福泰製藥 (VRTX) 2021 Q3 法說會逐字稿

Good evening. This is Michael Partridge. Welcome to the Vertex Third Quarter 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. Dr. Bastiano Sanna, Executive Vice President and Chief of Cell and Genetic Therapies at Vertex, will join us for Q&A.

晚安.我是邁克爾·帕特里奇。歡迎參加Vertex公司2021財年第三季財務業績電話會議。今晚，Vertex公司執行長兼總裁雷什瑪·凱瓦拉馬尼博士、營運長史都華·阿巴克爾和財務長查理·瓦格納將發表事先準備好的演講。 Vertex公司執行副總裁兼細胞與基因療法主管巴斯蒂亞諾桑納博士將參與問答環節。

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

我們建議您在收聽本次電話會議的同時查看網路直播投影片。本次電話會議正在錄音，錄音回放將在我們的網站上提供。

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and 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.

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。

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

我還想指出，我們今晚電話會議上將要討論的部分財務表現和指引是非GAAP準則的。

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

現在我將把電話轉給雷什瑪·凱瓦拉瑪尼醫生。

Thanks, Michael. I'm very pleased to be here with you tonight to discuss Vertex's progress through the first 3 quarters of 2021. During this year, we've meaningfully increased our leadership in cystic fibrosis, both with our approved CFTR modulators and with the CF programs advancing in our pipeline.

謝謝，麥可。我很高興今晚能和大家一起探討Vertex在2021年前三個季度的進展。今年，我們在囊性纖維化領域的領先地位得到了顯著提升，這體現在我們已批准的CFTR調節劑以及我們正在研發的囊性纖維化專案方面。

We've expanded and accelerated our R&D pipeline beyond CF, and these programs are now delivering clinical results. We have continued to demonstrate exceptional financial performance with significant growth in revenue, high operating margins and increasing cash flow. Let me elaborate more on each of these 3 points.

我們已將研發管線拓展並加速推進至囊性纖維化以外的領域，這些計畫目前已取得臨床成果。我們持續展現卓越的財務業績，收入顯著成長，營運利潤率高，現金流不斷增加。下面我將詳細闡述這三點。

Starting with CF, from a commercial perspective, third quarter product revenues were $1.98 billion, representing almost 30% growth year-over-year. This growth was driven by the performance of TRIKAFTA in the U.S., including the launch in children ages 6 to 11, and strong uptake OUS, where KAFTRIO has been reimbursed, including most recently in France and Italy.

從商業角度來看，CF業務第三季產品營收為19.8億美元，較去年同期成長近30%。這一增長主要得益於TRIKAFTA在美國的良好表現，包括其在6至11歲兒童中的上市，以及KAFTRIO在海外市場的強勁增長，KAFTRIO已在這些地區獲得醫保報銷，包括最近在法國和意大利的報銷。

Based on the strong performance, we are again increasing our revenue guidance and now expect total product revenues for 2021 to be between $7.4 billion and $7.5 billion. As we look forward, we expect that our CF business will continue to show robust growth in the years ahead as there are approximately 30,000 CF patients yet to be treated with our CFTR modulators.

基於強勁的業績表現，我們再次上調了營收預期，目前預計2021年產品總營收將在74億美元至75億美元之間。展望未來，我們預期囊性纖維化（CF）業務將在未來幾年繼續保持強勁成長，因為目前仍有約3萬名CF患者尚未接受我們的CFTR調節劑治療。

We've made important progress with our CF R&D pipeline programs this year as well. Based on strong preclinical and clinical results from our next-in-class triple combination regimen of VX-121, tezacaftor and VX-561 that demonstrate the potential for superior benefit to existing CFTR modulators, we've accelerated this program into pivotal studies. Both of the Phase III studies are head-to-head trials versus TRIKAFTA. Both studies are up and running and enrolling patients.

今年，我們在囊性纖維化（CF）研發管線計畫方面也取得了重要進展。基於我們新一代三聯療法（VX-121、tezacaftor 和 VX-561）的強勁臨床前和臨床結果，該療法展現出優於現有 CFTR 調節劑的潛力，我們已將該計畫加速推進至關鍵性研究階段。這兩項 III 期研究均為與 TRIKAFTA 的頭對頭試驗。目前兩項研究均已啟動並正在招募患者。

And we are not stopping there. We have identified even more promising regimens in our labs, building on 20 years of success translating our proprietary insights in CF biology into groundbreaking medicines. We are confident that these regimens will allow us to reach our long-standing goal of bringing CF patients to carrier levels of sweat chloride.

我們並未止步於此。在過去20年將我們獨有的囊性纖維化生物學見解轉化為突破性藥物的成功經驗基礎上，我們在實驗室中發現了更多前景廣闊的治療方案。我們相信，這些方案將幫助我們實現長期以來的目標，即讓囊性纖維化患者的汗液氯化物水平達到載體水平。

For the approximately 10% of people with CF who cannot benefit from a CFTR modulator, we're working on genetic therapies, including an mRNA approach. We and our partner, Moderna, have for some time now been able to synthesize mRNA constructs that restore CFTR protein function in vitro. The biggest challenge for us and for everyone in the field has been delivery of the mRNA to the target cells.

對於約10%無法從CFTR調節劑中獲益的囊性纖維化患者，我們正在研發基因療法，包括mRNA療法。我們和合作夥伴Moderna公司已經能夠合成在體外恢復CFTR蛋白功能的mRNA構建體一段時間了。對我們以及該領域所有人來說，最大的挑戰是如何將mRNA遞送到目標細胞。

I am very pleased to report that we and Moderna have made a significant breakthrough in delivery this past year. We have now demonstrated that we can efficiently deliver full-length CFTR mRNA to human bronchial epithelial cells in vitro to provide high levels of CFTR function and in vivo through the delivery of nebulized lipid nanoparticles to the bronchial epithelial cells in nonhuman primates.

我非常高興地報告，我們和 Moderna 在過去一年中在遞送技術方面取得了重大突破。我們現在已經證明，我們可以在體外高效地將全長 CFTR mRNA 遞送至人類支氣管上皮細胞，從而提供高水平的 CFTR 功能；並且在體內，我們可以透過霧化脂質奈米顆粒遞送至非人靈長類動物的支氣管上皮細胞，從而實現這一目標。

Based on these results, IND-enabling studies for our CFTR mRNA therapy are already underway, and we plan to file an IND and start clinical development in 2022. To close out on CF, I will note that just a few months from now, we will mark the 10th anniversary of the first approval of KALYDECO, our first CFTR modulator. And last month, marked 2 years since the U.S. approval for TRIKAFTA.

基於這些結果，我們針對CFTR mRNA療法的IND申報研究已經啟動，我們計劃於2022年提交IND申請並啟動臨床開發。關於囊性纖維化，我想指出，再過幾個月，我們將迎來首個CFTR調節劑KALYDECO核准十週年紀念日。而上個月，TRIKAFTA獲美國批准也已滿兩年。

For the Phase III clinical trials, our CF medicines have always been appreciated for their outstanding short-term benefits, not just significant increase in ppFEV1, but decreases in pulmonary exacerbations, increases in weight and increases in quality of life. We're now in a position where we have tens of thousands of patient years of safety data, and we could appreciate more fully the breadth of clinical benefit with analysis of longer-term real-world data.

在III期臨床試驗中，我們的囊性纖維化藥物一直因其卓越的短期療效而備受讚譽，不僅顯著提高了第一秒用力呼氣容積（ppFEV1），還減少了肺部急性加重，增加了體重，並提高了生活品質。如今，我們已累積了數萬名患者年的安全性數據，透過分析更長期的真實世界數據，我們可以更全面地了解其臨床效益的廣度。

What we find truly remarkable is that with KALYDECO, we now have data based on an average of 6 years of follow-up in patients 6 years and older and that includes a 78% reduction in the mortality rate and an 89% reduction in the rate of lung transplantation compared to patients who are not eligible for treatment.

我們發現真正令人矚目的是，KALYDECO 使 6 歲及以上患者的平均追蹤時間縮短至 6 年，結果顯示死亡率降低了 78%，肺移植率降低了 89%，而未接受治療的患者則沒有這樣的效果。

With TRIKAFTA, we now have data showing no decline in lung function after 2 years of follow-up from the pivotal trials. And this is a first for any CF medicine. I'd like to emphasize that from our perspective, it is these kinds of long-term data that ultimately determine physician and patient choice of regimens, particularly in CF where patients take CFTR modulators chronically over a lifetime.

TRIKAFTA 的數據顯示，在關鍵性試驗的兩年追蹤期內，患者的肺功能並沒有下降。這在囊性纖維化藥物中尚屬首次。我想強調的是，在我們看來，正是這類長期數據最終決定了醫生和患者對治療方案的選擇，尤其是在囊性纖維化領域，患者需要終生長期服用 CFTR 調節劑。

Let me turn to our pipeline outside of CF. First, to our type 1 diabetes programs and the unprecedented clinical data we recently shared. The pathophysiology of type 1 diabetes is well known. It results from the autoimmune destruction of pancreatic islet cells. Daily injections of insulin have saved the lives of these patients, but patients still suffer from severe long-term vascular complications of the disease, resulting in premature mortality.

接下來，我想談談我們在囊性纖維化以外的研發項目。首先，我想談談我們的第1型糖尿病計畫以及我們近期分享的前所未有的臨床數據。 1型糖尿病的病理生理機制已廣為人知，它是由自體免疫攻擊破壞胰島細胞引起的。每日註射胰島素挽救了這些患者的生命，但患者仍然會遭受嚴重的長期血管併發症，最終導致過早死亡。

And unfortunately, the treatment itself can lead to severe hypoglycemic episodes that can be associated with unresponsiveness, seizures and even death. Therefore, the holy grail for type 1 diabetes for decades has been to replace the damaged pancreatic islet cells and restore insulin production. Early clinical space using cadaveric islets have demonstrated the curative potential of this approach. The problem has been produced sufficient quality and quantity of islet cells to treat the millions of people with this disease.

不幸的是，這種治療本身會導致嚴重的低血糖發作，甚至可能引發意識喪失、癲癇發作，甚至死亡。因此，幾十年來，治療第1型糖尿病的終極目標一直是替換受損的胰島細胞，恢復胰島素分泌。早期利用屍體胰島進行的臨床試驗已經證實了這種方法的治癒潛力。問題在於，如何生產足夠數量和品質的胰島細胞來治療數百萬1型糖尿病患者。

Vertex has developed a proprietary process to make industrial quantities of allogeneic, stem cell-derived, fully differentiated islet cells that could serve the more than 2.5 million patients with type 1 diabetes. The clinical data from this first patient treated in our VX-880 program with these cells are truly remarkable with a single infusion at half the target dose combined with standard immunosuppression, routinely used in transplantation, we observed substantial improvements across multiple measures of islet cell function that were rapid, robust and durable through day 90.

Vertex公司開發了一種專有工藝，可大規模生產同種異體幹細胞衍生的完全分化胰島細胞，可望造福超過250萬1型糖尿病患者。我們VX-880計畫中首例接受此細胞治療的患者的臨床數據令人矚目：僅需單次輸注目標劑量的一半，並配合移植中常用的標準免疫抑制方案，我們便觀察到胰島細胞功能的多項指標均有顯著改善，且療效迅速、穩定，並持續至第90天。

Our stem cell-derived islets produce basal levels of insulin and increased insulin secretion appropriately in response to glucose stimulation. And in the 90 days following infusion, there was a significant reduction in blood glucose as measured by hemoglobin A1C despite a 91% reduction in exogenous insulin requirements. On the safety side, VX-880 was generally well tolerated. These cells are the product. They are the common denominator across our type 1 diabetes programs and these results derisk each of our 3 programs.

我們利用幹細胞衍生的胰島能夠產生基礎水平的胰島素，並在葡萄糖刺激下適當增加胰島素分泌。輸注後90天內，儘管外源性胰島素需求量減少了91%，但糖化血紅素A1c水平仍顯著降低。在安全性方面，VX-880整體耐受性良好。這些細胞是關鍵產品，也是我們所有1型糖尿病計畫的共同基礎，這些結果降低了我們三個項目的風險。

In the cells alone program, we use standard pharmacologic immunosuppressives. In the next program, we're using our proprietary device for immunoprotection of these cells. The IND-enabling studies for this program are already underway, and we plan to file the IND in 2022. And these same cells are the starting product for our gene-editing program designed to produce hypoimmune islet cells that can evade the immune system.

在目前的細胞單藥治療計畫中，我們使用標準的藥物免疫抑制劑。在下一個專案中，我們將使用我們自主研發的免疫保護裝置來保護這些細胞。該計畫的IND申報研究已經啟動，我們計劃於2022年提交IND申請。這些細胞也是我們基因編輯計畫的起始產品，該計畫旨在生產能夠逃避免疫系統攻擊的低免疫胰島細胞。

In cell and gene therapies, it is clear that the curative potential of these approaches is very high, and therefore, these therapeutics have potentially rapid path to registration involving a reasonable number of patients and a reasonable amount of follow-up. It is with this in mind that we're working with urgency on the VX-880 program.

在細胞和基因療法領域，這些療法的治癒潛力顯然非常高，因此，只要納入足夠數量的患者並進行合理的隨訪，這些療法就有可能快速獲得批准。正是基於此，我們正加緊推進VX-880專案。

Moving on to CTX001. CTX001 is our nonviral ex vivo gene-editing therapy that is designed as a onetime curative approach for sickle cell disease and beta thalassemia. It also stands out as a clear example of how we have accelerated our pipeline in 2021.

接下來是CTX001。 CTX001是我們研發的非病毒體外基因編輯療法，旨在一次治癒鐮狀細胞貧血症和β地中海貧血症。它也清楚地展現了我們在2021年如何加速推動研發管線。

CTX001 is our most advanced program outside of CF and continues to have strong momentum. We've now fully enrolled the target number of patients in both the sickle cell disease and beta-thalassemia clinical studies. Based on the clinical data we've presented to date, physician and patient interest in these trials has been high, and we have additional patients beyond the target 45 in each trial who are now completing eligibility assessments and will be enrolled this month.

CTX001 是我們除囊性纖維化領域外進展最快的項目，目前勢頭強勁。鐮狀細胞疾病和β-地中海貧血的臨床研究均已完成目標患者招募。根據我們迄今為止公佈的臨床數據，醫生和患者對這些試驗的興趣很高，每項試驗中還有超過45名目標患者正在完成資格評估，並將於本月入組。

We anticipate closing out our regulatory discussions in the near term and submitting regulatory filings for approval of CTX001 by year-end 2022 based on these clinical results. We have high confidence that CTX001 will be our next launched medicine. Stuart will comment on the progress of our commercial preparedness in his remarks.

我們預計在近期完成監管方面的磋商，並基於這些臨床結果，於2022年底前提交CTX001的上市申請。我們非常有信心CTX001將成為我們下一個上市的藥物。 Stuart將在演講中介紹我們商業化準備工作的進展。

On to VX-147 and where we will have results from the Phase II proof-of-concept study this quarter. This Phase II study of VX-147 is fully enrolled and focuses on patients with the form of FSGS that is mediated by APOL1. Our goal is to establish APOL1 inhibition as a new mechanism that can be used more broadly beyond FSGS, and in APOL1-mediated nondiabetic proteinuric kidney disease.

接下來是VX-147，我們將在本季公佈其II期概念驗證研究的結果。這項VX-147的II期研究已完成全部受試者招募，主要針對由APOL1介導的局部節段性腎小球硬化症（FSGS）患者。我們的目標是確立APOL1抑制劑作為一種新的治療機制，使其能夠更廣泛地應用於FSGS以外的疾病，以及APOL1介導的非糖尿病蛋白尿腎病變。

Based on the human genetics, the strongly validated target and the performance of VX-147 across a number of in vitro and in vivo assays we see our APOL1-mediated kidney disease or AMKD program as having a high probability of success. Some of the preclinical data from this program are the subject of a presentation at the American Society of Nephrology Meeting taking place later this week.

基於人類遺傳學數據、經過充分驗證的標靶以及VX-147在多項體外和體內試驗中的優異表現，我們認為我們的APOL1介導的腎臟疾病（AMKD）計畫具有很高的成功機率。該計畫的部分臨床前數據將在本週稍後舉行的美國腎臟病學會年會上進行報告。

In this Phase II study, we're assessing the safety of VX-147, and the key efficacy marker is reduction of proteinuria. Proteinuria is the clinically relevant endpoint and one that regulators have expressed openness to accepting in a homogeneous proteinuric kidney disease population. If our Phase II study in APOL1-mediated FSGS is successful, it would represent a first-in-class demonstration of proof-of-concept for an APOL1-mediated kidney disease and would propel us into pivotal development in the AMKD population, which includes, but is not limited to FSGS. In total, this represents approximately 100,000 people with AKD.

在這項 II 期研究中，我們正在評估 VX-147 的安全性，關鍵療效指標是蛋白尿的減少。蛋白尿是具有臨床意義的終點，監管機構已表示願意在同質性蛋白尿腎病變族群中接受此指標。如果我們在 APOL1 介導的 FSGS 患者中進行的 II 期研究取得成功，這將是針對 APOL1 介導的腎病的首個概念驗證，並將推動我們進入 APOL1 介導的腎病 (AMKD) 患者的關鍵性開發階段，該人群包括但不限於 FSGS。總計約有 10 萬名 APOL1 介導的腎臟病 (AKD) 患者。

I'll conclude the pipeline discussion with a few words on our pain program. We have high confidence in the NaV1.8 target for 3 main reasons. One, NaV1.8 is genetically validated. Two, NaV1.8 is also pharmacologically validated with our very own 3 positive Phase II proof-of-concept studies in acute, neuropathic and musculoskeletal pain.

最後，我想簡單談談我們的疼痛治療項目。我們對NaV1.8靶點充滿信心，主要有三個原因。首先，NaV1.8已通過基因驗證。其次，NaV1.8也通過藥理學驗證，我們自身進行的三項II期概念驗證研究均取得了積極成果，分別針對急性疼痛、神經性疼痛和肌肉骨骼疼痛。

And third, our lead molecule in the program, VX-548, has the key drug-like properties that we are looking for, including high selectivity and potency. The 2 Phase II dose-ranging studies in acute pain, bunionectomy and abdominoplasty with VX-548 are well underway. Based on enrollment progress, we currently expect data from these studies in Q1 of 2022.

第三，我們計畫中的先導化合物VX-548具備我們正在尋找的關鍵藥物特性，包括高選擇性和高效力。目前，VX-548在急性疼痛、拇外翻切除術和腹部整形術中的兩項II期劑量探索研究正在順利進行中。根據目前的入組進展，我們預計將於2022年第一季獲得這些研究的數據。

With that, I'll now turn it over to Stuart to review the commercial progress.

接下來，我將把工作交給斯圖爾特，讓他來評估商業進展。

Thanks, Reshma. I'll begin by reviewing the Q3 revenue performance of our CF medicines, which reached nearly $2 billion in Q3. U.S. revenues were $1.38 billion, an increase of 13% compared to the prior year, driven by the performance of TRIKAFTA, including the launch in the 6- to 11-year-old population.

謝謝，雷什瑪。我先回顧我們囊性纖維化藥物第三季的營收表現，該季營收接近20億美元。美國收入為13.8億美元，比上年同期增長13%，這主要得益於TRIKAFTA的出色表現，包括在6至11歲人群中的上市。

The launch in the 6- to 11-year olds is progressing rapidly, which is not surprising given the profile of the medicine and the recognition of the importance of early treatment of this relentlessly progressive disease. Outside the U.S., revenues were $601 million, an increase of more than 90% over the third quarter last year, driven by the ongoing launch of KAFTRIO in the 12-plus population.

該藥物在6至11歲兒童中的上市進展迅速，考慮到該藥物的特性以及人們對早期治療這種進展迅速的疾病重要性的認識，這並不令人意外。在美國以外，該藥物的收入為6.01億美元，比去年第三季度增長超過90%，這主要得益於KAFTRIO在12歲及以上人群中的持續上市。

In particular, KAFTRIO was off to a strong start in France and Italy, 2 major markets where we achieved reimbursement in June of this year.

尤其值得一提的是，KAFTRIO 在法國和義大利這兩個主要市場取得了強勁的開局，我們在今年 6 月就實現了這兩個市場的健保報銷。

We also signed a letter of intent for public reimbursement of TRIKAFTA in patients 12 and over in Canada. And since then, we've achieved multiple provincial reimbursement agreements and some 90% of patients covered by government insurance now have reimbursed access to TRIKAFTA.

我們也簽署了一份意向書，計劃在加拿大為12歲及以上的患者提供TRIKAFTA的公共報銷。自那以後，我們已與多個省份達成報銷協議，目前約90%的政府健保覆蓋患者已可報銷TRIKAFTA費用。

We have achieved reimbursement agreements for KAFTRIO/TRIKAFTA in more than 20 countries outside the U.S., just over 1 year since approval. And importantly, we've continued to achieve reimbursement at levels that reflect the high value of the triple combination regimen.

自 KAFTRIO/TRIKAFTA 獲批上市僅一年多，我們就已在美國以外的 20 多個國家達成了健保報銷協議。更重要的是，我們持續獲得與該三聯療法高價值相符的報銷水準。

As Reshma mentioned in her remarks, the profile of our CF medicines continues to be enhanced by term data. The start of the North American CF conferences tonight, and among several important abstracts, our data from the ongoing 192-week open-label extension study of TRIKAFTA, which shows there has been no loss of lung function during long-term follow-up. This is a first for any CFTR modulator to date, an important milestone for the field.

正如Reshma在發言中提到的，我們CF藥物的療效正不斷透過長期數據提升。今晚北美CF大會開幕，在眾多重要摘要中，我們公佈了正在進行的TRIKAFTA 192週開放標籤擴展研究的數據，該數據顯示，在長期隨訪期間，患者的肺功能未出現下降。這是迄今為止所有CFTR調節劑的首例，也是該領域的一個重要里程碑。

All previous long-term data for our other medicines showed a slowing of lung function decline. In contrast, these data show no loss of lung function for patients on TRIKAFTA after 96 weeks of follow-up.

先前我們其他藥物的所有長期數據顯示，肺功能下降速度均有所減緩。相較之下，這些數據顯示，服用 TRIKAFTA 的患者在 96 週的追蹤後，肺功能未出現下降。

Real-world data also being presented at the conference on KALYDECO show at an average of 6 years of follow-up, a 78% reduction in the mortality rate and an 89% reduction in the rate of lung transplantation compared to patients who were not eligible for the treatment. These data are very important for patients and the medical community because they more fully illustrate how our medicines address the long-term progression and complications of the disease.

在本次會議上公佈的關於 KALYDECO 的真實世界數據顯示，平均追蹤 6 年後，與不符合治療條件的患者相比，死亡率降低了 78%，肺移植率降低了 89%。這些數據對患者和醫學界都至關重要，因為它們更全面地展示了我們的藥物如何應對疾病的長期進展和併發症。

These data also have important implications for the future competitive landscape as they raise the bar in terms of what will be required to compete effectively.

這些數據對未來的競爭格局也具有重要意義，因為它們提高了有效競爭所需的標準。

Now turning to some of the other opportunities in our pipeline beyond CF. Our commercial experience in CF provides foundational capabilities, which we will be able to leverage to commercialize our next wave of transformative medicines. As Reshma mentioned, regulatory submissions for CTX001 are planned for the end of 2022. And so our launch preparation activities are well underway to ensure we are able to bring this potential medicine to patients globally immediately upon approval.

現在讓我們來看看囊性纖維化以外的其他研發機會。我們在囊性纖維化領域的商業經驗為我們提供了基礎能力，我們將能夠利用這些能力來實現下一批變革性藥物的商業化。正如Reshma所提到的，CTX001的監理申報計畫於2022年底進行。因此，我們的上市準備工作正在順利進行，以確保一旦獲得批准，我們就能立即將這種潛在藥物帶給全球患者。

We see CTX001 as a potential onetime curative approach for the approximately 32,000 patients with severe sickle cell disease or transfusion-dependent beta thalassemia in the U.S. and Europe. We've developed a deep understanding of the sickle cell and beta thalassemia markets, including where patients with these diseases are and the role that key referral and treatment centers will play to facilitate the treatment journey for patients.

我們認為 CTX001 有望成為美國和歐洲約 32,000 名重症鐮狀細胞疾病或輸血依賴型 β 地中海貧血患者的一次性治癒方案。我們對鐮狀細胞疾病和 β 地中海貧血市場有著深入的了解，包括這些疾病患者的分佈情況，以及關鍵轉診和治療中心在促進患者治療過程中所發揮的作用。

Consistent with our own internal market research, published physician surveys in the U.S. consistently indicate that they would expect 1/4 to 1/3 of their patients with sickle cell disease to be good candidates for a onetime curative approach using the current conditioning regimen, which is in line with the estimates of the numbers of patients with severe disease, approximately 25,000 sickle cell disease patients.

與我們自己的內部市場研究一致，美國已發表的醫生調查始終表明，他們預計有 1/4 到 1/3 的鐮狀細胞病患者適合使用目前的預處理方案進行一次性治愈，這與重症患者人數的估計相符，大約有 25,000 名鐮狀細胞病患者。

We are focused on 3 key areas of launch preparation for CTX001. First, people. We've hired many of the key people who will support the launch. Second, manufacturing. This is an area we have focused on from the earliest days of our work on CTX001 to ensure we can supply a consistent and high-quality product to the large number of patients we believe will benefit from the medicine on day 1 of the launch.

我們目前專注於CTX001上市準備工作的三個關鍵領域。首先是人員。我們已經聘請了許多關鍵人員來支援上市工作。其次是生產。從CTX001研發之初，我們就一直專注於生產環節，以確保在上市首日就能為眾多患者提供穩定、高品質的產品。我們相信，這些患者將從中受益。

Importantly, we are using the same manufacturing sites and processes for commercialization that we are using for our clinical trials. And third, patients, making sure we really listen, understand them and their experience, so we can provide them at launch with the information, resources and support they need as they consider treatment with CTX001.

重要的是，我們在商業化生產中採用與臨床試驗相同的生產基地和製程。第三，患者至上，我們確保真正傾聽、理解患者及其經歷，以便在產品上市時為他們提供所需的資訊、資源和支持，幫助他們考慮接受 CTX001 治療。

Now turning to pain. With our acute pain study is well underway, I thought I would remind you of the large market opportunity there. Acute pain accounts for 1.8 billion treatment days a year in the U.S. alone. And despite more than 90% of prescriptions being generic, this is still today a $4 billion market. That's typical branded pain medicine pricing of approximately $10 a day, a new medicine that takes even a portion of the current treatment days has multibillion dollar potential.

現在我們來談談疼痛。我們的急性疼痛研究進展順利，我想提醒大家，這方面蘊藏著巨大的市場機會。光是在美國，急性疼痛每年就佔用18億個治療日。儘管超過90%的處方藥都是仿製藥，但如今這仍然是一個價值40億美元的市場。這相當於品牌止痛藥每天約10美元的典型價格，一種新藥即使只佔用部分現有治療日，也具有數十億美元的潛在市場價值。

In light of the unprecedented data for VX 880, it's also worth highlighting the market opportunity in type 1 diabetes, which is very large. Let me start with the disease. Type 1 diabetes is a disease affecting more than 2.5 million people in the U.S. and Europe alone. It is a severely debilitating and life-shortening disease in which due to autoimmune destruction of pancreatic islet cells, the body produces little to no insulin.

鑑於VX 880前所未有的數據，值得一提的是，第1型糖尿病市場蘊藏著巨大的機會。首先，讓我們來了解一下這種疾病。光是在美國和歐洲，就有超過250萬人患有第1型糖尿病。這是一種嚴重的殘疾疾病，會縮短患者的壽命。由於自體免疫系統破壞胰島細胞，導致人體幾乎無法產生胰島素。

There are 2 patient populations to consider. First, those with severe enough diabetes for whom the benefit risk profile is positive for the cells alone plus standard immunosuppressive therapy. And secondly, the broader population who would be candidates for the cells encapsulated in our proprietary device or hyperimmune cells, where immunosuppression would not be needed. There are at least 60,000 patients with type 1 diabetes in the U.S. and Europe who are potential candidates for the first approach with VX-880. This group is made up of people who have severe, difficult to control forms of type 1 diabetes, characterized by impaired awareness of hyperglycemia and severe hyperglycemic events that can be life-threatening. There are approximately 45,000 patients in this category.

需要考慮兩類患者群體。第一類是病情嚴重的糖尿病患者，對他們而言，僅使用細胞療法合併標準免疫抑制療法即可獲得大於風險獲益。第二類是更廣泛的患者群體，他們可能適合使用我們專有裝置封裝的細胞或高免疫細胞，而無需免疫抑制治療。在美國和歐洲，至少有 6 萬名第 1 型糖尿病患者可能適合使用 VX-880 進行第一種治療。這部分患者患有嚴重的、難以控制的第 1 型糖尿病，其特徵是高血糖感知受損和可能發生危及生命的嚴重高血糖事件。這類患者約有 4.5 萬名。

And then there are people with type 1 diabetes who have had previous organ transplants, primarily kidney, and so are already on immunosuppression. There are about 15,000 patients in this category. Cadaveric islet and whole pancreas transplants are already performed, albeit in small numbers of these patients and give some sense of the value of this type of intervention in a patient with severe disease.

還有一些患有第1型糖尿病且曾接受過器官移植（主要是腎臟移植）的患者，他們本身就需要服用免疫抑制劑。這類患者約有15000人。雖然目前這類患者數量不多，但已經進行了屍體胰島移植和全胰臟移植手術，這在一定程度上體現了此類幹預措施對重症患者的價值。

For illustrative purposes, if you benchmark price in the U.S. for a pancreatic transplant of approximately $400,000 per patient as the price for a cell-based treatment, treating even a minority of the eligible patients would represent a multibillion-dollar opportunity.

舉例來說，如果以美國胰臟移植手術的價格（每位患者約 40 萬美元）作為細胞療法的價格基準，那麼即使只治療少數符合條件的患者，也將帶來數十億美元的商機。

Beyond VX-880, the cells plus device program which encapsulates the same cells for which we recently reported the unprecedented clinical data into our proprietary device that protects these cells from the immune system, could address the broader type 1 diabetes population, 2.6 million patients in the U.S. and Europe.

除了 VX-880 之外，細胞加設備計劃將我們最近報道了前所未有的臨床數據的相同細胞封裝到我們專有的設備中，該設備可以保護這些細胞免受免疫系統的攻擊，該計劃可以惠及更廣泛的 1 型糖尿病人群，即美國和歐洲的 260 萬患者。

In summary, I'm pleased with our continued progress in bringing our CF medicines to more patients around the world and excited about the many opportunities in our pipeline.

總而言之，我對我們不斷取得進展，將我們的 CF 藥物帶給世界各地更多的患者感到滿意，並對我們研發管線中的眾多機會感到興奮。

And with that, I'll turn it over to Charlie.

那麼，接下來就交給查理了。

Thanks, Stuart. In the third quarter of 2021, Vertex's long-term track record of strong revenue growth continued. Total product revenues were $1.98 billion, a 29% increase compared to the third quarter of 2020. Notably, TRIKAFTA represented nearly 80% of third quarter revenues as most eligible patients have switched to TRIKAFTA.

謝謝，斯圖爾特。 2021年第三季度，Vertex公司延續了其長期以來強勁的營收成長動能。產品總營收達19.8億美元，較2020年第三季成長29%。值得注意的是，TRIKAFTA的營收佔第三季總營收的近80%，因為大多數符合條件的患者都已轉用TRIKAFTA。

Our third quarter revenues included $1.38 billion in the U.S. and $601 million outside the U.S. Ex U.S. revenues for the quarter grew 92% over the prior year driven by continued strong uptake for KAFTRIO.

第三季度，我們的營收包括美國境內的 13.8 億美元和美國境外的 6.01 億美元。由於 KAFTRIO 的持續強勁成長，本季美國境外的營收比去年同期成長了 92%。

Our third quarter combined R&D and SG&A expenses were $561 million compared to $497 million for the third quarter of 2020, driven largely by investment in our clinical stage programs and our research pipeline. We expect our R&D investments will continue to be substantial as we advance our mid- and late-stage programs and make further clinical and regulatory progress across the pipeline.

第三季研發銷售、管理及行政費用合計為5.61億美元，而2020年第三季為4.97億美元，主要得益於臨床階段專案和研發管線的投資。我們預計，隨著中後期專案的推進以及管線在臨床和監管方面取得進一步進展，我們的研發投入將繼續保持強勁勢頭。

Our continued growth in revenues, combined with disciplined growth in OpEx translates to a year-to-date operating margin of 59%. And with our strong revenue and profitability, we ended the second quarter with $7 billion in cash.

營收持續成長，加上營運支出穩定成長，使得今年迄今的營業利潤率達到 59%。憑藉強勁的營收和獲利能力，我們在第二季末擁有 70 億美元的現金儲備。

Now to guidance. We are again revising our 2021 guidance upward for total product revenues in the range of $7.4 billion to $7.5 billion. This increase reflects continued outperformance as well as the rapid uptick we have seen with new launches. Year-over-year, this guidance represents 20% growth at the midpoint.

現在來說說業績展望。我們再次調高了2021年產品總營收預期，目標區間為74億美元至75億美元。此次上調反映了我們持續優異的業績表現，以及新產品上市帶來的快速成長。與上年相比，此預期中位數為20%。

As Stuart highlighted, the 6 to 11 launch in the U.S. and the uptake in France and Italy are proceeding very rapidly. Even with the outstanding growth in the number of patients treated this year, we have approximately 30,000 patients left to treat with our CFTR modulators.

正如史都華所強調的，6至11歲族群在美國的上市以及在法國和義大利的推廣進展非常迅速。即使今年接受治療的患者人數取得了顯著增長，我們仍有大約3萬名患者需要使用我們的CFTR調節劑進行治療。

Given our proven track record of securing new reimbursement agreements in additional markets, executing successful launches and expanding access to younger age groups, we are confident that we will be able to reach the vast majority of these patients with our medicines. We are maintaining our non-GAAP OpEx guidance for full year 2021 at; $2.25 billion to $2.3 billion. And for our non-GAAP tax rate, we continue to guide to a range of 21% to 22% this year.

鑑於我們在拓展市場、成功達成新的醫保報銷協議、成功推出新產品以及擴大年輕患者群體用藥範圍方面擁有良好的業績記錄，我們有信心能夠讓絕大多數患者受益於我們的藥物。我們維持2021財年非GAAP營運支出預期為22.5億美元至23億美元。此外，我們預計今年的非GAAP稅率仍為21%至22%。

In conclusion, 2021 will be another year of rapid growth for Vertex, and we are confident in our continued growth trajectory in CF and our ability to lead in this therapeutic area over the long term. TRIKAFTA is an exception medicine that sets a very high bar for efficacy and safety with IP that extends to the late 2030s.

總之，2021年對於Vertex而言將是另一個快速成長的年份，我們對在囊性纖維化領域的持續成長勢頭以及長期在該治療領域的領先地位充滿信心。 TRIKAFTA是一種卓越的藥物，其療效和安全性樹立了極高的標準，其智慧財產權保護期可延續至2030年代末。

With the emerging profile of our next regimens beyond TRIKAFTA as well progress we are making in genetic therapies for CF, we are well on our way to fulfilling our vision for achieving carrier levels in all CF patients.

隨著 TRIKAFTA 之後我們後續治療方案的逐漸成型，以及我們在囊性纖維化基因治療方面取得的進展，我們正朝著實現所有囊性纖維化患者達到攜帶者水平的願景穩步前進。

The VX-121/tezacaftor/VX-561 regimen is the only regimen with clinical data that shows the potential to meet or exceed the performance of TRIKAFTA and is years ahead of any other regimens in development.

VX-121/tezacaftor/VX-561 方案是唯一擁有臨床數據表明其有可能達到或超過 TRIKAFTA 療效的方案，並且比任何其他正在開發的方案領先數年。

Our pipeline beyond CF is both advancing and delivering. Progress with CTX001 and more recently, VX-880, continues to demonstrate the value we can create by investing in external innovation. We look forward to sharing additional data with you as ongoing trials come to completion in the coming months. We anticipate Phase II data for VX-147 in APOL1-mediated FSGS and Phase II data for VX-548 in acute pain in the near term.

除了囊性纖維化（CF）領域，我們的研發管線也正在穩步推進並取得成果。 CTX001 和近期推出的 VX-880 的進展持續展現了我們透過投資外部創新所能創造的價值。我們期待在未來幾個月內，隨著正在進行的臨床試驗的完成，與您分享更多數據。我們預計近期將公佈 VX-147 治療 APOL1 介導的局部節段性腎小球硬化症（FSGS）的 II 期臨床試驗數據，以及 VX-548 治療急性疼痛的 II 期臨床試驗數據。

With growing revenues and margins at the top of our peer group, we will deliver strong cash flows as we continue to reinvest in internal and external innovation to drive future growth. We are confident that the execution of our business strategy will continue to drive exceptional results for patients and the medical community as well as for our shareholders.

憑藉著在同業中領先的營收和利潤率，我們將繼續加大對內部和外部創新投入，推動未來成長，從而實現強勁的現金流。我們堅信，業務策略的有效執行將繼續為患者、醫療界以及股東帶來卓越的成果。

We will now open up the call to questions.

現在開始接受提問。

(Operator Instructions) Our first question comes from Salveen Richter with Goldman Sachs.

（操作員說明）我們的第一個問題來自高盛的薩爾文·里希特。

Two on the pipeline here. With regard to your collaboration with Moderna, I recognize that you're moving forward nicely with the -- with delivering mRNA via LNPs. Could you just talk about where you stand with using mRNA to explore the use of gene editing in lung cells?

這裡有兩個正在進行的項目。關於您與 Moderna 的合作，我了解到你們在透過脂質奈米顆粒遞送 mRNA 方面進展順利。您能否談談目前利用 mRNA 探索基因編輯在肺細胞中的應用進展？

And then secondly, on the development plan in type 1 diabetes, maybe you could touch base on the expanded collaboration with Arbor and how that fits into the outlook here.

其次，關於第 1 型糖尿病的發展計劃，您能否談談與 Arbor 擴大合作的情況，以及這如何融入我們目前的展望中？

Yes. Salveen, this is Reshma. Two questions in there. One about the mRNA program with Moderna. And another question, I think, on type 1 diabetes, but specifically with regard to our collaboration with Arbor and how we're thinking about the hypoimmune cell programs. Let me break it up into 2 parts. And maybe I'll expand a little bit on type 1 diabetes even beyond the collaboration with Arbor.

是的。薩爾文，我是雷什瑪。這裡有兩個問題。一個是關於與莫德納合作的mRNA計畫。另一個問題，我想，是關於第1型糖尿病的，特別是關於我們與A​​rbor的合作以及我們如何考慮低免疫細胞計畫。我把它分成兩個部分。也許我還會就第1型糖尿病，甚至在與Arbor的合作之外，再做一些補充說明。

Let's start with Moderna. We are very excited about the recent breakthrough we made that I shared in my prepared remarks on the mRNA program for the last 10% of patients with CF who simply don't make any CFTR protein, right? And when you step back and think about what do you really need to do to make a breakthrough here, it's really about 3 things. It's about the HBE cells, it's about the mRNA construct itself and then for shorts about delivery.

我們先來談談Moderna公司。我們最近取得了一項突破性進展，我之前在準備好的演講稿中也提到過，這項進展是關於針對最後10%的囊性纖維化患者的mRNA療法，這些患者體內根本不產生任何CFTR蛋白。我們對此感到非常興奮。仔細想想，要真正突破，關鍵在於三點：HBE細胞、mRNA構建體本身，以及遞送技術。

And it's this last one, delivery that's been a vexing problem for us in the field as a whole. And that's really the exciting news for today.

而這最後一個問題，也就是交付，一直是整個領域困擾我們的難題。這才是今天真正令人振奮的消息。

With regard to the HBE cells, these have been the workhorse for the 4 medicines that we have brought forward already. And I say that because they are the only model that translates from the bench to the bed side, right? And it's not only qualitatively so, but quantitatively so. And it's -- these HBE cells that have also been the workhorse for the program with Moderna.

就HBE細胞而言，它們一直是我們已推出的四種藥物研發的主力。之所以這麼說，是因為它們是唯一能夠從實驗室研究轉化為臨床應用的模型，對吧？而這種轉換不僅體現在品質上，也體現在數量上。這些HBE細胞也一直是與Moderna合作計畫的核心。

The second is the mRNA construct itself. And a number of years ago, we have struck up a partnership with Moderna, arguably the best company in the space of mRNA. And in all honesty, we have for some time been able to express full-length CFTR mRNA, the protein, and demonstrate its functionality. We've been able to do all that in vitro and HBE.

第二點是mRNA構建體本身。幾年前，我們與Moderna公司建立了合作關係，Moderna可以說是mRNA領域最優秀的公司。坦白說，我們已經能夠表達全長CFTR mRNA及其對應的蛋白質，並驗證其功能。我們已經在體外和人類支氣管內（HBE）完成了所有這些實驗。

But over the last several months, what we have now been able to do is demonstrate that we can deliver using nebulized LNPs to the appropriate cells. So that is to say, to bronchial epithelial cells, and we've done this in small animals and large, and we can see that we've delivered them to -- deliver the mRNA construct to the bronchial epithelial cells. No one else has claimed to do this, and certainly, no one else has been able to do this. So that's the big advancement that allows us to go and start our GLP-enabling studies. Those are already underway, and I do expect the IND to go in next year.

但在過去幾個月裡，我們已經證明，我們可以利用霧化脂質奈米顆粒（LNP）將藥物遞送至目標細胞，也就是支氣管上皮細胞。我們已經在小型動物和大型動物身上進行了實驗，並觀察到我們成功地將mRNA構建體遞送至支氣管上皮細胞。此前沒有人聲稱能夠做到這一點，當然，也沒有人能夠做到這一點。因此，這項重大進展使我們能夠啟動符合GLP規範的研究。這些研究已經展開，我預計明年就能提交新藥臨床試驗申請（IND）。

On type 1 diabetes, Salveen, there are the cells themselves. And then there are the mechanisms to cloak the cells, right? In the first program with VX-880, we use simple off-the-shelf pharmacologic immunosuppresses. In the second program, it's cells plus device. Those IND studies are already underway, IND next year. The third program is using these same cells. And for the cloaking, we use -- or plan to use gene editing, for example, to make hypoimmune cells. I'm going to ask Bastiano to comment just a little bit more on the hypoimmune program. Bastiano?

薩爾文，關於1型糖尿病，首先是細胞本身，其次是掩蓋這些細胞的機制，對吧？在第一個VX-880專案中，我們使用簡單的現成藥物免疫抑制劑。在第二個項目中，我們使用細胞加裝置。這些IND研究已經在進行中，預計明年提交IND申請。第三個項目使用相同的細胞。至於掩蓋機制，我們正在使用——或計劃使用——基因編輯技術，例如，製造低免疫細胞。我想請巴斯蒂亞諾再詳細談談低免疫計畫。巴斯蒂亞諾？

Absolutely. Thanks, Reshma. Thanks, Salveen, for the question. So like Reshma said, the product is actually the cell, the fully differentiated allogeneic beta cells. Aiding cells to cloak them from the immune system is a complex scientific challenge in general, specific to type 1 diabetes is -- represents are even more complicated because the call, that type 1 is an autoimmune disease.

當然。謝謝，雷什瑪。謝謝，薩爾文，你的提問。正如雷什瑪所說，產品其實是細胞，完全分化的同種異體β細胞。幫助細胞躲避免疫系統的攻擊本身就是一個複雜的科學挑戰，而對於第1型糖尿病來說，情況則更加複雜，因為第一型糖尿病是一種自體免疫疾病。

So we have to cloak the cells from the general allogeneic response, but also from the autoimmunity. And of course, it's fairly obvious that allogeneic rejection is something that has been worked on in the past, I would say, 2 decades. And of course, knocking out MHC Class 1 and 2 is the usual place where most people will go, and we're doing that internally.

所以我們必須保護這些細胞免受一般同種異體免疫反應以及自體免疫反應的侵害。當然，很明顯，同種異體排斥反應是過去二十年來人們一直在研究的問題。當然，敲除MHC I類和II類分子是大多數人通常會採取的策略，而我們也在內部進行這項工作。

There are other mechanisms we are exploring internally into collaboration to be sure that we take care of both types of immunity, the allogeneic rejection and autoimmunity.

我們正在內部探索其他合作機制，以確保我們能夠處理好兩種類型的免疫反應，即同種異體排斥和自體免疫。

Our next question comes from Michael Yee with Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

Good afternoon. I had 2 questions. It's been a long day. One is actually the announcement this quarter that you had moved your new CF program into Phase III. And I would like for you to comment about it in the context of how much clear differentiation, you're confident, it is from TRIKAFTA, but also in the context of the fact that everybody knows there's a competitor with coming -- data coming and how we should interpret that in the context of your data that you put out in the press release and how differentiated they could be.

午安.我有兩個問題。今天真是漫長的一天。第一個問題是關於您本季宣布的新囊性纖維化（CF）計畫已進入第三期臨床試驗。我想請您就此發表一下看法，您認為該專案與TRIKAFTA相比究竟有多大的差異化優勢？同時，考慮到大家都知道競爭對手即將發布數據，我們該如何解讀這些數據，並結合您在新聞稿中公佈的數據，來判斷該項目與TRIKAFTA的差異化程度。

The second question is more a question around the fact that you had commented about M&A earlier this year. In fact, Reshma had commented even about areas like Huntington's. And I just wanted you to refresh that view in the fact that you haven't really commented about that so much like you did earlier this year in the recent prior quarters.

第二個問題主要是關於您今年早些時候曾就併購發表過評論。事實上，雷什瑪甚至還評論過亨廷頓銀行等領域。我只是想請您重申您在這方面的觀點，因為在最近幾個季度，您不像今年早些時候那樣經常就此發表評論了。

Sure. Michael, let's do the CF question first, and then I'll come to capital allocation and M&A. So we have obviously established ourselves as a leader in CF over the last decade plus. And over the recent few years, we've expanded that leadership first with TRIKAFTA that can serve up to 90% of people with CF. And then with the specific program that you're asking about VX-121/561/tez, which preclinically in these HBE cells that are a model that translates from bench to bedside have demonstrated the potential to have even better efficacy than TRIKAFTA and in the clinical program from the Phase II results that we shared earlier in the year, where it looks that 121/561/tez has the ability to provide even more benefit than TRIKAFTA.

好的。邁克爾，我們先來討論囊性纖維化（CF）的問題，然後再談資本配置和併購。過去十多年來，我們顯然已經確立了在囊性纖維化領域的領先地位。近幾年，我們進一步鞏固了這一領先地位，首先是TRIKAFTA，它能夠惠及高達90%的囊性纖維化患者。然後是您提到的VX-121/561/tez項目，該項目在HBE細胞（一種能夠將實驗室研究成果轉化為臨床應用的模型）的臨床前研究中，已展現出比TRIKAFTA更優的療效潛力。此外，根據我們今年稍早公佈的II期臨床試驗結果，121/561/tez似乎能夠帶來比TRIKAFTA更大的益處。

Now make no mistake about it. TRIKAFTA sets an incredibly high bar. It's an extraordinary medicine with a very high benefit risk profile. But 121 frankly is the competitor to TRIKAFTA. It's years ahead of anything else in the field.

毋庸置疑，TRIKAFTA 樹立了極高的標竿。它是一種療效非凡的藥物，具有極高的獲益風險比。但坦白說，121 才是 TRIKAFTA 的真正競爭對手。它在該領域遙遙領先其他任何藥物。

If I just stand back and look at this, Mike, we have the best medicine for CF today in the form of TRIKAFTA. We have the best medicine for CF tomorrow in the form of 121/561/tezacaftor. And as I look long term, when you really think about CF, a chronic disease, children are born with this disease, they're going to take medicine for a lifetime chronically, you're going to need long-term data, the kind of data that Stuart talked about in his prepared remarks, mortality, lung transplantation, rate of decline. And to be clear, the only company that has the term data and the long-term data is Vertex.

麥克，如果我退後一步，客觀地看待這個問題，我們現在擁有治療囊性纖維化最好的藥物——TRIKAFTA。明天我們又將擁有治療囊性纖維化最好的藥物－121/561/tezacaftor。從長遠來看，囊性纖維化是一種慢性疾病，兒童出生時就患有此病，他們需要終生長期服藥，因此我們需要長期數據，就像史都華在事先準備好的發言稿中提到的那種數據，例如死亡率、肺移植率和病情惡化速度。需要明確的是，目前只有Vertex公司擁有中期和長期數據。

With regard to capital allocation, Charlie, I'll ask you to comment on that one.

關於資本配置問題，查理，我想請你談談你的看法。

Yes. Thanks, Reshma. And Mike, thanks for the question. Listen, it's very clear to us that innovation is the greatest driver of value in this industry. And we have shown that in CF that innovation that leads to transformative medicines for serious disease, create tremendous value both for patients and for shareholders. And we hope to do that in a number of other disease areas that are represented across our broad pipeline.

是的。謝謝，雷什瑪。麥克，謝謝你的提問。我們非常清楚，創新是這個產業價值的最大驅動力。我們在囊性纖維化領域已經證明，能夠帶來治療嚴重疾病的變革性藥物的創新，可以為患者和股東創造巨大的價值。我們希望在我們廣泛的研發管線涵蓋的其他疾病領域也能做到這一點。

So when it comes to capital allocation, our primary focus is on reinvestment in innovation, both internally and externally. You can see in the numbers, we've never invested more internally than we are today. And you can also see in the pipeline, the benefit of some of the smart external investments that we've made over the last couple of years, I would call out CRISPR and Semma specifically, but there are many others.

因此，在資本配置方面，我們的首要重點是創新再投資，包括內部和外部投資。從數據可以看出，我們目前的內部投資金額達到了歷史新高。同時，從專案儲備中也可以看出，過去幾年我們進行的一些明智的外部投資帶來了顯著成效，我特別想提及CRISPR和Semma，當然還有很多其他項目。

And so from a capital allocation standpoint, that reinvestment in innovation will continue to be the top priority. We've not commented specifically on types of deals because we're not looking for a certain type of deal. We're looking for tools and technologies and assets that fit and are well aligned with our research strategy. And as we identify those, you can expect that we'll continue to be disciplined and move quickly when we see an opportunity.

因此，從資本配置的角度來看，對創新進行再投資仍將是重中之重。我們沒有具體評論交易類型，因為我們並非在尋找特定類型的交易。我們尋找的是符合我們研究策略的工具、技術和資產。一旦發現合適的項目，我們將繼續保持嚴謹的態度，並在機會出現時迅速採取行動。

Our next question comes from Phil Nadeau with Cowen & Company.

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

Two from us, if that's okay, one commercial, one pipeline. On the commercial, the growth quarter-over-quarter was pretty impressive. Could you give us some sense of where you think you are penetrating the 6- to 11-year-olds in the U.S. And then those ex U.S. markets that you highlighted like France, Italy and Canada, and whether the type of growth that we've seen could continue into future quarters?

我們這裡有兩個問題，可以嗎？一個是商業通路，一個是產品線。關於商業管道，季度環比成長非常顯著。您能否簡單介紹一下您認為在美國6至11歲兒童市場滲透率如何？還有您提到的法國、義大利和加拿大等美國以外的市場，我們目前看到的成長動能能否延續到未來幾季？

And then second, on the pipeline in FSGS, as the data approaches, we're just curious to hear your most recent thoughts on what would be proof-of-concept for the molecule and what gives you confidence to go from the narrow FSGS population to the broader APOL1-mediated kidney disease population based on this initial data?

其次，關於 FSGS 的治療方案，隨著數據的臨近，我們很想聽聽您最近的想法，對於該分子的概念驗證是什麼，以及基於這些初步數據，是什麼讓您有信心從狹窄的 FSGS 人群擴展到更廣泛的 APOL1 介導的腎臟疾病人群？

I'm going to ask Stuart to comment on the question around CF and how we see growth, and then I'll come back and tell you a little bit more about the FSGS program. Stuart?

我打算請史都華就囊性纖維化（CF）以及我們如何看待其發展發表一些看法，之後我會回來再詳細介紹一下FSGS計畫。史都華？

Phil, yes, thanks very much for the question. And yes, I'm enormously proud of our execution in this third quarter that led to the results that you commented on and led us to increasing our revenue guidance today. It's hard to comment specifically on kind of quarter-on-quarter, what our growth rate is going to be, but I'll give you a sense for where we are in our overall growth trajectory. As you said, we got the approval for the 6- to 11-year-olds for TRIKAFTA in June, so just prior to this quarter starting. We also secured new reimbursement agreements in important markets like Italy and France and also most recently in Canada, and the launches there are underway.

菲爾，是的，非常感謝你的提問。是的，我對我們第三季的執行力感到非常自豪，而正是這些執行力帶來了你剛才提到的業績，也促使我們今天提高了營收預期。很難具體預測季度環比成長率，但我可以向你介紹我們整體的成長軌跡。正如你所說，我們在6月份獲得了TRIKAFTA用於6至11歲兒童的批准，也就是在本季開始之前。我們也在義大利、法國等重要市場以及最近在加拿大達成了新的報銷協議，這些市場的上市工作正在進行中。

What I can tell you is that the level of enthusiasm for 6- to 11-year-old TRIKAFTA here in the U.S. and overseas for a KAFTRIO is exceptionally high, in line with that, that we've seen in every other market where we've launched TRIKAFTA/KAFTRIO. So those launches are off to a strong start. Obviously, we're in the first few months of those launches.

我可以告訴大家的是，在美國和海外，6至11歲兒童對TRIKAFTA和KAFTRIO的熱情都非常高漲，這與我們在其他所有推出TRIKAFTA/KAFTRIO的市場所觀察到的情況一致。因此，這些產品的上市開局強勁。當然，目前我們還處於上市的最初幾個月。

So looking ahead, what do I see? Despite the fact that we've had really successful launches for TRIKAFTA and KAFTRIO, we're still actually only treating today about half of all the patients with CF who could benefit from our medicines overall. And specifically for CFTR modulators, there's about 30,000 patients yet to go in terms of patients who could benefit from our medicines.

展望未來，我看到了什麼？儘管TRIKAFTA和KAFTRIO的上市非常成功，但目前我們實際治療的囊性纖維化患者僅佔所有潛在受益者總數的一半左右。具體到CFTR調節劑，還有大約3萬名潛在受益者尚未接受治療。

Now you might ask yourself who are those patients? Well, those patients are patients in countries where we have reimbursement, where we're early in the launch sequence some of the markets I just described. They're in countries where we have regulatory approvals with most of the world now, but where we have yet to secure reimbursement agreements. But -- and they're in younger age groups, obviously, 6- to 11-year-olds. Outside the U.S., we don't yet have an approval. And also, we're going to be pursuing approvals for TRIKAFTA/KAFTRIO down to even younger age groups as we have done with KALYDECO and ORKAMBI.

你可能會問，這些患者是誰？嗯，這些病患來自我們已經獲得健保報銷的國家，也就是我剛才提到的那些市場，我們目前正處於產品上市初期。他們來自我們已經獲得全球大部分地區監管部門批准，但尚未達成健保協議的國家。而且──很明顯，他們的年齡都比較小，6到11歲。在美國以外，我們尚未獲得批准。此外，我們將像KALYDECO和ORKAMBI一樣，繼續爭取TRIKAFTA/KAFTRIO在更小年齡層人群中的應用。

So given our track record in securing approvals, getting reimbursement and successfully launching, I have no doubt that we're going to get to the vast majority of those 30,000 patients over the coming years. And so I see substantial growth for our CF franchise between now and the middle of the next decade. And then as we announced today, we've also made great progress with our mRNA program, which has the prospect of developing a medicine for the 10% or so of patients who don't respond to CFTR modulators. So I think we've got substantial growth runway yet to go in CF. And Reshma, back to you.

鑑於我們在獲得審批、醫保報銷和成功上市方面的良好記錄，我毫不懷疑，在未來幾年內，我們將惠及這3萬名患者中的絕大多數。因此，我認為從現在到下一個十年中期，我們的囊性纖維化（CF）業務將顯著成長。此外，正如我們今天宣布的那樣，我們的mRNA計畫也取得了巨大進展，該計畫有望為大約10%對CFTR調節劑無反應的患者開發出有效的藥物。所以我認為，我們在CF領域仍有巨大的成長空間。雷什瑪，現在把麥克風交給你。

Still on the question of the VX-147 program. Okay. So on that one, I have high confidence in the Phase II proof-of-concept study. And I say that for really 3 reasons. The first is the human genetics for APOL1-mediated kidney disease is strong. In fact, they're very strong. People who have kidney disease, who have proteinuria have 2 APOL1 alleles. They have universally poor outcomes. And the target, therefore, is really exceptionally well validated.

關於VX-147項目，我還是想說一下。好的。就這個計畫而言，我對二期概念驗證研究非常有信心。我這麼說主要有三個原因。首先，APOL1介導的腎臟疾病的人類遺傳學證據非常充分。事實上，證據非常充分。患有腎臟疾病或蛋白尿的人通常攜帶兩個APOL1等位基因。他們的預後普遍較差。因此，該靶點的有效性得到了非常充分的驗證。

The second is our in vitro and in vivo studies. We've done portfolio of studies in vitro as well as in animal studies, we find good potency, good selectivity and really strong reductions in proteinuria. And the third is that VX-147 is all of the drug-like properties that we seek. As a nephrologist, I find this opportunity really very exciting for the following reason. So in Phase II, we're studying APOL1 -mediated FSGS. That is one kind of APOL1-mediated kidney disease. It's a very aggressive form of renal disease, about 10,000 people who have that.

第二點是我們的體外和體內研究。我們進行了一系列體外和動物研究，發現VX-147具有良好的效力、選擇性，並且能顯著降低蛋白尿。第三點是VX-147具備我們所尋求的所有藥物特性。身為腎臟科醫生，我對此機會感到非常興奮，原因如下。在II期臨床試驗中，我們正在研究APOL1介導的局部節段性腎絲球硬化症（FSGS）。這是一種APOL1介導的腎臟疾病，病情發展非常迅速，約有10,000人患有此病。

But APOL1-mediated proteinuric, let's say, prime proteinuric kidney disease, I know it's a mouthful, there's about 100,000 people who have that. And if the Phase II study is positive in FSGS, what that really tells you is that we have now, for the first time, found a small molecule that interdicts on APOL1 and can potentially be a therapy for the broad FSGS, not only FSGS, but the broad AMKD market, so the full 100,000.

但是，比如說，APOL1介導的蛋白尿，或者說原發性蛋白尿腎病變（我知道這聽起來很拗口），大約有10萬人患有這種疾病。如果II期研究在FSGS中取得陽性結果，那就意味著我們首次發現了一種能夠阻斷APOL1的小分子，它有可能成為治療FSGS（不僅是FSGS）以及整個AMKD市場（即全部10萬名患者）的療法。

And then with regard to what would we consider successful? Okay. So the Phase II study is in FSGS, right, and the entry criteria is such that it's a very severe population. It's APOL1-mediated FSGS with a high burden of proteinuria and we allow stable doses of standard of care therapy. So these patients are already on ACEs, ARBs, immunosuppressives and steroids.

那麼，我們要如何定義成功呢？好的。這項 II 期研究針對的是局部節段性腎絲球硬化症 (FSGS)，對吧？入組標準要求患者病情非常嚴重，屬於 APOL1 介導的 FSGS，伴隨高蛋白尿，並且允許患者接受穩定劑量的標準治療。也就是說，這些患者已經在使用血管緊張素轉換酶抑制劑 (ACEI)、血管緊張素受體阻斷劑 (ARB)、免疫抑制劑和類固醇。

So in that kind of patient population with an aggressive disease with high levels of proteinuria already in standard of care, double-digit improvements in proteinuria that would be impressive. Now of course, higher is better, but double-digit improvements in proteinuria, that would not only be important, it would be something that we've not seen before.

因此，對於這類病情進展迅速、蛋白尿水平已經很高的患者群體來說，即使接受標準治療，如果蛋白尿水平能改善兩位數，那將非常顯著。當然，改善幅度越大越好，但蛋白尿量改善兩位數不僅意義重大，而且也是我們以前從未見過的。

Our next question comes from Brian Abrahams with RBC Capital.

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

Congrats on the quarter. I'd love to learn more about the mRNA program. And I guess I'm curious how translatable nonhuman primate lungs are to human CF lungs, especially given the, I guess, the mucus layer. Do you have any sense of what the, I guess, the half-life or the resident time in the lung would be in terms of what type of frequency of administration one might look at or a general range. And might you see any opportunity down the line for this to be usable, perhaps in combination for the other 90% of patients who don't have non-transmutations but with CF.

恭喜你本季取得佳績。我很想了解更多關於mRNA計畫的資訊。我很好奇非人靈長類動物的肺部模型與人類囊性纖維化（CF）肺部模型的可比性如何，尤其是在考慮到粘液層的情況下。你是否了解mRNA在肺部的半衰期或停留時間，以及給藥頻率或大致範圍？你認為未來是否有可能將其應用於其他90%沒有非突變型但患有CF的患者，例如與其他療法合併使用？

Brian, really important questions on the mRNA program, and there's a few different questions in there. So let me parse it out. There's a question in there about dose targeting it to the right cells and how translatable the model is. And then there's another question in there about how do we think about the 90%.

布萊恩，關於mRNA項目，你提出了一些非常重要的問題，其中包含幾個不同的問題。讓我來逐一分析。其中一個問題是關於如何將藥物靶向輸送到正確的細胞，以及該模型的轉化應用程度。另一個問題是關於我們如何看待90%這個數字。

Okay. So I'm going to be circumspect with my comments. The insights are commercially sensitive, but here's what I can tell you. We have been very, very diligent and deliberate about dose and making sure that the mRNA transcript and protein expression are in the right cells. I would say that in drug development in this area, that's the most important part that many others have not gotten right. And that's specifically why I talked about the HBE assays in vitro, and the small and large animal studies and the targeting of the mRNA construct to the relevant cells, which are the bronchial epithelial cells. And I feel very good about the dose selection, about the schedule of dosing and the targeting to the appropriate cells.

好的。我會謹慎發言。這些資訊涉及商業機密，但我可以透露一些資訊。我們在劑量方面非常謹慎，確保mRNA轉錄本和蛋白質表現在正確的細胞中發揮作用。我認為，在這個領域的藥物研發中，這是最關鍵的環節，也是許多其他公司未能做好的地方。也因為如此，我特別提到了體外HBE檢測、小型和大型動物實驗，以及將mRNA構建體靶向相關細胞（即支氣管上皮細胞）。我對劑量選擇、給藥方案以及標靶目標細胞都非常滿意。

Now with regard to the question about down the line, do we think this could be extended to the other 90%. I would actually look at it the other way. CF is a systemic disease, it's not only a lung disease. And so the real value of small molecule correction of the CFTR protein is that you get systemic benefit. So in the setting of the last 10%, what I would contemplate is -- if our -- we are successful with our mRNA program when we're in the clinic next year, it's combining the mRNA with a small molecule. We're obviously the only ones who could do that. And I think the opportunity to bring benefit to the last 10% is therefore tremendous.

至於未來發展的問題，我們是否認為這種方法可以推廣到其餘90%的患者？我其實會從另一個角度來看這個問題。囊性纖維化是一種全身性疾病，它不僅僅是肺部疾病。因此，小分子藥物矯正CFTR蛋白的真正價值在於它能帶來全身性益處。所以，對於剩下的10%的患者，我的想法是──如果我們明年在臨床試驗階段的mRNA計畫取得成功，我們將把mRNA與小分子藥物結合。顯然，我們是唯一能夠做到這一點的團隊。我認為，讓剩下的10%的患者受益的機會是巨大的。

Our next question comes from Robyn Karnauskas with Truist Securities.

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

So 2 quick ones. So for patients on TRIKAFTA, you show that great data showing lung stability. In the real world, what percentage of the population would benefit from, you think, the new drugs that you're developing, meaning that their sweat chloride levels are below the normal range and you might be able to put them into that bucket?

兩個簡短的問題。對於服用 TRIKAFTA 的患者，你們展示了出色的數據，顯示他們的肺部狀況穩定。在現實世界中，你們正在研發的新藥能使多少比例的人群受益？也就是說，這些人的汗液氯化物水平低於正常範圍，你們可以將他們歸類為適用人群嗎？

And second question I've had is for your device for diabetes. How does the device -- I know you've talked about how getting the cells in, they go to the liver and then blood vessels form and that's how they interact with the liver to function. How does the device not only protect the cells from the attack by the immune system, but also allow them to have the interaction with blood vessels to work and function. So how does it work? So I was just wondering if it might not be able to interact with the blood vessels because it's in a device.

我的第二個問題是關於您用於治療糖尿病的設備。我知道您之前提到過，細胞被植入後會到達肝臟，然後形成血管，細胞透過血管與肝臟相互作用發揮功能。那麼，這個設備是如何做到既保護細胞免受免疫系統攻擊，又能讓細胞與血管相互作用，從而正常運作的呢？我擔心的是，由於細胞被植入設備中，它們是否可能無法與血管相互作用。

Yes. Yes. There are 2 different questions in there, Robyn. One about type 1 diabetes and the device; and then a separate question about how we think about VX-121/561/tez and maybe I'll expand that to the next, next generation of CFTR modulators. Let's do CF first, and then we'll -- let's do type 1 diabetes next.

是的，是的。羅賓，這裡面有兩個不同的問題。一個是關於第1型糖尿病和這種設備的；另一個是關於我們如何看待VX-121/561/tez的問題，也許我還會把話題擴展到下一代CFTR調節劑。我們先討論囊性纖維化，然後再討論第1型糖尿病。

So Robyn, you know this, the TRIKAFTA/KAFTRIO medicine can treat up to 90% of people with CF and it has really extraordinary efficacy. And what we see is that large numbers of patients, as you saw in the clinical trials program get benefit in the double-digit improvements in ppFEV1, significant improvements in sweat chloride in weight and quality of life.

羅賓，你知道，TRIKAFTA/KAFTRIO這種藥物可以治療高達90%的囊性纖維化患者，而且療效非常顯著。正如你在臨床試驗項目中看到的那樣，大量患者受益，他們的第一秒用力呼氣容積（ppFEV1）改善幅度達到兩位數，汗液氯化物水平、體重和生活質量也得到顯著改善。

Now what we are trying to do and our long-term goal is to get all CF patients to carrier levels of sweat chloride. And the reason we want to do that is because carriers really manifest almost no disease. And what I can tell you, 121/561/tez in our preclinical experiments in these HBE cells that have this quantitative and quantitative relationship to what we see in the clinic, the 121/tez/561 has the potential to be even better than TRIKAFTA in that dimension. But we've already identified another generating molecules that in our HBE assays, look like they're going to get us to that ultimate goal of getting all patients with CF, the 90% to carrier levels.

我們現在正在努力實現的長期目標是讓所有囊性纖維化患者的汗液氯化物水平達到攜帶者水平。我們這樣做的原因是，帶因者幾乎不會表現出任何疾病症狀。我可以告訴大家的是，在我們的臨床前實驗中，121/561/tez 在 HBE 細胞中表現出與臨床觀察結果高度一致的定量關係，並且在這一方面，121/tez/561 的潛力甚至優於 TRIKAFTA。此外，我們已經發現了另一種生成分子，在我們的 HBE 檢測中，它們似乎能夠幫助我們實現最終目標，即讓 90% 的囊性纖維化患者達到攜帶者水平。

With regard to the device program, I'll ask Bastiano to comment, but here's the important thumbnail sketch of the field and what the real breakthrough that we have made. The problem with device historically has been foreign body reactions or fibrosis. And the second challenge with devices has been vascularization. Both of those challenges are what we tackled with our program and what we do not see with our device.

關於器械項目，我會請巴斯蒂亞諾先生評論，但這裡我先簡要概述一下該領域以及我們取得的真正突破。器械一直以來面臨的問題是異物反應或纖維化。第二個挑戰是血管化。這兩個挑戰正是我們透過專案解決的，也是我們器械所不存在的問題。

So what we do not see is fibrosis or for body reaction. And what we do see is really excellent vascularization. Bastiano had a comment about the materials and the geometry and the configuration of the device that allows us to have the kind of effect that we have. Bastiano?

所以，我們沒有看到纖維化或身體反應。我們看到的是非常好的血管化。巴斯蒂亞諾對這種裝置的材料、幾何形狀和結構發表了評論，正是這些因素使我們能夠達到這樣的效果。巴斯蒂亞諾？

Thanks, Reshma. And Robyn, I just want to maybe start with making clear that this is a completely novel device that is made with different materials, different geometry, different configuration from everything else that has been described by others in the field. It was specifically -- [actually] designed to exactly address the causes of failure in the field of encapsulation like Reshma said, which is foreign body response and vascularization. It's called channel array device for that particular reason. It's purportedly designed to really minimize fibrosis and to allow the device to integrate in the body, allow vascular beds to form throughout the device on top and the bottom.

謝謝，雷什瑪。羅賓，我想先說明一下，這是一種全新的裝置，它採用的材料、幾何形狀和結構都與該領域其他已描述的裝置截然不同。正如雷什瑪所說，它的設計初衷正是為了解決封裝領域中常見的失敗原因，即異物反應和血管化。正因如此，它才被稱為通道陣列裝置。據稱，它的設計旨在最大限度地減少纖維化，並使裝置能夠與人體整合，在裝置的頂部和底部形成血管床。

So the cells are always optimally distant to a source of oxygen and nutrient, allowing for insulin and glucose, of course, to be exchanged. This is completely different from you think what was in the field, and we have evidence in our preclinical models that we do not see foreign body response. We see robust neo-vascularization. We see rapid insulin responsiveness and immunoprotection even in immunocompetent animals.

因此，細胞始終與氧氣和營養來源保持最佳距離，從而確保胰島素和葡萄糖的交換。這與您想像中的實際情況截然不同，我們的臨床前模型也證實，我們沒有觀察到異物反應。我們觀察到了強烈的新血管生成。即使在免疫功能正常的動物中，我們也觀察到了快速的胰島素反應和免疫保護作用。

Our next question comes from Liisa Bayko with Evercore ISI.

我們的下一個問題來自 Evercore ISI 的 Liisa Bayko。

I wanted to ask about CTX001. So when you file at the end of next year, can you talk about sort of how much data and follow-up data you'll have on how many patients? And then I also wanted to ask just a commercial question as you're doing a lot of your commercial rep, can you maybe describe like what the -- how many patients per year can be treated in the U.S. in kind of -- given that hospital environment and all that kind of stuff? So how should we think about kind of what -- at time of launch, what that will look like and then how that may evolve over time?

我想問一下關於CTX001的問題。你們明年年底提交申請的時候，能否談談屆時會有多少患者接受治療的數據和追蹤數據？另外，鑑於你們經常進行商業推廣，我還想問一個商業方面的問題，能否描述一下，考慮到醫院環境等因素，在美國每年大概能治療多少患者？我們應該如何看待上市初期的情況，以及隨著時間的推移，情況可能會如何改變？

Liisa, I think you're asking about how we see commercial launch for CTX001?

Liisa，我想你是想問我們如何看待 CTX001 的商業化發表吧？

Yes, I kind of wanted to know like what the throughput of patients like capacity-wise is. Is there some upper limit on that, that we should think about as we think about the population, it's quite a big population in fact. But I'm trying to understand what the capacity is in the United States, at least. And how you think that may evolve over time, but from the onset, what that would look like?

是的，我有點想了解醫院的病人吞吐量，也就是醫療容量方面的狀況。是否存在某種上限，我們在考慮人口規模時應該考慮到這一點，畢竟人口確實相當龐大。但我試著去了解至少在美國，醫療容量究竟如何。而您認為隨著時間的推移，醫療容量會如何變化，但從一開始，情況又會如何？

Yes. Yes, sure thing. Let me ask Stuart to comment on how we see the CTX001 launch and the launch dynamics, taking into account the question specifically about whether there are capacity constraints and such. And I'll come back and tell you a little bit more about how we see the filing. Stuart?

好的，沒問題。我請Stuart談談我們對CTX001上市以及上市動態的看法，特別是考慮到是否有產能限制等問題。稍後我會再詳細說說我們對申請文件的看法。 Stuart？

Yes. Thanks, Liisa, for the question. So we start at the highest level with the overall opportunity, and then I'll get to your question about the kind of launch dynamics or our views on them at this kind of early stage. So in terms of people who have severe sickle cell disease and beta thalassemia, between the U.S. and the EU, we think there's about 32,000 we estimate patients who have severe disease in both of those in the combined populations of sickle cell and beta thalassemia. In sickle cell, it's about 25,000 and because of the nature of the disease, the vast majority of those are in the United States. And that number is kind of validated by external physician surveys, which would indicate that -- they think they would treat between 25% and 1/3 of all their sickle cell disease patients with a onetime curative approach with the existing conditioning regimens. So we think that's about the order of magnitude of patients who might be eligible for this initial phase of a gene-editing curative treatment.

是的。謝謝Liisa的提問。我們先從整體機會談起，然後再回答你關於早期階段的啟動策略或我們的看法。就患有嚴重鐮狀細胞貧血症和β地中海貧血的患者而言，我們估計美國和歐盟加起來大約有32,000名患者患有這兩種疾病的重症。其中鐮狀細胞貧血症患者約25,000人，由於這種疾病的特殊性，絕大多數患者都在美國。外部醫師的調查也證實了這個數字，調查顯示，他們認為使用現有的預處理方案，一次性治癒25%到三分之一的鐮狀細胞貧血症患者是可行的。所以我們認為，符合基因編輯治癒性治療初始階段條件的患者人數大致是如此。

In terms of launch dynamics, it's really going to be a function of probably 4 things. The first one is sort of physician and patient interest in the technology. And based on the results that we've seen to date and the enthusiasm we've seen in the field, particularly as it translates into interest in our clinical trials, we expect the enthusiasm from the community to be high. At the other end, it's going to be a function of our ability to manufacture.

就產品上市而言，主要取決於四個因素。首先是醫生和病人對這項技術的興趣。根據我們目前所取得的成果以及業界的正面反響，特別是他們對我們臨床試驗的參與熱情，我們預期業界的積極性會很高。其次，這取決於我們的生產能力。

And as you can imagine, we're working diligently on our manufacturing processes to make sure that we have capacity to treat patients. But the bottleneck is likely to be in treatment centers. And as you know, the treatment is going to be administered in transplant centers. There's a limited number of those in the U.S., and they also have competing priorities with malignant hematology conditions. And so that is likely to be the rate-limiting step. We're obviously in the initial throes of evaluating those treatment centers and working with them.

正如您所想，我們正在努力改進生產流程，以確保有足夠的產能來治療患者。但瓶頸很可能在於治療中心。您也知道，治療將在移植中心進行。美國的移植中心數量有限，而且它們還要優先處理其他惡性血液疾病患者。因此，這很可能成為限制產能的環節。我們目前正處於評估這些治療中心並與之合作的初期階段。

Again, we do think that enthusiasm to treat these patients is going to be high given the very significant unmet need in sickle cell disease and thalassemia and the outstanding results we've seen to date. So without commenting specifically because I wouldn't know the exact answer to that at this early stage, Liisa, those are likely to be some of the pinch points as it were in terms of the launch dynamics. What I can tell you, though, is we are expecting demand to be very, very substantial amongst those 32,000 patients given the unmet need and the results we've seen.

再次強調，鑑於鐮狀細胞疾病和地中海貧血症領域存在著巨大的未滿足需求，以及我們迄今為止的卓越成果，我們認為人們對治療這些患者的熱情將會很高。所以，莉薩，由於目前階段尚無法給出確切答案，因此我無法就此發表具體評論，但這些很可能是產品上市初期的一些瓶頸。不過，我可以告訴你的是，鑑於未滿足的需求以及我們已取得的成果，我們預計這32,000名患者的需求將會非常非常巨大。

Liisa, on the question on where are we with our filing and how are we thinking of the size, the data set size, I'll just step back for one moment to remind that we have had the benefit of having virtually every regulatory designation known both here and in the EU with RMAT and orphan and PRIME. That's allowed us to have a number of engagements with the agency and to be able to address a number of their questions.

Liisa，關於我們申報工作的進展以及我們如何考慮規模和資料集大小的問題，我想先回顧一下，我們受益於幾乎所有已知的監管認定，包括RMAT、孤兒藥和PRIME，這些認定涵蓋了英國和歐盟。這使我們能夠與監管機構進行多次溝通，並解答他們提出的許多問題。

We're really at the tail end of those conversations. And the 2 areas on which we're wrapping up our discussions are, one, what is the sample size that is -- that they will require; and two, what's the duration of follow-up? I expect we're going to finish those discussions in the next couple of months. And I do expect that the filing will go in towards the tail end of next year.

這些討論已經接近尾聲了。我們即將結束討論的兩個面向是：第一，他們需要的樣本量是多少；第二，後續調查將持續多久？我預計我們將在未來幾個月內完成這些討論。而且我預計，申請文件將在明年年底提交。

Our next question comes from Cory Kasimov of JPMorgan.

我們的下一個問題來自摩根大通的科里·卡西莫夫。

I wanted to follow up as well on CTX001. And just to piggyback on the filing, I recognize we should get more clarity in the coming months. But can you talk about your comfort level on the regulatory front when it comes to addressing any CMC requirements. We see -- frequently see delays there with regards to cell and gene therapies. And then also, you speak about the 32,000 patients between the U.S. and Europe. I wanted to ask about your comfort level with Europe as we recently saw bluebird back out of that market with LentiGlobin for beta thal based on the fact that they couldn't come to agreements on pricing. So your comfort level that you can get around this.

我還想跟進一下CTX001的狀況。順便提一下，我知道未來幾個月我們應該會更清楚一些。您能否談談您在監管方面，尤其是在CMC（化學、製造和控制）要求方面，有哪些信心？我們經常看到細胞和基因療法在這方面出現延誤。另外，您提到了美國和歐洲共有32,000名患者。我想問您對歐洲市場的信心，因為我們最近看到Bluebird公司因為無法就價格達成一致，而退出了歐洲市場，其用於治療β-地中海貧血的LentiGlobin藥物也未能獲得批准。所以，您認為您能否克服這些困難？

Yes. Cory, let me start with telling you a little bit more about the regulatory process and something a little bit more on manufacturing, which is your specific question. And then I'll ask Stuart to comment on Europe. Obviously, we are -- we have the opportunity not only in Europe but the opportunities certainly including Europe to lead from the front with our CTX001 for both beta thalassemia and sickle cell disease.

是的。科里，首先讓我再詳細說說監管流程和生產製造方面的問題，這也是你具體問的。然後我會請史都華談談歐洲的情況。顯然，我們有機會——不僅在歐洲，當然也包括在歐洲——憑藉我們的CTX001在治療β地中海貧血和鐮狀細胞貧血方面發揮引領作用。

Okay. So Cory, on the regulatory filings, because of these designations we've had a benefit of multiple conversations with the agency and as I said earlier, been able to address most of their questions, and we're really now wrapping up conversations around 2 clinical points, which is how big is the database and what's the duration of follow-up.

好的。科里，關於監管文件，由於這些認定，我們得以與監管機構進行多次溝通，正如我之前所說，我們已經能夠解答他們的大部分問題，現在我們正在圍繞兩個臨床要點進行最後的討論，即數據庫有多大以及隨訪持續時間有多長。

On the manufacturing side, we are using the same processes and actually the same sites as we did for the clinical trials for the commercial product. And in the grand scheme of things, when you think about what we are doing with CTX001, it's ex vivo gene editing. And really, it's the Cas enzyme and the guide RNA. And in the grand scheme of things, that's just simply an easier manufacturing situation than other manufacturing challenges.

在生產方面，我們採用與商業化產品臨床試驗相同的製程和場地。從整體來看，CTX001 本質上是一種體外基因編輯技術，主要涉及 Cas 酶和引導 RNA。因此，與其他生產挑戰相比，這無疑更容易實現。

So I feel very good about our conversations with the agency. We've been able to derisk by addressing their questions along the way. And we are using the same processes and the same sites that we used in the clinical trials for the commercial product.

所以我對我們與監管機構的溝通感到非常滿意。我們透過逐步解答他們的問題，有效降低了風險。而且，我們沿用了商業化產品臨床試驗的流程和試驗場地。

Stuart, a couple of comments maybe from you about Europe and CTX001.

Stuart，關於歐洲和 CTX001，你或許有幾點看法。

Yes, Cory, thanks for the question. I feel very confident in the team that we have on the ground in Europe and their ability to secure reimbursement and access for patients who have rare diseases for transformative medicines like this. I think they've got a demonstrated capability to capture and describe the unmet need in these types of conditions to gather and generate evidence on the both economic and clinical benefits of our medicines to translate those into value propositions, which makes sense to payers and then work creatively with payers to develop bespoke solutions country by country to secure reimbursement and access for our medicines.

是的，科里，謝謝你的提問。我對我們在歐洲的團隊充滿信心，相信他們有能力為患有罕見疾病的患者爭取像我們這樣具有變革意義的藥物的報銷和用藥機會。我認為他們已經展現出卓越的能力，能夠準確把握並描述這類疾病領域尚未滿足的需求，收集並產生我們藥物在經濟和臨床效益方面的證據，並將這些轉化為對支付方而言合理的價值主張。之後，他們會與支付者進行創新合作，針對不同國家製定客製化的解決方案，以確保我們的藥物獲得報銷和用藥機會。

I think we've demonstrated that very, very successfully in CF, and I'm looking forward to us being able to use those same capabilities to get access for patients with sickle cell disease and beta thalassemia in Europe.

我認為我們在囊性纖維化領域已經非常成功地證明了這一點，我期待著我們能夠利用同樣的能力，讓歐洲的鐮狀細胞病和β地中海貧血患者也能獲得治療。

Our next question comes from Geoff Meacham with Bank of America.

下一個問題來自美國銀行的傑夫‧米查姆。

This is Olivia Brayer on for Geoff. I've got 2 follow-ups on the next-gen triplet program. First is, can you give us a better sense for when we might start to see those Phase III data and now both those trials are up and running. And whether there could be an opportunity for an earlier look at one or maybe both of those trials as we get into next year.

這裡是奧莉薇亞·布雷耶，由代傑夫發言。關於下一代三胞胎項目，我有兩個後續問題。首先，您能否更準確地告訴我們何時能看到第三期臨床試驗的數據？目前這兩項試驗都已經啟動。其次，明年是否有可能提前看到其中一項或兩項試驗的結果？

And then I know you guys have talked about moving forward even more next-gen triplets at some point. So are there specific areas where you're maybe more focused on when you think about the optimization or differentiation of those newer assets? And just as a follow-up to that, could there be some potential ways to accelerate development time lines once those agents move into the clinic?

我知道你們之前討論過未來會推出更多下一代三聯體藥物。那麼，在考慮如何優化或區分這些新藥物時，你們是否更關注某些特定領域？另外，一旦這些藥物進入臨床試驗階段，是否有可能加速研發進程？

Yes. With regard to your questions, which really center around the next wave, whether it's 121/561/tezacaftor, which is already in the clinic in Phase III clinical trials or the molecules that we've identified in San Diego that are going to be coming into the clinic. How are we thinking about this? How quickly can we go? What's the overall goal?

是的。關於您提出的問題，這些問題主要圍繞著下一階段的藥物研發，無論是已經進入III期臨床試驗的121/561/tezacaftor，還是我們在聖地牙哥發現的即將進入臨床試驗的分子，我們是如何考慮的？我們能以多快的速度推進？整體目標是什麼？

So to be clear, the goal here is to bring all patients with cystic fibrosis to carrier levels of sweat chloride. That is our long-stated goal and that is what we are aiming for. And I feel really good about where we are with 121/561/tez based on the preclinical results that I shared and the Phase II results that we shared earlier this year. And the next wave of molecules look like they can be even better. So we are well on our path to bringing forward therapies that can bring all CF patients to carrier levels of sweat chloride.

所以，明確一點，我們的目標是讓所有囊性纖維化患者的汗液氯化物水平達到載體水平。這是我們長期以來的目標，也是我們努力的方向。基於我先前分享的臨床前研究結果以及今年稍早公佈的第二期臨床試驗結果，我對121/561/tez的研發進展感到非常滿意。而且，下一批候選藥物看起來效果會更好。因此，我們正朝著研發出能讓所有囊性纖維化患者汗液氯化物水準達到載體水準的療法穩步前進。

With regard to speed and how fast can we go, right? I don't think that anybody can go faster than us in cystic fibrosis for a couple of reasons. One, we've already demonstrated that we can do this very quickly. In TRIKAFTA, we went from the bench, so first synthesis of the molecule to U.S. approval in less than 4 years. Outside of oncology, it's one of the fastest drug development programs ever.

至於速度，以及我們能做到多快，對吧？我認為在囊性纖維化領域，沒有人能比我們更快，原因有二。首先，我們已經證明我們能以極快的速度完成研發。以 TRIKAFTA 為例，我們從實驗室合成到獲得美國批准，只花了不到 4 年的時間。除了腫瘤領域，這絕對是有史以來最快的藥物研發計畫之一。

The second reason I say that we do this really fast as we have a lot of experience in this, right? We've already done it with 4 medicines on the market, the fifth one being 121/tez/561.

我說我們速度很快的第二個原因是，我們在這方面有很多經驗，對吧？我們已經成功地將 4 種藥物推向市場，第五種是 121/tez/561。

And with regard to when should we expect results and such. Remember, the trials for TRIKAFTA, we enrolled in about 6 months. So that's a benchmark for the last set of clinical trials we did. I expect us to continue to use the -- what we know and our experience to move fast with 121/561/tez and the molecules behind that.

至於何時能預期結果等等，請記住，TRIKAFTA 的試驗我們大約花了 6 個月就完成了受試者招募。這為我們上一輪臨床試驗樹立了標竿。我預計我們將繼續利用我們已知的知識和經驗，快速推進 121/561/tez 及其相關分子的研發。

Okay. Thank you all for tuning into the call tonight. If you have additional questions, please reach out to the Investor Relations team. We are in the office tonight and happy to follow up. Have a good evening.

好的。感謝各位今晚收聽電話會議。如果您還有其他問題，請聯絡投資者關係團隊。我們今晚在辦公室，很樂意為您解答。祝您晚安。

This does conclude the program. You may now disconnect.

程式到此結束，您可以斷開連線了。