福泰製藥 (VRTX) 2022 Q1 法說會逐字稿

Good evening. This is Michael Partridge. Welcome to Vertex's First Quarter 2022 Financial Results Conference Call.

晚安.我是邁克爾·帕特里奇。歡迎參加Vertex公司2022年第一季財務業績電話會議。

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, Chief of Vertex Cell and Genetic Therapies and Dr. David Altshuler, Chief Scientific Officer, will join for Q&A.

在今晚的電話會議上，Vertex 的執行長兼總裁 Reshma Kewalramani 博士、營運長 Stuart Arbuckle 和財務長 Charlie Wagner 將發表事先準備好的演講；Vertex 細胞和基因療法負責人 Bastiano Sanna 博士和首席科學官 David Altshuler 博士將參加問答環節。

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. 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。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。

Before we begin, as this will be Michael Partridge's last quarterly call with us, I'd like to take a moment to recognize Michael for his outstanding service and contributions to Vertex.

在我們開始之前，由於這將是 Michael Partridge 與我們進行的最後一次季度電話會議，我想藉此機會感謝 Michael 對 Vertex 的傑出服務和貢獻。

For 25 years, he has been the face of Vertex with analysts and investors and with his calm and steady approach, Michael has led our IR team through countless milestones and many evolutions of the company. More recently, through the launch of all 4 of our marketed cystic fibrosis medicines and the emergence of our broad, mid- and late-stage pipeline, Michael has been an integral part of the Vertex leadership team, helping share our story with the world. Michael has shown a true passion for Vertex and the patients we serve. We are grateful for his dedication, and I want to personally thank Michael for all that he's done for Vertex.

25年來，Michael一直是Vertex在分析師和投資者面前的代表人物。他沉穩冷靜的作風帶領著我們的投資人關係團隊，見證了公司無數的里程碑式成就和發展歷程。近年來，隨著我們所有四款已上市的囊性纖維化藥物的推出，以及我們廣泛的中後期研發管線的建立，Michael一直是Vertex領導團隊不可或缺的一員，幫助我們向世界講述Vertex的故事。 Michael對Vertex以及我們服務的患者群體展現出了真正的熱情。我們感謝他的奉獻，我自己也想藉此機會感謝Michael為Vertex所做的一切。

On to the quarterly review. Vertex is off to an excellent start across the board with strong performance in the CF business, rapid advancement of the pipeline and continued operational excellence. Q1 CF product revenues grew 22% year-on-year to $2.1 billion, reflecting continued growth in the number of CF patients treated globally. And despite continued significant investment in internal and external innovation, our non-GAAP operating margins remained industry leading at 56%.

接下來是季度回顧。 Vertex 各方面開局都非常出色，囊性纖維化 (CF) 業務表現強勁，產品線快速推進，營運效率持續卓越。第一季 CF 產品營收年增 22% 至 21 億美元，反映出全球接受治療的 CF 患者人數持續成長。儘管我們持續增加對內部和外部創新的投入，但我們的非 GAAP 營業利潤率仍保持在行業領先水平，達到 56%。

We maintained a rapid pace of progress in research and across the clinical stage pipeline with a half a dozen programs now post the POC stage. And we finished the quarter with a strong balance sheet and $8.2 billion in cash and investments.

我們在研發和臨床階段產品線方面保持了快速進展，目前已有六個專案完成了概念驗證階段。本季末，我們的資產負債表穩健，現金及投資總額達82億美元。

CF has been the exemplar of our R&D strategy. The last 6 to 12 months have made it clear. Our R&D strategy is proving itself beyond CF with the discovery and development of small molecules and cell and genetic therapies across a number of disease areas. This serial innovation enables the potential to transform, if not cure, multiple diseases and in so doing help more patients and drive long-term growth for the company.

囊性纖維化一直是我們研發策略的典範。過去6到12個月的成果更加印證了這一點。我們的研發策略已超越囊性纖維化領域，在多個疾病領域透過小分子藥物、細胞療法和基因療法的發現和開發，展現出卓越的成效。這種持續創新有望改變甚至治癒多種疾病，從而幫助更多患者，並推動公司的長期發展。

Fundamentally, the goal of our strategy grounded in causal human biology, validated targets and biomarkers that translate from bench to bedside and all the way through pivotal development is to increase the odds of success in drug discovery and development. With the data we've generated in CF, in sickle cell disease and beta thalassemia, and now in rapid succession with positive proof of concept in APOL1-mediated kidney disease, pain and type 1 diabetes, our clinical stage pipeline has never been broader in terms of the number of disease areas, more diverse in terms of modalities or more advanced.

從根本上講，我們以人類因果生物學為基礎，採用已驗證的靶點和生物標誌物，將研究成果從實驗室轉化為臨床應用，並貫穿關鍵性開發階段，其戰略目標是提高藥物發現和開發的成功率。憑藉我們在囊性纖維化、鐮狀細胞病和β地中海貧血領域積累的數據，以及目前在APOL1介導的腎病、疼痛和1型糖尿病領域迅速取得的積極概念驗證，我們的臨床階段研發管線在疾病領域數量、治療方式和研發進度方面都達到了前所未有的高度。

The company is now at a new inflection point with continued growth in CF, the advancement of our broad clinical pipeline with 6 programs in mid- and late-stage development, representing multibillion dollar opportunities and the potential from the next wave of therapies approaching the clinic. In this next group of programs that have initiated IND-enabling studies is our mRNA program in CF, the cells plus device program in type 1 diabetes, the next wave of small molecule correctors in AATV and our in vivo gene editing program in DMD. A number of these programs are on track for IND filings later this year with clinical trials beginning thereafter. Our R&D strategy combined with our business model positions us well for continued innovation and sustained growth as we work to bring additional transformative medicines to more patients around the globe.

公司目前正處於新的轉捩點，囊性纖維化（CF）領域持續成長，我們廣泛的臨床研發管線也取得了進展，目前有6個計畫處於中後期開發階段，蘊藏著數十億美元的商機，而即將進入臨床階段的新一代療法也極具潛力。在已啟動IND申報所需研究的下一批項目中，包括我們的CF mRNA項目、1型糖尿病細胞+器械項目、AATV新一代小分子矯正劑以及DMD體內基因編輯項目。其中一些項目預計在今年稍後提交IND申報，隨後將啟動臨床試驗。我們的研發策略與商業模式相結合，使我們能夠持續創新並保持成長，致力於為全球更多患者帶來變革性藥物。

With this as context, I'll now review the R&D highlights for the quarter.

有了以上背景，我現在將回顧本季的研發亮點。

Looking to our future in CF, we continue to strengthen our leadership for the long term. Our real-world experience with TRIKAFTA continues to accumulate, and as Stuart will discuss, raises the bar for any regimens in development. That said, if it is possible to outperform TRIKAFTA, we're determined to be the one to do so. Our next-in-class triple combination of VX-121/tezacaftor/561 is rapidly progressing through pivotal development. More than 180 clinical trial sites are open and enrolling patients in our Skyline Phase III program. We expect to complete enrollment by late 2022 or early 2023.

展望我們在囊性纖維化領域的未來，我們將繼續鞏固長期領先地位。 TRIKAFTA 的實際應用經驗不斷積累，正如 Stuart 將要闡述的，它為所有在研療法樹立了新的標竿。即便如此，如果有可能超越 TRIKAFTA，我們決心成為第一個做到的人。我們下一代三聯療法 VX-121/tezacaftor/561 正在快速推進關鍵性研發。目前，超過 180 個臨床試驗中心正在招募患者參與我們的 Skyline III 期臨床試驗計畫。我們預計將於 2022 年底或 2023 年初完成病患招募。

As a reminder, VX-121/tezacaftor/561 has the potential for greater clinical benefit than TRIKAFTA and is a more convenient once-daily treatment that carries a lower royalty obligation for Vertex.

提醒大家，VX-121/tezacaftor/561 比 TRIKAFTA 具有更大的臨床效益潛力，而且是更方便的每日一次治療方案，Vertex 的專利費義務也更低。

For the more than 5,000 patients who do not make any CFTR protein and cannot benefit, therefore, from a CFTR modulator, we are developing an mRNA therapy together with our partner, Moderna. IND-enabling studies for this program have been completed, and we remain on track to submit an IND in the second half of 2022 with clinical development starting thereafter.

對於超過5000名無法產生CFTR蛋白因而無法從CFTR調節劑中獲益的患者，我們正與合作夥伴Moderna共同開發一種mRNA療法。該計畫IND申報的研究已完成，我們仍按計畫於2022年下半年提交IND申請，隨後啟動臨床開發。

Turning to the pipeline beyond CF. Starting with CTX001, our gene editing approach designed to provide a potential functional cure for sickle cell disease and beta thalassemia. We plan to submit for U.S. and EU regulatory approvals for CTX001 for beta thalassemia and sickle cell disease by the end of 2022, and we expect this to be our next commercial launch. Enrollment in both Phase III studies is complete, and we have now dosed more than 75 patients across both programs. We look forward to sharing more clinical data on CTX001, including longer-term follow-up and more patients at medical forums this year.

接下來，我們來看看囊性纖維化以外的研發管線。首先是CTX001，這是一種基因編輯療法，旨在為鐮狀細胞貧血症和β地中海貧血提供潛在的功能性治癒方案。我們計劃在2022年底前向美國和歐盟監管機構提交CTX001用於治療β地中海型貧血和鐮狀細胞貧血的上市申請，並預計這將是我們下一個商業化產品。兩項III期臨床試驗均已完成患者招募，目前已在兩個項目中為超過75名患者進行了給藥。我們期待在今年的醫學論壇上分享更多關於CTX001的臨床數據，包括更長期的追蹤數據和更多患者的數據。

Moving on to VX-147, our first-in-class small molecule inhibitor for people with APOL1-mediated kidney disease or AMKD, which has made rapid progress into pivotal development. In December, we reported unprecedented Phase II proof-of-concept results. In patients with FSGS, a particular kind of APOL1-mediated kidney disease, treatment with VX-147 led to a 47.6% reduction in proteinuria compared to baseline. VX-147 was generally well-tolerated. There were no SAEs related to VX-147, and all AEs were mild to moderate in severity.

接下來介紹VX-147，這是我們首個針對APOL1介導的腎臟病（AMKD）患者的小分子抑制劑，目前已快速進入關鍵性開發階段。去年12月，我們公佈了前所未有的II期概念驗證結果。在FSGS（一種特殊的APOL1介導的腎臟病）患者中，VX-147治療使蛋白尿較基線降低了47.6%。 VX-147整體耐受性良好。未發生與VX-147相關的嚴重不良事件（SAE），所有不良事件（AE）的嚴重程度均為輕度至中度。

In late March, we initiated pivotal development of VX-147 following agreement with FDA and the design of the program, which included: one, a single adaptive Phase II/III study design in people with 2 APOL1 mutations, proteinuria and decreased renal function; two, evaluation of VX-147 in the broad AMKD population representing approximately 100,000 people in the U.S. and Europe with this disease; and three, the ability to conduct an interim analysis, which, if positive, could provide a pathway to accelerated approval in the U.S.

3 月下旬，我們與 FDA 達成協議並製定了 VX-147 的關鍵性開發方案，該方案包括：一、針對攜帶 2 個 APOL1 突變、蛋白尿和腎功能下降的患者開展一項適應性 II/III 期研究設計；二、評估 VX-147 在廣泛的 AMKD 人群中的療效，該人群代表了美國和歐洲和歐洲的療效約 10萬名患有此病的患者；三、能夠進行中期分析，如果結果為陽性，則可能為在美國獲得加速批准提供途徑。

Transitioning now to our pain program. In late March, we announced that VX-548, a novel first-in-class, non-opioid NaV1.8 inhibitor achieved statistically significant and clinically meaningful relief in 2 Phase II studies of acute pain, meeting our high expectations. In the 2 studies, one following abdominoplasty and one following bunionectomy, VX-548 at the highest dose tested showed a rapid, sustained and consistent decrease in pain intensity compared to placebo on the primary endpoint of SPID48, a time-weighted sum of the pain intensity difference from time of first dose to 48 hours.

現在我們來談談疼痛治療項目。 3月下旬，我們宣布，新型首創的非鴉片類NaV1.8抑制劑VX-548在兩項II期急性疼痛研究中取得了具有統計意義和臨床意義的顯著緩解，達到了我們預期的高標準。在這兩項研究中，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，在最高測試劑量下，VX-548在主要終點SPID48（首次給藥至48小時疼痛強度變化的時間加權總和）上顯示出與安慰劑相比，疼痛強度的快速、持續且穩定下降。

In assessing the SPID48 score, it's important to note, higher scores indicate greater pain relief. VX-548 was superior to placebo with a statistically significant mean SPID48 of 37.8 in abdominoplasty, and 36.8 in bunionectomy. In the reference arm of the study, standard of care opioid therapy showed a mean SPID48 difference from placebo of 12.5 and 14.7, respectively.

在評估 SPID48 評分時，需要注意的是，分數越高表示疼痛緩解效果越好。 VX-548 在腹部整形術的平均 SPID48 值顯著高於安慰劑，分別為 37.8 和 36.8。在研究的對照組中，標準鴉片類藥物治療組的平均 SPID48 值與安慰劑組相比，差異分別為 12.5 和 14.7。

From a safety and tolerability perspective, VX-548 was well-tolerated at all doses. There were no serious adverse events related to VX-548 and the majority of adverse events were mild or moderate.

從安全性和耐受性角度來看，VX-548 在所有劑量下均具有良好的耐受性。未發生與 VX-548 相關的嚴重不良事件，且大多數不良事件為輕度或中度。

Given the high unmet need for an efficacious and well-tolerated, non-opioid pain medicine, we are working with urgency to advance VX-548. Our goal is to bring forward a novel class of pain treatment with the potential to provide effective pain relief without the addictive potential or adverse side effects of opioids. We plan to advance VX-548 into pivotal development for acute pain in the second half of 2022, pending discussions with regulators.

鑑於目前對高效且耐受性良好的非鴉片類鎮痛藥的巨大未滿足需求，我們正加緊推進VX-548的研發。我們的目標是推出一種新型鎮痛療法，預計在有效緩解疼痛的同時，避免阿片類藥物的成癮性和不良副作用。我們計劃在2022年下半年將VX-548推進至急性疼痛的關鍵性開發階段，具體時間取決於與監管機構的諮詢結果。

I'll conclude with the type 1 diabetes program and VX-880, our stem cell-derived fully differentiated islet cell replacement therapy that could offer a functional cure for people living with type 1 diabetes. In the U.S. and Europe alone, type 1 diabetes affects more than 2.5 million people. As we announced earlier this week, the VX-880 program has been placed on clinical hold in the U.S. by the FDA and we're working with urgency to understand more. At that time, we also shared the safety and efficacy data from the first 3 patients treated to date.

最後，我想談談第一型糖尿病計畫和VX-880。 VX-880是一種源自幹細胞的完全分化胰島細胞替代療法，可望為第1型糖尿病患者提供功能性治癒方案。光是在美國和歐洲，就有超過250萬人患有第1型糖尿病。正如我們本週稍早宣布的那樣，VX-880計畫已被美國食品藥物管理局（FDA）暫停臨床試驗，我們正在加緊努力以了解更多資訊。當時，我們也分享了迄今為止首批3名接受治療的患者的安全性和有效性數據。

To recap, the first patient was treated with half the target dose of cells, has achieved insulin independence at day 270, with a hemoglobin A1C level of 5.2%. The second patient also a half dose had positive results through day 150. The patient achieved robust increases in measures of pancreatic islet cell function and improved glucose control while simultaneously experiencing a 30% decrease in exogenous insulin use.

綜上所述，第一位患者接受了目標劑量一半的細胞治療，在第270天實現了胰島素非依賴性，糖化血紅蛋白A1c水平為5.2%。第二位患者同樣接受了半劑量治療，並在第150天取得了積極療效。該患者的胰島細胞功能指標顯著提高，血糖控制得到改善，同時外源性胰島素用量減少了30%。

Taken together, the results from patients 1 and patients 2, both treated at half dose, demonstrate proof of concept for VX-880.

綜合來看，接受半劑量治療的患者 1 和患者 2 的結果證明了 VX-880 的概念。

The third patient who is the first to receive a full dose of VX-880 has reached the day 29 milestone. As of day 29, the patient showed encouraging early indications of efficacy, with increasing C-peptide levels and improving glycemic control. The first detailed assessment of pancreatic islet function and glycemic control for patients in the study occurs at the day 90 visit. Across the program, in the 3 patients dosed to date, there are no SAEs related to VX-880. The majority of adverse events are mild to moderate, and the overall safety profile is consistent with the immunosuppressive regimen used in the study and the perioperative period.

第三位接受全劑量VX-880治療的患者已達到第29天的治療里程碑。截至第29天，該患者顯示出令人鼓舞的早期療效跡象，C肽水平升高，血糖控制改善。研究中所有患者胰島功能和血糖控制的首次詳細評估將在第90天進行。迄今為止，所有3位接受VX-880治療的患者均未發生與VX-880相關的嚴重不良事件（SAE）。大多數不良事件為輕度至中度，整體安全性與研究中使用的免疫抑制方案和圍手術期相符。

These are the data to date. Of course, all 3 patients will be continued to be followed per study protocol. We look forward to working constructively and expeditiously with the FDA to understand and address their questions so that we can resume the trial as soon as possible in the U.S.

以上是目前為止的數據。當然，所有3名患者將繼續依照研究計畫接受追蹤。我們期待與FDA進行建設性且高效的合作，以了解並解答他們的問題，以便盡快在美國恢復試驗。

To close out on type 1 diabetes, a quick word on our cells plus device program. We continue to make progress with our sales and device approach. In this program, instead of using immunosuppression to protect the cell from the immune system, the immunoprotective device is designed to serve that function. We remain on track for an IND filing for this program later this year.

關於第1型糖尿病，最後簡單介紹一下我們的細胞+器械項目。我們在銷售和器械方面持續取得進展。在這個計畫中，我們不再使用免疫抑制劑來保護細胞免受免疫系統攻擊，而是設計了一種免疫保護器械來發揮這一作用。我們預計今年稍後將按計劃提交該項目的IND申請。

In summary, Vertex continues to deliver significant growth in CF, we're making rapid progress with programs in 6 disease areas in mid- and late-stage development, including 5 programs that are already in or entering pivotal development, with another wave of programs on track to enter the clinic starting later this year. We have a strong financial profile and balance sheet that enables continued investment to drive serial innovation.

總而言之，Vertex在囊性纖維化領域持續保持顯著成長，我們在6個疾病領域的中後期研發項目均取得快速進展，其中包括5個已進入或即將進入關鍵性研發階段的項目，另有一批項目預計將於今年晚些時候進入臨床試驗。我們擁有穩健的財務狀況和資產負債表，能夠持續投資以推動持續創新。

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 in CF, our clear path towards future growth in CF and our plans for expansion into additional disease areas.

今晚我很高興地回顧我們在囊性纖維化領域持續強勁的商業表現，我們在囊性纖維化領域未來增長的明確路徑，以及我們向其他疾病領域擴張的計劃。

Vertex's CF business continues to grow at a rapid pace, driven by consistent performance of TRIKAFTA in the U.S. and the continued robust uptake of TRIKAFTA/KAFTRIO outside the U.S., following significant reimbursement progress internationally over the past year. Q1 CF product revenue of $2.1 billion grew 22% year-over-year as more patients have come on therapy. U.S. revenues grew 9% to $1.37 billion in the first quarter of 2022 driven by additional patients starting treatment with TRIKAFTA, most notably children ages 6 to 11, following the mid-2021 approval. Revenue outside the U.S. increased 55% over the first quarter of 2021 to $729 million, driven by rapid uptake of TRIKAFTA/KAFTRIO in countries where we reached reimbursement agreements.

Vertex的囊性纖維化（CF）業務持續快速成長，這主要得益於TRIKAFTA在美國市場的穩定表現，以及TRIKAFTA/KAFTRIO在美國以外市場持續強勁的市場接受度。過去一年，TRIKAFTA/KAFTRIO在國際報銷方面取得了顯著進展。 2022年第一季度，CF產品收入達21億美元，年增22%，主要得益於更多患者開始接受治療。 2022年第一季度，美國市場收入成長9%至13.7億美元，這主要得益於更多患者開始接受TRIKAFTA治療，尤其是6至11歲的兒童，該藥物於2021年中期獲得批准。 2022年第一季度，美國以外市場收入年增55%至7.29億美元，主要得益於TRIKAFTA/KAFTRIO在已達成報銷協議的國家/地區的快速普及。

We started the year with more than 25,000 patients in North America, Europe and Australia, who could benefit from a CFTR modulator but were not yet on therapy. These patients fell primarily into 1 of 3 categories: one, patients who have not yet initiated treatment, largely in countries where we are recently reimbursed and therefore, are early in the launch curve; two, patients in geographies where we are not yet reimbursed; and three, younger age groups who will be addressed through ongoing label expansions. We are confident in our ability to reach the vast majority of these patients over time.

年初，我們在北美、歐洲和澳洲有超過25,000名患者可能受益於CFTR調節劑，但尚未接受治療。這些患者主要分為三類：第一類是尚未開始治療的患者，他們大多來自我們近期獲得醫保報銷的國家，因此處於市場推廣的早期階段；第二類是來自我們尚未獲得醫保報銷地區的患者；第三類是年齡較小的患者群體，我們將透過持續的適應症擴展來涵蓋他們。我們有信心，隨著時間的推移，我們能夠惠及絕大多數這類患者。

TRIKAFTA/KAFTRIO are now available and reimbursed in more than 25 countries. We have continued to reach new reimbursement agreements with the most notable reached example being Australia, where TRIKAFTA is now reimbursed for eligible patients ages 12 and above. We also continue to make progress extending treatment to younger patients. In January, we secured approval for KAFTRIO in Europe and the U.K. for children ages 6 to 11. And in April, Health Canada granted marketing authorization for TRIKAFTA for the same patients. In the U.S., we recently submitted an sNDA for approval of ORKAMBI for children ages 1 to less than 2 years. We also completed enrollment in the Phase III study of TRIKAFTA in children ages 2 to 5 and anticipate submitting for U.S. approval for this age group before the end of 2022.

TRIKAFTA/KAFTRIO 目前已在超過 25 個國家/地區上市並獲得醫療保險報銷。我們持續達成新的健保報銷協議，其中最值得一提的是與澳洲的合作，TRIKAFTA 現已納入澳洲 12 歲及以上符合資格患者的健保報銷範圍。我們也在不斷推進將治療範圍擴大到更年輕的患者群。今年 1 月，KAFTRIO 在歐洲和英國獲準用於 6 至 11 歲兒童。 4 月，加拿大衛生部批准 TRIKAFTA 用於相同年齡層的患者。在美國，我們近期提交了 ORKAMBI 用於 1 至 2 歲以下兒童的補充新藥申請 (sNDA)。此外，我們已完成 TRIKAFTA 用於 2 至 5 歲兒童的 III 期臨床試驗的患者招募，預計將於 2022 年底前向美國衛生部提交該年齡段的上市申請。

As Reshma mentioned, powerful real-world and long-term experience with TRIKAFTA further strengthens the clinical value proposition of this combination. We have previously shown evidence that treatment with our medicines, KALYDECO, ORKAMBI and SYMDEKO slows lung function decline, one of the hallmarks of disease progression for CF patients. We now have data that compares lung function over time for patients treated with TRIKAFTA to untreated matched controls. And these data show that patients on TRIKAFTA on average, do not lose any lung function over a 2-year follow-up period. Generally, CF patients lose 1% to 3% of lung function every year. WE will be presenting these important new data at an upcoming medical forum.

正如Reshma所提到的，TRIKAFTA強大的真實世界長期經驗進一步強化了此聯合療法的臨床價值。我們先前已證實，使用我們的藥物KALYDECO、ORKAMBI和SYMDEKO治療可延緩肺功能下降，而肺功能下降是囊性纖維化（CF）患者疾病進展的標誌性特徵之一。現在，我們獲得了比較接受TRIKAFTA治療的患者與未接受治療的匹配對照組患者肺功能隨時間變化的數據。這些數據表明，接受TRIKAFTA治療的患者在2年的追蹤期內平均肺功能沒有下降。通常情況下，CF患者每年肺功能會下降1%至3%。我們將在即將舉行的醫學論壇上公佈這些重要的新數據。

As Reshma noted, the last 6 to 12 months have been a remarkable period for Vertex as multiple programs reached late-stage development. I would like to provide a few thoughts on 2 programs in late-stage development that could be among our next commercial opportunities.

正如雷什瑪所指出的，過去6到12個月對Vertex來說是個意義非凡的時期，多個計畫都進入了後期研發階段。我想就其中兩個處於後期研發階段的專案談談我的看法，它們可能成為我們下一個商業化機會。

Starting 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. Commercial and launch preparation activities for sickle cell disease and beta thalassemia are well underway. Over the past year, we have developed a deep understanding of the sickle cell and TDT markets, including where patients with these diseases are concentrated, the physicians who would refer them for treatment and the key treatment centers that will facilitate the patient journey. With our submissions planned for later this year, our launch preparation activities are progressing rapidly. Key leadership positions and teams are in place across multiple functions, including medical, commercial and manufacturing. A small number of centers of excellence in the U.S. and Europe will treat the vast majority of severe sickle cell and thalassemia patients.

首先是我們的CRISPR/Cas9基因編輯療法CTX001，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。鐮狀細胞疾病和β地中海貧血的商業化和上市準備工作正在順利進行中。過去一年，我們對鐮狀細胞疾病和TDT市場有了深入的了解，包括這些疾病患者的集中分佈、轉診醫生以及能夠為患者提供治療支援的關鍵治療中心。我們計劃在今年稍後提交申請，上市準備工作正在快速推進。包括醫療、商業和生產在內的多個職能部門的關鍵領導職位和團隊已經到位。美國和歐洲的少數幾家卓越中心將為絕大多數重症鐮狀細胞疾病和β地中海貧血患者提供治療。

Our research suggests that about 90% of U.S. patients reside in 24 states and about 75% of patients in Europe reside in 4 countries. We have identified the potential centers and their referral networks in these countries. We are already engaging with public and commercial payers in the U.S. and EU, and we are developing robust patient service programs to support patients throughout the treatment journey. We continue to see tremendous potential for CTX001 to help patients, and we look forward to the possibility of bringing this groundbreaking therapy to those living with sickle cell disease and beta thalassemia.

我們的研究表明，美國約90%的患者居住在24個州，歐洲約75%的患者居住在4個國家。我們已確定了這些國家潛在的治療中心及其轉診網絡。我們已開始與美國和歐盟的公共和商業支付方接洽，並正在開發完善的患者服務項目，以在整個治療過程中為患者提供支援。我們持續看到CTX001在幫助患者方面具有巨大的潛力，並期待將這項突破性療法帶給鐮狀細胞貧血症和β地中海貧血患者。

Finally, with the recent completion of the 2 Phase II studies in acute pain and the positive POC results in both studies, as Reshma noted, we now plan to advance VX-548 into pivotal development in acute pain in the second half of this year.

最後，正如 Reshma 所指出的那樣，隨著最近 2 項 II 期急性疼痛研究的完成以及兩項研究均取得積極的 POC 結果，我們現在計劃在今年下半年將 VX-548 推進到急性疼痛的關鍵性開發階段。

Let me review with you briefly the market opportunity we see in pain. There is a vast unmet need in the treatment of moderate to severe pain and especially for medicines with an improved benefit risk profile, including avoiding the side effects and addictive qualities of standard of care opioids. To give you some perspective on the market for acute pain, which is our initial target market for VX-548, every year, there are more than 1.5 billion treatment days for acute pain in the U.S. with a large proportion of these including a prescribed opioid. It is an unfortunate fact that some of these scripts result in addiction problems for some patients and contribute to the opioid epidemic in the U.S. Provisional data from the CDC's National Center for Health Statistics for the latest 12-month period ending April 2021 recently estimated that there were more than 75,000 overdose deaths from opioids in the U.S., an increase of 35% compared to the prior 12-month period.

讓我簡要地和大家回顧一下我們看到的疼痛市場機會。中重度疼痛的治療存在巨大的未滿足需求，尤其需要具有更佳獲益風險比的藥物，例如避免標準鴉片類藥物的副作用和成癮性。為了讓大家對急性疼痛市場（VX-548 的初始目標市場）有所了解，美國每年有超過 15 億個急性疼痛治療​​日，其中很大一部分都使用了處方阿片類藥物。令人遺憾的是，部分處方會導致一些患者出現成癮問題，並加劇美國的鴉片類藥物濫用危機。美國疾病管制與預防中心 (CDC) 下屬的國家衛生統計中心最近發布的截至 2021 年 4 月的 12 個月的初步數據顯示，美國因阿片類藥物過量死亡的人數超過 75,000 人，比前 12 個月增加了 35%。

A novel, highly effective class of medicines that does not have these safety concerns would therefore have tremendous potential. For instance, one can imagine a step therapy paradigm in which a patient is started on NSAIDs, escalated to a NaV1.8 inhibitor, and only as a last resort, prescribed an opioid. The first indication we are pursuing for VX-548 is moderate to severe acute pain, and we see this segment of the market as a specialty market that fits the Vertex commercialization model well. But the mechanism is applicable to other types of pain, as demonstrated by VX-150 which showed positive POC across acute, neuropathic and musculoskeletal pain. We look forward to discussing plans in these indications on future calls.

因此，一種新型的、高效的、且不存在這些安全隱患的藥物將具有巨大的潛力。例如，我們可以設想一種階梯療法模式：首先使用非類固醇抗發炎藥（NSAIDs），然後逐步升級為NaV1.8抑制劑，只有在萬不得已的情況下才使用鴉片類藥物。我們目前正在研究VX-548的首個適應症是中度至重度急性疼痛，我們認為這個細分市場是一個非常適合Vertex商業化模式的特殊市場。但正如VX-150所證明的那樣，該藥物的作用機制也適用於其他類型的疼痛，VX-150在急性疼痛、神經性疼痛和肌肉骨骼疼痛方面均顯示出積極的初步療效。我們期待在未來的電話會議上討論這些適應症的計劃。

I am very excited about our continued progress in bringing our CF medicines to more patients globally and about the promise of our late-stage pipeline. I will now turn the call over to Charlie.

我非常高興看到我們在將囊性纖維化藥物推廣給全球更多患者方面取得的持續進展，也對我們後期研發管線的前景感到振奮。現在我將把電話交給查理。

Thanks, Stuart.

謝謝你，斯圖爾特。

Vertex is off to an excellent start in 2022 as our R&D pipeline continued to deliver significant milestones, and we again delivered strong financial performance in the first quarter. First quarter total product revenues were $2.1 billion, an increase of 22% compared to the first quarter of 2021.

Vertex在2022年開局良好，我們的研發管線持續取得重大進展，第一季財務表現也表現強勁。第一季產品總營收達21億美元，較2021年第一季成長22%。

Our growth was again primarily driven by new patients coming on therapy compared to the prior year, including continued robust uptake of KAFTRIO internationally, following expanded reimbursement access in a number of geographies over the past year as well as continued growth of TRIKAFTA in the U.S. Our first quarter 2022 combined non-GAAP R&D and SG&A expenses were $687 million compared to $531 million in Q1 2021. The year-over-year increase in expenses was driven by increased research costs and investments in our advancing pipeline with multiple programs now in mid- and late-stage development. Additionally, we continue to make investments in CTX001 pre-commercial activities in anticipation of regulatory filing by the end of this year.

與上年相比，我們的成長主要得益於接受治療的新患者數量增加，其中包括KAFTRIO在國際市場上的持續強勁增長（過去一年，該藥物在多個地區擴大了醫保覆蓋範圍），以及TRIKAFTA在美國市場的持續增長。 2022年第一季度，我們非GAAP研發及銷售、管理及行政費用合計為6.87億美元，2021年第一季為5.31億美元。費用年增率主要源自於研發成本的增加以及在研產品線的投資，目前多個項目已進入中後期研發階段。此外，我們正持續投資CTX001的商業化前期活動，預計今年底前提交監管申請。

Starting in the first quarter of 2022 and going forward, consistent with reporting practices that have been recently adopted by peer companies, we no longer exclude from our non-GAAP results, research and development charges from upfront or contingent milestone payments in connection with collaborations, asset acquisitions or the licensing of third-party IP. We have also updated prior year reported non-GAAP figures to be consistent with the new basis of presentation. This change in reporting affects only our non-GAAP numbers and the impacts on reported results for Q1 '22 and Q1 '21 were not material.

自2022年第一季起，我們將與同業公司近期採用的報告慣例保持一致，不再從非GAAP財務報表中剔除與合作、資產收購或第三方知識產權許可相關的預付款或或有里程碑付款中的研發費用。同時，我們也已更新了往年報告的非GAAP財務數據，使其與新的列報基礎保持一致。此項報告變更僅影響我們的非GAAP財務數據，對2022年第一季和2021年第一季的報告業績影響不大。

Our continued strong revenue growth combined with our efficient operating model resulted in Q1 non-GAAP operating margin of 56% and non-GAAP operating income of $1.17 billion, an increase of 16% year-over-year. Our non-GAAP effective tax rate for the first quarter of 2022 was 22%. We ended the quarter with $8.2 billion in cash and short-term investments as we continue to maintain a very strong balance sheet profile.

持續強勁的營收成長，加上高效率的營運模式，使得我們第一季的非GAAP營業利潤率達到56%，非GAAP營業收入達到11.7億美元，較去年同期成長16%。 2022年第一季的非GAAP實際稅率為22%。截至季末，我們持有現金及短期投資82億美元，資產負債表依然穩健。

Now to guidance. We are maintaining our previously issued guidance for full year 2022 CF product revenue and non-GAAP effective tax rate. We are adjusting our guidance for combined non-GAAP R&D and SG&A expenses to reflect the change in reporting of upfronts and milestones as I described moments ago. Specifically, our guidance for total CF product revenue remains at $8.4 billion to $8.6 billion. At the midpoint, this is a year-over-year increase of approximately $1 billion or 12% growth. Non-GAAP operating expenses are now projected in a range of $2.82 billion to $2.92 billion, including potential upfront and milestone payments from existing or ongoing collaborations.

現在來說說業績指引。我們維持先前發布的2022財年CF產品全年收入和非GAAP實際稅率指引。我們調整了非GAAP研發和銷售、管理及行政費用的指引，以反映我剛才提到的預付款和里程碑付款報告方式的變化。具體而言，我們對CF產品總收入的指引仍為84億美元至86億美元。取中間值，這意味著年增約10億美元，增幅達12%。非GAAP營運費用預計在28.2億美元至29.2億美元之間，其中包括現有或正在進行的合作項目中可能收到的預付款和里程碑付款。

Finally, we continue to project a non-GAAP effective tax rate in a range of 21% to 22%. As we look out to the remainder of the year and into 2023, we have a number of important pipeline milestones that will demonstrate our continued progress, and these are shown on Slide 16 of the webcast.

最後，我們繼續預期非GAAP有效稅率在21%至22%之間。展望今年剩餘時間和2023年，我們有許多重要的專案里程碑將展現我們持續取得的進展，這些內容已在網路直播的第16頁幻燈片中列出。

In summary, we are on track for our 8th consecutive year of double-digit revenue growth in 2022. The CF business is strong, and we have invested to maintain leadership in CF for the long term. At the same time, we are now going through an inflection point as a company well on our way to diversifying Vertex into new disease areas beyond CF as the broad pipeline of potentially transformative medicines advances. As a result, our unique business strategy, which enables significant reinvestment in internal and external innovation while sustaining high profitability leaves us exceptionally well-positioned for further significant value creation over time. We look forward to updating you further as we progress through the year.

總而言之，我們預計在2022年實現連續第八年兩位數的營收成長。囊性纖維化（CF）業務表現強勁，我們已投入資金以保持在該領域的長期領先地位。同時，隨著一系列具有變革意義的藥物研發管線的推進，我們正處於公司發展的轉折點，並正穩步推進Vertex的業務多元化，拓展至CF以外的其他疾病領域。因此，我們獨特的商業策略——既能對內部和外部創新進行大量再投資，又能保持高盈利能力——使我們擁有得天獨厚的優勢，能夠在未來創造更大的價值。我們期待在今年後續進展中與您分享更多資訊。

Let's now open the call to questions.

現在開始接受提問。

(Operator Instructions)

（操作說明）

And the first question will come from Cory Kasimov with JPMorgan.

第一個問題將來自摩根大通的科里·卡西莫夫。

Just want to say thanks to Michael, first of all, for all his help over the years. It's obviously been very much appreciated.

首先，我要感謝麥可多年來的幫助。我們對此感激不盡。

So my question is on your Phase III trial for VX-147 and AMKD. And I'm curious about kind of your confidence in the potential for an accelerated filing at the 48-week time point based on the predictive nature of reduction in proteinuria materially impacting the slope of eGFR curves at that time?

我的問題是關於您針對VX-147和AMKD的III期臨床試驗。我很好奇，基於蛋白尿減少對48週時eGFR曲線斜率的預測作用，您對在48週時加速提交上市申請的可能性有多大信心？

Yes. Cory, with regard to the 147 program, the key features of the study design are that it's a singular Phase II/III study. It is a study that will enroll the broad population, so the full 100,000 patients that could be eligible for this drug. And the third feature of the study is the one you asked about. We have built in a prespecified interim analysis at the 48-week time point. And if that analysis is positive, that provides the pathway to accelerated approval.

是的。 Cory，關於147項目，該研究設計的關鍵特點在於它是一項獨立的II/III期研究。這項研究將納入廣泛的人群，即所有可能符合該藥物治療條件的10萬名患者。研究的第三個特點正是您所提到的。我們預先設定了在48週時進行中期分析。如果該分析結果為陽性，則可加速核准。

The relationship between proteinuria, that's what we studied in Phase II, is very tight, high correlation with eGFR, which is a measure of renal function. And the reason I have such high confidence in the interim analysis is because the reduction in proteinuria that we saw in Phase II is an unprecedented 47.6% in this very specific and a very aggressive form of AMKD called FSGS. So with that 47.6% reduction in proteinuria and you do the translations to what you would expect in terms of GFR, what I come out with is a high confidence level for the interim analysis. That was why it was so important that these 3 features that I mentioned were agreed upon with the agency when we went to them at the end of Phase II meeting.

我們在第二期臨床試驗中研究的蛋白尿與腎小球濾過率（eGFR，一種腎功能指標）之間的關係非常密切，具有高度相關性。我對中期分析結果充滿信心的原因在於，我們在二期臨床試驗中觀察到的蛋白尿減少幅度高達47.6%，這在一種名為局部節段性腎小球硬化症（FSGS）的特殊且侵襲性極強的急性髓系白血病（AMKD）類型中是前所未有的。因此，考慮到蛋白尿減少了47.6%，並將其轉化為預期的腎小球濾過率（GFR）變化，我對中期分析結果的信心非常高。正因如此，在二期臨床試驗結束會議時，我們與監管機構就上述三個關鍵特徵達成一致才顯得尤為重要。

The next question will come from Geoff Meacham with Bank of America.

下一個問題將來自美國銀行的傑夫·米查姆。

This is Jason on for Geoff. Congratulations on the quarter. And again, want to extend our congratulations to Michael.

我是傑森，替傑夫發言。恭喜你本季取得佳績。再次恭喜邁克爾。

A few quick if I may. Could you discuss how the pain programs fit in strategically within the commercial portfolio, given the focus on rare diseases. Basically, is this an asset you're potentially thinking about partnering with? Is it advances? Or are you kind of looking at maybe establishing the necessary commercial infrastructure? And then it does sound like the clinical hold on 80 was a bit of a surprise. But then again, regulators have seemingly started operating with, I guess, an abundance of caution for gene and cell therapies. And do you see any potential negative read-throughs to the upcoming CTX001 submission? Or have regulators seem fairly comfortable with the safety and efficacy package as is?

如果可以的話，我想快速問幾個問題。鑑於貴公司專注於罕見疾病領域，能否談談疼痛治療項目在商業組合中的策略定位？基本上，貴公司是否考慮與相關方合作？是進行技術開發？還是正在考慮建立必要的商業基礎設施？另外，80號藥物的臨床試驗暫停似乎有點出乎意料。不過，監管機構似乎對基因和細胞療法更加謹慎了。您認為即將提交的CTX001申請會受到哪些潛在的負面影響？或者監管機構是否對目前的安全性和有效性數據感到滿意？

Jason, there's a few different questions in there. Let me try to parse it out into pain and how we see CTX001.

傑森，這裡麵包含幾個不同的問題。讓我試著把它們梳理成疼痛以及我們如何看待CTX001這兩個面向。

On CTX001, we've been very pleased with the momentum that we've seen in the study. As I said in my prepared remarks, the enrollment is complete. We've dosed more than 75 patients. We've secured really every regulatory designation available, PRIME, RMAT, Orphan here and in Europe. And we are planning forward for our filing towards the tail end of this year.

關於CTX001，我們對目前的研究進度非常滿意。正如我在事先準備好的演講稿中所說，病患招募工作已經完成。我們已經為超過75名患者進行了給藥。我們幾乎獲得了所有可用的監管認定，包括美國和歐洲的PRIME、RMAT和孤兒藥認定。我們正在積極籌備，並計劃在今年底提交上市申請。

On the pain program, let me make 2 comments, and I'm going to turn it over to Stuart to give you some more color. We see acute pain and neuropathic pain as fully Vertexian. I don't feel the same way about musculoskeletal pain or something like back pain or knee pain or some such pain that will categorize as musculoskeletal. That being said, based on the pharmacologic validation with our own VX-150 and the genetic validation, I do expect this mechanism to be effective across the 3 pain states.

關於疼痛治療方案，我想先提兩點，然後把麥克風交給斯圖爾特，讓他補充更多細節。我們認為急性疼痛和神經性疼痛完全屬於Vertexian的範疇。但我對肌肉骨骼疼痛，例如背痛、膝痛或其他類似的肌肉骨骼疼痛，持不同看法。即便如此，基於我們自主研發的VX-150的藥理驗證和基因驗證，我預期這個機制對這三種疼痛狀態都有效。

Stuart, a little more color on the commercialization.

斯圖爾特，再詳細說說商業化方面的情況。

Yes. And Jason, I think there is a bit of a misconception about us as a company that we're a rare or an orphan company. And as Reshma described that's not how we define ourselves. Our research strategy is to focus on specific diseases where we understand the human biology, where there are validated targets, as Reshma said, either genetically or in the case of NaV1.8 now pharmacologically and they're in markets where we can access them with a specialty infrastructure. And we think pain fits that description perfectly.

是的。傑森，我認為大家對我們公司有些誤解，認為我們是一家專注於罕見疾病或孤兒藥的公司。正如雷什瑪所說，我們並非這樣定義自己。我們的研究策略是專注於我們了解其人類生物學機制的特定疾病，這些疾病擁有已驗證的靶點，正如雷什瑪所說，這些靶點可能是基因層面的，也可能是像NaV1.8那樣，是藥物層面的。而且，這些疾病的市場定位也符合我們利用專業基礎設施進行推廣的條件。我們認為疼痛疾病完全符合這些條件。

As Reshma said, there's various different segments of the pain market that you can think about: acute, neuropathic and the chronic musculoskeletal. The commercial opportunity in the acute pain segment is enormous. Acute pain accounts for over $1.5 billion with the B treatment days a year in the U.S. alone. And despite more than 90% of those prescriptions being generic, the market is valued at $4 billion. So if we are able to bring forward an asset that has opioid or better efficacy, without the side effect liability of opioids and other pain medications, we think the opportunity is very, very significant in acute pain, multibillion dollar in acute pain opportunity. And as Reshma said, similarly in neuropathic pain, multibillion-dollar opportunity. That's also a specialty market that we could service through a specialty infrastructure.

正如雷什瑪所說，疼痛市場可以細分為多個領域：急性疼痛、神經性疼痛和慢性肌肉骨骼疼痛。急性疼痛領域的商業機會巨大。光是在美國，急性疼痛每年就佔用超過15億美元的醫療資源，治療天數高達B天。儘管超過90%的處方藥都是仿製藥，但該市場的價值仍高達40億美元。因此，如果我們能夠推出一種療效堪比甚至優於阿片類藥物，且沒有阿片類藥物和其他止痛藥副作用的產品，我們認為在急性疼痛領域，這是一個非常非常大的機會，市場規模可達數十億美元。正如雷什瑪所說，神經性疼痛領域也蘊藏著類似的數十億美元商機。這也是一個我們可以透過專業基礎設施來服務的專業市場。

Next question will come from Robyn Karnauskas with Truist Securities.

下一個問題將來自 Truist Securities 的 Robyn Karnauskas。

Michael, I'm sad to see you go, but congratulations on all the hard work.

邁克爾，我很遺憾你離開，但祝賀你付出的所有努力。

So a few quick ones. Few quick ones, some inclusion criteria for your Phase III trial for AMKD. How challenging do you think the enrollment might be? You've indicated there's 100,000 patients. How many are actually genotypes, are seeking treatment? Do you have to do more work to actually get the genotype?

幾個簡短的問題。關於你們針對AMKD的III期臨床試驗的入組標準，你們認為招募病人會有多大的挑戰？您提到有10萬名患者。其中有多少人已經確定了基因型並正在尋求治療？你們是否需要做更多工作來獲取基因型資訊？

And second question is really on CTX001. Could you just give us some more color as you've been talking to more of the centers, maybe buckets of patients that would be the initial patients most likely to one drug and what their characteristics are? And are you creating a registry or a list of patients who might be willing to start therapy.

第二個問題確實與CTX001有關。您能否詳細介紹一下您與更多中心交流的情況，例如，哪些患者群體最有可能對這種藥物產生反應，以及他們的特徵是什麼？您是否正在建立一個登記冊或可能願意接受治療的患者名單？

I'm going to start on AMKD, and then I'll ask Stuart to provide some color on the patients for both sickle cell disease and beta thalassemia for the CTX001 program.

我打算先從 AMKD 開始，然後我會請 Stuart 為 CTX001 計畫提供一些關於鐮狀細胞疾病和 β 地中海貧血患者的詳細資訊。

Robyn, the key criteria for entry into the AMKD study is proteinuria, reduced renal function and 2 APOL1 alleles by genotyping. The actual genotyping test is fairly simple. It's a simple blood test, but you are right that it is not commonly performed. And the reason it's not commonly performed is because before now, we didn't really have anything to offer our patients who had APOL1-mediated kidney disease. Recognizing that, we've added some features into our Phase II/III clinical trial to ensure that we will have the kind of enrollment that we seek and that we can bring this medicine forward with speed.

Robyn，AMKD 研究的關鍵入組標準是蛋白尿、腎功能下降以及基因分型顯示存在 2 個 APOL1 等位基因。基因分型檢測本身相當簡單，只需進行簡單的血液檢查即可。但你說得對，這種檢測並不常用。之所以不常用，是因為在此之前，我們對於患有 APOL1 介導的腎臟病的患者幾乎沒有有效的治療方案。有鑑於此，我們在 II/III 期臨床試驗中增加了一些措施，以確保達到我們預期的患者入組目標，並加快藥物的研發進程。

The first is it's a global study with many sites up and running in the U.S. and in the EU. The second is all patients are on standard of care. So there is no patient who is going to have to go on to placebo to be part of the study. This is a study where one arm gets standard of care plus VX-147 and the other arm gets standard of care. And third, we have a concurrent genotyping study up and running where patients can get genotyped and they can, if they wish, then enroll in the Phase II/III study. I think that those measures are going to be very helpful as we make progress on the enrollment.

首先，這是一項全球性研究，在美國和歐盟設有多個研究中心。其次，所有患者均接受標準治療。因此，沒有患者需要接受安慰劑治療才能參與研究。本研究分為兩組，一組接受標準治療加上VX-147，另一組僅接受標準治療。第三，我們同時進行了一項基因分型研究，患者可以進行基因分型，如果願意，可以隨後加入II/III期研究。我認為這些措施將對我們推動病患招募工作大有裨益。

Stuart, I'm going to turn it over to you for CTX001 and patients that you see.

斯圖爾特，我將把 CTX001 和你接診的病人交給你負責。

Yes, Robyn, thanks for the question.

是的，羅賓，謝謝你的提問。

So -- as we've commented previously, there's about 150,000 patients who have sickle cell disease or transfusion development -- transfusion dependent thalassemia in the U.S. and the EU. However, as you can imagine, we don't think that there are -- that that is the entire population that's going to be eligible for CTX001 given the current conditioning regimen. So based on the inclusion criteria with our study, but also our research and other people's research, talking to physicians about the types of patients that they think are likely to be potential candidates, we think that's around 32,000 of the 150,000. Of that 32,000, about 25,000 of those are sickle cell, the majority of which are here in the U.S. So that is the patients that we think are likely to be potential candidates for CTX001 with the existing busulfan-based conditioning regimen.

正如我們之前提到的，美國和歐盟大約有15萬名鐮狀細胞疾病或輸血依賴型地中海貧血患者。然而，正如您所想，我們認為，在目前的預處理方案下，這並非全部符合CTX001治療條件的患者。因此，根據我們研究的納入標準，以及我們和其他研究者的研究，並結合與醫生的交流，我們認為這15萬名患者中約有3.2萬人符合資格。在這3.2萬人中，約有2.5萬人患有鐮狀細胞疾病，其中大部分在美國。因此，我們認為，在現有的基於白消安的預處理方案下，這部分患者可能符合CTX001治療條件。

The next question will come from Salveen Richter with Goldman Sachs.

下一個問題將來自高盛的薩爾文·里希特。

Michael, it has been a pleasure working with you. You'll be very missed here. Two clinical questions. One on CTX001. On the commercial front, how much precedent has been set on the payer front globally by bluebird, particularly given their difficulty with the EU? And then secondly, on the Duchenne gene editing program. Could you just provide some details on the construct? And is this in partnership with CRISPR.

邁克爾，和你一起工作非常愉快。我們會非常想念你。我有兩個臨床方面的問題。第一個是關於CTX001的。在商業方面，考慮到bluebird公司與歐盟的合作困難，它在全球範圍內與支付方達成合作的先例有多大？第二個問題是關於杜氏肌肉營養不良症基因編輯計畫。可否詳細介紹一下該藥物的建構方法？這個計畫是與CRISPR公司合作的嗎？

Salveen, I'm going to start with the DMD question, and then I'm going to turn it over to Stuart to talk through CTX. The DMD program is one, I know, Salveen, you've asked me about before, in just one second, I'm going to turn it over to Bastiano. We have made really nice progress on that program. This is a gene editing-based program, and we are in IND-enabling studies with the IND plan for next year.

薩爾文，我先回答關於杜氏肌肉營養不良症（DMD）的問題，然後把麥克風交給斯圖爾特，讓他談談CTX計畫。我知道薩爾文，你之前問過我關於DMD專案的問題，我馬上就把麥克風交給巴斯蒂亞諾。我們在這個專案上取得了非常好的進展。這是一個基於基因編輯的項目，我們正在進行IND申報所需的各項研究，IND申報計劃明年開始。

Bastiano, can I ask you to give a little bit more color on this?

巴斯蒂亞諾，你能再詳細說說這件事嗎？

Sure. So our approach to DMD is a little bit different than all the other gene therapy approaches because we have deliberately actually chosen to go with like a near full-length exon skipping dystrophin approach, which is based on human genetics because as you know, patients with Duchenne dystrophy, for example, have a near full line dystrophin and for the very mild disease. The gene therapy approaches that are used by -- in other contexts, they only deliver a truncated version of the dystrophin of various lengths, but it's called micro dystrophin for a reason. Gene editing is actually only approach that has the potential to deliver the near full-length protein, which is required for what we believe is going to be a durable transformational functional cure.

當然。我們治療杜氏肌肉營養不良症 (DMD) 的方法與其他基因療法略有不同，因為我們特意選擇了接近全長的外顯子跳躍肌營養不良蛋白療法，這是基於人類遺傳學。如您所知，例如，杜氏肌肉營養不良症患者體內就存在接近全長的肌肉營養不良蛋白，而且病情通常較輕。其他基因療法通常只能遞送長度不一的截短肌營養不良蛋白，之所以稱之為“微型肌營養不良蛋白”，是有原因的。基因編輯是唯一有可能遞送接近全長的蛋白質的方法，而這正是我們認為能夠實現持久、徹底治癒的關鍵。

You remember that this program came to us through the acquisition of Exonics. And since then, we have worked really, really hard on both analytical and process development for our technology because given what has happened in the field that we really pay close attention to those purity and other things like analytical development and process development to be sure that we have the best product technology-wise as opposed -- together with science.

您還記得這個項目是透過收購 Exonics 公司獲得的。從那時起，我們就一直在努力進行技術分析和製程開發，因為鑑於該領域發生的情況，我們非常關注純度以及其他方面，例如分析開發和製程開發，以確保我們在技術方面擁有最好的產品——與科學相結合。

So we feel very optimistic about our approach and as Reshma said, very pleased to be in IND-enabling studies and we aim to file the IND in 2023 and beginning clinical development soon thereafter.

因此，我們對我們的方法感到非常樂觀，正如 Reshma 所說，我們很高興能夠進行 IND 申報研究，我們的目標是在 2023 年提交 IND 申請，並在此之後儘快開始臨床開發。

Salveen, on transformative therapies and kind of payment models, which I think was the basis of the question. I don't think what happened with bluebird has set a precedent that transformative onetime functional cures are never going to get paid for in the EU or elsewhere. Clearly, there's disappointment in the community about the license withdrawal. However, we, as part of our prelaunch planning are engaging with payers, both here in the U.S. and overseas. And based on the capabilities that our team has demonstrated in securing reimbursement for CF, given the transformative potential that CTX001 holds, I'm optimistic that we're going to be able to bring that medicine to patients around the world pending license approval.

Salveen，關於變革性療法和支付模式，我認為這才是問題的核心。我不認為Bluebird的案例開創了先例，意味著變革性的一次性功能性療法在歐盟或其他地區永遠無法獲得報銷。顯然，業界對許可證撤銷感到失望。然而，作為上市前規劃的一部分，我們正在與美國和海外的支付方進行溝通。鑑於我們團隊在為囊性纖維化患者爭取報銷方面所展現出的能力，以及CTX001所蘊含的變革性潛力，我樂觀地認為，一旦獲得許可，我們將能夠把這種藥物帶給世界各地的患者。

The next question will come from Michael Yee with Jefferies.

下一個問題將來自傑富瑞集團的邁克爾·伊。

Thanks for the question. And thanks to Mike as well. We really appreciate it.

謝謝你的提問。也謝謝麥克。我們非常感謝。

We have 2 questions on APOL1-mediated kidney disease. And the first question was just around your confidence in enrolling the Phase II portion and whether or not you expect that data at the end of the year and what you can say about that? So going back to sort of a follow-up in terms of identifying these patients and speed and confidence of getting these people enrolled. And the second question relates to the Phase III portion, which is on eGFR and whether or not you have a good idea around the slope of decline over a time period for these patients and whether or not there's any heterogeneity between the different diseases within AMKD and what you're assuming for in the Phase III on decline?

我們有兩個關於APOL1介導的腎臟疾病的問題。第一個問題是關於您對II期臨床試驗入組工作的信心，以及您是否預計年底能獲得相關數據，您對此有什麼看法？這實際上是對識別這些患者、入組速度以及入組信心的後續跟進。第二個問題與III期臨床試驗有關，主要關注eGFR，您是否對這些患者的eGFR隨時間推移的下降趨勢有較好的了解，以及AMKD不同疾病之間是否存在異質性，您對III期臨床試驗中eGFR下降的預期是什麼？

Yes. Mike, with regard to enrollment, it is really simply too early to comment on enrollment dynamics for VX-147. We presented and shared the Phase II data just in December and the Phase III started just 3 months after that in March. So a little too early to call. But as I commented, I think the genotyping study, the number of trial sites that we are opening around the globe and the fact that this is a study where both arms get treatment will help with enrollment.

是的。麥克，關於入組情況，現在評論VX-147的入組動態還為時過早。我們去年12月才公佈了第二期臨床試驗數據，三期臨床試驗也僅僅在三個月後的3月就啟動了。所以現在下結論還太早。但正如我之前提到的，我認為基因分型研究、我們在全球各地開設的試驗中心數量，以及這項研究中兩組患者均接受治療的特點，都將有助於入組。

On the GFR question in the Phase III portion, the -- this group of patients, those with 2 APOL1 alleles have a very rapid decline. And when I say that, I mean north of 5 CCs per year. And when you have that kind of rapid decline, it gives you the opportunity to assess the impact of your drug, which is why this 1-year accelerated endpoint potential is really important. So what we demonstrated in Phase II is reduction in proteinuria. That was the approximately 50% reduction, 47.6%. That is very tightly correlated with the eGFR, the measure of kidney function and the measure of kidney function in people with 2 APOL1 alleles, regardless of whether you call it FSGS or you call it another disease, is very high. So I feel very good about where we are in terms of getting the clinical trial up and running and very good about the way we've designed the endpoint on both proteinuria and eGFR.

在III期臨床試驗中，關於腎絲球濾過率（GFR）的問題，攜帶兩個APOL1等位基因的病患群體，其GFR下降速度非常快。我指的是每年下降超過5毫升。這種快速下降為我們評估藥物療效提供了機會，這也是為什麼一年加速終點指標如此重要的原因。我們在II期臨床試驗中證實了蛋白尿的減少。蛋白尿減少了約50%，即47.6%。這與腎功能指標eGFR有密切關係。攜帶兩個APOL1等位基因的患者的腎功能指標非常高，無論你稱之為局部節段性腎小球硬化症（FSGS）還是其他疾病。因此，我對我們目前臨床試驗的啟動和運行情況以及我們設計的蛋白尿和eGFR這兩個終點指標都非常滿意。

The next question will come from Phil Nadeau with Cowen and Company.

下一個問題將來自 Cowen and Company 的 Phil Nadeau。

Michael, let me add my thanks for all your help over the years. Best of luck in your next adventures. You're certainly going to be missed here. 2 questions from us. First, brief commercial and then VX-880. On the commercial last quarter, you called out inventory build. You haven't mentioned inventory yet on the call. So curious where inventory stands and whether there's destocking in the quarter.

邁克爾，請容許我再次感謝你多年來的幫助。祝你未來一切順利。我們一定會非常想念你。我們有兩個問題。首先，請簡單介紹一下公司業務，然後是關於VX-880的。在上個季度的商務會議上，你提到了庫存增加。但在這次電話會議上，你還沒有提到庫存問題。所以我們很想知道目前的庫存狀況，以及本季是否會進行去庫存。

Then second on VX-880, appreciating it's still early days since the clinical hold that was initiated. But do you have any sense of why the FDA is not convinced. I think in the press release, you mentioned they didn't believe the benefit risk was positive. Is that because they don't think you need more benefit, or is there some risk they're worried about? And then second on VX-880, you have 1 ex U.S. trial site. Any desire to increase the numbers to continue enrolling patients what the U.S. hold is instituted. And last, of course, if you have any preliminary thoughts on what you need to do to release the hold? We would all be curious to hear.

其次是關於VX-880，我知道臨床試驗暫停至今時間尚短。但您是否了解FDA為何不認同該藥物？我記得在新聞稿中您提到，他們認為該藥物的獲益風險並不大於風險。這是因為他們認為無需增加獲益，還是他們擔心某些風險？另外，關於VX-880，目前只有一個美國以外的試驗中心。在美國暫停試驗期間，您是否計劃增加試驗中心數量以繼續招募患者？最後，當然，您是否對解除暫停試驗有任何初步想法？我們都很想聽聽您的看法。

Let me ask Charlie to start with your question on the inventory for the quarter. Charlie, do you want to talk a little bit about the revenues for the quarter and how you see inventory?

我先請查理回答你關於本季庫存的問題。查理，你想談談本季的收入以及你對庫存的看法嗎？

Yes. Thanks for the question. As we've mentioned previously, it's not at all uncommon for us to see channel inventory and patient inventory fluctuations quarter-to-quarter on the order of magnitude of $20 million to $50 million. We called out an inventory increase in the fourth quarter. We did see some destocking in the first quarter. We just didn't call it out specifically.

是的，謝謝你的提問。正如我們之前提到的，通路庫存和患者庫存出現季度環比波動，金額在2000萬美元到5000萬美元之間，這種情況並不罕見。我們曾在第四季報告過庫存增加，第一季也確實出現了一些去庫存，只是當時沒有特別提及。

And with regard to your questions on VX-880, Phil, what we shared earlier this week is what we know. By regulation, the agency has 30 days to provide us their list of questions or their information request. We are highly confident in this program and deeply committed to type 1 diabetes. And we're looking forward to constructively and expeditiously working with the agency to resume the trial in the U.S. as soon as possible. The trial is up and running, as you rightfully point out, in 2 regions right now in the U.S. and in Canada. The trial remains up and running in Canada. We have not received any word from Health Canada for any questions or concerns that they have.

關於您提出的VX-880的問題，Phil，我們本週早些時候分享的資訊就是我們目前所了解的情況。根據規定，監管機構有30天的時間向我們提供他們的問題清單或資訊請求。我們對這個計畫充滿信心，並致力於第1型糖尿病的治療。我們期待與監管機構進行建設性且高效的合作，盡快在美國恢復試驗。正如您所指出的，目前該試驗已在美國和加拿大的兩個地區啟動並運行。在加拿大，試驗仍在進行中。我們尚未收到加拿大衛生部就任何問題或疑慮的任何回應。

And with regard to opening up additional sites, that's always been in the plan. It has nothing to do with the hold in the U.S., and we intend to have more sites coming on in time.

至於開設更多站點，這始終在我們的計劃之中。這與美國的業務停滯無關，我們計劃在適當的時候推出更多站點。

The next question will come from Colin Bristow with UBS.

下一個問題將來自瑞銀集團的柯林布里斯托。

This is Colin. Congrats on the quarter. Michael, thank you for the help and all the best in the future. David and Reshma, we had previously spoken before the AbbVie readout, and you talked about the amount of competitive intelligence work you have done, and this ultimately gave you confidence that the AbbVie triplet would not be a threat. Clearly this was on point. I'm curious if you had any early thoughts or insight into next-gen corrector? I think it's AbbVie 576 that they plan to advance into the clinic. And then also on the competition side, there was some press recently about Affinia Therapeutics, which have assets targeting the NBD1 domain. So I'd be curious to get your take on this approach also.

我是科林。恭喜你們本季業績出色。邁克爾，感謝你的幫助，祝你未來一切順利。大衛和雷什瑪，在艾伯維公佈業績之前，我們曾有過交流，你們談到了你們所做的大量競爭情報工作，最終讓你們確信艾伯維的三重奏不會構成威脅。顯然，你們的判斷是正確的。我很好奇你們對下一代矯正劑有什麼初步的想法或見解嗎？我記得艾伯維計劃推進臨床試驗的是576。另外，在競賽方面，最近媒體報導了一些關於Affinia Therapeutics的消息，他們有一些針對NBD1結構域的藥物。所以我也想聽聽你們對這種療法的看法。

Yes. Colin, I'll start and then I'm going to ask David to add a little comment.

是的。柯林，我先開始，然後我會請大衛補充一點意見。

Colin, I won't speak directly to any competitor. That's not my practice. But let's talk about CF in general. Over the years, we've established a leadership position in CF, and we've not only sustained it, but we've expanded it. And our goal of out innovating ourselves and if possible, even bringing more efficacious medicines forward than TRIKAFTA, and absolutely, in the case of the last 5,000 patients, bringing forward a nucleic acid therapy for them, that remains unchanged. TRIKAFTA is the standard of care today. And the closest competitor to TRIKAFTA has been and remains today our own VX-121/561/tezacaftor. I'm going to ask David to just give you a few comments on why we have so much confidence in our molecules and the HBE assays, which are really the workhorse and the translational element of what we do.

柯林，我不會直接和任何競爭對手說話。這不是我的慣例。但我們來談談囊性纖維化（CF）這個主題。多年來，我們在CF領域確立了領先地位，而且我們不僅保持了這一地位，還擴大了這一地位。我們始終致力於創新，力求超越自身，並盡可能研發出比TRIKAFTA更有效的藥物，尤其是在最近5,000名患者身上，我們更是積極研發核酸療法。 TRIKAFTA目前是標準療法。 TRIKAFTA最直接的競爭對手一直是我們自己的VX-121/561/tezacaftor。接下來，我想請大衛談談我們為什麼對我們的分子和HBE檢測如此充滿信心。 HBE檢測是我們工作的核心和轉化醫學的關鍵。

David, a few comments from you on our confidence and why we know when we have something in the lab, it translates into the clinic.

David，你對我們的信心以及為什麼我們知道實驗室裡所取得的成果能夠轉化為臨床應用有什麼看法？

Absolutely, Reshma. As you've seen over the years, the Vertex' deployment of the HBE assay has proven itself over and over again to be translationally relevant and predict clinical outcomes. And that's been true through KALYDECO, ORKAMBI, SYMDEKO, VX-445, TRIKAFTA and also with VX-121, that triple where we saw improved chloride transport in the HBE assay. We also, as you remember, did a Phase II study that showed improved sweat chloride and other very promising attributes such as the FEV1 change. So we really believe in that assay, and we've proven it out. We do continue to work on small molecules to outdo not just TRIKAFTA, but the VX-121 which is in Phase III. And we do follow everything that goes on, and we believe that the most promising molecules that could possibly challenge VX-445 are our own 121 triple and those things we might bring beyond it.

當然，Reshma。如你多年來所見，Vertex公司應用的HBE檢測方法已反覆證明其具有轉化意義，並能預測臨床結果。 KALYDECO、ORKAMBI、SYMDEKO、VX-445、TRIKAFTA以及VX-121（一種三重療法）都證實了這一點，我們在HBE檢測中觀察到氯離子轉運的改善。你也記得，我們​​進行了一項II期研究，結果顯示汗液氯化物水平有所改善，以及其他一些非常有前景的特性，例如FEV1的變化。因此，我們對該檢測方法充滿信心，並且已經證明了這一點。我們仍在持續研發小分子藥物，力求超越TRIKAFTA以及正在進行III期臨床試驗的VX-121。我們密切關注所有進展，並相信最有希望挑戰VX-445的分子是我們自主研發的VX-121三聯療法以及我們未來可能推出的其他療法。

The next question will come from Mohit Bansal with Wells Fargo.

下一個問題將來自富國銀行的莫希特·班薩爾。

And again, my congratulations, and thank you very much for Michael as well. So maybe a couple of questions on the diabetes program. Could you comment on the C-peptide levels for the first patient at day 270. Was there an increase after day 150. And do you -- when do you expect to see a plateau flattering effect for C-peptide? And last one related is that do you have a target C-peptide level for these patients that might lead to insulin independence eventually?

再次恭喜您，也非常感謝Michael的幫忙。關於糖尿病治療方案，我有幾個問題。您能否談談第一位患者在第270天的C肽濃度？ C肽濃度在第150天後是否有升高？您預計C肽水平何時會達到平台期並趨於平穩？最後一個相關問題是，您是否為這些患者設定了C肽目標水平，以期最終實現胰島素非依賴？

Yes. Well, it's really good questions. I'm going to reframe the question a little bit and ask Bastiano to comment, but I want to make sure I explain this well. The way you know that a patient is insulin independent actually is by a very strict criteria. And that strict criteria is they don't take insulin any longer, exogenous insulin. Their fasting glucose level is less than 126 and their postprandial, that's to say after food, glucose level is less than 180. And the reason we're able to declare patient #1 as insulin independent is because they meet all of those criteria.

是的。這確實是個好問題。我稍微調整一下問題，請巴斯蒂亞諾來解釋一下，但我希望確保我能解釋清楚。判斷一位患者是否擺脫了胰島素依賴，實際上是透過非常嚴格的標準。這些嚴格的標準是：他們不再需要注射胰島素，也就是外源性胰島素。他們的空腹血糖低於126，餐後血糖低於180。我們之所以能夠宣布1號患者擺脫了胰島素依賴，是因為他們符合所有這些標準。

Now you asked a good question about what do we expect in terms of durability of effect. And I'm going to turn it over to Bastiano to talk about the experience with cadaveric transplants, the quantity and quality of our cells and why we think that our approach is a durable -- long-term durable approach. Bastiano?

您剛才問了一個很好的問題，關於我們預期療效的持久性如何。接下來，我將把這個問題交給巴斯蒂亞諾，讓他談談遺體移植的經驗、我們細胞的數量和質量，以及我們為什麼認為我們的方法是一種持久的——長期有效的療法。巴斯蒂亞諾？

Thanks, Reshma. And it actually allows me to talk about what is really important in this problem, which is the quality and the nature of our cells. So our cells are fully differentiated, undistinguishable from naturally occurring beta cells. So they share a common biology. Now what we know about the biology of beta cells is that at first, they pretty much all set when it comes to their numbers and their differentiation, which means that they last a lifetime. That is what is known about these cells. That is actually consistent with what has been learned over the years with cadaveric islets, where when the patients are compliant with immunosuppressive therapy and the transplant is therefore successful, these cells can last for a very, very long time.

謝謝，雷什瑪。這實際上讓我有機會談談這個問題中真正重要的部分，那就是我們細胞的品質和性質。我們的細胞已經完全分化，與天然存在的β細胞沒有區別。它們擁有共同的生物學特性。我們對β細胞生物學的了解是，它們的數量和分化程度在最初階段幾乎就完全穩定下來，這意味著它們可以終生存活。這就是我們對這些細胞的了解。這與多年來對屍體胰島的研究結果一致：當患者能夠堅持免疫抑制治療，移植成功時，這些細胞可以存活非常非常長的時間。

So our cells, we believe that being of the same biology and in the context of a similar therapeutic approach being cadaveric transplant, we believe that there is the potential for the cells to last as long as the natural beta cells do, which is a lifetime. When it comes to the...

因此，我們相信，由於我們的細胞與天然β細胞具有相同的生物學特性，並且在類似的治療方法（即屍體移植）下，這些細胞有可能像天然β細胞一樣存活終生。至於…

I think that was a (inaudible).

我想那是（聽不清楚）。

The next question will come from Evan Seigerman with BMO Capital Markets.

下一個問題將來自 BMO 資本市場的 Evan Seigerman。

I'll just add, Michael, thank you for everything over the years. You will be missed greatly. Charlie, one for you. I love if you could speak to the impact of FX on OUS sales. I don't think you mentioned anything in your prepared remarks. Did that factor into your decision not to raise guidance despite expanded reimbursement, I'm not pointing to kind of what you announced in Australia recently.

我還要補充一點，邁克爾，感謝你這些年來所做的一切。我們會非常想念你。查理，這個問題問你。我很想知道外匯波動對海外銷售的影響。我記得你在準備的發言稿裡好像沒提到。這是否影響了你儘管擴大了報銷範圍卻仍然不提高業績預期的決定？我指的不是你最近在澳洲宣布的那項措施。

Yes. Evan, thanks for the question. Again, just to remind folks, the reiterated guidance for revenue, $8.4 billion to $8.6 billion sets us up for another really strong year. That's $1 billion above 2021 and 12% growth. As we reiterated the guidance, we considered a number of puts and takes. Australia, of course, is good news that we've had this year. We also considered things like inventory fluctuations in FX, which is a very modest headwind. And all of that taken together, we feel is accurately captured in the $200 million range between the low end and the high end of guidance.

是的，埃文，謝謝你的提問。再次提醒大家，我們重申了營收預期，預計在84億美元至86億美元之間，這將使我們迎來另一個強勁的年份。這比2021年高出10億美元，成長12%。在重申預期時，我們考慮了許多因素。當然，澳洲市場今年傳來利好消息。我們也考慮了匯率波動等因素，這些因素帶來的不利影響非常有限。綜合所有因素，我們認為2億美元的預期區間能夠準確反映預期的上下限。

Excellent. And then no real impact on FX or kind of -- can you speak more to that?

太好了。那麼對外匯市場或其他方面沒有實際影響嗎？能詳細說說嗎？

Yes. It's pretty modest. 2/3 of our revenues are in the U.S., 1/3 ex U.S. We have a very active and very effective hedging program that blunts some of the impact of foreign exchange changes. And so for us the impact -- with again -- with sort of a baseline 12% growth rate, the relative impact of FX is pretty modest and very small compared to some of our peers.

是的，影響相當有限。我們三分之二的收入來自美國，三分之一來自美國以外。我們擁有非常積極有效的避險策略，可以減輕匯率波動帶來的部分影響。因此，對我們而言，在12%的基準成長率下，匯率波動的相對影響非常有限，與某些同業相比更是微乎其微。

Operator, we have time for one more question.

操作員，我們還有時間再問一個問題。

Your next question will come from Liisa Bayko with Evercore ISI.

下一個問題將來自 Evercore ISI 的 Liisa Bayko。

I guess we'll be the last one to thank Michael for all of his hard work. And we'll hope you'll keep in touch with us.

我想我們大概是最後一個感謝麥可辛苦付出的人了。我們希望你們能繼續和我們保持聯繫。

You bet.

當然。

I just want to see if we get a little more detail on some of the type 1 diabetes metrics. Like for example, we don't have some of the HBA1c number for patient 2 at day 90. And it would just be nice to see how that's tracking. I know there was a reduced exogenous inflow news, so that's good. And then some of the other -- I guess, are you saying if you didn't mention the C-peptides, maybe it hadn't reached an appropriate level yet. I'm just curious because the peak simulator wasn't shown either for some of those endpoints -- those time points. So just curious to fill in some of the holes here.

我只是想了解更多關於第1型糖尿病的一些指標的細節。例如，我們沒有2號患者第90天的糖化血紅素（HbA1c）數值。如果能看到它的追蹤情況就太好了。我知道有消息稱外源性血液流入量減少了，這很好。還有一些其他指標——我想，您是否是說，如果您沒有提到C肽，可能意味著它還沒有達到合適的水平？我只是好奇，因為某些終點指標（時間點）的峰值模擬器數據也沒有顯示。所以，我只是想弄清楚一些細節。

Yes. Sure thing. Liisa, we shared a fair amount of data on all 3 patients dosed to date, the first 2 patients at half dose and the first full dose patient who is at the day 30 milestone. Across all of the patients in terms of efficacy, we see really good efficacy. And we've shared now out to day 270 on patient #1, who is insulin independent. You're right, we haven't shared all of the details at all of the time points across the patients. but you should expect us to share all of the details in terms of hemoglobin A1c, C-peptide levels, stimulated and fasting as well as the CGM, that's the continuous glucose monitoring data and, of course, all safety at upcoming congresses this year. So you will see all of the data on the patients with all of the follow-up.

是的，當然可以。莉薩，我們已經分享了迄今為止所有3位接受治療的患者的數據，前兩位患者接受的是半劑量治療，第一位接受全劑量治療的患者目前已達到第30天的里程碑。就所有患者的療效而言，我們觀察到了非常好的療效。現在我們已經分享了1號患者（他已無需胰島素治療）第270天的數據。你說得對，我們還沒有分享所有患者在所有時間點的全部細節。但您可以期待我們在今年即將召開的會議上分享所有關於糖化血紅蛋白A1c、C肽水平（包括刺激後和空腹血糖）以及CGM（持續血糖監測）數據的詳細信息，當然還有所有安全性數據。所以您將會看到所有患者的所有追蹤數據。

Okay. Great. And then just one more question, if I may. Sorry, I might have missed this earlier, but for CTX001, have you finalized what you need to file with FDA? And then if you could give us an indication of where you're going to present the data, the next data out there, that would be great.

好的，太好了。如果可以的話，我還有一個問題。抱歉，我可能之前錯過了，關於CTX001，你們是否已經完成了向FDA提交的所有文件？另外，如果您能告知我們您打算在哪裡發布數據，也就是下一批數據，那就太好了。

Yes. on CTX001, we shared last data on, I believe, 22 patients last year at the European Hematology meeting. We now have dosed over 75 patients. So we have substantially more information, and you should expect to see that at upcoming congresses this year.

是的。關於CTX001，我們去年在歐洲血液學會議上分享了22位病患的最新數據。現在我們已經對超過75例患者進行了給藥。因此，我們掌握了更多信息，您應該會在今年即將召開的會議上看到這些信息。

With regard to the data package for the agency, what we need to do, as we've discussed, is complete our discussions with them. And the 2 outstanding areas of discussion are the number of patients and the duration of follow-up that they would like to see in the filing. You know we have all of the designations like RMAT and Orphan and such. So we've had the opportunity to have conversations that bring us to this point. It's now wrapping up those conversations with both the U.S. and the EU to wrap up on the discussion of numbers and duration.

關於提交給監管機構的資料包，正如我們之前討論過的，我們需要完成與他們的討論。目前還有兩個需要討論的重點：患者數量和他們希望在申請文件中看到的追蹤時間長度。我們擁有所有必要的認定，例如RMAT（再獲得性藥物認定）和孤兒藥認定等等。因此，我們有機會進行溝通，最終達成共識。現在，我們正在與美國和歐盟完成最後的溝通，以最終確定患者數量和追蹤時長這兩個問題。

Great. And it seems like you've done a bunch of work on sort of the market and it looks like the markets are relatively concentrated. Do you have any sense of sort of capacity and how we should think about how many patients could be treated in the current scenario on a yearly basis?

太好了。看來您對市場做了很多研究，而且市場似乎相對集中。您對目前的市場容量有什麼看法？在目前情況下，我們應該如何估算每年可以治療多少患者？

Yes. Liisa, I think you're asking about in the U.S. and EU, how do we see bed capacity for patients to be able to come in and have the procedure for CTX001.

是的。莉薩，我想你問的是美國和歐盟的情況，我們如何看待床位容量，以便患者能夠前來接受 CTX001 手術。

Since we're out of time, I'll just take it really quickly. Stuart and the team have mapped this out. It is very concentrated, the overwhelming majority of patients in the EU who qualify for this therapy are concentrated in 4 countries. The overwhelming majority of patients in the U.S. who qualify for this therapy are concentrated in less than 25 states, and we have mapped out the centers where they would be treated. And yes, we see that the numbers of patients that we expect to be treated are going to have a way to have that done in centers with the right expertise.

由於時間有限，我就簡單說一下。史都華和他的團隊已經制定了方案。患者分佈非常集中，歐盟絕大多數符合此療法條件的患者集中在四個國家。美國絕大多數符合這種療法條件的患者集中在不到25個州，我們已經規劃好了他們將接受治療的中心。是的，我們看到，我們預計需要治療的患者數量將能夠妥善安排，在具備相應專業知識的中心接受治療。

This concludes our question-and-answer session. I would like to turn the conference back over to Mr. Michael Partridge for any closing remarks. Please go ahead.

問答環節到此結束。現在我把會議交還給麥可‧帕特里奇先生，請他作總結發言。請開始吧。

Thanks, operator. Thanks, everybody, for joining the call tonight. Thank you also for all of your kind words, very much appreciated. It has been an honor and a privilege to represent Vertex, and it's also been fun to always interact with all of you. As always, the team and I are in the office tonight if you have additional questions. Take care, and have a good evening.

謝謝接線生。感謝各位今晚參加電話會議。也感謝大家的鼓勵與讚揚，非常感謝。能夠代表Vertex公司是我的榮幸，與大家交流也一直非常愉快。像往常一樣，如果大家還有其他問題，我和我的團隊今晚都會在辦公室。祝大家一切順利，晚安。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議已結束。感謝您參加今天的報告。您可以斷開連線了。