福泰製藥 (VRTX) 2024 Q3 法說會逐字稿

Good day and welcome to the Vertex Pharmaceuticals third-quarter 2024 earnings call. (Operator Instructions) Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead, ma'am.

大家好，歡迎參加 Vertex Pharmaceuticals 2024 年第三季財報電話會議。（操作員指示）請注意，此事件正在被記錄。現在我想將會議交給蘇西麗莎女士。請繼續，女士。

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 third-quarter 2024 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.

大家晚上好。我的名字是 Susie Lisa，身為投資者關係資深副總裁，我很高興歡迎您參加我們 2024 年第三季財務業績電話會議。在今晚的電話會議上，我們邀請了 Vertex 執行長兼總裁 Reshma Kewalramani 博士發表準備好的演講； Stuart Arbuckle，營運長；以及財務長查理·瓦格納（Charlie Wagner）。

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. 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.

我們建議您在收聽此電話會議時存取網路廣播投影片。這次通話正在錄音，重播將在我們的網站上提供。我們將在本次電話會議上做出前瞻性陳述，這些陳述受今天的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的影響。

These statements, including, without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, and beta thalassemia, our pipeline, including the potential near-term launches of the vanzacaftor triple in CF and suzetrigine in moderate-to-severe acute pain, and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

這些聲明包括但不限於有關Vertex 已上市的囊性纖維化、鐮狀細胞病和β地中海貧血藥物的聲明、我們的產品線，包括可能於近期推出的用於治療CF 的vanzacaftor 三聯療法和用於治療中度至重度急性痛苦以及 Vertex 未來的財務表現均基於管理階層目前的假設。實際結果和事件可能會有重大差異。

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.

我還要指出的是，我們將在今晚的電話會議上審查的部分財務結果和指引是以非 GAAP 為基礎呈現的。

I will now turn the call over to Reshma.

現在我將電話轉給 Reshma。

Thanks, Susie. Good evening, all, and thank you for joining us on the call today. Third-quarter performance extended our strong momentum for the year with continued outstanding commercial execution in both CF and the early launch of CASGEVY, as well as launch preparedness for two potential near-term approvals in early 2025.

謝謝，蘇西。大家晚上好，感謝您今天的電話會議。第三季的業績延續了我們今年的強勁勢頭，CF 和 CASGEVY 的早期推出繼續表現出色，並為 2025 年初兩項潛在的近期批准做好了準備。

We also continue to rapidly progress programs in our clinical pipeline and achieved a significant milestone with three new programs advancing into Phase 3 clinical trials in just the last quarter. In CF, we are reaching more patients and delivered $2.77 billion in revenue, representing 12% growth this quarter versus Q3 2023.

我們也繼續快速推進臨床項目，並在上個季度取得了重要的里程碑，三個新項目進入了第三階段臨床試驗。在 CF 領域，我們接觸到的患者越來越多，實現了 27.7 億美元的收入，與 2023 年第三季相比，本季成長了 12%。

Based on the strong growth year-to-date and our Q4 outlook, we are increasing our full-year product revenue guidance to $10.8 billion to $10.9 billion while maintaining our previous operating expense guidance.

基於今年迄今的強勁成長和我們對第四季的展望，我們將全年產品營收預期上調至 108 億美元至 109 億美元，同時維持先前的營運費用預期。

With CASGEVY, the early launch is going very well. The enthusiasm from patients and physicians remains high and we are pleased with the ATC and patient cell collection metrics. I'm particularly pleased to share that in Q3, the first patient received commercial CASGEVY, resulting in the first revenue recognition for this medicine.

CASGEVY 的早期發布進展非常順利。患者和醫生的熱情仍然很高，我們對 ATC 和患者細胞收集指標感到滿意。我特別高興地分享，在第三季度，第一位患者接受了商業化 CASGEVY，從而首次確認了該藥物的收入。

With respect to the overall pipeline, we remain on track to deliver our January 2023 5-in-5 ambition with five new product launches over five years as we advance into this new era of revenue diversification.

就整體產品線而言，隨著我們進入收入多元化的新時代，我們仍有望在五年內推出五款新產品，實現 2023 年 1 月的「五年五大目標」。

Specifically, in addition to the CASGEVY launches in sickle cell disease and beta thalassemia, we are preparing for potential third and fourth product launches in early 2025, the vanzacaftor triple in CF globally and suzetrigine in moderate to severe acute pain in the US.

具體而言，除了推出用於治療鐮狀細胞疾病和β地中海貧血的CASGEVY 外，我們還在為2025 年初推出第三和第四種產品做準備，即全球用於治療CF 的vanzacaftor 三聯療法和美國用於治療中度至重度急性疼痛的suzetrigine。

Beyond that, the programs in Phase 3 development inaxaplin in APOL1-mediated kidney disease, suzetrigine in Diabetic Peripheral Neuropathy, povetacicept in IgA nephropathy and VX-880 in type 1 diabetes are all progressing nicely, and we're also making strong progress in our mid-stage clinical pipeline with potentially transformative medicines, VX-993 in acute and peripheral neuropathic pain VX-670 in myotonic dystrophy type 1, or DM1, and povetacicept in indications beyond IgA nephropathy.

此外，處於 3 期開發階段的 APOL1 介導腎病的 inaxaplin、糖尿病周圍神經病變的 suzetrigine、IgA 腎病的 povetacicept 和 1 型糖尿病的 VX-880 項目都進展順利，而且我們在具有潛在變革性的中期臨床管線藥物包括用於治療急性和周邊神經性疼痛的VX-993、用於治療1 型強直性肌肉營養不良症(DM1) 的VX-670 以及用於治療IgA 腎病以外適應症的povetacicept。

Tonight, I'll focus my R&D comments on CF, and four additional programs that have made notable advancements this quarter. First, in CF, our four marketed medicines are treating the underlying cause of disease in more than 68,000 patients around the world.

今晚，我將重點介紹 CF 以及本季取得顯著進展的另外四個項目。首先，在 CF 領域，我們上市的四種藥物正在幫助全球超過 68,000 名患者治療疾病的根本原因。

This includes children as young as one month with KALYDECO as young as one year with ORKAMBI and as young as two years with TRIKAFTA, we are poised for the potential approval of the vanzacaftor triple, our fifth medicine for people with cystic fibrosis, six years of age and older.

其中包括使用KALYDECO 治療的1 個月大的兒童、使用ORKAMBI 治療的1 歲大的兒童以及使用TRIKAFTA 治療的2 歲大的兒童。患者的第五種藥物，6 歲以上的年齡及以上。

We have a PDUFA date of January 2 in the US, and we have also completed submissions in the EU, the UK, Canada, Australia, New Zealand and Switzerland. Reviews in these jurisdictions are underway. We have also already initiated the clinical trial in children with CF ages two to five.

我們的美國 PDUFA 日期為 1 月 2 日，我們也已在歐盟、英國、加拿大、澳洲、紐西蘭和瑞士完成了提交。這些司法管轄區的審查正在進行中。我們也已針對 2 至 5 歲 CF 兒童啟動臨床試驗。

Finally, in CF VX-522, our CFTR mRNA therapy in development with our partners at Moderna has completed the single ascending dose portion of the Phase 1/2 study, and continues in the multiple ascending dose or MAD portion. This therapy seeks to provide treatment for the more than 5,000 people with CF who do not make any CFTR protein, and we expect to share both safety and efficacy results from the MAD in the first half of 2025.

最後，在 CF VX-522 中，我們與 Moderna 的合作夥伴共同開發的 CFTR mRNA 療法已經完成了 1/2 期研究的單次遞增劑量部分，並繼續進行多次遞增劑量或 MAD 部分。該療法旨在為 5,000 多名不產生任何 CFTR 蛋白的 CF 患者提供治療，我們預計將在 2025 年上半年分享 MAD 的安全性和有效性結果。

Next, in type 1 diabetes, VX-880 is the stem cell-derived fully differentiated islet cell investigational therapy for people with type 1 diabetes and impaired hypoglycemic awareness, who experienced severe hypoglycemic events or SAEs despite optimal medical care.

其次，在1 型糖尿病中，VX-880 是一種幹細胞衍生的完全分化胰島細胞研究療法，適用於患有1 型糖尿病和低血糖意識受損的患者，這些患者儘管接受了最佳醫療護理，但仍經歷了嚴重的低血糖事件或SAE。

I am very pleased to share that we have completed our end of Phase 2 meetings with FDA, EMA, and MHRA and following the successful regulatory interactions we have reached agreement with regulators to advance the current Phase 1/2 VX-880 study to pivotal development and convert the trial into a Phase 1/2/3 study.

我很高興地告訴大家，我們已經完成了與FDA、EMA 和MHRA 的第2 階段會議，並且在成功的監管互動之後，我們已與監管機構達成協議，將當前的第1/2 階段VX-880研究推進到關鍵開發階段並將試驗轉化為1/2/3期研究。

This trial will include a total of 50 patients with difficult to control diabetes and severe hypoglycemic events despite optimal medical management. In this Phase 1/2/3 study, the primary endpoint is the proportion of patients achieving insulin independence with the absence of severe hypoglycemic events.

這項試驗將納入總共 50 名儘管採取了最佳醫療管理但仍難以控製糖尿病和出現嚴重低血糖事件的患者。在此項 1/2/3 期研究中，主要終點是實現胰島素獨立且沒有嚴重低血糖事件的患者比例。

We are excited to be in pivotal development for this groundbreaking potentially curative therapy for patients suffering from the most severe form of type 1 diabetes, it is particularly noteworthy that the first-ever pivotal trial of an allogeneic regenerative cell therapy for type 1 diabetes is beginning less than a year after we received the first-ever approval for CRISPR/Cas9 gene-edited cell therapy with CASGEVY, we are proud of the progress represented by these advancements in the cell and gene therapy space.

我們很高興能夠參與這項具有突破性、可能治愈 1 型糖尿病患者的療法的關鍵開發，尤其值得注意的是，首次針對 1 型糖尿病的同種異體再生細胞療法的關鍵試驗即將開始在我們通過CASGEVY在獲得CRISPR/Cas9 基因編輯細胞療法的首個批准後不到一年，我們為這些細胞和基因治療領域的進步所代表的進展感到自豪。

To close out on the VX-880 program, I'll provide a quick recap on the data presented at EASD this September. These remarkable data form the basis of our recent regulatory discussions and included more patients with longer duration of follow-up compared to the ADA presentation. These data showed four patients had 12 months of follow-up and all four achieved the primary and secondary end points.

為了結束 VX-880 計劃，我將快速回顧今年 9 月 EASD 上展示的數據。這些卓越的數據構成了我們最近監管討論的基礎，與 ADA 報告相比，其涵蓋了更多的患者並且隨訪時間更長。這些數據顯示，四名患者進行了 12 個月的隨訪，並且都達到了主要和次要終點。

Specifically, they had elimination of severe hypoglycemic events achieved insulin independence and achieved the ADA recommended hemoglobin A1c levels of less than 7%. Also at EASD, we shared that an additional five patients were off exogenous insulin as they progressed towards the 12-month primary endpoint evaluation. Safety and tolerability with this latest data cut were consistent with the June ADA presentation.

具體來說，他們消除了嚴重的低血糖事件，實現了胰島素獨立，並達到了 ADA 推薦的糖化血紅蛋白 A1c 水平低於 7%。此外，在 EASD，我們分享了另外五名患者在進行 12 個月主要終點評估時停止使用外源胰島素的情況。此次最新數據的安全性和耐受性與 6 月份 ADA 報告的結果一致。

Beyond VX-880, our cell + device or VX-264 program encapsulates the same VX-880 cells in a proprietary device designed to eliminate the need for immunosuppressants. We are currently enrolling and dosing patients in Part B, which is at the full target dose with the stagger between patients. The next stage, Part C of the trial, is at the full target dose without a stagger. We expect to share data from Parts A and B of the VX-264 study in 2025. Moving now to the povetacicept program.

除了 VX-880，我們的細胞+設備或 VX-264 程序將相同的 VX-880 細胞封裝在專有設備中，旨在消除對免疫抑制劑的需求。我們目前正在招募 B 部分的患者並對他們進行給藥，該部分採用全目標劑量，但患者之間需要錯開用藥時間。下一階段，即試驗的 C 部分，將採用全目標劑量，不間斷治療。我們預計將在 2025 年分享 VX-264 研究 A 部分和 B 部分的數據。現在轉到 povetacicept 程式。

Pove is a dual antagonist of the BAF and APRIL cytokines, which play key roles in the pathogenesis of B cell-mediated autoimmune diseases. This dual inhibition mechanism of action, the preclinical and clinical data to date plus pove's once-monthly dosing frequency with small volume subcutaneous route of administration give us high confidence in the promise of povetacicept as a transformative medicine for patients with IgA nephropathy and potentially additional B-cell-mediated diseases.

Pove 是 BAF 和 APRIL 細胞因子的雙重拮抗劑，在 B 細胞介導的自體免疫疾病的發病機制中起關鍵作用。這種雙重抑製作用機制、迄今為止的臨床前和臨床數據，加上 pove 每月一次的小劑量皮下給藥頻率，讓我們對 povetacicept 作為 IgA 腎病患者的轉化藥物以及潛在的額外 B -細胞介導的疾病。

Pove recently hit multiple milestones. First, I'm very pleased to share that we began the global Phase 2 RAINIER study of pove in patients with IgA nephropathy. This study is a randomized double-blind trial of pove 80 milligrams versus placebo on top of standard of care.

波夫最近取得了多項里程碑。首先，我很高興地告訴大家，我們已啟動針對 IgA 腎病患者的 pove 全球第 2 期 RAINIER 研究。這項研究是在標準治療基礎上進行 80 毫克 pove 與安慰劑的隨機雙盲試驗。

The trial is underway with screening, enrollment and dosing ongoing across multiple clinical sites globally. Importantly, the trial is designed with a preplanned interim analysis to evaluate proteinuria when a certain number of patients reach the 36-week time point this preplanned interim analysis could support a potential accelerated approval in the US.

該試驗目前正在全球多個臨床地點進行篩選、招募和給藥。重要的是，該試驗設計有一個預先計劃的中期分析，以評估蛋白尿，當一定數量的患者達到 36 週的時間點時，這個預先計劃的中期分析可以支持在美國獲得潛在的加速批准。

For full approval, the study will continue through week 104 and assess GFR. Second, the recently initiated RAINIER Phase 3 study was supported by positive data that we shared at the recent American Society of Nephrology Meeting. In IgA nephropathy, updated Phase 2 data on patients with IgA nephropathy who received 80 milligrams of povetacicept continue to demonstrate pove's best-in-class potential with a mean 66% reduction from baseline in UPCR at 48 weeks with stable renal function.

為了獲得全面批准，該研究將持續到第 104 週並評估 GFR。其次，最近啟動的 RAINIER 第 3 階段研究得到了我們在最近的美國腎臟學會會議上分享的積極數據的支持。在 IgA 腎臟病方面，接受 80 毫克 povetacicept 的 IgA 腎病患者的最新 2 期數據繼續證明 pove 的最佳潛力，48 週時 ​​UPCR 較基線平均降低 66%，且腎功能穩定。

These results were accompanied by a 63% achievement or five out of the eight study participants of clinical remission defined as UPCR of less than 0.5 grams per gram negative hematuria and stable renal function. We are very excited about these results and the potential they represent for IgAN patients globally, including the approximately 130,000 patients diagnosed in the US.

這些結果伴隨著 63% 或 8 名研究參與者中的 5 名達到了臨床緩解，臨床緩解定義為每克陰性血尿的 UPCR 少於 0.5 克且腎功能穩定。我們對這些結果以及它們對全球 IgAN 患者（包括美國約 13 萬名確診患者）的潛力感到非常興奮。

Third, at ASN, we shared emerging pove data from another renal B-cell mediated disease, primary membranous nephropathy a disease that affects 60,000 patients in the US with no approved targeted therapies. These data are from three patients who received pove at 80 milligrams subcutaneously every four weeks.

第三，在 ASN，我們分享了另一種腎臟 B 細胞介導疾病即原發性膜性腎病變的新興數據，這種疾病影響了美國 60,000 名患者，且尚未獲得批准的針對性療法。這些數據來自三名每四周皮下注射 80 毫克 pove 的患者。

On proteinuria, at 24 weeks, treatment with pove resulted in a mean 62% reduction from baseline in UPCR, and two of the three patients achieved partial clinical remission defined as UPCR of less than 3.5 grams per gram and greater than 50% reduction in UPCR from baseline.

在蛋白尿方面，在24 週時，使用pove 治療可使UPCR 較基線平均減少62%，三名患者中有兩名達到部分臨床緩解（定義為UPCR 低於每克3.5 克且UPCR 減少超過50% ）從基線開始。

In addition, anti-PLA2R1 antibodies, a biomarker of disease activity declined by a mean of 87% at week 20 in these patients. Across the renal studies, pove was well tolerated and most adverse events were mild or moderate. We look forward to updating you as the pove programs progress. Shifting gears now from pove to the pain portfolio and starting with acute pain.

此外，這些患者的疾病活動生物標記抗 PLA2R1 抗體在第 20 週平均下降了 87%。在腎臟研究中，pove 耐受性良好，大多數不良事件為輕度或中度。我們期待向您通報 pove 計劃的進展。現在將焦點從pove轉移到疼痛組合併從急性疼痛開始。

The FDA review of suzetrigine in moderate-to-severe acute pain is well underway with a PDUFA date of January 30, 2025. The Phase 3 data from the two RCTs and the single-arm safety and effectiveness trial that form the basis of the acute pain regulatory submission were presented for the first time at the recent American Society of Anesthesiology Annual Meeting.

FDA 對 Suzetrigine 治療中度至重度急性疼痛的審查正在順利進行中，PDUFA 日期為 2025 年 1 月 30 日。作為急性疼痛監管提交基礎的兩項 RCT 和單臂安全性和有效性試驗的 3 期數據在最近的美國麻醉學會年會上首次公佈。

There was very strong physician interest and positive feedback to the presentation of this data set. And we now look forward to the completion of the regulatory review, potential approval and launch of suzetrigine. Stuart will provide more detail on the acute pain launch readiness.

醫生對該數據集的展示表現出了濃厚的興趣和積極的回饋。我們現在期待完成 Suzetrigine 的監管審查以及可能的批准和上市。史都華將提供有關急性疼痛啟動準備的更多細節。

As suzetrigine progresses through its regulatory review, additional assets in the pain portfolio are also advancing through clinical development our next-generation NaV1.8 inhibitor VX-993 is being studied in two acute pain studies, a Phase 2 study post bunionectomy with the oral formulation and a Phase 1 study with the IV formulation.

隨著Suzetrigine 的監管審查不斷推進，疼痛產品組合中的其他資產也在透過臨床開發取得進展，我們的下一代NaV1.8 抑制劑VX-993 正在兩項急性疼痛研究中進行研究，一項是拇趾囊切除術後口服製劑的2 期研究及採用 IV 配方的 1 期研究。

We also continue to make strong preclinical progress with our NaV1.7 pain signal inhibitor program that may be used alone or in combination with NaV1.8 inhibitors. In peripheral neuropathic pain, or PNP. In diabetic peripheral neuropathic pain, which is one type of PNP, for which an estimated 2 million Americans seek a prescription pain medicine annually. I'm very pleased to share two updates. First, we have initiated the Phase 3 pivotal program for suzetrigine.

我們的 NaV1.7 疼痛訊號抑制劑計畫也繼續在臨床前取得重大進展，該計畫可單獨使用或與 NaV1.8 抑制劑聯合使用。在周邊神經性疼痛（PNP）中。糖尿病性週邊神經性疼痛是 PNP 的一種，估計每年有 200 萬美國人尋求處方止痛藥。我很高興分享兩個最新消息。首先，我們已經啟動了 Suzetrigine 的 3 期關鍵研究計畫。

Second, we have also initiated a Phase 2 study with the oral formulation of VX-993 and in lumbosacral radiculopathy or LSR, another type of PNP that impacts more than 4 million Americans each year and for which there are no specifically approved medicines in the US we have completed the Phase 2 trial. We remain on track to share Phase 2 results from this study by the end of this year.

其次，我們也啟動了VX-993 口服劑型的2 期研究，用於治療腰骶神經根病變（LSR），這是另一種PNP，每年影響超過400 萬美國人，而美國目前尚無專門批准的藥物我們已經完成了第二階段試驗。我們將在今年年底前分享研究的第二階段結果。

As a reminder, this is a 12-week trial of about 200 patients randomized to either suzetrigine 69 milligrams or placebo. The primary endpoint is the within group change in the NPRS score from baseline to the end of the 12-week study.

提醒一下，這是一項為期 12 週的試驗，約有 200 名患者隨機接受 69 毫克 Suzetrigine 或安慰劑治療。主要終點是從基線到 12 週研究結束的組內 NPRS 評分變化。

The design allows for an efficient evaluation of the magnitude of the treatment effect for suzetrigine as well as the placebo group, so that we may appropriately size a potential Phase 3 trial if the Phase 2 data support advancement.

此設計可以有效評估 Suzetrigine 組和安慰劑組的治療效果大小，以便我們在第 2 階段數據支持進展的情況下，適當地確定潛在的第 3 階段試驗的規模。

To wrap up the discussion on the pipeline today, a brief update on the myotonic dystrophy type 1 or DM1 program. DM1 is the most prevalent type of muscular dystrophy impacting 110,000 patients in the US and Europe and four of which there are no approved therapies.

為了總結今天關於管道的討論，我們簡要介紹 1 型強直性肌肉營養不良症或 DM1 計劃的最新進展。DM1 是最常見的肌肉營養不良症類型，影響美國和歐洲的 110,000 名患者，其中四種尚無核准的治療方法。

Our Phase 1/2 clinical study of VX-670 initiated late last year, and I am pleased to share that the program has accelerated, the SAD portion of the Phase 1/2 clinical trial has completed dosing, and we have initiated the MAD portion of the study.

我們的 VX-670 1/2 期臨床研究於去年底啟動，我很高興地告訴大家，該計畫已經加速推進，1/2 期臨床試驗的 SAD 部分已經完成給藥，我們已經啟動了 MAD 部分研究。

In the MAD, we will be collecting both safety and efficacy data. the primary endpoint of safety and the secondary endpoint is the change from baseline in the splicing index on muscle biopsy. We are excited about the progress and potential for VX-670 and look forward to providing updates on this program as it advances.

在 MAD 中，我們將收集安全性和有效性資料。主要終點是安全性，次要終點是肌肉活檢剪接指數相對於基線的變化。我們對 VX-670 的進展和潛力感到非常興奮，並期待在該計劃進展過程中提供最新消息。

With that review of the R&D highlights, I'll now turn it over to Stuart for a commercial update.

回顧完研發亮點後，我現在將其交給 Stuart 進行商業更新。

Thanks, Reshma. I'll begin by discussing CF and then provide some highlights of the ongoing CASGEVY launch and the outlook for suzetrigine in acute pain. Once again, we delivered strong results in CF as we further grew the number of eligible patients taking our CFTR modulators in both the US and outside the US. We have made rapid regulatory and reimbursement progress with our CF therapies.

謝謝，Reshma。我將首先討論 CF，然後提供正在進行的 CASGEVY 發布的某些亮點以及 Suzetrigine 在急性疼痛治療​​中的前景。我們在 CF 領域再次取得了強勁的業績，美國國內和美國以外地區服用 CFTR 調節劑的合格患者數量進一步增加。我們的 CF 療法在監管和報銷方面取得了快速進展。

Notably, KAFTRIO now has regulatory approval and reimbursed access in every single country in the EU. We expect sustained revenue growth in CF over the short, medium- and long term. In the near term, we remain focused on reaching more eligible patients around the globe with our currently approved medicines.

值得注意的是，KAFTRIO 現已獲得歐盟每個國家的監管部門批准並獲得報銷。我們預計 CF 的短期、中期和長期收入都將持續成長。短期內，我們仍將致力於透過目前核准的藥物惠及全球更多符合資格的患者。

We anticipate the launch of our vanzacaftor triple combination therapy will drive further growth in CF. We expect this new treatment option, if approved, will be of interest both to those patients on a CFTR modulator and the more than 6,000 patients who have discontinued one of our current CFTR modulators.

我們預計 vanzacaftor 三聯療法的推出將推動 CF 的進一步成長。我們預計，這種新的治療方案一旦獲得批准，將引起使用 CFTR 調節劑的患者和超過 6,000 名已停止使用我們現有的一種 CFTR 調節劑的患者的興趣。

And longer term, the potential successful development of VX-522 for the more than 5,000 people with CF who do not respond to CFTR modulators would drive additional growth in CF. Now turning to CASGEVY our transformative onetime therapy for patients with sickle cell disease and beta thalassemia. CASGEVY has been enthusiastically received by patients, physicians, and policymakers and the launch is gathering momentum across all regions.

從長遠來看，VX-522 預計將成功治療 5,000 多名對 CFTR 調節劑沒有反應的 CF 患者，從而推動 CF 的進一步成長。現在轉向 CASGEVY，這是我們針對鐮狀細胞疾病和β地中海貧血患者的變革性一次性療法。CASGEVY 受到了患者、醫生和政策制定者的熱烈歡迎，並且在各個地區的推出都勢頭強勁。

Two important markers of our launch progress are ATC activations and patient cell collections. On ATC activation, we now have 45 authorized treatment centers, up from just over 35 in Q2 and are well on our way to our goal to activate approximately 75 total ADCs globally.

我們啟動進展的兩個重要標誌是 ATC 活化和患者細胞收集。在 ATC 活化方面，我們現在擁有 45 個授權治療中心，高於第二季度的 35 個，並且正在順利實現在全球範圍內激活約 75 個 ADC 的目標。

On patient cell collections, approximately 40 patients have already had at least one cell collection, up from approximately 20 as noted on our Q2 call. We've also now had the first commercial patients receive their infusions of CASGEVY.

在患者細胞採集方面，大約有 40 名患者已經進行過至少一次細胞採集，而我們第二季度電話會議上記錄的患者人數約為 20 人。現在，我們已經有第一批商業患者接受了 CASGEVY 的輸注。

On the payer landscape, we continue to work to secure access for patients. Coverage has not been a significant obstacle to patient access for this life-changing therapy in the US. And we were very pleased that in the UK, a positive coverage agreement for TDT was reached in September with NHS England less than six months after regulatory approval.

在付款人方面，我們繼續努力確保患者的治療機會。在美國，保險覆蓋範圍並未成為患者獲得這種改變生活的療法的重大障礙。我們非常高興，在英國，在獲得監管部門批准後不到六個月，就於 9 月與 NHS England 達成了 TDT 的積極覆蓋協議。

Furthermore, we have now also entered into commercial discussions with the NHS to secure access for sickle cell disease patients. We also continue to make exciting progress on the regulatory front with approvals in the quarter for both sickle cell disease and TDT in Switzerland and Canada.

此外，我們現在也已與 NHS 展開商業討論，以確保鐮狀細胞疾病患者能夠獲得治療。我們在監管方面也繼續取得令人興奮的進展，本季獲得了瑞士和加拿大對鐮狀細胞疾病和 TDT 的批准。

And in the Middle East, we anticipate CASGEVY regulatory submissions in [Q8] and the United Arab Emirates by the end of this year. Given our confidence in the growing patient demand we are seeing for CASGEVY, we are investing in additional manufacturing capacity. And in September, we were pleased to attain approval for a third manufacturing facility for CASGEVY with our partner, Lonza.

在中東，我們預計 CASGEVY 將於今年底在 [Q8] 和阿拉伯聯合大公國提交監管申請。鑑於我們對 CASGEVY 不斷增長的患者需求的信心，我們正在投資增加生產能力。9 月份，我們很高興與合作夥伴 Lonza 共同獲得了為 CASGEVY 建立第三家製造工廠的批准。

We are focused on a strong finish to the year for CASGEVY. We continue to see high interest levels and recognition of the value of CASGEVY among patients, physicians, governments and other stakeholders, and we remain confident in our view that CASGEVY represents a multibillion-dollar opportunity as it helps more and more patients around the world. We have built a strong foundation for this transformational therapy and we look forward to the momentum it will carry into 2025.

我們致力於讓 CASGEVY 在今年取得圓滿成功。我們繼續看到患者、醫生、政府和其他利益相關者對CASGEVY 的價值表現出濃厚的興趣和認可，我們仍然堅信CASGEVY 代表著一個價值數十億美元的商機，因為它可以幫助世界各地越來越多的患者。我們為這種轉化療法奠定了堅實的基礎，並期待它能繼續保持這種勢頭到 2025 年。

Shifting now to suzetrigine in acute pain as we are approximately three months from our US PDUFA date and potential launch. Our field teams are fully hired and trained, and we are launch ready. suzetrigine has the potential to provide a transformative treatment option for the 80 million people who seek a prescription therapy for moderate-to-severe acute pain each year in the US.

現在我們正轉向使用 Suzetrigine 治療急性疼痛，因為距離美國 PDUFA 日期和潛在上市時間還有大約三個月的時間。我們的現場團隊已全部受聘並接受培訓，我們已做好啟動準備。在美國，每年有 8,000 萬名患者因中度至重度急性疼痛尋求處方治療，而 Suzetrigine 有望為他們提供變革性的治療選擇。

And in doing so, we believe we will have the opportunity to build another multibillion-dollar franchise for Vertex. Despite existing therapies, patients and providers across the US recognize the high unmet need for effective and well-tolerated pain management options.

我們相信，透過這樣做，我們將有機會為 Vertex 打造另一個價值數十億美元的特許經營權。儘管有現有的治療方法，但美國各地的患者和服務提供者都認識到，對於有效且耐受性良好的疼痛管理方案的需求仍未得到滿足。

This was underscored by a recent nationwide survey we commissioned. The State of Pain Survey included responses for more than 500 providers and 1,000 patients and highlighted the significant challenges with current moderate-to-severe acute pain treatment.

我們最近委託進行的一項全國性調查強調了這一點。疼痛狀況調查涵蓋了 500 多名醫療服務提供者和 1,000 多名患者的回复，並強調了當前中度至重度急性疼痛治療​​的重大挑戰。

Among many notable survey findings, I'd note that in contrast to the view held by some that opioid use disorder is only a risk of long-term opioid use for chronic conditions, 78% of the health care providers surveyed expressed concerns over the side effects of opioids and potential for developing addiction when treating patients for acute pain.

在許多值得注意的調查結果中，我注意到，與某些人認為阿片類藥物使用障礙只是長期使用阿片類藥物導致慢性疾病的風險的觀點相反，78% 接受調查的醫療保健提供者對副作用表示擔憂在治療急性疼痛患者時，鴉片類藥物的作用和產生成癮的可能性。

Additionally, nearly 90% of providers reported that the risk of side effects of existing therapies limits their ability to treat acute pain adequately. And two-thirds of patients indicated they would request a non-opioid option if they experience acute pain again.

此外，近 90% 的服務提供者報告稱，現有療法的副作用風險限制了他們充分治療急性疼痛的能力。三分之二的患者表示，如果再次感到劇烈疼痛，他們會要求使用非鴉片類藥物治療。

These survey findings were similar to sentiments related in our conversations with anesthesiologists and pain specialists at the recent ASA Annual Meeting, where our Phase 3 results were well received, confirming our belief that physicians are eager for a new therapeutic option to fill the gap between NSAIDs and opioids.

這些調查結果與我們在最近的ASA 年會上與麻醉師和疼痛專家的對話中表達的情緒相似，我們的第3 階段結果得到了好評，證實了我們的信念，即醫生渴望找到一種新的治療選擇來填補NSAID 之間的空白和阿片類藥物。

The views expressed in the State of Pain Survey and at ASA are not surprising given the tragic statistics surrounding opioid use. For instance, approximately 10% of acute pain patients treated initially with an opioid will go on to have prolonged opioid use, and 85,000 will develop opioid use disorder within the first year.

考慮到阿片類藥物使用的悲慘統計數據，疼痛狀況調查和 ASA 所表達的觀點並不令人驚訝。例如，最初使用鴉片類藥物治療的急性疼痛患者中約有 10% 會繼續長期使用鴉片類藥物，且 85,000 名患者會在第一年內出現鴉片類藥物使用疾患。

Overall, the cost of the opioid crisis remains stubbornly high at $180 billion per year. $60 billion of this spend is on health care costs, including an estimated $10 billion to $20 billion for the health care costs of opioid use disorder that are attributable to opioids initially prescribed for acute pain.

整體而言，鴉片類藥物危機的成本仍然高居不下，每年高達 1,800 億美元。其中 600 億美元用於醫療保健費用，包括估計 100 億至 200 億美元的阿片類藥物使用障礙的醫療保健費用，這些費用歸因於最初為治療急性疼痛而開出的阿片類藥物。

We are hearing the same survey sentiments directly in our pre-approval information exchange conversations with payers as well as targeted IDN and hospital formulary decision-makers. These conversations are going well. and we are working to accelerate both formulary and payer coverage decisions by engaging early to quantify the unmet need and highlight suzetrigine's benefit risk profile.

當我們與付款人以及目標 IDN 和醫院處方集決策者進行預先批准資訊交換對話時，我們直接聽到了同樣的調查情緒。這些對話進展順利。我們正在努力透過儘早參與來量化未滿足的需求並強調 Suzetrigine 的效益風險狀況，從而加快處方集和付款人覆蓋範圍的決策。

Ultimately, our goal is to fundamentally change the way pain is treated. Our key commercial focus for suzetrigine in 2025 is securing broad access and investing to ensure a seamless experience for patients and physicians.

最終，我們的目標是從根本上改變疼痛的治療方式。2025 年，我們對 Suzetrigine 的主要商業重點是確保廣泛的使用機會並進行投資，以確保患者和醫生獲得無縫體驗。

Therefore, we have made the strategic decision to invest in initiatives that enable smooth rapid access for patients prescribed suzetrigine. This is critical given the time-bound nature of treating acute pain. One key initiative is our work to secure national retail distribution.

因此，我們做出了策略決策，投資於能夠讓患者順利快速獲得 Suzetrigine 處方的措施。鑑於治療急性疼痛的時間限制，這一點至關重要。我們的一項重要措施是確保全國零售分銷。

Another initiative is the creation of financial and co-pay assistance programs for patients that will support patient access given expected strong demand from physicians and patients ahead of the typical payer coverage time lines. This will enable patients who are prescribed suzetrigine to receive the medicine that they and their physician think is right for them.

另一項措施是為患者制定財務和共同支付援助計劃，鑑於醫生和患者在典型的付款人覆蓋時間線之前預計會有強勁需求，該計劃將支持患者獲得醫療服務。這將使接受 Suzetrigine 處方的患者能夠獲得他們和他們的醫生認為適合他們的藥物。

Together, these elements of the launch plan will enable us to build a strong base of prescribers that will benefit the acute pain program for the long term. Our goal is to maximize the long-term value of the significant innovations in our pain pipeline, including suzetrigine in peripheral neuropathic pain, IV and oral formulations, VX-993, NaV1.7s, and potential combination therapies.

總之，啟動計畫的這些要素將使我們能夠建立強大的處方人員基礎，這將使急性疼痛計畫長期受益。我們的目標是最大限度地發揮我們疼痛治療產品線中重大創新的長期價值，包括用於治療週邊神經性疼痛的 Suzetrigine、靜脈注射和口服製劑、VX-993、NaV1.7s 和潛在的聯合療法。

We look forward to beginning to deliver on this transformational vision starting with patients with moderate-to-severe acute pain post the potential approval of suzetrigine in early 2025. Finally, we continue to see momentum on the policy front. The NOPAIN Act, which goes into effect on the first of January 2025 includes an add-on payment for novel oral non-opioids when used in the hospital outpatient and ambulatory surgery center settings.

我們期待在 2025 年初 Suzetrigine 獲得批准後，從中度至重度急性疼痛患者開始實現這一變革願景。最後，我們繼續看到政策方面的動能。《NOPAIN 法案》將於 2025 年 1 月 1 日生效，其中包括在醫院門診和門診手術中心使用新型口服非鴉片類藥物時的附加付費。

Furthermore, the proposed alternatives to PAIN Act is now cosponsored by 64 members of Congress from both parties, given its logical appeal to equalize branded and generic co-pays as well as prohibit requirements to step through opioids before a branded non-opioid can be used for Medicare Part D patients.

此外，PAIN 法案的替代方案提案現已得到兩黨64 名國會議員的共同支持，因為該提案具有合理的吸引力，可以平衡品牌藥和仿製藥的自付費用，並禁止在使用品牌非阿片類藥物之前要求使用鴉片類藥物適用於 Medicare Part D 患者。

Additionally, all 50 states have guidelines limiting opioid use and approximately 1/3 of all states require or encourage prescribers to consider non-opioid alternatives. Furthermore, there is good momentum. Over one-third of states are considering legislation to ensure that patients have equal access to non-opioid options in Medicaid and/or state-regulated plans. To conclude, there has never been a more exciting time to be at Vertex.

此外，所有 50 個州都有限制阿片類藥物使用的指導方針，大約 1/3 的州要求或鼓勵處方者考慮非阿片類藥物替代品。此外，目前發展勢頭良好。超過三分之一的州正在考慮立法，以確保患者能夠平等地獲得醫療補助和/或州監管計劃中的非鴉片類藥物選擇。總而言之，現在是 Vertex 最令人興奮的時刻。

We continue to drive sustained growth in CF with the anticipated launch of the vanzacaftor triple early next year. And we are in a new and exciting era of commercial diversification with the ongoing launch of CASGEVY in the US, Europe and the Middle East. We are executing on our launch preparations for suzetrigine in acute pain while looking forward to multiple programs in Phase 3 development and even more in the early and mid-stage pipeline.

隨著預計明年初推出 vanzacaftor 三聯療法，我們將繼續推動 CF 的持續成長。隨著 CASGEVY 在美國、歐洲和中東的持續推出，我們正處於商業多元化的全新且令人興奮的時代。我們正在進行用於治療急性疼痛的 Suzetrigine 的上市準備，同時期待著第 3 階段開發的多個項目以及早期和中期階段的更多項目。

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

我現在將電話轉給查理審查財務狀況。

Thanks, Stuart. Vertex's excellent Q3 results demonstrate once again our consistent strong performance and attractive growth profile. Third quarter 2024 revenue grew 12% year over year to $2.77 billion, with strong growth of 10% in the US and 14% outside the US. Year-to-date revenue of $8.1 billion represents 10% growth over the comparable nine-month period in 2023, including 9% growth in the US and 13% growth outside the US.

謝謝，斯圖爾特。Vertex 出色的第三季業績再次證明了我們持續強勁的業績和誘人的成長前景。2024 年第三季營收年增 12% 至 27.7 億美元，其中美國地區強勁成長 10%，美國以外地區成長 14%。年初至今的營收為 81 億美元，較 2023 年同期成長 10%，其中美國成長 9%，美國以外成長 13%。

Reported third-quarter revenue included $2 million from the first patient dosed with CASGEVY. On the expense front, Q3 2024 combined non-GAAP R&D acquired AIPR&D and SG&A expenses were $1.08 billion compared to $993 million in the third quarter of 2023.

據報道，第三季的收入包括第一位使用 CASGEVY 的患者產生的 200 萬美元。在費用方面，2024 年第三季非 GAAP 研發合併收購的 AIPR&D 和 SG&A 費用為 10.8 億美元，而 2023 年第三季為 9.93 億美元。

The Q3 operating expenses include $15 million in AIPR&D charges compared to $52 million in Q3 '23. Q3 2024 non-GAAP R&D expenses of $764 million increased 5% year over year reflecting ongoing investment in the advancement of our broad R&D portfolio, including multiple clinical trials and the absorption of Alpine Immune Sciences expenses partially offset by the transition of certain costs from R&D to COGS and inventory following Phase 3 clinical successes.

第三季的營運費用包括 1,500 萬美元的 AIPR&D 費用，而 23 年第三季為 5,200 萬美元。2024 年第三季非GAAP 研發費用為7.64 億美元，年增5%，反映了對我們廣泛研發組合推進的持續投資，包括多項臨床試驗和吸收Alpine Immune Sciences 的費用，但部分費用從研發轉移中得到抵銷在第 3 階段臨床成功之後，轉向 COGS 和庫存。

Within R&D specifically, the Q3 sequential step-up in non-GAAP R&D expenses reflects the advancement of multiple studies, including suzetrigine, pove and inaxaplin in Phase 3 programs VX-993 in Phase 2 acute and peripheral neuropathic pain studies and our ongoing work in T1D.

具體而言，在研發方面，第三季非GAAP 研發費用的連續成長反映了多項研究的進展，包括第3 階段計畫中的suzetrigine、pove 和inaxaplin，第2 階段急性和周邊神經性疼痛研究中的VX-993，以及我們正在進行的T1D。

Q3 '24 non-GAAP SG&A expenses of $300 million increased 39% versus prior year, primarily as a result of investments in the commercial organization, including launch activities for CASGEVY and onboarding of the full field force for suzetrigine in acute pain.

24 年第三季非公認會計準則銷售、一般及行政開支為3 億美元，較上年同期增長39%，主要由於對商業組織的投資，包括CASGEVY 的發布活動以及急性疼痛用藥suzetrigine 的全體現場工作人員的加入。

We reported third quarter 2024 non-GAAP operating income of $1.31 billion compared to $1.17 billion in Q3 '23. Our non-GAAP tax rate for the quarter was 19.8%, in line with the 19.4% reported in Q3 '23. We ended the quarter with $11.2 billion in cash and investments.

我們報告 2024 年第三季非 GAAP 營業收入為 13.1 億美元，而 23 年第三季為 11.7 億美元。我們本季的非公認會計準則稅率為 19.8%，與 23 年第三季報告的 19.4% 一致。截至本季末，我們的現金和投資總額為 112 億美元。

We deployed over $300 million of cash in the third quarter to repurchase 640,000 shares. And year-to-date, we have deployed over $750 million to repurchase over 1.7 million shares. Now switching to guidance. We are raising our 2024 total product revenue guidance, with one quarter remaining in the year, we have a strong line of sight to a revenue range of $10.8 billion to $10.9 billion, representing 10% revenue growth at the midpoint at current exchange rates.

我們在第三季投入了超過 3 億美元現金來回購 64 萬股股票。今年迄今為止，我們已投入超過 7.5 億美元回購超過 170 萬股。現在轉到指導。我們正在上調 2024 年總產品收入預期，在今年還剩一個季度的情況下，我們預計將收入範圍提高到 108 億美元至 109 億美元，按當前匯率計算，中間值代表 10% 的收入增長。

For Vertex operating expenses, our non-GAAP guidance continues to be a range of $4.2 billion to $4.3 billion in combined R&D and SG&A expenses, which is unchanged from the guidance provided on our last earnings call.

對於 Vertex 營運費用，我們的非 GAAP 指引繼續為 42 億美元至 43 億美元的綜合研發和銷售、一般及行政費用，這與我們上次財報電話會議上提供的指引保持不變。

For acquired IPR&D, we continue to expect approximately $4.6 billion for the year, including the Alpine asset acquisition charge recorded in the second quarter. Given that the Q2 2024 Alpine AIPR&D charge was not deductible for tax purposes, we expect the non-GAAP full year 2024 tax rate of approximately 90%.

對於收購的智慧財產權與開發 (IPR&D)，我們繼續預期今年的營收約為 46 億美元，其中包括第二季記錄的阿爾派資產收購費用。鑑於 2024 年第二季 Alpine AIPR&D 費用不可抵扣稅款，我們預計 2024 年全年非 GAAP 稅率約為 90%。

Aside from the impact of the nondeductible Alpine AIPR&D charge, our underlying full year 2024 non-GAAP effective tax rate would have remained in the range of 20% to 21%. As a result, the fourth quarter non-GAAP tax rate is also expected to be 20% to 21%.

除了不可扣除的 Alpine AIPR&D 費用的影響外，我們 2024 年全年的基本非 GAAP 有效稅率將保持在 20% 至 21% 的範圍內。因此，第四季非GAAP稅率預計也為20%至21%。

In closing, Vertex posted excellent results yet again as we delivered double-digit revenue growth, advanced our CASGEVY launch, prepared for important anticipated regulatory approvals in early 2025, progressed our pipeline to be in four Phase 3 studies, and continue to develop our mid- and earlier-stage pipeline. These and other anticipated milestones of continued progress in multiple disease areas are detailed on slide 19.

最後，Vertex 再次取得了優異的成績，我們實現了兩位數的收入增長，推進了CASGEVY 的上市，為2025 年初重要的預期監管批准做好了準備，推進了我們的產品線，進入了四項3 期研究，並繼續開發我們的中期- 以及早期階段的管道。投影片 19 詳細介紹了這些以及其他預期在多個疾病領域持續取得進展的里程碑。

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

我們期待在未來的電話會議上向您通報我們的進展情況，現在我將請蘇西開始問答環節。

(Operator Instructions) Jessica Fye, JP Morgan.

（操作員指示） Jessica Fye，摩根大通。

Hey, guys. Good evening. Thanks for taking my question and congrats on the povetacicept at ASN I believe you're targeting an at-home monthly dosing profile for that product, but we noticed the Phase 3 RAINIER trial involves post-dose monitoring.

嘿，大家好。晚安.感謝您回答我的問題，並祝賀 povetacicept 在 ASN 上取得成功，我相信您的目標是該產品的每月家庭用藥方案，但我們注意到第 3 階段 RAINIER 試驗涉及給藥後監測。

Can you talk about the work you would need to do in order to get this approved for at home delivery? Do you need to run like a human factor trial, some bridging study? And could all of that be accomplished maybe during an open-label extension portion of the trial so that the product could launch with at home dosing. Thank you.

您能談談為了獲得送貨上門的批准需要做哪些工作嗎？您是否需要進行類似人為因素試驗之類的橋接研究？所有這些是否都可以在試驗的開放標籤延長部分完成，以便產品可以以家庭用藥的方式推出。謝謝。

Hey, Jess. Let me take that question. This is Reshma. Thanks very much for the kind words. And yeah, we were very excited about the results that we showed at ASN not only on proteinuria, but the emerging GFR results as well as the results on hematuria and then, of course, the results in a related but separate B-cell-mediated condition called membranous nephropathy.

嘿，傑西。請讓我來回答這個問題。這是 Reshma。非常感謝您的善意言辭。是的，我們對在 ASN 上展示的結果感到非常興奮，不僅是關於蛋白尿的結果，還有新出現的 GFR 結果以及血尿的結果，當然還有相關但獨立的 B 細胞介導的結果這種疾病稱為膜性腎病變。

You're right, in the current protocol, there is an injection that's administered by a health care professional in the office, and as would be expected and is conventional in biologics development, we fully expect and are planning for and have had all of our regulatory interactions to have povetacicept ready to be delivered at-home monthly for commercial approval.

你說得對，在目前的協議中，有一種注射是由辦公室裡的醫療保健專業人員進行的，正如生物製劑開發的預期和常規做法一樣，我們完全預期並正在計劃，並且已經擁有了我們所有的監管互動，以便 Povetacicept 能夠每月送貨上門，獲得商業批准。

So yeah, all those plans are in place and we fully expect that for commercialization. It will be at home, monthly, small volume, subcutaneous administration.

是的，所有這些計劃都已到位，我們完全期待它們會商業化。它將在家中進行，每月一次，小容量，皮下給藥。

Thank you.

謝謝。

You bet.

當然。

Salveen Richter, Goldman Sachs. Please go ahead.

高盛的薩爾文·里希特（Salveen Richter）。請繼續。

It's nice to see the progress here. For the upcoming Phase 2 suzetrigine data and LSR, could you help frame what Vertex is looking for in the delta and the NPRS score, for the drug versus baseline, but also versus placebo recognizing that you're not powered on this front just in order to decide to move forward into this Phase 3. And Separately, if you could just help us understand the confidence in defining this patient population for your trial?

很高興看到這裡的進展。對於即將進行的2 期Suzetrigine 數據和LSR，您能否幫助構建Vertex 在增量和NPRS 評分中尋找的內容，以了解藥物與基線以及與安慰劑的對比情況，同時認識到您在這方面的能力並非僅為了決定進入第三階段。另外，您能否幫助我們了解您在試驗中確定這群患者的信心？

Yeah. Sure thing. Salveen, we are very close to having the results. So I'll let the results speak for themselves. And as I said in the prepared remarks, I do fully expect for us to be able to share them before the end of the year.

是的。當然可以。薩爾文，我們很快就要得到結果了。因此，我將讓結果來說明一切。正如我在準備好的演講中所說，我確實完全希望我們能夠在今年年底之前分享這些內容。

In terms of framing the study and what do we want to gain from the study, I would say three things. Obviously, we're looking for a good safety profile. So we're looking at the safety. But I think your question really pertains to efficacy. So on efficacy, it's a measurement within group of the VX-548 NPRS score, baseline to 12 weeks.

關於研究的框架以及我們想從研究中獲得什麼，我想說三件事。顯然，我們正在尋找良好的安全性。因此，我們正在關注安全性。但我認為你的問題實際上與功效有關。因此，就療效而言，這是對 VX-548 NPRS 評分的組內測量，從基線到 12 週。

We're looking for that number to be statistically significant. We're also looking for the magnitude, the sheer number of that NPRS score, the magnitude of that treatment effect. Same thing for the placebo arm. We're looking for the magnitude of that treatment effect. And as you rightfully pointed out, we did not power the study to be able to measure the change from baseline 548 versus placebo because that's what we intend to do in the Phase 3 study.

我們希望該數字具有統計意義。我們也正在尋找 NPRS 評分的量級、絕對數量以及治療效果的量級。安慰劑組也出現同樣的情況。我們正在尋找治療效果的程度。正如您正確指出的那樣，我們並沒有對這項研究進行動力來測量與安慰劑相比從基線 548 的變化，因為這是我們打算在第 3 階段研究中做的事情。

We need the magnitude of these treatment effects so that we can appropriately size the Phase 3 trial, assuming Phase 2 is positive. With regard to the confidence in the trial, as I said before, the results were available for the acute Phase 2 and then Phase 3, the DPN Phase 2, and now as we await the LSR data I have high confidence, and that comes from three places.

我們需要這些治療效果的大小，以便我們可以適當地確定第 3 階段試驗的規模，假設第 2 階段是正面的。關於對試驗的信心，正如我之前所說，急性第 2 階段和第 3 階段、DPN 第 2 階段的結果已經出來了，現在我們正在等待 LSR 數據，我對試驗的信心很高，這來自於三個地方。

One is the mechanism of action. Two is the building body of clinical evidence, not only in acute pain, and DPN from 548, but the predecessor molecule VX-150. And one thing that you asked directly about, which is the selection of patients, the LSR study was designed to think through what the placebo effect might be to make sure that sites were appropriately trained to make sure that we selected patients who really had LSR lumbosacral radiculopathy.

一是作用機制。二是不斷累積的臨床證據，不僅反映在急性疼痛，還有來自548的DPN，還有前身分子VX-150。您直接問到的一件事，即患者的選擇，LSR 研究旨在思考安慰劑效應可能是什麼，以確保站點經過適當的培訓，以確保我們選擇的患者確實患有 LSR 腰骶神經根病變。

And we've done that carefully through patient selection on physical exam, which is really the best way to identify these patients. So I have high confidence based on all three of those factors, including the patient selection.

我們透過體檢選擇患者仔細地完成了這項工作，這確實是識別這些患者的最佳方法。因此，基於包括患者選擇在內的所有三個因素，我都充滿信心。

Terence Flynn, Morgan Stanley

摩根士丹利的 Terence Flynn

Hi, good evening. This is Chris on for Terence. Thanks for taking our questions. Just one question on Susie. We know that you won't comment directly on its pricing, but can you provide some of the inputs that you are considering as you make decisions on how to price the drug? Thank you.

嗨，晚上好。這是克里斯，代替特倫斯。感謝您回答我們的問題。關於蘇西，我只有一個問題。我們知道您不會直接對其定價發表評論，但您能否提供一些您在決定如何為該藥品定價時考慮的意見？謝謝。

Absolutely. Stuart?

絕對地。史都華？

Yes, Chris, we're going to be taking into account the same considerations we always do for all of our medicines, and that's driven by the level of clinical benefit that we believe suzetrigine delivers. And also the unmet need that it is solving both at an individual patient level, but as importantly, at a societal level, and we'll be taking all of those inputs into account and making our pricing decision much closer to the approval time.

是的，克里斯，我們將考慮與所有藥物相同的因素，這是由我們認為 Suzetrigine 可帶來的臨床益處水平決定的。此外，它還在個人患者層面和同樣重要的社會層面解決尚未滿足的需求，我們會考慮所有這些因素，並使我們的定價決策更接近批准時間。

Thank you.

謝謝。

Mohit Bansal, Wells Fargo.

富國銀行的莫希特·班薩爾 (Mohit Bansal)。

Great. Thank you very much for taking my question. I would ask another question on LSR. So if you look at -- so the question is two parts. One, when you look at Lyrica's mechanism of action, can you just compare in contrast versus 548 and how direct VX-548 versus Lyrica? And Lyrica also, if you look at some of the subgroup analysis where people looked at neuropathic pain specifically, it does seem to have some impact in neuropathic pain. Can you confirm that? Even in LSR-related neuropathic pain. Can you confirm that? Thank you.

偉大的。非常感謝您回答我的問題。我想問另一個有關 LSR 的問題。所以如果你看一下——問題分為兩部分。首先，當您觀察 Lyrica 的作用機制時，您能否將其與 548 進行比較，以及 VX-548 與 Lyrica 的直接對比情況如何？另外，如果您看一下人們專門針對神經性疼痛進行的某些亞組分析，您會發現 Lyrica 似乎對神經性疼痛確實有一定影響。你能否證實？即使在與 LSR 相關的神經性疼痛中。你能否證實？謝謝。

Sure. So Mohit, you asked some really good questions about gabapentin or gabapentinoids. So Lyrica is an example of that versus suzetrigine. Let's tackle mechanism of action first. The mechanisms of action are completely different.

當然。所以 Mohit，你問了一些關於加巴噴丁或加巴噴丁類藥物的非常好的問題。因此，Lyrica 就是與 Suzetrigine 相對照的一個例子。讓我們先來討論一下作用機制。作用機製完全不同。

So the gabapentinoids work because they are -- they were discovered and developed originally as antiepileptic medicines, and what they do is depress the central nervous system. That's how those medicines work. It doesn't really have anything to do with pain, neuropathic pain or otherwise. The way that the suzetrigine molecule or VX-548 works, is it specifically acts on NaV1.8 channels that are specifically found in sea fibers, that are only in the peripheral nervous system.

加巴噴丁類藥物之所以有效，是因為它們最初是作為抗癲癇藥物被發現和開發的，它們的作用是抑制中樞神經系統。這些藥物就是這樣起作用的。它實際上與疼痛、神經性疼痛或其他疼痛沒有任何關係。Suzetrigine 分子或 VX-548 的作用方式是，它專門作用於海纖維中特有的 NaV1.8 通道，而海纖維僅存在於週邊神經系統中。

And the reason for the confidence based on mechanism of action, again, when we were waiting for the acute pain results and the DPN results in the same confidence frankly, here as we wait for LSR results is because of that very specific mechanism of action, pain signal the way we feel paid is by way of the action potential being propagated by what are called these NAV channels.

再次強調，當我們等待急性疼痛結果和 DPN 結果時，我們之所以有信心，是因為作用機制具有這種信心，坦白說，當我們等待 LSR 結果時，是因為這種非常具體的作用機制，疼痛訊號，我們感受到回報的方式是透過所謂的NAV 通道傳播的動作電位。

So that's on the mechanism of action. On Lyrica and where did they have positive results. I can speak to the high level of gabapentinoids and the gabapentin noise have had positive results. And as you know, they are indicated for diabetic peripheral neuropathy. However, they did not have positive results for LSR.

這就是作用機制。關於 Lyrica 以及他們在哪裡取得了積極成果。我可以說高水準的加巴噴丁類藥物和加巴噴丁噪音已經產生了正面的結果。如您所知，它們適用於治療糖尿病週邊神經病變。然而，他們對 LSR 並未取得積極成果。

Now it is entirely possible that in some studies or in some subgroups there could have been some signal, but I won't comment on that. I will tell you that it is not approved in the US for LSR.

現在完全有可能在某些研究或某些亞群中出現一些訊號，但我不會對此發表評論。我要告訴你的是，美國尚未批准使用 LSR。

Helpful. Thank you.

很有幫助。謝謝。

Sure thing.

當然可以。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Hi, guys, good evening. Thanks for taking questions. As we think about LSR and read-throughs to the other indications that you're pursuing, regardless of whatever the data shows for LSR, should we try to have a read-through as to what the results could mean for example, which I think is reading out next year. And then secondly, I did want to ask about news from a competitor Orion Corporation.

大家好，晚上好。感謝您的提問。當我們考慮 LSR 並通讀您正在研究的其他適應症時，無論 LSR 數據顯示什麼，我們是否應該嘗試通讀結果可能意味著什麼，例如，我認為明年會完成。其次，我確實想詢問有關競爭對手 Orion Corporation 的消息。

I believe, recently announced that it's NaV1.8 ODM-111 was discontinued in both acute as well as chronic pain studies, they said in the press release due to a narrow therapeutic window. I was curious if there was any interpretation to make from that molecule not moving forward given the similarity and mechanism of action. Thanks.

我相信，他們最近宣布其 NaV1.8 ODM-111 在急性和慢性疼痛研究中都已停止使用，他們在新聞稿中說，原因是治療窗口狹窄。我很好奇，考慮到相似性和作用機制，是否可以對該分子無法向前移動做出任何解釋。謝謝。

Sure thing. Tazeen, let's take on the question you asked about the molecule that was discontinued it doesn't surprise me, and I won't comment directly on that molecule. But the reason I say it doesn't surprise me is that many, many companies have worked for many, many years, if not decades, to try and tackle NaV1.7 and NaV1.8, including ourselves.

當然可以。Tazeen，讓我們來回答一下你提出的關於停產分子的問題，這並不讓我感到驚訝，而且我不會直接對該分子發表評論。但我之所以說這並不讓我感到驚訝，是因為包括我們自己在內的許多公司都已經努力了很多年，甚至幾十年，試圖解決 NaV1.7 和 NaV1.8 問題。

And the challenge has long been -- let me start with the reason people have been targeting Nav1.7, 1.8 many people call it the holy grail of potential targets in pain conditions because it is so specific to the transmission of pain. The challenge has been that the NaV1.1 through NaV1.9 channels are similar, and as people have tried to discover drugs that target NaV1.7 or 1.8, they run into serious challenges in coming up with molecules with specificity, which is why I say I'm not surprised at all.

而挑戰一直存在——讓我先從人們瞄準 Nav1.7、1.8 的原因開始說起，許多人稱它為疼痛狀況下潛在目標的聖杯，因為它對疼痛的傳遞非常具體。挑戰在於 NaV1.1 到 NaV1.9 通道相似，當人們試圖發現針對 NaV1.7 或 1.8 的藥物時，他們在提出具有特異性的分子方面遇到了嚴峻的挑戰，這就是為什麼我說我一點也不驚訝。

Our molecule is 40,000 fold more specific. It is very, very specific for the NaV1.8 channel versus anything else. I'll tackle your second question about how should we think about LSR versus DPN. Well, the commonality is that there are both types of peripheral neuropathic pain. But no, I wouldn't see any reason to relate the LSR data to the DPN data the 548 same molecule that's already in DPN is in Phase 3 development.

我們的分子特異性提高了40,000倍。與其他任何通道相比，它對於 NaV1.8 通道來說都非常非常具體。我將回答您的第二個問題：我們應該如何看待 LSR 與 DPN。嗯，共同點是兩種類型的周邊神經性疼痛都存在。但不，我看不出將 LSR 資料與 DPN 資料關聯起來的任何理由，DPN 中已經存在的 548 個相同分子正處於第 3 階段開發中。

We've already had regulatory interactions. We've completed our end of Phase 2 meetings. We -- as I said in my prepared remarks, we are well on our way in terms of the Phase 3 trial, screening, enrollment and dosing and I don't expect any changes.

我們已經進行了監管互動。我們已經結束了第二階段的會議。正如我在準備好的演講中所說，我們在第 3 階段試驗、篩選、招募和劑量方面進展順利，我預計不會有任何變化。

Michael Yee, Jefferies.

傑富瑞 (Jefferies) 的麥可餘 (Michael Yee)。

We had two pipeline questions. We are excited about the idea you have 993 as well, which is the second compound for NaV1.8. I just wanted to understand if there is a significant benefit other than potency. Because I don't recall the 548 with PK or exposure limited. So I think that you're getting plenty of drug on board, and you've already had some pretty good results.

我們有兩個管道問題。我們對您擁有 993 的想法感到非常興奮，它是 NaV1.8 的第二種化合物。我只是想知道除了效力之外是否還有其他顯著的好處。因為我不記得 548 有 PK 或曝光限制。因此我認為你已經使用了足夠的藥物，並且已經取得了一些相當不錯的效果。

So I just wanted to understand if 993 despite being more potent -- significant other properties that would get better on the NaV1.8 channel in the clinic. Our second question is actually a simple one on APOL1, which I know is -- hasn't been talked about too much here, but given the positive regulatory environment that we are seeing in IgAN, I was just wondering if you believe that on the one-year interim you could probably file on UPCR, just remind us what you've said and what you think you could do on the one-year data?

因此，我只是想了解 993 儘管功效更強，但其其他重要特性在臨床上是否會在 NaV1.8 通道上變得更好。我們的第二個問題實際上是關於 APOL1 的一個簡單問題，我知道這裡還沒有討論太多，但考慮到我們在 IgAN 中看到的積極監管環境，我只是想知道您是否認為您可能可以在UPCR 上提交一年期中期報告，只要提醒我們您說過什麼以及您認為您可以對一年期數據做些什麼？

Yeah. Sure thing. Let me tackle 991. Michael, as you know, across our entire portfolio, every single lead asset has a follow-on asset, and that is because if it is humanly possible to do better, just like we did in CF, we are committed to be the ones who do so. So one purpose of 993 is in that vein of serial innovation.

是的。當然可以。讓我來解決 991。Michael，如你所知，在我們的整個投資組合中，每一項領先資產都有一項後續資產，這是因為如果人力可以做得更好，就像我們在CF 中所做的那樣，我們致力於於成為這樣做。所以993的一個目的就是要實現連續創新。

And if we can do better, we're going to be the ones who do it. The second reason specifically is we seek to really be broad in the pain space. VX-548 cannot be formulated into an IV formulation, 993 can. So that's the second reason for 993. And the third reason is we're making good progress with our NaV1.7 program.

如果我們能夠做得更好，我們就會成為這樣做的人。具體來說，第二個原因是我們尋求真正拓寬痛苦空間。VX-548 不能配製成 IV 製劑，而 993 可以。這就是 993 的第二個原因。第三個原因是我們的 NaV1.7 計畫取得了良好進展。

That's still in preclinical development. But as that program progresses, we'd like to identify the best potential NaV1.8 to be used with NaV1.7, whether that's 548, whether it's 993 and/or other molecules is a third reason that we're developing 993. So we have the most optionality for the best pairing of the NaV1.7 program, which could be used alone or in combination with NaV1.8.

該技術仍處於臨床前開發階段。但隨著該專案的進展，我們希望確定與 NaV1.7 一起使用的最佳潛在 NaV1.8，無論是 548，還是 993 和/或其他分子，這是我們開發 993 的第三個原因。因此我們對 NaV1.7 程序的最佳搭配擁有最大的選擇性，既可以單獨使用，也可以與 NaV1.8 結合使用。

And then moving to the question on inaxaplin, this is a program in APOL1-mediated kidney disease. This program is in Phase 3 development, and we are continuing with the enrollment in this program. You asked a really interesting question about the regulatory environment. It does seem to be evolving right in front of our eyes here in renal medicine, particularly in homogeneous proteinuric kidney diseases. We had our end of Phase 2 meeting with the regulator some time ago.

然後轉到有關 inaxaplin 的問題，這是一個 APOL1 介導的腎臟疾病的項目。該計劃目前處於第 3 階段開發，我們正在繼續進行該計劃的招生工作。您問了一個有關監管環境的非常有趣的問題。在腎臟醫學領域，它似乎確實正在我們眼前發展，特別是在均質性蛋白尿性腎臟病領域。我們不久前與監管機構舉行了第二階段會議。

So before the more recent discussions in FSGS and what we've said in our agreements pertain to a potential accelerated approval with a certain number of patients at the 1-year time point with endpoint read on GFR slope. But it's terrific to see the discussions continue on whether proteinuria in and of itself can be an endpoint for other proteinuric kidney diseases.

因此，在最近關於 FSGS 的討論之前，我們在協議中所說的內容涉及在 1 年時間點對一定數量的患者進行潛在的加速批准，並以 GFR 斜率作為終點讀數。但很高興看到關於蛋白尿本身是否可以成為其他蛋白尿性腎病變的終點的討論仍在繼續。

Evan Seigerman, BMO Capital Markets.

埃文·塞格曼 (Evan Seigerman)，BMO 資本市場。

Okay. Thank you so much for taking my question. So now that you had a patient go through the full CASGEVY commercial process, can you discuss what you learned about the administration? What went well? What do you hope to optimize further? And when do you expect to dose the next patient? Thank you.

好的。非常感謝您回答我的問題。那麼，現在您已經讓病患經歷了完整的 CASGEVY 商業流程，您能討論一下您對管理的了解嗎？哪些方面進展順利？您希望進一步優化什麼？您預計什麼時候給下一位病人服藥？謝謝。

Yeah. Sure thing. Let me turn that over to Stuart, Evan.

是的。當然可以。讓我把這個交給斯圖爾特，埃文。

Yes, Evan. I think I covered much of this on our Q2 call actually that we've learned an awful lot, as you always do when you were out there post approval, commercializing a medicine in the real world as it were. And I think we've learned or reinforced our learnings that we went into that we know that this is a very big decision for a patient and the physician, but particularly for the patient to make to embark on what is a lengthy treatment journey, but we know that there is significant enthusiasm for that because there is the potential for lifetime future benefit.

是的，埃文。我想我在第二季電話會議上已經討論了很多這方面的內容，實際上我們學到了很多東西，就像你在獲得批准後在現實世界中將藥物商業化時總是做的那樣。我認為我們已經學到或強化了我們的知識，我們知道這對患者和醫生來說是一個非常重大的決定，但對於患者來說，特別是要開始一段漫長的治療之旅，但我們知道，人們對此有很高的熱情，因為這有可能為人們的未來帶來終生利益。

So we've learned that it is a big decision and that is taking a lot of time for physicians and patients to have those discussions to want -- to embark on that journey. And that includes discussions at the beginning before the cell collection process begins, but also includes discussions at the end of the process when scheduling the actual CASGEVY infusion because obviously, that part of the process entails the patient being an inpatient for a number of weeks.

因此，我們了解到這是一個重大的決定，醫生和患者需要花費大量時間進行討論並踏上這段旅程。這包括在細胞收集過程開始之前的討論，也包括在過程結束時安排實際的 CASGEVY 輸注時的討論，因為顯然，該部分過程需要患者住院數週。

And obviously, that is a significant disruption to anybody's life. And so that is something in which they need to think very carefully about when they are, they're going to take time out from their normal life to go through the final step in the process. I guess a couple of the other things that we've learned is that authorized treatment centers are also very keen to sign up for the potential to be able to provide CASGEVY to their patients.

顯然，這會對任何人的生活帶來嚴重干擾。因此，他們需要非常仔細地考慮這一點，他們需要從日常生活中抽出時間來完成這個過程的最後一步。我想，我們也了解到的其他一些事情是，授權治療中心也非常熱衷於簽約，希望能夠為他們的患者提供 CASGEVY。

And I'd say the last thing that we've learned is that, the enthusiasm that payers and policymakers showed when the product was initially approved around the scientific advance that CASGEVY represents has really translated into excitement to want to be able to provide this medicine to their patients.

我想說的是，我們了解到的最後一件事是，當該產品最初獲得批准時，付款人和政策制定者對CASGEVY 所代表的科學進步表現出的熱情，實際上已經轉化為希望能夠提供這種藥物的興奮給他們的病人。

And we've seen that here in the US where reimbursement is not an access barrier to patients initiating. And we've seen that we've been able to secure reimbursement agreements in, for instance, the UK for TDT. We have early access programs, for instance, in Italy. And also, we have good access in Saudi Arabia, which is as we've said before, has a particularly high prevalence of disease.

我們已經看到，在美國，報銷並不是病人就醫的障礙。我們已經能夠在英國等地達成 TDT 的報銷協議。例如，在義大利，我們有早期訪問計劃。而且我們在沙烏地阿拉伯也有良好的管道，正如我們之前所說，沙烏地阿拉伯的疾病發生率特別高。

So I say we learn things on all elements, patients, physicians and payers and policymakers and we'll continue to learn as we move forward.

所以我說我們要從各個方面學習，包括病人、醫生、付款人和政策制定者，而且我們會在前進的過程中繼續學習。

Phil Nadeau, TD Cowen.

菲爾·納多（Phil Nadeau），TD Cowen 公司。

Good afternoon and congrats on the progress. And a question for Stuart as well on suzetrigine's commercializations. Stuart, you mentioned in the prepared remarks that contracting discussions are underway. And then you also gave I think one example of strategic initiatives in the co-pay assistance programs. Could you further characterize the contracting discussions, how are those going?

下午好，祝賀你的進展。還有一個問題要問斯圖爾特，關於 Suzetrigine 的商業化。斯圖爾特，您在準備好的發言中提到，合約談判正在進行中。我認為您也給出了共同支付援助計劃中的策略舉措的一個例子。您能否進一步描述簽約談判的進展？

Does insurance understand the need for new non-opioid options. And then in terms of the strategic initiatives, is it mainly on co-pay assistance? Or are there other strategic initiatives that are also underway.

保險公司是否了解新的非鴉片類藥物選擇的必要性。那麼就策略措施而言，主要是共同支付援助嗎？或者還有其他正在進行的策略性舉措。

Yes, Phil, thanks for the question. So I would say that the conversations with payers are going very well. There is a high degree of appreciation for the unmet need, not surprisingly. And there is a lot of enthusiasm for a new treatment option, which has the benefit risk profile that suzetrigine has, the first novel, non-opioid medicine for literally decades. So high level of enthusiasm for it, not surprisingly, payers are aware of just how many patients suffer from acute pain in the United States.

是的，菲爾，謝謝你的提問。所以我想說與付款人的對話進展非常順利。毫不奇怪，人們高度重視尚未滿足的需求。人們對這種新的治療選擇抱有很高的熱情，它具有與 Suzetrigine 相同的益處和風險特徵，Suzetrigine 是幾十年來第一種新型非鴉片類藥物。人們對它的熱情如此之高，毫不奇怪，付款人知道美國有多少患者患有急性疼痛。

And so they are thinking their way through budget impact. So we're very early in those discussions. But our focus, and I would like to think there is to make sure that as close as possible to approval, we can make sure that we have reimbursed access so that physicians and patients can get access to the medicine that they want to use. So I would say those discussions are going very well. I pointed to a couple of initiatives that I think are really, really important, [Evan].

因此他們正在思考如何解決預算影響。所以我們對這些問題的討論還處於早期階段。但我們的重點是，我想確保盡可能接近批准，我們可以確保擁有報銷管道，以便醫生和患者可以獲得他們想要使用的藥物。所以我想說這些討論進展非常順利。我指出了幾個我認為非常非常重要的舉措，[埃文]。

You picked up on one of them. whilst the discussions are going very well, we know that there is often a lag between approval and having reimbursed access as payers have to work through their normal process. And obviously, we're trying to accelerate that. But we are anticipating there will be some lag for some patient groups. And there, you really have two choices.

你選了其中一個。雖然討論進展順利，但我們知道，由於付款人必須通過正常流程，因此批准和報銷之間往往存在滯後。顯然，我們正在努力加速這一進程。但我們預期某些患者族群會感到有些延遲。其實，你有兩個選擇。

You can accept there's going to be a lack -- a gap, sorry, and some patients don't have reimbursed access and so therefore, won't get access. Or you can try and solve that problem whilst the plans are working on reimbursed access and coming up with their final policies. And we've chosen to solve it. We know there's going to be a lot of enthusiasm from physicians and patients who want to try suzetrigine. We want to make sure that we are doing everything we can to make that a seamless experience even if the plan hasn't yet made a final decision.

你可以接受存在不足 — — 存在差距，很抱歉，有些病人沒有報銷資格，因此無法獲得治療。或者，您可以在計劃進行報銷訪問並製定最終政策的同時嘗試解決該問題。我們選擇解決這個問題。我們知道，醫生和患者將會非常熱情地嘗試 Suzetrigine。即使該計劃尚未做出最終決定，我們也希望確保盡一切努力提供無縫體驗。

The one other area I would share with you, which I pointed out is retail distribution. Obviously, patients in acute pain can't wait. And so when they turn up at a retail pharmacy with a prescription for suzetrigine, that's suzetrigine needs to be there on the shelf so that the pharmacist can dispense it. And so one of the other areas that we are spending a lot of time focused on is ensuring there's national retail distribution of suzetrigine, again, as close as possible to approval as we can. So that's a couple of areas that we are working on.

我想與大家分享的另一個領域，也就是我所指出的零售分銷。顯然，處於急性疼痛中的病人不能等待。因此，當他們拿著蘇金剛處方來到零售藥局時，貨架上就必須有蘇金剛處方，以便藥劑師可以配發。因此，我們花費大量時間關注的另一個領域是確保 Suzetrigine 的全國零售分銷盡可能接近批准。這是我們正在努力的幾個領域。

Debjit Chattopadhyay, Guggenheim Partners.

古根漢合夥人公司的 Debjit Chattopadhyay。

A good evening and thank you for questions, which is on inaxaplin. Given the recent traction when should we expect enrollment completion? And additionally, given the historically low compliance rates for antihypertensive? How big could inaxaplin be in the growing Vertex renal franchise? Thanks.

晚上好，感謝您的提問，主題是 inaxaplin。鑑於最近的發展勢頭，我們什麼時候可以完成招生？此外，鑑於歷史上抗高血壓的依從率較低？在不斷增長的 Vertex 腎臟疾病特許經營中，inaxaplin 能佔多大比重？謝謝。

Debjit, this is Reshma. I'll turn it over to Stuart to give you a sense of the commercial opportunity here. With regard to enrollment completion, we haven't given guidance on that, and I'm going to leave it at that for now. I will just remind Debjit, that there's two enrollments to be aware, one is enrollment to get us to the time point for accelerated approval. And then second is the enrollment for the completion of the full study.

Debjit，這是 Reshma。我將把話題交給斯圖爾特，讓他讓你了解這裡的商業機會。關於完成入學，我們還沒有給予指導，現在我就不會再說了。我只想提醒 Debjit，有兩項註冊需要注意，一項是註冊以讓我們達到加速批准的時間點。第二是入學，完成整個學習。

Obviously, it's going to be faster to get to the enrollment number, which we also haven't shared, but it's a subset of the overall enrollment for the accelerated enrollment time point. Stuart, do you want to comment a little bit on commercial opportunity for inaxaplin, and Debjit points out, there is a large growing renal franchise here.

顯然，取得入學人數會更快，我們還沒有分享這個數字，但這是加速入學時間點的整體入學人數的子集。斯圖爾特，你想對 inaxaplin 的商業機會發表一些評論嗎？

Yes. So in terms of commercial potential, we know that there is approximately 100,000 or so patients living with AMKD between the US and Europe. The vast majority of which are here in the United States. So there is a very, very significant commercial opportunity if we can deliver on the first product, which is actually treated the underlying cause of disease for these patients.

是的。因此就商業潛力而言，我們知道美國和歐洲大約有 10 萬名 AMKD 患者。其中絕大多數都在美國。因此，如果我們能夠推出第一個能夠真正治療這些患者疾病根本原因的產品，那麼這將是一個非常非常重要的商業機會。

Now I say there are about 100,000 or estimated to be about 100,000 patients living with the disease. Many of them are undiagnosed and not genotyped at this point in time, given the fact that the gene was only discovered approximately 14 years or so ago.

現在我說大約有10萬，或估計大約有10萬名患者患有這種疾病。由於該基因僅發現於大約 14 年前，因此其中許多疾病目前尚未被診斷和基因分型。

And so this is a very new disease. So obviously, this is going to require a large amount of disease awareness, increases in diagnosis and certainly genotyping, and we are already supporting initiatives like that. But in terms of total potential, as I say, over 100,000 patients, and therefore, we think in explant has a multibillion-dollar opportunity ahead of it.

這是一種非常新的疾病。因此顯然，這將需要大量的疾病意識、增加診斷和基因分型，我們已經在支持這樣的措施。但就總潛力而言，正如我所說，超過100,000名患者，因此，我們認為植入物面前有數十億美元的機會。

Olivia Brayer, Cantor Fitzgerald.

奧莉維亞·布雷爾，費茲傑拉領唱者。

Hi, good afternoon and thank you for the question. I wanted to follow up on LSR. What's the internal bar for actually moving VX-548 into a registrational program? Do you need to see a certain delta versus what the placebo arm shows at 12 weeks? Or would a faster separation in the initial first few weeks on treatment versus placebo actually be enough of a signal to take it forward. I guess what I'm asking, right, is if those two curves were to come together at the end of 12 weeks, what signal would be enough to move it forward, if that makes sense. Thank you.

大家下午好，感謝您的提問。我想跟進 LSR。將 VX-548 實際移入註冊程序的內部標準是什麼？您是否需要查看與 12 週時安慰劑組的具體差異？或者，與使用安慰劑相比，治療前最初幾週內更快的分離是否足以作為繼續推進治療的信號。我想問的是，如果這兩條曲線在 12 週結束時匯合在一起，什麼訊號足以推動它向前發展，如果這說得通的話。謝謝。

Yes, hi, Olivia, this is Reshma. I really do understand the question. what I said earlier, I think, is the best way to understand what we're looking for. We're looking for good safety.

是的，你好，奧利維亞，我是 Reshma。我確實明白這個問題。我認為，我之前所說的是理解我們在尋找什麼的最好方式。我們正在尋求良好的安全。

And we're looking for the magnitude of the treatment effect in the 548 arm and the magnitude of the treatment effect in the placebo arm. You're very right to point out that there's going to be consideration that we give to when the curve separate, we're going to look at all of the details of the NPRS score, we're going to look at subgroups.

我們正在尋找 548 組的治療效果大小和安慰劑組的治療效果大小。您指出得非常正確，我們會考慮曲線分離的情況，我們會查看 NPRS 分數的所有細節，我們會查看子群。

We're going to do all of the things that you would expect us to do. The key point is we want to see the magnitude of the treatment effect, so we can appropriately size that Phase 3 trial, assuming that the data are supportive. As I said before, it's not too much longer that we have to wait.

我們將會做所有你們期望我們做的事情。關鍵是我們希望看到治療效果的大小，因此，如果數據支持，我們就可以適當地確定第 3 階段試驗的規模。正如我之前所說，我們不需要等待太久。

And then once we have the data, we'll certainly be able to talk in a very fulsome manner about exactly what the basis of our decision making is and talk further about the potential Phase 3 study. Olivia, I'll just use this moment to correct on the question that I think it was -- Mohit, who asked earlier, it could have been to seem it is 30,000 fold more sensitive to NaV1.8 than anything else. I said 40,000.

一旦我們獲得了數據，我們肯定能夠以非常全面的方式談論我們決策的基礎究竟是什麼，並進一步討論潛在的第三階段研究。奧莉維亞，我只是想利用這個時間來糾正這個問題，我認為是——莫希特之前問過，它對 NaV1.8 的敏感度似乎比其他任何東西都要高 30,000 倍。我說的是4萬。

And we can go on to the next question then. Then it will be our last question, please. Yes, Matt,

那我們可以繼續討論下一個問題。那麼這是我們的最後一個問題。是的，馬特，

Liisa Bayko, Evercore ISI.

Liisa Bayko，Evercore ISI。

Hi, thanks for squeezing me in. I was curious to follow up on something that Stuart had indicated earlier, and that was the anticipation of no prior authorization for suzetrigine? And what are the factors that you can influence that can decide that? And how confident are you that will be the case? Because that seems that we did a doc call and it seems like the no barriers to getting drug is really critical. And it seems like this would be a really key one and you honed in on it. So curious how confident you are, what leverage you have there. Thanks.

你好，謝謝你擠進來。我很好奇，想跟進一下斯圖爾特之前提到的一點，那就是預計 Suzetrigine 不會獲得事先授權？那麼您可以影響哪些因素來決定這一點呢？您對於這種情況有多大信心？因為這似乎已經是我們打過電話給醫生了，而且看起來獲取藥物的無障礙確實至關重要。這似乎是一個非常關鍵的問題，而你對它進行了深入研究。所以很好奇你有多自信，你有什麼影響力。謝謝。

Stuart, maybe you could comment both on the policy front and the other work that you're doing on the commercial front.

斯圖爾特，也許你可以就政策方面以及你在商業方面所做的其他工作發表評論。

Yes. So Lisa, thanks for the question. So on the policy side of things, we've already seen that there are a significant sensitivity to the fact that the utilization management controls that can get put in place, particularly for brands versus generics could be a barrier to suzetrigine being launched, which is why we referred to the alternatives to PAIN Act, which is looking to prohibit exactly that thing for our Medicare Part D beneficiaries. In our discussions with the other plans that we are talking to through our preapproval information exchanges that is one of the topics that we are talking about. Obviously, there is the level of unmet need.

是的。所以麗莎，謝謝你的提問。因此，在政策方面，我們已經看到，人們對可能實施的使用管理控制（特別是針對品牌藥與仿製藥）非常敏感，這可能會成為 Suzetrigine 上市的障礙，這就是為什麼我們要提及PAIN 法案的替代方案，該法案旨在禁止我們的聯邦醫療保險D 部分受益人做這樣的事情。當我們透過預先批准的資訊交換與其他計劃進行討論時，這是我們正在討論的主題之一。顯然，還有一定程度的需求未被滿足。

Obviously, we are able to talk in a compliant way about the benefit risk profile of suzetrigine, but we are also talking about what are some of the conditions which people might seek to use to provide reimbursed access. Obviously, different providers and plans have different controls often prior authorizations are required, even if they aren't combined with other types of controls.

顯然，我們能夠以合規的方式談論 Suzetrigine 的效益風險狀況，但我們也在談論人們可能尋求使用哪些條件來提供報銷服務。顯然，不同的提供者和計劃有不同的控制，通常需要事先授權，即使它們不與其他類型的控制相結合。

So for instance, I could still imagine somebody needing to have a prior authorization for a suzetrigine prescription certainly before a plan has made a definitive coverage decision. What I couldn't imagine is somebody having a prior roll-off, which requires a patient to step through a generic opioid before getting to suzetrigine.

因此，例如，我仍然可以想像，在計劃做出最終的承保決定之前，某人肯定需要獲得 Suzetrigine 處方的事先授權。我無法想像有人會經歷先前的停藥，這需要患者在服用 Suzetrigine 之前先服用通用鴉片類藥物。

So I don't think there's really one answer to your question, Lisa, because prior offs they used in very, very different ways. But we are looking to make it as easy as possible for physicians and patients because we know there is going to be such broad enthusiasm for suzetrigine when it's approved, hopefully in the early part of 2025.

因此，麗莎，我認為你的問題實際上沒有一個答案，因為他們之前使用的方式非常非常不同。但我們希望盡可能為醫生和患者提供便利，因為我們知道，當 Suzetrigine 獲得批准時，人們將對其產生廣泛的熱情，希望在 2025 年初。

Thank you.

謝謝。

This will conclude our question-and-answer session as well as our conference call for today. 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 using replay access code 10187025. Thank you for your participation today. You may now disconnect.

我們的問答環節以及今天的電話會議到此結束。感謝您參加今天的演講。通話結束後不久即可撥打 1-877-344-7529 或 1-412-317-0088（重播接入碼 10187025）收聽今天活動的重播。感謝您今天的參與。您現在可以斷開連線。