項針對囊性纖維化（CF）的下一代療法VX-121/tezacaftor/VX-561的全球III期臨床研究；完成了CTX001關鍵性研究的患者招募；VX-147在一種名為局灶節段性腎小球硬化症（FSGS）的APOL1介導的腎病中取得了概念驗證；VX-880在1型糖尿病中取得了早期但非常令人鼓舞的結果；並將VX-548推進到兩項針對急性疼痛的概念驗證研究，預計將於本季度公佈結​​果。這些進展涵蓋小分子藥物、基因編輯和細胞療法，以及包括囊性纖維化在內的六大疾病領域。

Fueled by our success in cystic fibrosis, our financial profile and balance sheet have been further strengthened, enabling both continued investment in internal and external innovation and industry-leading operating margins. We provided a detailed overview of Vertex at our webcast 2 weeks ago at the JPMorgan Conference. Tonight, our prepared remarks will recap the high points around our CF franchise and our pipeline and also review our commercial performance and financial expectations for 2022, starting with CF.

由於我們在囊性纖維化領域的成功，我們的財務狀況和資產負債表得到了進一步加強，從而能夠持續投資於內部和外部創新，並保持行業領先的營運利潤率。兩週前，我們在摩根大通會議的網路直播中詳細介紹了Vertex公司。今晚，我們將發表準備好的發言，回顧我們在囊性纖維化領域的業務亮點和研發管線，並展望我們2022年的商業業績和財務預期，首先從囊性纖維化領域談起。

For the 90% of CF patients who can benefit from a CFTR modulator, we see continued significant growth ahead as we have more than 25,000 patients who could benefit from TRIKAFTA and our other CF medicines but who are not yet on treatment. Stuart will discuss the opportunity ahead of us and our high confidence that we will reach these patients in his prepared remarks.

對於90%可從CFTR調節劑中獲益的囊性纖維化（CF）患者而言，我們預計未來將持續顯著增長，因為目前有超過25,000名患者可能受益於TRIKAFTA和其他CF藥物，但他們尚未接受治療。 Stuart將在事先準備好的演講稿中探討我們面臨的機遇，並表達我們對惠及這些病人的高度信心。

Approved first in the U.S. in October of 2019, TRIKAFTA set a high bar in terms of both clinical trials and real-world data and has become the standard of care for patients with CF today. To recap, in late 2021, we shared 96-week data from the extension of the TRIKAFTA pivotal trial, where we saw no decline in mean lung function. This was a first for any CFTR modulator.

TRIKAFTA於2019年10月率先在美國獲批，其臨床試驗和真實世界數據均樹立了極高的標準，如今已成為囊性纖維化患者的標準治療方案。回顧一下，我們在2021年底公佈了TRIKAFTA關鍵性試驗擴展研究的96週數據，結果顯示患者的平均肺功能沒有下降。這在CFTR調節劑中尚屬首次。

We now have the first real-world data for TRIKAFTA from the U.S. CF Foundation registry. Across approximately 16,000 patients treated with TRIKAFTA and represented in the registry in 2020, relative to patients eligible for TRIKAFTA in the year prior to approval, we see an 87% reduction in the risk of lung transplant, a 77% reduction in pulmonary exacerbations and a 74% reduction in the risk of death.

我們現在獲得了來自美國囊性纖維化基金會註冊中心的首批 TRIKAFTA 真實世界數據。在 2020 年接受 TRIKAFTA 治療並被納入註冊中心的約 16,000 名患者中，與 TRIKAFTA 獲批前一年符合治療條件的患者相比，我們發現肺移植風險降低了 87%，肺部急性加重風險降低了 77%，死亡風險降低了 74%。

Nonetheless, if it is possible to deliver better clinical outcomes in TRIKAFTA, we are determined to be the ones who do so. And our next-in-class triple combination of VX-121/tezacaftor/561, which holds that potential, is already in pivotal development. We expect completion of enrollment in both Phase III SKYLINE trials in late 2022 or early 2023. This combination has the potential for greater clinical benefit, more convenient once-daily dosing and a significantly lower royalty obligation.

儘管如此，如果TRIKAFTA能夠帶來更佳的臨床療效，我們決心成為實現這一目標的先驅。我們極具潛力的下一代三重療法VX-121/tezacaftor/561已進入關鍵性開發階段。我們預期兩個III期SKYLINE試驗將於2022年底或2023年初完成病患招募。此聯合療法有望帶來更大的臨床效益、更便捷的每日一次給藥方案以及顯著降低的專利使用費。

For the last 10% of CF patients who do not make any CFTR protein, with our partners at Moderna, we've now demonstrated that we can not only efficiently deliver full-length CFTR mRNA to human bronchial epithelial cells in vitro, but also to bronchial epithelial cells in nonhuman primates, solving a long-standing delivery challenge and marking a significant step forward in bringing a treatment for the last 10% of CF patients. Based on these results, IND-enabling studies for our CFTR mRNA program are now underway. We plan to file the IND this year with clinical trials beginning thereafter.

對於最後10%不產生CFTR蛋白的囊性纖維化（CF）患者，我們與Moderna的合作夥伴已證實，我們不僅能夠高效地將全長CFTR mRNA遞送至體外培養的人類支氣管上皮細胞，還能遞送至非人靈長類動物的支氣管上皮細胞，從而解決了長期以來遞送了問題，還能遞送至非人靈長類動物的支氣管上皮細胞，從而解決了長期以來遞送了這一重要問題，並標誌著CF最後10%的重要方面。基於這些成果，我們目前正在進行CFTR mRNA計畫的IND申報研究。我們計劃今年提交IND申請，隨後啟動臨床試驗。

Beyond CF, we have a pipeline that is broad and deep and delivering and considerably more advanced compared to a year ago. I'll review a few of our clinical stage programs, each of which is a first-in-class or best-in-class program has the potential to serve a large number of patients and represents a multibillion dollar opportunity.

除了囊性纖維化領域，我們的研發管線範圍廣泛、深度充足，並且與一年前相比取得了顯著進展。我將重點介紹幾個處於臨床階段的項目，每個項目都是同類首創或同類最佳，具有服務大量患者的潛力，並代表著數十億美元的市場機會。

Beginning with CTX001, our onetime gene editing treatment with the potential to provide a functional cure for sickle cell disease and beta thalassemia. This is our most advanced program outside of CF, and we expect this will be our next commercial launch.

首先是CTX001，這是我們一次性基因編輯療法，可望為鐮狀細胞貧血症和β地中海貧血提供功能性治癒方案。這是我們在囊性纖維化以外的最先進項目，我們預計這將是我們下一個商業化上市的產品。

We're wrapping up discussions with regulators to finalize our submission data package for CTX001, including the number of patients and duration of follow-up. This program accelerated significantly last year based on strong physician and patient interest. We completed enrollment in both Phase III studies, both were oversubscribed. And to date, we've dosed more than 70 patients. We look forward to sharing more clinical data with CTX001, longer-term follow-up and many more patients at a medical forum later this year, on the way to our planned global regulatory filings by year-end 2022.

我們正在與監管機構完成最後的磋商，以最終確定CTX001的申報資料包，其中包括病患人數和追蹤時間長度。由於醫生和患者的濃厚興趣，該計畫去年進展顯著加快。我們已完成兩項III期研究的患者招募，且兩項研究均超額完成。迄今為止，我們已為70多名患者給藥。我們期待在今年稍後的醫學論壇上分享更多CTX001的臨床數據、更長期的追蹤結果以及更多患者的數據，為2022年底前向全球監管機構提交申請做好準備。

Moving on to VX-147 and the APOL1-mediated kidney disease program. In renal medicine, one of the most important genetic discoveries of the last decade was the realization that mutations in the APOL1 gene are a key driver of significant kidney disease. VX-147, our small molecule inhibitor, specifically targets this APOL1 protein and in so doing, targets the underlying cause of APOL1-mediated kidney disease.

接下來我們來談談VX-147及其在APOL1介導的腎臟疾病治療的應用。在腎臟醫學領域，過去十年最重要的遺傳學發現之一是認識到APOL1基因突變是嚴重腎臟疾病的關鍵驅動因素。我們的小分子抑制劑VX-147能夠特異性地靶向APOL1蛋白，從而從根本解決APOL1介導的腎臟疾病問題。

In the Phase II single-arm study of 16 patients with APOL1-mediated FSGS, VX-147 demonstrated unprecedented reductions in proteinuria, a marker of kidney damage, and was generally well tolerated. Importantly, the 47.6% mean reduction in proteinuria was on top of standard of care. These Phase II results propel the advancement of VX-147 into pivotal development. Our next step is an end of Phase II meeting with the FDA, and our goal is to initiate pivotal development, targeting the broad AMKD population of approximately 100,000 patients including, but not limited to those with APOL1-mediated FSGS later this quarter.

在針對16名APOL1介導的局部節段性腎絲球硬化症（FSGS）患者的II期單臂研究中，VX-147展現出前所未有的蛋白尿降低效果（蛋白尿是腎損傷的標記），且整體耐受性良好。值得注意的是，蛋白尿平均降低47.6%是在標準治療的基礎上實現的。這些II期研究結果推動VX-147進入關鍵性開發階段。下一步，我們將與FDA召開II期研究結束會議，目標是在本季稍後啟動關鍵性開發，目標族群為約10萬名APOL1介導的FSGS患者。

Turning to type 1 diabetes and VX-880. Type 1 diabetes results from autoimmune destruction of pancreatic islet cell, and we have known for some time that whole pancreas or cadaveric islet cell transplantation can be curative. The challenge has been quality and quantity of donor tissue. We believe we've overcome this challenge. We are the only company that has shown we can make allogeneic, stem cell-derived, fully differentiated, insulin-producing islet cells and make them at industrial scale.

接下來談談第1型糖尿病和VX-880。第1型糖尿病是由自體免疫疾病破壞胰島細胞引起的，我們早就知道，全胰臟移植或屍體胰島細胞移植可以治癒這種疾病。一直以來的挑戰在於捐贈者組織的品質和數量。我們相信我們已經克服了這個挑戰。我們是唯一一家能夠大規模生產同種異體、幹細胞衍生、完全分化、具有胰島素分泌功能的胰島細胞的公司。

Our goal with our type 1 diabetes program is to develop a functional cure for this disease, including for the more than 2.5 million people living with type 1 diabetes in the U.S. and Europe. We shared day 150 results approximately 2 weeks ago from the first patient treated with VX-880. This patient had severe, long-standing type 1 diabetes and prior treatment with VX-880, had difficult to control sugar levels and multiple severe hypoglycemic events with no detectable endogenous insulin as measured by C-peptide. He had a hemoglobin A1C of 8.6% and was taking 34 units of exogenous insulin daily.

我們1型糖尿病計畫的目標是開發一種能夠治癒這種疾病的有效療法，造福美國和歐洲超過250萬的第一型糖尿病患者。大約兩週前，我們分享了首例接受VX-880治療的患者治療150天的結果。該患者患有嚴重的長期第1型糖尿病，先前曾接受VX-880治療，血糖控制困難，並多次發生嚴重低血糖事件，且C肽檢測顯示內源性胰島素水平極低。他的糖化血紅素A1c為8.6%，每日需注射34單位外源性胰島素。

The results from this first patient treated with half the targeted dose of VX-880 are remarkable. Fasting C-peptide, a measure of endogenous insulin production, is now over 400 picomole. Hemoglobin A1C is down to 6.7%. And the patient is on minimal exogenous insulin. VX-880 was generally well tolerated and the patient remains free of symptomatic hypoglycemic events since the [periodic operative period].

首例接受目標劑量一半VX-880治療的患者療效顯著。空腹C肽（內源性胰島素分泌的指標）現已超過400皮摩爾。糖化血紅素A1c降至6.7%。且該患者僅需極少量外源性胰島素。 VX-880整體耐受性良好，自[週期性手術期]以來，該患者未再發生任何症狀性低血糖事件。

I mentioned at the JPMorgan Conference earlier this month and it bears repeating why these results are so foundational. Achieving durable results in type 1 diabetes requires 2 things: high-quality insulin-producing islet cells, we have that; and a method to protect these cells from the immune system. We can address the immune response in several different ways. Today, with VX-880, we're combining the stem cell islets with standard immunosuppression in the Phase I/II study. We can shield the same stem cell islets with an immunoprotective device. In this approach, immunosuppressives would not be needed.

我在本月初的摩根大通會議上提到過，而且有必要再次強調這些結果為何如此基礎。在第1型糖尿病治療中取得持久療效需要兩點：一是高品質的胰島素分泌胰島細胞，我們已經擁有了；二是保護這些細胞免受免疫系統攻擊的方法。我們可以透過多種方式來應對免疫反應。目前，我們正在進行VX-880的I/II期臨床試驗，將幹細胞胰島與標準免疫抑制劑合併使用。我們也可以使用免疫保護裝置來保護這些幹細胞胰島。在這種方法中，就不需要使用免疫抑制劑了。

This approach is in IND-enabling studies, and we expect to file the IND later this year with clinical trials beginning thereafter. And in earlier stages, we're using gene editing technology to make so-called hypoimmune pancreatic islets, yet another approach that eliminates the need for immunosuppressive.

這項研究目前正處於IND申報前的準備階段，我們預計今年稍後提交IND申請，隨後啟動臨床試驗。此外，在早期階段，我們正在利用基因編輯技術製造所謂的低免疫胰島，這是另一種無需使用免疫抑制劑的方法。

The VX-880 Phase I/II clinical trial is up and running at multiple sites. The trial continues to enroll in dose patients. We anticipate sharing data from more patients and longer duration of follow-up this year.

VX-880 的 I/II 期臨床試驗已在多個中心啟動並進行。該試驗仍在繼續招募患者。我們預計今年將公佈更多患者和更長追蹤期的數據。

I'll conclude the pipeline overview with VX-548, a novel selective inhibitor of NaV1.8, which is in clinical proof-of-concept studies for acute pain. Two proof-of-concept studies in acute pain were initiated in the second half of 2021, one in patients following abdominoplasty surgery, and one in patients following bunionectomy. These studies are dose-ranging, placebo-controlled studies and both include an opioid reference arm. The abdominoplasty study has now completed enrollment and dosing, and the bunionectomy study will complete in the coming weeks. We anticipate having results from both studies this quarter and announcing both results together.

最後，我將介紹VX-548，這是一種新型的NaV1.8選擇性抑制劑，目前正在進行急性疼痛的臨床概念驗證研究。 2021年下半年，我們啟動了兩項急性疼痛的概念驗證研究，一項針對腹部整形術後患者，另一項針對拇外翻切除術後患者。這兩項研究均為劑量範圍探索性、安慰劑對照研究，且均設有鴉片類藥物對照組。腹部整形術研究現已完成患者招募和給藥，拇外翻切除術研究將在未來幾週內完成。我們預計將在本季度獲得這兩項研究的結果，並同時公佈。

With that, I'll turn it over to Stuart.

這樣，我就把麥克風交給史都華了。

Thanks, Reshma.

謝謝你，雷什瑪。

I'm pleased to review tonight our continued strong commercial performance. Our CF business performed exceptionally well in the fourth quarter and for the full year in 2021. Our Q4 global revenues were $2.07 billion. Full year revenues were $7.6 billion, an increase of 22% over 2020.

今晚我很高興向大家報告我們持續強勁的商業業績。我們的CF業務在2021年第四季和全年表現都非常出色。第四季全球營收為20.7億美元。全年營收為76億美元，比2020年成長22%。

U.S. CF product revenues grew 10% to $5.3 billion in 2021, driven mainly by the launch of TRIKAFTA in the 6- to 11-year-old patient population following its approval last June. Our product revenues outside the U.S. increased 66% over 2020 to $2.3 billion. We signed more than 15 new reimbursement agreements in 2021. And following these agreements, we have seen strong uptake of KAFTRIO and TRIKAFTA matching the launch dynamics in the U.S.

2021年，美國囊性纖維化產品收入成長10%，達53億美元，主要得益於TRIKAFTA在去年6月核准後，面向6至11歲患者族群上市。 2021年，美國以外地區的產品收入較2020年成長66%，達到23億美元。 2021年，我們簽署了超過15項新的健保報銷協議。這些協議簽署後，KAFTRIO和TRIKAFTA的市場需求強勁成長，與美國市場的上市情況相符。

Looking to the future in 2022 and for the next several years, we expect significant continued revenue growth as there are more than 25,000 patients remaining who are addressable with our CFTR modulators, but who are not yet treated. These patients fall into 3 categories. Patients who have not yet initiated treatment, largely in countries where we are recently reimbursed and therefore, are early in the launch curve. This includes countries such as Canada, Spain and the Netherlands. Patients in geographies where we are not yet reimbursed such as Australia. And finally, younger patients who will be addressed through ongoing label expansions.

展望2022年及未來幾年，我們預期收入將持續顯著成長，因為仍有超過25,000名患者符合我們CFTR調節劑的治療條件，但尚未接受治療。這些患者可分為三類：尚未開始治療的患者，主要來自我們近期獲得醫保報銷的國家，因此仍處於市場推廣初期，例如加拿大、西班牙和荷蘭；尚未獲得醫保報銷的國家，例如澳大利亞；以及我們將通過持續擴展適應症來惠及的年輕患者。

We continue to make progress in addressing younger and younger patients. As examples, we secured approval for KAFTRIO in 6- to 11-year-old patients in Europe and the U.K. just a few weeks ago. And our submission for approval of TRIKAFTA in these younger patients is also currently under review in Canada. And in 2022, we plan to file for approval for ORKAMBI in patients 12 to 24 months of age in the U.S. and Europe based on the recently completed Phase III study.

我們在滿足較年輕患者的需求方面持續取得進展。例如，就在幾週前，我們剛在歐洲和英國獲準用於治療6至11歲的患者，用於治療KAFTRIO。目前，我們提交的用於治療這些年輕患者的TRIKAFTA的上市申請也在加拿大接受審查。此外，我們計劃在2022年基於近期完成的III期臨床研究，向美國和歐洲提交用於治療12至24個月齡患者的ORKAMBI的上市申請。

In addition, with our mRNA program in IND-enabling studies, we are making real progress in developing a medicine for the additional 5,000-plus patients that we cannot address with our current CFTR medicines, but who are potentially addressable with the successful development of an mRNA therapy.

此外，我們的 mRNA 計畫正在進行 IND 申報研究，我們正在取得真正的進展，為另外 5000 多名我們目前無法用 CFTR 藥物治療的患者開發藥物，但如果 mRNA 療法成功開發，這些患者就有可能得到治療。

The recent long-term and real-world data, as discussed by Reshma in her prepared remarks, have significantly strengthened our competitive position and highlight the benefits of our medicines for CF patients. For a genetic disease like CF, where patients start medicines at an early age and take them chronically over their lifetime, long term and real-world data like these are incredibly important to patients and physicians. They take many years and thousands of patients to generate and set a very high bar for any future therapy to meet.

正如雷什瑪在事先準備好的演講稿中所提到的，近期獲得的長期真實世界數據顯著增強了我們的競爭優勢，並凸顯了我們藥物對囊性纖維化患者的益處。對於囊性纖維化這種遺傳性疾病，患者需要從很小就開始服藥，並終生長期服用，因此這類長期真實世界數據對患者和醫生都至關重要。這些數據需要多年時間和成千上萬的患者才能獲得，並為未來的任何療法設定了極高的標準。

I would now like to provide a commercial perspective on 2 programs that are in or entering pivotal development that highlight our future diversification beyond cystic fibrosis. I'll start with CTX001, our CRISPR-Cas9-based gene editing therapy for hemoglobinopathies, which we plan to file for regulatory approval before the end of this year. In terms of market opportunity, we see tremendous potential for CTX001. We estimate that there are more than 150,000 patients in the U.S. and Europe who have beta thalassemia or sickle cell disease, approximately 32,000 of whom have severe disease. 25,000 of these are patients with severe sickle cell disease, and the vast majority of these are in the U.S.

現在，我想從商業角度談談兩個正在或即將進入關鍵性研發階段的項目，這兩個項目凸顯了我們未來在囊性纖維化之外的多元化發展方向。首先是CTX001，這是我們基於CRISPR-Cas9技術的基因編輯療法，用於治療血紅蛋白疾病，我們計劃在今年年底前提交監管審批申請。就市場機會而言，我們看到了CTX001的巨大潛力。據估計，美國和歐洲有超過15萬名β地中海貧血或鐮狀細胞疾病患者，其中約3.2萬名患者病情嚴重。在這3.2萬名患者中，有2.5萬名是重症鐮狀細胞疾病患者，而絕大多數患者都居住在美國。

Published physician surveys in the U.S. consistently indicate that they expect 1/4 to 1/3 of their sickle cell disease patients would be good candidates for a onetime, curative approach using the current busulfan-based conditioning regimen, which is in line with our own estimates of the numbers of severe patients. With global regulatory submissions planned for CTX001 toward the end of this year, our launch preparation activities are well underway, including building our market access, patient support and health care professional-facing teams as well as finalizing our manufacturing and supply chain network.

美國已發表的醫生調查一致表明，他們預計有四分之一到三分之一的鐮狀細胞病患者適合採用目前基於白消安的預處理方案進行一次性治愈，這與我們對重症患者數量的估計相符。我們計劃於今年底向全球監管機構提交CTX001的上市申請，目前上市準備工作正在順利進行，包括組成市場准入、病患支援和醫護人員服務團隊，以及完善生產和供應鏈網路。

Finally, as Reshma noted, we plan to advance VX-147 to pivotal development this quarter. So I would like to comment on the opportunity we see in APOL1-mediated kidney disease or AMKD. In the Phase II study, we enrolled patients with 2 APOL1 mutations who had focal segmental glomerulosclerosis, FSGS, as demonstrated by biopsy. This was an ideal population to test the clinical hypothesis of APOL1 inhibition. There are approximately 10,000 patients with APOL1-mediated FSGS. However, we estimate that the population of people with 2 APOL1 mutations and kidney disease primarily driven by APOL1 is much larger, approximately 100,000 patients. This is the initial target population that we will seek to address with VX-147, and so this represents a multibillion-dollar opportunity.

最後，如Reshma所指出的，我們計劃在本季推動VX-147進入關鍵性開發階段。因此，我想談談我們在APOL1介導的腎臟病（AMKD）領域看到的機會。在II期研究中，我們招募了攜帶兩個APOL1突變且經腎活檢證實患有局部性節段性腎小球硬化症（FSGS）的患者。這部分族群是驗證APOL1抑制劑臨床假設的理想族群。目前約有10,000名APOL1介導的FSGS患者。然而，我們估計攜帶兩個APOL1突變且主要由APOL1驅動的腎臟病患者群體要大得多，約有100,000名。這是我們將使用VX-147著力治療的首要目標族群，因此，這代表著一個價值數十億美元的市場機會。

Awareness of diagnosis and genotyping of patients with AMKD are all low. So in parallel with the planned progression of VX-147 to pivotal development in 2022, we expect to begin increasing awareness of APOL1-mediated kidney disease with treating physicians with a focus on the importance of genotyping.

目前，人們對AMKD患者的診斷和基因分型的認知度都很低。因此，在VX-147計畫於2022年進入關鍵性開發階段的同時，我們希望開始提高臨床醫師對APOL1介導的腎臟疾病的認識，並專注於基因分型的重要性。

I'll close by noting that we are about to celebrate the tenth anniversary of the approval of our first CF medicine, KALYDECO. It has been an extraordinary 10 years as we have developed and launched not only KALYDECO, but 3 additional transformative medicines to address the underlying cause of disease for CF patients. I'm excited for the opportunity in 2022 to bring TRIKAFTA, KAFTRIO to even more patients around the globe and the potential to commercialize multiple potentially transformative therapies outside of CF in the near future, starting with sickle cell disease and beta thalassemia.

最後，我想指出，我們即將慶祝首個囊性纖維化（CF）藥物 KALYDECO 獲準十週年。這十年可謂非凡，我們不僅研發並推出了 KALYDECO，還開發並推出了另外三種具有變革意義的藥物，旨在解決 CF 患者的根本原因。我很高興有機會在 2022 年將 TRIKAFTA 和 KAFTRIO 帶給全球更多患者，並期待在不久的將來將多種具有潛在變革意義的療法商業化，這些療法將應用於 CF 以外的領域，首先是鐮狀細胞病和 β 地中海貧血。

I will now turn it over to Charlie.

現在我把它交給查理。

Thanks, Stuart.

謝謝你，斯圖爾特。

In the fourth quarter of 2021, Vertex continued to demonstrate very strong financial performance. Fourth quarter total product revenues were $2.07 billion, a 27% increase compared to Q4 of 2020. I would note that it is typical for channel inventory to fluctuate from quarter-to-quarter. And in Q4 2021, revenues benefited from moderately higher channel inventory. We expect these inventory levels to normalize in Q1 of 2022. Our full year revenues of $7.6 billion, represents an increase of 22% compared to 2020 revenues of $6.2 billion. 2021 revenue growth was driven by strong international uptake of KAFTRIO and 6 to 11 uptake of TRIKAFTA in the U.S. And with full year sales of $5.7 billion, TRIKAFTA, KAFTRIO now represents 75% of total company revenues.

2021年第四季度，Vertex持續保持強勁的財務表現。第四季產品總營收達20.7億美元，較2020年第四季成長27%。需要指出的是，渠道庫存通常會隨季度波動。 2021年第四季度，收入受益於略高的通路庫存。我們預計庫存水準將在2022年第一季恢復正常。全年營收達76億美元，較2020年的62億美元成長22%。 2021年營收成長主要得益於KAFTRIO在國際市場的強勁表現以及TRIKAFTA在美國市場6至11歲人群的廣泛應用。 TRIKAFTA和KAFTRIO全年銷售額達57億美元，目前占公司總收入的75%。

Other notable milestones are that the U.S. CF product sales exceeded $5 billion for the first time and ex-U.S. CF product sales exceeded $2 billion for the first time. Our fourth quarter 2021 combined R&D and SG&A expenses were $703 million compared to $539 million for 2020, and our full year expenses were $2.33 billion compared to $1.98 billion in 2020.

其他值得關注的里程碑包括：美國CF產品銷售額首次突破50億美元，美國以外CF產品銷售額首次突破20億美元。 2021年第四季研發及銷售、管理及行政費用合計為7.03億美元，2020年同期為5.39億美元；全年費用為23.3億美元，2020年同期為19.8億美元。

Increased expenses were driven by investment in our research pipeline, advancement of multiple mid- and late-stage clinical programs, incremental costs for our growing CF business and investments in precommercial activities for CTX001. Our continued revenue growth, combined with disciplined spending, resulted in a 2021 operating margin of 57% and non-GAAP operating income of $4.34 billion, an increase of 24% compared to 2020. Our non-GAAP tax rate for 2021 came in at 21%.

支出增加主要源自於對研發管線的投資、多個中後期臨床項目的推進、囊性纖維化業務成長帶來的額外成本以及對CTX001商業化前活動的投入。持續的收入成長，加上嚴格的支出控制，使得2021年營業利潤率達到57%，非GAAP營業收入為43.4億美元，較2020年增長24%。 2021年非GAAP稅率為21%。

With continued revenue growth and profitability, we finished 2021 with $7.5 billion in cash. And consistent with our corporate strategy, our top priority for capital deployment is reinvestment in innovation both internally in our R&D programs and externally with business development aligned to our R&D strategy. We have invested approximately $3 billion in collaborations and acquisitions since 2019. Additionally, we have made more than $2 billion in share repurchases to offset dilution over that same time frame.

憑藉持續的營收成長和獲利能力，我們在2021年底持有75億美元的現金。與公司策略一致，我們資本部署的首要任務是再投資於創新，包括內部研發專案和與研發策略相契合的外部業務拓展。自2019年以來，我們已在合作和收購方面投資約30億美元。此外，同期我們也進行了超過20億美元的股票回購，以抵銷股權稀釋的影響。

Now to guidance. Our 2021 performance reflected strong uptake for TRIKAFTA in the U.S. and for KAFTRIO in multiple countries around the world. For 2022, we project that we will achieve total product revenues of $8.4 million to $8.6 billion. At the midpoint, that's an increase of nearly $1 billion or 12% growth over 2021. I'd like to remind you, as is our practice, this guidance reflects our expectations for approved products in countries where we have already secured reimbursement.

現在談談業績展望。 2021 年，我們的業績反映了 TRIKAFTA 在美國市場的強勁表現，以及 KAFTRIO 在全球多個國家的良好市場表現。我們預計 2022 年產品總收入將達到 840 萬美元至 86 億美元。取中間值，這將比 2021 年增長近 10 億美元，增幅達 12%。我想提醒各位，按照慣例，此業績展望僅反映我們在已獲得醫保報銷的國家/地區已獲批准產品的預期。

For non-GAAP OpEx, we are guiding to a range of $2.7 billion to $2.75 billion. Consistent with our innovation strategy, we expect to continue to allocate greater than 70% of our OpEx to R&D with year-over-year growth largely driven by investment in our pipeline in order to advance key programs through mid- and late-stage development. Finally, we expect our non-GAAP tax rate for 2022 to be in the range of 21% to 22%.

對於非GAAP營運支出，我們預計在27億美元至27.5億美元之間。秉承創新策略，我們預期將持續把70%以上的營運支出用於研發，研發投入的同比增長主要得益於對產品線的投資，以推進關鍵項目進入中後期開發階段。最後，我們預計2022年的非GAAP稅率將在21%至22%之間。

In closing, 2021 was a very important and successful year for the company. We significantly expanded our leadership position in CF by treating more patients, generating key long-term and real-world data, advancing the next-in-class CFTR modulator program into Phase III and continuing to innovate for all CF patients. We also accelerated our R&D pipeline in 2021 and obtained key data readouts across multiple programs and multiple modalities. We further strengthened our financial position, enabling continued investment in internal and external innovation while delivering industry-leading operating margins. Most importantly, these advances set the foundation which positions us for multiple milestones and significant value creation in 2022 and beyond.

綜上所述，2021年對公司而言是至關重要且碩果累累的一年。我們透過治療更多患者、產生關鍵的長期和真實世界數據、推進新一代CFTR調節劑計畫進入III期臨床試驗以及持續為所有CF患者進行創新，顯著鞏固了我們在囊性纖維化領域的領先地位。此外，我們在2021年加速了研發管線，並在多個項目和多種治療模式中獲得了關鍵數據。我們進一步增強了財務實力，從而能夠持續投資於內部和外部創新，同時保持業界領先的營運利潤率。最重要的是，這些進展為我們在2022年及以後實現多個里程碑和創造顯著價值奠定了基礎。

We look forward to updating you as we progress through the year. Let's now open the call to questions.

我們期待在今年的工作進展中及時向您報告最新情況。現在，讓我們開始接受提問。

Certainly. And first, I'd like to hand the program over to Michael Partridge, Senior Vice President of Investor Relations.

當然。首先，我想把這個節目交給投資者關係高級副總裁邁克爾·帕特里奇。

Thanks, operator. I would just want to note to everybody before we start the Q&A that our conference from audio has cut out. We're all on our cell phones and we'd like to proceed with Q&A, so please bear with us. Thank you.

謝謝接線生。在開始問答環節之前，我想提醒大家，我們的電話會議音訊中斷了。我們都用手機參加，希望繼續進行問答環節，請大家耐心等待。謝謝。

(Operator Instructions) Our first question comes from the line of Michael Yee from Jefferies.

（操作說明）我們的第一個問題來自 Jefferies 的 Michael Yee。

Congrats on a great year-end. We had a question on APOL1. I know that you are certainly meeting with FDA soon and trying to start a pivotal study. So you must have some thoughts around both the design, the endpoints and what you expect out of the FDA and what you plan to do. Maybe you could give some color on that, both on primary and key secondary endpoints you'd expect to be an agreement with FDA.

恭喜您年末取得佳績！我們有一個關於APOL1的問題。我知道您很快就要和FDA會面，並計劃啟動一項關鍵性研究。所以您肯定對研究設計、終點指標以及您對FDA的預期和計劃都有一些想法。您能否就主要終點和關鍵次要終點，以及您希望與FDA達成的共識，做一些詳細說明？

Sure. Michael, thanks very much for the question and for the kind words for the year. With regard to the VX-147 program, the important point here to discuss is that in Phase II, what we did was study APOL1-mediated FSGS, which is one kind of APOL1-mediated kidney disease. APOL1-mediated kidney disease as a whole, that's to say where patients have 2 APOL1 alleles and kidney disease driven by those 2 alleles, that overall population is 100,000 patients in Europe and the U.S. The FSGS population that we study is about 10,000 patients.

當然。邁克爾，非常感謝你的提問和對我的新年祝福。關於VX-147項目，這裡需要討論的重點是，在二期臨床試驗中，我們研究的是APOL1介導的局部節段性腎小球硬化症（FSGS），這是APOL1介導的腎臟疾病的一種。 APOL1介導的腎臟疾病整體而言，即患者攜帶兩個APOL1等位基因且腎臟疾病由這兩個等位基因驅動，這類患者在歐洲和美國的總人數約為10萬人。我們研究的FSGS患者群體約為1萬人。

So why did we do that? This was a very deliberate decision because the FSGS group are a very severe group of patients with heavy proteinuria, rapid progression to end-stage renal disease and no available therapy. Reasoning that if we could have impact in those patients, then we could go forward into Phase III with confidence that we would be able to impact the broad AMKD population. The results from our Phase II study are, and I don't use this word loosely, they are unprecedented, 47.6% reduction in proteinuria on top of standard of care in an APOL1-driven FSGS population is an impressive result.

那麼，我們為什麼要這樣做呢？這是一個經過深思熟慮的決定，因為FSGS組的患者病情非常嚴重，他們普遍存在大量蛋白尿，病情進展迅速，最終發展為終末期腎病，而且目前尚無有效的治療方法。我們認為，如果我們能夠對這些患者產生影響，那麼我們就可以更有信心地進入III期臨床試驗，並相信我們能夠對更廣泛的AMKD患者群體產生影響。我們的II期臨床試驗結果——我絕非誇張——是前所未有的：在APOL1基因突變驅動的FSGS患者群體中，在標準治療的基礎上，蛋白尿減少了47.6%，這是一個令人矚目的結果。

With regard to the study design for the next stage, we are -- as you rightfully point out, Michael, we are going to have our end of Phase II meeting with the FDA in the near term. That is just something we haven't done yet, although we have had the benefit of conversations with the agency.

關於下一階段的研究設計，正如您所指出的，邁克爾，我們將在近期與FDA召開二期臨床試驗結束會議。雖然我們已經與FDA進行過溝通，但這件事我們尚未著手進行。

The important parameters I'll put on the table are the following: proteinuria, which is what we measured in Phase II, that is a measure of kidney damage. It's an important endpoint in and of itself. The community and the agency have had discussions over the last many years about that endpoint being a potential regulatory enabling endpoint for accelerated approval in homogenous proteinuric kidney diseases. So that's just one point to mention.

我要重點提及的參數如下：蛋白尿，這是我們在第二期臨床試驗中測量的指標，它代表腎臟損傷程度。蛋白尿本身就是一個重要的終點指標。過去幾年，業界和監管機構一直在討論，蛋白尿是否可以作為加速審批同質性蛋白尿腎病藥物的潛在監管審批終點。以上僅是其中一點。

The second point is what would the endpoints be? We're talking about proteinuria. And certainly, the hard endpoint would be time to ESRD, a decrease in the GFR slope and death. It's usually a composite endpoint for the hard endpoint.

第二點是最終指標是什麼？我們討論的是蛋白尿。當然，硬終點指標應該是進展至末期腎病變的時間、腎小球濾過率下降斜率、死亡。通常情況下，硬終點指標是一個複合終點指標。

So that's really what we're looking at. We are very excited about the program. We are looking to have our end of Phase II meeting with the FDA in the near term, and we're looking to start our pivotal development towards the end of this quarter. I hope that's helpful.

這就是我們目前關注的重點。我們對這個項目感到非常興奮。我們計劃近期與FDA召開二期臨床試驗結束會議，並計劃在本季末啟動關鍵性開發階段。希望這些資訊對您有所幫助。

Our next question comes from the line of Phil Nadeau from Cowen and Company.

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

Maybe just a follow-up to Michael's. In terms of the specific endpoint, you just mentioned proteinuria and then the composite endpoint of more clinical results. In the recent past, it seems like the renal division of the FDA has been shying away from surrogate markers and focusing companies on the more clinical endpoints. So can you talk a bit more about your optimism for -- maybe in proteinuria as a primary endpoint? Would you actually seek an SPA if you get an agreement on that endpoint to try to lock the FDA in? And maybe how likely is it that you actually have to do a clinical endpoint-based trial? If so, how long of a study would that end up being?

或許可以作為對邁克爾問題的補充。關於具體的終點指標，您剛才提到了蛋白尿，以及包含更多臨床結果的綜合終點。最近，FDA腎臟部門似乎一直在迴避替代指標，而是引導企業關注更具臨床意義的終點指標。那麼，您能否再談談您對以蛋白尿作為主要終點指標的樂觀態度呢？如果就該終點指標達成一致，您是否會尋求特別授權協議（SPA）來鎖定FDA？您認為進行基於臨床終點指標的試驗的可能性有多高？如果需要，這項研究最終會持續多久？

Yes. Phil, thanks for the follow-up question there. Okay. So with regard to what is the likelihood of proteinuria being the endpoint and such, we have to simply have our end of Phase II meeting, and we're going to know that soon enough. So no need to speculate. The end of Phase II meeting is going to happen in the near term, and we will know.

是的，菲爾，謝謝你的後續提問。好的。關於蛋白尿作為終點的可能性等等，我們只需要召開二期臨床試驗結束會議，很快就會知道結果。所以沒必要猜測。二期臨床試驗結束會議近期就會召開，到時候我們就知道了。

What I can tell you is that the agency has been open for many years now for proteinuria to be an acceptable surrogate for accelerated approval in homogeneous kidney diseases. And when I say that, inherent in that statement is -- and then, of course, you'd have to do the continuation of the trial to get to the hard outcome. So those are the conversations we're going to enter into.

我可以告訴大家的是，多年來，該機構一直對蛋白尿作為同質性腎臟疾病加速審批的可接受替代指標持開放態度。我這麼說，其隱含的意思是──當然，之後還需要繼續進行試驗才能得出最終結果。所以，這些就是我們接下來要討論的內容。

Obviously, and I think you know this, but I'll mention it just in case. The degree of proteinuria is really important because, one, not only could proteinuria be a potential accelerated endpoint, but two, the degree of proteinuria is directly related to the hard outcome. So when you see an improvement in proteinuria of almost 50%, it bodes well for many reasons.

顯然，我想您也知道這一點，但我還是提一下以防萬一。蛋白尿的程度非常重要，原因有二：首先，蛋白尿不僅可能預示著病情加速惡化；其次，蛋白尿的程度與最終的臨床結局直接相關。因此，當蛋白尿改善近50%時，從許多方面來看，這都是一個好兆頭。

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。

Just wanted to shift a little bit to sickle cell. And I know, obviously, you guys are heading towards kind of a submission hopefully. But can you talk a little bit about where you stand on conditioning regimens and some of the work that you may be doing going forward to kind of maybe make them kind of less onerous for patients with sickle cell?

我想稍微聊聊鐮狀細胞貧血症。我知道你們肯定正在準備提交論文。但能否談談你們對治療方案的看法，以及你們未來可能會進行哪些工作，以減輕鐮狀細胞貧血症患者的負擔？

Yes, yes, great question. Alethia, let me just step one step back and make sure everyone is tracking with you on where we are with the CTX001 program today and then where we're going with conditioning regimens that we're looking to improve. Okay. So where are we today? Across the sickle cell and beta thalassemia programs, we have completed enrollment. The initial target was 45 patients in each program. Each of the studies was oversubscribed, and we have more patients than that and we have completed enrollment. We have dosed more than 70 patients. And we are looking, as I said in my prepared remarks, towards a filing towards the end of this year. This program is with busulfan-based, single-agent myeloablative therapy. And we think that, that regimen with the benefit risk that it provides would be applicable to about 32,000 people in the U.S. and Europe with sickle cell and beta thal. 25,000 of those would be sickle cell patients and the majority of those in the U.S.

是的，是的，問得好。 Alethia，我先退一步，確保大家都了解我們目前在CTX001專案上的進展，以及我們正在努力改進的預處理方案。好的。那麼，我們目前的進展如何？在鐮狀細胞貧血和β地中海貧血計畫中，我們已經完成了病患招募。最初的目標是每個項目招募45名患者。每個研究都超額完成了招募，我們招募的患者人數超過了預期，並且已經完成了招募。我們已經為70多名患者進行了給藥。正如我在準備好的演講稿中所說，我們計劃在今年年底前提交申請。本計畫採用的是基於白消安的單藥清髓療法。我們認為，考慮到該方案的獲益風險，它將適用於美國和歐洲約32,000名鐮狀細胞貧血和β地中海貧血患者。其中 25,000 人是鐮狀細胞貧血症患者，而美國的患者大多是鐮狀細胞貧血症患者。

But to unlock the full potential, which is, I would say, about 150,000 patients in the U.S. and Europe, we do see gentler conditioning regimens being key to that. We have programs internally at Vertex. We have recruited a world-renowned team in our, what we call, VCGT, Vertex Cell and Gene Therapies (sic) [Vertex Cell and Genetic Therapies] division. We -- our partners at CRISPR also have programs in improved conditioning as do a number of other academic and biotechnology -- other biotech companies.

但要充分發揮其潛力——我認為，這大約能惠及美國和歐洲的15萬名患者——我們認為更溫和的預處理方案至關重要。 Vertex公司內部就有相關的項目。我們組建了一支世界一流的團隊，隸屬於我們稱為VCGT（Vertex細胞和基因療法）的部門。我們－以及我們在CRISPR的合作夥伴，還有其他一些學術機構和生技公司，也都在進行改善預處理方案的計畫。

I will say, Alethia, that I think that this is a problem that will be solved. And I say that for 2 reasons. One, we have line of sight on to the biology. We understand the cell surface markers and the ligands that we could use to pursue the cell types that we are trying to deplete selectively. And two, because this kind of approach, this gentler conditioning regimen would have applicability beyond sickle cell and beta thal in oncology. And so I do think that this is a problem that is going to be solved.

阿萊西亞，我認為這個問題終將得到解決。原因有二。第一，我們已經掌握了其中的生物機制。我們了解細胞表面標記和配體，可以利用它們來選擇性地清除我們想要清除的細胞類型。第二，這種方法，這種較溫和的預處理方案，其應用範圍不僅限於鐮狀細胞貧血和β地中海貧血，也可能擴展到腫瘤治療領域。因此，我確實認為這個問題終將得到解決。

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 have a couple also on CTX001. The first one is from a regulatory perspective, what would you highlight, Reshma, that regulators may need to see? Is it stuff like number of patients, median follow-up? Or is it better clarity on things like manufacturing scale up?

關於CTX001，我也有幾個問題。第一個問題是從監管角度出發的，Reshma，您認為監管機構可能需要關注哪些方面？是患者數量、中位追蹤時間之類的資訊嗎？還是生產規模擴大等方面的更清晰說明？

And then on the commercial front, I'm just trying to think of the arguments you can make with the curative approach and the cost savings you can make. So is there an evaluation ongoing on treatment costs that you're doing maybe in parallel to support reimbursement? Things along those lines.

在商業方面，我正在思考如何論證這種治療方法的療效以及它能帶來的成本節約。你們是否正在進行治療成本評估，以支持報銷？諸如此類的問題。

Yes, sure thing, Geoff. Geoff, I'm going to start, and then I'll turn it over to Stuart to tell you a little bit about how we see the burden of this disease with regard to the regulatory next steps. The most important thing to share with you is that we are the beneficiaries of almost every regulatory designation you could imagine on both sides of the pond. PRIME, Orphan, RMAT, which is the cell and genes for breakthrough designation, so we've had the benefit of having discussions with the regulators over time. You are right about the 2 outstanding items. It's about the number of patients and the duration of follow-up.

好的，當然可以，傑夫。傑夫，我先來，然後我把麥克風交給斯圖爾特，讓他簡單談談我們是如何看待這種疾病在監管方面的後續影響的。最重要的是，我們幾乎獲得了大西洋兩岸所有你能想到的監管認定。例如PRIME認定、孤兒藥認定、RMAT（突破性療法認定，即細胞與基因療法認定），所以我們一直以來都受惠於與監管機構的討論。你說得對，還有兩個懸而未決的問題。一個是患者數量，另一個是追蹤時間。

With regard to your question on manufacturing, in the grand scheme of things, Geoff, this is an easier manufacturing approach. I don't mean to suggest it's easy, but it is easier because it's an ex-vivo approach and it requires just the Cas9 enzyme and the guide RNA.

關於你提出的生產製造方面的問題，Geoff，從整體來看，這是一種更簡單的生產方法。我並不是說它很容易，但它的確更簡便，因為它是一種體外方法，只需要Cas9酶和引導RNA。

Our partners at CRISPR were very thoughtful. And from the start, we planned for the manufacturing that we are using in clinical trials to be the same process that we use in our commercial program. And not only that, it's also the same site, the same exact sites that we are using to manufacture in our clinical trials program are the same sites that we expect to use when we commercialize. So that all is proceeding to plan.

我們在CRISPR的合作夥伴考慮得非常周到。從一開始，我們就規劃臨床試驗中使用的生產流程與商業化專案所使用的流程完全一致。不僅如此，生產地點也完全相同，臨床試驗計畫使用的生產基地與我們商業化計畫預期使用的生產基地完全相同。所以一切都在按計劃進行。

I'm going to ask Stuart to comment on the burden of disease and how we see that. Stuart?

我想請史都華談談疾病負擔以及我們是如何看待它的。史都華？

Yes, Geoff, so you asked a great question, these are obviously lifetime conditions and have a significant clinical but also economic burden on patients and on the health care system. There are some published data on this topic. They're not terribly up to date, many of them. So as you might expect, we are working to develop updated estimates of the economic impact of sickle cell and beta thalassemia. It is very, very significant.

是的，傑夫，你問了一個很好的問題。這些顯然都是終身疾病，不僅對患者造成巨大的臨床負擔，也對醫療保健系統造成沉重的經濟負擔。關於這方面的數據已經有一些發表，但其中許多數據都不是最新的。所以正如你所料，我們正在努力更新鐮狀細胞貧血症和β地中海貧血的經濟影響評估。其影響非常巨大。

It's obviously impacted by things like in sickle cell disease, the cost of the vaso-occlusive crisis, particularly if they lead to hospitalizations and the other medications that patients take. In thalassemia, it's obviously the burden of transfusions and then also some of the additional care that patients can require because of the transfusion such as iron chelation and other supportive care. So we are working to generate updated estimates of the economic and indeed, social burden of sickle cell disease and thalassemia, and that will be an important part of the context to demonstrating the cost effectiveness of a onetime curative therapy like CTX001.

顯然，鐮狀細胞疾病等疾病的治療成本會受到多種因素的影響，例如血管阻塞危象的治療費用，尤其是當危象導致住院治療以及患者服用其他藥物的費用。地中海貧血的治療成本則主要體現在輸血負擔上，以及患者因輸血而可能需要的其他護理，例如鐵螯合治療和其他支持性治療。因此，我們正在努力更新鐮狀細胞疾病和地中海貧血的經濟和社會負擔估算，這將成為論證CTX001這類一次性治癒療法成本效益的重要組成部分。

Our next question comes from the line of 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。

Congratulations on the quarter and the year. You've obviously shown very promising data from the first patients with the VX-880 for diabetes. And I guess I'm curious, how consistent should we expect the effects to be patient to patient with this type of approach? How are you feeling overall about the safety profile as you've continued to enroll patients? And what will be your aim as you move from half to full doses? Would it be generating a more rapid response -- an even more rapid response than you've seen or potentially moving towards complete normalization of some of the key parameters?

恭喜您本季和本年度的出色表現。您顯然已經展示了VX-880用於治療糖尿病的首批患者的非常令人鼓舞的數據。我想問的是，採用這種方法，我們應該預期療效在不同患者之間有多大的一致性？隨著您持續招募患者，您對該藥物的安全性有何整體感受？從半劑量過渡到全劑量時，您的目標是什麼？是希望獲得更快的起效速度－比您目前觀察到的更快，還是希望最終能使某些關鍵指標完全恢復正常？

Yes, great question. There's a number of questions in there. And I think if I try to wrap up what you are foundationally asking is how do we see this program progressing and what should you expect when we get to full dose because the one patient's data that we shared at half dose are really pretty impressive.

是的，問得好。這裡麵包含了很多問題。我想，如果我試著總結你最根本的問題是：我們如何看待這個專案的進展？當我們達到全劑量時，你們該期待什麼？因為我們分享的半劑量治療的那位患者的數據確實非常令人印象深刻。

Okay. So as you know, Brian, the really important part of these data and the reason we shared the data from the first patient are threefold: One, it was at half dose, yet the results, whether you look at the endogenous C-peptide levels -- and remember, this patient has 30 years of diabetes and made no endogenous insulin. That result was pretty impressive. The second is hemoglobin A1C, and the really significant decline in insulin was what made us share those results. It has not been -- results like that have simply not been seen in this field.

好的。布萊恩，如你所知，這些數據中真正重要的部分，也是我們分享第一位患者數據的原因有三點：第一，雖然劑量只有一半，但結果卻令人印象深刻。無論是內源性C肽水平－要知道，這位患者患有糖尿病30年，而且體內完全沒有胰島素。這個結果非常驚人。第二點是糖化血紅素A1c，胰島素水平的顯著下降促使我們分享這些結果。此前，在這個領域從未出現過這樣的結果。

With regard to consistency, what we are aiming for here is a functional cure for this disease. So we are expecting patients to consistently have elevations in C-peptide, decreases in hemoglobin A1C and improvements, if not elimination of exogenous insulin.

就療效的穩定性而言，我們的目標是實現這種疾病的功能性治癒。因此，我們預期患者的C肽水平會持續升高，糖化血紅蛋白A1c水平會持續降低，並且外源性胰島素的使用會得到改善，甚至最終能夠完全停用。

With regard to the safety profile, I'm only going to comment on the data that we've already shared. And as I said, the therapy was well-tolerated in my prepared remarks. And importantly, because as you think about hemoglobin A1C decreasing, you have to think about the patient not suffering from low glucose levels, and that didn't happen. This patient has been free of severe hypoglycemic episodes since the periodic operative period.

關於安全性方面，我只會就我們已經分享的數據發表評論。正如我在準備的演講稿中所說，這種療法的耐受性良好。重要的是，因為在考慮糖化血紅蛋白A1c降低的同時，也必須考慮患者是否會出現低血糖，而這種情況並沒有發生。自從定期手術以來，這位患者一直沒有嚴重的低血糖事件。

So as we look forward, what are we looking to? The study is up and running in multiple sites. We are looking to enroll more patients, dose more patients. And the reason we are looking to go to full dose is because the -- we are going for a curative approach. And when you look at the history and the experience of cadaveric islet transplants, the quality and quantity of cells are very related to the durability of the response.

展望未來，我們的目標是什麼？這項研究已在多個中心啟動並進行。我們計劃招募更多患者，並增加接受治療的患者人數。我們之所以計劃採用全劑量治療，是因為我們追求的是治癒性治療。回顧屍體胰島移植的歷史和經驗，細胞的品質和數量與療效的持久性密切相關。

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。

What is the bar here for the 2 Phase II acute pain programs that are reading out this quarter in terms of moving forward? And then separately, could you speak to your capital allocation plans?

本季公佈結果的兩項二期急性疼痛治療​​項目，其後續進展的目標為何？另外，能否單獨談談貴公司的資金配置計畫？

Yes, sure thing, Salveen. Let's take the pain studies first. We are in 2 acute pain studies, 1 in abdominoplasty, a model of soft tissue pain and 1 in bunionectomy, which is seen as a model for pain in a "hard tissue." Both studies are very similarly designed. They are dose-ranging studies with a placebo control arm and an opioid reference group.

好的，沒問題，薩爾文。我們先來看疼痛研究。我們目前有兩項急性疼痛研究，一項是腹部整形術，屬於軟組織疼痛模型；另一項是拇外翻切除術，屬於「硬組織」疼痛模型。這兩項研究的設計非常相似，都是劑量範圍研究，設有安慰劑對照組和鴉片類藥物參考組。

What we're really looking for here is therapeutic pain relief without the side effects of opioids. And obviously, the most important one of that is the addictive potential. I don't have to tell you about the opioid epidemic raging in the U.S. and we have very high confidence in VX-548 on the safety side and the lack of addictive potential because there is simply no receptors for NaV1.8 in the central nervous system.

我們真正追求的是既能有效緩解疼痛，又沒有鴉片類藥物副作用的藥物。顯然，其中最重要的副作用就是成癮性。美國鴉片類藥物濫用危機的嚴重程度無需贅述，我們對VX-548的安全性和無成癮性充滿信心，因為中樞神經系統中根本不存在NaV1.8受體。

On the efficacy side, we go into this with confidence for 3 reasons; one, this is a genetically validated target; two, this is also a pharmacologically validated target with our own VX-150 data that you'll remember had positive proof-of-concept across acute, neuropathic and, let's call it, musculoskeletal pain; and three, this particular molecule, VX-548, amongst its other properties is also multifold, more potent. So that's really what we're expecting, and that's how we are looking at the 548 program.

在療效方面，我們對此充滿信心，原因有三：第一，這是一個經過基因驗證的靶點；第二，這也是一個經過藥理學驗證的靶點，我們自己的VX-150數據已經證實了這一點，您可能還記得，VX-150在治療急性疼痛、神經性疼痛以及我們還稱之為肌肉骨骼疼痛方面都取得了積極的概念，第三分子這就是我們對VX-548專案的預期，也是我們看待這個專案的方式。

With regard to capital allocation, Salveen, we've been very consistent as we've talked about our capital allocation strategy that we believe that the greatest value we can create is by investing our capital in innovation, both internal and external. We've never invested more than we are today in internal innovation. And you see the results of that with VX-147 with the Phase II results and its progress into pivotal development.

關於資本配置，薩爾文，我們一直堅持一個非常一致的理念：我們的資本配置策略是，將資本投資於創新，包括內部創新和外部創新，以創造最大的價值。我們從未像今天這樣大力投資內部創新。 VX-147 的二期臨床試驗結果及其進入關鍵性開發階段的進展證明了這一點。

With the 2 Phase II studies we just spoke about in the pain program, not to mention the VX-121/561/tezacaftor program in CF in Phase III. And you also see it with our investments that we've made in business development with the Semma acquisition and the really terrific results, albeit early from the VX-880 program.

我們剛才提到的疼痛治療項目中的兩項 II 期研究，更不用說正在進行的囊性纖維化 VX-121/561/tezacaftor III 期計畫了。此外，您還可以看到我們在業務發展方面的投資，例如收購 Semma，以及 VX-880 專案取得的非常出色的成果，儘管目前還處於早期階段。

And going forward, what you can expect is the same. Our strategy is working, and we expect that we will continue to invest in both internal and external innovation.

展望未來，情況依然如此。我們的策略行之有效，我們將持續加大對內部和外部創新的投入。

Our next question comes from the line of Colin Bristow from UBS.

我們的下一個問題來自瑞銀集團的 Colin Bristow。

Congrats on the quarter and the strong '22 guide. Not to sort of flog a dead horse, but we're obviously getting closer to a competitor CF trip at readout. And I'd love you to remind us specifically, what is it that gives you comfort around the level of competitive threat or the lack of?

恭喜貴公司本季業績出色，並發布了強勁的2022年業績指引。雖然不想老生常談，但我們顯然越來越接近在業績公佈時與競爭對手進行財務預測的階段。我想請您具體說明一下，是什麼讓您對當前的競爭威脅程度（或缺乏競爭威脅）感到放心？

And then just a quick one on your type 1 diabetes [one, the 880], on the encapsulation device, you said you've overcome fibrosis and vascularization issues. Is there a drug-eluting component to this device?

然後，關於您的第1型糖尿病（880型），關於封裝裝置，您提到您已經克服了纖維化和血管化問題。這個裝置有藥物洗脫組件嗎？

Yes, Colin, thanks so much for the kind words and for the question. Let's do type 1 diabetes first, and then we'll go back and do CF landscape.

是的，科林，非常感謝你的鼓勵和提問。我們先來了解第1型糖尿病，再回頭探討囊性纖維化的情況。

All right. The -- we talked a little bit about the results on patient #1 and the progress to full dose and why we're doing that and what our real goal is and to restate that, we're looking to bring a functional cure forward for this disease. The other reason those results in that first patient are so important is because those same cells, exactly those same cells, are the cells that are in the cell plus device program. And that cells plus device program is now in its IND-enabling study space, and we do expect to file that IND this year.

好的。我們剛剛簡單聊了聊1號患者的治療結果、達到全劑量治療的進展、我們這樣做的原因以及我們的真正目標。重申一下，我們的目標是為這種疾病找到有效的治癒方法。首例患者的治療結果之所以如此重要，另一個原因是，這些細胞，正是我們「細胞+器械」計畫中所使用的細胞。目前，「細胞+器械」項目正處於IND申報前的準備階段，我們預計今年將提交IND申請。

I will keep my comments about the encapsulation at a high level. But what I can tell you is that the device has been specifically configured to allow vascularization and exchange of oxygen and nutrients, to allow insulin to go back and forth and for it to sense glucose but to keep the immune system out. I'll also tell you that it's not just the materials, but it's the geometry. And our studies to date, including in large animal models, tell us that we've overcome the historic complications with foreign body response and the lack of the ability to properly oxygenate and provide nutrients to the cells.

關於封裝技術，我將只做簡單介紹。但我可以告訴大家的是，裝置經過特殊設計，能夠促進血管化和氧氣、營養物質的交換，使胰島素能夠來回流動並感知葡萄糖，同時又能防止免疫系統的攻擊。我還想說，關鍵不僅在於材料，還在於其幾何結構。我們迄今為止的研究，包括大型動物模型研究，顯示我們已經克服了以往異物反應以及細胞供氧和營養供應不足等難題。

With regard to the CF landscape and we've talked about it before, but I'll remind that as you look at the CF landscape today, the bottom line is that TRIKAFTA has simply set a very high bar. More patients around the globe are treated with a VERTEX CFTR modulator today than ever before. And the vast majority of that is with TRIKAFTA.

關於囊性纖維化（CF）的治療現狀，我們之前也討論過，但我還是要強調，縱觀當今的CF治療格局，TRIKAFTA無疑樹立了極高的標準。如今，全球接受VERTEX CFTR調節劑治療的患者數量比以往任何時候都多，而其中絕大多數患者使用的是TRIKAFTA。

TRIKAFTA's clinical trial data are remarkable. You remember the ppFEV1 at 14% from the clinical trial results. But it's not just the acute changes in lung function. As I shared in my prepared remarks, TRIKAFTA now has long-term data from the 96-week follow-up study from the pivotal trials. And what it shows is no decline in mean lung function over time, the first for any CFTR modulator. And now we also have data, real-world data from the CF registry. And that shows improvements in really important measures like transplantation, pulmonary exacerbation and death. And so you put this all together and what you really have is if there's any medicine that will compete with TRIKAFTA, it has to go head-to-head against TRIKAFTA in clinical trials. That's exactly what we're doing with 121/561/tezacaftor. It has to have improved benefit. And you have to have the long-term data. The only company that has that is Vertex. And the most advanced competitor to TRIKAFTA is our own 121/561/tezacaftor, which is already in Phase III studies.

TRIKAFTA 的臨床試驗數據令人矚目。您可能還記得臨床試驗結果中 ppFEV1 達到 14% 的數值。但這不僅體現在肺功能的急性變化。正如我在事先準備好的演講稿中所述，TRIKAFTA 現在擁有來自關鍵性試驗 96 週追蹤研究的長期數據。數據顯示，隨著時間的推移，平均肺功能沒有下降，這是所有 CFTR 調節劑的首例。此外，我們現在還有來自囊性纖維化登記處的真實世界數據。這些數據表明，在移植、肺部急性惡化和死亡等重要指標方面均有所改善。因此，綜合所有數據，我們得出結論：任何想要與 TRIKAFTA 競爭的藥物，都必須在臨床試驗中與 TRIKAFTA 進行直接比較。這正是我們正在對 121/561/tezacaftor 所做的。它必須具有更佳的療效，並且必須擁有長期數據。目前只有Vertex公司擁有這種技術。而TRIKAFTA最先進的競爭對手是我們自己的121/561/tezacaftor，它已經進入III期臨床試驗階段。

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

我們的下一個問題來自 Truist Securities 的 Robyn Karnauskas。

So a real quick one. So just for 548, can -- does that new molecule has the ability to work in neuropathic pain? I notice that you didn't do a trial this time with that molecule. And then on type 1 diabetes program, there is going to be some patient data coming out of Viacyte and CRISPR with an edited embryonic stem cell program that they have. And I was just curious like when we see that data, like how do you see that as a read to whether or not your edited program will work without immune suppressants?

簡單問一下。就548這個新分子而言，它是否能夠治療神經性疼痛？我注意到這次你們沒有用這個分子做臨床試驗。另外，關於1型糖尿病項目，Viacyte公司和他們的CRISPR基因編輯胚胎幹細胞計畫將會公佈一些患者數據。我很好奇，當我們看到這些數據時，您如何看待這些數據，並以此來判斷您們的基因編輯計畫在不使用免疫抑制劑的情況下是否有效？

I know it's a less differentiated program potentially than [your cell line] versus your iPSC [cell line -- or your cell line]. And so just trying to understand the read that we should expect or how you're looking at that data when it comes out to the potential for using an edited version without immune suppression for your program?

我知道這可能不如[您的細胞系]與您的iPSC[細胞系—或您的細胞系]之間的差異化程度高。所以，我只是想了解，當涉及到在您的專案中使用未經免疫抑制的編輯版本時，我們應該預期得到什麼樣的結果，或者您是如何看待這些數據的？

Yes, yes, really great questions, Robyn. Let me take the neuropathic pain question first with 548 and then let's do type 1 diabetes.

是的，是的，羅賓，你問的問題都很好。我先回答關於神經性疼痛的問題（548），然後再討論第1型糖尿病。

Okay. the NaV1.8 axis, as I described earlier, is an exciting one. It's an exciting target for us because of the genetic validation but also because of the pharmacologic validation with VX-150, which had positive results not only in acute, but also neuropathic pain. So yes, I do expect VX-548 has potential in neuropathic pain.

好的。正如我之前提到的，NaV1.8軸是一個令人興奮的靶點。它之所以對我們來說是一個令人興奮的靶點，不僅是因為它已經通過基因驗證，還因為VX-150的藥理學驗證，VX-150不僅在急性疼痛中取得了積極成果，而且在神經性疼痛中也取得了積極成果。所以，是的，我確實認為VX-548在治療神經性疼痛方面具有潛力。

Unlike acute pain, which as the name implies, is a short-lived pain syndrome, neuropathic pain is a chronic disease state. So the kind of preclinical data and the work that we need to do and the package we need to put together is different, and that's what we're doing right now. But I do expect that the NaV1.8 axis and that target will be important in neuropathic pain. And I point you to the [NaV, 150 results] as the clearest reason to believe.

與急性疼痛（顧名思義，是一種短暫的疼痛症候群）不同，神經性疼痛是一種慢性疾病狀態。因此，我們需要收集的臨床前數據、需要進行的工作以及需要整合的資源都有所不同，而這正是我們目前所做的。但我確實認為NaV1.8軸及其靶點在神經性疼痛中發揮重要作用。而[NaV，150個結果]正是支持這一觀點最有力的證據。

With regard to the question around potentially getting to a point of having fully differentiated, allogeneic, insulin-producing pancreatic islet cells that could be edited to evade the immune system, here's the most important thing, you have to have the cells. It's not actually about the editing. It's not actually about the device. It's not actually about the off-the-shelf immunosuppressives. Those are 3 different ways to protect the cells from the immune system, but it's actually about the cells. And the only company that has these allogeneic, fully differentiated, pancreatic islet cells that make insulin and can make these cells in industrial quantities is Vertex. And we are working on multiple approaches to protect these cells from the immune system. VX-180 -- 880 uses the off-the-shelf immunosuppressives. The -- we call it VX-264. That's the cells plus device program that uses a device to protect the cells from the immune system. And then, of course, we have our program to edit the cells. But the key is it's the cells.

關於能否獲得完全分化、同種異體、能產生胰島素的胰島細胞，並對其進行基因編輯以逃避免疫系統攻擊的問題，最關鍵的是，你必須擁有這些細胞。關鍵不在於基因編輯，也不在於設備，更不在於現成的免疫抑制劑。這三種方法都可以保護細胞免受免疫系統攻擊，但關鍵在於細胞本身。目前，唯一擁有這些同種異體、完全分化、能產生胰島素的胰島細胞，並且能夠工業化生產這些細胞的公司是Vertex。我們正在研究多種方法來保護這些細胞免受免疫系統攻擊。 VX-180-880方案使用了現成的免疫抑制劑。而我們稱為VX-264的方案，則採用了一種結合細胞和設備的療法，利用設備來保護細胞免受免疫系統攻擊。當然，我們還有用來編輯單元格的程式。但關鍵在於單元格本身。

Our next question comes from the line of Mohit Bansal from Wells Fargo.

我們的下一個問題來自富國銀行的莫希特·班薩爾。

My congratulations as well. Maybe another one on VX-147. How well understood is the homogeneous nature of APOL1-mediated kidney diseases with proteinuria being the key marker here? I'm asking it because genetic testing is not routinely performed in these patients. So trying to understand if there is a lack of data that could be a gating factor for the FDA from making the leap from FSGS to broader APOL1-mediated kidney diseases.

我也要祝賀你們。或許可以再寫一篇關於VX-147的文章。目前對於以蛋白尿為關鍵標誌的APOL1介導的腎臟疾病的同質性了解多少？我之所以這麼問，是因為這些患者通常不會進行基因檢測。所以我想了解是否存在數據不足的問題，這是否會成為FDA在批准VX-147用於治療FSGS以外的更廣泛的APOL1介導的腎臟疾病時遇到的阻礙。

Yes. Mohit, thanks so much. So let me tell you a little bit about the background of APOL1-mediated kidney disease, and I think it will help you understand where we are and what it means for the future. And you're right about the fact that testing is low and that we need to do more in order to get patients tested. But as you also know, when we have a disease for which we have no therapy to offer patients, which is the case today with APOL1-mediated kidney disease, the motivation for patients and physicians understandably is not high to get a genetic diagnosis for something we can do nothing to be helpful.

是的，莫希特，非常感謝。那麼，讓我先簡單介紹一下APOL1介導的腎臟病背景，我認為這有助於您了解我們目前的狀況以及它對未來的意義。您說得對，檢測率確實很低，我們需要做更多工作來提高患者的檢測率。但您也知道，對於我們目前尚無有效療法的疾病（例如APOL1介導的腎臟病），患者和醫生自然不會有很高的積極性去做基因診斷，因為我們對此無能為力。

Okay. So the one APOL1 story is a very recent story. It's only about a decade, 12 years old that we have actually come to understand that the large amount of kidney disease, proteinuric kidney disease that we previously didn't understand in patients of African origin is APOL1-mediated kidney disease. This is only something we've figured out in the last 10 to 12 years.

好的。關於APOL1的研究是一個非常新的課題。我們直到大約12年前才真正認識到，先前在非洲裔患者中發現的大量腎病，特別是蛋白尿性腎病，是由APOL1介導的。這是我們在過去10到12年間才弄清楚的。

The homogeneity of the disease is clear, and I would even say obvious. And I say that because it's found in people who have kidney disease with proteinuria and 2 APOL1 alleles. That's how you define this group. And the underlying thread, therefore, is having 2 APOL1 alleles. There have been studies done in patients who have proteinuria and have 2 APOL1 alleles versus not. And when you have 2 APOL1 alleles, your outcomes are uniformly worse, you progress the kidney disease faster. That's the homogeneity.

這種疾病的同質性非常明顯，甚至可以說顯而易見。之所以這麼說，是因為它只見於患有腎臟病、伴有蛋白尿且攜帶兩個APOL1等位基因的人。這就是我們對這類人群的定義。因此，其根本特徵在於攜帶兩個APOL1等位基因。已有研究比較了攜帶兩個APOL1等位基因的蛋白尿患者和不攜帶兩個APOL1等位基因的患者。結果表明，攜帶兩個APOL1等位基因的患者預後較差，腎病變進展更快。這就是疾病的同質性所在。

Now the question you also ask is, is this well-known? Is this well understood? Because the -- our understanding of the genetics itself is fairly recent, there is an education effort, and that is part of what we're doing. We, ourselves, are working on [503c] diagnostic to accompany VX-147, and we're working with patients and physicians to ensure that diagnosis is supported.

現在您可能還會問，這是否廣為人知？是否已被充分理解？因為我們對遺傳學本身的理解還比較新，目前正在進行教育工作，這也是我們工作的一部分。我們自己也在研發與 VX-147 配套的 [503c] 診斷試劑，並與患者和醫生合作，確保診斷得到支持。

Our next question comes from the line of Evan Seigerman from BMO Capital Markets.

我們的下一個問題來自 BMO 資本市場的 Evan Seigerman。

One for you, Reshma. So from your view as a nephrologist, how important is EGFR as the measure of kidney disease progression? Is this change in proteinuria [confirm] the same measurement in your view?

雷什瑪，我有個問題想問你。身為腎臟科醫生，你認為EGFR作為衡量腎臟疾病進展的指標有多重要？你認為蛋白尿的變化是否也代表了同樣的指標？

Yes, it's a really great question, Evan. The thing I would share with you that's topmost on my mind is a -- if I wear my nephrology hat is that the hope that VX-147 offers is something that is truly novel and a big deal, a big deal in the renal community. The reason I say that is that this is one of the few genetically defined kidney diseases that we understand. And it is one of the first, if not the first precision medicine approach to a genetically driven kidney disease where we're targeting the underlying cause of the kidney disease.

是的，埃文，你問的這個問題非常好。我最想跟你分享的是——如果我以腎臟病專家的身份來說——VX-147帶來的希望是真正意義上的創新，意義重大，對腎臟病領域來說尤其如此。之所以這麼說，是因為這是我們目前了解的為數不多的幾種基因明確的腎臟疾病之一。而且，它也是針對基因驅動的腎臟疾病的首批精準醫療方法之一，甚至可能是第一個，我們旨在找到腎臟疾病的根本原因。

There is a relationship between proteinuria and GFR. So GFR is simply a measure of kidney function, right? Just like ppFEV1, which we're all very familiar with is a measure of lung function. And the relationship is this. Proteinuria measures kidney damage. It tells you that protein, which is supposed to stay on one side of the membrane is leaking out into the urine. When you have that and it progresses, the next step is decreases in GFR, a measure a function of the kidney. And unfortunately, the next steps after that are continued decline leading to either transplantation, dialysis or death. So these are very related measures. I think they are individually important and collectively very telling about the course of a patient.

蛋白尿與腎絲球濾過率（GFR）之間存在關聯。 GFR 簡單來說就是腎功能的指標，對吧？就像我們都很熟悉的肺功能指標 ppFEV1 一樣。它們之間的關係是這樣的：蛋白尿反映腎臟損傷。它顯示原本應該停留在腎小球濾過膜一側的蛋白質滲漏到了尿液中。當這種情況持續發展時，下一步就是 GFR 下降，而 GFR 是衡量腎功能的指標。不幸的是，之後腎功能會繼續惡化，最終可能導致腎臟移植、透析甚至死亡。所以，這些指標密切相關。我認為它們各自都很重要，而且綜合起來，能夠很好地反映患者的病情發展過程。

But maybe clinically speaking, what I would say is when you see a patient who has a proteinuric kidney disease, what are we trying to do in the clinic? We are trying to reduce proteinuria because there is a clear correlation between proteinuria and the hard outcomes of transplantation, dialysis and death.

但從臨床角度來說，我想說的是，當我們遇到患有蛋白尿腎病變的患者時，我們在臨床上該做什麼？我們努力降低蛋白尿，因為蛋白尿與腎臟移植、透析和死亡等嚴重後果之間有明顯的關聯。

Operator, we'll take 2 more questions.

接線員，我們再回答兩個問題。

Certainly. Our next question comes from the line of Hartaj Singh from Oppenheimer.

當然。我們的下一個問題來自奧本海默公司的哈塔吉·辛格。

I'll ask Stuart a question here, Reshma, to give you just a quick break.

雷什瑪，我在這裡問史都華一個問題，讓你稍微休息一下。

Stuart, on cystic fibrosis, you're doing -- you'll do close to $9 billion by the end of this year in cystic fibrosis. You've penetrated about 2/3, 75% of the population by then. How to think about where you can get to -- can you get to 90%-plus penetration with our CFTRs aside from the approach of Moderna?

斯圖爾特，關於囊性纖維化，你們今年年底在囊性纖維化領域的收入將接近90億美元。屆時，你們的療法將涵蓋約三分之二，也就是75%的人。除了Moderna的模式之外，你們的CFTR療法還能達到90%以上的覆蓋率嗎？

And then just quickly, assuming you get approval for sickle cell disease and beta thalassemia, how do you see an uptake? I mean would there be a warehousing in the beginning? Would there not be? Would the uptake be still on study? Just any color there.

然後，簡單問一下，假設你們的藥物獲準用於治療鐮狀細胞貧血症和β地中海貧血症，你們覺得市場接受度如何？我的意思是，初期會出現囤貨現象嗎？不會嗎？市場接受度會不會還在研究階段？請告訴我一些情況。

Great, Hartaj, thank you. So yes, our guidance for 2022 is $8.4 billion to $8.6 billion, as Charlie said in his prepared remarks, and that is a reflection of the momentum we have coming into 2022 from 2021, where we launched 6 to 11 TRIKAFTA in the U.S. and also secured numerous reimbursement agreements outside of the U.S. So our guidance incorporates that momentum and countries where we already have reimbursement agreements.

太好了，哈塔吉，謝謝。是的，正如查理在事先準備好的演講稿中所說，我們2022年的業績預期是84億至86億美元，這反映了我們延續2021年的發展勢頭。 2021年，我們在美國推出了6至11項TRIKAFTA計劃，並在美國以外地區達成了多項報銷協議。因此，我們的業績預期包含了這一發展勢頭以及我們已簽署報銷協議的國家/地區的業績。

As you said, though, we still have a lot of the CF population who could potentially benefit from a CFTR modulator, who are not yet being treated, somewhere north of 25,000. And we have a lot of confidence that we're going to get to the vast majority of those patients because they are in sort of 3 categories that we've demonstrated that we can address.

正如您所說，我們仍然有許多囊性纖維化患者可能受益於 CFTR 調節劑，但他們尚未接受治療，人數超過 25,000 人。我們非常有信心能夠惠及其中絕大多數患者，因為他們大致可以分為三類，而我們已經證明我們可以針對這三類患者進行治療。

The first one is patients who are in countries where we have reimbursement agreements but patients haven't been initiated. And that's largely because we're early in the launch curve, so think of countries like the Netherlands and Spain.

第一類患者來自我們已簽署健保報銷協議但尚未開始接受治療的國家。這主要是因為我們仍處於市場推廣的早期階段，例如荷蘭和西班牙這樣的國家。

The second category is countries where we have regulatory approval, but don't yet have reimbursement. So think countries like Australia.

第二類是我們已經獲得監管部門批准，但尚未納入醫保報銷範圍的國家，例如澳洲。

And the third category is younger patient groups where we've demonstrated with KALYDECO and ORKAMBI, but we can develop our products down into younger and younger age ranges.

第三類是年輕患者群體，我們已經用 KALYDECO 和 ORKAMBI 證明了這一點，但我們可以將我們的產品開發到越來越年輕的年齡層。

And as I said, TRIKAFTA is now approved for 6 to 11 here in the U.S. Very recently, KAFTRIO was approved for 6- to 11-year-old patients in both the EU and the U.K., and we're continuing to look at developing it for even younger patient group. So we have a lot of confidence that we're going to be able to get to the vast majority of those 25,000 patients over the next few years, and that's going to drive significant revenue growth for several years to come.

正如我所說，TRIKAFTA目前已在美國獲準用於6至11歲的兒童。最近，KAFTRIO也在歐盟和英國獲準用於6至11歲的患者，我們正在繼續努力，爭取將其開髮用於更小的患者群體。因此，我們非常有信心在未來幾年內惠及這25,000名患者中的絕大多數，這將推動未來幾年內顯著的收入成長。

And then as you mentioned, in addition to that, there's an additional 5,000-plus patients who aren't going to be able to respond to CFTR modulators because they produce no protein. And those other patients, we're seeking to address with our mRNA therapy. And as Reshma said in her prepared remarks, we've made good progress with that. So we have a lot of confidence. There's a lot of growth left in our CF franchise over the next several years.

正如您所提到的，除此之外，還有5000多名患者無法對CFTR調節劑產生反應，因為他們本身無法產生蛋白質。而對於這些患者，我們正致力於透過mRNA療法來解決。正如Reshma在事先準備好的演講稿中所說，我們在這方面取得了顯著進展。因此，我們充滿信心。未來幾年，我們的囊性纖維化治療業務仍有很大的成長空間。

In terms of the sickle cell and transfusion-developed thalassemia patient populations, again, we see a very significant opportunity there. As Reshma mentioned, approximately 32,000 patients who have severe disease between the U.S. and the EU. So we see a significant multibillion-dollar opportunity just treating those severe patients. Obviously, this is a different type of condition. This is a different therapy, and so I wouldn't be thinking of an uptake curve like we've seen in CF. It's not going to be anywhere as dramatic as that. But certainly, in that severe sickle cell and thalassemia populations, we see a multibillion-dollar opportunity ahead of us.

就鐮狀細胞貧血症和輸血誘發的地中海型貧血患者族群而言，我們看到了非常巨大的市場機會。正如雷什瑪所提到的，美國和歐盟大約有32,000名重症患者。因此，光是治療這些重症患者就蘊藏著數十億美元的巨大商機。顯然，這是一種不同的疾病，需要不同的療法，因此我不會設想像囊性纖維化那樣出現快速增長的趨勢。它不會像囊性纖維化那麼迅速。但可以肯定的是，在重症鐮狀細胞貧血症和地中海貧血患者族群中，我們看到了數十億美元的市場機會。

Then our final question for today comes from the line of Debjit Chattopadhyay from Guggenheim Securities.

那麼，我們今天的最後一個問題來自古根漢證券的 Debjit Chattopadhyay。

I want to go back to VX-147 with a 3-part question. #1, has the agency signaled a threshold for proteinuria reduction for accelerated approval? #2, if I understood your prior comments, the hard endpoints will be collected in the same study and will convert the subpart edge to a full approval? And #3, does the broader high-risk APOL1 proteinuric kidney disease population, is this also a double-hit disease? And do they progress to ESRD at the same speed at FSGS?

我想就VX-147提出三個問題。 #1，監管機構是否已明確規定了蛋白尿減少的閾值，以此作為加速批准的條件？ #2，如果我理解您先前的評論沒錯，關鍵終點數據將在同一項研究中收集，並最終轉化為完全批准？ #3，更廣泛的高危險APOL1蛋白尿腎病族群，是否也屬於雙重打擊疾病？他們進展為末期腎病變的速度是否與局部節段性腎絲球硬化症（FSGS）患者相同？

Yes, Debjit, you asked 3 important and related questions to the 147 program in AMKD. So let me try to answer them in this way. When we talk about the 147 program and targeting our pivotal development so that we can address the 100,000 people with 2 APOL1 alleles and proteinuric kidney disease, these people already have kidney disease, these are not people at risk for kidney disease. So the double-hit hypothesis is a good point. That's for "at risk to develop" disease. These people we are talking about already have disease.

是的，Debjit，你問了三個關於AMKD 147專案的重要且相關的問題。讓我試著這樣回答一下。當我們談到147項目，以及我們旨在透過關鍵性研發來解決10萬名攜帶兩個APOL1等位基因且患有蛋白尿性腎病的患者時，這些人已經患有腎病，而不是腎病高危險群。所以「雙重打擊」假說很有道理。它適用於「有患病風險」的人。而我們討論的這些人已經患有腎臟病。

The second question is a related question around proteinuria, its potential use as a surrogate endpoint for accelerated approval, and then how you do these studies in terms of the hard endpoint. As I said before, we simply haven't had our end of Phase II meeting. We'll have it soon enough, and then I can share details of the program with you. But generally speaking, the way that studies are done when proteinuria is the endpoint for accelerated approval is in the same study. The study continues and you go on to the composite endpoint of change in GFR, time to ESRD or death. And that's how you collect that hard endpoint.

第二個問題與蛋白尿相關，即它作為加速審批替代終點的潛在用途，以及如何就硬終點進行這些研究。正如我之前所說，我們還沒有召開二期臨床試驗結束會議。會議很快就會召開，屆時我可以與您分享專案詳情。但總的來說，當蛋白尿作為加速審批的終點時，研究方法是在同一項研究中進行的。研究持續進行，並持續觀察腎絲球濾過率（GFR）變化、進展至末期腎病變（ESRD）或死亡時間等複合終點。這就是收集硬終點資料的方法。

Okay. Operator, thanks very much. We appreciate everybody joining us tonight, the Investor Relations team in the office tonight. And happy to talk to you if you have additional questions. And you may now disconnect. Thank you very much.

好的。接線員，非常感謝。感謝今晚所有到場的投資人關係團隊成員。如果您還有其他問題，歡迎隨時提問。您可以掛斷電話了。非常感謝。

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。本次會議到此結束，您可以斷開連線了。祝您今天愉快。