Agios Pharmaceuticals Inc (AGIO) 2025 Q3 法說會逐字稿

Good morning, and welcome to Agios Pharmaceuticals third-quarter 2025 Conference Call. (Operator Instructions) Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Please go ahead, ma'am.

早安，歡迎參加Agios Pharmaceuticals 2025年第三季業績電話會議。 （操作說明）請注意，本次電話會議應Agios要求錄音。現在我將把電話會議交給Agios投資者關係主管Morgan Sanford女士。請您發言。

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals third-quarter 2025 financial results and business highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. Next slide, please.

謝謝接線生。大家早安。感謝各位參加本次Agios Pharmaceuticals 2025年第三季財務業績及業務亮點討論會。您可以在我們網站agios.com的「投資者關係」版塊查看本次電話會議的幻燈片。下一張投影片。

Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

請注意，我們今天將做出一些前瞻性陳述。由於各種風險、不確定性和其他因素，包括我們在最近向美國證券交易委員會提交的文件以及我們未來可能向美國證券交易委員會提交的任何其他文件中所述的風險、不確定性和其他因素，實際事件和結果可能與任何前瞻性陳述中明示或暗示的內容存在重大差異。

Our third quarter earnings call agenda is shown on the next slide. Joining me on today's call are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development.

我們的第三季財報電話會議議程請見下一張投影片。今天與我一同參加電話會議的有：執行長布萊恩·戈夫；首席財務官塞西莉亞·瓊斯；首席商務官茨維塔·米拉諾娃；以及首席醫療官兼研發主管莎拉·格恩斯博士。

Following prepared remarks, we will open the call for questions.

在發言結束後，我們將開放提問環節。

With that, please move to the next slide, and I am pleased to turn the call over to Brian.

那麼，請進入下一張幻燈片，我很高興將通話交給布萊恩。

Thanks, Morgan. Good morning, everyone, and thank you for joining us on today's call to discuss our third quarter highlights beginning on the next slide.

謝謝摩根。大家早安，感謝各位參加今天的電話會議，我們將從下一張投影片開始討論我們第三季的亮點。

With steady progress and a focused strategy, we have a clear path to unlock long-term shareholder value. First, we have multiple high-value catalysts in the coming months that position PYRUKYND, our foundational PK activator, to achieve its multibillion-dollar potential across PK deficiency, thalassemia, and sickle cell disease.

憑藉著穩步推進和專注的策略，我們已明確了釋放股東長期價值的路徑。首先，未來幾個月我們將迎來多項高價值催化劑，這將使我們的基礎PK活化劑PYRUKYND在PK缺乏症、地中海貧血和鐮狀細胞貧血領域實現數十億美元的市場潛力。

Following the FDA's recent request for a REMS program, our PDUFA date for PYRUKYND thalassemia supplemental NDA has been extended to December 7. We are actively engaged with the FDA and are leveraging this additional time to strengthen our engagement with the thalassemia community and further refine our launch planning.

鑑於 FDA 最近要求我們實施 REMS 計劃，我們 PYRUKYND 地中海貧血補充新藥申請的 PDUFA 日期已延長至 12 月 7 日。我們正在積極與 FDA 溝通，並利用這段額外的時間加強與地中海貧血群體的聯繫，並進一步完善我們的上市計劃。

Additionally, we look forward to sharing top line results from the RISE UP Phase 3 trial of PYRUKYND in sickle cell disease by year-end. Meanwhile, we continue to advance our early and mid-stage pipeline, which includes our other PK activator, tebapivat, for lower-risk myelodysplastic syndromes or MDS and sickle cell disease; AG-181 for phenylketonuria; and AG-236 for polycythemia vera.

此外，我們期待在年底前公佈 PYRUKYND 治療鐮狀細胞疾病的 RISE UP III 期臨床試驗的主要結果。同時，我們也持續推進早期和中期研發管線，其中包括我們用於治療低危險群骨髓增生異常症候群 (MDS) 和鐮狀細胞疾病的另一種 PK 活化劑 tebapivat；用於治療苯酮尿症的 AG-181；以及用於治療真性紅血球增多症的 AG-236。

Importantly, our strong balance sheet, with approximately $1.3 billion in cash and investments, positions us to invest in a disciplined manner to both support our potential US launches and advance our rare disease pipeline. Our third quarter highlights are summarized on the next slide.

重要的是，我們穩健的資產負債表，擁有約13億美元的現金和投資，使我們能夠以審慎的方式進行投資，從而支持我們在美國的潛在產品上市，並推進我們的罕見疾病產品線。第三季亮點總結見下一頁。

In the third quarter, we reported $12.9 million in net revenue, underscoring the strong value proposition of PYRUKYND. In August, we announced approval for PYRUKYND in adults with thalassemia in Saudi Arabia, our first global regulatory approval for this indication. And earlier this month, we also received a positive CHMP opinion recommending PYRUKYND for marketing authorization in Europe for the treatment of adults with thalassemia. And lastly, we achieved a key R&D priority by completing enrollment in the Phase 2b trial of tebapivat in lower-risk MDS, and we anticipate top line data early next year.

第三季度，我們實現淨收入1290萬美元，凸顯了PYRUKYND的強勁價值主張。 8月，我們宣布PYRUKYND在沙烏地阿拉伯獲準用於治療成人地中海貧血，這是我們第一個獲得全球監管部門批准用於該適應症的藥物。本月初，我們也收到人用藥品委員會（CHMP）的正面意見，建議在歐洲批准PYRUKYND用於治療成人地中海貧血。最後，我們完成了一項重要的研發重點，即完成了tebapivat治療低危險性MDS的IIb期臨床試驗的患者招募，預計將於明年初獲得初步數據。

With continued momentum across our commercial portfolio and pipeline, our team has demonstrated strong execution and agility, keeping us firmly focused on our mission to deliver transformative medicines for patients. That agility is a competitive advantage as we work to transform the treatment landscape for thalassemia and sickle cell disease. Feedback from these communities through our recent global engagements reinforces the critical need for treatment innovation.

憑藉我們商業產品組合和研發管線的持續發展勢頭，我們的團隊展現了強大的執行力和敏捷性，始終專注於為患者提供變革性藥物的使命。這種敏捷性是我們致力於改變地中海貧血和鐮狀細胞疾病治療格局的競爭優勢。近期我們與全球各界人士的互動也印證了治療創新至關重要。

Please move to the next slide, and I'll turn the call over to Cecilia to provide commentary on our third quarter performance and full-year outlook. Cecilia?

請切換到下一張投影片，接下來我將把電話交給塞西莉亞，請她對我們第三季的業績和全年展望進行點評。塞西莉亞？

Thank you, Brian. Next slide, please. Our third-quarter 2025 financial results can be found in the press release issued this morning and additional details can be found in our 10-Q which will be filed later today.

謝謝布萊恩。請看下一張投影片。我們2025年第三季的財務業績已在今天上午發布的新聞稿中公佈，更多詳情請見我們今天稍後提交的10-Q表格。

Let me now take a moment to provide some context and highlight a few key points. Third quarter net PYRUKYND revenue was $12.9 million, an increase of 44% compared to $9 million in the third quarter of 2024 and an increase of 3% compared to $12.5 million in the second quarter of 2025.

現在讓我花點時間提供一些背景資訊並強調幾個關鍵點。 PYRUKYND 第三季淨收入為 1,290 萬美元，比 2024 年第三季的 900 萬美元成長了 44%，比 2025 年第二季的 1,250 萬美元成長了 3%。

Third quarter net revenue growth reflects continued commercial execution in PKD ahead of potential US approval for thalassemia. Looking ahead, fourth quarter performance will benefit from an additional ordering week compared to the third quarter. And we anticipate PYRUKYND net revenue will continue to reflect continued focus on PK deficiency ahead of potential approval for thalassemia in the US.

第三季淨收入成長反映了在多囊性腎病變（PKD）領域持續的商業化運作，為未來可能在美國獲準用於地中海型貧血鋪平了道路。展望未來，第四季業績將受益於比第三季多一週的訂單量。我們預計，在PYRUKYND有望獲得美國批准用於地中海貧血症之前，我們將繼續專注於PK缺乏症領域的業務，從而提升其淨收入。

On a full-year basis, given the strong execution of our sales force to-date, we anticipate net revenues in 2025 to show robust growth compared to 2024, although we recognize this growth is on a relatively small revenue base.

從全年來看，鑑於我們銷售團隊迄今為止的出色表現，我們預計 2025 年的淨收入將比 2024 年實現強勁增長，儘管我們也意識到這一增長是在相對較小的收入基礎上實現的。

Cost of sales for the quarter was $1.7 million. R&D expenses were $86.8 million, an increase of $14.3 million compared to the third quarter of 2024. This increase was primarily driven by increased clinical trial costs associated with our PK activation franchise. SG&A expenses were $41.3 million in the third quarter, an increase of $2.7 million compared to the prior year, driven by disciplined investments ahead of the potential commercial launch of PYRUKYND in thalassemia. We ended the third quarter with cash, cash equivalents, and marketable securities of approximately $1.3 billion. Next slide, please.

本季銷售成本為170萬美元。研發費用為8,680萬美元，較2024年第三季增加1,430萬美元。這一增長主要源自於我們PK活化產品線相關的臨床試驗成本增加。第三季銷售、管理及行政費用為4,130萬美元，較上年同期增加270萬美元，主要是由於在PYRUKYND用於治療地中海型貧血的潛在商業化上市前，我們進行了審慎的投資。截至第三季末，我們持有的現金、現金等價物及有價證券約為13億美元。請看下一張投影片。

Our capital allocation strategy, backed by a strong balance sheet, enables strategic investment in future growth and delivery of our ongoing pipeline programs.

我們憑藉穩健的資產負債表，制定了資本配置策略，從而能夠對未來的成長進行策略性投資，並推進我們正在進行的專案。

First, we have built a capital-efficient global commercial model, prioritizing our investment in potential US launches which represents the largest commercial opportunities. We have executed partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe, both of which are structured as revenue sharing arrangements that favor Agios over the long term. We will record our share of sales as net revenues.

首先，我們建構了一個資本高效的全球商業模式，優先投資於具有最大商業潛力的美國市場。我們與海灣合作委員會（GCC）的NewBridge Pharmaceuticals和歐洲的Avanzanite Bioscience建立了合作關係，這兩項合作均採用收益分成模式，有利於Agios的長期發展。我們將把我們的銷售分成計入淨收入。

Second, we will continue to invest in our ongoing early and mid-stage clinical programs. And third, we are opportunistically looking for ways to expand and diversify our pipeline through internal efforts or externally sourced assets.

其次，我們將繼續投資於正在進行的早期和中期臨床項目。第三，我們將抓住機遇，透過內部研發或外部收購，拓展和豐富我們的產品線。

In closing, I am confident that our balance sheet will enable us to continue to execute from a position of strength.

最後，我相信我們的資產負債表將使我們能夠繼續保持強勁的實力。

Please advance to the next slide and I will turn the call over to Tsveta to share commercial highlights for the quarter.

請翻到下一張投影片，接下來我將把電話交給 Tsveta，讓她分享本季的商業亮點。

Thank you, Cecilia. Next slide, please. In the third quarter, we delivered $12.9 million in PYRUKYND net revenues, up 3% sequentially, once again reflecting strong execution by our commercial team. To date, 262 patients have completed prescription enrollment forms, including 14 in the third quarter, representing a 6% increase sequentially. This has translated into 149 patients currently on therapy, up 5% from the second quarter.

謝謝塞西莉亞。請看下一張投影片。第三季度，PYRUKYND 的淨收入為 1,290 萬美元，環比成長 3%，再次體現了我們商業團隊的出色執行力。截至目前，已有 262 名患者完成了處方登記表，其中第三季新增 14 名，季增 6%。這意味著目前有 149 名患者正在接受治療，比第二季度增加 5%。

These results underscore the strength of our commercial model and the foundation we are building for future growth. We are well-positioned to deliver on potential US launches for thalassemia and sickle cell disease. Please move to the next slide.

這些結果凸顯了我們商業模式的優勢，以及我們為未來成長奠定的基礎。我們已做好充分準備，迎接未來在美國推出的地中海貧血和鐮狀細胞貧血治療產品。請看下一張投影片。

Let's turn to thalassemia and our global commercialization strategy for PYRUKYND. Following the three-month extension of our PDUFA goal date to December 7, we remain confident in our ability to deliver a successful launch, pending regulatory approval. This confidence is further reinforced by our recent engagement with physicians, patients, and advocacy groups, which I will touch on shortly.

接下來我們來談談地中海貧血症以及PYRUKYND的全球商業化策略。在PDUFA目標日期延長三個月至12月7日之後，我們仍然有信心在獲得監管機構批准後成功上市。我們近期與醫生、病人和倡議團體的溝通進一步增強了我們的信心，稍後我將詳細介紹這些溝通內容。

Outside of the US, we have implemented a capital-efficient global commercialization strategy through partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe. These partnerships allow us to retain full rights to PYRUKYND while preserving our capital investment for US launches.

在美國以外，我們透過與海灣合作委員會（GCC）的NewBridge Pharmaceuticals公司和歐洲的Avanzanite Bioscience公司建立合作關係，實施了一項資本效率高的全球商業化策略。這些合作關係使我們得以保留PYRUKYND的全部權利，同時又能保障我們在美國上市所需的資本投入。

In August, we announced SFDA approval of PYRUKYND for the treatment of adult thalassemia patients in Saudi Arabia, marking our first global approval for thalassemia. Launch activities are underway in Saudi. Our partner, NewBridge, is providing early patient access on case-by-case basis with the potential to expand access after securing national procurement agreements over the next couple of years.

今年8月，我們宣布沙烏地阿拉伯食品藥物管理局（SFDA）批准PYRUKYND用於治療沙烏地阿拉伯的成人地中海貧血患者，這是我們第一個獲得全球批准的地中海貧血治療藥物。目前，沙烏地阿拉伯的上市活動正在進行中。我們的合作夥伴NewBridge正在根據具體情況為患者提供早期用藥，並計劃在未來幾年內達成國家採購協議後，進一步擴大用藥範圍。

In Europe, we anticipate a European Commission regulatory decision in early 2026, following the positive recommendation from the CHMP. And we are actively working with our partner, Avanzanite Bioscience, to refine our launch strategy. Please move to the next slide.

在歐洲，我們預計歐盟委員會將於2026年初做出監管決定，此前人用藥品委員會（CHMP）已提出積極建議。我們正與合作夥伴Avanzanite Bioscience積極合作，完善我們的上市策略。請翻到下一頁。

In the US, there are approximately 6,000 diagnosed adult thalassemia patients. It is important to remember that thalassemia is considered a spectrum of disease, not a single phenotype. Patients range from those who require regular transfusions, to those who are non-transfusion-dependent but still face debilitating fatigue and meaningful complications over time.

美國約有6000名確診的成年地中海貧血患者。需要注意的是，地中海貧血被認為是一種疾病譜，而非單一表型。患者的病情輕重不一，有的需要定期輸血，有的雖然不依賴輸血，但隨著時間的推移，仍然會面臨嚴重的疲勞和各種併發症。

The goal of treatment across the disease centers on three key aspects: to address patients' chronic anemia and hemolysis, increase their quality of life, and reduce the risk of comorbidities that can be caused by primary or secondary iron overload. Care for these patients happens in both academic centers and community hematology practices. And we are equipped to support both.

此疾病的治療目標主要圍繞三個方面：解決患者的慢性貧血和溶血問題，提高患者的生活質量，並降低原發性或繼發性鐵過載引起的併發症風險。這些患者的診療工作既在學術中心進行，也在社區血液科診所進行。我們有能力為兩者提供支援。

Over the past year, we have profiled and prioritized accounts across settings. We also engaged prescribers where patients are managed, and delivered disease education to them.

過去一年，我們對不同環境下的帳戶進行了分析和優先排序。我們也與患者就診的處方醫生進行了溝通，並向他們提供了疾病教育。

Following the announcement of our PDUFA goal date extension, we have taken the opportunity to continue our engagement with the thalassemia community. Through these ongoing interactions, stakeholders consistently recognize the clear and compelling potential of PYRUKYND. Advocacy leaders and clinicians emphasize the magnitude of the unmet need facing thalassemia patients and continue to stress the urgency for novel treatments like PYRUKYND.

在宣布延長PDUFA目標日期後，我們藉此機會繼續與地中海貧血患者群體保持溝通。透過這些持續的互動，各利害關係人始終認可PYRUKYND的顯著潛力。倡議者和臨床醫生強調了地中海貧血患者面臨的巨大未滿足需求，並持續強調開發PYRUKYND等新型療法的迫切性。

Additionally, it has become clear that providers have strong familiarity and experience with REMS across both academic and community settings and do not view a potential REMS program as a barrier to prescribing.

此外，很明顯，無論是在學術界還是社區，醫療服務提供者都對 REMS 有著豐富的了解和經驗，並且不認為潛在的 REMS 計劃是開處方的障礙。

Our established rare disease infrastructure gives us a clear advantage in launching PYRUKYND in thalassemia. With high-touch patient services and a single specialty pharmacy model, we are well-positioned to execute swiftly and compliantly within a REMS framework.

我們完善的罕見疾病基礎設施使我們在地中海貧血症領域推出 PYRUKYND 時擁有明顯的優勢。憑藉著貼心的患者服務和單一專科藥房模式，我們能夠迅速合規地在風險評估和緩解策略 (REMS) 框架內執行相關工作。

The team is ready and we look forward to potential thalassemia approval before year end, and we are confident in our ability to deliver a successful launch.

團隊已做好準備，我們期待在年底前獲得地中海貧血的批准，我們有信心成功上市。

And with that, please move to the next slide, and I will hand the call over to Sarah to cover key R&D highlights from the quarter.

那麼，請進入下一張投影片，我將把電話交給 Sarah，讓她介紹本季研發的主要亮點。

Thank you, Tsveta. Next slide, please. In the third quarter, we continued to make strong progress across our pipeline. In early August, we announced PYRUKYND approval for adults with thalassemia in Saudi Arabia. And earlier this month, we received a positive CHMP opinion recommending PYRUKYND for marketing authorization in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha or beta thalassemia in Europe. And we look forward to a final regulatory decision by early next year.

謝謝，茨維塔。請看下一張投影片。第三季度，我們的研發管線持續取得顯著進展。 8月初，我們宣布PYRUKYND在沙烏地阿拉伯獲準用於治療成人地中海貧血。本月初，我們收到人用藥品委員會（CHMP）的正面意見，建議在歐洲批准PYRUKYND上市，用於治療成人輸血依賴型和非輸血依賴型α或β地中海貧血相關貧血。我們期待明年年初獲得最終的監管審批決定。

Finally, our reviews remain ongoing in the United Arab Emirates and in the US where we continue to progress towards our new PDUFA goal date of December 7.

最後，我們在阿聯酋和美國的審查工作仍在進行中，我們正朝著新的 PDUFA 目標日期 12 月 7 日繼續前進。

Beyond PYRUKYND, we were pleased to announce enrollment completion in the Phase 2b trial of tebapivat for the treatment of lower-risk MDS. Tebapivat, our more potent PK activator, has the potential to be the first oral therapy to address anemia due to ineffective erythropoiesis in patients with lower-risk MDS. I will share more on this potential opportunity shortly. Please move to the next slide.

除了 PYRUKYND 之外，我們很高興地宣布，用於治療低風險 MDS 的 tebapivat 的 IIb 期臨床試驗已完成患者招募。 Tebapivat 是我們效力更強的 PK 活化劑，有望成為首個用於治療低危險群 MDS 患者因無效性紅血球生成引起的貧血的口服療法。稍後我將詳細介紹這項潛在機會。請翻到下一張投影片。

As we approach the anticipated top line results for the Phase 3 RISE UP trial, I wanted to take a moment to highlight the significant need in this community as well as our potential to deliver a disease-modifying novel treatment with PYRUKYND.

隨著我們即將迎來 RISE UP 3 期試驗的預期主要結果，我想藉此機會強調一下該群體中存在的巨大需求，以及我們利用 PYRUKYND 提供疾病改善型新療法的潛力。

There are approximately 100,000 diagnosed adult and pediatric patients with sickle cell disease in the United States and a significantly larger number worldwide. Sickle cell disease remains profoundly underserved. The lack of suitable treatment options contributes to a high mortality rate that has, in fact, worsened with US life expectancy in the late 30s, underscoring a significant opportunity for therapeutic innovation.

美國約有10萬名確診的成人和兒童鐮狀細胞疾病患者，全球患者人數遠高於此。鐮狀細胞疾病的治療仍然嚴重不足。缺乏合適的治療方案導致該疾病死亡率居高不下，而隨著美國人均預期壽命接近30歲，死亡率實際上有所上升，這凸顯了治療創新方面的巨大機會。

PYRUKYND is a potential first-in-class oral therapy for sickle cell disease, targeting both hemolysis and vasal occlusion through a unique PK activation mechanism of action, activating both PKR and PKM2 isoforms, decreasing 2,3-DPG, limiting hemoglobin S polymerization, and increasing ATP to support red blood cell health. Please move to the next slide.

PYRUKYND 是一種潛在的首創口服鐮狀細胞疾病療法，它透過獨特的 PK 活化機制，同時靶向溶血和血管阻塞，激活 PKR 和 PKM2 同工酶，降低 2,3-DPG 水平，限制血紅蛋白 S 聚合，並增加 ATP 以維持紅血球健康。請移至下一張投影片。

Guided by extensive engagement with the sickle cell community, we designed the Phase 3 RISE UP trial to align with clinical needs, positioning PYRUKYND to potentially reshape the treatment landscape for sickle cell disease.

在與鐮狀細胞疾病患者群體廣泛交流的指導下，我們設計了 3 期 RISE UP 試驗，以滿足臨床需求，使 PYRUKYND 有可能重塑鐮狀細胞疾病的治療模式。

One of the two primary endpoints investigates hemoglobin increase, which addresses chronic anemia and thereby potentially reduces organ damage and improves how patients feel and function. Our other primary endpoint evaluates the reduction in annualized rate of sickle cell pain crises which are linked to organ dysfunction, early mortality, and a decreased quality of life for many patients.

兩項主要終點之一是研究血紅蛋白升高情況，這有助於改善慢性貧血，可能減少器官損傷，並改善患者的感受和功能。另一個主要終點是評估鐮狀細胞疼痛危象年發生率的降低情況，這些危機與器官功能障礙、早期死亡以及許多患者生活品質下降有關。

Importantly, one of our key secondary endpoints will investigate potential improvement in fatigue which is an overlooked symptom. In fact, chronic fatigue in sickle cell disease patients have been shown to be comparable to fatigue experienced by patients with other debilitating diseases like cancer and cystic fibrosis.

值得注意的是，我們的一項關鍵次要終點將研究疲勞症狀的潛在改善情況，而疲勞往往被忽略。事實上，研究表明，鐮狀細胞疾病患者的慢性疲勞程度與其他衰弱性疾病（如癌症和囊性纖維化）患者的疲勞程度相當。

In the trial, we will assess the improvement from baseline on the PROMIS Fatigue 13a scale, a validated measure of fatigue for this population. We look forward to sharing top line results of the Phase 3 RISE UP trial by the end of this year. Please move to the next slide, where we present high-level view of the trial design and statistical plan.

在試驗中，我們將評估受試者在 PROMIS 疲勞 13a 量表（一種針對該族群的有效疲勞評估工具）上的基線改善情況。我們期待在今年年底前分享 RISE UP III 期試驗的主要結果。請翻到下一張投影片，其中概述了試驗設計和統計方案。

As a reminder, since the trial includes two primary endpoints, the trial is positive if statistical significance is achieved on either one of the endpoints. The pre-specified statistical testing strategy allows testing of the key secondary endpoints if at least one of the primary endpoints is met, thereby preserving the opportunity to show benefit on other key features of the disease, including fatigue.

需要提醒的是，由於該試驗包含兩個主要終點，因此只要其中一個終點達到統計學顯著性，試驗結果即為陽性。預先設定的統計檢定策略允許在至少一個主要終點達到時檢驗關鍵次要終點，從而保留證明該療法對疾病其他關鍵特徵（包括疲勞）有益的機會。

We remain confident in PYRUKYND's potential to become transformative therapy for sickle cell patients and underserved and unrepresented population with significant unmet need. Next slide, please.

我們仍然堅信 PYRUKYND 有潛力成為鐮狀細胞貧血症患者以及其他醫療需求未被充分滿足的弱勢群體的變革性療法。請看下一張投影片。

I'd like to take a moment to highlight our second more potent pyruvate kinase activator, tebapivat, which is being investigated in ongoing Phase 2 trials for two rare disease indications, low-risk myelodysplastic syndrome and sickle cell disease.

我想藉此機會重點介紹我們的第二種更有效的丙酮酸激酶激活劑 tebapivat，目前正在進行 2 期臨床試驗，研究其對兩種罕見疾病適應症的療效，即低風險骨髓增生異常綜合徵和鐮狀細胞病。

Low-risk MDS accounts for approximately 70% of all myelodysplastic syndrome. Symptomatic anemia is the primary concern for most patients. Therefore, the primary treatment goal is to improve quality of life by managing the underlying anemia caused by ineffective erythropoiesis.

低危險群骨髓增生異常症候群約佔所有骨髓增生異常症候群的70%。症狀性貧血是大多數患者的主要問題。因此，治療的主要目標是透過控制無效性紅血球生成引起的貧血來改善患者的生活品質。

Decreased lipolytic activity has been seen in MDS patients where they may show decreased PK activity and an abnormal pyruvate kinase/hexokinase symptomatic ratio. Tebapivat is designed to correct red blood cell metabolism by increasing ATP production and normalizing the PK/HK ratio. Today, there are limited treatment options to address low-risk MDS, and we believe tebapivat has the potential to be the first oral medicine to address anemia due to ineffective erythropoiesis.

骨髓增生異常症候群（MDS）患者有脂肪分解活性降低的情況，表現為丙酮酸激酶（PK）活性降低以及丙酮酸激酶/己糖激酶（PK/HK）比值異常。替巴匹伐（tebapivat）旨在透過增加ATP生成和使PK/HK比值正常化來糾正紅血球代謝。目前，針對低風險MDS的治療選擇有限，我們相信替巴匹伐有望成為第一個用於治療無效性紅血球生成所致貧血的口服藥物。

We completed the Phase 2 portion in November 2023 and progressed to the Phase 2b portion, which evaluates three higher doses than were evaluated in the Phase 2a portion. This trial will investigate 10 milligrams, 50 milligrams and 20-milligram doses of tebapivat daily versus placebo over 24 weeks. Today, we announced that we achieved enrollment completion and we continue to expect top line data in early 2026.

我們於2023年11月完成了第二期臨床試驗，並進入第二期b期臨床試驗階段。此階段將評估比二期a期臨床試驗更高的三個劑量。這項試驗將研究每日服用10毫克、50毫克和20毫克替巴匹伐特與安慰劑相比，在24週內的療效。今天，我們宣布已完成受試者招募，並繼續預計2026年初獲得初步數據。

We are also investigating tebapivat for the treatment of sickle cell disease. Enrollment remains ongoing in the Phase 2 trial, and we look forward to providing updates in the coming months. Please move to the next slide.

我們也正在研究tebapivat用於治療鐮狀細胞疾病。二期臨床試驗仍在進行中，我們期待在未來幾個月提供最新進展。請移至下一張投影片。

We continue to advance our early-stage rare disease pipeline with AG-181, an oral PAH stabilizer intended for the treatment of phenylketonuria; and AG-236, our siRNA selectively targeting TMPRSS6 for the treatment of polycythemia vera.

我們繼續推進早期罕見疾病產品線，包括用於治療苯酮尿症的口服 PAH 穩定劑 AG-181；以及用於治療真性紅血球增多症的選擇性靶向 TMPRSS6 的 siRNA AG-236。

Our first early-stage program is AG-181 for the treatment of PKU. There are 15,000 to 20,000 patients diagnosed with phenylketonuria in the US where patient symptoms can range from mild to severe. Currently available treatment options have demonstrated limited efficacy or significant safety issues, leaving patients with a gap in treatment and limited to phenylalanine restricted diet, therefore, significantly impacting the patient's quality of life. Our Phase 1 multiple ascending dose trial in healthy volunteers is currently ongoing and we look forward to providing updates on this trial in the future.

我們首個早期研發計畫是用於治療苯酮尿症（PKU）的AG-181。美國約有15,000至20,000名苯酮尿症患者，其症狀輕重不一。目前可用的治療方案療效有限或有顯著的安全性問題，導致患者治療中斷，只能進行苯丙胺酸限制飲食，嚴重影響患者的生活品質。我們正在健康志願者中進行一項I期多劑量遞增試驗，並期待未來能提供該試驗的最新進展。

Our second early-stage program is AG-236 for the treatment of polycythemia vera, a rare hematologic disease that affects approximately 100,000 patients in the US. PV causes an excessive production of red blood cells, increasing blood volume and viscosity, and can result in thrombosis, cardiovascular events, or death. Current treatment options are limited to phlebotomy, hydroxyurea, and other cytoreductive therapies. However, these medicines do not effectively control hematocrit for more severe patients.

我們的第二個早期研發項目是AG-236，用於治療真性紅血球增多症（PV）。 PV是一種罕見的血液系統疾病，在美國約有10萬名患者。 PV會導致紅血球過度生成，增加血液容量和血液粘度，並可能導致血栓形成、心血管事件甚至死亡。目前的治療方案僅限於放血療法、羥基脲和其他細胞減滅療法。然而，對於病情較重的患者，這些藥物無法有效控制血球容積比。

We believe AG-236 has the potential to address the remaining unmet need with a potentially improved safety and efficacy profile and less frequent dosing. Last quarter, we received IND clearance and dosed the first subject in the Phase 1 trial in healthy volunteers and look forward to providing updates as the trial progresses.

我們相信AG-236有望滿足目前尚未滿足的醫療需求，並具有潛在的更高安全性和有效性，且給藥頻率更低。上個季度，我們獲得了新藥臨床試驗申請（IND）批准，並在健康志願者中完成了首例I期臨床試驗的給藥。我們將隨著試驗的進展及時更新資訊。

With that, please move to the next slide, and I will hand the call back to Brian for closing remarks.

那麼，請進入下一張投影片，我將把電話交還給布萊恩，讓他做總結發言。

Thank you, Sarah. Next slide, please. In the third quarter, we delivered meaningful progress across our 2025 R&D priorities, once again showcasing our ability to execute swiftly and effectively.

謝謝莎拉。請看下一張投影片。第三季度，我們在2025年研發重點專案上取得了顯著進展，再次展現了我們迅速且有效率的執行能力。

Looking ahead, the fourth quarter holds exciting milestones. We are sharpening our launch planning in anticipation of the new December 7 PDUFA goal date for PYRUKYND in thalassemia. And we expect to report top line results from the Phase 3 RISE UP trial of PYRUKYND in sickle cell disease by year end. Please move to the next slide.

展望未來，第四季將迎來令人振奮的里程碑。我們正在完善上市計劃，以期在12月7日之前完成PYRUKYND治療地中海貧血的PDUFA新目標日期。此外，我們預計在年底前公佈PYRUKYND治療鐮狀細胞貧血的3期RISE UP試驗的主要結果。請翻到下一頁。

Our fundamentals remain strong. Backed by a seasoned leadership team with a proven track record, we continue to advance our pipeline and deliver meaningful impact for the rare disease communities we serve, communities whose insights guide us and are vital to our success.

我們的基本面依然穩健。在經驗豐富、績效卓著的領導團隊的帶領下，我們不斷推動產品研發，為我們所服務的罕見疾病群體帶來實際的影響。這些群體的真知灼見指引著我們前進，對我們的成功至關重要。

We are operating from a position of strength, backed by a balance sheet that not only supports our potential US launches and advancement of existing clinical programs, but also enables us to pursue strategic business development opportunities to further expand and diversify our pipeline and ensure we can create long-term shareholder value.

我們擁有雄厚的實力，穩健的資產負債表不僅支持我們在美國的潛在產品上市和現有臨床項目的推進，而且還使我們能夠尋求戰略業務發展機會，進一步擴大和多元化我們的產品線，並確保我們能夠創造長期的股東價值。

Before we move to Q&A, I want to take a moment to recognize the continued dedication of our employees whose relentless focus and commitment continue to drive meaningful impact for patients with rare diseases. Their work, together with the voices of the communities we serve, is foundational to our mission. As we look ahead, we remain resolute in our pursuit of transformative medicines, advancing innovation with the aim of delivering long-term value for both patients and shareholders.

在進入問答環節之前，我想藉此機會感謝我們員工的持續奉獻，他們孜孜不倦的專注和投入，持續為罕見病患者帶來意義深遠的影響。他們的工作，以及我們所服務社區的聲音，是我們使命的基石。展望未來，我們將繼續堅定不移地追求變革性藥物，推動創新，旨在為患者和股東創造長期價值。

With that, I'd like to open the call for questions. Operator, please open the line.

接下來，我想開始接受提問。接線員，請接通電話。

(Operator Instructions)

（操作說明）

Eric Schmidt, Cantor.

埃里克·施密特，坎托爾。

Thank you for the opportunity to ask questions. Maybe first just on the thalassemia review process, it's been almost two months now since you've got the PDUFA extension. Do you have a better sense of what type of a REMS program the FDA is interested in here? I know there's a spectrum of maybe more or less onerous REMS programs.

感謝您給我提問的機會。首先我想問一下關於地中海貧血審查流程的問題，您獲得PDUFA延期已經快兩個月了。您是否更清楚FDA對哪種類型的REMS方案感興趣？我知道REMS方案的繁瑣程度可能有所不同。

And then just a second follow-up question. I think both Cecilia and Brian mentioned actively looking for external assets. What type of BD makes sense for the company at this stage? And would you wait until the sickle cell readout to transact?

還有一個後續問題。我記得Cecilia和Brian都曾提到正在積極尋找外部資產。在這個階段，什麼樣的業務拓展模式對公司來說是適當的？你們會等到鐮狀細胞貧血症的檢測結果出來後再進行交易嗎？

Good morning, Eric. Thanks a lot for the question. I'll have Sarah take the first one and then, I can pick up with the external pursuit question. And Sarah, let me turn it over to you.

早安，埃里克。非常感謝你的提問。我先讓莎拉回答第一個問題，然後我再來回答關於外在追求的問題。莎拉，現在輪到你了。

Yes. Thanks, Eric, for the question. So in regards to REMS and labels, as you know, the review is ongoing with our extended PDUFA date of December 7. We, per process, don't comment on the details of REMS and the labels. However, indeed, to your point, there are many different forms of REMS. And as you know, the REMS is requested because of hepatocellular injury, so you can anticipate that it will include monitoring and some form of education.

是的。謝謝Eric的提問。關於風險評估和緩解策略（REMS）以及藥品標籤，正如您所知，審查仍在進行中，我們的處方藥用戶付費法案（PDUFA）延期截止日期為12月7日。根據流程，我們不對REMS和藥品標籤的細節發表評論。不過，正如您所說，REMS確實有許多不同的形式。而且您也知道，此次申請REMS是因為肝細胞損傷，所以您可以預期它會包括監測和某種形式的教育。

And Eric, on your second question in terms of continuing to expand our pipeline, our pursuit really is not timed to anything in particular. I'm really proud of the work that the team does to cast the net wide and continue to look at a number of different opportunities. And this goes externally, but it's also organically internally to see if there are other indications, for example, that we should pursue. But again, that's not timed to anything per se.

艾瑞克，關於你提出的第二個問題，也就是我們是否會繼續拓展業務管道，我們的拓展工作並沒有特定的時間節點。我為團隊所做的工作感到非常自豪，他們廣泛撒網，並持續關注各種不同的機會。這既包括外部的拓展，也包括內部的自然調查，例如，我們會觀察是否有其他跡象表明我們應該繼續前進。但再次強調，這本身並沒有特定的時間節點。

In general, I mean, our sweet spot, of course, is rare diseases. We look for therapies that have transformative potential for patients, early de-risking opportunities, if we're talking about earlier phase assets.

總的來說，我們的優勢領域當然是罕見疾病。我們尋找對患者俱有變革性潛力的療法，以及早期降低風險的機會，尤其是在早期階段的資產方面。

And then I would say another opportunity would be if we find something that doesn't have to be first-in-class, but we always set the bar for best-in-class, which we feel very proud of with our current organic pipeline. So that work continues ongoing. And like I said, I'm really proud of the capabilities that our team has, both with internal opportunities as well as external.

然後，我想說，另一個機會在於，如果我們找到一些不一定是同類首創的項目，但我們始終以做到最好為目標，而我們目前自主研發的項目也確實做到了這一點，我們為此感到非常自豪。所以這項工作仍在繼續。正如我所說，我為我們團隊的能力感到非常自豪，無論是在內部還是外部，我們都擁有這樣的能力。

Thanks. Good luck with the upcoming readouts.

謝謝。祝您接下來的數據發布一切順利。

Alec Stranahan, Bank of America.

亞歷克·斯特拉納漢，美國銀行。

Hey, guys. Thanks for taking our questions. Just a couple from us. It's been interesting to see how the different geographies have approached the risk of liver injury for mitapivat in thalassemia. Maybe could you just remind us what sort of liver monitoring requirements are so far being required in Saudi and potentially in EU if it's approved as well? And do you think this could change depending on the US label? And then maybe second, as a follow-up, curious how this monitoring requirement is changing maybe your commercial approach in these different areas. Thank you.

大家好。感謝你們回答我們的問題。我們還有幾個問題。不同地區對米他匹伐治療地中海貧血的肝損傷風險評估方式很有意思。能否請你們提醒一下，目前沙烏地阿拉伯以及如果米他匹伐獲批後歐盟的情況如何，對肝臟監測有哪些要求？你們認為這些要求會因為美國藥品標籤的變更而有所改變嗎？另外，作為後續問題，我們也很好奇這些監測要求會如何影響你們在不同地區的商業策略。謝謝。

Thanks, Alec. Again, Sarah can start with the labeling so far. And I'll just preempt by saying the label we have right now, of course, at this point, only exists in Saudi Arabia, and Sarah can comment on that. And then we're still in process with FDA. And in Europe, it's a CHMP positive opinion, but we're still awaiting the conclusion of that review in the coming couple of months and expect that by early next year. And then I'll have Tsveta comment in terms of the impact of some of these scenarios. Sarah, do you want to start?

謝謝，Alec。 Sarah可以先從目前的標籤情況說起。我先說明一下，我們目前的標籤當然只在沙烏地阿拉伯有效，Sarah可以就此發表意見。我們目前還在等待FDA的審批。在歐洲，CHMP已經給出了積極的意見，但我們仍在等待未來幾個月的審查結果，預計明年年初就能出結果。之後我會請Tsveta談談這些情況可能帶來的影響。 Sarah，妳想先說嗎？

Sure. So in regards to the label, yes, indeed, for Saudi, it's in line with our proposal of once-a-month monitoring for the first six months, and that label is now available. For the European Union, we indeed are very pleased that we received a positive CHMP opinion which, from their perspective, confirms the benefit risk profile that we saw. Obviously, the label will only be final when you have the EC decision. So the details will become available at that point in time. And Brian already mentioned it, the US, the review is still ongoing.

當然。關於標籤，是的，沙烏地阿拉伯的標籤符合我們提出的前六個月每月監測一次的建議，目前標籤已經發布。對於歐盟，我們非常高興地收到了人用藥品委員會（CHMP）的正面意見，這從他們的角度來看，證實了我們所看到的獲益風險概況。顯然，標籤只有在歐盟委員會做出決定後才能最終確定。屆時，我們將公佈詳細資訊。布萊恩已經提到，美國的審查仍在進行中。

Thanks, Sarah. And then, Tsveta, comments on potential impact of REMS?

謝謝，莎拉。那麼，茨維塔，你對風險評估和緩解策略（REMS）的潛在影響有什麼看法？

Absolutely. So as we all know and there are very few treatment options for the thalassemia patients across the board and with regards to non-transfusion-dependent, transfusion-dependent patients, we remain very convicted behind the strong benefit risk profile of PYRUKYND for these patients, and that has been reiterated and confirmed by all of our stakeholders, including all the clinicians that interacted with recently in the field after the announcement of REMS for the potential US label.

當然。眾所周知，目前地中海貧血患者的治療選擇非常有限，無論是非輸血依賴型還是輸血依賴型患者，我們都堅信 PYRUKYND 對這些患者俱有顯著的獲益風險比，這一點也得到了所有利益相關者的重申和確認，包括在宣布美國潛在標籤的風險評估和緩解策略 (REMS) 後，近期與我們進行過交流的所有臨床醫生。

I can tell you, the team is prepared for the launch. We are taking advantage of the additional time to continue the engagement with the community and do disease education. And when it comes to REMS in the US, we don't anticipate that to be a barrier to prescribing or have an impact on our commercial opportunity because we know that both the academic as well as the community hematology, oncology practices, they have an experience with REMS. And when I connected both with academics and the community prescribers, they confirmed that to me, and the team is confirming that in the field on a daily basis.

我可以告訴大家，團隊已經為產品上市做好充分準備了。我們正在利用這段額外的時間繼續與社區保持聯繫，並進行疾病教育。至於美國的REMS（風險評估和緩解策略），我們預計它不會成為處方障礙，也不會影響我們的商業機會，因為我們知道，無論是學術界還是社區的血液腫瘤科，他們都對REMS有所了解。當我與學術界和社區的處方醫生交流時，他們都向我證實了這一點，團隊也在日常工作中不斷驗證這一點。

(Operator Instructions)

（操作說明）

Emily Bodnar with H.C. Wainwright & Co.

Emily Bodnar 與 H.C. Wainwright & Co.

Good morning. This is [Joey], on for Emily. Congrats for a great quarter. Thanks for taking our questions. Shifting focus to tebapivat. How are you guys looking at what will be considered positive data in LRMDS given the data for luspatercept and imetelstat? And then a follow-up, could you also remind us of the Avanzanite strategy for the European thalassemia launch and how the cadence could look like for that? Thank you.

早安.我是Joey，替Emily發言。恭喜你們本季表現出色。感謝你們回答我們的問題。接下來我們來談談tebapivat。鑑於luspatercept和imetelstat的數據，你們如何看待LRMDS中哪些數據會被視為陽性結果？還有一個後續問題，能否再介紹Avanzanite在歐洲地中海型貧血症上市的策略以及可能的上市節奏？謝謝。

Thanks a lot. I think we're going to follow the same order of entry here. So Sarah can get started on tebapivat and how we think about the potential in low-risk MDS, which is a very high unmet need area with -- is classic across all of our diseases that we're pursuing very limited treatment options. And then Tsveta can comment on Avanzanite and also probably tuck in some comments about NewBridge too. We have two very valued partners outside the US. Sarah, do you want to start?

非常感謝。我想我們這次會沿用之前的發言順序。 Sarah可以先談談tebapivat，以及我們如何看待它在低危險MDS中的應用潛力。低危險MDS是亟待解決的重大醫療需求領域－這也是我們所有疾病治療選擇非常有限的典型例子。然後Tsveta可以談談Avanzanite，或許還可以順便提一下NewBridge的狀況。我們在美國以外有兩個非常重要的合作夥伴。 Sarah，妳想先開始嗎？

Sure. Thanks for the question. So in regards to the positive data for lower-risk MDS, we are very pleased that we were able to announce enrollment of our Phase 2b trial today. So more data will come at the beginning of next year for our program. Obviously, we are going to take the ecosystem around us into account when we look at the data that this program will generate.

當然。謝謝你的提問。關於低危險MDS的正面數據，我們非常高興地宣布今天啟動了2b期臨床試驗的病患招募。明年年初我們將公佈更多項目數據。顯然，在分析該項目產生的數據時，我們會將周圍的生態系統因素納入考量。

But what is important, I think, is what Brian just mentioned. There is a huge unmet need for this patient population, specifically as the goal for this population tends to be really also now more and more focused on quality of life. And as you know, like for PK activators, quality of life has been an important component of their benefit profile. So that is something that we were definitely hoping to deliver too.

但我認為，布萊恩剛才提到的才是最重要的。這部分患者群體存在巨大的未滿足需求，尤其因為他們的目標越來越傾向於提高生活品質。如您所知，對於藥物動力學活化劑而言，生活品質一直是其療效的重要組成部分。因此，這正是我們希望能夠實現的。

Thanks, Sarah. And, Tsveta, pivoting then to Avanzanite. And since you've also spent some time outside the US, recently in Saudi Arabia, maybe you can comment on NewBridge as well and the preparation of our partners.

謝謝，莎拉。還有，茨維塔，接下來我們聊聊Avanzanite。鑑於你最近也在美國以外的地方待過一段時間，例如沙烏地阿拉伯，或許你也可以談談NewBridge以及我們合作夥伴的準備工作。

Absolutely. So starting with Avanzanite, first of all, we are very [Technical Difficulty] about the potential EC decision and approval of PYRUKYND for thalassemia in Europe coming early next year. We're working very closely with Avanzanite team to refine our strategy for Europe.

當然。首先，就 Avanzanite 而言，我們非常關注歐盟委員會可能在明年初批准 PYRUKYND 用於治療地中海貧血的決定和批准。我們正與 Avanzanite 團隊緊密合作，以完善我們在歐洲的策略。

It's important to remember that in Europe, after a regulatory decision and approval, each of the countries needs to undergo a pricing and reimbursement process. So at the moment, we are going with Avanzanite, assessing the market opportunities, prioritizing market where to submit for pricing and reimbursement first.

需要注意的是，在歐洲，獲得監管部門的批准後，每個國家都需要進行定價和報銷流程。因此，目前我們選擇的是Avanzanite，正在評估市場機會，並確定優先提交定價和報銷申請的市場。

But the pricing and reimbursement process in the European countries can take 12 to 18 months. So just keep in mind that we wouldn't see kind of the immediate impact of an approval on the commercial opportunity in Europe after a EC decision is announced.

但歐洲各國的定價和報銷流程可能需要12到18個月。因此，請記住，歐盟委員會的決定公佈後，我們不會立即看到批准對歐洲商業機會產生影響。

But we prioritize Avanzanite as our selected partner because they have a very strong rare disease capabilities and expertise as well as the pricing and market access capabilities. And we look forward to continue to work with them to provide access to patients in Europe.

但我們優先選擇Avanzanite作為合作夥伴，因為他們在罕見疾病領域擁有非常強大的實力和專業知識，以及定價和市場准入方面的能力。我們期待繼續與他們合作，為歐洲患者提供治療方案。

As Brian mentioned, I actually had the opportunity to spend some time with the team in Saudi towards the FDA approval in August. And again, very senior team here in Saudi Arabia. We consistently hear the high unmet need for thalassemia patients. Strong excitement about the benefit risk profile of PYRUKYND and the value it can bring to that community.

正如布萊恩所提到的，我八月有機會和沙烏地阿拉伯的團隊一起參與了FDA的審批流程。沙烏地阿拉伯的團隊經驗非常豐富。我們一直聽到地中海貧血患者的巨大未滿足需求。他們對PYRUKYND的獲益風險比以及它能為群體帶來的價值感到非常興奮。

But as a reminder, again, in Saudi Arabia, the process after approval starts with one-on-one requests from physicians for individual patients for PYRUKYND early and patient access and market access. And it's going to take about a couple of years until we get to the stage of a national procurement agreement which will open access more broadly and see the commercial opportunity there.

但再次提醒，在沙烏地阿拉伯，PYRUKYND核准後的流程首先是醫生為個別患者單獨提出申請，爭取早期用藥和市場准入。大約需要兩年時間才能達成國家採購協議，屆時將更廣泛地開放用藥管道，並展現其商業潛力。

Marc Frahm, TD Cowen.

馬克·弗拉姆，TD Cowen。

Hi. Thanks for taking my questions. Just back on the liver events, can you maybe just as you've continued to dose people and follow them for longer and longer, just kind of comment on if any additional events have been observed kind of across the PKR trials? And to the extent any have, have they continued to conform to the kind of description before of occurring within six months and importantly, the patient returning to baseline whenever they do stop mitapivat as a result?

您好。感謝您回答我的問題。關於肝臟不良事件，隨著您持續給予患者用藥並延長追蹤時間，能否談談在PKR試驗中是否觀察到其他不良事件？如果有，這些不良事件是否仍然符合先前的描述，即在六個月內發生，重要的是，患者在停用米他匹伐後是否恢復到基線水平？

And then maybe on the commercial side, I recognize it will take quite a while to work through case-by-case access and actually get to revenue for any of those patients, let alone the reimbursement negotiations. But maybe can you comment on just any level of demand you're already seeing in the Gulf to kind of start that process?

至於商業方面，我意識到要逐個病例地解決准入問題，並最終讓所有患者都獲得收入，還需要相當長的時間，更不用說報銷談判了。您能否談談目前在海灣地區觀察到的需求水平，以便啟動這一進程？

Sure. Thanks, Marc. Sarah, maybe you could just start then with the question Marc has around the hepatocellular injury and have there been additional cases that have met the pattern that we observed in thalassemia. And then Tsveta again can talk about the green shoots, I could say, of demand so far.

當然。謝謝你，馬克。莎拉，或許你可以先回答馬克關於肝細胞損傷的問題，看看是否有其他病例符合我們在地中海貧血中觀察到的模式。然後，茨維塔可以再談談目前為止需求方面出現的一些正面跡象。

Sure. So in regards to the observations that we had in the thalassemia program that allowed us to determine the hepatocellular injury risk for thalassemia specifically, so nothing has changed the way we have assessed the risk. So safety profile remains exactly the same as when we declared this hepatocellular injury risk and we have not observed anything across the program that warrants us to update the safety profile the way we currently understand it.

當然。關於我們在地中海貧血計畫中觀察到的、能夠確定地中海貧血肝細胞損傷風險的現象，我們評估風險的方式沒有任何改變。因此，安全性概況與我們當初宣布肝細胞損傷風險時完全相同，而且我們在整個專案中也沒有觀察到任何需要我們更新目前安全性概況的情況。

Thanks, Sarah. Tsveta?

謝謝，莎拉。茨維塔？

So yes, I actually had the opportunity to meet with some key customers in Saudi Arabia this week in some of the biggest hospitals. And as I said, we definitely hear the interest in PYRUKYND profile, the desire to try it in individual patients and gain experience with the product.

是的，本週我的確有機會在沙烏地阿拉伯的一些大型醫院會見了重要的客戶。正如我所說，我們確實感受到了他們對PYRUKYND產品的興趣，他們希望在個別患者身上試用產品，並累積使用經驗。

At the very beginning in the country, it's a very burdensome process which actually takes months from an individual patient prescription and a request until approval at the hospital level and securing the budget. So we expect that to be a slow process, slow and steady, as the individual patient requests get approved, the experience gets stronger and stronger. But definitely, the interest from the community is there and it's high. It's just the process in the country takes time.

在我國初期，這確實是一個非常繁瑣的過程，從患者開立處方並提出申請，到醫院層級批准並獲得預算，實際上需要數月時間。因此，我們預計這將是一個緩慢而穩定的過程，隨著個別患者申請的獲批，經驗會越來越豐富。但可以肯定的是，社區對此表現出了濃厚的興趣。只是在我國，整個流程需要時間。

And Marc, what I would add is what's unique about Saudi Arabia is, of course, the prevalence is quite different from what we see in the US on a per capita basis, it's about 8 to 9 times more common. So on the less rare side, for sure, most clinicians certainly have a good working knowledge of thalassemia. However, the common denominator that we see across all geographies really is a function of the limited treatment options available is the need for us to continue to educate, particularly the burden that non-transfusion-dependent thalassemia patients face on a daily basis because they're subjected to chronic hemolysis. And all the downstream consequences that come from that, we're doing our part to make sure that clinicians have that top of mind as they think about the potential that mitapivat, PYRUKYND could offer. So that's one thing that's not unique to geography. It's across all markets in the world.

馬克，我想補充的是，沙烏地阿拉伯的獨特之處在於，其地中海型貧血的盛行率與美國人均盛行率截然不同，大約是美國的8到9倍。當然，在不那麼罕見的病例中，大多數臨床醫生對地中海貧血症都有相當的了解。然而，我們在所有地區都看到的共同點是，由於治療選擇有限，我們需要繼續進行教育，特別是那些無需輸血的地中海貧血患者每天面臨的負擔，因為他們會遭受慢性溶血。我們正在盡一切努力確保臨床醫生在考慮米他匹伐（PYRUKYND）的潛在療效時，能夠充分認識到這些後果。所以，這並非地域獨有的問題，而是全球所有市場都面臨的問題。

(Operator Instructions)

（操作說明）

Tessa Romero, JPMorgan.

Tessa Romero，摩根大通。

Hey, Brian and team. Thanks so much for taking our questions. So for the Phase 3 portion of RISE UP, has the last patient exited the trial yet? And what are any considerations in terms of the steps and timing to get to your top line? And then I have a follow-up.

嗨，Brian 和團隊。非常感謝你們回答我們的問題。關於 RISE UP 的第三期臨床試驗，最後一位患者是否已經退出試驗了？在達到主要終點指標的過程中，你們在步驟和時間安排上有哪些需要考慮的因素？我還有一個後續問題。

Okay. Well, I will allow Sarah to comment. I will just remind that we will not be more refined on our timing guidance for the RISE UP data that we're also eagerly awaiting. We'll be more refined by saying that we're on track for that data by year end. And Sarah, I'm not sure if you want to say anything additional about where we are on that process.

好的。那麼，我允許莎拉發言。我只想提醒一下，我們不會就 RISE UP 資料的發佈時間給出更精確的預測，我們同樣也在翹首以盼這項資料的發布。我們只能說，我們預計在年底前按計劃發布該數據。莎拉，我不知道你是否還有什麼想補充的，關於我們目前在這個流程上的情況。

No, I think you summarized it, Brian. So indeed, we're not commenting on individual patient status, but we are indeed on track to deliver the top line data by year end. And since we are very -- we have delivered several Phase 3 clinical trials per our milestone, we are a well-oiled machine at this point in time to get from database locks to top line results.

不，布萊恩，我覺得你總結得很好。所以，我們確實不對個別患者的病情發表評論，但我們確實有望在年底前公佈主要數據。而且，由於我們已經按里程碑完成了多項三期臨床試驗，目前我們運作非常高效，能夠迅速從資料庫鎖定到獲得主要結果。

And I'll just say -- I mean, Tess, if I can just add, I am really pleased with the continued excellence in operations from the team because, of course, we have a lot of moving parts underway simultaneously. We have launch preparation. You've heard from Tsveta. We've got Sarah's team working on labeling for our PDUFA date that's approaching for thalassemia, December 7. And then, of course, getting ready for a data readout for RISE UP. So this team is really delivering, and I'm really pleased with the operational excellence.

我還要補充一點——Tess，如果可以的話，我想說，我對團隊持續卓越的營運表現非常滿意，因為我們同時進行著很多工作。我們有上市準備工作，Tsveta也提到了。 Sarah的團隊正在為即將到來的地中海貧血PDUFA審批日期（12月7日）進行標籤製作。當然，我們也要準備RISE UP的資料解讀。所以，這個團隊真的非常出色，我對他們的卓越營運感到非常滿意。

Okay. So you can't tell us if your top line will be before or after your PDUFA date?

好的。所以您無法告訴我們您的主線產品會在PDUFA日期之前還是之後上市？

What an excellent follow-up question, and I'm going to stick to by year-end.

這個問題提得很好，我會在年底前堅持下去。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

This is [Lydia], on for Salveen. Thanks so much for taking the questions. Maybe just another one on the REMS program. Do you anticipate the requirements to apply kind of across the label to PKD and sickle cell as well? And have you received any physician feedback on how this might impact uptake, particularly with sickle cell where some of these treatment centers might not see PKD and thalassemia patients as well? Thanks so much.

我是莉迪亞，代表薩爾文提問。非常感謝您回答這些問題。關於風險評估和緩解策略（REMS）項目，我還有一個問題。您預計這些要求也會適用於多囊性腎病變（PKD）和鐮狀細胞貧血症嗎？您是否曾收到醫生關於這可能會如何影響藥物使用情況的回饋，特別是對於鐮狀細胞貧血症，因為一些治療中心可能不會接診多囊性腎病和地中海貧血患者？非常感謝。

I think, Lydia, I might just start on this one to say, first of all, the REMS request has been specific to thalassemia. So that's an important point. And with respect to any potential outcome or impact, rather, in sickle cell disease, the most important step is what we literally just had discussed is getting to the point of the RISE UP Phase 3 data. That's the most important next step. And then from there, we'll be better guided around the benefit risk profile.

莉迪亞，我想，我先從這一點說起。首先，REMS（風險評估和緩解策略）申請是專門針對地中海貧血的。這一點很重要。至於任何潛在的結果或影響，就鐮狀細胞貧血而言，最重要的一步，正如我們剛才討論的，就是獲得RISE UP III期臨床試驗的數據。這是下一步最重要的步驟。之後，我們才能更好地評估獲益風險比。

Thank you. I'm showing no further questions at this time. I would like to hand the conference back over to Brian Goff for closing remarks.

謝謝。目前我沒有其他問題要問。現在我將會議交還給布萊恩·戈夫，請他作閉幕致詞。

Thanks, Michelle. Thank you very much, everyone, for joining us on this morning's call. As you've seen and as I just mentioned, we've delivered on many of our milestones this year. So we have two of our most anticipated inflection points approaching by year end. As you can imagine, this is a very exciting time at Agios. And we truly believe that we are poised to deliver transformative new therapies for patients and create significant long-term value for shareholders. Thanks again and we look forward to speaking with you again soon.

謝謝米歇爾。非常感謝各位參加今天上午的電話會議。如大家所見，也正如我剛才所提到的，我們今年已經實現了許多里程碑目標。因此，我們最受期待的兩個轉折點即將在年底到來。如大家所想，Agios 目前正處於一個令人興奮的時刻。我們堅信，我們已做好準備，為患者提供變革性的新療法，並為股東創造顯著的長期價值。再次感謝，期待很快與大家再次交流。

This concludes today's conference call. Thank you for participating and you may now disconnect. Everyone, have a great day.

今天的電話會議到此結束。感謝各位的參與，現在可以掛斷電話了。祝大家今天過得愉快。