福泰製藥 (VRTX) 2026 Q3 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals third-quarter 2026 earnings call. (Operator Instructions) Please note this event is being recorded.

各位好，歡迎參加 Vertex Pharmaceuticals 2026 年第三季財報電話會議。(接線員指示) 請注意，本活動將被錄音。

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

現在我想將會議交給 Susie Lisa 女士。請開始。

Good evening, all. 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 2026 financial results conference call.

各位晚安。我叫 Susie Lisa，身為投資人關係資深副總裁，我很高興歡迎各位參加我們 2026 年第三季財務結果電話會議。

On tonight’s call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex’s CEO and President; Charlie Wagner, Chief Operating Officer and Chief Financial Officer; and Duncan McKechnie, Chief Commercial Officer. Given the January 1 transition by Charlie to the COO role solely, please note that this is his last quarterly earnings call. His successor, Jonathan Poole, our current SVP of Finance, will join us for our Q4 2026 call in February. 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.

今晚的電話會議中，將由 Vertex 執行長兼總裁 Reshma Kewalramani 醫師、營運長兼財務長 Charlie Wagner，以及商務長 Duncan McKechnie 發表事先準備的談話。鑑於 Charlie 將於 1 月 1 日轉任僅擔任營運長（COO）的職務，請注意這將是他最後一次季度財報電話會議。他的繼任者、現任財務資深副總裁（SVP）Jonathan Poole，將於 2 月的 2026 年第四季（Q4 2026）電話會議加入我們。我們建議您在收聽本次電話會議時，同步開啟網路直播簡報投影片。本次電話會議將被錄音，重播將於我們的網站提供。

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.

我們將在本次電話會議中作出前瞻性陳述，該等陳述受今日新聞稿及我們向美國證券交易委員會（SEC）提交之文件中所詳述的風險與不確定性影響。

These statements, including without limitation those regarding Vertex’s marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia, moderate to severe acute pain, and acromegaly, our pipeline, the recently completed acquisition of Crinetics Pharmaceuticals and the expected benefits of that transaction, and Vertex’s future financial performance are based on management’s current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis.

這些陳述（包括但不限於）關於 Vertex 已上市之囊性纖維化、鐮狀細胞疾病、β 地中海型貧血、中度至重度急性疼痛與肢端肥大症藥物，我們的研發管線，近期完成對 Crinetics Pharmaceuticals 的收購及該交易的預期效益，以及 Vertex 未來財務表現，均係基於管理層目前的假設。實際結果與事件可能出現重大差異。我也要指出，今晚電話會議中將檢視的部分財務結果與財測指引係以非 GAAP 基礎呈現。

I’ll now turn the call over to Reshma.

接下來我把電話交給 Reshma。

Thanks, Susie. Good evening, all, and thank you for joining us on the call today. I’m pleased to note that Vertex achieved another quarter of excellent commercial results and pipeline advancement.

謝謝你，Susie。各位晚安，感謝各位今天加入我們的電話會議。我很高興指出，Vertex 再次達成一個季度的優異商業成果與研發管線推進。

Third quarter total revenue grew 12% year on year. Revenue growth was nicely balanced, coming from both the US and international, from CF, and from our two more recently launched medicines, CASGEVY and JOURNAVX, as well as a contribution from PALSONIFY for the month of September, post-close of the Crinetics acquisition. Rare endocrine is now our fourth commercial pillar, and with the PDUFA date later this month for povetacicept in IgA nephropathy, or IgAN, we plan to soon establish our fifth in renal.

第三季總營收年增 12%。營收成長來源相當均衡，來自美國與國際市場、來自囊性纖維化（CF），以及我們近期推出的兩項藥物 CASGEVY 與 JOURNAVX；此外，Crinetics 收購案完成交割後，PALSONIFY 亦在 9 月份貢獻了一個月的營收。罕見內分泌現已成為我們第四個商業支柱；而隨著本月稍晚 povetacicept 用於 IgA 腎病變（IgA nephropathy，或 IgAN）的 PDUFA 日期到來，我們計畫很快在腎臟領域建立第五個支柱。

Before turning to the R&D update, I want to acknowledge Charlie’s final and 31st earnings call as CFO. Charlie’s leadership, integrity, judgment, and intellectual rigor are unparalleled. He has deftly helped lead our transition from a CF-only company with $4 billion in revenue in 2019 to a company soon to be commercialized in five disease areas with more than triple the revenue, with our guidance for over $13 billion in 2026.

在進入研發（R&D）更新之前，我想先致意 Charlie 作為財務長（CFO）的最後一次、也是第 31 次財報電話會議。Charlie 的領導力、正直、判斷力與嚴謹的智識水準無人能及。他巧妙地協助帶領我們從 2019 年一家僅有 CF 產品、營收 40 億美元的公司，轉型為一家即將在五個疾病領域實現商業化、營收超過三倍的公司；我們對 2026 年的指引為超過 130 億美元。

I look forward to continuing to work with Charlie in his role as COO, driving forward the Crinetics integration and our key priorities as we grow and scale the company. I can't think of no better successor to Charlie than Jonathan Poole, our Senior Vice President and current Head of Finance, who will take over as CFO January 1, 2027.

我期待在 Charlie 擔任營運長（COO）的角色下持續與他合作，推動 Crinetics 的整合，以及我們在公司成長與規模化過程中的關鍵優先事項。我想不到有比我們的資深副總裁、現任財務主管 Jonathan Poole 更適合接任 Charlie 的人選；Jonathan 將於 2027 年 1 月 1 日接任財務長（CFO）。

Moving now to the R&D update for the quarter. I will cover four disease areas: CF, endocrinology, both rare endocrine disorders and type 1 diabetes, and renal in detail.

接下來進入本季研發（R&D）更新。我將詳細涵蓋四個疾病領域：囊性纖維化（CF）、內分泌（包含罕見內分泌疾病與第一型糖尿病），以及腎臟領域。

But first, let me start with quick highlights from 4 other programs. In severe sickle cell disease and transfusion-dependent beta thalassemia, we were pleased to have recently received approval for CASGEVY in patients ages 2 to 11 in the US, UAE, Bahrain, as well as in patients ages 5 to 11 in the UK.

但首先，讓我先快速重點更新另外 4 個專案。在重度鐮狀細胞疾病與需輸血之 β 地中海型貧血方面，我們很高興近期已在美國、阿聯酋、巴林核准 CASGEVY 用於 2 至 11 歲患者，並在英國核准用於 5 至 11 歲患者。

In pain, along with the strong growth in prescriptions, we are also seeing fast growth in the body of compelling JOURNAVX real-world data emerge, such as a recent paper detailing 80% or greater freedom from opioid use following total knee replacement when the pain management regimen included JOURNAVX. In chronic pain, both Phase 3 studies in painful diabetic peripheral neuropathy remain on track to complete enrollment by the end of this year, and for us to be able to share results by mid-2027.

在疼痛領域，除了處方量強勁成長之外，我們也看到令人信服的 JOURNAVX 真實世界數據快速累積，例如近期一篇論文指出，在疼痛管理方案包含 JOURNAVX 的情況下，全膝關節置換術後有 80% 或以上的患者可不使用鴉片類藥物。在慢性疼痛方面，兩項針對疼痛性糖尿病周邊神經病變的第 3 期研究均按計畫進行，預計在今年底前完成收案，並使我們能在 2027 年年中分享結果。

In myotonic dystrophy type 1, or DM1, we remain on track to share interim results from the GALILEO global Phase 1/2 clinical trial of VX-670 before the end of the year. In generalized myasthenia gravis, we have completed enrollment of the ETNA Phase 2 dose-ranging study of povetacicept and expect to share proof-of-concept data in the first half of 2027.

在第一型肌強直性肌肉失養症（myotonic dystrophy type 1，或 DM1）方面，我們仍按計畫在今年底前分享 VX-670 的 GALILEO 全球第 1/2 期臨床試驗期中結果。在全身型重症肌無力方面，我們已完成 povetacicept 的 ETNA 第 2 期劑量探索研究收案，並預期於 2027 年上半年分享概念驗證（proof-of-concept）數據。

Moving on to the more detailed R&D review, starting with cystic fibrosis. We see ALYFTREK as the most effective medicine approved for CF. With once-daily dosing, ALYFTREK can treat up to 95% of people with CF. And in our trials, more than 75% of ALYFTREK-treated patients ages 12 and older achieve sweat chloride levels in the range of CF carriers. That is to say, ALYFTREK-treated patients are achieving sweat chloride levels associated with no manifestation of CF disease nor reduced life expectancy. On the regulatory front, we continue our work to expand to treating younger patients and have initiated global submissions for ALYFTREK approval in children ages two to five.

接著進入更詳細的研發回顧，先從囊性纖維化開始。我們認為 ALYFTREK 是目前核准用於 CF 的最有效藥物。ALYFTREK 為每日一次給藥，可治療多達 95% 的 CF 患者。而在我們的試驗中，超過 75% 接受 ALYFTREK 治療、年齡 12 歲以上的患者，其汗氯（sweat chloride）可達到 CF 帶因者的範圍。也就是說，接受 ALYFTREK 治療的患者，其汗氯水準達到與不出現 CF 疾病表現、且不會降低預期壽命相關的水準。在法規申請方面，我們持續推進擴大至更年幼患者的治療，並已啟動 ALYFTREK 用於 2 至 5 歲兒童的全球送件申請。

Lastly, in CF, an update on our next-generation 3.0 correctors. We studied VX-828 as part of a triple combination in a cohort of 8 people with CF and as a dual therapy in another cohort of 8. All 16 patients had F/MF mutations, which is a more challenging population to treat than patients with F/MF mutations. In this F/MF population, the VX-828 dual combination did not alter sweat chloride relative to the TRIKAFTA baseline.

最後，在 CF 方面，更新我們下一代 3.0 校正劑（correctors）的進展。我們在一組 8 位 CF 受試者中研究 VX-828 作為三合一組合療法的一部分，並在另一組 8 位受試者中研究其作為雙重療法。全部 16 位患者皆為 F/MF 突變，這是一個比 F/F 突變患者更具治療挑戰的人群。在此 F/MF 人群中，VX-828 雙重組合相較於 TRIKAFTA 基線並未改變汗氯水準。

In the triple combination versus a baseline on TRIKAFTA, VX-828 delivered a 6.6 millimole per liter reduction in sweat chloride at day 28, and a 9.4 millimole reduction through day 28. The VX-828 regimen is oral, once daily, with a good safety, tolerability, and DDI profile. In short, these are excellent results.

在三合一組合方面，相較於 TRIKAFTA 的基線，VX-828 在第 28 天使汗氯降低 6.6 毫摩爾/公升，且至第 28 天期間的降低幅度為 9.4 毫摩爾。VX-828 方案為口服、每日一次，且具良好的安全性、耐受性與藥物交互作用（DDI）特性。簡而言之，這些結果非常出色。

However, given the very high bar set by ALYFTREK, we intend to wait for all the data from the NG 3.0 family of molecules before determining next steps, namely advancement into pivotal development. VX-581 and VX-272, the other NG 3.0 correctors, are currently in first-in-human studies, and the next-gen 4.0 molecules are in late preclinical development.

然而，鑑於 ALYFTREK 設下的門檻非常高，我們打算在決定下一步（亦即是否推進至關鍵性試驗開發）之前，先等待 NG 3.0 分子家族的所有數據。其他 NG 3.0 校正劑 VX-581 與 VX-272 目前正處於首次人體試驗（first-in-human）研究階段，而下一代 4.0 分子則處於後期臨床前開發階段。

Moving to our newest pillar, rare endocrinology. With the Crinetics acquisition now closed, PALSONIFY in acromegaly is our eighth commercialized medicine, and Duncan will provide details on the ongoing US launch. On the R&D side, the most advanced molecule after PALSONIFY is atumelnant in congenital adrenal hyperplasia, or CAH, which has orphan drug designation in the US, EU, and Japan, and where the Phase 3 pivotal trial is well underway.

接下來談到我們最新的支柱：罕見內分泌學。隨著對 Crinetics 的收購現已完成，PALSONIFY 用於肢端肥大症已成為我們第八款已商業化藥物，Duncan 將就目前在美國的上市推進提供細節。在研發方面，繼 PALSONIFY 之後最先進的分子是 atumelnant，用於先天性腎上腺增生症（congenital adrenal hyperplasia，CAH）。該藥物已在美國、歐盟與日本獲得孤兒藥資格認定，且其第 3 期關鍵性試驗正在順利進行中。

The primary efficacy endpoint for this Phase 3 study is the proportion of patients achieving the combination of normalization of androgens and physiologic glucocorticoid dose levels. This is the true goal in CAH therapy, and it is what was demonstrated in the Phase 2 trial. It is also what no other CAH medicine to date has attempted to achieve.

此項第 3 期研究的主要療效終點為：達成「雄激素正常化」與「生理性糖皮質激素劑量水準」兩者組合的患者比例。這才是 CAH 治療真正的目標，而這一點已在第 2 期試驗中得到證實。同時，迄今為止尚無任何其他 CAH 藥物嘗試達成這一目標。

In adult CAH, we are targeting completion of enrollment in the Phase 3 study in Q1 2027. The study then calls for 32 weeks of dosing. In pediatric CAH, atumelnant is in a Phase 2 dose-ranging study. Our goal is to rapidly advance the pediatric program into pivotal development following planned regulatory interactions.

在成人 CAH 方面，我們的目標是在 2027 年第 1 季完成第 3 期研究的受試者入組。該研究接著需要 32 週的給藥期。在兒科 CAH 方面，atumelnant 正在進行第 2 期劑量探索研究。我們的目標是在按計畫完成與監管機構的互動後，迅速將兒科計畫推進至關鍵性開發階段。

In addition, the adaptive Phase 2/3 global study of atumelnant in ACTH-dependent Cushing syndrome is already underway outside the US, and was recently granted orphan drug designation in the US. We have planned engagements with the FDA to confirm their expectations for this program and look forward to updating you in the coming months.

此外，atumelnant 用於 ACTH 依賴型庫欣症候群的適應性第 2/3 期全球研究已在美國以外地區啟動，且近期在美國獲授予孤兒藥資格認定。我們已規劃與 FDA 進行交流，以確認其對此計畫的期望，並期待在未來幾個月向各位更新進展。

Let me now turn to T1D. After careful analysis, we have chosen to prioritize acceleration of VX-017 as our lead program. Recall, VX-017 is an allogeneic, off-the-shelf, glucose-responsive, insulin-producing, fully differentiated islet cell therapy. It has a similar target product profile to zimislecel, but is designed for people with all blood types. This doubles the eligible patient population to about 120,000 people. The potential to bring transformative benefit to even more patients is the key reason to focus on VX-017, given the resource intensity, complexity, and manufacturing demands of cell therapy programs.

接下來談到第一型糖尿病（T1D）。經過審慎分析後，我們決定優先加速 VX-017 作為我們的領先計畫。請回想，VX-017 是一種同種異體、可即取即用（off-the-shelf）、具葡萄糖反應性、可產生胰島素、且完全分化的胰島細胞療法。其目標產品特性（target product profile）與 zimislecel 類似，但設計上可適用於所有血型的人群。這使符合條件的患者人數增加一倍，約達 120,000 人。鑑於細胞療法計畫在資源投入、複雜度與製造需求方面的高強度，能為更多患者帶來具變革性的潛在效益，是我們聚焦 VX-017 的關鍵原因。

We have already begun dosing patients with VX-017 in a Phase 1/2 study. Our near-term goals are to demonstrate proof of concept and to scale up manufacturing, with the goal of moving to pivotal development next year.

我們已在一項第 1/2 期研究中開始對患者施用 VX-017。我們的近期目標是證明概念驗證（proof of concept）並擴大製造規模，目標是在明年推進至關鍵性開發。

Finally, we continue to progress our serial innovation work in T1D, focused on improved immunosuppression and on generating hypoimmune islets, with the goal of making this potentially curative therapy available to even more people.

最後，我們也持續推進在 T1D 領域的連續創新工作，重點在於改善免疫抑制，以及產生低免疫原性（hypoimmune）胰島，目標是讓這項可能具治癒性的療法能惠及更多人。

Turning now to renal, where we have four programs in mid and late-stage development. Starting with pove and IgAN, we are both excited and ready for our PDUFA date on November 30th, just weeks away. Duncan will address our launch readiness. We just wrapped up a sparkling ASN annual meeting with the RAINIER Phase 3 interim analysis presentation and publication in the New England Journal of Medicine, supporting what we believe is a differentiated, potentially best-in-class profile for pove in IgAN.

接著談到腎臟領域，我們在中後期開發階段共有四個計畫。先從 pove 與 IgAN（IgA 腎病變）開始，我們對 11 月 30 日的 PDUFA 日期感到振奮且已做好準備，距今僅剩數週。Duncan 將說明我們的上市準備情況。我們剛結束一場精彩的 ASN 年會，會中發表並在《新英格蘭醫學雜誌》刊登了 RAINIER 第 3 期期中分析結果，支持我們所認為的：pove 在 IgAN 上具差異化、且可能為同類最佳（best-in-class）的特性。

Simply put, pove will offer a trifecta of excellence in efficacy, tolerability, and patient-centric administration features. I will focus tonight just on the patient-centric features. The commercial presentation of pove is clearly differentiated, with a small volume, 0.46 mils, once every four weeks, subcutaneously dosed via auto-injector at home.

簡而言之，pove 將在療效、耐受性與以患者為中心的給藥特性三方面同時展現卓越表現。今晚我將僅聚焦於以患者為中心的特性。pove 的商業化劑型呈現具有明顯差異化：小容量 0.46 毫升，每四週一次，透過自動注射器在家中進行皮下注射給藥。

On this point, this advantage is reflected in the poster presented by If et al. at the recent ASN of a qualitative survey study of about 25 adults with IgAN in the US, that revealed 96% of patients preferred an auto-injector relative to injection via a prefilled syringe, and 80% preferred dosing every four weeks versus weekly. Our ambition is to launch pove globally. To that end, we have already completed our filing for potential accelerated approval in the Kingdom of Saudi Arabia, where it has been granted breakthrough status. We estimate KSA represents an incremental 7,000-patient opportunity.

在這一點上，這項優勢也反映在 If 等人於近期 ASN 發表的海報中。該海報呈現一項在美國針對約 25 位 IgAN 成人所做的質性調查研究，結果顯示：相較於使用預充式注射器注射，96% 的患者偏好自動注射器；且相較於每週給藥，80% 的患者偏好每四週給藥一次。我們的企圖心是將 pove 推向全球上市。為此，我們已完成在沙烏地阿拉伯王國（KSA）申請潛在加速核准的送件，且已獲授予突破性療法地位。我們估計 KSA 可帶來額外約 7,000 名患者的機會。

We are planning forward for our regulatory submissions in other regions, including Europe and Asia, when the study completes and the two-year eGFR data are available. On pove in membranous nephropathy, our OLYMPUS Phase 2/3 pivotal trial is ongoing, with Phase 3 enrollment and dosing well underway at the selected dose of 80 milligrams subcutaneously every four weeks.

我們也在為其他地區（包括歐洲與亞洲）的法規申請提前規劃，待研究完成並取得兩年期 eGFR 數據後進行提交。在膜性腎病（membranous nephropathy）的 pove 方面，我們的 OLYMPUS 第 2/3 期關鍵性試驗正在進行中，第 3 期的入組與給藥也在所選定劑量（每四週一次、皮下注射 80 毫克）下順利推進。

Recall, this study has a 104-week endpoint. On inaxaplin in AMKD, we have two pieces of news since our last earnings call. First, to recap the exciting results from the AMPLIFIED study. In cohort 1 of patients with AMKD and modest proteinuria, treatment with inaxaplin on top of optimized standard of care led to a 42.7% reduction in urine albumin-to-creatinine ratio, or UACR, at week 13 compared to baseline, with the UPCR down 44.7%. This is remarkably consistent with the treatment effect previously shared in the Phase 2 data in AMKD published in the New England Journal of Medicine.

請記得，該研究的終點為 104 週。關於 inaxaplin 用於 AMKD，自上次財報電話會議以來我們有兩項消息。首先，回顧 AMPLIFIED 研究令人振奮的結果。在 AMKD 且蛋白尿程度較輕的第 1 隊列患者中，在最佳化標準治療（standard of care）基礎上加用 inaxaplin，於第 13 週相較基線使尿白蛋白/肌酸酐比（urine albumin-to-creatinine ratio，UACR）下降 42.7%，同時尿蛋白/肌酸酐比（UPCR）下降 44.7%。這與先前已分享、並刊登於《新英格蘭醫學雜誌》的 AMKD 第 2 期數據所呈現的治療效果高度一致。

In cohort 2 of people with AMKD and type 2 diabetes, treatment with inaxaplin led to a 17.3% reduction in UACR and a 25.4% reduction in UPCR at week 13. Of note, the majority of patients in both cohorts did not have a diagnosis of FSGS. Inaxaplin was generally safe and well-tolerated with no serious adverse events related to inaxaplin. All adverse events were mild or moderate in severity. We look forward to discussing these results with regulators in the context of the AMPLITUDE study next year.

在 AMKD 且合併第 2 型糖尿病的第 2 隊列人群中，inaxaplin 治療於第 13 週使 UACR 下降 17.3%，UPCR 下降 25.4%。值得注意的是，兩個隊列中的多數患者並未被診斷為 FSGS。inaxaplin 整體而言安全且耐受性良好，未出現與 inaxaplin 相關的嚴重不良事件。所有不良事件的嚴重程度均為輕度或中度。我們期待明年在 AMPLITUDE 研究的脈絡下，與監管機構討論這些結果。

The second key milestone was that we completed full enrollment in the pivotal AMPLITUDE Phase 2/3 trial, and we are fully on track to share the results from the interim analysis of AMPLITUDE early next year. If positive, this interim analysis will support potential accelerated approval in the US, rounding out on renal enrollment in the VX-407-AGLOW Phase 2 study in ADPKD completed enrollment, and we are now on track for study readout next year.

第二個關鍵里程碑是：我們已完成關鍵性 AMPLITUDE 第 2/3 期試驗的全部入組，並完全按計畫於明年年初分享 AMPLITUDE 的期中分析結果。若結果為正向，該期中分析將支持在美國申請潛在加速核准；此外，在腎臟領域的入組方面，VX-407-AGLOW 於 ADPKD 的第 2 期研究已完成入組，我們目前也按計畫於明年取得研究讀出結果。

With that, I will turn the call over to Duncan for a commercial update.

接下來，我將把電話會議交給 Duncan，請他提供商業化更新。

Thanks very much, Reshma. Our commercial story continues to be one of excellence in launch execution across CF, heme, pain, and most recently, rare endocrinology. Through the first nine months of the year, our ongoing launches of ALYFTREK, CASGEVY, and JOURNAVX have generated over $2 billion in revenue, led by over $1.7 billion in ALYFTREK sales and more than $350 million in combined CASGEVY and JOURNAVX sales.

非常感謝，Reshma。我們的商業化故事持續展現為：在囊性纖維化（CF）、血液疾病（heme）、疼痛，以及最近的罕見內分泌學領域，皆具卓越的上市執行力。今年前九個月，我們持續推進的 ALYFTREK、CASGEVY 與 JOURNAVX 上市已帶來超過 20 億美元營收，其中 ALYFTREK 銷售額超過 17 億美元，CASGEVY 與 JOURNAVX 合計銷售額超過 3.5 億美元。

To give you a brief overview and put quarter three revenue, patient, and prescription growth in context, in CF, we delivered $3.3 billion in revenue with strong switching to ALYFTREK and over 18,000 patients benefiting from ALYFTREK around the world. In heme, CASGEVY achieved $99 million in quarterly revenue with approximately 200 infusions completed since launch and a fourth consecutive quarter with more than 100 patient initiations.

為了簡要概述並將第三季的營收、患者數與處方成長放在脈絡中說明：在 CF 方面，我們實現 33 億美元營收，ALYFTREK 的轉換表現強勁，且全球已有超過 18,000 名患者受益於 ALYFTREK。在血液疾病方面，CASGEVY 單季營收達 9,900 萬美元，自上市以來約完成 200 次輸注，並連續第四個季度有超過 100 名患者開始治療。

In moderate to severe acute pain, JOURNAVX reported over 750,000 prescriptions and $58 million in revenue. More than 1.6 million patients have now been treated with JOURNAVX in the US, and JOURNAVX is now the number one prescribed branded oral analgesic in the US.

在中度至重度急性疼痛領域，JOURNAVX 已通報超過 75 萬張處方，並帶來 5,800 萬美元營收。目前在美國已有超過 160 萬名病患接受 JOURNAVX 治療，而 JOURNAVX 現已成為美國處方量第一的品牌口服鎮痛藥。

And in rare endocrinology, PALSONIFY contributed $10 million in revenue for the month of September following the close of the acquisition. For the full third quarter, PALSONIFY revenue was approximately $24 million.

在罕見內分泌領域，PALSONIFY 於收購案完成後的 9 月份貢獻了 1,000 萬美元營收。第三季全季而言，PALSONIFY 營收約為 2,400 萬美元。

I will now cover these disease areas in more detail, starting with CF. The Q3 $3.3 billion in global CF revenue represents 8% year-over-year growth. Global growth overall was led by ALYFTREK, which delivered $706 million in worldwide sales in Q3.

接下來我將更詳細說明這些疾病領域，先從 CF 開始。第三季全球 CF 營收 33 億美元，代表年增 8%。整體全球成長主要由 ALYFTREK 帶動，其第三季全球銷售額達 7.06 億美元。

In the US, ALYFTREK sales year to date have now surpassed $1 billion. In both the US and outside the US, ALYFTREK sales continue to build primarily from patients switching from TRIKAFTA and new patients with rare mutations. Outside the US, we now have ALYFTREK reimbursement in 31 countries. Looking ahead, our CF growth drivers remain consistent and clear. Label expansions in rare mutations, penetration into younger age groups, additional geographies, and by the underlying survival benefit of patients on CFTR modulators.

在美國，ALYFTREK 今年迄今的銷售額現已突破 10 億美元。無論在美國或美國以外，ALYFTREK 的銷售持續成長，主要來自由 TRIKAFTA 轉換用藥的病患，以及具有罕見突變的新病患。在美國以外，我們目前已在 31 個國家取得 ALYFTREK 的給付。展望未來，我們在 CF 的成長動能仍一致且清晰。包括在罕見突變上的適應症擴增、向更年幼年齡層滲透、拓展更多地理市場，以及 CFTR 調節劑為病患帶來的存活效益所驅動。

Turning to CASGEVY in severe sickle cell disease and transfusion-dependent beta thalassemia, where $99 million in Q3 revenue reflects 30% sequential growth. We have infused twice as many patients in the first nine months of 2026 as all of 2025. Since launch, we have initiated over 750 patients worldwide on CASGEVY, and with four consecutive quarters of initiation numbers exceeding 100 patients, we now have patients at all stages of the treatment journey.

接著談 CASGEVY，用於重度鐮狀細胞疾病與需輸血之 β 地中海型貧血；第三季營收 9,900 萬美元，反映季增 30%。我們在 2026 年前九個月輸注的病患數，是 2025 年全年的兩倍。自上市以來，我們已在全球啟動超過 750 名病患接受 CASGEVY，且連續四個季度啟動人數皆超過 100 名，因此目前在治療旅程各階段皆已有病患。

We have also continued to enhance the patient journey, shortening the overall time from referral to infusion and decreased the number of mobilizations. We have excellent visibility into the number of infusions, which is when we recognize revenue, for the rest of this year, as well as into 2027. That said, infusion timing reflects patient choice with some expected seasonality in quarter four, so I would encourage you to focus on the strong annual performance rather than any single quarter. CASGEVY will contribute meaningfully to our greater than $500 million non-CF revenue goal this year and is on its way to achieving its own blockbuster potential.

我們也持續優化病患旅程，縮短從轉介到輸注的整體時間，並降低動員（mobilization）的次數。我們對今年剩餘期間以及 2027 年的輸注數量（亦即我們認列營收的時點）具有極佳的可視性。不過，輸注時點會反映病患的選擇，且第四季預期會有一定季節性，因此我建議各位聚焦於強勁的年度表現，而非單一季度。CASGEVY 將對我們今年非 CF 營收超過 5 億美元的目標做出重要貢獻，並正朝其自身具備重磅藥（blockbuster）的潛力邁進。

With JOURNAVX in moderate to severe acute pain, we are building a franchise for the long term and are focused on the following critical markers of success: broad payer coverage, prescription growth, breadth and depth of prescribing, the addition of JOURNAVX to hospital pathways, and revenue. These are the building blocks of a sustainable, long-term, multi-billion dollar pain business.

在中度至重度急性疼痛的 JOURNAVX 方面，我們正打造長期的產品版圖，並聚焦於以下關鍵成功指標：廣泛的支付方給付覆蓋、處方成長、開立處方的廣度與深度、將 JOURNAVX 納入醫院治療路徑，以及營收。這些是建立可持續、長期、數十億美元規模疼痛業務的基石。

Let me start with prescriptions because that’s the best indicator of underlying physician and patient demand. In the third quarter, JOURNAVX prescriptions totaled over 750,000, up more than 40% sequentially from quarter 2 2026. At the end of quarter three 2026, we are well on our way to achieving our guidance of more than 3 times the number of prescriptions in 2026 versus 2025. Prescriptions continue to split roughly 50/50 between hospital and retail channels.

我先從處方談起，因為這是反映醫師與病患底層需求的最佳指標。第三季 JOURNAVX 處方總量超過 75 萬張，較 2026 年第二季季增超過 40%。截至 2026 年第三季末，我們正穩步邁向達成指引：2026 年處方數較 2025 年增加超過 3 倍。處方仍大致以約 50/50 分布於醫院與零售通路。

Third quarter JOURNAVX revenue of $58 million, up 18% quarter over quarter, reflects continued high gross-to-net with the patient support savings program remaining on.

第三季 JOURNAVX 營收為 5,800 萬美元，季增 18%，反映在病患支持節省方案仍持續啟用的情況下，毛額到淨額（gross-to-net）仍維持偏高。

Let me walk you through the revenue growth dynamics. A significant driver of gross-to-net is continued utilization of our patient support program. We have chosen to leave the PSP in place and extend it into 2027 so that people who are prescribed JOURNAVX, but whose plans do not yet cover it, can receive the therapy.

我來帶各位了解營收成長的動態。毛額到淨額的一項重要驅動因素，是我們病患支持計畫的持續使用。我們選擇讓 PSP 持續運作並延長至 2027 年，使那些已被開立 JOURNAVX、但其保險計畫尚未給付的民眾仍能取得治療。

Accordingly, when we sunset the PSP mid-next year, we continue to expect gross-to-net to stabilize at a level close to other mass market brands in the range of 50% to 60%. In addition, in quarter three, gross-to-net and revenue were both affected by the one-time impact of securing broad Medicare Part D access in July. As that access came online, previously uncontracted prescriptions shifted to contracted, rebated pricing, resulting in a one-time reset in net revenue. This is in line with our overall strategy to secure broad, sustained access across commercial and government plans, so we can successfully convert physician practices to JOURNAVX for all their patients.

因此，當我們在明年年中逐步終止 PSP 時，我們仍預期毛額到淨額將穩定在接近其他大眾市場品牌的水準，約落在 50% 至 60% 的區間。此外，第三季的毛額到淨額與營收也受到一次性因素影響：我們於 7 月取得廣泛的 Medicare Part D 准入。隨著該准入上線，先前未簽約的處方轉為已簽約且含回扣的定價，導致淨營收出現一次性重置。這與我們整體策略一致：在商業與政府保險計畫中取得廣泛且可持續的准入，從而成功推動醫師診所將 JOURNAVX 用於其所有病患。

This quarter marks our first opportunity to speak about PALSONIFY as part of Vertex following the deal close at the beginning of September, and we are pleased with the launch trajectory to date. Let me briefly describe the disease, the unmet need, and frame the key metrics at this stage in the launch. Acromegaly is a symptomatic disease that affects approximately 20,000 patients in the US and a similar number in the five largest European markets, plus Japan.

本季是我們在 9 月初交易完成後，首次以 Vertex 的一部分來談 PALSONIFY；我們對目前的上市進展感到滿意。我將簡要說明該疾病、未被滿足的需求，並在此上市階段框定關鍵指標。肢端肥大症是一種具症狀的疾病，在美國約影響 2 萬名病患；在歐洲五大市場加上日本，患者數量也大致相當。

Although surgery is the first line of treatment, only 40%-50% of people achieve durable remission, so the majority of patients need lifelong treatment. In the US, they’re treated by approximately 3,000 endocrinologists. Until the launch of PALSONIFY, the main option has been monthly injections with somatostatin receptor ligands, or SRLs, delivered using large gauge needles. These treatments have three limitations.

雖然手術是第一線治療，但僅有 40% 至 50% 的人能達到持久緩解，因此多數病患需要終身治療。在美國，約由 3,000 名內分泌科醫師進行治療。在 PALSONIFY 上市之前，主要選項為每月注射的生長抑素受體配體（somatostatin receptor ligands, SRLs），且需使用大口徑針頭施打。這些治療有三項限制。

Firstly, they can cause painful injection site reactions at the beginning of the month. Secondly, their efficacy tends to taper off in the latter part of the month, leading to breakthrough symptoms such as joint pain, swelling, and fatigue. And thirdly, the recurring logistical challenges and burden of chronic depot therapy.

第一，月初可能造成疼痛的注射部位反應。第二，其療效往往在月底後段逐漸減弱，導致出現突破性症狀，例如關節疼痛、腫脹與疲勞。第三，長期緩釋注射治療反覆帶來的物流挑戰與負擔。

The unmet need is therefore significant. The ideal treatment for patients would be a highly effective, easy to take, well-tolerated oral medicine that provides sustained control of the disease, and one that has a broad indication for both naive and switch patients. This is the exact profile of PALSONIFY as the first and only once-daily oral SST2-selective agonist. As we integrate the Crinetics business, there are three areas of focus for the success of PALSONIFY, building on the excellent base of 80% reimbursed coverage.

因此，未被滿足的需求相當顯著。對病患而言，理想治療應是高療效、易於服用、耐受性良好的口服藥物，能提供對疾病的持續控制，並且在適應症上能廣泛涵蓋初治與轉換用藥的病患。這正是 PALSONIFY 的完整特徵：作為第一且唯一每日一次的口服 SST2 選擇性致效劑。在我們整合 Crinetics 業務的同時，PALSONIFY 成功的三大聚焦領域，是在 80% 已獲給付覆蓋的優秀基礎上持續推進。

Firstly, build a broad base of repeat HCP writers for PALSONIFY. Secondly, drive growth in both the new and switch settings. And thirdly, deliver on our revenue goals. We are very pleased with the progress that the Crinetics team, and now the integrated Vertex team, are making against these goals. Approximately 500 endocrinologists are writing PALSONIFY prescriptions, and there was a significant increase in the number of repeat writers in quarter three compared to the first half of 2026. PALSONIFY now has the leading brand share at over 40% among patients initiating or switching therapy.

第一，建立廣泛且持續重複開立 PALSONIFY 的醫療專業人員（HCP）基礎。第二，推動新治療與轉換治療兩種情境的成長。第三，達成我們的營收目標。我們對 Crinetics 團隊，以及如今整合後的 Vertex 團隊在這些目標上的進展感到非常滿意。約有 500 名內分泌科醫師正在開立 PALSONIFY 處方，且第三季的重複開立者數量相較 2026 年上半年顯著增加。在啟動或轉換治療的病患中，PALSONIFY 目前以超過 40% 的市占率居於品牌領先地位。

And lastly, we see continued strong growth in patient enrollments, leading to $10 million in revenue in September, $24 million in quarter three, and approximately $60 million for the first three quarters of 2026. Our focus is on excellence in execution to further accelerate the US performance and prepare for international launches.

最後，我們看到病患註冊人數持續強勁成長，使 9 月營收達 1,000 萬美元、第三季達 2,400 萬美元，且 2026 年前三季合計約 6,000 萬美元。我們的重點在於卓越執行，以進一步加速美國市場表現，並為國際上市做準備。

Let me conclude with an update on our commercial readiness for pove in IgAN. Reshma Kewalramani has already highlighted the trifecta of efficacy, safety, and patient-centric dosing of povetacicept.

最後，我想就我們在 IgAN 適應症上對 pove 的商業化就緒情況做個更新。Reshma Kewalramani 已經強調了 povetacicept 在療效、安全性以及以病患為中心的給藥方式這三大要素。

Put simply, with the PDUFA date just days away now, we are 100% ready, and we are incredibly excited to bring pove to patients with IgAN. Our field team is fully hired, trained, and ready to go. Over 90% of the team have deep nephrology experience, and many of them have been engaging with nephrologists in IgAN disease educational activities since early this year.

簡而言之，距離 PDUFA 日期只剩下幾天，我們已經 100% 準備就緒，並且非常期待將 pove 帶給 IgAN 病患。我們的外勤團隊已全數招募完成、受訓完畢並隨時可出發。團隊中超過 90% 具備深厚的腎臟科經驗，且其中許多人自今年年初起就已透過 IgAN 疾病教育活動與腎臟科醫師持續互動。

We also know that the patient experience is of supreme importance in biologics, and IgAN is no different. Based on years of providing comprehensive patient support to our CF patients, we have built a people-based and tech-enabled patient support program to facilitate patients to get their pove as fast and as easily as possible. In addition, our payer conversations continue to proceed very well.

我們也知道，在生物製劑領域，病患體驗至關重要，IgAN 也不例外。基於多年為囊性纖維化（CF）病患提供全面病患支持的經驗，我們建立了一套以人為本、以科技賦能的病患支持計畫，協助病患以最快、最便利的方式取得其 pove。此外，我們與支付方的對話也持續進展得非常順利。

Payers understand the significant unmet need, are very familiar with pove's clinical profile, and have responded positively to its differentiation and overall value proposition. We have had many engagements with nephrologists over the last few months, including at the excellent ASN Kidney Week meeting last month. They are looking for treatments that meaningfully and rapidly reduce proteinuria, have a favorable tolerability profile, and offer convenient dosing alongside a seamless treatment experience built on access and patient support.

支付方理解顯著的未被滿足醫療需求，對 pove 的臨床特性非常熟悉，並對其差異化與整體價值主張給予正面回應。過去幾個月我們與腎臟科醫師進行了多次交流，包括上個月非常出色的 ASN Kidney Week 會議。他們正在尋找能夠有意義且快速降低蛋白尿、具備良好耐受性特徵，並在便利給藥的同時，提供以可近性與病患支持為基礎的無縫治療體驗的療法。

Our discussions with physicians over the last quarter have increasingly revealed the importance of dosing frequency, dose volume and viscosity, and method of administration. We continue to believe that, in addition to an excellent efficacy and safety profile, the low-dose, easy-to-use, at-home auto-injector will be an important differentiator for pove.

我們在上一季與醫師的討論中，越來越顯示給藥頻率、給藥體積與黏度，以及給藥方式的重要性。我們仍然相信，除了優異的療效與安全性特徵之外，低劑量、易於使用、可在家中使用的自動注射器將成為 pove 的重要差異化優勢。

I will now turn the call over to Charlie Wagner.

接下來我把電話會議交給 Charlie Wagner。

Thanks, Duncan. Vertex delivered strong third quarter results with total revenue growth of 12% year-over-year, reflecting revenue growth of 10% in the US and 16% internationally. Results include an approximate 1 percentage point favorable impact from foreign exchange and $10 million of revenue from Crinetics following the close of the transaction.

謝謝，Duncan。Vertex 第三季交出強勁成果，總營收年增 12%，反映美國營收成長 10%，國際市場成長 16%。本季結果包含外匯帶來約 1 個百分點的正面影響，以及在交易完成後來自 Crinetics 的 1,000 萬美元營收。

Globally, CF revenue grew 8% year-over-year with 5% growth in the US and 12% outside the US, or 10% on a constant currency basis. On a non-GAAP basis, third quarter gross margin was 85.6%. On a GAAP basis, gross margin of 84.7% includes intangible asset and inventory step-up amortization resulting from the purchase accounting for the Crinetics acquisition. Turning to Q3 operating expenses, which include approximately $60 million of Crinetics operating and integration-related expenses in September. Third quarter non-GAAP R&D expense was $936 million, an increase of $74 million, or 9% year over year.

在全球範圍內，CF 營收年增 8%，其中美國成長 5%，美國以外成長 12%；若以固定匯率計算則為 10%。以非 GAAP 基礎計，第三季毛利率為 85.6%。以 GAAP 基礎計，毛利率 84.7% 包含因收購 Crinetics 之購買會計處理所產生的無形資產與存貨增值（step-up）攤銷。接著看第三季營業費用，其中包含 9 月份約 6,000 萬美元的 Crinetics 營運與整合相關費用。第三季非 GAAP 研發費用為 9.36 億美元，年增 7,400 萬美元（或 9%）。

Approximately $30 million of the increase was attributable to Crinetics. Non-GAAP SG&A expense was $556 million, an increase of $187 million, or 51% year over year. Nearly 80% of the incremental spend was to enhance our commercial capabilities. Within the increase in commercial spend, the biggest drivers were pove and renal and JOURNAVX, and then PALSONIFY.

其中約 3,000 萬美元的增幅可歸因於 Crinetics。非 GAAP 銷售、一般及行政（SG&A）費用為 5.56 億美元，年增 1.87 億美元（或 51%）。新增支出中近 80% 用於強化我們的商業化能力。在商業化支出增加的項目中，最大的驅動因素是 pove 與腎臟領域以及 JOURNAVX，其次是 PALSONIFY。

Approximately $30 million of the incremental SG&A spend is related to Crinetics. We also recorded $41 million in acquired IPR&D expense in the quarter, including a $28 million upfront payment for new business development agreement with AbCellera.

新增的 SG&A 支出中約 3,000 萬美元與 Crinetics 相關。我們本季也認列 4,100 萬美元的取得之進行中研發（IPR&D）費用，其中包含與 AbCellera 新業務開發協議的 2,800 萬美元預付款。

During Q3, we incurred approximately $50 million in non-operating costs associated with the Crinetics transaction financing, including higher interest expense due to the new bank loans and other related costs. In addition, interest income was $15 million lower than it otherwise would have been as a result of lower cash balances after the acquisition.

第三季我們因 Crinetics 交易融資而產生約 5,000 萬美元的非營業成本，包括因新增銀行貸款導致的較高利息費用及其他相關成本。此外，由於收購後現金餘額降低，利息收入也比原本情況少了 1,500 萬美元。

Our third quarter non-GAAP effective tax rate was 18%, up approximately 40 basis points compared to Q3 2025. Third quarter 2026 non-GAAP net income was $1.21 billion, and third quarter 2026 non-GAAP earnings per share were $4.76.

我們第三季非 GAAP 有效稅率為 18%，較 2025 年第三季上升約 40 個基點。2026 年第三季非 GAAP 淨利為 12.1 億美元，2026 年第三季非 GAAP 每股盈餘為 4.76 美元。

Turning to the balance sheet. We ended the quarter with approximately $9.8 billion in cash and investments following the close of the Crinetics acquisition. Note that we raised $4.5 billion of term loans to fund a portion of the acquisition, currently bearing interest at approximately 4.8%. Even with a busy period for BD, we also deployed approximately $120 million during the quarter to repurchase roughly 250,000 shares. Year to date, we have repurchased approximately 2 million shares for $921 million.

接著看資產負債表。在完成 Crinetics 收購後，我們於季末持有約 98 億美元的現金與投資。請注意，我們為了支付部分收購資金而籌措了 45 億美元的定期貸款，目前利率約為 4.8%。即使在業務開發（BD）活動繁忙的期間，我們本季仍投入約 1.2 億美元回購約 25 萬股股份。年初至今，我們已回購約 200 萬股，金額為 9.21 億美元。

Our strategy for capital deployment remains unchanged, with the priority on investing in innovation, including external innovation, and an additional allocation for share repurchases.

我們的資本配置策略維持不變，優先投資於創新（包括外部創新），並額外配置資金用於股份回購。

Now turning to guidance. For total revenue guidance, we are raising our prior range of $13.1 billion to $13.2 billion to a revised range of $13.15 billion to $13.25 billion. The increase reflects the addition of Crinetics, which we expect to contribute $40 million to $50 million to full-year 2026 revenue. The underlying drivers of our revenue outlook are unchanged. Continued CF performance, including the ongoing ALYFTREK launch, together with growing contributions from heme, pain, and now rare endocrinology.

接下來談財測指引。在總營收指引方面，我們將先前 131 億至 132 億美元的區間上調至 131.5 億至 132.5 億美元。上調反映納入 Crinetics，我們預期其將為 2026 全年營收貢獻 4,000 萬至 5,000 萬美元。我們營收展望的基本驅動因素維持不變。CF 業務持續表現（包括 ALYFTREK 持續上市推進），再加上血紅素疾病（heme）、疼痛領域，以及如今罕見內分泌領域的貢獻持續成長。

We continue to expect more than $500 million in revenue from CASGEVY and JOURNAVX, with additional contribution from four months of PALSONIFY. Consistent with prior guidance, our outlook continues to include an expected full-year benefit from foreign exchange of roughly 150 basis points. Given our visibility into the drivers of our business, and with just two months of the year remaining, we have a high degree of certainty in our revenue guidance range.

我們仍預期 CASGEVY 與 JOURNAVX 的營收合計將超過 5 億美元，並加上 PALSONIFY 四個月的額外貢獻。與先前指引一致，我們的展望仍包含外匯帶來約 150 個基點的全年正面效益。鑑於我們對業務驅動因素的可見度，以及全年僅剩兩個月，我們對營收指引區間具有高度確定性。

We continue to expect full-year gross margin slightly below 86%. On operating expenses, we are revising our prior combined non-GAAP operating expense guidance of $5.65 billion to $5.75 billion to a revised estimate of approximately $6 billion. The standalone Vertex business remains at the high end of our prior range, and the increase in guidance is attributable to the inclusion of approximately $250 million of Crinetics operating expenses and integration-related costs. This updated operating expense guidance reflects continued investment in our late-stage clinical pipeline and the commercial infrastructure supporting our launches and revenue diversification.

我們仍預期全年毛利率略低於 86%。在營業費用方面，我們將先前合併的非 GAAP 營業費用指引（56.5 億至 57.5 億美元）修正為約 60 億美元。Vertex 單體業務仍位於先前區間的高端，而指引上調可歸因於納入約 2.5 億美元的 Crinetics 營運費用與整合相關成本。此更新後的營業費用指引反映我們持續投資於後期臨床產品線，以及支撐產品上市與營收多元化的商業化基礎設施。

For the full year of 2026, we expect total non-operating costs of approximately $105 million related to the financing of Crinetics, including higher interest expense and other related costs. In addition, interest income is projected to be approximately $60 million lower than it otherwise would have been as a result of lower cash balances after the acquisition. lease see slide 23 of the earnings presentation for full details on the impact of Crinetics upon Q3 results and full-year 2026 guidance. We continue to expect our full-year non-GAAP effective tax rate to be between 19.5% to 20.5%.

針對 2026 全年，我們預期與 Crinetics 融資相關的非營業成本合計約為 1.05 億美元，包括較高的利息費用及其他相關成本。此外，由於收購後現金餘額降低，利息收入預計將比原本情況少約 6,000 萬美元。有關 Crinetics 對第三季結果及 2026 全年指引影響的完整細節，lease see slide 23 of the earnings presentation。我們仍預期全年非 GAAP 有效稅率介於 19.5% 至 20.5%。

In summary, Vertex delivered strong third quarter results with 12% revenue growth and increasing revenue diversification beyond our leading CF business. The integration of Crinetics is well underway, and with the strong commitment of the Crinetics team, we are accelerating commercial, clinical, and valuable preclinical programs.

總結而言，Vertex 第三季交出強勁成果，營收成長 12%，且營收來源多元化程度持續提升，已不僅限於我們領先的 CF 業務。Crinetics 的整合進展順利，在 Crinetics 團隊的高度投入下，我們正加速商業化、臨床以及具價值的臨床前計畫。

Our continued leadership in CF, the increasing contribution of CASGEVY and JOURNAVX, momentum in rare endocrinology, and with pove on the doorstep of launch, we are well-positioned for continued attractive growth and profitability for years to come. We look forward to updating you on our continued progress across multiple disease areas with key upcoming milestones detailed on slide 24.

憑藉我們在 CF 的持續領導地位、CASGEVY 與 JOURNAVX 貢獻度提升、罕見內分泌領域的動能，以及 pove 即將上市，我們已具備條件在未來多年持續實現具吸引力的成長與獲利能力。我們期待在第 24 張投影片所列的多項即將到來的關鍵里程碑上，向各位更新我們在多個疾病領域的持續進展。

I’ll now ask Susie to begin the Q&A period.

接下來我請 Susie 開始問答環節。

Thanks, Charlie. Chuck, can you please open it up to questions?

謝謝，Charlie。Chuck，你可以請大家開始提問嗎？

(Operator Instructions) Cory Kasimov, Evercore.

（接線員指示）Cory Kasimov，Evercore。

Great. Good afternoon, guys. Thanks for taking the question. And Charlie, congrats on the new role. It’s very well deserved.

太好了。各位下午好。謝謝讓我提問。另外 Charlie，恭喜你擔任新職務。這是你實至名歸。

On pove, I wanted to ask about the recent citizen petition that raises the question of whether RAINIER’s IgG monitoring and dose hold rules need to be carried into clinical practice. So I guess, how frequently do patients actually fall below the IgG threshold or require treatment interruptions? And what do those data support or potentially indicate in terms of monitoring requirements in the commercial label? Thank you.

關於 pove，我想請教近期有一份公民請願（citizen petition），其中提出 RAINIER 的 IgG 監測與暫停給藥規則是否需要延伸到臨床實務。所以我想問的是，實際上病患有多常會低於 IgG 門檻或需要中斷治療？而這些數據對於商業化標籤中的監測要求，有何支持或可能暗示？謝謝。

Hey, Cory, it’s Reshma. Let me take that one. With regard to the citizens petition, there are about 200 or so of these that happen every year. About 80% or so of them are from named individuals or companies, and about 20% of them are anonymous. This one, as you know, was anonymous.

嗨 Cory，我是 Reshma。我來回答這題。關於公民請願，每年大約會有 200 件左右。其中約 80% 來自具名個人或公司，約 20% 是匿名提出。如你所知，這一件是匿名的。

If the question behind your question is how do we feel about the label, where are our conversations with the agency, everything that you would expect to be happening with the FDA is happening, and we’re really looking forward to our PDUFA date.

如果你問題背後的問題是：我們對標籤的看法、與主管機關的溝通進度如何——所有你預期會與 FDA 進行的事項都正在進行中，我們也非常期待我們的 PDUFA 日期。

On the specific of how can we think about what values IgG levels can achieve, the bottom line is before this wave of B-cell modulating therapies, the way a lot of folks thought about IgG levels were from congenital diseases of immunologic basis, and that’s where a lot of these values came from.

至於具體來說，該如何看待 IgG 濃度可能達到的數值，重點是：在這一波 B 細胞調節療法出現之前，許多人對 IgG 濃度的認知主要來自先天性、以免疫學為基礎的疾病，而許多這些數值門檻也源自於此。

In this day and age, what numbers could IgG levels come to? I think the best examples to look at are the clinical trials. In our example, we studied over 500 people. We measured every four weeks. If the IgG was going to go down, we certainly would have found it because we looked, and we considered a single excursion to be worth noting.

在現今這個時代，IgG 濃度可能降到什麼程度？我認為最好的參考就是臨床試驗。以我們為例，我們研究了超過 500 位受試者。我們每四週測量一次。如果 IgG 真的會下降，我們一定會發現，因為我們確實有去觀察，而且我們把單次偏離（excursion）也視為值得記錄的事件。

I would say the most important point to think about is infections. On that note, there are no opportunistic infections, as you know, in the pove program. The SAEs of infection are balanced. It’s exactly 0.5% in POVI and 0.5% in the placebo group, and the rest of the infections are mild to moderate. You put this together, and you can see why we’re so excited about the PDUFA date.

我認為最重要需要思考的是感染。就這點而言，如你所知，在 pove 計畫中沒有出現任何伺機性感染（opportunistic infections）。感染相關的嚴重不良事件（SAE）在兩組之間是平衡的。POVI 組為 0.5%，安慰劑組也為 0.5%，其餘感染多為輕度至中度。把這些綜合起來，你就能理解為什麼我們對 PDUFA 日期如此興奮。

That’s very helpful, Reshma. I appreciate it.

這非常有幫助，Reshma。謝謝你。

You bet.

不客氣。

Jessica Fye, JPMorgan.

Jessica Fye，摩根大通（JPMorgan）。

Hey, guys. Good afternoon. Thanks for taking my question. Can you help set expectations for what would represent a win coming out of the AMPLITUDE on both proteinuria and eGFR? Thank you.

嗨，各位。下午好。謝謝讓我提問。你們能否協助設定一下預期：在 AMPLITUDE 試驗中，無論是蛋白尿或 eGFR，什麼樣的結果可被視為「勝利」？謝謝。

Yeah. On the AMPLITUDE study, that is the one that is completed full enrollment, and it completed the interim analysis cohort enrollment last year, setting us up for the interim analysis early in 2027. A win would be a statistically significant result on the eGFR slope. I say that because, of course, we are going to measure proteinuria and eGFR, but our agreement with the FDA on what would be acceptable for accelerated approval is eGFR.

好的。關於 AMPLITUDE 研究，該研究已完成全數收案，並且在去年完成期中分析隊列的收案，讓我們能在 2027 年初進行期中分析。所謂「勝利」將是 eGFR 斜率（slope）達到統計上顯著的結果。我這麼說是因為，當然我們會測量蛋白尿與 eGFR，但我們與 FDA 對於加速核准（accelerated approval）可接受的指標之共識是 eGFR。

That is where they are on the disease AMKD. I expect the Phase 3 to look a whole hell of a lot like the Phase 2 in terms of proteinuria, but the key element here is eGFR, and it is a statistically significant difference between the inaxaplin-treated group and the placebo on top of standard of care. I will not share with you the power analysis and such, but that is what we are looking for because eGFR is what the accelerated approval agreement with the FDA is based on.

這就是他們在 AMKD 這個疾病上的立場。我預期第三期在蛋白尿方面的表現會非常接近第二期，但關鍵要素在於 eGFR：在標準治療（standard of care）基礎上，inaxaplin 治療組相較安慰劑組必須呈現統計上顯著的差異。我不會與各位分享檢定力分析（power analysis）等細節，但這就是我們在尋找的結果，因為與 FDA 的加速核准協議是以 eGFR 為基礎。

Salveen Richter, Goldman Sachs.

Salveen Richter，高盛（Goldman Sachs）。

Thank you. Good afternoon. Just a follow-up on Cory and Jess’ questions. With regard to pove, can you speak to your comfort and history with the manufacturer? And with regard to inaxaplin, can you just walk through further for the reasons for confidence into the 48-week interim data early next year, specifically how we get comfortable thinking about the separation between drug and placebo at that time point, and just the read-through from some of the data sets that you have generated to date?

謝謝。下午好。我想延續 Cory 和 Jess 的問題。關於 pove，你能談談你們對該製造商的信心以及合作歷史嗎？另外關於 inaxaplin，能否再進一步說明你們為何對明年初的 48 週期中數據有信心，特別是我們如何更有把握地看待在該時間點藥物與安慰劑之間的差距（separation），以及你們迄今產出的部分數據集能提供哪些推論（read-through）？

You bet. So Salveen, let’s do pove first, and then let’s get to inaxaplin.

當然可以。Salveen，我們先談 pove，接著再談 inaxaplin。

On pove, the specific question you had is, how is it going with manufacturing? We’ve been with the same manufacturer all through Phase 3 and through to the lead up for our PDUFA date. We feel really good about where we are. As you know, in addition to the review of safety and efficacy clin pharm, there’s also review of the CMC manufacturing package, and all of the interactions that you would expect us to be having with the FDA are occurring. So overall, I feel very good about where we are.

關於 pove，你的具體問題是：製造方面進展如何？我們從第三期一路到 PDUFA 日期前的準備，都與同一家製造商合作。我們對目前進度感到非常放心。如你所知，除了安全性、有效性與臨床藥理（clin pharm）的審查之外，也會審查 CMC（化學、製造與管制）製造資料包，而我們與 FDA 之間所有你預期會發生的互動都正在進行。因此整體而言，我對目前狀況非常有信心。

Moving then to inaxaplin, but staying within renal, one way to think about the inaxaplin program and GFR, because to date, in both the original Phase 2a study that we published in the New England, that was the one that had the 47.6% reduction in proteinuria, and the more recent AMPLIFIED results, which were from the more cohort 1, the more modest proteinuria, that one was a 44.7% reduction in UPCR.

接著談 inaxaplin，但仍在腎臟領域之內。思考 inaxaplin 計畫與 GFR 的一種方式是：截至目前，無論是在我們發表於《新英格蘭醫學期刊》的原始第二期 a（Phase 2a）研究——該研究蛋白尿降低 47.6%——或是較近期的 AMPLIFIED 結果（來自較新的 cohort 1、蛋白尿較為溫和），其 UPCR 降幅為 44.7%。

I think the best way to think about that in terms of GFR, which is the endpoint we’ve agreed upon with FDA, is in these two ways. One, substantial reductions in proteinuria, in glomerular proteinuric kidney disease, have time and again, been linked to improvements in GFR. That’s one general statement.

我認為就 GFR（這是我們與 FDA 同意的終點）而言，最佳的理解方式有兩點。第一，在腎小球蛋白尿型腎病（glomerular proteinuric kidney disease）中，蛋白尿的大幅下降一再與 GFR 的改善相關聯。這是一個一般性的論述。

Maybe a second way to look at this is talking about IgA nephropathy. We used to talk about IgA nephropathy as a fairly indolent disease, but as you can see from the placebo arm of IgAN trials, those patients are losing about 5 ccs per mil per year, right? AMKD is a rapidly progressive disease, so more than that; 6, 7, 8 ccs per mil per year.

第二種看法是以 IgA 腎病（IgA nephropathy）為例。我們過去常把 IgA 腎病視為相對惰性的疾病，但從 IgAN 試驗的安慰劑組可以看到，這些病患每年大約會流失 5 ccs per mil，對吧？AMKD 是進展快速的疾病，因此流失幅度更大；每年 6、7、8 ccs per mil。

The FDA themselves have said in IgAN that they are going to be comfortable accepting one-year GFR differences. So when I put that all together, it adds to my confidence level of what we’re going to see with AMPLITUDE. But I’d say those are two ways to think about inaxaplin in AMKD.

FDA 自己也已表示，在 IgAN 中，他們會願意接受一年期的 GFR 差異。所以當我把這些因素綜合起來時，這讓我對我們將在 AMPLITUDE 看到的結果更有信心。但我會說，這是思考 AMKD 中 inaxaplin 的兩種方式。

Geoff Meacham, Citi.

Geoff Meacham，花旗。

Guys, thanks for the question. I also want to offer up some congrats to Charlie. I just have a couple of quick ones.

各位，謝謝提問。我也想向 Charlie 表達祝賀。我只有幾個簡短的問題。

On pove, Reshma, you mentioned data should continue to mature post-approval, including the two-year eGFR data. I guess the question is, how much of a factor do you think this will play in your competitive position ultimately? I wasn’t sure if you looked at this as maybe a tipping point in terms of what the payer and physician community is going to look at.

關於 pove，Reshma，你提到核准後數據會持續成熟，包括兩年期 eGFR 數據。我想問的是，你認為這最終會在多大程度上影響你們的競爭地位？我不確定你們是否把這視為付款方與醫師社群在評估時的一個可能「轉捩點」。

The second one, real quick on pain. I know, looks like the trials are continuing to enroll mid-year data next year. Maybe just at a high level, give us some context for kind of what you think at this point a win would look like, kind of in DPN for suzetrigine. Thank you.

第二個問題，很快關於疼痛。我知道，看起來試驗仍在持續收案，明年年中會有數據。也許請你從較高層次，給我們一些背景：就目前而言，你認為 suzetrigine 在 DPN 上所謂的「勝利」會長什麼樣子？謝謝。

Yeah. Let’s do DPN first, and then I’ll split the pove question with Duncan McKechnie. On DPN, we are fully on track to complete enrollment in both the two Phase 3 VX-548 or suzetrigine trials, and on track to complete the enrollment in the VX-993 DPN trial. That would put us for results somewhere mid of next year. A win would be the suzetrigine arm beating placebo treatment in the two DPN studies.

好的。我們先談 DPN，然後我會把 pove 的問題分給 Duncan McKechnie 一起回答。在 DPN 方面，我們完全按計畫推進，將完成兩項第三期 VX-548（或 suzetrigine）試驗的收案，也按計畫完成 VX-993 DPN 試驗的收案。這會讓我們在明年年中左右取得結果。所謂的勝利，就是 suzetrigine 組在兩項 DPN 研究中優於安慰劑治療。

In one of the studies, we have a gabapentin arm to give us context, but a win would be beating placebo. That’s the regulatory enabling endpoint. On pove, I’ll just give you a top-line comment. We’re going to go to the two-year eGFR full completion of the trial as originally designed, because our ambition is to launch pove around the globe.

其中一項研究我們設有 gabapentin 組作為參照背景，但勝利仍是優於安慰劑。那是可用於法規申請的主要終點。至於 pove，我先給你一個總體評論。我們會依照原始設計，將試驗完整做到兩年期 eGFR，因為我們的企圖是把 pove 推向全球上市。

The FDA has said that they’re comfortable with one-year GFR, but other regulators have different expectations. That’s why we’re going to full completion, and I do think the results are fully mature at that point, and that’s another advantage for all of us to have fully mature two-year data. Duncan McKechnie, do you want to talk a little bit about differentiation, GFR, and the pove launch in the US?

FDA 表示他們對一年期 GFR 感到可接受，但其他監管機構的期待不同。這就是為什麼我們會做到完整結束；而我確實認為到那個時間點結果會完全成熟，對我們所有人而言，擁有完全成熟的兩年期數據也是另一項優勢。Duncan McKechnie，你要不要談談差異化、GFR，以及 pove 在美國的上市？

Indeed. Hi, Geoff. So we’ve thought about this question quite a lot, as you can imagine. We’ve discussed it with nephrologists, and I would encourage you to think about it this way. Nephrologists already had a very strong level of conviction in the connection between proteinuria and eGFR, especially in IgAN. And I would say the data that has come out from the APRIL/BAFF inhibitors over the last couple of months has only served to strengthen that conviction.

當然。嗨，Geoff。如你所想，我們對這個問題思考了很多。我們也和腎臟科醫師討論過，我會建議你用這種方式來看。腎臟科醫師早就對蛋白尿與 eGFR 之間的關聯有非常強的信念，尤其是在 IgAN。並且我會說，過去幾個月 APRIL/BAFF 抑制劑所釋出的數據，只是進一步強化了這種信念。

So we believe, on the basis of that pove continues to have best-in-class potential through its excellent efficacy profile, impact on proteinuria, hematuria, Gd-IgA1 in just 36 weeks, as well as being well tolerated, and as Reshmaalluded to in her prepared remarks, an incredible profile from a patient point of view with a low volume, low viscosity, at-home once-a-month autoinjector.

因此我們相信，基於這些，pove 仍具備同類最佳（best-in-class）的潛力：其優異的療效特徵、對蛋白尿的影響、血尿、以及在僅 36 週內對 Gd-IgA1 的影響，同時耐受性良好；而且如 Reshma 在事先準備的發言中提到，從病患角度看也有極佳的特性：低容量、低黏度、可在家中每月一次使用的自動注射器。

So when we’ve been engaging with nephrologists on this topic, which we’ve done a lot over the last couple of months, including, of course, at ASN Week, they’re very excited in the profile of povetacicept and looking forward to trying it post-approval. So we’re very comfortable with where we’re at.

所以當我們在這個主題上與腎臟科醫師互動時——過去幾個月我們做了很多，當然也包括在 ASN Week——他們對 povetacicept 的特性非常興奮，並期待在核准後嘗試使用。因此我們對目前的進展非常有信心。

Great. Thank you.

很好。謝謝。

Evan Seigerman, BMO Capital Markets.

Evan Seigerman，BMO 資本市場。

Hi, guys. Thank you so much for taking my question. So we’re seeing some good traction with JOURNAVX, but you’re keeping the PSP on through the rest of the year, and now pointing to gross-to-net normalization around mid-2027. Can you help us think about kind of the bridge between prescription growth and eventually reported revenue as the PSP rolls off, and whether you expect revenue growth to reflect as normalization occurs? Thank you so much.

嗨，各位。非常感謝讓我提問。我們看到 JOURNAVX 有不錯的動能，但你們會把 PSP 持續到今年年底，並且現在指向毛到淨（gross-to-net）在 2027 年年中左右正常化。你們能否協助我們理解：當 PSP 逐步退場時，處方成長與最終揭露的營收之間的銜接（bridge）應該怎麼看？以及你們是否預期隨著正常化發生，營收成長會相應反映出來？非常感謝。

Sure thing. Duncan, maybe you could take that one for us?

當然可以。Duncan，也許你可以替我們回答這題？

Yeah. So just to step back a little bit, Evan, just to make a couple of points, and then I will dive into the PSP program, gross-to-net, and revenue. We are very pleased with the performance of JOURNAVX. This is hard work. We are changing decades of ingrained prescribing behavior and seeking to convert practices over to the use of JOURNAVX. So, 750,000 prescriptions in one quarter, 1.6 million Americans treated, the number one oral branded analgesic, would all indicate that we are making great progress.

好的。Evan，我先稍微退一步，先講幾點，然後再深入談 PSP 計畫、毛到淨，以及營收。我們對 JOURNAVX 的表現非常滿意。這是辛苦的工作。我們正在改變數十年根深蒂固的處方習慣，並試圖讓診所轉而使用 JOURNAVX。

As far as the gross-to-net is concerned, I would make the comment that obviously negotiated agreements to secure access for the full population with payers are important to the long-term sustainable growth of the product. And so, it is important that we are able to get those plans in place. For example, the two Medicare Part D plans that came in place in July this year.

至於毛到淨，我想補充的是：顯然，與付款方談妥協議、以確保全體人群的可近性（access），對產品長期可持續成長非常重要。因此，我們能把這些方案建置到位很重要。例如，今年 7 月生效的兩個 Medicare Part D 計畫。

At this point, we have about 82% managed lives covered, but that does mean that there are patients who are yet to be covered, and we want to make sure that those patients have a great experience. So, we are taking the strategic decision to keep the PSP program switched on. We will sunset it by the middle of 2027, and at that point, you can expect, as we have said before, I think, gross-to-net to stabilize at the sort of normal oral branded level of 50%-60%, and revenue growth to grow commensurately.

目前我們大約覆蓋了 82% 的受管理人群（managed lives），但這也意味著仍有一些病患尚未被覆蓋，而我們希望確保這些病患也能有很好的體驗。因此，我們做出策略性決定，讓 PSP 計畫持續啟用。我們會在 2027 年年中之前逐步終止（sunset）該計畫；到那時，你可以預期——如我們先前所說——毛到淨會穩定在一般口服品牌藥的正常水準，大約 50%–60%，而營收成長也會相應提升。

Great. Thank you.

很好。謝謝。

Brian Abrahams, RBC Capital Markets.

Brian Abrahams，RBC 資本市場。

Hey, good afternoon. Thanks for taking our question, and congrats to Charlie from us as well. Just on the pove launch, I am just wondering what is the right way to think about how initial uptake might balance both the growing awareness and enthusiasm versus the potential that a lot of nephrotic patients may have already come onto therapy with a drug in the class?

嘿，午安。謝謝讓我們提問，我們也要恭喜 Charlie。關於 pove 的上市，我想知道應該如何看待初期採用（uptake）的平衡：一方面市場認知與熱情正在升溫；另一方面也可能有不少腎病症候群患者已經開始使用同一類別的藥物治療？

And then just secondarily, ALYFTREK conversion looks like it has been picking up steam the last few quarters. I am just wondering the right way to think about the continued trajectory there. Thanks.

另外，ALYFTREK 的轉換看起來在過去幾季正在加速。我想請教，接下來的持續走勢應該怎麼看？謝謝。

You bet. Brian, I am going to ask Duncan to comment on both. Let us do your second question first, and then we will go back to pove.

當然沒問題。Brian，我會請Duncan就這兩點一起回應。我們先回答你的第二個問題，然後再回到pove。

Yeah, Brian. ALYFTREK is being driven predominantly by new reimbursement agreements, obviously outside the US. We have had another slew of those agreements in quarter three. It is also being driven by the new rare mutation indications, which obviously offer a de novo patient population to the CFTR modulator class writ large in some cases, and certainly ALY specifically. Those are essentially the two main drivers of ALY growth over the last couple of months, which we are particularly happy with. In terms of pove and uptake, a couple of comments there.

是的，Brian。ALYFTREK的成長主要是由新的給付／報銷協議所驅動，顯然是在美國以外。我們在第三季又簽下了一批這類協議。同時也受到新的罕見突變適應症所帶動；這些適應症在某些情況下，為整體CFTR調節劑類別帶來全新的病患族群，當然也特別有利於ALY。基本上，這就是過去幾個月ALY成長的兩大主要驅動因素，我們對此特別滿意。至於pove與導入／採用（uptake），我有幾點補充。

Firstly, as with say, CASGEVY and JOURNAVX, we will be providing you with the metrics that we think are most useful to look at in our earnings call at the beginning of 2027. I would say you make a great point. The physician enthusiasm for the new BAFF inhibitor or BAFF/APRIL inhibitors has been incredible, and that is certainly driving success in the market.

第一，正如CASGEVY與JOURNAVX一樣，我們會在2027年初的財報電話會議上，提供我們認為最有用、最值得關注的指標。我會說你提得很好。醫師對新的BAFF抑制劑或BAFF/APRIL抑制劑的熱情非常驚人，而這確實正在推動市場上的成功。

The numbers are a little bit unclear at this point, but let’s say, sorry, not pove, VOYXACT and TRUTAKNA close the year with about 3,000 patients on medicine, which is probably roughly where they’re going to end up. That leaves us with 163,000 yet to go.

目前數字還有點不太明確，但假設——抱歉，不是pove——VOYXACT和TRUTAKNA在年底時合計約有3,000名病患正在用藥，這大概就是它們最終會落在的水準。這表示我們還有163,000名病患尚待覆蓋。

So, with the level of nephrology enthusiasm for advanced therapy and treating early in the disease, for the nephrologist enthusiasm for povetacicept specifically, both its clinical profile and the patient experience, and that vast number of patients who still need treatment, remember, 75% of patients with IgAN have a proteinuria above 1 gram, we think there’s a huge opportunity here.

因此，考量到腎臟科對進階治療以及在疾病早期介入治療的高度熱情、腎臟科醫師對povetacicept本身的熱忱（包括其臨床特性與病患使用體驗），再加上仍有如此龐大的未治療病患數——請記得，75%的IgAN病患蛋白尿高於1克——我們認為這裡有非常巨大的機會。

Thanks.

謝謝。

Michael Yee, UBS.

UBS的Michael Yee。

Hey, guys. Mike Yee at UBS. Two questions on inaxaplin. Reshma, you made some great comments about some of the previous data we already know in Phase 2. I guess one new thing that has come out is obviously some of the IgAN data that shows significant eGFR benefits even at nine months on just a couple mil per minute deltas and similar proteinuria reductions you’re seeing with the inaxaplin.

嗨，各位。我是UBS的Mike Yee。關於inaxaplin有兩個問題。Reshma，你對我們在第二期已經知道的一些既有數據做了很好的評論。我想最近出現的一個新點是：顯然有一些IgAN數據顯示，即使在僅九個月時，eGFR也有顯著受益，增量大概是每分鐘幾個mL的差異，且蛋白尿下降幅度也與你們在inaxaplin上看到的相近。

So my question is, given the significant benefits you’re seeing and given a 12-month time point, our math suggests that a 2 mil per minute benefit should be stat sig. Just wanted to understand your view about the IgAN data and how that translates here given the deltas you see.

所以我的問題是：鑑於你們看到的顯著效益，以及12個月這個時間點，我們的計算顯示每分鐘2 mL的改善應該會達到統計顯著。想請教你對IgAN數據的看法，以及在你們看到的增量（delta）下，這些結果如何對應到這裡。

The second question is PARASOL, I think the working group has been trying to push proteinuria as an endpoint. Was there any color that you got out of their working group and how that may be an accelerated endpoint? Thank you.

第二個問題是關於PARASOL。我想該工作小組一直在推動以蛋白尿作為終點。你們從他們的工作小組那邊是否得到任何進一步資訊，說明這可能如何成為加速核准的終點？謝謝。

Yeah. Mike, first let’s do PARASOL. PARASOL is a very important and influential group. They’ve come together multiple times over time and worked with the FDA to evolve endpoints. In FSGS and their work with the agency, I do think helped to move the agency to a protein-based endpoint. We are members of the broader PARASOL community. The thing that I’m paying most attention to is the community clearly seem interested in moving to a proteinuria endpoint for AMKD.

好的。Mike，我們先談PARASOL。PARASOL是一個非常重要且具影響力的團體。他們在不同時間點多次集結，並與FDA合作推動終點的演進。在FSGS以及他們與主管機關的合作上，我確實認為這有助於推動主管機關轉向以蛋白為基礎的終點。我們是更廣泛PARASOL社群的一員。我最關注的是：整個社群顯然對於在AMKD採用蛋白尿終點很有興趣。

And at the same time, the FDA and our agreement is indeed with GFR. Given that, we’re focused on GFR. On your math for GFR, I won’t argue with your math. Seems reasonable enough.

同時，FDA以及我們的協議確實是以GFR為主。因此，我們會聚焦在GFR。至於你對GFR的計算，我不會反駁你的數學。看起來相當合理。

The thing to say, Mike, is I think what we’re learning from the example of IgA nephropathy, because there’s so many different classes now that have been used in IgAN, it matters not only that you get the proteinuria down, it matters how you get the proteinuria down. Decreasing proteinuria by way of APRIL/BAFF inhibition has more beneficial impact on GFR than perhaps other methods of reducing proteinuria.

Mike，我想要說的是：從IgA腎病的例子我們正在學到的是，因為現在IgAN已經有很多不同的治療類別被使用，不僅要把蛋白尿降下來，還要看你是用什麼方式把蛋白尿降下來。透過APRIL/BAFF抑制來降低蛋白尿，對GFR的正面影響可能比其他降低蛋白尿的方法更大。

The thing that I take away from it is targeting the underlying cause of disease is always a better move than going upstream or downstream. It’s actually another reason I have confidence in AMPLITUDE, because it’s another example of a proteinuric kidney disease where we’re targeting the underlying biology.

我從中得到的結論是：鎖定疾病的根本原因，永遠比在上游或下游動手更好。這也是我對AMPLITUDE有信心的另一個原因，因為這是另一個以蛋白尿為特徵的腎臟疾病案例，而我們正在鎖定其根本生物學機制。

I think both in the dimension of quantity of protein reduction, but also the how, the quality of protein reduction in IgAN APRIL/BAFF upstream in the four-hit hypothesis has beneficial effect. I think that’s what we’re going to see with AMPLITUDE, because inaxaplin is equally targeting that underlying cause.

我認為在IgAN中，不僅是蛋白下降的「量」，也包括「如何」下降——也就是蛋白下降的「質」。在四擊假說中，於上游透過APRIL/BAFF路徑來降低蛋白尿，會帶來有利的效果。我認為我們在AMPLITUDE也會看到同樣情況，因為inaxaplin同樣是在鎖定那個根本原因。

Perfect. Thank you.

很好。謝謝。

Tazeen Ahmad, Bank of America.

美國銀行的Tazeen Ahmad。

Hi. Thanks for taking my question. Let’s go back to the CF franchise for a second. Can you just give us your thoughts, Reshma Kewalramani, on how the data for VX-828 compare to your expectations, just based on the preclinical data that you looked at? Then, if you think about the other CFTR modulators that you have, where do you think is the biggest unmet need at this point, and where is the most room for improvement over what you have with ALYFTREK? Thanks.

嗨，謝謝讓我提問。我們回到CF產品線談一下。Reshma Kewalramani，你能否談談VX-828的數據與你們的預期相比如何，特別是基於你們先前看到的臨床前數據？另外，若你回頭看你們其他的CFTR調節劑，目前最大的未被滿足需求在哪裡？相較於ALYFTREK，你認為還有哪些地方最有改善空間？謝謝。

You ask such a good question, Tazeen Ahmad, around what is the unmet need? Let me just take a step back and tell you about VX-828 and then where we’re going. The VX-828, if you look, and I think we provided it on the slide, if you look at the range of outcomes, the decrease in sweat chloride, certainly the range of outcomes covers our expectations, on sweat chloride reduction, that is. But it is obviously a small study. It’s N equals 8.

Tazeen Ahmad，你問了一個非常好的問題：未被滿足的需求是什麼？我先退一步，先談VX-828，再談我們接下來的方向。就VX-828而言，如果你看——我想我們在投影片上也有提供——若看結果的範圍，汗氯（sweat chloride）的下降幅度，其結果範圍確實涵蓋了我們的預期，指的是汗氯下降這件事。但這顯然是一個小型研究。樣本數N等於8。

The reason we are not advancing VX-828 in and of itself, although the results are excellent, if you were at a different company, you would just be over the moon with results like this, right? At 28 days, we’re more than 6 points of sweat chloride improvement, and through 28 days, we’re touching 10 points of sweat chloride.

我們之所以不單獨推進VX-828本身，儘管結果非常出色，是因為——如果你在另一家公司，看到這樣的結果大概會欣喜若狂，對吧？在28天時，汗氯改善超過6個點；到28天為止，我們甚至接近10個點的汗氯改善。

Those are good numbers, especially when you take into account it’s versus TRIKAFTA. This is not versus a placebo baseline. So, those are excellent results. It’s once a day, good DDI, it’s favorable safety.

這些數字很不錯，尤其是考量到這是相對於TRIKAFTA的比較；這不是相對於安慰劑基線。所以，這些都是非常優秀的結果。它是每日一次，藥物交互作用（DDI）表現良好，且安全性有利。

The thing for us is we have three medicines in this NG 3.0 family, and we want to pick the best one. We’re going to have the results from the other two medicines, VX-581 and VX-272, next year. When we have all of those results, we’ll pick the one that’s best suited to move forward. If you say, what is the residual unmet need?

對我們而言，關鍵在於：我們在這個NG 3.0家族裡有三個藥物，我們想選出最好的那一個。明年我們會拿到另外兩個藥物VX-581與VX-272的結果。當我們拿到所有結果後，我們會選出最適合往前推進的那一個。如果你問，剩餘的未被滿足需求是什麼？

I think, Tazeen, that’s a very, very hard question to answer, because when we look at the data with ALYFTREK, we are almost superimposable onto the Gaussian distribution of sweat chloride of normal people. So, really, it is a matter of now not almost being superimposable, but being fully superimposable. So, a little bit more sweat chloride, more patients getting to less than 30. That is what we are looking for.

我認為，Tazeen，這是一個非常、非常難回答的問題，因為當我們看 ALYFTREK 的數據時，我們幾乎與正常人汗氯的高斯分佈完全重疊。所以，實際上，現在的問題不是「幾乎」重疊，而是要做到「完全」重疊。因此，汗氯再多改善一點，讓更多病人降到 30 以下。這就是我們在尋求的。

Akash Tewari, Jefferies.

Akash Tewari，Jefferies。

Hey, thanks so much. Can you talk a bit more about your decision to file on two-year eGFR data? I know you were going to make a decision, I was anticipating sometime next year. It sounds like you are making the call now. Just from a statistical perspective, if a patient on placebo starts another APRIL/BAFF drug during that one- to two-year window, how are they actually accounted for statistically? Are they included in the eGFR final analysis? Thank you.

嗨，非常感謝。你能否再多談一點你們決定以兩年期 eGFR 數據來申報的考量？我知道你們原本會做出決定，我原先預期是在明年某個時候。聽起來你們現在就做出決定了。從統計角度來看，如果安慰劑組的病人在那一到兩年的期間內開始使用另一個 APRIL/BAFF 藥物，統計上實際會如何處理？他們會被納入 eGFR 的最終分析嗎？謝謝。

Yeah. I just want to make sure I understood your question about the decision for two years. I think you were saying, why continue two-year GFR? Did I understand correctly?

好的。我只是想確認我理解了你關於兩年期決策的問題。我想你是在問，為什麼要繼續做到兩年期的 GFR？我理解得對嗎？

Right. Why make the call now? I know you had previously talked about regulators in a global setting wanting two-year data, but we already knew that. So, what led to the decision to go forward with two-year today?

對。為什麼現在就做這個決定？我知道你們之前談過，在全球監管的情境下，監管機構希望看到兩年期數據，但我們其實已經知道這點了。那麼，是什麼促使你們今天決定要往兩年期推進？

Yeah. Obviously, we can decide if we wish to cut the data and do a one-year cut. We could do that at any time. Our decision to indicate that we are going to continue to two years is because people have asked us the question, including our clinical trial sites, about what our goal is and how we see this.

是的。顯然，我們可以決定是否要截取數據並做一個一年期的截點分析。我們任何時候都可以這麼做。我們之所以表明會繼續做到兩年，是因為有人問過我們這個問題，包括我們的臨床試驗中心，關於我們的目標是什麼，以及我們如何看待這件事。

So, to allow preparation for everyone, we’ve let folks know that our intention is and our ambition is global filings. And that’s going to require two-year GFR because ex-US, not all the regulators have agreed to one-year GFR. So, that’s the rationale for that.

因此，為了讓大家都能提前準備，我們已經讓各方知道，我們的意圖與企圖心是進行全球申報。而這將需要兩年期的 GFR，因為在美國以外，並非所有監管機構都同意只用一年期的 GFR。所以，這就是其背後的理由。

With regard to how our patients manage, there are clear rules in the statistical analysis plan that not only the FDA, but global regulators have set forward for management of dropouts, missing data, and how to handle if patients are no longer in the study. So, we’re simply going to follow the rules that are very clearly laid out. I won’t go through all of them in excruciating detail, but they are in excruciating detail.

至於病人管理方式，統計分析計畫中有明確規則，這些規則不僅由 FDA，也由全球監管機構提出，用於處理退組、缺失數據，以及當病人不再參與研究時該如何處理。所以，我們只是會遵循那些已非常清楚列出的規則。我不會在這裡把所有細節講到鉅細靡遺，但它們確實寫得非常鉅細靡遺。

Terence Flynn, Morgan Stanley.

Terence Flynn，Morgan Stanley。

Great. Thanks so much for taking the question. I guess, one more on inaxaplin. I was just wondering, on the AMPLIFIED data, I know there has been some questions about the breadth of response in the moderate proteinuria cohort. So, just maybe, Reshma, you could provide a little bit more detail. I just want to ensure that there wasn’t a small subset of FSGS patients that was driving that proteinuria reduction that was broader based. Maybe you could talk about the response rate across the population in that cohort one. Thank you.

很好。非常感謝讓我提問。我想再問一個關於 inaxaplin 的問題。我在想，關於 AMPLIFIED 的數據，我知道外界對於中度蛋白尿隊列的反應廣度有一些疑問。所以也許 Reshma，你可以提供更多一點細節。我只是想確認，蛋白尿下降並不是由一小部分 FSGS 病人所驅動，而是更廣泛地發生。也許你可以談談在第一隊列中，整體族群的反應率。謝謝。

Yeah. So, Terence Flynn, on AMPLIFIED and cohort one, that, let’s call it the modest proteinuria group, because this was the 0.3 to 0.7 UPCR proteinuria cohort, the majority of patients did not have FSGS. So, they didn’t have a biopsy and they didn’t have FSGS, which you would expect because their proteinuria is modest. You are correct. The response, therefore, was not driven by an FSGS cohort because there weren’t many of them. Most people in the study were non-FSGS patients.

好的。Terence Flynn，關於 AMPLIFIED 與第一隊列，也就是我們稱之為蛋白尿較溫和的族群，因為這是 UPCR 0.3 到 0.7 的蛋白尿隊列，多數病人並沒有 FSGS。因此他們沒有做活檢，也沒有 FSGS；以他們蛋白尿較溫和的情況來看，這是符合預期的。你說得沒錯。因此，反應並不是由 FSGS 隊列所驅動，因為那樣的病人並不多。研究中的大多數人是非 FSGS 病人。

One more question, please, Charlie Wagner.

再一個問題，拜託，Charlie Wagner。

Mohit Bansal, Wells Fargo.

Mohit Bansal，Wells Fargo。

Great. Thank you very much for taking my question and congrats on all the progress. My question is kind of circling back to pove manufacturing, and one concern is around the potential use of continuous manufacturing in this process, which is relatively new for biologics at this point. Should we worry about it at all, or do you think FDA has been involved enough from the beginning here for us to feel comfortable about this? Thank you.

很好。非常感謝讓我提問，也恭喜你們取得所有進展。我的問題想回到 pove 的製造，其中一個疑慮是這個流程可能使用連續式製造（continuous manufacturing），而就目前而言，這對生物製劑來說相對較新。我們需要擔心這點嗎？或者你認為 FDA 從一開始就已充分參與，讓我們可以對此感到放心？謝謝。

Hi, Mohit. On whether the agency has been involved, yes, the agency has been involved, and we’re now coming towards the end of the process, right? We’re at the point where all data has been submitted. There’s an entire module on CMC and manufacturing, and you know we filed towards the end of March of this year, so they’ve had all that data now for a long time. All of the discussions that you expect us to be having, we’re having. If you asked me if I was feeling good about the filing, all included, including manufacturing, I’d say yes, I feel good about the filing.

嗨，Mohit。關於主管機關是否有參與，是的，主管機關一直有參與，而我們現在也正接近流程的尾聲，對吧？我們已經到了所有資料都已提交的階段。有一整個模組是關於 CMC 與製造；你也知道我們是在今年三月底左右遞交申請，所以他們已經掌握那些資料很長一段時間了。所有你預期我們會進行的討論，我們都正在進行。如果你問我對這次申報是否有信心，包含所有面向、也包含製造在內，我會說是的，我對這次申報感覺良好。

Thank you.

謝謝。

You bet.

不客氣。

Chuck, could you please wrap us up?

Chuck，你可以幫我們做個總結嗎？

Will do. This will conclude our question-and-answer session, as well as our conference call for today. A replay will be available shortly after the call concludes by dialing 1-855-669-9658 or 1-412-317-0088 using replay access code 10208189. Thank you for your attendance today. You may now disconnect.

沒問題。今天的問答環節以及電話會議到此結束。會議結束後不久即可收聽重播，請撥打 1-855-669-9658 或 1-412-317-0088，並輸入重播存取碼 10208189。感謝各位今天的參與。各位現在可以掛線。