福泰製藥 (VRTX) 2022 Q4 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals Fourth Quarter and Full Year 2022 Conference Call. (Operator Instructions) Please note this event is being recorded.

您好，歡迎參加Vertex Pharmaceuticals 2022年第四季及全年業績電話會議。 （操作說明）請注意，本次會議正在錄音。

I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

現在我將會議交給蘇西·麗莎女士。請開始吧。

Good evening, everyone. My name is Susie Lisa, and as the Senior Vice President of Investor Relations for Vertex, it is my pleasure to welcome you to our fourth quarter and full year 2022 financial results conference call.

各位晚上好。我是蘇西·麗莎，身為Vertex公司投資者關係資深副總裁，我很高興歡迎各位參加我們2022年第四季及全年財務業績電話會議。

On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex' CEO and President; Stuart Arbuckle, Chief Operating Officer; and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website.

在今晚的電話會議上，Vertex公司執行長兼總裁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。我們建議您在收聽本次電話會議的同時查看網路直播投影片。本次電話會議將進行錄音，錄音回放將在我們的網站上提供。

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex' marketed cystic fibrosis medicines, our pipeline, and Vertex' 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 that we will review on the call this evening are presented on a non-GAAP basis. In addition, the impact of the foreign exchange is presented inclusive of our foreign exchange risk management program. I'll now turn the call over to Reshma.

我還想指出，今晚電話會議上我們將要討論的部分財務表現和指引是以非GAAP準則編制的。此外，外匯影響的列示已包含我們的外匯風險管理計畫。現在我將把電話會議交給雷什瑪。

Thanks, Susie. Good evening all, and thank you for joining us on the call today. We are pleased to have closed out a strong 2022 with full year global CF product revenue up 18% versus 2021. Our full year 2023 product revenue guidance is $9.55 billion to $9.7 billion, representing 7% to 9% growth year-on-year, inclusive of FX headwind of approximately 1.5%.

謝謝蘇西。各位晚上好，感謝大家今天參加我們的電話會議。我們很高興2022年圓滿收官，全年全球CF產品營收較2021年成長18%。我們預計2023年全年產品收入為95.5億美元至97億美元，年增7%至9%，其中已計入約1.5%的匯率不利影響。

We have more than 20,000 patients still to reach with CFTR modulators, and we continue to work with focus and urgency to reach all patients with CF around the globe who may benefit from our therapies. It is an exciting time for Vertex. Our medicines have transformed CF, and the growth of our CF business has transformed Vertex.

我們仍有超過2萬名CFTR調節劑尚未惠及患者，我們將繼續全力以赴，以緊迫感和專注力，讓全球所有可能受益於我們療法的囊性纖維化患者都能獲得治療。對於Vertex而言，這是一個激動人心的時刻。我們的藥物改變了囊性纖維化的治療格局，而囊性纖維化業務的成長也改變了Vertex的面貌。

Our differentiated R&D approach led to our multiple life-changing therapies in cystic fibrosis and is designed to deliver transformative medicines for serious diseases at high rates of success, agnostic to modality. It is delivering just that.

我們差異化的研發方法催生了多種改變囊性纖維化患者生命的療法，其目標是為各種嚴重疾病提供高成功率的變革性藥物，且不受治療方式的限制。而它也正朝著這個目標邁進。

In aggregate, our mid- and late-stage clinical pipeline holds the promise to deliver potentially transformative benefit for patients across 8 disease areas as detailed on Slide 5. Each program holds the potential to be best-in-class and transform the disease, and each represents a multibillion-dollar market opportunity.

整體而言，我們的中後期臨床研發管線可望為8個疾病領域的患者帶來潛在的變革性益處，詳情請參閱投影片5。每個項目都有可能成為同類最佳，並改變疾病的治療現狀，每個項目都代表著數十億美元的市場機會。

Furthermore, we see the opportunity to launch new products into 5 of these disease areas within the next 5 years or our 5-in-5 goal. And we're not done. The next wave of innovation is also making progress and advancing through preclinical development, including programs in Duchenne's muscular dystrophy and myotonic dystrophy Type 1.

此外，我們看到了在未來五年內，也就是我們「五年內五項」目標實現之前，針對其中五個疾病領域推出新產品的機會。而且，我們並未止步於此。下一波創新浪潮也在穩步推進，並正經歷臨床前開發階段，其中包括杜氏肌肉營養不良症和1型強直性肌肉營養不良症的計畫。

This breadth of pipeline success accelerated pace of clinical trial progress and build-out of commercial capabilities for upcoming product launches warrant continued investments in 2023. As such, we are strategically investing and focusing on execution to drive forward this significant opportunity. With a uniquely strong and durable CF franchise, a deep, broad and advancing R&D pipeline with multiple potentially near-term commercial opportunities, a strong balance sheet and a deeply talented and committed team, Vertex is well-positioned to deliver for patients and shareholders for years to come.

如此廣泛的產品線成功加速了臨床試驗的進展，並加快了即將上市產品的商業化能力建設，為2023年的持續投資奠定了基礎。因此，我們正進行策略性投資，並專注於執行，以掌握這一重大機會。憑藉強大且持久的囊性纖維化產品線、深度且不斷推進的研發管線（其中包含多個潛在的近期商業機會）、穩健的資產負債表以及一支才華橫溢且敬業的團隊，Vertex 已做好充分準備，在未來幾年內為患者和股東創造價值。

With that overview, I'll turn to the details of recent R&D progress, starting with CF. We'll continue our journey in cystic fibrosis as we serially innovate to bring highly efficacious therapies to all CF patients. Our next-in-class vanzacaftor triple combination completed enrollment in its 2 Phase III clinical trials, SKYLINE 102 and SKYLINE 103 and in patients ages 12 years and older in Q4 of 2022.

概述完畢後，我將詳細介紹近期研發進展，首先從囊性纖維化（CF）領域開始。我們將繼續在囊性纖維化領域深耕，不斷創新，力求為所有CF患者帶來高效療法。我們新一代的vanzacaftor三合療法已於2022年第四季完成了兩項III期臨床試驗（SKYLINE 102和SKYLINE 103）的患者招募，受試者為12歲及以上族群。

While TRIKAFTA sets a very high bar, our enthusiasm for this vanzacaftor program is also high. This program could deliver even greater benefits to patients, given, one, our highly predictive in vitro human bronchial epithelial or HBE cell assays, a showed the vanza triple was superior to TRIKAFTA in improving chloride transport, a direct measure of CFTR function.

儘管 TRIKAFTA 的療效已達到極高水平，但我們對 vanzacaftor 計畫也充滿熱情。鑑於我們高度預測性的體外人類支氣管上皮細胞 (HBE) 檢測顯示，vanza 三聯療法在改善氯離子轉運（CFTR 功能的直接指標）方面優於 TRIKAFTA，該計畫有望為患者帶來更大的益處。

Two, our Phase II clinical data also suggests the potential for greater efficacy for vanzacaftor versus TRIKAFTA. And three, the vanzacaftor triple also has the benefit of once-daily oral dosing and a substantially reduced royalty burden relative to TRIKAFTA. The Phase III trials are currently in the 52-week dosing period, and we anticipate their completion towards the end of this year.

第二，我們的第二期臨床數據也表明，與TRIKAFTA相比，vanzacaftor可能具有更高的療效。第三，vanzacaftor三重療法還具有每日一次口服給藥的優勢，與TRIKAFTA相比，其專利使用費負擔大幅降低。目前，三期臨床試驗已進入52週給藥期，我們預計今年底完成。

Another important program is the VX-522 program, our CFTR mRNA approach that we are developing in partnership with Moderna for CF patients who cannot benefit from our CFTR modulators. In December of 2022, and the FDA cleared the IND for VX-522, and the single ascending dose study in CF patients was initiated last year, a major milestone for Vertex and the field.

另一個重要的項目是VX-522項目，這是我們與Moderna合作開發的CFTR mRNA療法，旨在幫助那些無法從我們的CFTR調節劑中獲益的囊性纖維化（CF）患者。 2022年12月，FDA批准了VX-522的IND申請，並於去年啟動了針對CF患者的單次遞增劑量研究，這對於Vertex公司和整個領域而言都是一個重要的里程碑。

We have high expectations given over 5 years of research that led to the discovery of VX-522 with the following properties: one, delivery of mRNA at high efficiency into HBE cells; two, expression of CFTR protein leading to high levels of chloride transport; and three, in both rodents and nonhuman primates, expression of CFTR protein in the desired cells; and lastly, a preclinical safety profile that supported advancement into human clinical trials. We are excited with the progress of VX-522, which brings hope to the more than 5,000 CF patients who are still waiting for a treatment that targets the underlying cause of their disease.

經過五年多的研究，我們最終發現了VX-522，並對其寄予厚望。 VX-522具有以下特性：一是能高效地將mRNA遞送至HBE細胞；二是能表達CFTR蛋白，從而實現高水平的氯離子轉運；三是能在囓齒動物和非人靈長類動物的目標細胞中表達CFTR蛋白；四是其良好的臨床前安全性，支持其進入人體臨床試驗。 VX-522的進展令我們倍感振奮，它為超過5000名仍在等待針對病因治療的囊性纖維化（CF）患者帶來了希望。

Turning now to exa-cel, our gene editing program for severe sickle cell disease and transfusion-dependent beta-thalassemia. This is our most advanced program outside of CF, and we expect exa-cel to be our next commercial launch.

接下來我們來談談exa-cel，這是我們針對重度鐮狀細胞疾病和輸血依賴型β-地中海貧血的基因編輯計畫。這是我們在囊性纖維化之外最先進的項目，我們預期exa-cel將成為我們下一個商業化產品。

In late Q4, we completed our regulatory submissions for exa-cel for both sickle cell disease and beta-thalassemia in the EU and U.K. Both the EMA and the MHRA have recently validated the MAA submissions. And in the U.S., we remain on track to complete our rolling BLA submission by the end of this quarter. The remarkable clinical benefits are evident in the data we've shared to date. exa-cel holds the promise to be the first CRISPR-based gene editing treatment to be approved and represents a near-term and significant market opportunity, which Stuart will detail.

在第四季末，我們完成了exa-cel在歐盟和英國治療鐮狀細胞貧血和β-地中海貧血的監管申報。歐洲藥品管理局（EMA）和英國藥品和保健產品監管署（MHRA）近期均已批准了上市許可申請（MAA）。在美國，我們仍按計劃推進，預計將於本季末完成滾動生物製品許可申請（BLA）的提交。我們迄今為止分享的數據已充分證明了其顯著的臨床療效。 exa-cel預計將成為首個獲準的基於CRISPR的基因編輯療法，並代表著近期巨大的市場機遇，Stuart將對此進行詳細闡述。

Turning next to VX-548 and our pain program. VX-548 is our novel selective NaV1.8 inhibitor that holds a promise of highly effective pain relief without the side effects or addictive potential of opioids. If approved, VX-548 would represent the first new class of pain medicine in decades with the potential to address the staggeringly high unmet need in acute pain.

接下來我們來談談VX-548以及我們的疼痛治療項目。 VX-548是我們研發的一種新型選擇性NaV1.8抑制劑，它有望在不產生鴉片類藥物副作用或成癮性的情況下，高效緩解疼痛。如果獲得批准，VX-548將成為數十年來首個具有突破性的新型疼痛藥物，有望解決急性疼痛領域巨大的未滿足需求。

VX-548 acts on the peripheral nerves to block the pain signal, and thus may be able to provide effective pain relief without the abuse potential, which is a central nervous system phenomenon. We have high expectations for this program because NaV1.8 is a genetically and pharmacologically validated target.

VX-548作用於週邊神經，阻斷疼痛訊號，因此有望在有效緩解疼痛的同時，避免中樞神經系統藥物濫用的風險。我們對該計畫寄予厚望，因為NaV1.8是一個經過基因和藥理學驗證的標靶。

Second, we have multiple positive proof-of-concept results with VX-150, a predecessor molecule to VX-548, and proof-of-concept with VX-548 itself. And lastly, our Phase III program in acute pain is substantially similar to the positive Phase II trials we have already conducted.

其次，我們已獲得VX-150（VX-548的前驅分子）的多項正向概念驗證結果，以及VX-548本身的概念驗證結果。最後，我們針對急性疼痛的III期臨床試驗項目與我們已進行的積極II期臨床試驗基本相似。

VX-548 has been granted Fast Track and breakthrough therapy designation in the U.S. We initiated pivotal development last year, and we are enrolling patients across 3 Phase III studies with the goal of seeking a broad, moderate-to-severe acute pain label. We anticipate completing the Phase III pivotal program towards the end of this year or the beginning of next, creating another potentially significant and near-term commercial opportunity, which Stuart will also discuss.

VX-548 已獲得美國快速通道和突破性療法認定。我們去年啟動了關鍵性開發，目前正在進行三項 III 期臨床試驗，旨在尋求一項廣泛的、針對中重度急性疼痛的適應症。我們預計將於今年底或明年年初完成 III 期關鍵性試驗，這將創造另一個潛在的、近期可觀的商業機會，Stuart 也將對此進行討論。

In addition to validation of NaV1.8 as a target in acute pain, it has also been validated as a target in neuropathic pain. I am pleased to share that in late Q4, we initiated a 12-week Phase II dose-ranging proof-of-concept study for VX-548 in peripheral neuropathic pain. We look forward to updating you as this Phase II program progresses and to sharing more on the market opportunity on future calls.

除了已證實 NaV1.8 可作為急性疼痛的標靶外，它也已被證實可作為神經性疼痛的標靶。我很高興地宣布，我們在第四季度末啟動了一項為期 12 週的 II 期劑量探索性概念驗證研究，旨在評估 VX-548 在周邊神經性疼痛中的療效。我們將持續關注此 II 期研究的進展，並在未來的電話會議上與您分享更多關於市場機會的資訊。

Transitioning now to inaxaplin, or VX-147, the first potential medicine to target the underlying cause of APOL1-mediated kidney disease or AMKD. Post the positive Phase II proof-of-concept study inaxaplin is now being studied in a single adaptive Phase II/III pivotal trial.

現在我們來談談inaxaplin（或VX-147），它是第一個針對APOL1介導的腎臟病（AMKD）根本病因的潛在藥物。在II期概念驗證研究取得正面成果後，inaxaplin目前正在進行一項適應性II/III期關鍵性試驗。

This study has a preplanned interim analysis at 48 weeks of treatment, which, if positive, could serve as the basis to seek accelerated approval in the U.S. Our goal is to complete the Phase II dose-ranging portion of the Phase II/III pivotal study this year, selected dose and then continue on to the Phase III portion.

本研究預先計劃在治療 48 週時進行中期分析，如果結果為陽性，則可作為在美國尋求加速批准的依據。我們的目標是今年完成 II/III 期關鍵性研究的 II 期劑量範圍部分，確定劑量，然後繼續進行 III 期部分。

We are also working to increase awareness, screening and diagnosis through multiple initiatives, given the high unmet need and the approximately 100,000 patients in the U.S. and Europe alone. With inaxaplin, we see the potential of bringing a first-in-class treatment to patients with AMKD and unlocking a multibillion-dollar market opportunity.

鑑於目前龐大的未滿足需求，光在美國和歐洲就有約10萬名患者，我們正透過多項措施努力提高公眾意識、加強篩檢和診斷。我們相信，inaxaplin有望為AMKD患者帶來首創療法，並開啟數十億美元的市場機會。

Moving to Type 1 diabetes, where our goal is to deliver a transformative, if not curative therapy for the more than 2.5 million patients with Type 1 diabetes in North America and Europe. We are advancing multiple programs. First, VX-880s are stem cell-derived fully differentiated insulin-producing islet cells, which use standard immunosuppressives to protect the cells from the immune system.

接下來，我們將目光轉向第1型糖尿病，我們的目標是為北美和歐洲超過250萬1型糖尿病患者提供一種變革性的、甚至是治癒性的療法。我們正在推進多個專案。首先，VX-880是由幹細胞衍生的完全分化的胰島素分泌胰島細胞，利用標準免疫抑制劑來保護細胞免受免疫系統的攻擊。

These cells are also foundational for the other 2 T1D programs. For VX-880, we achieved proof-of-concept last year with the first 2 patients treated in Part A of the VX-880 study. We have now fully enrolled Part B where patients will receive the target dose on a staggered basis.

這些細胞也是另外兩個1型糖尿病計畫的基礎。對於VX-880，我們去年在VX-880研究A部分中對首批兩名患者進行了治療，從而驗證了其概念。目前，B部分已完成全部入組，患者將分階段接受目標劑量。

The next phase is Part C, expected to initiate later this year in which patients will be treated concurrently with the target dose. We look forward to sharing VX-880 data from more patients and with longer duration of follow-up at medical congresses this year.

下一階段是C部分，預計今年稍後啟動，屆時患者將接受與目標劑量同步的治療。我們期待在今年的醫學大會上分享更多患者接受VX-880治療後更長追蹤期的數據。

Second, VX-264 or the cells plus device program, which encapsulates these same fully differentiated insulin-producing islet cells in a proprietary device that shields the cells from the body's immune system, and hence, there is no requirement for immunosuppressants.

其次，VX-264 或細胞加裝置方案，將這些完全分化的胰島素分泌胰島細胞封裝在一個專有裝置中，該裝置可以保護細胞免受人體免疫系統的攻擊，因此無需使用免疫抑制劑。

In late Q4, we simultaneously filed a CTA in Canada as well as the IND in the U.S. As we shared last month, the CTA has cleared, and we look forward to initiating enrollment and dosing of patients in Canada in the coming months. In the U.S., the IND has not cleared. We've received and responded to the FDA's questions. We look forward to working with the agency with urgency so that we can initiate the study in the U.S. as soon as possible.

第四季末，我們同時在加拿大提交了臨床試驗申請（CTA），並在美國提交了新​​藥臨床試驗申請（IND）。正如我們上個月所分享的，CTA已獲批准，我們期待在未來幾個月內在加拿大啟動患者招募和給藥。在美國，IND尚未獲批。我們已收到並回覆了FDA的問詢。我們期待與FDA盡快合作，以便盡快在美國啟動這項研究。

Third, in our hypoimmune program, we are editing the same fully differentiated insulin-producing islets to cloak them from the immune system, another path to obviating the need for immunosuppressives. This program continues to progress in preclinical development.

第三，在我們的低免疫療法計畫中，我們正在對完全分化的胰島素分泌胰島進行基因編輯，使其免受免疫系統的攻擊，這是避免使用免疫抑制劑的另一個途徑。該計畫目前正處於臨床前開發階段，並持續取得進展。

Let me close the T1D section with an update on the ViaCyte acquisition through which we gained intellectual property, tools and capabilities that hold the potential to accelerate our goal of developing transformative treatments for this disease. We have now completed our data and portfolio review and are very pleased with the progress to date. We have begun executing our integration plans.

最後，我想就第1型糖尿病（T1D）部分做個總結，介紹一下我們收購ViaCyte的最新進展。透過此次收購，我們獲得了智慧財產權、工具和能力，這些都有望加速我們開發針對該疾病的變革性療法的目標。目前，我們已完成數據和產品組合審查，並對迄今為止的進展感到非常滿意。我們已經開始執行整合計劃。

On the clinical side, a Phase I/II study of VCTX-211, a hypoimmune cell program that originated with ViaCyte and that Vertex is now developing in partnership with CRISPR Therapeutics, has been initiated and is ongoing. All other ViaCyte clinical trials have completed enrollment and dosing and are in the follow-up stage.

在臨床方面，一項針對VCTX-211的I/II期研究已經啟動並正在進行中。 VCTX-211是一種低免疫細胞療法，最初由ViaCyte公司研發，目前Vertex公司正與CRISPR Therapeutics公司合作開發。 ViaCyte公司的其他所有臨床試驗均已完成受試者招募和給藥，目前處於追蹤階段。

I'll finish up with the alpha-1 antitrypsin deficiency, or AATD program. Both a Phase I study of VX-634, the first in a series of next-wave AAT correctors and a 48-week Phase II study of VX-864, our first-generation AAT corrector, are ongoing. We look forward to updating you as these programs advance.

最後，我將介紹α1-抗胰蛋白酶缺乏症（AATD）計畫。目前，VX-634（我們新一代AAT矯正劑系列中的首個產品）的I期臨床試驗和VX-864（我們的第一代AAT矯正劑）的48週II期臨床試驗都在進行中。我們將持續關注並及時向您報告專案進度。

I'll now ask Stuart to review our commercial progress.

現在我將請史都華評估我們的商業進展。

Thanks, Reshma. Today, I will review our continued strong performance and outlook in CF as well as potential near-term commercial launches in new disease areas with exa-cel and VX-548.

謝謝，雷什瑪。今天，我將回顧我們在囊性纖維化領域持續強勁的業績和前景，以及近期在新的疾病領域推出exa-cel和VX-548的潛在商業計劃。

Starting with CF, where we continue to bring our transformative medicines to many more patients globally. Last month, we raised our estimate for the number of patients with cystic fibrosis in the U.S., Europe, Australia and Canada to 88,000, up from our previous estimate of 83,000.

首先是囊性纖維化領域，我們將繼續把變革性藥物帶給全球更多患者。上個月，我們將美國、歐洲、澳洲和加拿大的囊性纖維化患者人數預估從先前的83,000人上調至88,000人。

The growth in the CF population can be attributed to more patients coming forward to receive treatment, better data capture in patient registries, and perhaps most importantly, people with CF are living longer due to improvements in patient care and the availability of truly effective therapies. For a baby born with CF in 2021, the Cystic Fibrosis Foundation predicts the median age of survival is now 65 years.

囊性纖維化患者人數的增長可歸因於更多患者主動尋求治療、患者登記數據收集的完善，以及或許最為重要的，由於患者護理水平的提高和真正有效療法的普及，囊性纖維化患者的壽命顯著延長。囊性纖維化基金會預測，2021年出生的囊性纖維化兒童的中位存活年齡目前為65歲。

In the U.S., our focus remains on maintaining the very high persistence and compliance rates we have seen with our therapies and extending the benefits into younger age groups. Outside the U.S., uptake of KAFTRIO/TRIKAFTA in countries with recent reimbursement agreements continues to drive growth, as has the rollout of KAFTRIO in children ages 6 to 11 years in countries where this indication has recently received reimbursed access such as France and Spain.

在美國，我們仍致力於維持我們療法一貫的高堅持率和依從性，並將療效擴展至更年輕的年齡層。在美國以外，KAFTRIO/TRIKAFTA 在近期達成醫保報銷協議的國家/地區的普及率持續推動市場增長，同時，KAFTRIO 在 6 至 11 歲兒童中的推廣也促進了市場增長，尤其是在法國和西班牙等近期已將該適應症納入醫保的國家/地區。

There are still more than 20,000 CF patients who could benefit from but are not on CFTR modulator treatment. These patients fall primarily into 2 categories: one, patients in countries where we are early on the launch curve; and two, younger patients, for whom we continue to pursue additional label and reimbursement extensions such as the recent U.S. approval of ORKAMBI for ages 1 to 2 years, and recent regulatory submissions for KALYDECO in children ages 1 to 4 months and for TRIKAFTA in ages 2 to 5 years, which has received priority review and a PDUFA date of April 28 in the U.S. We are confident that we will reach the vast majority of these patients over time, which will continue to drive revenue growth in the near and long term.

目前仍有超過2萬名囊性纖維化（CF）患者能夠從CFTR調節劑治療中獲益，但尚未接受治療。這些患者主要分為兩類：第一類是那些我們正處於產品上市初期階段的國家的患者；第二類是年齡較小的患者，我們正持續為他們爭取更多適應症和醫保報銷範圍的擴展，例如ORKAMBI近期已獲美國批准用於1至2歲兒童， KALYDECO近期已提交用於1至4個月嬰兒的監管申請，TRIKAFTA近期已提交用於2至5歲兒童的監管申請，後者已獲得優先審評資格，並已確定於4月28日在美國獲得處方藥用戶付費法案（PDUFA）批准。我們相信，隨著時間的推移，我們將惠及絕大多數此類患者，這將持續推動我們近期和長期的收入成長。

We also see exciting growth potential for our vanzacaftor triple combo given the anticipated clinical profile more convenient once-daily dosing and the potential to offer a new option for patients who have discontinued prior CFTR modulator therapy.

鑑於預期的臨床特性、更方便的每日一次給藥以及為已停止先前 CFTR 調節劑治療的患者提供新選擇的可能性，我們也看到了 vanzacaftor 三聯療法令人興奮的增長潛力。

Finally, in CF, as Reshma mentioned, our CFTR mRNA program, VX-522 is being developed for the more than 5,000 CF patients worldwide who currently do not have any therapies that treat the underlying cause of their disease. I will now detail our commercial readiness efforts and the market opportunity for 2 potential product launches outside of CF, exa-cel and VX-548.

最後，如Reshma所提到的，在囊性纖維化（CF）領域，我們的CFTR mRNA計畫VX-522正在開發中，旨在為全球超過5000名目前尚無針對其疾病根本原因的療法的CF患者提供幫助。接下來，我將詳細介紹我們在CF以外的兩個潛在產品上市方面的商業準備工作，以及Exa-cel和VX-548的市場機會。

Exa-cel holds curative potential for patients with sickle cell disease and transfusion-dependent beta-thalassemia, and we are making significant progress with launch preparation activities. Our initial launch of exa-cel will focus on the approximately 32,000 individuals in the U.S. and Europe for whom these diseases are most severe, presenting a significant clinical, humanistic and economic burden.

Exa-cel有望治癒鐮狀細胞疾病和輸血依賴型β-地中海貧血患者，我們在上市準備方面取得了顯著進展。 Exa-cel的初期上市將重點關注美國和歐洲約32,000名病情最為嚴重的患者，這些患者承受著巨大的臨床、人道主義和經濟負擔。

The estimated 25,000 severe sickle cell disease patients have multiple hospitalizations annually for vaso-occlusive crises, while the estimated 7,000 TDT patients undergo near-monthly transfusions. There is also a considerable financial burden, both for these patients and to the health care system.

據估計，約有25,000名重症鐮狀細胞病患者每年因血管阻塞危像多次住院治療，而約有7,000名輸血依賴型血小板減少症（TDT）患者幾乎每月都要接受輸血。這給患者和醫療保健系統都帶來了沉重的經濟負擔。

In the U.S., economic models project the lifetime treatment costs for severe sickle cell disease patients to be between $4 million and $6 million. Recent market research indicates that physicians have a strong preference and interest in gene editing over other potentially curative approaches and that patients with sickle cell disease are increasingly optimistic about the potential role for curative therapies in the treatment of their disease.

在美國，經濟模型預測重症鐮狀細胞疾病患者終生治療費用將在400萬至600萬美元之間。近期市場調查顯示，醫生們對基因編輯療法比其他潛在的治癒方法更感興趣，並且對基因編輯療法抱有濃厚的興趣；鐮狀細胞病患者也越來越樂觀地認為，治癒性療法在其疾病治療中能夠發揮越來越重要的作用。

In addition, payers view the emerging clinical data for exa-cel as highly impactful, most notably the reductions in vaso-occlusive crises and hospitalizations. Importantly, for our specialty commercial model, these 32,000 severe patients are concentrated geographically, and we believe can be served effectively with a network of approximately 50 authorized treatment centers or ATCs in the U.S. and approximately 25 in Europe. We have established the needed supply chain and manufacturing infrastructure to support the launch, including validated chain of identity and chain of custody systems, global shipping infrastructure and the needed manufacturing capacity to support uptake following approval.

此外，支付方認為exa-cel的新興臨床數據意義重大，尤其值得關注的是其在減少血管阻塞危象和住院方面的作用。對於我們的專業商業模式而言，這32,000名重症患者在地理位置上較為集中，我們相信，透過在美國設立約50家授權治療中心（ATC），並在歐洲設立約25家，即可有效地為他們提供服務。我們已建立必要的供應鏈和生產基礎設施以支援產品上市，包括經過驗證的身份鏈和監管鏈系統、全球運輸基礎設施以及獲批後所需的生產能力。

And finally, we continue to work with key commercial and government payers and policymakers in the U.S. and Europe to ensure they understand the significant burden of these diseases and that broad patient access and reimbursement are in place if and when exa-cel is approved. To date, we have engaged with all U.S. state Medicaid agencies, some 150 unique U.S. commercial payers as well as multiple health technology assessment bodies in Europe, including NICE and GBA to share important information about exa-cel and our commitment to working collaboratively to provide access to this therapy.

最後，我們繼續與美國和歐洲的主要商業和政府支付方及政策制定者合作，確保他們了解這些疾病帶來的巨大負擔，並確保在exa-cel獲批後，患者能夠廣泛獲得治療和報銷。迄今為止，我們已與美國所有州醫療補助機構、約150家美國商業支付方以及包括NICE和GBA在內的多家歐洲衛生技術評估機構接洽，分享有關exa-cel的重要信息，並重申我們致力於攜手合作，確保患者能夠獲得這種療法。

Shifting now to VX-548, which we believe has the potential to play an important role across the pain spectrum, including acute pain and chronic pain conditions. I'll focus my comments on acute pain, which is a near-term commercial opportunity.

現在讓我們來談談VX-548，我們認為它有潛力在疼痛治療的各個方面發揮重要作用，包括急性疼痛和慢性疼痛。我將重點討論急性疼痛，因為這在短期內是一個商業機會。

There are 4 aspects critical to framing the acute pain opportunity for Vertex. One, there is a significant unmet need due to the limitations and drawbacks of currently available treatments. Two, the market is large today, even with 90% generic prescribing. Three, prescribing is concentrated in the hospital setting and thus addressable with a specialty commercial infrastructure. And four, there is broad stakeholder recognition of the need for new therapies, which also helps provide a clear path to future patient access and reimbursement.

對Vertex而言，要掌握急性疼痛治療​​領域的機遇，關鍵在於以下四個面向。首先，由於現有療法的限制和不足，存在著巨大的未滿足需求。其次，即使90%的處方藥為仿製藥，目前的市場規模依然龐大。第三，處方主要集中在醫院，因此可以透過專業的商業基礎設施來滿足需求。第四，利害關係人普遍認識到開發新療法的必要性，這也有助於為未來的病患用藥和健保報銷鋪路。

Firstly, millions in the U.S. suffer from acute pain each year, yet it is often difficult to manage effectively given the limitations of existing therapies. The current standards of care are NSAIDs and acetaminophen at one end of the spectrum, which are non-addicting but offer limited pain relief and can pose GI and liver toxicity concerns.

首先，美國每年有數百萬人遭受急性疼痛的折磨，但由於現有療法的局限性，往往難以有效控制疼痛。目前的標準治療方案主要包括非類固醇抗發炎藥物（NSAIDs）和對乙醯氨基酚，這些藥物雖然不會成癮，但止痛效果有限，並且可能引起胃腸道和肝臟毒性。

And at the other end of the spectrum are opioids, which provide effective pain relief but have many undesirable side effects, including nausea and somnolence and have significant abuse potential. Many large hospital systems and all 50 states have adopted restrictions for the use of opioids. This leaves a vast gap in the treatment landscape for a medicine like VX-548 and with strong efficacy, a desirable benefit-risk profile, and without abuse potential, given it is peripherally acting.

另一方面，阿片類藥物雖然能有效緩解疼痛，但副作用眾多，包括噁心和嗜睡，且濫用風險極高。許多大型醫院系統和美國所有50個州都已對鴉片類藥物的使用加以限制。這就使得像VX-548這樣療效顯著、風險效益比理想且無濫用風險（因為它作用於週邊組織）的藥物在治療領域存在巨大的空白。

Second, the acute pain market is very large, valued in the U.S. at $4 billion despite 90% of prescriptions being generic. Third, this highly concentrated market can be served with a specialty commercial model. Of the 1.5 billion treatment days for acute pain annually, some 2/3 or 1 billion are driven by hospital prescribing, following inpatient or outpatient procedures such as surgeries or emergency room visits.

其次，急性疼痛市場規模龐大，光在美國就價值40億美元，儘管其中90%的處方藥都是仿製藥。第三，這種高度集中的市場可以透過專業的商業模式來服務。每年15億個急性疼痛治療​​日中，約有三分之二（即10億個）是由醫院開立的處方，這些處方通常用於住院或門診手術或急診就診等治療後。

Furthermore, these hospital-driven prescriptions are concentrated among approximately 1,700 hospitals that aggregate to roughly 220 integrated delivery networks. Thus, we believe we can reach a large proportion of this market with a specialty sales and marketing infrastructure and have begun to hire for key positions.

此外，這些由醫院主導的處方集中在約1700家醫院，這些醫院組成了大約220個整合醫療服務網絡。因此，我們相信憑藉專業的銷售和行銷體系，我們可以涵蓋該市場的大部分份額，目前我們已開始招募關鍵職位。

Fourth and finally, given the wide stakeholder recognition of the limitations of current treatments and the unmet need, we see both high demand and a clear path to access and reimbursement for a medicine with a profile like VX-548. A key example of the path to reimbursement and access is the recently passed NOPAIN or Non-Opioids Prevent Addiction in the Nation Act signed into law last December.

第四，也是最後一點，鑑於各利益相關者普遍認識到現有療法的局限性和未被滿足的需求，我們看到，像VX-548這樣具有獨特療效的藥物，既有很高的需求，也有明確的獲取和報銷途徑。最近通過的《非鴉片類藥物預防成癮法案》（NOPAIN）就是一個取得和報銷途徑的關鍵例證，該法案已於去年12月簽署生效。

Through the NOPAIN Act, Congress has directed CMS to make a separate add-on payment to hospitals in the outpatient and ambulatory surgery center setting for non-opioids for the treatment of pain. We believe this new law is an important sign of the growing movement to remove barriers for hospitals, providers and patients to utilize non-opioid treatment options.

透過《無鴉片類藥物止痛法案》（NOPAIN Act），國會指示美國醫療保險和醫療補助服務中心（CMS）向門診和日間手術中心的醫院提供額外的補貼，用於支付非鴉片類藥物止痛的費用。我們認為，這項新法案是消除醫院、醫護人員和病患使用非鴉片類藥物治療方案障礙的重要標誌。

In closing, we are excited about the opportunity to extend the benefits of our CF medicines to more patients around the globe and the near-term potential to commercialize transformative treatments for patients with sickle cell disease, beta-thalassemia and acute pain.

最後，我們很高興有機會將我們的 CF 藥物的益處擴展到全球更多患者，並且近期有可能將針對鐮狀細胞病、β 地中海貧血和急性疼痛患者的變革性療法商業化。

I will now turn the call to Charlie to review the financials.

現在我將把電話轉給查理，讓他審核財務數據。

Thanks, Stuart. Vertex' fourth quarter full year 2022 results represent another year of strong execution and exceptional financial performance. Fourth Quarter 2022 revenue increased 11% year-over-year to $2.3 billion. Growth was led by a 24% year-over-year increase outside the U.S. on continued strong TRIKAFTA/KAFTRIO in markets with recently achieved reimbursement as well as label extensions into younger age groups. U.S. CF revenue grew 5% year-over-year with ongoing consistent performance.

謝謝，斯圖爾特。 Vertex 2022 年第四季全年業績體現了公司又一年強勁的執行力和卓越的財務表現。 2022 年第四季營收年增 11%，達到 23 億美元。成長主要得益於美國以外地區 TRIKAFTA/KAFTRIO 的持續強勁銷售，這些產品在近期獲得醫保報銷的市場以及標籤擴展至更年輕的年齡群體，使得美國以外地區的營收同比增長 24%。美國 CF 業務營收年增 5%，業績持續穩定。

Full year 2022 revenue of $8.93 billion represents 18% growth versus 2021, marking Vertex' eighth consecutive year of at least double growth. Full year 2022 International revenue of $3.23 billion increased 41% and full year U.S. revenue of $5.7 billion increased 8% compared to 2021. For the full year 2022, we estimate the changes in foreign exchange negatively impacted our global revenue growth rate by approximately 1.5 percentage points, inclusive of our foreign exchange risk management program.

2022年全年營收達89.3億美元，較2021年成長18%，標誌著Vertex連續第八年實現至少翻倍的成長。 2022年全年國際營收達32.3億美元，較2021年成長41%；全年美國營收達57億美元，較2021年成長8%。我們預計，2022年全年匯率波動對全球營收成長率的影響約為1.5個百分點，該影響已計入我們的外匯風險管理計畫。

Fourth quarter 2022 combined non-GAAP R&D, acquired IPR&D and SG&A expenses were $872 million, an increase of 5% compared to the fourth quarter of 2021. Full year 2022 combined non-GAAP R&D, acquired IPR&D and SG&A expenses were $3.07 billion, a decrease of 11% versus the prior year.

2022 年第四季非 GAAP 研發、收購的智慧財產權研發及銷售、管理及行政費用合計為 8.72 億美元，較 2021 年第四季成長 5%。 2022 年全年非 GAAP 研發、收購的智慧財產權研發及銷售、管理及行政費用合計為 30.7 億美元，較上年下降 11%。

Recall that 2021 results were impacted by $1.1 billion of acquired IPR&D charges, including the onetime $900 million payment to CRISPR compared to $116 million of such charges in 2022. Acquired IPR&D aside throughout 2022, we continued to invest in research in our advancing pipeline, which includes mid-and late-stage clinical assets across 8 different disease areas.

需要注意的是，2021 年的業績受到 11 億美元的收購智慧財產權及研發費用的影響，其中包括向 CRISPR 支付的 9 億美元的一次性款項，而 2022 年的此類費用為 1.16 億美元。除 2022 年的收購智慧財產權及研發費用外，我們繼續投資於我們正在推進的研發管線，其中包括 8 個不同疾病領域的中後期臨床資產。

The year-over-year increase in spending reflects stepped-up investments in programs where we made notable clinical progress, particularly in pain, the new vanza triple as well as Type 1 diabetes. We also continued to invest in the pre-commercial build-out activities for exa-cel and preparation for other potential near-term launches. Given these programs' potentially transformative benefit to patients and multibillion-dollar market opportunities, we will continue to invest accordingly.

支出年增率反映了我們在一些取得​​顯著臨床進展的項目上加大了投入，尤其是在疼痛治療、新型Vanza三聯療法以及1型糖尿病治療方面。我們也繼續投資於Exa-Cel的商業化前期建設工作，並為其他潛在的近期上市項目做好準備。鑑於這些項目可能為患者帶來變革性的益處，以及數十億美元的市場機遇，我們將繼續加大投入。

Fourth quarter 2022 non-GAAP operating margin was 50%, and we generated non-GAAP operating income of $1.15 billion in the quarter, an increase of 15% versus the prior year period. Full year 2022 non-GAAP operating margin was 54%, and full year non-GAAP operating income was $4.79 billion, up 48% versus 2021. We ended the quarter with $10.8 billion in cash and investments as our cash flow generation and balance sheet remain very strong.

2022年第四季非GAAP營業利益率為50%，當季非GAAP營業收入為11.5億美元，較上年同期成長15%。 2022年全年非GAAP營業利益率為54%，全年非GAAP營業收入為47.9億美元，較2021年成長48%。截至季末，公司持有現金及投資108億美元，現金流和資產負債表依然穩健。

On the business development front, in Q4, we announced a global collaboration with Entrada Therapeutics focused on therapeutics for DM1. The HSR period expired last night and the transaction is expected to close within days. As a result, our Q1 2023 results are anticipated to include an approximate $224 million up-front payment recorded in our income statement and an approximate $26 million equity investment recorded on the balance sheet.

在業務拓展方面，第四季我們宣布與Entrada Therapeutics達成全球合作，專注於第1型糖尿病（DM1）的治療藥物研發。哈特-斯科特-羅迪諾反壟斷改進法案（HSR）的審查期已於昨晚結束，預計交易將在幾天內完成。因此，我們預計2023年第一季的業績將包括損益表中記錄的約2.24億美元的預付款，以及資產負債表中記錄的約2,600萬美元的股權投資。

Now switching to guidance. We are establishing 2023 product revenue guidance of $9.55 billion to $9.7 billion, representing 7% to 9% year-over-year growth at current exchange rates. Note that this guidance includes an expected approximate 1.5 percentage point headwind to our revenue growth, inclusive of our foreign exchange risk management program.

現在轉入業績指引。我們預計2023年產品營收為95.5億美元至97億美元，以目前匯率計算，年增7%至9%。請注意，該指引已包含約1.5個百分點的收入成長阻力，其中包括我們的外匯風險管理計畫。

Also note that 2023 product revenue guidance reflects revenue from cystic fibrosis products only. Exa-cel is not included in guidance as potential approval and launch dates in the EU, U.K. and U.S. are still to be determined.

另請注意，2023年產品收入預期僅包含囊性纖維化產品的收入。 Exa-cel未包含在預期範圍內，因為其在歐盟、英國和美國的潛在批准和上市日期尚未確定。

For our CF franchise in 2023, we see continued strong performance of TRIKAFTA/KAFTRIO in all major markets, further uptake in markets with recent reimbursement agreements and expansion into younger patient populations. Of note, with 4 years of TRIKAFTA experience, the majority of international reimbursement agreements secured and recent revisions in epidemiology, we have strong visibility to our 2023 revenue guidance range and another year of attractive growth for our CF product portfolio.

展望2023年，我們的囊性纖維化（CF）產品組合預計將繼續保持強勁的業績，TRIKAFTA/KAFTRIO 在所有主要市場均表現出色，在近期達成醫保報銷協議的市場將進一步擴大市場份額，並拓展至更年輕的患者群。值得注意的是，憑藉 TRIKAFTA 四年來的經驗積累、已達成的大部分國際醫保報銷協議以及近期流行病學數據的修訂，我們對2023年的收入預期範圍充滿信心，並預計我們的囊性纖維化產品組合將在新的一年裡繼續保持可觀的增長。

We are also providing 2023 guidance for combined non-GAAP R&D, acquired IPR&D and SG&A expenses in a range of $3.9 billion to $4 billion, which includes approximately $300 million of upfronts and milestones from known collaborations including the expected up-front payment in Q1 2023 for Entrada.

我們也提供了 2023 年非 GAAP 研發、收購的智慧財產權研發和銷售、一般及行政費用的綜合指引，範圍為 39 億美元至 40 億美元，其中包括來自已知合作的約 3 億美元的預付款和里程碑付款，包括預計在 2023 年第一季度向 Entrada 支付的預付款。

This targeted investment increase is consistent with the significant continued progress of our multiple mid-and late-stage clinical development programs and the expansion of our commercial and manufacturing capabilities in anticipation of the multibillion-dollar market opportunities represented by our programs with near-term launch potential.

此次有針對性的投資增加，與我們多個中後期臨床開發項目的持續顯著進展以及我們為迎接近期上市潛力項目所帶來的數十億美元市場機會而擴大的商業和生產能力相一致。

Our guidance for projected full year 2023 non-GAAP effective tax rate is a range of 21% to 22%. Lastly, we announced today a new $3 billion multiyear share repurchase authorization.

我們對2023年全年非GAAP實際稅率的預期範圍為21%至22%。最後，我們今天宣布了一項新的30億美元多年期股票回購授權。

In closing, Vertex performed exceptionally well in 2022. We grew revenue double digits for the eighth consecutive year, maintained our strong balance sheet, invested internally and externally and accelerated programs across our diverse pipeline. In 2023, we look forward to further important milestones as highlighted on this slide to mark our continued progress in multiple disease areas.

綜上所述，Vertex在2022年表現優異。我們連續第八年實現了兩位數的營收成長，維持了穩健的資產負債表，並加大了內部和外部投資，同時加速推進了多元化產品線中的各項計畫。展望2023年，我們期待取得更多重要里程碑，如本頁幻燈片所示，這將標誌著我們在多個疾病領域持續取得進展。

We look forward to updating you on future calls, and I'll ask Susie to begin the Q&A period.

我們期待在以後的電話會議中向您報告最新情況，接下來我將請 Susie 開始問答環節。

(Operator Instructions)

（操作說明）

And the first question will come from Salveen Richter with Goldman Sachs.

第一個問題將來自高盛的薩爾文·里希特。

Can you frame what we're going to see from the VX-880 program this year and when? And also, on the second program, the cells and device program, how you overcome challenges here and your confidence level that you'll be able to kind of get to the bars that you want to see?

您能否概述一下今年VX-880計畫將取得哪些成果，以及何時能夠實現？另外，關於第二個項目，即電池和裝置項目，您如何克服挑戰？您對最終達到預期目標有多大信心？

Yes. Thanks for the question, Salveen. With regard to the 880 program, remember, this is the program that is, let's call it, the naked cell program that requires off-the-shelf immunosuppressives. This is the program that we demonstrate proof-of-concept with the half-dose patients last year.

是的，謝謝你的提問，Salveen。關於880項目，請記住，這是一個我們稱為「裸細胞」的項目，它需要使用現成的免疫抑制劑。去年，我們用半劑量患者驗證了這個計畫的概念。

Where we are now is we fully enrolled this Part B. That's where patients received the target dose, but in a staggered manner. And the real importance here is -- and our excitement is to get to Part C, because then we can dose patients concurrently.

目前我們已經完成了B部分的全部入組工作。在這一部分，患者接受了目標劑量，但給藥方式是分批進行的。而真正重要的是──也是我們最期待的──是進入C部分，因為到那時我們就可以同時給予病人了。

You should expect data this year at congresses. And there are a couple of important diabetes congresses that occur each year that will have longer duration of follow-up and more patients' worth of data. And the dimension on which you can expect us to share information are what we've already done with the first 2 patients. That's to say see C-peptide levels, decreases in exogenous insulin, improvements in hemoglobin 1Ac.

今年您應該會在大會上看到相關數據。每年都會舉辦幾場重要的糖尿病大會，這些大會將提供更長的追蹤數據和更多患者的數據。您可以期待我們分享的資訊主要來自我們已經對前兩位患者所做的研究，例如C肽水平、外源性胰島素用量減少以及糖化血紅蛋白A1c的改善。

With regard to the cells and device program, historically, in the field, the challenge with devices has been fibrosis, lack of oxygen getting to the cells inside these devices as well as the inability for nutrients to go in and for insulin, in this instance, to be secreted out.

就細胞和設備項目而言，從歷史上看，該領域面臨的挑戰是纖維化、設備內部細胞缺氧以及營養物質無法進入和胰島素無法分泌。

We have worked long and hard to develop a proprietary, what we call a channel array device. This device has particular features in terms of geometry, materials and proximity of blood and oxygen to ourselves to overcome these historic areas. And what I'll say, to just give you a little bit more on this point, is in small animal models and large, with our proprietary device, we have seen no evidence of fibrosis.

我們投入了大量時間和精力，研發出一種我們稱為通道陣列的專有裝置。該裝置在幾何形狀、材料以及血液和氧氣與人體的接近程度等方面都具有獨特的優勢，從而克服了以往的不足。我還要補充一點，在小型動物模型和大型動物模型中，使用我們專有的裝置後，我們沒有觀察到任何纖維化的跡象。

Last thing to point out, of course, the same 880 cells that we've already shown proof-of-concept with, those are the same cells in the cells plus device presentation as well as in our hypoimmune presentation.

最後要指出的是，我們已經使用以證明概念的 880 個細胞，與細胞加設備展示以及我們的低免疫展示中使用的細胞相同。

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。

I just have 2. for VX-548, is the communication strategy here to have all the Phase III data in acute pain and neuropathic pain and then disclose everything before filing? I wasn't sure what the plan was there.

我只有兩個問題。關於VX-548，你們的溝通策略是不是先把急性疼痛和神經性疼痛的III期數據全部公佈，然後再提交申請？我不太清楚你們的計劃是什麼。

And then, Stuart, given the hospital setting, what role do you think that treatment algorithms and cost/benefit studies will play commercially? This is obviously a pretty different market than you guys are typically used to.

那麼，斯圖爾特，考慮到醫院的環境，你認為治療方案和成本效益研究在商業上會發揮什麼作用？這顯然與你們通常熟悉的市場截然不同。

And then for 522, I don't have a doubt that you guys can express the FTR, but obviously, it has to be in the right tissues. Can you talk maybe about the technical challenges here with an mRNA strategy and your development plan just at a high level?

至於522，我毫不懷疑你們能夠表達FTR，但顯然，它必須在正確的組織中表達。能否請你們大致談談採用mRNA策略所面臨的技術挑戰以及你們的研發計畫？

Yes. Sure thing, Geoff. Let me start with the VX-522 question, which is the mRNA program that we are developing in collaboration with Moderna and then we'll switch to the 548 program in pain. So with regard to VX-522 in the mRNA program, the biggest challenge we and others have faced through the development of this approach for those last 5,000 patients who cannot benefit from CFTR modulators because they simply don't make any protein, it's been delivery.

好的，當然可以，傑夫。我先回答VX-522的問題，這是我們與Moderna合作開發的mRNA療法，之後我們再談談用於治療疼痛的548療法。關於mRNA療法中的VX-522，我們和其他研究人員在開發這種療法時面臨的最大挑戰是藥物傳遞。這種療法旨在幫助最後5,000名無法從CFTR調節劑中獲益的患者，因為他們根本無法產生任何CFTR蛋白。

That is really what we have been working on for years. And it was only about 12, 18 months ago that we really had a big breakthrough that area. The reason for our excitement for this program is that we can now deliver with our LNPs into our HBE cells using those same assays that are not only qualitatively translated to what we see in the clinic, but quantitatively so.

這正是我們多年來一直致力於的研究方向。大約在12到18個月前，我們才在這個領域取得了重大突破。我們對這個計畫感到興奮的原因在於，我們現在可以利用相同的檢測方法，將我們的脂質奈米顆粒（LNP）遞送到人類支氣管上皮細胞（HBE細胞）中。這些檢測方法不僅在定性上與臨床觀察到的結果相符，而且在定量上也完全一致。

Second, we also can show that the protein expression levels with that mRNA delivery is high with high chloride transport. That's the direct readout for CFTR function.

其次，我們也可以證明，透過該mRNA遞送，蛋白質表現量高，氯離子轉運也高。這是CFTR功能的直接體現。

And then lastly, we have taken this mRNA LNP construct and administered it to small animals and large, and we can deliver it to the right cells. That's a really important part of doing this in patients. So that's the technical challenges we've overcome and it's really been all about delivery.

最後，我們利用這種mRNA LNP構建體，將其應用於小型和大型動物，並成功將其遞送至目標細胞。這對於在患者身上應用至關重要。以上就是我們克服的技術挑戰，關鍵就在於遞送。

With regard to VX-548 yes, you're right. The plan is to complete the studies, all 3 Phase III studies, the 2 RCTs, which are very similar to what we've already done in Phase II and the 1 single-arm study, let's call it, an all-comer study, so we get different pain types. We are projecting that we're going to complete those trials towards the end of this year, beginning of next, and we'll share all the data at the same time.

關於VX-548，您說得對。我們的計劃是完成所有研究，包括全部3項III期臨床試驗、2項隨機對照試驗（RCT）（與我們已完成的II期臨床試驗非常相似）以及1項單臂​​研究（我們稱之為「全人群研究」），以便納入不同類型的疼痛患者。我們預計將在今年年底或明年年初完成這些試驗，屆時我們將公佈所有數據。

Stuart, over to you for commercial potential.

斯圖爾特，接下來就看你的商業潛力了。

Yes. So Geoff, as we've described before, this is a very big market opportunity with 1.5 billion treatment days of acute pain therapy prescribed per year. Just to dimensionalize that, I talked, in my prepared remarks, about 2/3 of those prescriptions are, either written and dispensed in a hospital or institution or ambulatory care center, or they are written institutional setting but given to a patient on discharge and therefore filled in the retail setting. And the combination of those 2 accounts for about 2/3 of the 1.5 billion treatment days.

是的。傑夫，正如我們之前所述，這是一個非常大的市場機遇，每年有15億個急性疼痛治療​​日。為了更直觀地說明這一點，我在準備的發言稿中提到，這些處方中約有三分之二是在醫院、醫療機構或門診中心開具和配藥的，或者是在醫療機構開具但患者出院時才拿到處方，因此需要在零售藥店配藥。這兩種情況加起來就佔了15億個治療日的三分之二左右。

When we've talked to stakeholders across the board, they are well aware of the unmet need for new therapies in the acute pain space, because all institutions and all states have put in place restrictions on the use of opioids. It's created this gap in the market for products like 548 that have a really positive benefit-risk profile.

我們與各利益相關方進行了溝通，他們都清楚地意識到急性疼痛領域對新療法的巨大需求，因為所有機構和州都對阿片類藥物的使用進行了限制。這就造成了市場空白，使得像548這樣具有極佳獲益風險比的產品能夠填補。

I do think we are beginning to see a sea change in terms of policies, which have been focused on limiting utilization of opioids to actually policies which are looking to remove barriers that might be created by cost sensitivity, and I'll point you to the NOPAIN Act, which I referred to in my prepared remarks, that directs CMS to develop a system of add-on payments for non-opioid pain medicines in addition to the bundled payment that they give to hospitals for the outpatient and the ACS setting.

我認為我們正在開始看到政策方面的巨大轉變，這些政策過去一直側重於限制阿片類藥物的使用，而現在則致力於消除成本敏感性可能造成的障礙。我還要指出我在準備好的發言稿中提到的《無鴉片類藥物止痛法案》，該法案指示美國醫療保險和醫療補助服務中心（CMS）除了向醫院提供門診和急性護理服務（ACS）的打包支付外，還要為非阿片類止痛藥制定附加支付制度。

I see that as a really important sea change and recognition that these are cost-sensitive segments, but this is a way of creating barriers or, sorry, reducing barriers or creating incentives to do the right thing and prescribe non-opioid pain management when they're available.

我認為這是一個非常重要的變革，它認識到這些領域對成本非常敏感，但這是一種製造障礙（或者，抱歉，減少障礙）或創造激勵措施的方式，讓人們在有非阿片類鎮痛藥可用時，採取正確的做法並開具處方。

Hey, Geoff, this is Reshma, again. Just to close out on pain and others may ask questions later, but I just wanted to make sure I also mentioned the peripheral neuropathic pain with VX-548. That Phase II study also began last year. And those results, we aren't calling yet when they would be available, but I wanted to make sure that you know that, that study is also ongoing.

嗨，傑夫，我是雷什瑪，我又來了。關於疼痛，我最後想再補充一點，因為其他人可能之後會問到相關問題，所以我想確保我之前也提到過VX-548治療週邊神經性疼痛的療效。這項二期臨床試驗也是去年啟動的。至於試驗結果何時公佈，我們目前還不能確定，但我希望你知道，這項研究仍在進行中。

The next question will come from Phil Nadeau with Cowen.

下一個問題將來自 Cowen 公司的 Phil Nadeau。

Congrats on the progress. Question on the expense side from us. It does seem like the guidance for cost for 2023 is a bit heavier than we had anticipated in. Even excluding the Entrada upfront it, it does seem like costs are growing a bit faster than revenue. So curious what are the push-pulls in the guidance. What elements are you including the guidance? Is there investment for prelaunch or heavy investment in R&D? Just kind of looking for a little bit more color on what is causing the expenses to rise so much.

恭喜你們的進展。我們想問一下關於費用方面的問題。 2023年的成本指引似乎比我們預期的要高一些。即使不計入Entrada的預付款，成本成長速度似乎略高於營收成長速度。所以，我們想了解影響成本指引的因素有哪些。你們的指引包含了哪些要素？是否有上市前的投資，或是研發方面的大量投入？我們只是想更詳細地了解一下導致成本大幅上升的原因。

I'm going to ask Charlie to take that one.

我打算讓查理去拍那張照片。

Yes. Phil, thanks for the question. And just so you get an overall sense of where we're thinking about things. Given the strong and predictable performance in CF and the recent success of the advancing pipeline with a number of first-in-class and best-in-class assets, including programs with significant near-term potential commercially, we see this is as absolutely the right time to be investing in the business.

是的，菲爾，謝謝你的提問。為了讓你對我們目前的想法有個大致了解，鑑於囊性纖維化（CF）業務強勁且穩定的業績，以及近期研發管線取得的成功——其中包含多項一流和同類最佳的資產，以及一些具有顯著近期商業潛力的項目——我們認為現在絕對是投資該業務的最佳時機。

If you look at 2023 specifically, over 70% of the planned increase in R&D and SG&A is expected in programs which are past POC and therefore, meaningfully derisked. Specifically, we've got trials for vanza, in pain in AMKD, in Type 1 diabetes. You've got the full year cost of the investments in commercial readiness for sickle cell and beta-thal, and we're making commercial investments for pain as well. Importantly, all of these programs are advancing rapidly and represent multibillion-dollar market opportunities.

具體來看2023年，超過70%的研發和銷售、管理及行政費用成長計畫將用於已完成概念驗證（POC）的項目，這些項目的風險已顯著降低。具體而言，我們正在進行萬扎（Vanza）治療AMKD疼痛和第一型糖尿病的臨床試驗。此外，我們也投入了鐮狀細胞貧血和β-地中海貧血商業化準備的全年投資，並在疼痛治療領域進行商業化投資。重要的是，所有這些項目都在快速推進，並代表著數十億美元的市場機會。

So from our perspective, it's the right time to invest. And the good news is that with our differentiated business model, we can deliver industry-leading profitability while we're investing for innovation and growth.

因此，從我們的角度來看，現在是投資的合適時機。好消息是，憑藉我們差異化的商業模式，我們可以在投資創新和成長的同時，實現業界領先的獲利能力。

Maybe one follow-up. Is there a long-term goal for, either operating margins or R&D and SG&A as a percent of sales?

或許還有一個後續問題。對於營業利益率或研發及銷售、管理及行政費用佔銷售額的百分比，是否有長期目標？

No, we have not established a long-term goal.

不，我們還沒有訂定長期目標。

The next question will come from Liis Bayko with Evercore ISI.

下一個問題將來自 Evercore ISI 的 Liis Bayko。

Could you just tell us a little bit more about VTCE-210 (sic) [VCTX-211] versus 211. I noticed before you were a little bit more focused on 210. Now we're talking about 211 and when -- what's the right form for data for there? And what should we be expecting to see?

能否再詳細介紹一下VTCE-210（原文如此）[VCTX-211]和211的差異？我注意到您之前更關注210。現在我們討論的是211，那麼──它的正確資料格式是什麼？我們應該預期看到什麼？

Yes. Sure. Liisa, this is Reshma. VCTX-211, a bit of a mouthful, is the study that Vertex is now running in collaboration with CRISPR Therapeutics. It's a hypoimmune program for Type 1 diabetes, where we're going to be assessing safety and efficacy. VCTX-210 was a safety study.

是的，當然。莉莎，我是雷什瑪。 VCTX-211，名字有點長，是Vertex公司目前與CRISPR Therapeutics公司合作進行的一項研究。這是一項針對第1型糖尿病的低免疫療法項目，我們將評估其安全性和有效性。 VCTX-210是一項安全性研究。

In terms of when you should expect data readouts and such, this study is just getting going. We haven't called when we will be sharing results, but it is just getting going.

至於何時能獲得數據結果等信息，這項研究才剛開始。我們尚未確定何時公佈結果，但研究確實才剛起步。

Okay. Great. And then just a quick question -- 2 quick questions actually on, regarding the CF franchise. Can you talk about the new 88,000 patients? Is that kind of equally distributed amongst the key world regions? Are you seeing that in certain areas than others?

好的，太好了。接下來還有兩個關於囊性纖維化（CF）的問題。能談談新增的88,000名患者嗎？這些患者在世界主要地區分佈是否均勻？還是說某些地區的分佈比其他地區更集中？

And then as for the long-term patents, how should we be thinking about exclusivity for vanzacaftor? And then I noticed you even have next-gen after vanzacaftor and maybe you could enlighten us about market exclusivity there.

那麼，關於長期專利，我們該如何考慮Vanzacaftor的獨佔權呢？我還注意到，你們甚至還有Vanzacaftor的下一代產品，或許你可以為我們解釋一下下一代產品的市場獨佔權問題。

Yes, sure. Liisa, let me tackle the IP questions, and then I'll turn it over to Stuart to talk about the CF epidemiology. The patent for TRIKAFTA goes out to at least 2037. And the reason, if you're wondering, gosh, how is it so long from when we launched, it's because of the rapid pace from when we had synthesized this molecule in the lab to when we got approval, starting with the U.S., which is about 3 years, 8 months or so.

好的，當然。莉薩，我先回答知識產權方面的問題，然後我把麥克風交給斯圖爾特，讓他談談囊性纖維化的流行病學。 TRIKAFTA 的專利至少到 2037 年才到期。如果你好奇為什麼從我們推出產品到獲得批准用了這麼長時間，那是因為我們從實驗室合成這種分子到獲得批准（首先是美國）的進展非常迅速，大約花了 3 年零 8 個月左右。

The vanzacaftor triple, we haven't given a specific date, but it's longer than the TRIKAFTA compound. And we have, indeed, identified potentiators and correctors behind vanzacaftor towards our goal of getting CF patients to sweat chloride levels in the carrier range, and those would be even longer than vanzacaftor.

我們尚未公佈vanzacaftor三聯療法的特定上市日期，但它的療程比TRIKAFTA複方製劑更長。事實上，我們已經找到了vanzacaftor的增強劑和校正劑，旨在使囊性纖維化患者的汗液氯化物水平達到載體範圍，這些藥物的療程甚至比vanzacaftor更長。

Let me turn it over to Stuart for CFP.

讓我把時間交給斯圖爾特，讓他來做CFP（註冊財務規劃師）的介紹。

Yes, Liisa. So as you said, we updated our estimate for the number of people living with CF to 88,000 for North America, Europe and Australia. That's an increase from our previous estimate from a couple of years ago of 83,000. It's really driven by 3 things: more patients coming forward for treatment; better data capture, and more complete data capture in registries around the world; and perhaps, most importantly, patients with cystic fibrosis are living longer due to improvements in the quality of care over the years and also the availability of truly effective medicines.

是的，莉薩。正如你所說，我們更新了北美、歐洲和澳洲囊性纖維化患者人數的估計，目前為88,000人。這比我們幾年前的估計值83,000人有所增加。這主要歸功於三點：更多患者前來就診；數據收集更加完善，全球各地的登記系統數據也更加完整；或許最重要的是，由於近年來醫療質量的提高以及真正有效藥物的普及，囊性纖維化患者的壽命延長了。

We see those trends occurring kind of across the globe in all of the regions that I mentioned. It's not just in one part of the world. Those trends are consistent. And I have to say we anticipate those trends will continue into the future.

我們看到這些趨勢幾乎遍及全球，在我提到的所有地區都有出現。這並非僅限於世界上的某個地方。這些趨勢是一致的。而且我必須說，我們預計這些趨勢將在未來持續下去。

The next question will come from David Risinger with SVB.

下一個問題將來自SVB的David Risinger。

So my question is on VX-548. I guess, first, could you talk about publication plans for detailed Phase II results in 2023? And if you are planning publications, what incremental point should we be expecting to focus on?

我的問題是關於VX-548的。首先，能否談談2023年詳細二期臨床試驗結果的發表計畫？如果計劃發表，我們應該關注哪些階段性進展？

And with respect to the commercialization scenarios, there is one in which VX-548 is non-inferior to active control and then another in which it's superior to active control. So it would be helpful to just understand the commercial opportunities in those 2 different scenarios.

至於商業化應用場景，有一種情況下VX-548的效果不遜於主動控制，另一種情況下它則優於主動控制。因此，了解這兩個不同場景下的商業機會將大有裨益。

And then one final tidbit for Charlie. Non-GAAP IPR&D was $116 million in '22. What is the figure that's incorporated in your guidance for '23, please?

最後還有一個問題想問查理。 2022年非GAAP下的IPR&D支出為1.16億美元。請問您在2023年的業績指引中納入的數字是多少？

All right. Dave, you've given us 3 different questions here. Let me save the 2 related to 548, and let me ask Charlie to talk about the IPR&D.

好的。戴夫，你這裡提出了三個不同的問題。我先保留兩個與548相關的問題，然後請查理談談IPR&D方面的問題。

David, the guidance includes an estimate of $300 million for IPR&D, and that's inclusive of the up-front for Entrada.

David，指引中估計智慧財產權研發費用為 3 億美元，其中包括支付給 Entrada 的預付款。

Let me now move to 548. Dave, I'm going to tell you a little bit more about the publication strategy and the study design. And I'm going to ask Stuart to tell you about the commercial potential and how we see it depending on the 2 scenarios that you laid out.

現在我們來看第548題。戴夫，我將向你詳細介紹發表策略和研究設計。然後我會請史都華談談商業潛力，以及我們根據你提出的兩種情景是如何看待它的。

548, and this target in particular, NaV1.8, has been the holy grail, NaV1.7 and 1.8 in the pain field for many, many years. And for that reason, because we are the first company to come forward with a highly specific and effective treatment that has shown effectiveness in Phase II across multiple pain models, not only with 548 but its predecessor molecule, the interest level in the community is very high. And our intent is to publish the full Phase II data, abdominoplasty, and bunionectomy in a high-profile journal this year.

548，尤其是其標靶NaV1.8，多年來一直是疼痛治療領域的聖杯，NaV1.7和NaV1.8也是如此。正因如此，我們是首家推出高度特異性和高效療法的公司，該療法在多種疼痛模型中均已在II期臨床試驗中展現出療效，不僅548，其前體分子也同樣有效，因此在業界引起了極大的關注。我們計劃今年在一家知名期刊上發表完整的II期臨床試驗數據，包括腹部整形術和拇外翻切除術的數據。

With regard to what additional information you will be able to look at, honestly, the key information we've already revealed in our press release, that is to say highly efficacious, statistically significant, clinically meaningful results versus placebo. And we've also already shared the numerical results for the opioid control arm, and you can -- while the control -- I'm sorry, the context arm, while that reference arm wasn't there for statistical comparisons, you can clearly look and see what the context is there.

至於您還能查看哪些額外信息，坦白說，關鍵信息我們已經在新聞稿中公佈了，那就是與安慰劑相比，療效顯著、具有統計學意義且臨床意義重大的結果。我們也已經分享了阿片類藥物對照組的數值結果，雖然對照組——抱歉，是背景組——雖然該參考組沒有用於統計比較，但您可以清楚地查看背景資訊。

And you'll have the full safety. The safety profile for 548 is looking very good. You might remember, there were no related SAEs in the Phase II study. In fact, there were no SAEs at all in bunionectomy.

而且安全性完全有保障。 548 的安全性非常好。您可能還記得，在 II 期研究中沒有發生任何相關的嚴重不良事件 (SAE)。事實上，在拇外翻切除術中根本沒有發生任何 SAE。

With regard to the study design, the way we set it up is that it is a study versus placebo, superiority versus placebo. Obviously, that's there to demonstrate the efficaciousness as well as the safety profile. And then we have the opportunity to also assess versus opioids. If you ask me what are we looking for, if we recapitulate the results in Phase II, that is a home run. Stuart?

關於研究設計，我們採用的是安慰劑對照試驗，即療效優於安慰劑的試驗。顯然，這樣做是為了證明藥物的有效性和安全性。此外，我們還有機會評估其與鴉片類藥物的療效。如果你問我想要什麼，如果我們能在第二期臨床試驗中重現這些結果，那就非常成功了。史都華？

Yes. As Reshma said about the design of the study, the primary endpoint is the comparison to placebo, and then we can compare it to the reference arm. I think in, either scenario that you described, Dave, what we've got here is a very significant commercial opportunity.

是的。正如雷什瑪所說，這項研究的設計主要終點是與安慰劑組進行比較，然後我們將其與對照組進行比較。戴夫，我認為無論你描述的哪種情況，我們都面臨著一個非常重要的商業機會。

If you are, in addition to being superior to placebo, as good as opioids from an efficacy point of view without all of their associated liabilities, which include addictive potential but aren't restricted to just addictive potential, then that is something that's going to be highly valued by the treating community.

如果一種藥物除了優於安慰劑之外，在療效方面與阿片類藥物一樣好，而且沒有阿片類藥物的所有相關弊端（包括成癮性，但不僅限於成癮性），那麼它將受到治療界的高度重視。

Obviously, if we're superior, that's even better. But something which is as good as opioids from an efficacy point of view, but without all the liabilities would be a very high-value medicine.

顯然，如果我們能研發出更優的藥物，那就更好了。但如果能研發出一種療效與鴉片類藥物相當，但又沒有其所有副作用的藥物，那將是一種極具價值的藥物。

The next question will come from Robyn Karnauskas with Truist.

下一個問題將來自 Truist 的 Robyn Karnauskas。

All right. I'll go quickly. So we get a lot of questions on Vertex' growth, despite you having a robust pipeline. Maybe talk about your thoughts around this 8%, and if you would think that would continue to slow or how you're thinking about it?

好的，我先簡短回答。儘管Vertex擁有強大的產品線，但我們仍然收到很多關於其成長的問題。能否談談您對這8%的成長有何看法？您認為這個成長速度會繼續放緩嗎？或者您對此有何想法？

And then with regard to next generation, despite, like, more robust efficacy, it still took some time to switch people over to the next-generation product. Maybe some color on what the bar might be to speed up switching.

至於下一代產品，儘管其療效較強，使用者過渡到下一代產品仍需要一些時間。或許可以探討一下加快過渡速度的必要條件。

And then my last question was on chronic pain. I mean, you've got a lot of key pain data in-house, more to come. I was just curious, is chronic pain partnerships still on the table, what you think partners are really looking for in order to take that forward.

我的最後一個問題是關於慢性疼痛的。我的意思是，你們內部有很多關鍵的疼痛數據，而且未來還會有更多。我只是好奇，你們是否還在考慮與慢性疼痛領域合作，以及你們認為合作夥伴在推動合作方面真正看重的是什麼。

Yes. Robyn, let me ask Stuart to go first with CF and talk about how we see vanzacaftor and the place for that in the marketplace.

是的。 Robyn，我先請Stuart和CF談談我們對vanzacaftor的看法，以及它在市場上的地位。

Yes. So Robyn, on vanzacaftor, as you know, based on our in vitro data, but also our Phase II data, we have good reasons to believe that the vanzacaftor triple combination could provide incremental clinical benefit even over TRIKAFTA, which, as you know, sets a very high bar, and that's the way the study is designed to be able to compare vanzacaftor to TRIKAFTA.

是的。 Robyn，關於vanzacaftor，如你所知，根據我們的體外數據以及II期數據，我們有充分的理由相信vanzacaftor三聯療法即使與TRIKAFTA相比也能帶來額外的臨床獲益，而TRIKAFTA，正如你所知，其療效標準非常高，這項研究的設計目的就是為了比較vanzacaftor和TRIKAFTA。

I think there are really 2 patient populations for whom that would be an attractive proposition if it delivers that profile. One is patients who are currently being treated with a CFTR modulator, who may be interested in switching to something which offers greater clinical benefit. In addition, we haven't really talked about this part of the population for a while, but there are some patients who've discontinued CFTR modulators for a variety of reasons over time.

我認為，如果這種療法能夠達到預期效果，那麼對兩類患者來說，它將極具吸引力。一類是目前正在接受CFTR調節劑治療的患者，他們可能希望換用其他療效較佳的藥物。此外，我們已經有一段時間沒有討論過這部分患者群體了，但隨著時間的推移，確實有一些患者由於各種原因停止了CFTR調節劑的治療。

Our persistence rates with our CFTR modulators are, let me just reemphasize, as high as I've ever seen for any chronic oral Medicaid, but we do have patients who have discontinued over time. And so I think those patients who want to be on a CFTR modulator but have had to discontinue, one of our previous generations may be interested in the vanzacaftor triple combination when a new treatment option is available. So I do think there is likely to be significant interest from physicians and patients if the vanzacaftor triple combination delivers incremental benefit.

我再次強調，我們CFTR調節劑的持續用藥率是我見過所有慢性口服醫療補助藥物中最高的，但我們也確實有一些患者隨著時間的推移而停藥。因此，我認為那些想要繼續服用CFTR調節劑但不得不停藥的患者，如果出現新的治療方案，他們可能會對我們上一代的vanzacaftor三聯療法感興趣。所以我認為，如果vanzacaftor三合療法能帶來額外的益處，那麼醫生和病人都可能會對此表現出濃厚的興趣。

Robyn, let me take the question about chronic pain next, and we'll end with growth. We see pain as 3 distinct categories: acute pain, that's what we've been talking about with VX-548, and this very near-term commercial opportunity, given we are well underway with our Phase III program, and it is only 48 hours of dosing.

羅賓，接下來我想回答關於慢性疼痛的問題，最後我們來談談成長。我們認為疼痛分為三個不同的類別：急性疼痛，也就是我們一直在討論的VX-548所針對的疼痛，以及鑑於我們的III期臨床試驗進展順利，且給藥時間僅需48小時，因此近期就有望實現商業化。

The second we see is neuropathic pain. Obviously, that's a version of chronic pain, but we distinguish that from musculoskeletal pain. For neuropathic pain, I see that as equally a Vertexian opportunity as is acute pain. There is a -- there are a discrete number of prescribers. It can be serviced with a specialty sales force. And we have already shown that this target, NaV1.8, with our predecessor molecule, VX-150, is effective for neuropathic pain. When Lyrica was a branded medicine, just to give you a sense of the market size, it was approximately a $5 billion market for Lyrica in this chronic neuropathic pain.

我們看到的第二種是神經性疼痛。顯然，這是一種慢性疼痛，但我們將其與肌肉骨骼疼痛區分開來。我認為，對於神經性疼痛，Vertex公司在治療方面擁有與治療急性疼痛同等的機會。目前，開立神經性疼痛處方的醫生數量有限，我們可以組建一支專業的銷售團隊來服務。我們已經證明，我們先前的分子VX-150針對NaV1.8靶點，對神經性疼痛有效。為了讓您對市場規模有所了解，Lyrica作為品牌藥上市時，在治療慢性神經性疼痛方面，其市場規模約為50億美元。

And then there's a third kind of pain which is musculoskeletal pain. It turns out that we've already studied that as well with our predecessor molecule, and it's effective in that kind of pain setting as well, which is actually quite unusual. There aren't very many medicines that work in acute neuropathic and musculoskeletal pain.

還有第三種疼痛，即肌肉骨骼疼痛。我們之前已經用一種前驅分子研究過這種疼痛，它對這類疼痛也有效，這其實相當罕見。目前能有效治療急性神經性疼痛和肌肉骨骼疼痛的藥物不多。

We are -- I don't see the musculoskeletal pain as a Vertex sales and marketing specialty opportunity, but we're absolutely going to serve all patients, and we would partner that. But our focus is on the 2 Vertexian opportunities right in front of us, acute pain, very near term; and the neuropathic pain that's already in Phase II and the predecessor molecule was successful there.

我不認為肌肉骨骼疼痛是Vertex公司銷售和行銷的重點領域，但我們絕對會服務所有患者，並且會尋求合作夥伴。不過，我們目前的重點是Vertex公司眼前的兩個重要機會：一是近期就能實現的急性疼痛；二是已經進入II期臨床試驗的神經性疼痛，其前驅分子在該領域取得了成功。

With regard to growth, let me ask Charlie to comment on the growth profile for the company.

關於公司的成長情況，請查理談談公司的成長前景。

Yes. The question -- so just a reminder, on the guidance, we gave $9.55 billion to $9.7 billion, 7% to 9% growth over 2022 and that's after a 1.5 percentage point headwind from FX. Stating it differently, it's a $700 million increment on our 2022 revenue of $9 billion, so a significant increase in 2023.

是的。問題是——提醒一下，關於業績指引，我們預計2023年營收將達到95.5億美元至97億美元，較2022年增長7%至9%，這已經扣除了匯率波動帶來的1.5個百分點的不利影響。換句話說，這意味著2023年營收將在2022年90億美元的基礎上增加7億美元，實現顯著成長。

And I think your question really was about where does growth come from. And so importantly, as has been mentioned, we've recently increased our estimate of epidemiology. Several years ago, we used to say 75,000, then it was 83,000. Now it's 88,000. So the patient population is growing.

我認為你的問題實際上是關於成長來自哪裡。正如前面提到的，我們最近提高了流行病學數據的估計。幾年前，我們估計是75,000人，後來是83,000人，現在是88,000人。所以患者人數正在增加。

Within that patient population, there are 20,000 patients or more who would benefit from a CFTR modulator, who are not on medicine today, and we intend to bring as many of those as possible onto medicine as we go with continued uptake across eligible patient groups in countries where we already have reimbursement or approvals, as we expand to younger age groups and to a lesser extent, as we add additional new reimbursements.

在該患者群體中，有 20,000 名或更多患者可以從 CFTR 調節劑中受益，但目前尚未接受藥物治療。我們計劃隨著在已獲得報銷或批准的國家/地區符合條件的患者群體中繼續推廣，盡可能多地讓這些患者接受藥物治療；同時，隨著我們擴展到更年輕的年齡組，並在較小程度上隨著我們增加新的報銷，我們也會繼續推廣。

And so we have high visibility into our guidance for 2023, those drivers, we see growth beyond '23 as well. And of course, we have the emerging opportunity from the vanza triple and the mRNA therapy in coming years. So overall, we're in a great position for continued growth in '23, and we see lots of opportunities for growth beyond '23.

因此，我們對2023年的業績指引以及相關驅動因素非常清晰，我們也看到了2023年以後的成長。當然，未來幾年Vanza三重療法和mRNA療法也為我們帶來了新的機會。總而言之，我們為2023年的持續成長奠定了堅實的基礎，並且我們看到了2023年以後的許多成長機會。

Robyn, I'll just add, we've been talking about long-term growth, our 5-in-5 goal. These are 5 new medicines launching in the next 5 years. And then if you think about what qualifies in there, the very near-term opportunities are exa-cel and sickle cell disease and beta-thalassemia, vanzacaftor in CF and VX-548 in pain, those are just right in front of us.

羅賓，我補充一點，我們一直在討論長期成長，也就是我們的「五年五新藥」目標。這指的是未來五年內推出的五種新藥。如果你仔細想想哪些符合條件，那麼近期內的機會就非常大了，例如Exa-Cel（用於治療鐮狀細胞疾病和β-地中海貧血）、Vanzacaftor（用於治療囊性纖維化）以及VX-548（用於治療疼痛），這些都近在眼前。

And then we have AMKD that's in Phase II/III with 147, the Type 1 diabetes program that we spoke about, the neuropathic pain program that we spoke about, and there's also the mRNA program and the AATD program, which is also in Phase II.

然後我們還有 AMKD 項目（目前處於 II/III 期，涉及 147 個細胞）、我們之前提到的 1 型糖尿病項目、我們之前提到的神經性疼痛項目，以及 mRNA 項目和 AATD 項目（目前也處於 II 期）。

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 maybe can you talk a little bit about the capital allocation priorities? I know you announced a buyback program today. But year 2022 year-end cash is almost 14% of your market capitalization at this point. Do you think, outside of internal R&D, you could think about some midsized acquisition at this point given the cash position and the market at this point?

能否談談資本配置的優先事項？我知道您今天宣布了一項股票回購計劃。但截至2022年底，您的現金儲備幾乎佔市值的14%。鑑於目前的現金狀況和市場狀況，您認為除了內部研發之外，是否可以考慮進行一些中等規模的收購？

Charlie?

查理？

Yes, Mohit, thanks for the question. On capital allocation, I'd probably sound like a broken record, but our priorities are the same, investing in innovation, both internal and external is the top priority. We clearly see that is the best way to create value for patients and for shareholders.

是的，莫希特，謝謝你的提問。關於資本配置，我可能又要老生常談了，但我們的優先事項始終如一：投資創新，包括內部和外部創新，是重中之重。我們清楚地認識到，這是為患者和股東創造價值的最佳途徑。

We have, for the last 5 years now, maintained a share buyback program, where we focus on offsetting dilution from employee share programs and for some opportunistic buying. And so we have this new larger authorization at $3 billion, but it's simply a reflection of the growing strength of our balance sheet and cash flow.

過去五年，我們一直維持著股票回購計劃，主要目的是抵消員工持股計畫造成的股權稀釋，以及進行一些機會性回購。因此，我們獲得了30億美元的新授權，這只反映了我們資產負債表和現金流的日益穩健。

Thank you. next question will come from Michael Yee with Jefferies.

謝謝。下一個問題將來自傑富瑞的邁克爾葉。

Appreciate it. Two pipeline questions for you. One on the vanza triple. I know that you have commented that you think it could be better. I recall that in the Phase II, there was, although difficult to compare across trials, some debate around whether it was truly better on FEV or more about sweat chloride, and you would see the effects, I think, more peripherally. Can you just comment on whether you actually think FEV actually would be better in the Phase III, given the chloride transport data is so much better? I know David Altshuler has also sort of comments on that.

謝謝。我有兩個關於藥物研發管線的問題。第一個是關於Vanza三重療法的。我知道您曾說過您認為它還有提升空間。我記得在二期臨床試驗中，雖然不同試驗之間難以直接比較，但當時存在一些爭論，爭論的焦點在於它究竟是提高了FEV1，還是更多地改善了汗液氯化物水平，而且我認為後者的療效可能更偏向於外周。鑑於氯化物轉運數據已大幅改善，您能否就三期臨床試驗中FEV1的改善發表一下看法？我知道David Altshuler也對此發表過一些評論。

And then on the mRNA program, 5Q2, I think you made a nice comment earlier on this call about how, at least in animal models, that was getting into tissue. Can you just reiterate what you were saying about your view of -- or testing in HBE assays about whether the LNP is actually getting in and how confident you are in CF tissue that the LNP is getting in?

關於mRNA計畫5Q2，我認為您之前在電話會議中很好地提到過，至少在動物模型中，該物質能夠進入組織。您能否再次重申您對LNP是否能夠進入組織的看法，或者說，您在HBE檢測中測試的結果，以及您對LNP能否進入CF組織有多大的信心？

Yes. Sure thing, Mike. With regard to the vanza triple, if you look at the Phase II data, and you're right, these are cross-study comparisons, but if you're trying to glean and get a general sense for what the data are telling you, in the Phase II trials, what you can see is, on average, the vanza triple, compared to what we have shown with TRIKAFTA, it's about 5 points better on sweat chloride. And if you look closely and look at the ppFEV1 values that we've generated, there are some patients in the vanza triple where we've seen 20% improvement in ppFEV1.

是的，沒問題，麥克。關於Vanza三聯療法，如果你查看二期臨床試驗數據，你說得對，這些是跨研究的比較，但如果你想了解二期臨床試驗數據所傳達的總體信息，你會發現，平均而言，與我們之前展示的TRIKAFTA相比，Vanza三聯療法在降低汗液氯化物方面大約有5個百分點的改善。如果你仔細觀察我們產生的ppFEV1值，你會發現Vanza三重療法組中有一些患者的ppFEV1值提高了20%。

So if you ask me, gosh, can the vanza triple be better than TRIKAFTA? Yes. And I would say that the strongest evidence for that is the chloride transport in our HBE assays, which have proven themselves time and time again as well as sweat chloride because that's simply a less variable measure. But if I look at ppFEV1 there are hints of that as well, but I would put that lower on the scale of evidence because the variability is greater.

所以，如果你問我，Vanza Triple 是否比 TRIKAFTA 更好？答案是肯定的。我認為最有力的證據是我們 HBE 檢測中的氯離子轉運情況，這項檢測已經反覆證明了其有效性，汗液氯化物也是如此，因為汗液氯化物本身就是一個變異性較小的指標。如果我查看 ppFEV1，也能發現一些端倪，但我認為它的證據強度略低，因為它的變異性更大。

With regard to mRNA and why we are so enthusiastic about this program, which we are running in collaboration with Moderna, it is really a combination of three things. The first is the ability to demonstrate that with these LNPs, we get the construct into the HBE cells, and that's important because of how reliable the HBE sells and how translatable they are.

關於mRNA以及我們為何對這項與Moderna合作的計畫如此充滿熱情，這主要源自於三點。首先，我們能夠證明利用這些LNP可以將構建體導入HBE細胞，這一點至關重要，因為HBE的可靠性和轉化應用價值都非常高。

Second, it is about the high expression of the protein. And third, in multiple animal models we can show, and this has been difficult for others to show. Some have not talked about it, and it's been difficult to gather whether they have or have not. But I can tell you, we have, in multiple animal models, demonstrated that the mRNA gets to the right cells in the lung.

其次，關鍵在於蛋白質的高表現。第三，我們在多種動物模型中都證明了這一點，而其他人卻很難做到這一點。有些人對此隻字未提，我們也很難了解他們是否已經證實。但我可以肯定地告訴大家，我們已經在多種動物模型中證明，mRNA能夠到達肺部的正確細胞。

The next question will come from Jessica Fye with JPMorgan.

下一個問題將來自摩根大通的傑西卡·費伊。

Just a couple of quick ones, maybe following up on the last. First, with the SAD trial for VX-522 completing this year, should we expect to see data from that trial this year or might not come until later once the MAD work is complete? And similar question on the Phase II/III kidney trial, you said you expected it to complete the Phase IIb dose-ranging portion this year. What will we hear at that point? Will we hear anything beyond the dose that's been selected? Will you communicate what that dose is?

再問幾個問題，可能是上次問題的後續。首先，VX-522 的 SAD 試驗今年已經完成，我們今年就能看到該試驗的數據嗎？還是要等到 MAD 試驗完成後才能看到？還有，關於 II/III 期腎臟試驗也有類似的問題。您說預計 IIb 期劑量探索階段今年會完成。到那時我們會聽到什麼消息？除了已經選定的劑量之外，還會有其他消息嗎？您會公佈最終選定的劑量嗎？

Yes. Jess, with regard to the SAD/MAD VX-522NCF, we do expect that the SAD will complete this year. And it's hard to say that we're going to see an effect because it is a single-dose study, right? But we've been wrong before. When patients started on TRIKAFTA, for example, they tell us they felt differently with the first dose.

是的。傑西，關於VX-522NCF的單次/多次給藥試驗（SAD/MAD），我們預計單次給藥試驗（SAD）將於今年完成。由於這是一項單劑量研究，很難說我們會看到效果，對吧？但我們以前也犯過錯。例如，當患者開始服用TRIKAFTA時，他們告訴我們，第一次給藥後感覺就不一樣了。

So we do expect that the SAD will finish, and we fully expect to initiate the MAD as well. And I do think that we will have a good line of sight on efficacy with the MAD. So we're not guiding yet to when the data will be available, but we do expect to finish the SAD. We expect to initiate the MAD. And yes, it's possible that data will be ready this year.

因此，我們預計SAD試驗將會完成，也完全有信心啟動MAD試驗。我認為，透過MAD試驗，我們將能夠更了解其療效。目前我們尚未給出數據何時可用的具體時間，但我們預計SAD試驗將會完成，MAD試驗也將啟動。是的，數據有可能在今年內準備就緒。

On the VX-147 program, inaxaplin and the Phase II/III study, you'll remember this one is particularly exciting because it's in kidney disease, where there has been, unfortunately, very little advancement and there are, really, no products in development for APOL1-mediated kidney disease and our Phase II results showed a 47.6% reduction in proteinuria, which is unprecedented in FSGS, let alone in APOL1-mediated FSGS.

關於 VX-147 計畫、inaxaplin 和 II/III 期研究，您可能還記得這項研究特別令人興奮，因為它針對的是腎臟疾病，而遺憾的是，腎臟疾病的治療進展甚微，目前尚無針對 APOL1 介導的腎臟疾病的在研產品。我們的 II 期研究結果顯示，蛋白尿減少了 47.6%，這在 FSGS 中是前所未有的，更不用說在 APOL1 介導的 FSGS 中了。

We do expect that the Phase II part of the study will be done this year. Because it's an ongoing study, it's adaptive II/III, which means we'll roll right into the Phase III once dose selection is made, I do not expect that we will be sharing results to maintain study integrity, but we will be sharing that we've completed that portion, we've selected a dose, and we've rolled into Phase III.

我們預計研究的二期部分將於今年完成。由於這是一項正在進行的研究，屬於適應性二/三期研究，這意味著一旦確定劑量，我們將直接進入第三期研究。為了維護研究的完整性，我們預計不會公佈研究結果，但我們會宣布我們已經完成了二期研究，確定了劑量，並已進入第三期研究。

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 wanted to ask on the IND for the cells plus device program for Type 1 diabetes. Can you provide kind of any color as to what exactly the FDA wants, and maybe color as to why Canada was more comfortable with moving into humans versus the FDA?

我想諮詢一下針對第1型糖尿病的細胞療法和設備計畫的IND申請。您能否透露FDA的具體要求，以及為什麼加拿大比FDA更傾向於推進人體試驗？

Yes. Evan, this is about cells plus device VX-264 in Type 1 diabetes. This is the program using the same cells as the 880 program, but encapsulated in a device so immunosuppressants are not necessary. The most important thing to tell you is we've received the FDA questions and we've already responded. No new data needed to be generated, no new experiments needed to be run. The questions and clarifications were ready at hand.

是的，埃文，這是關於第1型糖尿病的細胞聯合VX-264裝置的研究。這個項目使用的細胞與880項目相同，但封裝在一個裝置中，因此無需使用免疫抑制劑。最重要的是，我們已經收到FDA的問詢並作出了回應。無需產生新的數據，也無需進行新的實驗。所有問題和說明都已準備就緒。

Evan, if you asked why was one regulatory agency more comfortable than another, that's just a tough question to answer, and I don't know that I have a good answer for you. What I can tell you is that it's a high-quality submission, and we are very excited to get this up and running with patients enrolled and dosed in Canada, and we're working with urgency to get the study in the U.S. as well.

艾文，如果你問為什麼有的監管機構比其他機構更放心，這確實是個很難回答的問題，我也不知道該如何回答。但我可以告訴你的是，這是一份高品質的申請文件，我們非常高興能在加拿大啟動這項研究，招募病人並開始給藥。同時，我們也在加緊努力，爭取在美國也進行這項研究。

Thanks, everyone. Chuck, will you please give the replay information?

謝謝大家。查克，你能提供一下回放資訊嗎？

Yes, ma'am. The conference has now concluded, and thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 1 (877) 344-7529 or 1 (412) 317-0088, and you can use the replay access code, which is 6823854, again, that access code at 6823845. Thank you.

是的，女士。會議已經結束，感謝您參加今天的會議。會議結束後不久，您可以撥打 1 (877) 344-7529 或 1 (412) 317-0088 收聽今天的錄音回放，回放接入碼為 6823854，再次提醒，接入碼為 6823845。謝謝。