福泰製藥 (VRTX) 2023 Q2 法說會逐字稿

Good afternoon, and welcome to the Vertex Pharmaceuticals Second Quarter 2023 Earnings Conference Call. (Operator Instructions) Please note, this event is being recorded.

下午好，歡迎參加Vertex Pharmaceuticals 2023年第二季財報電話會議。 （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 Susie Lisa, Senior Vice President, Investor Relations. Please go ahead.

現在我將會議交給投資者關係高級副總裁蘇西·麗莎女士。請您開始吧。

Good evening, everyone. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our second quarter 2023 financial results conference call. On tonight's call making prepared remarks we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating Officer; and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website.

各位晚上好。我是蘇西·麗莎，身為投資者關係資深副總裁，我很高興歡迎各位參加我們2023年第二季財務業績電話會議。今晚出席會議並作發言的有Vertex執行長兼總裁雷什瑪·凱瓦拉瑪尼博士、首席營運長斯圖爾特·阿巴克爾以及首席財務官查理·瓦格納。我們建議您在收聽本次電話會議的同時查看網路直播投影片。本次電話會議將進行錄音，錄音回放將在我們的網站上提供。

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed cystic fibrosis medicines, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受制於今天新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性。這些聲明，包括但不限於有關Vertex已上市的囊性纖維化藥物、我們的研發管線以及Vertex未來財務表現的聲明，均基於管理層目前的假設。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 foreign exchange is presented inclusive of our foreign exchange risk management program.

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公認會計準則（non-GAAP）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。

I'll now turn the call over to Reshma.

現在我將把電話交給雷什瑪。

Thanks, Susie. Good evening all, and thank you for joining us on the call today. After a strong start to the year, we saw continued momentum into the second quarter across all aspects of the company. Our CF business continues to grow, and we are reaching more patients than ever. In the second quarter, this expanded reach drove 14% global safe product revenue growth versus the prior year period. And with this first half performance, we are raising our full year 2023 CF product revenue guidance to a revised range of $9.7 billion to $9.8 billion.

謝謝蘇西。各位晚上好，感謝大家今天參加我們的電話會議。今年開局強勁，公司各方面在第二季都維持了成長動能。我們的囊性纖維化（CF）業務持續成長，涵蓋的患者數量也比以往任何時候都多。第二季度，這一成長帶動了全球安全產品收入年增14%。鑑於上半年的優異表現，我們將2023年全年CF產品收入預期上調至97億美元至98億美元。

As we continue to deliver in CF, we're also investing for future commercial excellence, ahead of multiple potential near-term launches. In exa-cel in both severe sickle cell disease and transfusion-dependent beta thalassemia, which we expect will be the first in our next wave of launches. In VX-548 for acute pain, another multibillion-dollar commercial opportunity and in our Vanzacaftor triple combination therapy for cystic fibrosis, which provides the opportunity to further extend our leadership in CF.

在囊性纖維化領域持續取得突破性進展的同時，我們也正著眼於未來的商業卓越發展，為近期多項潛在上市產品做好準備。例如，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exa-cel，預計將成為下一波上市浪潮的首款產品。此外，我們也正在積極研發用於治療急性疼痛的VX-548，這是一個價值數十億美元的商業機會；以及用於治療囊性纖維化的Vanzacaftor三聯療法，這將進一步鞏固我們在囊性纖維化領域的領先地位。

In addition to these 4 disease areas, our mid-stage clinical pipeline continues to develop rapidly and marked progress towards our 5 launches in 5 years goal. Recent achievements include: the VX-147 or Inaxaplin pivotal trial remains on track to complete the Phase IIB portion of the study by the end of this year. In our type 1 diabetes program, both VX-880, the naked cells and VX-264, the cells plus device programs are now in the clinic and dosing patients. Additionally, we announced a strategic long-term manufacturing agreement with Lonza for our type 1 diabetes cell therapy programs. And finally, an accelerated time line for the VX-548 Phase II study in peripheral neuropathic pain, where we now expect the study to complete by the end of 2023.

除了上述四個疾病領域外，我們的中期臨床研發管線也在快速發展，並朝著五年內推出五款產品的目標取得了顯著進展。近期成果包括：VX-147（或稱Inaxaplin）的關鍵性試驗進展順利，預計今年底完成IIB期研究。在我們的第一型糖尿病計畫中，裸細胞療法VX-880和細胞聯合器械療法VX-264都已進入臨床試驗階段，並開始對患者進行給藥。此外，我們宣布與Lonza公司就我們的1型糖尿病細胞療法計畫達成一項策略性長期生產協議。最後，VX-548治療週邊神經性疼痛的II期研究進度加快，預計2023年底完成。

In total, we're advancing programs in 8 disease areas through mid- and late-stage development, 6 of which are now past the proof-of-concept stage as detailed on Slide 5. Beyond our clinical pipeline, we're also advancing the next wave of research stage assets, reflecting programs sourced from both internal and external innovation. This includes programs in Duchenne's muscular dystrophy, myotonic dystrophy type 1, the NaV1.7 program for pain and gentler conditioning agents for use with exa-cel. In the CF franchise, in R&D and across the business, this quarter, Vertex has continued to make meaningful advancements to bring our CFTR portfolio to more patients around the globe and bring additional first-in-class or best-in-class potentially transformative medicines to multiple new disease areas.

我們目前在8個疾病領域推進中後期研發項目，其中6個項目已完成概念驗證階段，詳情請見幻燈片5。除了臨床研發管線外，我們還在推動下一階段的研究項目，這些項目源自於內部和外部創新。其中包括杜氏肌肉營養不良症、1型強直性肌肉營養不良症、用於緩解疼痛的NaV1.7項目以及與exa-cel聯合使用的更溫和的調理劑。在本季度，Vertex在囊性纖維化（CF）業務的研發和整個業務領域持續取得重大進展，致力於將我們的CFTR產品組合惠及全球更多患者，並為多個新的疾病領域帶來更多同類首創或同類最佳的潛在變革性藥物。

With that overview, I'll turn to the details of recent R&D progress, starting with CF. While TRIKAFTA delivers tremendous benefit for patients. If it's possible to do better, we're committed to being the ones who do so, and that is the goal for our next-in-class vanzacaftor triple combination therapy. I am pleased to share we expect to complete all 3 Phase III studies, SKYLINE 102 and 103 in patients ages 12 years and above and the RIDGELINE study in patients ages 6 to 11 by the end of 2023 and release results from these 3 studies in early '24.

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。雖然TRIKAFTA已為患者帶來顯著益處，但如果有可能做得更好，我們致力於成為做得更好的那一家，這也是我們下一代同類藥物vanzacaftor三聯療法的目標。我很高興地宣布，我們預計將於2023年底前完成全部三項III期臨床試驗，包括針對12歲及以上患者的SKYLINE 102和103研究，以及針對6至11歲患者的RIDGELINE研究，並於2024年初公佈這三項研究的結果。

We have high expectations from the vanzacaftor triple program to lead to further improvements in CFTR function based on the totality of the evidence generated to date. The most direct readout of higher CFTR function is chloride transport in vitro and sweat chloride in patients. In vitro, our human bronchial epithelial cell assays with the vanzacaftor triple showed greater restoration of chloride transport than with TRIKAFTA. And in Phase II in patients the vanzacaftor triple clinical studies showed correspondingly lower levels of sweat chloride than in previous studies with TRIKAFTA. We, therefore, believe the vanzacaftor triple has the potential to provide patients with enhanced clinical benefit, the convenience of once-daily dosing. And additionally, the Vanza Triple carries a substantially lower royalty burden.

基於目前已獲得的全部證據，我們對vanzacaftor三聯療法寄予厚望，期待其能進一步改善CFTR功能。 CFTR功能提升最直接的指標是體外氯離子轉運和患者汗液氯離子水平。體外實驗中，我們使用vanzacaftor三聯療法對人類支氣管上皮細胞進行的檢測顯示，其氯離子轉運的恢復程度優於TRIKAFTA。在患者II期臨床試驗中，vanzacaftor三合療法也顯示出患者汗液氯離子水平顯著低於既往TRIKAFTA研究。因此，我們相信vanzacaftor三聯療法有望為患者帶來更佳的臨床益處，並具有每日一次給藥的便利性。此外，vanzacaftor三重療法也顯著降低了專利使用費。

Another important program in our CF portfolio is VX-522, our CFTR mRNA therapy in development with our partners at Moderna for the more than 5,000 CF patients who cannot benefit from CFTR modulators. We have enthusiasm for this approach for 3 key reasons, based on what we've achieved to date: first, the delivery of mRNA at high efficiency into HBE cells in vitro; second, expression of CFTR protein leading to high levels of chloride transport; and third, successful nebulize delivery of mRNA in both small and large animals resulting an expression of CFTR protein in the desired cells.

我們囊性纖維化（CF）產品組合中的另一個重要項目是VX-522，這是我們與Moderna公司合作開發的CFTR mRNA療法，旨在為5000多名無法從CFTR調節劑中獲益的CF患者提供治療。我們對此療法充滿信心，主要基於我們迄今為止所取得的成果，原因有三：首先，我們已成功在體外將mRNA高效遞送至人類支氣管上皮細胞（HBE細胞）；其次，CFTR蛋白的表達能夠顯著提高氯離子轉運水平；第三，我們已成功在小型和大型動物體內通過霧化方式通過霧化方式遞送mRNA，並在遞送目標細胞中誘導CF蛋白的目標細胞中。

We continue to enroll and dose CF patients in the single ascending dose or SAD study of VX-522. And we expect to complete the SAD portion and initiate the multiple ascending dose portion of the study this year.

我們正在繼續招募囊性纖維化患者參與VX-522的單次遞增劑量（SAD）研究。我們預計今年完成SAD部分研究，並啟動多次遞增劑量研究。

Turning now to exa-cel, our CRISPR/Cas9-based gene editing program for sickle cell disease and transfusion-dependent beta-thalassemia, which targets the most severe patients and an estimated patient population of approximately 32,000. Exa-cel holds the promise to be a onetime functional cure for these diseases.

現在我們來看看 exa-cel，這是我們基於 CRISPR/Cas9 的基因編輯項目，用於治療鐮狀細胞疾病和輸血依賴型β-地中海貧血，主要針對病情最嚴重的患者，預計患者人數約為 32,000 人。 Exa-cel 有望成為這些疾病的一次性功能性治癒方案。

On the regulatory front, the FDA has accepted our filings and granted priority review in sickle cell disease with the December 8 PDUFA date. Along with a standard review in beta-thalassemia with the March 30, 2024 PDUFA date. The FDA has indicated an advisory committee will be held, and we look forward to the opportunity to discuss the high unmet need, share results from the exa-cel studies and discuss the transformative potential exa-cel holds for patients.

在監管方面，FDA已受理我們的申請，並授予我們針對鐮狀細胞疾病的優先審查資格，PDUFA截止日期為12月8日。同時，針對β-地中海貧血的標準審查資格也已授予，PDUFA截止日期為2024年3月30日。 FDA表示將召開諮詢委員會會議，我們期待有機會討論目前尚未滿足的龐大醫療需求，分享exa-cel研究的結果，並探討exa-cel對病患的變革性潛力。

Outside the U.S., in the EU and the U.K., reviews for our exa-cel filings are also well underway. Our oral presentation, the most recent EHA meeting in June, provided new data that were the basis of the EMA and MHRA regulatory filings. Both trials met the primary and key secondary endpoints with follow-up in some patients of more than 36 months.

在美國以外，歐盟和英國對我們exa-cel藥物的審批流程也進展順利。我們在6月舉行的最近一次歐洲血液學協會（EHA）會議上作了口頭報告，提供了新的數據，這些數據也成為我們向歐洲藥品管理局（EMA）和英國藥品和保健產品監管署（MHRA）提交監管文件的基礎。兩項試驗均達到了主要終點和關鍵次要終點，部分患者的追蹤時間超過36個月。

The exa-cel EHA results continue to demonstrate transformative, consistent and durable benefit for patients as measured by freedom from severe vaso-occlusive crises for 94% of SCD patients, and transfusion independence in 89% of TDT patients. The safety profile was generally consistent with busulfan conditioning and bone marrow transplantation.

exa-cel EHA 的結果持續顯示，該療法為患者帶來變革性的、持續的、持久的益處，具體表現為：94% 的鐮狀細胞病 (SCD) 患者不再發生嚴重血管阻塞危象，89% 的輸血依賴型血小板減少症 (TDT) 患者不再需要輸血。其安全性與白消安預處理及骨髓移植基本一致。

Another significant opportunity for exa-cel is in younger patients, and the pediatric trials in both sickle cell disease and beta thalassemia are underway. We have enrolled more than half the target number of patients in both pediatric studies and have dosed multiple patients. This is an important area of focus given the opportunity to intervene earlier and potentially prevent organ damage and other complications before they ever occur. As the PDUFA dates approach in the U.S. and reviews come to conclusion in the U.K. and EU, we look forward to bringing this onetime potentially curative therapy to thousands of patients with severe sickle cell disease and transfusion-dependent beta-thalassemia.

exa-cel 的另一個潛在應用領域是年輕患者，目前針對鐮狀細胞疾病和β地中海貧血的兒科臨床試驗正在進行中。兩項兒科研究均已完成目標患者人數的一半以上，並已對多名患者進行了給藥。鑑於有機會更早進行幹預，從而在器官損傷和其他併發症發生之前就加以預防，因此這是一個重要的研究方向。隨著美國 PDUFA 截止日期臨近，以及英國和歐盟的審查即將完成，我們期待將這種一次性、潛在治癒性的療法帶給成千上萬患有重症鐮狀細胞病和輸血依賴型β地中海貧血的患者。

Turning next to our pain program and VX-548, our novel, highly selective NaV1.8 inhibitor that holds the promise of effective pain relief without the side effects or addictive properties of opioids. In acute pain, I am pleased to share that all 3 Phase III studies, 2 randomized controlled trials and a single-arm safety and efficacy study will complete by the end of this year, with results available in late 2023 or early '24.

接下來談談我們的疼痛治療項目以及VX-548，這是一種新型的高選擇性NaV1.8抑制劑，有望在有效緩解疼痛的同時，避免鴉片類藥物的副作用和成癮性。在急性疼痛方面，我很高興地宣布，所有3項III期臨床試驗、2項隨機對照試驗和1項單臂安全性和有效性研究都將於今年年底前完成，結果將於2023年底或2024年初公佈。

The pace of this Phase III program has been rapid which we see as indicative of the high unmet need and strong interest in an efficacious, non-opioid acute pain therapy. We have high confidence in the outlook for these Phase III studies given: one, the genetic and pharmacologic validation of the target; two, multiple proof-of-concept trials with the predecessor molecule and with VX-548 itself; and three, the similar methodology, design and endpoints of our Phase III studies compared to the Phase II program.

此III期計畫的進展迅速，我們認為這顯示市場對高效、非鴉片類急性疼痛療法有巨大的未滿足需求和濃厚興趣。鑑於以下幾點，我們對這些III期研究的前景充滿信心：第一，標靶已得到基因和藥理學驗證；第二，已開展多項使用前體分子和VX-548本身的概念驗證試驗；第三，與II期項目相比，我們的III期研究在方法、設計和終點方面均相似。

Closing on acute pain, recall that the phase III program has been designed to support a broad model-to-severe acute pain level, which would enable prescribing and usage across mule setting including in Hospital or the ambulatory surgical center post-discharge and in the home.

最後，關於急性疼痛，需要注意的是，第三階段計劃旨在支持從嚴重急性疼痛到其他各種疼痛的廣泛模式，這將使藥物能夠在各種環境中進行處方和使用，包括出院後在醫院或門診手術中心以及在家中。

We are also studying VX-548 in diabetic peripheral neuropathy or DPN. A type of peripheral neuropathic pain that represents yet another significant area of unmet need and another multibillion-dollar market opportunity. We have previously delivered positive proof-of-concept data in peripheral neuropathic pain with the predecessor molecule VX-150. The current study in DPN with VX-548 is a 12-week Phase II dose-ranging proof-of-concept study. I am pleased to share the time line for this DPN study has accelerated and we have recently completed enrollment. This study will complete by the end of this year, and we expect to share results in late 2023 or early '24.

我們目前也正在研究VX-548在糖尿病週邊神經病變（DPN）的應用。 DPN是一種週邊神經性疼痛，代表著另一個尚未滿足的重大醫療需求領域，以及一個價值數十億美元的市場機會。先前，我們已利用前驅分子VX-150在周邊神經性疼痛領域獲得了積極的概念驗證數據。目前，VX-548在DPN領域的研究是一項為期12週的II期劑量探索性概念驗證研究。我很高興地宣布，這項DPN研究的進度已經加快，我們最近已完成病患招募。研究將於今年底完成，我們預計在2023年底或2024年初公佈研究結果。

Moving now to type 1 diabetes, where we're evaluating stem cell-derived, fully differentiated insulin-producing islet cells for people with type 1 diabetes. Our goal is to develop a functional cure for the millions of people living with type 1 diabetes, including the more than 2.5 million patients in North America and Europe alone.

接下來我們轉向第1型糖尿病，我們正在評估幹細胞衍生的、完全分化的胰島素分泌胰島細胞對第1型糖尿病患者的療效。我們的目標是為數百萬1型糖尿病患者開發出有效的治癒方法，光是北美和歐洲就有超過250萬名患者。

The VX-880 program is our foundational cell therapy program for T1D in which we have already demonstrated proof of concept. In the VX-880 trial or the naked cell program, patients take standard immunosuppressants to protect the islets from the immune system. We presented updated clinical data on Parts A and B of the study at the recent American Diabetes Association Meeting. The presentation at the ADA showed that all 6 patients treated with VX-880 engrafted islet cells, produced endogenous insulin and had improved glycemic control while reducing or eliminating exogenous insulin use.

VX-880計畫是我們針對第1型糖尿病的基礎細胞療法項目，我們已證實其概念有效。在VX-880試驗或裸細胞療法計畫中，患者服用標準免疫抑制劑以保護胰島免受免疫系統攻擊。我們在近期舉行的美國糖尿病協會年會上公佈了該研究A部分和B部分的最新臨床數據。年會報告顯示，所有6名接受VX-880治療的患者均成功植入胰島細胞，產生內源性胰島素，血糖控制改善，同時減少或停止使用外源性胰島素。

Importantly, the 2 patients with at least 1 year follow-up saw a complete elimination of severe hypoglycemic events, maintained hemoglobin A1Cs below 7% and were insulin independent. Further, patients who were earlier on their course of therapy were on a similar trajectory as the 2 patients with long-term follow-up. Based on these results, the VX-880 trial has now advanced to Part C, where patients are treated concurrently at the full target dose. And as part of our global study plan, we've now opened clinical trial sites in Europe in addition to those already open in the U.S. and Canada.

值得注意的是，至少追蹤1年的兩名患者完全消除了嚴重低血糖事件，糖化血紅蛋白A1c維持在7%以下，且無需胰島素治療。此外，早期接受治療的患者也呈現出與這兩位長期追蹤患者相似的治療軌跡。基於這些結果，VX-880試驗現已進入C部分，患者將同時接受全劑量標靶治療。作為我們全球研究計畫的一部分，除了在美國和加拿大開設的臨床試驗中心外，我們目前已在歐洲開設了新的臨床試驗中心。

Our second program, VX-264, the cells plus device program encapsulates these same cells, which have already demonstrated proof of concept in a proprietary immunoprotective device. And hence, there is no requirement for immunosuppressants. I am pleased to share that enrollment in the VX-264 study has initiated and we have already dosed the first patient.

我們的第二個項目VX-264，即細胞加裝置項目，將這些細胞封裝在一種專有的免疫保護裝置中，該裝置已證實了這些細胞的有效性。因此，無需使用免疫抑制劑。我很高興地宣布，VX-264研究已啟動患者招募，並且我們已經為首位患者進行了給藥。

The third program is our hyperimmune program in which we edit the same fully differentiated cells to cloak them from the immune system. This represents another path to obviating the need for immunosuppressants. In March, we expanded our collaboration with CRISPR Therapeutics into type 1 diabetes to use CRISPR/Cas9 to make these edits, and we continue to make progress in this research stage program.

第三個項目是我們的超免疫項目，該項目透過編輯完全分化的細胞，使其免受免疫系統的攻擊。這代表著擺脫對免疫抑制劑依賴的另一途徑。今年三月，我們擴大了與 CRISPR Therapeutics 的合作，將 CRISPR/Cas9 技術應用於第 1 型糖尿病領域，以進行基因編輯。目前，我們在這個研究階段的專案上正持續取得進展。

Transitioning now to Inaxaplin or VX-147, the first potential medicine to target the underlying cause of APOL1-mediated kidney disease or AMKD, a genetically defined disease that affects approximately 100,000 patients in the U.S. and Europe alone. Recall the Inaxaplin pivotal program for patients with AMKD is a single adaptive Phase II/III study with a pathway to accelerate approval in the U.S. The Phase IIB dose-ranging portion of the study continues to enroll and dose and remains on track to complete this year.

現在我們來談談Inaxaplin（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。 AMKD是一種基因明確的疾病，光在美國和歐洲就影響約10萬名患者。 Inaxaplin針對AMKD患者的關鍵性研究計畫是一項適應性II/III期臨床試驗，旨在加速其在美國的審批流程。該研究的IIB期劑量探索部分仍在進行中，預計今年完成。

We also continue to work to enhance AMKD disease awareness and genetic testing availability to support diagnosis, including through partnerships with Natera, a leader in genetic testing and Arkana, a leader in renal pathology services.

我們也將繼續努力提高人們對 AMKD 疾病的認識，並提高基因檢測的普及程度，以支持診斷，包括與基因檢測領域的領導者 Natera 和腎臟病理服務領域的領導者 Arkana 建立合作關係。

To close an update on our Alpha-1 antitrypsin deficiency or AATD program, our small molecule approach targets both the lung and liver manifestations of this disease that affects an estimated 100,000 people in North America and Europe. Our program is exploring 2 hypotheses: first, longer treatment duration with VX-864; and second, a more potent molecule with VX-634. The Phase II program for VX-864, a 48-week study in patients with AATD that assesses both liver clearance of Z polymer and functional plasma AAT levels is ongoing and is anticipated to complete enrollment later this year. VX-634, the next-in-class molecule with multifold greater potency and better drug-like properties is projected to complete its Phase I trial by the end of this year. Overall, the AATD program remains on track, and we look forward to sharing results in 2024.

關於我們α1-抗胰蛋白酶缺乏症（AATD）計畫的最新進展，我們的小分子療法旨在同時針對疾病的肺部和肝臟病變。據估計，北美和歐洲約有10萬人受此疾病影響。我們的計畫正在探索兩個假設：首先，延長VX-864的治療療程；其次，開發效力較強的分子VX-634。 VX-864的II期臨床試驗正在進行中，這是一項為期48週的AATD患者研究，旨在評估Z聚合物的肝臟清除率和血漿功能性AAT水平，預計今年稍後完成患者招募。 VX-634是同類藥物中的佼佼者，具有更高的效力和更優的成藥特性，預計今年底完成I期臨床試驗。整體而言，AATD計畫進展順利，我們期待在2024年分享研究成果。

With that, I'll turn it over to Stuart to provide a commercial update, including details on our launch preparations for exa-cel.

接下來，我將把麥克風交給斯圖爾特，讓他介紹一下商業方面的最新進展，包括我們為 exa-cel 進行的發射準備工作的細節。

Thanks, Reshma. From a commercial perspective, we had strong second quarter results as we continue our focus on reaching all patients eligible for our CFTR modulators and maintaining high levels of adherence for patients treated with our medicines. In addition, we continue to prepare for multiple potential near-term launches, including exa-cel in severe sickle cell disease and transfusion-dependent beta-thalassemia VX-548 in moderate to severe acute pain and the vanzacaftor triple combination in CF. At the same time, we are developing new capabilities to support the commercialization of other pipeline assets. such as disease awareness for AMKD and investing in our manufacturing capabilities for type 1 diabetes.

謝謝，Reshma。從商業角度來看，我們第二季度業績強勁，這得益於我們持續專注於讓所有符合CFTR調節劑使用條件的患者都能獲得治療，並保持接受我們藥物治療的患者的高依從性。此外，我們正持續為近期可能推出的多個產品做準備，包括用於治療重度鐮狀細胞病的exa-cel、用於治療輸血依賴型β-地中海貧血的VX-548（用於治療中重度急性疼痛）以及用於治療囊性纖維化的vanzacaftor三聯療法。同時，我們正在開發新的能力來支持其他在研產品的商業化，例如提高人們對AMKD的認識，以及投資我們用於治療第1型糖尿病的生產能力。

Given our nearest term opportunity is exa-cel in hemoglobinopathies where we have completed our regulatory filings in Europe and the U.S. and also being granted PDUFA dates in the U.S. This quarter, I will focus my comments about our pipeline on prelaunch activities for exa-cel.

鑑於我們近期最有希望推出的藥物是用於治療血紅蛋白病的 exa-cel，我們已經在歐洲和美國完成了監管申報，並且在美國也獲得了 PDUFA 日期。本季度，我將重點放在 exa-cel 的上市前活動，並就我們的產品線發表看法。

But briefly first on CF. At the beginning of this year, there were more than 20,000 people with CF in North America, Europe and Australia, who could benefit, but were not yet being treated with a CFTR modulator. We continue to bring our medicines to these patients through new approvals and uptake following additional reimbursements with a focus on reaching younger patients, and this will continue to be a driver of near-term growth for our business.

但首先簡單談談囊性纖維化（CF）。今年年初，北美、歐洲和澳洲有超過2萬名CF患者，他們可能受益於CFTR調節劑，但尚未接受治療。我們正透過新的審批和額外的報銷，持續為這些患者提供藥物，尤其關注年輕患者群體，這將繼續成為我們近期業務成長的驅動力。

Second quarter 2023 CF revenue growth of 14% was consistent with this outlook and was driven primarily by expanded use of our medicines in younger age groups. Following U.S. TRIKAFTA approval in children ages 2 to 5 in late April, we've seen strong interest from the CF community with the first prescription written just hours after the approval and uptake across all eligible patients.

2023年第二季囊性纖維化（CF）業務收入成長14%，與預期相符，主要得益於我們藥物在低齡人口中的使用量增加。繼4月下旬美國批准TRIKAFTA用於2至5歲兒童後，我們看到了CF群體對該藥物的濃厚興趣，首張處方在獲批後數小時內即已開出，且所有符合條件的患者均已開始使用該藥物。

Outside the U.S., KAFTRIO growth has continued to be strong in patient ages 16 and older, following approval, reimbursement and successful launches in multiple geographies. In addition, we received EU approval for ORKAMBI in children ages 1 to 2 in early July, and we continue to expect approval for KAFTRIO in the EU in children ages 2 to 5 by the end of this year. We are also actively enrolling our KAFTRIO study in children ages 1 to 2.

在美國以外，KAFTRIO 在 16 歲及以上患者群體中持續保持強勁增長勢頭，這得益於其在多個地區獲得批准、納入醫保報銷並成功上市。此外，我們在 7 月初獲得了歐盟對 ORKAMBI 用於 1 至 2 歲兒童的批准，並預計 KAFTRIO 將於今年年底前獲得歐盟對 2 至 5 歲兒童的批准。目前，我們正在積極進行 KAFTRIO 針對 1 至 2 歲兒童的研究。

Overall, we see continued growth for our portfolio of CFTR modulators, driven by approvals, reimbursement and uptake of our medicines in younger patients. In addition, approvals of future CF medicines will also drive growth. Notably, our next-generation vanzacaftor triple seeks to provide improved efficacy for patients and a new treatment option for those who have discontinued prior CFTR modulator therapy. And longer term, VX-522, our mRNA approach could offer a therapy for the more than 5,000 patients who cannot benefit from CFTR modulators.

總體而言，我們預期CFTR調節劑產品組合將持續成長，這主要得益於藥物的核准、健保報銷以及年輕患者的用藥率提升。此外，未來CF藥物的核准也將推動成長。值得一提的是，我們的下一代vanzacaftor三合一療法旨在提高患者的療效，並為那些已停止CFTR調節劑治療的患者提供新的治療選擇。從長遠來看，我們的mRNA療法VX-522有望為超過5,000名無法從CFTR調節劑中獲益的患者提供新的治療方案。

Shifting now to exa-cel, which holds curative potential for patients with severe sickle cell disease and transfusion-dependent beta thalassemia both chronic diseases that can be disabling and life-shortening and have an extremely high burden of care. On previous quarterly earnings calls, I provided details for exa-cel on the estimated eligible patient population, the geographic concentration of those patients and our proposed ATC network of 50 centers in the U.S. and 25 in Europe. The hiring and training of our field and medical education teams and insights from physician and patient market research.

現在讓我們來談談exa-cel，它有望治癒重度鐮狀細胞疾病和輸血依賴型β地中海貧血患者。這兩種慢性疾病都可能導致殘疾、縮短壽命，並給患者帶來極其沉重的照護負擔。在先前的季度財報電話會議上，我詳細介紹了exa-cel的預期適用病患群體、這些病患的地理分佈情況，以及我們計劃在美國建立的50個ATC中心和在歐洲建立的25個ATC中心組成的網路。此外，我還介紹了我們的現場團隊和醫學教育團隊的招募和培訓情況，以及來自醫生和患者市場調查的見解。

This quarter, I'd like to provide our perspective on access and reimbursement and our discussions globally with payers and policymakers. Our teams continue to make excellent progress in pre-approval discussions with both government and commercial payers in the U.S. and Europe. With more than a dozen cell and gene therapies on the market, payers across different channels are increasingly experienced with these transformative types of therapies.

本季度，我想就准入和報銷問題，以及我們與全球支付方和政策制定者的討論，分享我們的觀點。我們的團隊在與美國和歐洲的政府及商業支付方進行審批前磋商方面，持續取得顯著進展。目前，市面上已有十餘種細胞和基因療法，不同管道的支付方對這些變革性療法的了解也日益豐富。

In the U.S., approximately 65% of patients with sickle cell disease or beta thalassemia, have coverage through government programs with the majority via Medicaid, and the remaining 35% of patients are covered by private insurance. Our teams have already engaged Medicaid administrators in all 50 states with a particular focus on the 24 states with the highest prevalence of sickle cell disease, accounting for an estimated 90% of Medicaid patients with SCD. We're encouraged by the enthusiasm from state Medicaid administrators for exa-cel as well as the proactive steps they are taking to prepare for the availability of therapies like exa-cel including the enablement of separate payment policies for coverage of the cost of the therapy, distinct from the cost of the bone marrow transplant procedure.

在美國，約65%的鐮狀細胞疾病或β地中海貧血患者透過政府計畫獲得醫療保障，其中大部分透過醫療補助計畫（Medicaid）獲得保障，其餘35%的患者則由私人保險承保。我們的團隊已與全美50個州的醫療補助計畫管理人員接洽，尤其關注鐮狀細胞病患病率最高的24個州，這些州的鐮狀細胞疾病患者約佔醫療補助計畫患者總數的90%。我們對各州醫療補助計劃管理人員對exa-cel的熱情以及他們為迎接exa-cel等療法的上市而採取的積極措施感到鼓舞，這些措施包括制定單獨的支付政策，用於支付治療費用，使其與骨髓移植手術費用分開。

The Medicaid-focused CMS cell and gene therapy access model also continues to make progress towards its anticipated launch in 2026. The model is clear evidence of the federal government's recognition of the potential transformative value of gene therapies like exa-cel to treat sickle cell disease and their interest in finding innovative payment solutions and pathways for state Medicaid programs.

以 Medicaid 為重點的 CMS 細胞和基因療法准入模式也繼續朝著 2026 年的預期啟動取得進展。該模式清楚地表明，聯邦政府認識到像 exa-cel 這樣的基因療法在治療鐮狀細胞疾病方面的潛在變革價值，以及他們有興趣為各州 Medicaid 計畫尋找創新的支付解決方案和途徑。

Shifting to commercial payers. We have had high levels of engagement with commercial payers, including the top 4 payers that account for approximately 80% of commercial lives. And our goal is to facilitate timely coverage decisions upon a potential exa-cel approval. Our pre-approval discussions have been encouraging and are focused on disease burden, epidemiology estimates, our clinical data and potential payment models.

轉向商業保險支付方。我們與商業保險支付方保持密切的溝通，其中包括佔商業保險業務約80%的前四大支付方。我們的目標是在Exa-Cel獲得潛在批准後，促進其及時做出核保決定。我們先前的審批前討論進展順利，主要圍繞著疾病負擔、流行病學估算、我們的臨床數據以及潛在的支付模式。

In Europe, the MAA reviews are well underway and thus, we are also working on paving the way to secure reimbursed access for patients in our targeted European markets. We have been engaging with health systems to educate them on the significant disease burden on patients, health care systems and society. In addition, we have been meeting with European health authorities to understand their interest in different payment models and to communicate the holistic value of a onetime potential functional cure.

在歐洲，上市許可申請（MAA）的審查工作正在順利進行，因此，我們也努力為目標歐洲市場的病人爭取醫保報銷。我們一直與醫療系統進行溝通，讓他們了解疾病對患者、醫療系統和社會帶來的巨大負擔。此外，我們也與歐洲衛生當局會面，了解他們對不同支付模式的興趣，並闡述一次性潛在功能性治癒的整體價值。

Given the urgent unmet need for new treatments for sickle cell disease and beta thalassemia, there is significant interest from patients and physicians, particularly in geographies with high concentrations of the eligible patient population.

鑑於鐮狀細胞疾病和β地中海貧血症迫切需要新的治療方法，患者和醫生對此表現出濃厚的興趣，尤其是在符合條件的患者群體高度集中的地區。

To conclude, it's a remarkable time to be at Vertex. We continue to make progress treating more CF patients while our excitement for the transformative promise of exa-cel for patients and the resulting multibillion-dollar market opportunity continues to grow as we approach potential approval. We are also preparing for multiple additional near-term launches, including the vanzacaftor triple in CF and VX-548 in acute pain, both of which have the potential to dramatically improve patients' lives.

總之，現在是加入Vertex的絕佳時機。我們不斷取得進展，致力於為更多囊性纖維化（CF）患者提供治療；隨著我們接近獲得潛在批准，我們對exa-cel的變革性療效以及由此帶來的數十億美元市場機會的信心與日俱增。此外，我們也正在積極籌備近期推出的多個新產品，包括用於治療CF的vanzacaftor三聯療法和用於治療急性疼痛的VX-548，這兩款產品都有望顯著改善患者的生活品質。

I'll now turn the call over to Charlie to review the financials.

現在我將把電話交給查理，讓他審核財務數據。

Thanks, Stuart. Vertex's excellent results in the second quarter of 2023 demonstrate once again our consistent strong performance and attractive growth profile. Second quarter 2023 revenue increased 14% year-over-year to $2.49 billion. Growth was led by a 26% year-over-year increase outside the U.S. on continued strong uptake of TRIKAFTA-KAFTRIO in markets with recently achieved reimbursement as well as label extensions in younger age groups. Similarly, expansion in younger age groups helped drive 7% U.S. revenue growth following the recent FDA approval of TRIKAFTA in patients ages 2 to 5. Second quarter and first half revenues also benefited from increases in channel inventory in certain international markets, which are expected to draw down in the second half.

謝謝，Stuart。 Vertex 2023年第二季的出色業績再次證明了我們持續強勁的業績表現和極具吸引力的成長前景。 2023年第二季營收年增14%，達24.9億美元。成長主要得益於美國以外地區26%的同比增長，這主要歸功於TRIKAFTA-KAFTRIO在近期獲得醫保報銷的市場以及針對更年輕年齡組的適應症擴展，其銷量持續強勁增長。同樣，在2至5歲患者中，TRIKAFTA近期獲得FDA批准，推動了美國地區營收成長7%，也帶動了較年輕年齡層市場的成長。此外，部分國際市場通路庫存的增加也促進了第二季和上半年營收的成長，預計下半年庫存將下降。

Second quarter 2023 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $1.04 billion compared to $750 million in the second quarter of 2022. Q2 2023 results include $110 million of acquired IP R&D charges compared to $62 million of such charges in the second quarter of 2022. Second quarter 2023, IP R&D expense reflects a $70 million milestone to CRISPR Therapeutics for progress made in our hypoimmune program for type 1 diabetes.

2023年第二季非GAAP研發、收購智慧財產權研發及銷售、管理及行政費用合計為10.4億美元，而2022年第二季為7.5億美元。 2023年第二季業績包含1.1億美元的收購智慧財產權研發費用，而2022年第二季該項費用為6,200萬美元。 2023年第二季的智慧財產權研發費用反映了公司向CRISPR Therapeutics支付的7,000萬美元里程碑付款，用於表彰我們在第1型糖尿病低免疫療法計畫方面取得的進展。

Aside from our investments in external innovation and the resulting higher acquired IP R&D charges, operating expense growth was driven as expected by continued investment in research and our advancing pipeline, which includes mid- and late-stage clinical assets across 8 different disease areas. The most significant areas of increased investment versus prior year included the clinical studies for the vanzacaftor Triple-NCF for VX-548 in acute pain and for type 1 diabetes. In addition, we continued our pre-commercial activities for exa-cel and other anticipated near-term launches, given the potentially transformative benefits to patients and multibillion-dollar market opportunities for our mid- and late-stage programs, we will continue to invest appropriately.

除了對外部創新進行的投資以及由此產生的更高的收購知識產權研發費用外，營運費用增長正如預期，主要得益於對研發的持續投入以及我們不斷推進的研發管線，其中包括涵蓋8個不同疾病領域的中後期臨床資產。與前一年相比，投資增幅最大的領域包括vanzacaftor Triple-NCF（VX-548）在急性疼痛和第一型糖尿病的臨床研究。此外，鑑於exa-cel和其他預期近期上市產品的潛在變革性療效以及我們中後期項目數十億美元的市場機遇，我們將繼續進行適當的投資。

Second quarter 2023 non-GAAP operating income was $1.15 billion compared to $1.19 billion in the second quarter of 2022. Second quarter non-GAAP earnings per share were $3.89, representing 8% growth compared to $3.60 in the second quarter of 2022. We ended the quarter with $12.6 billion in cash and investments.

2023年第二季非GAAP營業收入為11.5億美元，而2022年第二季為11.9億美元。第二季非GAAP每股盈餘為3.89美元，較2022年第二季的3.60美元成長8%。本季末，公司持有現金及投資126億美元。

Now switching to guidance. Given our strong first half results and our consistent execution, including the successful launch of TRIKAFTA in patients ages 2 to 5 in the U.S., we are increasing our 2023 revenue guidance as detailed on Slide #16, for the full year 2023, we now expect CF net product revenue of $9.7 billion to $9.8 billion, an increase of $100 million to $150 million compared to our prior range of $9.55 billion to $9.7 billion. Note that this revenue guidance includes an expected approximate 150 percentage point headwind to our revenue growth rate, consistent with our prior expectations.

現在轉入業績指引。鑑於我們上半年強勁的業績和持續穩定的執行力，包括在美國成功推出針對2至5歲患者的TRIKAFTA，我們上調了2023年全年營收指引（詳見幻燈片16）。目前，我們預計2023年全年囊性纖維化（CF）產品淨收入為97億美元至98億美元，較先前95.5億美元至97億美元的預期增加1億美元至1.5億美元。請注意，此營收指引已包含約150個百分點的預期成長阻力，與我們先前的預期一致。

In addition, given our December 8 U.S. PDUFA date for exa-cel and sickle cell disease, 2023 product revenue guidance continues to reflect revenue from cystic fibrosis products only. We are also raising our 2023 guidance for combined non-GAAP R&D, acquired IP R&D and SG&A expenses to a range of $4.1 billion to $4.2 billion, an increase of $200 million from prior guidance. This increase reflects higher IP R&D expenses from new business development, including collaborations with Entrada in DM1 and with CRISPR in type 1 diabetes. Our 2023 non-GAAP operating expense guidance now includes approximately $500 million of upfronts and milestones compared to the $300 million projected at the start of the year.

此外，鑑於我們針對exa-cel和鐮狀細胞疾病的美國處方藥用戶付費法案（PDUFA）審批日期為12月8日，2023年產品收入預期仍僅反映囊性纖維化產品的收入。同時，我們將2023年非GAAP研發、收購智慧財產權研發及銷售、管理及行政費用（SG&A）的綜合預期上調至41億美元至42億美元，較先前預期增加2億美元。此次上調反映了新業務開發帶來的知識產權研發支出增加，包括與Entrada在第1型糖尿病（DM1）領域的合作以及與CRISPR在第1型糖尿病領域的合作。我們2023年非GAAP營運費用預期目前包含約5億美元的預付款和里程碑付款，而年初的預期為3億美元。

We continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid- and late-stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near-term launch potential while continuing to leverage an attractive business model afforded by our focus in specialty markets. Our guidance for projected full year 2023 non-GAAP effective tax rate of 21% to 22% is unchanged.

鑑於我們多個處於中後期臨床開發階段的專案進展順利，我們將繼續把大部分營運支出投入研發。同時，我們也加大對商業化能力的投入，以期抓住近期有望上市的項目所帶來的數十億美元商機。此外，我們將繼續利用專注於專業市場所帶來的極具吸引力的商業模式。我們對2023財年非GAAP實際稅率的預期維持在21%至22%不變。

In closing, Vertex delivered excellent results for the second quarter of 2023. We delivered strong revenue growth, completed important regulatory milestones, updated on significant clinical trial programs and invested internally and externally. As we continue to advance our programs in 2023, we anticipate further important milestones as highlighted on Slide 17 to mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

最後，Vertex 公佈了 2023 年第二季的出色業績。我們實現了強勁的營收成長，完成了重要的監管里程碑，更新了重要的臨床試驗計畫進展，並進行了內部和外部投資。隨著我們在 2023 年繼續推進各項計劃，我們預計將取得更多重要的里程碑，如投影片 17 所述，這將標誌著我們在多個疾病領域持續取得進展。我們期待在未來的電話會議上向您報告最新進展，現在請 Susie 開始問答環節。

Thanks, Charlie. Gary, can you please view the first question?

謝謝，查理。加里，你能看一下第一個問題嗎？

(Operator Instructions) Our first question is from Phil Nadeau with Cowen and Company.

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

Just a couple on exa-cel. In the prepared remarks you mentioned or at least in the press release, you mentioned that an advisory committee is likely, does Vertex have any sense of what is likely to be discussed or debated at the advisory committee?

關於Exa-Cel，我有幾個問題。在您提到的準備好的發言稿中，或至少在新聞稿中，您提到可能會成立一個諮詢委員會，Vertex是否了解諮詢委員會可能會討論或辯論哪些內容？

And then second, for Stuart, thanks for all your comments on the commercial prep. We have seen gene and cell therapy launches get off to a relatively slow starts of late with some not actually having patients dosed for 7 or so months after approval. What does Vertex learn from that? What could you do to increase the speed at which patients are adopting exa-cel post approval?

其次，Stuart，感謝您對商業化準備工作的所有評論。我們看到，近來基因和細胞療法的上市進展相對緩慢，有些療法甚至在核准後長達7個月左右仍未開始給患者用藥。 Vertex公司從中吸取了哪些經驗教訓？在Exa-Cel核准後，您可以採取哪些措施來加快患者接受治療的速度？

Phil, this is Reshma. Let me take the first part of your question, and then I'll ask Stuart to comment on the commercial launch readiness. With regard to exa-cel, the FDA has informed us that there will be an advisory committee. This is not unexpected as we've discussed in the past, given the new mechanism of action.

菲爾，我是雷什瑪。我先回答你問題的第一部分，然後我會請史都華談談商業上市的準備。關於艾斯西酞普蘭（Exa-Cel），FDA已經通知我們將會成立一個諮詢委員會。考慮到它新的作用機制，這並不出乎我們的意料，我們之前也討論過。

We don't have further details. Those will be forthcoming. And I expect we'll know more as we approach the date of the AdCom, which we don't have today either. However, conventionally, the advisory committees usually take place about 1 to 2 months before the PDUFA date. So that's the general framework that we're looking at. We are very excited to have the opportunity to share our data, to talk about the benefit risk and to talk about the transformative potential and to have the patient's voices heard at the advisory committee.

我們目前沒有更多細節，這些資訊稍後會公佈。我預計隨著諮詢委員會會議日期的臨近（目前我們還沒有確定會議日期），我們會了解更多資訊。不過，依照慣例，諮詢委員會會議通常在處方藥使用者付費法案（PDUFA）生效日期前1到2個月舉行。這就是我們目前所關注的大致框架。我們非常高興有機會分享我們的數據，探討獲益風險和變革潛力，並讓患者的聲音在諮詢委員會中得到傾聽。

Let me turn it over to Stuart to comment on launch readiness.

讓我把麥克風交給斯圖爾特，讓他談談發布準備情況。

Yes, Phil, so thanks for the question. Obviously, the first most important step to provide the conditions for a successful launch are going to be to secure access and reimbursement because as you know, without access and reimbursement, there really is no opportunity for patients to get treated. And that's why I focus my comments on that, and we are doing everything we can with payers, both in the U.S. and internationally try and get access and reimbursement as close to regulatory approval as we possibly can. Obviously, that's not entirely within our control, but that's what we're working on.

是的，菲爾，謝謝你的提問。顯然，成功上市的首要條件是確保醫療服務和報銷，因為如你所知，如果沒有醫療服務和報銷，病人就根本沒有機會接受治療。所以我的發言重點就在於此，我們正在盡一切努力與美國和國際上的支付方合作，爭取盡快獲得監管部門的批准。當然，這並非完全由我們掌控，但這正是我們努力的方向。

In terms of the kind of uptake curve in the future, now, obviously, that's going to depend on the interest from physicians and patients. We know that, that is very high. But I would remind you that, as I've said on previous calls, we do expect the uptake with exa-cel to be slower, obviously, than we see with our CF medicines where the launches are almost vertical.

至於未來的市場接受度曲線，顯然，這取決於醫生和病人的興趣。我們知道，他們的興趣非常高。但我還是要提醒大家，正如我在之前的電話會議中提到的，我們預期Exa-Cel的市場接受度成長速度會比我們其他囊性纖維化藥物慢，後者的上市成長幾乎是垂直的。

And that's largely because, as you know, this is a multi-month process that a patient has to go through to get treated with exa-cel. Obviously, they have to decide with their physician that they want to go through a gene therapy. They have to have their cells collected. The cells then have to be edited, returned to the site and then the patient has to schedule coming in for essentially the equivalent of a bone marrow transplant before they're actually dosed with the exa-cel drug product.

這主要是因為，如您所知，患者接受Exa-Cel治療是一個長達數月的過程。顯然，他們必須先與醫生商定是否接受基因治療。然後，他們需要採集自身細胞。這些細胞需要進行基因編輯，再送回治療中心。之後，患者需要安排時間進行類似骨髓移植的治療，才能最終接受Exa-Cel藥物治療。

So it is a multi-month process from start to finish for any individual patient. And so that's why we've always said this launch, we do expect to be slightly slower in uptake rate than in cystic fibrosis, but we continue to believe there's a lot of interest. It's a big market opportunity and we see exa-cel as a multibillion-dollar opportunity in the future.

因此，對於任何一位患者來說，從開始到結束都需要數月的時間。正因如此，我們一直強調，此次上市的Exa-Cel的接受速度預計會比囊性纖維化領域略慢，但我們仍然相信市場對此非常感興趣。這是一個巨大的市場機遇，我們認為Exa-Cel未來將擁有數十億美元的市場價值。

Great. One follow-up, if I may. On the reimbursement, we've seen warranty agreements put in place by one recent gene therapy launch. Is that something you're considering or you think would be helpful?

好的。如果可以的話，我還有一個後續問題。關於報銷方面，我們看到最近一家基因療法公司推出了保固協議。您是否也在考慮這樣做，或者您認為這會有幫助嗎？

Sorry, Phil, I didn't quite catch the question. Can you say it again?

抱歉，菲爾，我沒聽清楚你的問題。你能再說一次嗎？

Yes. In terms of reimbursement in the structure of reimbursement agreements, one recent gene therapy launch included a warranty as part of the reimbursement agreement. Is that something Vertex is considering or would think would be helpful for a launch like exa-cel?

是的。就報銷協議的結構而言，最近一項基因療法上市就將質保作為報銷協議的一部分。 Vertex公司是否正在考慮這樣做，或者認為這對像exa-cel這樣的新療法上市會有幫助？

Yes. We are considering a range of different options, Phil. The reason for that is kind of if you ask 1 payer, what they're looking for, you get 1 answer. If you ask another pay, you get another answer. So I think much as we've done with cystic fibrosis, we're going to look to be flexible. There are some who are going to be interested in just a straight price and just paying upfront for the benefits of onetime functional cures. Others are looking at more things like outcomes-based agreements on that. And so right now, we're in kind of listening mode and defining and designing what the nature of our payment models will be. But I think the key word is probably flexibility.

是的，菲爾，我們正在考慮一系列不同的方案。原因在於，如果你問一家支付方他們想要什麼，你會得到一個答案；如果你問另一家支付方，你會得到另一個答案。所以，我認為就像我們之前在囊性纖維化治療方面所做的那樣，我們會力求靈活。有些人可能更傾向於一次性支付固定價格，為一次性功能性治癒的益處預先付費。而有些人則更關注基於療效的協議。因此，目前我們正在傾聽各方意見，並定義和設計我們的支付模式。但我認為，關鍵在於「靈活」。

The next question is from Liisa Bayko with Evercore ISI.

下一個問題來自 Evercore ISI 的 Liisa Bayko。

Congratulations on the good quarter. Just wondering if you could give us a view on sort of the next data readout for your type 1 diabetes program, both the cells and the cells plus pouch?

恭喜你們本季業績出色。請問您能否透露一下關於你們1型糖尿病計畫（包括細胞療法和細胞療法聯合儲袋療法）的下一份數據報告？

Sure thing. Liisa, with regard to the T1D program, on the VX-880 side, that's, let's call it the naked cells program. You should expect to have a data readout at the fall diabetes conference where there will be an oral presentation. On the 264 program, that's the cells plus device program, we've just initiated enrollment. We've just dosed, as you heard in my prepared remarks, the first patient. And you should expect to hear from us with regard to results from that cells plus device program, which does not require immunosuppressants, either when we reached a milestone in terms of data readout or we have a decision to communicate. We won't be sharing results patient by patient.

當然可以。莉薩，關於第一型糖尿病項目，VX-880這邊，我們暫且稱之為「裸細胞計畫」。您應該會在秋季糖尿病大會上看到相關數據，屆時我們會進行口頭報告。至於264項目，也就是細胞聯合裝置項目，我們剛剛啟動了病患招募。正如您在我之前的演講稿中聽到的，我們已經給第一位患者用藥。關於這個無需使用免疫抑制劑的細胞聯合裝置專案的結果，我們將在達到數據解讀的里程碑或做出決定後與您聯繫。我們不會逐一分享結果。

Okay. Fair enough. And then as you think about your kind of commercial path for pain, are you going to be focusing on certain types of centers? I mean this could be obviously a very broad market and opportunity. How are you thinking about the rollout and where? I'm curious on that kind of -- the market estimates could be -- have a very wide range depending on how you think about it.

好的，沒問題。那麼，當您考慮疼痛治療的商業模式時，您會專注於哪些類型的醫療中心？我的意思是，這顯然是一個非常廣泛的市場和機會。您是如何規劃推廣的？推廣地點在哪裡？我很好奇這方面——市場預測可能會有很大的波動，這取決於您如何看待這個問題。

Sure. Liisa, you're right. We see this as an enormous opportunity. Let me ask Stuart to tell you how we plan to approach that opportunity. Stuart?

當然。莉莎，你說得對。我們認為這是一個絕佳的機會。我請史都華來告訴你我們打算如何把握這個機會。史都華？

Yes. So acute pain, obviously, which is going to be our first launch indication subject to the studies being positive is -- 2 things can be true at the same time, Liisa. I'd say one is acute pain therapies are prescribed by a wide range of prescribers. That is indeed true, but it's equally true that a large percentage of the prescriptions are concentrated in institutions, ambulatory surgical centers, settings like that, where patients are either prescribed and dispensed their acute pain medicine whilst they're in the institution or the facility.

是的。所以，很明顯，急性疼痛將是我們首個上市適應症，前提是相關研究結果積極——莉薩，兩件事可以同時成立。我認為，第一點是，很多醫生都會開立急性疼痛治療​​藥物。這的確如此，但同樣不可否認的是，其中很大一部分處方集中在醫療機構、門診手術中心等場所，患者在院內或就診期間即可獲得急性疼痛藥物的處方和配藥。

And then they're also prescribed and given a prescription on discharge for their ongoing pain management when they leave the facility. That accounts for a large percentage of the prescriptions in acute pain. Those prescriptions are concentrated in somewhere around just shy of 200 sites covered by about 220 or so IDNs. And that is going to be the primary focus of our commercialization activities. We think we can cover that universe of centers with a sales force approximately in the 150 range, which fits very nicely with our focus on specialty markets.

此外，患者出院時還會獲得持續疼痛管理的處方。這佔急性疼痛處方總量的很大一部分。這些處方集中在約200個醫療機構，這些機構由大約220個綜合醫療網絡（IDN）覆蓋。這將是我們商業化活動的主要重點。我們認為，大約150人的銷售團隊就能涵蓋這些醫療中心，這與我們專注於專科市場的策略非常契合。

(Operator Instructions)

（操作說明）

The next question is from Salveen Richter with Goldman Sachs.

下一個問題來自高盛的薩爾文·里希特。

Just a follow-up on the acute pain program. Just can you help us understand, apart from -- upon a positive data outcome here, and given the target prescribers you mentioned, what needs to be done logistically to ensure a successful launch with regard to just the marketing aspect, the -- whether there's kind of any understanding that needs to be played out with regard to contracts and how the no pain law kind of falls into this? Just any idea of how you can ensure this plays out well.

關於急性疼痛治療​​項目，我想跟進一下。除了假設數據結果積極之外，考慮到您提到的目標處方醫生，在行銷方面，還需要做哪些後勤工作來確保專案成功啟動？在合約方面是否需要達成共識？以及「無痛法」如何融入其中？您能否就如何確保專案順利進行提出一些建議？

Sure. Salveen, I'll ask Stuart to comment.

當然。薩爾文，我會請史都華發表意見。

Yes, Salveen, thanks for the question. I think there's a couple of other things that are likely to be supportive of VX-548 in acute pain. One is, I think we are likely to see a number of the existing pain treatment guidelines, consider updates their guidelines once there is the availability of a safe and effective non-opioid medicine.

是的，Salveen，謝謝你的提問。我認為還有幾點可能對VX-548在急性疼痛治療​​的應用有所幫助。首先，我認為一旦安全有效的非鴉片類藥物問世，我們可能會看到一些現有的疼痛治療指南考慮更新。

In addition, and you mentioned one of them, I think we are increasingly going to see policies change their focus. The policies that have been put in place in states and hospitals over the last few years for understandable reasons have largely all have been about restricting prescriptions, restricting who can prescribe for which patient types for what length of time.

此外，正如您所提到的其中一點，我認為我們將越來越看到政策的重點發生轉變。過去幾年，各州和醫院出於可以理解的原因而實施的政策，大多都集中在限制處方上，限制哪些醫生可以為哪些類型的患者開處方，以及處方的持續時間。

I think we are beginning to see the focus of those policy initiatives changed to being supportive of non-opioid pain medicines like VX-548. And I think that that's a very welcome systemic change, which will potentially support the uptake of the VX-548 subsequent to it getting approved. So in addition to our own commercialization efforts, I think there's a number of supportive at the launch.

我認為我們開始看到這些政策舉措的重點轉向支持像VX-548這樣的非鴉片類止痛藥。我認為這是一個非常值得歡迎的系統性轉變，預計在VX-548獲批後促進其市場推廣。因此，除了我們自身的商業化努力之外，我認為在上市初期也會有許多支持。

Question is from Geoff Meacham with Bank of America.

問題來自美國銀行的傑夫·米查姆。

Just had a follow-up on exa-cel. I know you guys are focused today on regulatory and commercial as well. But when you think about the improved conditioning regimen, I wanted to know kind of what we should expect from that optimization of that? What are kind of the -- what does success look like, I guess, for that? And what are the time lines, I think, that we'll see some data for?

剛剛跟進了一下關於Exa-Cel的問題。我知道你們現在主要關注的是監管和商業方面的問題。但是，關於改進後的體能訓練方案，我想了解一下，我們對這個優化方案的期望是什麼？成功的標準是什麼？我們大概什麼時候可以看到一些數據？

Sure. Geoff, as we think about the busulfan based conditioning regimen, which is what exa-cel will launch with, we see that as having a positive benefit risk profile for the approximately 32,000 people with the most severe forms of sickle cell disease and beta thalassemia. And with the improved or gentler conditioning, we see the opportunity to serve the full 150,000 people with sickle cell disease and beta thalassemia in Europe and the U.S.

當然。傑夫，當我們考慮以白消安為基礎的預處理方案時（這也是Exa-Cel即將推出的方案），我們認為該方案對大約32,000名患有最嚴重鐮狀細胞病和β地中海貧血症的患者來說，具有積極的獲益風險比。而且，透過改進或更溫和的預處理方案，我們看到了為歐洲和美國全部150,000名鐮狀細胞疾病和β地中海貧血患者提供服務的機會。

What this program looks like, and we have an active set of programs internally, our partners at CRISPR are working on this problem, other academia and biotechs are working on this problem. And so I do see this as a problem that will be solved. It's not a tomorrow solution, but I see this happening in the coming months and years.

這個計畫目前已經啟動，我們內部也有一系列積極的項目，我們的CRISPR合作夥伴正在研究這個問題，其他學術機構和生物技術公司也在研究這個問題。所以我認為這個問題終將得到解決。雖然這並非一朝一夕就能解決，但我相信在未來幾個月或幾年內，這個問題將會得到解決。

What we see is the opportunity to have a conditioning regimen that very specifically targets the compartment and the cells that are limited to those hematopoietic stem cells sparing all of the other cells. And in so doing, not have the side effects of busulfan, including the very significant cytopenias that you see with busulfan. So I do think that this is an area that we will see a solution for because we and others are working on it and because of the broad application, and I do think you'll see progress in the coming months and in our years. I don't mean decades.

我們看到的是一個機會，可以開發一種預處理方案，它能夠非常精準地靶向造血幹細胞，同時保護其他所有細胞。這樣一來，就能避免白消安的副作用，包括白消安引起的非常嚴重的血球減少症。所以我認為，在這個領域我們終將找到解決方案，因為我們和其他研究者都在為此努力，而且鑑於其廣泛的應用前景，我相信在未來幾個月甚至幾年內，我們會看到進展。我指的不是幾十年。

Our next question is from Robyn Karnauskas with Truist Securities.

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

Sorry for the noise. I'm on board a plane and we're departing. So the question is, what is the bar for neurotrophic mean? I know your previous study with your previous drug kind of looks similar to Lyrica. Maybe you could step that for us in a second. We've done some due diligence in the chemo-related peripheral neuropathy is a huge unmet need. I wanted to know whether you thought it might work in this population as well.

抱歉打擾了，我正在飛機上，馬上就要起飛了。所以問題是，神經營養作用的閾值是多少？我知道您之前用另一種藥物做的研究看起來和普瑞巴林（Lyrica）有點像。您能不能馬上給我們詳細說明一下？我們已經做了一些盡職調查，發現化療相關的周邊神經病變是亟待解決的龐大醫療需求。我想知道您是否認為這種藥物對這類人群也有效。

Yes. So Robyn, the bar for neuropathic pain is to have a better overall profile benefit risk taken together than existing therapies. As you know, the existing therapy has limitations in terms of efficacy, but there are also limitations on the safety/AE side. And the reason for that is what we use for neuropathic pain is frankly, a recycled medicine that comes from fundamentally central nervous system depression that we are reusing for neuropathic pain because that's the best we have.

是的。所以羅賓，治療神經性疼痛的標準是，綜合考慮獲益和風險，新療法必須比現有療法具有更好的整體效果。如你所知，現有療法在療效方面有其局限性，在安全性和不良反應方面也有其限制。原因在於，我們目前用於治療神經性疼痛的藥物，坦白說，是一種回收的藥物，其主要作用機制是抑制中樞神經系統，我們之所以將其用於治療神經性疼痛，是因為這是我們目前所能獲得的最佳方案。

So what we're going to be looking for is improvement in diabetic peripheral neuropathic pain scores, change from baseline and our Phase II dose-ranging proof-of-concept study also has a Lyrica arm for context. So we'll be able to see the magnitude of the treatment effect as well as a Lyrica arm for context.

因此，我們將關注的是糖尿病週邊神經性疼痛評分的改善情況，以及與基線相比的變化。我們的 II 期劑量範圍概念驗證研究也設有 Lyrica 組作為對照。這樣，我們就能觀察到治療效果的程度，並能從 Lyrica 組獲得對比資訊。

The next question is from David Risinger with Leerink Partners.

下一個問題來自 Leerink Partners 的 David Risinger。

Yes. I wanted to change gears, please, to your 2 AAT candidates. Could you frame the efficacy results to watch in 2024? And potential time line for those readouts next year?

是的。我想換個話題，談談你們的兩款AAT候選藥物。能否介紹一下2024年需要關注的療效結果？以及明年可能公佈結果的時間安排？

Sure. David, I think you're asking about the AATD program. And just to ground everyone on that one, this is our program where we have 2 molecules, VX-864, which is in a Phase II study and VX-634, which is making its way through a Phase I study. Our excitement for this particular program and disease comes from the fact that it fits the Vertex strategy like a glove. We are seeking to target both the liver and lung manifestations of this disease. And our small molecule approach is the only one that holds the potential to treat both liver and lung manifestations. And I do believe you need to treat both in order to have a transformative medicine.

當然。 David，我想你問的是AATD計畫。為了讓大家更了解這個項目，我們先簡單介紹一下：目前我們有兩個分子，VX-864正在進行II期臨床試驗，VX-634正在進行I期臨床試驗。我們對這個計畫和這種疾病充滿熱情，是因為它與Vertex的策略完美契合。我們致力於同時治療這種疾病的肝臟和肺部病變。而我們的小分子療法是唯一有可能同時治療肝臟和肺部病變的療法。我相信，要研發出具有改變意義的藥物，就必須同時治療肝臟和肺部病變。

Our VX-864 study, which is in Phase II is a long-term study. It's a 48-week study. And there, we are looking at the impact of long-term dosing on both functional AAT levels in the blood and clearance of liver polymer. You might recall that on a post-hoc analysis of our VX-864 Phase II data from a few years ago, we saw a 90-plus percent reduction in serum Z polymer levels, which is why we're so interested in the liver polymer. And in the 634 study, we are going through our first in-human studies.

我們的VX-864研究目前處於II期，這是一項長期研究，為期48週。研究旨在觀察長期給藥對血液中功能性AAT水平和肝臟聚合物清除率的影響。您可能還記得，幾年前我們對VX-864 II期數據進行的事後分析顯示，血清Z聚合物水平降低了90%以上，這也是我們對肝臟聚合物如此感興趣的原因。此外，我們正在進行VX-864的首次人體試驗，即634研究。

So I expect that we'll have all the results from both of these trials by sometime next year, so 2024, and I expect that we'll be able to share the results at that time. Exact timing, we're going to need to get a few more months under our belt to look at the enrollment dynamics, but I do expect we'll be sharing results by sometime next year. So it's a '24 milestone.

所以我預計到明年，也就是2024年，我們就能拿到這兩項試驗的所有結果，屆時我們就可以分享這些結果了。具體時間我們還需要幾個月的時間來觀察入組情況，但我確實預計明年某個時候就能分享結果。所以這是2024年的一個里程碑。

The next question is from Terence Flynn with Morgan Stanley.

下一個問題來自摩根士丹利的特倫斯·弗林。

Stuart, you mentioned there were about 20,000 patients not on drug at the start of the year that could potentially be eligible. Just wondering where that figure will end, assuming you achieve your new 2023 guidance?

斯圖爾特，你提到年初時大約有2萬名未接受藥物治療的患者可能符合資格。我想知道，假設你們實現了2023年的新指導方針，這個數字最終會是多少？

Yes, Terence. So we've kind of gone away over the last few years of kind of giving detail to the forensic accounting of all the different patient numbers. And so I'm not going to kind of give you an updated estimate at this time. But as Charlie said in his remarks and I set in mine, we've continued to make good progress in treating more patients, including in younger age groups and including in other countries where we've secured reimbursements and launches. But other than that, we're not going into more detail at this time.

是的，特倫斯。過去幾年，我們不再詳細公佈所有患者人數的具體統計資料。因此，目前我無法提供最新的估算數據。但正如查理在發言中提到的，我也在發言中闡述過，我們在治療更多患者方面持續取得良好進展，包括年輕患者群體，以及在其他國家/地區獲得報銷並開展業務。除此之外，我們目前不便透露更多細節。

We may -- if there's a substantial change, we may update those numbers as we've done in the last couple of years or so at the beginning of next year when we talk about our guidance for the following year.

如果情況發生重大變化，我們可能會像過去幾年一樣，在明年年初談到下一年的業績預期時更新這些數字。

Next question is from Mohit Bansal with Wells Fargo.

下一個問題來自富國銀行的莫希特·班薩爾。

Just wanted to get some color on how do you -- talked about sweat chloride improvement with the vanzacaftor trial. Is there a correlation between the amount of sweat chloride you reduced versus the [SCD] improvement. If I'm not mistaken, the improved -- the sweat chloride improvement was about 30% more than the dry cast combo, this combo. So just trying to understand how should we think about the bar for SEB that this new combined?

我只是想了解一下您是如何看待範扎卡夫托試驗中汗液氯化物改善的。您提到的汗液氯化物減少量與[SCD]改善是否有相關性？如果我沒記錯的話，這種組合療法的汗液氯化物改善比乾石膏組合療法高出約30%。所以我想弄清楚，我們該如何看待這種新組合療法對汗液氯化物改善的預期標準？

Mohit, I think you're talking about the vanzacaftor triple, that's our next-in-class regimen for CF. This is the program that's in Phase III, and we expect to complete both studies in the 12-plus-year-old age group and the 6 plus year age group this year with results from that pivotal program early next year.

莫希特，我想你指的是範扎卡夫托三合一療法，那是我們治療囊性纖維化的下一代療法。該計畫目前處於三期臨床試驗階段，我們預計今年將完成針對12歲以上年齡層和6歲以上年齡組的兩項研究，並於明年初公佈這項關鍵性研究的結果。

With regard to your question on sweat chloride and ppFEV1, yes. There is a very strong association between improvements in sweat chloride and improvements in lung function. And you can see that across all of our previous CFTR modulators, all the way from KALYDECO through ORKAMBI SIM and TRIKAFTA. So that relationship is strong.

關於您提出的汗液氯化物和ppFEV1的問題，答案是肯定的。汗液氯化物水平的改善與肺功能的改善之間存在非常強的相關性。您可以在我們之前所有的CFTR調節劑中都觀察到這一點，從KALYDECO到ORKAMBI SIM再到TRIKAFTA，都是如此。所以這種相關性非常強。

In terms of what you should expect from the vanzacaftor triple. Or let me put it another way, the reason we have such high enthusiasm for the vanzacaftor triple, in the preclinical experiments, including the very important HBE assays, which have been not only qualitatively predictive, but quantitatively so, the vanzacaftor triple, I know this is hard to believe in a tall order, but the vanzacaftor triple preclinically is even better than TRIKAFTA in our HPE cells.

就您對範扎卡夫托三聯療法的預期而言，或者換句話說，我們對範扎卡夫托三聯療法如此充滿熱情的原因在於，在臨床前實驗中，包括非常重要的HBE檢測，這些檢測不僅具有定性預測性，而且具有定量預測性，範扎卡夫托三聯療法——我知道這很難讓人相信，但範扎卡夫三聯療法在臨床上在臨床研究中表現更好的關係。

And when we look across the Phase II studies that have been done, the vanzacaftor triple have better sweat chloride than even TRIKAFTA. It's hard to call -- make a call on ppFEV1 because in the Phase II studies, the sample sizes are obviously smaller and ppFEV1 is a more variable endpoint. So I think the right measure to look at is indeed sweat chloride. And from all of the data we've collected, vanza is even better than TRIKAFTA on that measurement of sweat chloride.

當我們回顧已完成的二期臨床研究時，發現凡扎卡夫托三聯療法（vanzacaftor triple）的汗液氯化物水平甚至優於TRIKAFTA。很難對ppFEV1做出判斷，因為二期臨床研究的樣本量明顯較小，而且ppFEV1本身就是一個變異性較大的終點指標。所以我認為，更適合的指標應該是汗液氯化物。根據我們收集的所有數據，凡扎卡夫託在汗液氯化物這一指標上甚至優於TRIKAFTA。

The next question is from Michael Yee with Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

You announced that the chronic pain neuropenic pain study, Phase II was complete enrollment. So that's super exciting and the data, I guess is end of '23, early '24. Can you talk a little bit about, I guess, on one side, you feel confident because of the biology and the acute data was also quite strong, there's also some early chronic data as well as the last gen. But also, I guess, historically, chronic pain studies can be challenging with placebos, even with vicoden and opioids, you can get mixed results. So I just wanted to ask about your confidence around this probability success versus the acute study, and how we should take this study into consideration from an expectation standpoint, give it just a Phase II?

您宣布慢性疼痛神經減少症研究的二期臨床試驗已完成入組，這真是令人振奮！我猜想數據將在2023年底或2024年初公佈。一方面，您之所以充滿信心，是因為該藥物的生物學特性以及急性期數據都非常強勁，此外還有一些早期慢性期數據以及上一代藥物的數據。但另一方面，我想，從歷史經驗來看，即使使用安慰劑，慢性疼痛研究，尤其是使用維可丁和鴉片類藥物，也可能會遇到挑戰，結果可能好壞參半。所以我想問您對這項研究成功機率的信心程度，以及與急性期研究相比，我們應該如何看待這項研究，從預期角度來看，是否應該將其視為一項二期臨床試驗？

Sure. My confidence level in the VX-548 program is equal for the acute pain studies in that Phase III program as it is for the diabetic peripheral neuropathy Phase II program. And you're right, that confidence comes from the pharmacologic validation of the target, which we ourselves conducted with our predecessor molecule, VX-150, and also the genetic validation of the 1 8 target.

當然。我對VX-548計畫的信心，無論是針對急性疼痛的III期臨床試驗，或是針對糖尿病週邊神經病變的II期臨床試驗，都一樣。你說得對，這種信心源自於我們對標靶的藥理驗證（我們自己用前驅分子VX-150進行了驗證），以及對18位標靶的基因驗證。

With regard to a double-click on what you could expect from both acute and the neuropathic pain studies, the acute pain program is 2 randomized clinical trials in the same bunionectomy, abdominoplasty. Those are 2 of the RCTs. And the third is a single-arm safety and efficacy study to allow a broad, moderate-to-severe acute pain label in the various settings that Stuart described in terms of use. And I expect that those results will be available late this year, early next.

關於急性疼痛和神經性疼痛研究的預期結果，急性疼痛項目包括兩個針對相同拇趾外翻切除術和腹部整形術患者的隨機對照試驗（RCT）。第三項研究是一項單組安全性和有效性研究，旨在為Stuart所描述的各種應用情境下的中度至重度急性疼痛提供廣泛的適應症。我預計這些結果將於今年底或明年初公佈。

And the goal there is, gosh, if we see what we saw in Phase II for VX-548 acute pain, that would be a home run. So the diabetic peripheral neuropathy program, this is a multiple-dose-ranging proof-of-concept study where we also have a gabapentin arm for context. So what you should be looking for there is improvement in the pain score from baseline to the 12-week time point when we have the pain endpoint and you'll be able to make assessments versus the gabapentin arm that's in their fourth context. That study is fully enrolled and should also be available in terms of results late this year, early next.

我們的目標是，如果能像VX-548在二期臨床試驗中治療急性疼痛那樣，在糖尿病週邊神經病變計畫中取得同樣的效果，那就太棒了。這是一項多劑量範圍的概念驗證研究，其中也設定了加巴噴丁對照組作為對照。因此，您應該關注的是疼痛評分從基線到12週時點的改善情況，屆時我們將以疼痛為終點，並能與加巴噴丁對照組（作為第四個對照）進行比較。該研究已完成全部受試者招募，預計今年底或明年初公佈結果。

The next question is from Evan Seigerman with BMO Capital Markets.

下一個問題來自 BMO 資本市場的 Evan Seigerman。

Kind of a follow-up to Mohit's question on the Vanza Triple, Talk about what the added benefit of the vanza triple needs to be versus TRIKAFTA to get patients to switch. You also mentioned getting patients to levels of carrier levels of sweat chloride. Could you ever get to a wild-type level of sweat chloride?

這是對 Mohit 關於 Vanza Triple 的問題的後續。請談談 Vanza Triple 相較於 TRIKAFTA 需要有哪些額外好處才能促使患者改用它。您也提到要讓患者的汗液氯化物水平達到載體水平。那麼，有可能達到野生型汗液氯化物水平嗎？

Yes. Let me take the second half of your question, Evan, and then I'll turn it over to Stuart to talk through how we're seeing the commercial opportunity for the vanza triple. So when you look at parents, so carriers of the CF mutation, for those who don't have disease. When you are at those carrier levels of sweat chloride, you have virtually no manifestation of disease. That's why we're targeting carrier levels of sweat chloride.

是的。埃文，我先回答你問題的後半部分，然後我會把麥克風交給斯圖爾特，讓他來談談我們是如何看待Vanza Triple的商業機會的。讓我們來看看那些攜帶囊性纖維化突變基因但自身沒有患病的父母。當他們的汗液氯化物水平處於帶因者水平時，幾乎不會出現任何疾病症狀。這就是為什麼我們把目標鎖定在攜帶者水平的汗液氯化物上。

You're fundamentally -- just like you and me, I don't -- I'm not a carrier and I'm not a patient with CF. But if you are a carrier of CF, you are fundamentally unaffected. That's why that's the highest bar to achieve. And that's why that's the bar we continue to chase. The TRIKAFTA triple gets some patients there, the vanzacaftor triple will get more patients there. But our research continues, and we've already identified additional potentiators and correctors that will get us to that ultimate goal of carrier levels of sweat chloride. Stuart?

從根本上來說——就像你我一樣，我不是囊性纖維化攜帶者，也不是病人。但如果你是囊性纖維化攜帶者，從根本上來說你不會受到影響。這就是為什麼這是最高的目標。這也是為什麼我們一直在努力追求的目標。 TRIKAFTA 三重療法可以幫助一些患者達到這個目標，vanzacaftor 三重療法可以幫助更多患者達到這個目標。但我們的研究仍在繼續，我們已經發現了其他一些增強劑和矯正劑，它們將幫助我們達到攜帶者水平的汗液氯化物這一最終目標。史都華？

Yes. So -- and in terms of the sort of uptake and what's attractive of the profile, we know from speaking with CF clinicians if vanzacaftor has the sort of profile that Reshma described earlier, where it's delivering increased levels of benefit in terms of CFTR function as measured through sweat chloride that, that in and of itself will be an attractive proposition because as Reshma said, the link between increases in CFTR function and improvements in outcomes has been demonstrated through our own work.

是的。所以——就接受度和產品特性的吸引力而言，我們從與囊性纖維化臨床醫生的交流中了解到，如果範扎卡夫托具有雷什瑪之前描述的那種特性，即透過汗液氯化物測量來提高 CFTR 功能，那麼這本身就是一個有吸引力的方案，因為正如雷什瑪所說，我們自己的研究已經證明了 CFTR 功能增強與療效改善之間的聯繫。

In addition, you were talking about patients potentially transitioning. I do think there's an important group we should also consider, which is -- there have been a number of patients who over the years have discontinued their CFTR modulators. It's probably somewhere north of 6,000 patients who we know want to be on a CFTR modulator, but have had to discontinue over the years. And I do think that's another population who will welcome an additional treatment option being available.

此外，您剛才提到了患者可能需要轉換治療方案的問題。我認為我們還應該考慮一個重要的群體，那就是——多年來，有不少患者停止了服用CFTR調節劑。據我們所知，大約有超過6000名患者希望繼續服用CFTR調節劑，但多年來不得不停止用藥。我認為，如果能有另一種治療選擇，這部分人將會非常歡迎。

The next question is from Colin Bristow with UBS.

下一個問題來自瑞銀集團的柯林布里斯托。

Congrats on the quarter. Maybe one of the CRISPR-based DMD program. Are you still on track to file the IND in the second half? And then assuming all goes to plan, would it be reasonable to expect some clinical data in 2024? And then maybe if I could just have a quick follow-on to the vanzacaftor triple question. Just what do you think you need to see for this to be a launch that is as a major component of switches versus just a new patient acquisition launch?

恭喜本季業績！或許可以談談基於 CRISPR 的 DMD 計畫。你們是否仍按計劃在下半年提交 IND 申請？如果一切順利，我們是否可以預期在 2024 年獲得一些臨床數據？另外，關於 Vanzacaftor 的三個問題，能否再補充一點？您認為需要達到什麼程度，才能使 Vanzacaftor 的上市成為患者群體轉換的重要組成部分，而不僅僅是新患者的獲取？

Colin, I think there are 2 separate questions in there. One about the vanza triple and what do we need to see and then one on DMD. Let me tackle the DMD, DM1 question, I'll come back to vanza. On the DMD question, I'm going to broaden it out to muscular dystrophies as a whole, and I'll talk about DMD. and DM1. We have programs in DMD that are going through IND-enabling studies now as well as in DM1. We actually have multiple programs in DM1. The lead program is the one that we in-licensed from Entrada. And that program also is already in IND-enabling studies and both of them should have those results in the second half of '23. And our timing remains to file the IND for both DMD and for DM1 for the lead program in DM1 in the second half of this year.

科林，我認為這裡包含兩個不同的問題。一個是關於Vanza三重療法以及我們需要觀察哪些方面，另一個是關於DMD。我先回答DMD和DM1的問題，稍後再談Vanza。關於DMD的問題，我會把範圍擴大到整個肌肉營養不良症領域，然後再談談DMD和DM1。我們目前在DMD和DM1領域都有正在進行IND申報前研究的項目。實際上，我們在DM1領域有多個項目。主要項目是我們從Entrada公司引進的。該項目也已進入IND申報前研究階段，這兩個項目都應該在2023年下半年獲得結果。我們計劃在今年下半年提交DMD和DM1主要項目的IND申請。

With regard to the vanza, I think Stuart just covered that. What we're looking to see in the way the study is designed is vanzacaftor in the Phase III program head-to-head versus TRIKAFTA and the primary endpoint is sweat chloride. And the reason for that is, again, with patients who -- with carriers, those with who have 1 CF gene, they have virtually no manifestations of disease. And that is measured assessed by the sweat chloride carrier level is a description of sweat chloride levels. So that's what we're measuring. We are, of course, going to have PPFEV1 in there.

關於Vanza，我想Stuart剛才已經提過了。我們希望透過這項研究的設計，在III期臨床試驗中直接比較Vanzacaftor和TRIKAFTA的療效，主要終點是汗液氯化物水平。原因在於，帶因者（即攜帶1個CF基因的患者）幾乎沒有疾病症狀。汗液氯化物水平可以反映帶因者汗液氯化物水平的變化。所以，這就是我們研究的重點。當然，我們也會檢測PPFEV1。

And as Stuart said, if the profile is, as I described it to be, improvement on sweat chloride levels, we expect it to have real value to patients. I'll also add that the vanzacaftor triple has a lower royalty burden than the TRIKAFTA combination.

正如史都華所說，如果該藥物的效果正如我所描述的那樣，能夠改善汗液氯化物水平，我們預計它將對患者真正有益。我還想補充一點，Vanzacaftor 三重療法的專利費負擔比 TRIKAFTA 組合療法低。

Thanks, Reshma. Thanks, Colin. Gary. That brings us to time. Could you close it out, please?

謝謝，雷什瑪。謝謝，科林。加里。現在到了時間問題。請你們結束這個話題好嗎？

This concludes the question-and-answer session, and the conference is also now concluded. Thank you for attending today's presentation. You may now disconnect.

問答環節到此結束，會議也正式結束。感謝您參加今天的報告。您可以斷開連線了。