Agios Pharmaceuticals Inc (AGIO) 2023 Q4 法說會逐字稿

Good morning and welcome to Agios' Fourth Quarter 2023 conference call. At this time, all participants are in a listen only mode. There'll be a question and answer session at the end. Please be advised that this call is being recorded our deals request.

早上好，歡迎參加 Agios 2023 年第四季電話會議。此時，所有參與者都處於只聽模式。最後將會有一個問答環節。請注意，此電話正在記錄我們的交易請求。

I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations and Corporate Communications for Agios. Please go ahead.

我現在想將電話轉給 Agios 投資者關係和企業傳播副總裁 Chris Taylor。請繼續。

Thank you, operator. Good morning, everyone, and welcome to Agios' conference call and webcast to discuss fourth quarter and full year 2023 financial results. And recent business highlights. You can access slides for today's call by going to the Investors section of our website at Agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff, Dr. Sarah Hewitt's, Chief Medical Officer and Head of Research and Development Center melanoma, our Chief Commercial Officer, and Cecilia Jones, Chief Financial Officer.

謝謝你，接線生。大家早安，歡迎參加 Agios 的電話會議和網路廣播，討論第四季和 2023 年全年財務業績。以及近期的業務亮點。您可以造訪我們網站 Agios.com 的投資者部分，查看今天電話會議的幻燈片。參加今天的電話會議的還有我們的執行長 Brian Goff、首席醫療官兼黑色素瘤研發中心負責人 Sarah Hewitt 博士、我們的首席商務官以及首席財務官 Cecilia Jones。

Before we get started I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result 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.

在我們開始之前，我想提醒大家，我們在這次電話會議中所做的一些陳述將包括前瞻性陳述。由於各種風險、不確定性和其他因素，包括我們最近向SEC 提交的文件以及我們可能未來提交的任何其他文件中所述的因素，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。與 SEC 合作。

With that, I'll turn the call over to Bryan.

這樣，我就把電話轉給布萊恩。

Thanks, Chris, and good morning, everyone, and thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. Driven by this goal, we continued to generate consistent and compelling data across our industry-leading PK activator franchise and with seamless cross-functional collaboration of the Agios team, we made remarkable progress advancing this mission in 2023. Highlighting this progress, we reported three key data readouts in the last 12 months. In June, we reported positive top line data from the Phase two portion of the rise up study of mitapivat, our lead PK activator in sickle cell disease, followed by the full data set in December at ASH, despite the field's recent progress in sickle cell disease, there are no novel oral therapies that improve that both improve anemia and reduce sickle cell pain crises, and that is precisely what we aim to deliver with mitapivat.

謝謝克里斯，大家早安，謝謝您加入我們。我們 Agios 的使命是開發和提供變革性藥物，以提高和延長罕見疾病患者的生命。在這一目標的推動下，我們繼續在業界領先的PK 活化劑系列中產生一致且令人信服的數據，並透過Agios 團隊的無縫跨職能協作，我們在2023 年推進這項使命方面取得了顯著進展。為了強調這項進展，我們報告了過去 12 個月的三個關鍵數據讀數。6 月，我們報告了mitapivat（我們在鐮狀細胞疾病中的主要PK 活化劑）上升研究第二階段的積極頂線數據，隨後於12 月在ASH 上發布了完整數據集，儘管該領域最近在鐮狀細胞疾病方面取得了進展目前還沒有新的口服療法可以改善貧血並減少鐮狀細胞性疼痛危機，而這正是我們透過 mitapivat 實現的目標。

In November, we reported positive data from the open-label Phase IIa study of our other PKR activator, AG nine four six in lower risk MDS with 40% of patients achieving the transfusion independence endpoint. And just last month, we reported positive data from the Phase three energize study of mitapivat in non-transfusion dependent thalassemia. As a reminder, non-transfusion dependent or NTD. thalassemia accounts for approximately two thirds of thalassemia in the US and has no FDA approved treatment option despite not requiring regular transfusions and TD. thalassemia patients experienced significant impact on quality of life, a wide range of serious morbidities and an elevated risk of premature death together, the consistency of data generated across the mitapivat development program bolsters our conviction in the probability of success of our ongoing studies, including two additional Phase three readouts we expect by the end of this year. And this data highlights the potential of our PKR activators to transform the course of multiple hematologic diseases. Sarah will provide more detail on our advancements and upcoming milestones across our pipeline in just a few minutes. Importantly, we believe our PK activation pipeline is well positioned with multiple near-term catalysts to become a multi-billion dollar franchise and deliver significant value in parallel with advancing the late-stage mitapivat development program across multiple indications. Our commercial organization is laser focused on building the infrastructure established through our current launch in PK deficiency to prepare for potential U.S. launches of mitapivat in thalassemia in 2025 and in sickle cell disease in 2026.

11 月，我們報告了我們的另一種 PKR 活化劑 AG 九四六在低風險 MDS 中的開放標籤 IIa 期研究的積極數據，其中 40% 的患者達到了輸血獨立終點。就在上個月，我們報告了 mitapivat 治療非輸血依賴性地中海貧血的第三期 energize 研究的正面數據。提醒一下，非輸血依賴性或 NTD。在美國，地中海貧血約佔地中海貧血的三分之二，儘管不需要定期輸血和 TD，但尚無 FDA 批准的治療方案。地中海貧血患者的生活品質受到重大影響，嚴重發病範圍廣泛，過早死亡的風險升高，整個mitapivat 開發計劃產生的數據的一致性增強了我們對正在進行的研究成功可能性的信心，其中包括兩項研究我們預計今年底將公佈更多第三階段數據。這些數據凸顯了我們的 PKR 活化劑改變多種血液疾病病程的潛力。莎拉將在短短幾分鐘內提供有關我們的進展和即將到來的里程碑的更多詳細資訊。重要的是，我們相信我們的PK 活化管道處於有利位置，具有多個近期催化劑，將成為價值數十億美元的特許經營權，並在推進跨多種適應症的後期mitapivat 開發計劃的同時提供巨大的價值。我們的商業組織專注於建造透過我們目前針對 PK 缺陷的推出而建立的基礎設施，為 2025 年在美國推出治療地中海貧血和 2026 年在美國推出治療鐮狀細胞病的 mitapivat 做好準備。

With that, I will provide greater detail on the commercial opportunities for mitapivat in thalassemia as well as an update on our current launch in PK deficiency.

接下來，我將更詳細地介紹 mitapivat 在地中海貧血症的商業機會，以及我們目前在 PK 缺乏症方面推出的最新情況。

And just a bit. Finally, as you'll hear from Cecilia, we ended 2023 with a strong cash position with approximately 806 million in cash and investments on the balance sheet. In addition, we continue to track surveys progress towards the potential FDA approval of where aside nib, given our retained economics for both milestone and royalties. This is truly an exciting time at Agios with four additional Phase three readouts and two potential launches expected on the horizon. We look forward to multiple opportunities to drive significant near term value creation for patients, caregivers and shareholders.

只是一點點。最後，正如您將從塞西莉亞那裡聽到的那樣，我們在 2023 年結束時擁有強勁的現金狀況，資產負債表上有約 8.06 億美元的現金和投資。此外，考慮到我們在里程碑和特許權使用費方面保留的經濟性，我們將繼續追蹤 FDA 可能批准 where except 筆尖的調查進度。這對 Agios 來說確實是一個激動人心的時刻，預計即將推出四個額外的第三階段讀數和兩個潛在的發射。我們期待有多種機會來推動為患者、照護者和股東創造重大的短期價值。

With that, I'll now turn the call over to Sarah.

這樣，我現在就把電話轉給莎拉。

Thanks, Brian. In 2023, our research and development organization made tremendous progress advancing our PKR activator development program, led by topping up the industry's most advanced PK activator now with over eight years of clinical experience. The consistent and compelling data we have generated to date in PK deficiency, CELsignia and sickle cell disease continue to derisk our ongoing development program and highlight the potential for this molecule to transform patients' function in quality of life. We are also enthusiastic about the potential for the rest of our growing pipeline, and we are pleased to note that we remain on track to deliver on our milestones, including enrolling the first patients in the Phase IIb trial for A. nine 46 in lower-risk MDS and for the Phase one trial for HT. one A. one, the compound name for our PH stabilizer for phenylketonuria, reading our top line data for the Phase three activated T study in regularly transfused pediatric patients with PK deficiency and completing enrollment of the Phase three activity study in pediatric patients with CKD.

謝謝，布萊恩。2023 年，我們的研發組織在推動 PKR 活化劑開發計畫方面取得了巨大進展，以補充業界最先進的 PK 活化劑（現已擁有超過八年的臨床經驗）為主導。到目前為止，我們在 PK 缺乏、CELsignia 和鐮狀細胞疾病方面獲得的一致且令人信服的數據繼續使我們正在進行的開發計劃面臨風險，並強調了該分子改變患者生活品質功能的潛力。我們也對我們不斷增長的管道的其餘部分的潛力充滿熱情，我們很高興地註意到，我們仍然在實現我們的里程碑的軌道上，包括在較低水平的A.9 46 的IIb 期試驗中招募第一批患者。風險 MDS 和 HT 第一階段試驗。一A.一，我們用於苯酮尿症的PH 穩定劑的化合物名稱，閱讀我們在定期輸血的PK 缺陷兒科患者中進行的第三階段激活T 研究的頂線數據，並完成在CKD 兒科患者中進行的第三階段活性研究的入組。

Turning to sickle cell disease, we were pleased to present detailed positive results from the Phase two portion of the Phase two three right study of mitapivat at ASH. In December, the study achieved its primary endpoint of hemoglobin response and in addition, an improvement in annualized rate of sickle cell pain crises was observed, and we have been delighted by the enthusiasm of the investigators. We continue to advance enrollment in the Phase three portion of this study and remain on track to complete enrollment by the end of this year. While the treatment landscape in sickle cell disease continues to evolve, there remains an urgent and unmet need for convenient, novel oral treatment options that address both anemia and sickle cell pain crises. And we believe firmly in the top of potential to deliver a best-in-class option for patients suffering from this devastating disease.

談到鐮狀細胞疾病，我們很高興在 ASH 上展示 mitapivat 二期三期研究的第二期部分的詳細正面結果。12 月，該研究實現了血紅蛋白反應的主要終點，此外，還觀察到鐮狀細胞疼痛危象的年化率有所改善，我們對研究人員的熱情感到高興。我們將繼續推進本研究第三階段的入組工作，並預計在今年年底前完成入組工作。儘管鐮狀細胞疾病的治療領域不斷發展，但對於解決貧血和鐮狀細胞疼痛危機的方便、新穎的口服治療方案仍然存在迫切且未滿足的需求。我們堅信，我們有潛力為患有這種毀滅性疾病的患者提供一流的選擇。

And finally, on thalassemia, I'll take a moment to highlight a few key elements of our program and the positive top-line Phase three data we reported last month in non-transfusion dependent thalassemia. As a reminder, the Phase three program of PI3-kinase delta senior and completing two Phase three randomized placebo-controlled trials. It was designed to deliver data across all populations of sound senior, such as Alpha and beta-thalassemia and populations with different transfusion. Both trials enroll patients with alpha or beta thalassemia, but involve different populations as it relates to transfusion, we want to highlight that energize is the first clinical program that included patients who are not regularly transfused and alpha thalassemia patients. As Brian mentioned, there are no FDA approved treatments for non-transfusion dependent thalassemia, which represents approximately two thirds of total thalassemia patients in the US. These patients suffer from a poor quality of life, a high rate of serious morbidities, including thrombosis and premature death. We were therefore very pleased to be able to announce positive results from the energize study. As a reminder, the NHI. study enrolled a total of 194 patients with either alpha or beta non-transfusion dependent thalassemia randomized 2 to 1 to 100 milligrams and above or placebo twice daily speed of enrollment and the actual number of patients enrolled in the study as well as a high completion and rollover rate supports the idea that people who are not regularly transfused were motivated to take action and speaks to the unmet need for this population. The primary endpoint of this study was hemoglobin response rate, defined as an increase of at least one gram per deciliter in average hemoglobin concentration from week 12 to week 24 compared to date. Key secondary endpoints of this study were changed from baseline in average Facet fatigue score and change from baseline in average hemoglobin concentrations. Also both assessed from week 12 to 24 on the primary endpoint treatment with mitapivat demonstrated a highly statistically significant results with 42.3% of patients in the treatment arm, achieving a hemoglobin response versus 1.6% of patients in the placebo arm in line with mitapivat novel mechanism of action, which focuses on overall red blood cell health and the data generated with mitapivat across additional disease areas. The beneficial effects of mitapivat in this study extended beyond hemoglobin alone, specifically treatment with 100 milligrams mitapivat resulted in statistically significant improvements in both key secondary endpoints, including a change from baseline in average Facet fatigue score, an important patient-reported measure of how patients feel and function. Importantly, across the primary and secondary endpoints, all prespecified subgroup analyses favored status as compared to placebo, suggesting that no single subgroup was responsible for driving the results which supports our plan to file for a broad label covering all CELsignia tests. It is therefore the first drug that not only improves hemoglobin but actually makes people without seeing at fields that are consistent with what we observed in patients with PKD and what we hope to be able to deliver for patients with sickle cell disease as well.

最後，關於地中海貧血，我將花點時間強調我們計劃的幾個關鍵要素以及我們上個月報告的非輸血依賴性地中海貧血的積極的第三階段數據。提醒一下，PI3-激酶δ高級的第三階段計劃並完成兩項第三階段隨機安慰劑對照試驗。它旨在提供所有健康老年人群體的數據，例如α和β地中海貧血以及接受不同輸血的人。這兩項試驗均招募了α或β地中海貧血患者，但涉及不同的人群，因為它與輸血有關，我們想強調的是，Energize是第一個包括不定期輸血患者和α地中海貧血患者的臨床項目。正如 Brian 所提到的，FDA 尚未批准治療非輸血依賴性地中海型貧血的治療方法，非輸血依賴性地中海型貧血患者約占美國地中海貧血患者總數的三分之二。這些患者的生活品質差，嚴重發生率高，包括血栓形成和過早死亡。因此，我們非常高興能夠宣布 energize 研究的正面結果。提醒一下，國民健康保險。研究共招募了 194 名患有 α 或 β 非輸血依賴性地中海貧血的患者，隨機服用 2 至 1 至 100 毫克及以上或每天兩次的安慰劑或安慰劑。翻滾率支持這樣一種觀點，即不定期輸血的人有動力採取行動，並說明了該族群的需求未被滿足。這項研究的主要終點是血紅蛋白反應率，定義為與迄今為止相比，從第 12 週到第 24 週，平均血紅蛋白濃度增加至少一克/分升。本研究的關鍵次要終點是平均 Facet 疲勞評分相對於基線的變化以及平均血紅素濃度相對於基線的變化。此外，在第12 週至第24 週對mitapivat 治療的主要終點進行的評估顯示，治療組中有42.3% 的患者達到了高度統計學顯著性結果，達到了血紅蛋白緩解，而安慰劑組中只有1.6 % 的患者達到了血紅蛋白緩解，符合mitapivat 的新機制行動，重點關注整體紅血球健康狀況以及 mitapivat 在其他疾病領域產生的數據。在這項研究中，mitapivat 的有益作用超出了單獨使用血紅蛋白的範圍，特別是使用100 毫克mitapivat 進行治療，在兩個關鍵的次要終點上均產生了統計學上顯著的改善，包括平均Facet疲勞評分較基線的變化，這是患者報告的一項重要的患者評估指標感覺和功能。重要的是，在主要和次要終點上，與安慰劑相比，所有預先指定的亞組分析都傾向於狀態，這表明沒有任何一個亞組負責推動結果，這支持我們計劃申請涵蓋所有CELsignia 測試的廣泛標籤。因此，它是第一種不僅可以改善血紅蛋白，而且實際上可以使人們看不見的視野與我們在 PKD 患者中觀察到的情況一致的藥物，以及我們希望能夠為鐮狀細胞病患者提供的效果。

Complementing the near term benefit of thalassemia patients reporting that they had less fatigue and felt better in the near term conditions in the trial and other care.

地中海貧血患者報告稱，在試驗和其他護理中，他們的近期狀況較少，感覺更好，這補充了近期的益處。

Well, appreciate the potential longer-term benefits of reducing markers of hemolysis and the longer term potential to reduce serious morbidities. We are very much looking forward to presenting the full data set at a medical meeting beyond the excitement we have for the enterprise data itself, the readout of the energize trials also gives us further confidence towards the readout of energize. The CELsignia is a hemolytic anemia, irrespective of whether a patient is in need of transfusions or not. In addition, the mechanism of action of and it's something that is not dependent on the need for transfusions. We have already demonstrated and improvements in hemolytic anemia in the energize trials. With a positive change in hemoglobin, we are now waiting to see the improvement in domestic anemia can also be documented via a reduction in transfusions in our Chesapeake. As a reminder, the primary endpoint of energize T is transfusion reduction response, defined as a 50% or greater reduction in transfused red blood cell units with a reduction of equal or more than two units of transfused red blood cells in any consecutive 12 week periods through week 48 compared to baseline like the energized study in non-transfusion dependent thalassemia. The design of the interchange fee trial enables us to demonstrate clinical meaningfulness in a variety of ways, see a reduction in transfusion burden, which also includes transfusion metrics in line with that other studies have used. We designed this study incorporating learnings from prior studies and agency feedback and believe a dynamic assessment period is important as patients on static in your disease. We look forward to the readout of this study by midyear and plan a single regulatory filing to the FDA and compacting data from both energized and energized team by the end of this year, seeking a label that will enable people living with balancing access to a convenient and differentiated oral treatment option. Overall, I'm very proud of the tremendous progress made by our R&D organization in 2023 and look forward to continuing this momentum in 2024.

嗯，了解減少溶血標記的潛在長期益處以及減少嚴重發病率的長期潛力。我們非常期待在醫學會議上展示完整的數據集，除了我們對企業數據本身的興奮之外，Energize 試驗的讀出也讓我們對 enerize 的讀出進一步充滿信心。CELsignia 是一種溶血性貧血，無論患者是否需要輸血。此外，它的作用機轉並不依賴輸血的需要。我們已經在 Energize 試驗中證明了溶血性貧血的改善。隨著血紅蛋白的積極變化，我們現在正在等待透過切薩皮克輸血的減少來記錄家庭貧血的改善。提醒一下，Energize T 的主要終點是輸血減少反應，定義為在任何連續 12 週期間輸注紅血球單位減少 50% 或更多，且輸注紅血球單位減少等於或超過 2 個單位到第48 週，與非輸血依賴性地中海型貧血的活力研究的基線進行比較。交換費試驗的設計使我們能夠以多種方式證明臨床意義，看到輸血負擔的減少，其中還包括與其他研究使用的輸血指標一致的輸血指標。我們設計了這項研究，結合了先前的研究和機構回饋的經驗，並相信動態評估期對於處於疾病靜態狀態的患者來說很重要。我們期待在年中之前公佈這項研究，併計劃在今年年底前向FDA 提交一份單一的監管文件，並壓縮來自充滿活力和充滿活力的團隊的數據，尋求一個標籤，使生活在平衡狀態的人們能夠獲得便利的和差異化的口腔治療選擇。總的來說，我對我們的研發組織在 2023 年取得的巨大進步感到非常自豪，並期待在 2024 年繼續保持這一勢頭。

With that, I will now turn the call over to Satya.

現在，我將把電話轉給薩蒂亞。

Thanks, Aram. Felicia remains an area of high unmet need with few treatment options. The burden of disease on the patients is significant regardless of their transfusion need. Celsignia patients experienced increased mortality compared to the general population and can be significantly worse in non regularly transfused than those who are regularly transfused. Patients in Europe have high rates of morbidity and increased complications as they age adult patients with non-transfusion dependent thalassemia may actually have similar or worse quality of life compared to transfusion dependent patients. Of course, this burden of disease correlates So increased health healthcare costs to address this unmet need and galvanized by the positive data from the Phase three energize study of mesothelioma. Our commercial organization is actively preparing for a potential launch in thalassemia next year, beginning with the U.S. In the U.S., there are approximately 6,000 diagnosed adult patients with the leukemia. Approximately 4,000 of these patients are non-transfusion dependent and have no available treatment options today. The remaining 20 patients are transfusion dependent and have no oral treatment option. Our goal with mitapivat is to address the unmet need of all adults living with California and become the first therapy approved for all subtypes of the disease. In addition to the data we are generating through them with the pivotal clinical development program. There are three key factors we believe have the potential to support adoption of mitapivat on multiple leukemia patients in the U.S. First, there is strong alignment between where in the US. These patients reside and where they receive treatments.

謝謝，阿拉姆。費利西亞仍然是一個需求未被滿足的地區，治療選擇很少。無論患者是否需要輸血，疾病負擔都是巨大的。與一般人群相比，Celsignia 患者的死亡率增加，且非定期輸血患者的死亡率可能明顯低於定期輸血患者。歐洲患者隨著年齡的增長，發病率很高，併發症也增加。與輸血依賴型患者相比，非輸血依賴型地中海貧血的成年患者實際上可能具有相似或更差的生活品質。當然，這種疾病負擔與為了解決這一未滿足的需求而增加的醫療保健成本相關，並受到間皮瘤第三階段活力研究的積極數據的刺激。我們的商業組織正在積極準備明年推出針對地中海貧血的藥物，首先從美國開始。在美國，大約有 6,000 名確診患有白血病的成年患者。其中約 4,000 名患者不依賴輸血，目前沒有可用的治療選擇。其餘 20 名患者則依賴輸血，沒有口服治療選擇。我們對 mitapivat 的目標是解決居住在加州的所有成年人未滿足的需求，並成為第一個被批准用於該疾病所有亞型的療法。除了我們透過關鍵臨床開發計劃產生的數據之外。我們認為三個關鍵因素有可能支持美國多例白血病患者採用米塔皮伐。首先，美國各地之間存在著強烈的一致性。這些患者居住在哪裡以及他們接受治療的地方。

The map on slide 26, patient prevalence overlaid with the arduous clinical trial site and for Centers of Excellence represented by the gold bars. Second, the diagnosis rate is high, driven by the availability of newborn screening and well-established ICD-10 codes. Many patients are diagnosed before adulthood.

第 26 張幻燈片上的地圖顯示，患者患病率與艱鉅的臨床試驗地點和金條代表的卓越中心重疊。其次，由於新生兒篩檢和完善的 ICD-10 代碼的可用性，診斷率很​​高。許多患者在成年之前就被診斷出來。

And finally, as shown on slide 21, there is concentration of patients and providers at selected centers. Approximately 50% of all diagnosed patients are treated at fewer than 150 affiliated hematology oncology practices in the U.S. providing a clear focus for our initial launch. Given these market dynamics and final time target product profile, we believe we are well positioned to provide a potential foundational treatment option for patients with pellet premia regardless of subtype. Therefore, our team is focused on four core areas of U.S. launch preparation for building on the foundational work we have already done we continue to deepen the sophistication of our market understanding. We are conducting extensive market research and claims data analysis to inform HCP targeting field force sizing and deployment for launch second we'll be rolling out a disease education campaign for both patients and clinicians, highlighting the long-term complications and burden of disease across all CELsignia subtypes. Our disease education engagement will also work to correct the historical misperception that non-transfusion dependent patients are less likely to experience the debilitating long-term effects of the leukemia. To support these initiatives, we are establishing capabilities to enable execution of our educational efforts across personnel and non-personnel channel sorry, we'll continue to strengthen our commercial capabilities by expanding our sales team in anticipation of the thalassemia launch, rightsizing the team for a broader rare disease.

最後，如幻燈片 21 所示，患者和提供者集中在選定的中心。大約 50% 的確診患者在美國不到 150 家附屬血液腫瘤診所接受治療，這為我們的首次推出提供了明確的重點。鑑於這些市場動態和最終目標產品概況，我們相信我們有能力為顆粒溢價患者提供潛在的基礎治療選擇，無論其亞型如何。因此，我們的團隊專注於美國上市準備的四個核心領域，以我們已經完成的基礎工作為基礎，繼續加深對市場的了解。我們正在進行廣泛的市場研究和索賠數據分析，以便為HCP 提供針對現場人員規模和部署的信息，以便啟動第二次我們將為患者和臨床醫生開展疾病教育活動，強調所有疾病的長期並發症和疾病負擔CELsignia 亞型。我們的疾病教育活動也將努力糾正歷史上的誤解，即非輸血依賴患者不太可能經歷白血病的長期衰弱影響。為了支持這些舉措，我們正在建立能力，以便能夠跨人員和非人員管道執行我們的教育工作。抱歉，我們將繼續加強我們的商業能力，透過擴大我們的銷售團隊來應對地中海貧血症的推出，調整團隊規模以適應地中海貧血症的需求。一種更廣泛的罕見疾病。

And lastly, in parallel with those efforts, we are preparing our market access team to engage with payers on disease state education in advance of the potential launch in thalassemia next year. Our team has obtained success in market access for PK deficiency, and we look forward to watching them pave the way in thalassemia, too, in addition to the well-established USD premium market. There are approximately 13,000 patients in the EU5 and approximately 70,000 for leukemia patients in the Gulf region. We aim to maximize the potential of these additional markets through coordinated regulatory filing, which we intend to pursue with partners. Taken together, we believe the potential launch of mitapivat in thalassemia represents a significant opportunity for IGO and a step forward as we prepare for potential back-to-back launches with sickle cell disease in 2023.

最後，在這些努力的同時，我們正在準備我們的市場准入團隊，以便在明年可能推出地中海貧血之前與付款人就疾病狀態教育進行接觸。我們的團隊在 PK 缺陷的市場准入方面取得了成功，除了成熟的美元溢價市場之外，我們期待看到他們在地中海貧血方面也鋪平道路。歐盟五國約有 13,000 名患者，海灣地區約有 7 萬名白血病患者。我們的目標是透過協調監管備案來最大限度地發揮這些額外市場的潛力，我們打算與合作夥伴共同努力。總而言之，我們認為 mitapivat 治療地中海貧血的潛在上市對 IGO 來說是一個重大機遇，也是我們為 2023 年針對鐮狀細胞病可能連續上市做準備的一步。

Now let me provide an update on the current launch of vital signs in PK deficiency. In the fourth quarter of 2023, we generated $7.1 million in net BioTime revenue compared to $7.4 million in the prior quarter. A total of 178 patients have completed a prescription enrollment form, including 18 in the fourth quarter of 2023, an 11% increase versus the third quarter this translated into net 109 patients on therapy, a 9% increase versus the third quarter. Patients on therapy continues to spend from a growing and diverse prescriber base of 154 physicians and represents a broader demographic and disease manifestation range that is consistent with the adult PK deficiency population. We continue to be encouraged by the persistency of patients on treatment and remain focused on efficiently identifying providers likely to treat patients with PK deficiency. The capabilities we continue to build and expand through the current launch, including efficient targeting analytics, patient awareness and education and patient access will provide a firm foundation from which we can maximize the potential U.S. launches in thalassemia in 2025 and in sickle cell disease in 2026 as we advance through this catalyst-rich period of Phase three data readout for mitapivat, we look forward to dramatically expanding the number of patients we serve.

現在讓我介紹一下目前 PK 缺乏生命徵象推出的最新情況。2023 年第四季度，我們的 BioTime 淨收入為 710 萬美元，而上一季為 740 萬美元。共有178 名患者填寫了處方登記表，其中2023 年第四季有18 名患者填寫，較第三季增加11%，這意味著淨接受治療的患者人數為109 名，較第三季度增加9% 。接受治療的患者繼續從由 154 名醫生組成的不斷增長且多樣化的處方者群體中支出，代表了更廣泛的人口和疾病表現範圍，這與成人 PK 缺乏人群一致。我們繼續對患者堅持治療的態度感到鼓舞，並繼續專注於有效地識別可能治療 PK 缺乏患者的提供者。我們透過目前的發布繼續建立和擴展的能力，包括高效的目標分析、患者意識和教育以及患者訪問，將為我們最大限度地提高2025 年在美國的地中海貧血和2026 年的鐮狀細胞病的潛在上市奠定堅實的基礎。隨著我們進入 mitapivat 第三階段數據讀出的催化劑豐富時期，我們期待大幅擴大我們服務的患者數量。

With that, I'll turn the call over to Cecilia.

這樣，我就把電話轉給塞西莉亞。

Thanks, Meta. Our fourth quarter 2023 financial results can be found in the press release we issued this morning and more detail will be included in our 10 K, which will be filed later today.

謝謝，梅塔。我們的 2023 年第四季財務業績可在我們今天早上發布的新聞稿中找到，更多詳細資訊將包含在我們將於今天晚些時候提交的 10 K 中。

Let me now take a moment to provide some context and highlight a few key points full year 2020 to be net Biocon revenue was $26.8 million compared with $11.7 million in Biocon revenue for 2020 to Q4 2023 net Paracon revenue was $7.1 million, a 4% reduction compared to the third quarter. The reduction was driven by lower number of weeks on hand of inventory compared to where we ended Q3, partially offset by favorability in gross-to-net adjustments. As a reminder, we anticipate low levels of inventory at any given time, given our limited distribution network, which consists of one specialty pharmacy and one specialty distributor, consistent with other rare disease launches. Gross to net is expected to be in the 10% to 20% range on an annual basis based on our learnings to date, given the ultra rare nature of the disease and the long lead times associated with initiating patients on therapy, we continue to expect slow and steady growth and quarter to quarter variability in 2024, similar to what we saw in 2023. Cost of sales for the fourth quarter was $0.6 million R&D expenses were $77 million for the fourth quarter and $296 million for the full year 2023, an increase of $16 million compared to the full year 2022. These changes reflect an increase in development costs for mitapivat and the upfront payments associated with a license agreement with Alnylam offset by a reduction in expenses associated with the evolution of our research organization and the sale of our oncology business to Servier.

現在讓我花點時間提供一些背景資訊並強調幾個關鍵點，2020 年全年Biocon 淨收入為2,680 萬美元，而2020 年至2023 年第四季Biocon 淨收入為1,170 萬美元，Paracon 淨收入為710 萬美元，減少了4%與第三季相比。與第三季末相比，庫存週數減少是造成這一減少的原因，但毛淨調整的有利性部分抵消了這一影響。提醒一下，鑑於我們有限的分銷網絡（由專業藥房和專業經銷商組成），我們預計任何特定時間的庫存水平都會較低，這與其他罕見疾病的推出一致。根據我們迄今為止的了解，考慮到該疾病的極其罕見性質以及與患者開始治療相關的較長準備時間，我們繼續預計，每年的毛淨比預計將在 10% 至 20% 的範圍內2024 年將出現緩慢而穩定的成長以及季度間的變化，與我們在2023 年看到的情況類似。第四季銷售成本為 60 萬美元，第四季研發費用為 7,700 萬美元，2023 年全年研發費用為 2.96 億美元，較 2022 年全年增加 1,600 萬美元。這些變化反映了 mitapivat 開發成本的增加以及與 Alnylam 許可協議相關的預付款的增加，這些費用被我們研究組織的發展以及將我們的腫瘤業務出售給施維雅相關的費用減少所抵消。

Sg&a expenses were $35 million for the fourth quarter and $120 million for the full year 2023, a decrease of $2 million compared to the full year 2022. As a reminder, as part of the divestiture of our oncology business to Servier, we retain rights to a potential $200 million milestone upon FDA approval of Veracyte and if and 15% royalties on potential U.S. net sales, certainly publicly communicated plans to file for approval before the end of 2023. So we are eager to track their progress. We ended the year with cash, cash equivalents and marketable securities of approximately $806 million. We expect that this balance, together with anticipated product revenue, interest income on the potential for aside any milestone would enable the Company to fund our operating expenses and capital expenditures through several value-creating milestones and at least into 2026. This guidance does not include cash inflows that could extend our runway beyond 2026, including the potential royalties or royalty monetization from Veracyte and at commercializing mitapivat outside of the US through one or more partnerships or other potential strategic business or financial agreements. We remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach as we prepare to support potential future launches of Fiberxon as we move toward additional potential value-creating milestones in the near term. I am confident that our strong balance sheet will enable us to execute from a position of strength as we continue to pursue ways to create shareholder value.

第四季的銷售、管理及行政費用為 3,500 萬美元，2023 年全年為 1.2 億美元，比 2022 年全年減少 200 萬美元。提醒一下，作為將我們的腫瘤業務剝離給施維雅的一部分，我們保留在FDA 批准Veracyte 後獲得潛在2 億美元里程碑的權利，以及潛在美國淨銷售額的15% 特許權使用費，當然公開傳達了申請批准的計劃2023 年底之前。因此，我們渴望追蹤他們的進展。年底，我們的現金、現金等價物和有價證券約為 8.06 億美元。我們預計，這項餘額，加上預期的產品收入、任何里程碑的潛在利息收入，將使公司能夠透過幾個創造價值的里程碑，至少到 2026 年，為我們的營運支出和資本支出提供資金。本指南不包括可能將我們的跑道延伸到2026 年之後的現金流入，包括來自Veracyte 的潛在特許權使用費或特許權使用費貨幣化，以及透過一個或多個合作夥伴關係或其他潛在策略業務或財務協議在美國境外將mitapivat 商業化的費用。我們仍然專注於創造股東價值，包括積極管理我們的成本基礎並部署嚴格的現金分配方法，因為我們準備好支持未來可能推出的 Fiberxon，同時我們在短期內朝著更多潛在的價值創造里程碑邁進。我相信，隨著我們繼續尋求創造股東價值的方法，我們強大的資產負債表將使我們能夠從優勢地位執行。

I will now turn the call back over to Brian for his closing remarks.

現在我將把電話轉回給布萊恩，讓他發表結束語。

I think Cecilia, as we turn the page on a highly productive 2023. We're focused on executing across the additional four Phase three readouts for mitapivat that we expect over the next two years, beginning with the Phase three energize T. study in transfusion dependent thalassemia in the middle of this year. As we continue to stack successes, positive data readouts for mitapivat, we are only growing more confident in the probability of success ahead. We're well positioned with a differentiated mechanism of action that improves red blood cell health beyond hemoglobin increase and allows us to pursue large commercial opportunities with substantial value and the potential for two additional first-in-class and best-in-class indications for pirate time as we build a multi-billion dollar franchise in PKR activation as we continue to take steps toward realizing our vision of becoming a leading rare disease company. We will continue to strive to be responsible stewards of our balance sheet and evaluate meaningful opportunities for value creation and finally, I'd like to thank all of our employees for their hard work and dedication to our mission of developing and delivering transformative medicines that elevate and extend the lives of patients living with rare diseases and all of our partners, including the patients, physicians, caregivers and participants in our clinical development programs.

當我們翻開高效能的 2023 年這一頁時，我想到了塞西莉亞。我們的重點是在未來兩年內執行 mitapivat 的另外四個三期讀數，從今年年中針對輸血依賴性地中海貧血的三期 energize T. 研究開始。隨著我們繼續累積 mitapivat 的成功和積極的數據讀數，我們對未來成功的可能性越來越有信心。我們處於有利位置，具有差異化的作用機制，可以改善紅血球健康，超越血紅蛋白增加，並使我們能夠追求具有巨大價值的巨大商業機會，並有可能獲得另外兩個一流和一流的適應症。我們在PKR 活化方面建立了數十億美元的特許經營權，同時我們繼續採取措施實現成為領先的罕見疾病公司的願景。我們將繼續努力成為我們資產負債表的負責任的管理者，並評估創造價值的有意義的機會。最後，我要感謝我們所有員工的辛勤工作和對我們開發和提供變革性藥物的使命的奉獻精神，以提升我們的使命。延長罕見疾病患者以及我們所有合作夥伴的生命，包括患者、醫生、照護者和我們臨床開發計畫的參與者。

With that, we will now open the call for questions.

現在，我們將開始提問。

Thank you to ask a question, you'll need to press star one one on your telephones. To withdraw your question, please press star one again. Please wait for your name to be announced, we ask that you please limit your questions to one and one follow up. Please standby while we compile the Q&A roster. One moment for our first question, please. Our first question comes from the line of Eric Schmidt with Cantor Fitzgerald. Your line is now open.

感謝您提出問題，您需要在電話上一一按星號。若要撤回您的問題，請再次按星號一。請等待您的名字被公佈，我們要求您將您的問題限制為一一跟進。我們正在整理問答名單，請您稍候。請稍等一下我們的第一個問題。我們的第一個問題來自埃里克·施密特和坎托·菲茨杰拉德的對話。您的線路現已開通。

Look, thanks for the question and congrats on all the recent development successes. I guess maybe one for Sarah, given the next milestone, next milestone at least might be the energize key study for mitapivat in transfusion dependent patients. Can you give us a little bit of a preview here or set up with regard to the primary endpoint, I know you're looking at transfusion reductions in a slightly different way than what we've been accustomed to seeing with the luspatercept data. So how might that primary endpoint definition changed the way we view the data and what might the hurdle be?

看，感謝您的提問，並祝賀最近所有的開發成功。我想莎拉可能會這麼做，考慮到下一個里程碑，下一個里程碑至少可能是米塔皮伐在輸血依賴患者中的關鍵研究。您能否在這裡給我們一些預覽或設置有關主要終點的信息，我知道您正在以與我們習慣於使用 luspatercept 數據看到的方式略有不同的方式來看待輸血減少。那麼，主要端點定義如何改變我們查看資料的方式以及可能的障礙是什麼？

Great. Thanks, Eric. Thanks a lot for the question. And I just before Serco's, I just wanted to welcome you back to our geos earnings calls. So sorry, do you want to get started?

偉大的。謝謝，埃里克。非常感謝您的提問。就在 Serco 之前，我只是想歡迎您回到我們的 geos 收益電話會議。很抱歉，您想開始嗎？

Sure. Thanks. Thanks for the question. Saying the dark endpoint. The primary endpoint has a different definition and the primary endpoint that was better suited to use in the sense that we are looking at a 50% reduction in any 12 week period rolling period, basically over the 48 weeks and patients are assessed, which we believe is a more on appropriate measure to assess a patient in the context of a dynamic disease over a longer stretch of time in which reflects better the real-world experience of patients may have some. We do have a similar endpoints like the spot as the primary endpoint in our secondary endpoints.

當然。謝謝。謝謝你的提問。說的是黑暗的終點。主要終點有不同的定義，並且更適合使用的主要終點是我們希望在任何 12 週的滾動期內減少 50%，基本上在 48 週內對患者進行評估，我們相信這一點是一種在較長時間內在動態疾病背景下評估患者的更適當的措施，其中更好地反映了患者可能有的現實世界經驗。我們確實有類似的端點，例如作為次要端點中的主要端點的點。

In regarding to the hurdles, it is it is a different end point. Indeed, the hurdle is not necessarily different in the sense that you have multiple assessments periods versus a fixed period in time. The bar of 50%, of course, is higher than 33%. But like I said, because it's every any 12 week periods, you have more shots on goal to speak. This was an endpoint that was better set also had in their assessment and in their review. But as it was not a prespecified like primary or secondary analysis that did not make it into the label.

就障礙而言，這是一個不同的終點。事實上，從有多個評估期與固定時間段的意義上來說，障礙並不一定有所不同。當然，50% 的標準高於 33%。但就像我說的，因為每 12 週一次，你就會有更多的射門機會來說話。這是一個在他們的評估和審查中也有更好設定的終點。但由於它不是預先指定的初級或次級分析，因此未將其納入標籤中。

Thank you very much.

非常感謝。

Thank you.

謝謝。

Thank you. One moment for our next question, please. Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open.

謝謝。請稍等一下我們的下一個問題。我們的下一個問題來自克里斯·雷蒙德和派珀·桑德勒的對話。您的線路現已開通。

Thanks. And maybe just a question on energize data that we got last months, we've gotten a few questions around from investors around that sort of the transition from the Phase two data. This to the Phase three data, there was a degradation in the hemoglobin response, but you measured these effects over different time points. I know you guys had said that there was no waning of efficacy over time, but maybe just square this difference that you saw and I've got a follow-up.

謝謝。也許只是關於我們上個月獲得的激勵數據的問題，我們從投資者那裡收到了一些關於第二階段數據轉變的問題。對於第三階段的數據，血紅蛋白反應有所下降，但您在不同的時間點測量了這些影響。我知道你們說過，隨著時間的推移，功效並沒有減弱，但也許只是平方你們看到的差異，我就有了後續行動。

Sure. Thanks for the question. So the primary endpoint that we used in Phase two was indeed different than the endpoint that we used in the Phase three, meaning that for the Phase two, we just looked at patients meeting the hemoglobin response at a single time point for the Phase three, we incorporated the duration in that endpoint over a longer stretch of time and measured at a later time point because it's a chronic disease. So them and from a safety perspective, you're truly looking for maintenance over a longer duration of time. So we averaged hemoglobin over 12 weeks versus that just single time point, which is much easier to reach as a bar.

當然。謝謝你的提問。因此，我們在第二階段使用的主要終點確實與我們在第三階段使用的終點不同，這意味著對於第二階段，我們只是觀察在第三階段的單一時間點達到血紅蛋白反應的患者，我們將較長時間內該終點的持續時間納入其中，並在稍後的時間點進行測量，因為它是一種慢性疾病。因此，從安全角度來看，您確實需要在較長時間內進行維護。因此，我們對 12 週內的血紅蛋白進行了平均，而僅對單個時間點進行了比較，作為條形圖更容易達到。

In regards to the waning, we don't see waning of our hemoglobin response of mitapivat in this trial behave very similarly to how it behaves in PKD. So once patients show a response, they tend to maintain that response over time. There's always a little bit of fluctuation on that hemoglobin over time. But overall, it's Steve of positive and aligned kind of stays horizontal in comparison to their baseline. So we feel very confident with the results that we have observed and energized. In addition, it's more than hemoglobin alone that we observed. We really saw an improvement on the Facet fatigue there as well, which we believe is extremely meaningful because now we are adding to the hemoglobin plus story here. Some of the things that we've observed in PKD now also have been observed in the non-transfusion dependent thalassemia population, and that continues to add to this consistent and compelling data story that we are continuing to generate.

關於減弱，我們在本試驗中沒有看到 mitapivat 的血紅素反應減弱，其表現與 PKD 的表現非常相似。因此，一旦患者表現出反應，他們往往會隨著時間的推移維持這種反應。隨著時間的推移，血紅素總是會有一點波動。但總的來說，史蒂夫的積極和一致的類型與他們的基線相比保持水平。因此，我們對我們觀察到和激發的結果非常有信心。此外，我們觀察到的不僅僅是血紅蛋白。我們也確實看到了 Facet 疲勞的改善，我們認為這是非常有意義的，因為現在我們在這裡添加了血紅蛋白加故事。我們在 PKD 中觀察到的一些現象現在也在非輸血依賴性地中海型貧血人群中觀察到，這將繼續豐富我們正在繼續生成的一致且令人信服的數據故事。

Okay, thanks. And then maybe just a follow-up to Eric's question on the success bogey of energized T. And I know it's you're talking but different measures is kind of an apples to apples comparison that was Pat or SAP, but some and just as you're thinking about the obvious difference in mitapivat is oral versus luspatercept, which is not just maybe talk in generalities, how you see these these two compounds sort of coexisting commercially?

好的謝謝。然後也許只是埃里克關於充滿活力的T的成功柏忌的問題的後續。我知道這是你在說的，但不同的衡量標準是一種蘋果與蘋果的比較，帕特或SAP，但有些就像你一樣我正在考慮 mitapivat 的明顯區別是口服藥物與 luspatercept 的區別，這可能不僅僅是籠統地說，您如何看待這兩種化合物在商業上共存？

Sure. So if we think about the non-transfusion dependent thalassemia patient population that currently have no therapy available so that he may talk about it. And with if we get it through, the next stages of development would be the therapy, then it would be available for non-transfusion dependent patient populations and is all the which is a huge benefit specifically for that population because patients aren't going to clinic as frequently. And if you have and it's a drug that requires frequent clinic visits and adds to the burden of disease. Typically for the transfusion dependent patient population, there is indeed a subcutaneous luspatercept available for transfusion-dependent beta thalassemia patients. Our program has studied all genotypes of balanced senior.

當然。因此，如果我們考慮目前沒有可用治療方法的非輸血依賴性地中海貧血患者群體，那麼他可能會談論這個問題。如果我們成功了，下一階段的開發將是治療，然後它將可用於非輸血依賴的患者人群，這對該人群來說是一個巨大的好處，因為患者不會經常去診所。如果您有這種藥物，則需要經常去診所就診，並會增加疾病負擔。通常對於輸血依賴性患者群體，確實有一種皮下注射的 luspatercept 可用於輸血依賴性β地中海貧血患者。我們的計畫研究了平衡老年人的所有基因型。

So that's one difference. The oral route of administration here is very relevant because it allows for almost a seamless incorporation into a transfusion scheduled amortizations may have versus requiring more visits on top of the transfusions scheduling. In that sense, it's also important to understand there's a very different mechanism of action between those two products on which you know, this person did stimulate red blood cell stimulator, while we're talking about, it's about trying to improve red blood cell health overall. And so we do see from that perspective there, they're vastly different

所以這是一個區別。這裡的口服給藥途徑非常重要，因為它幾乎可以無縫地納入輸血計畫攤銷中，而不是在輸血計畫之外需要更多的就診。從這個意義上說，了解這兩種產品之間存在非常不同的作用機制也很重要，您知道，這個人確實刺激了紅血球刺激劑，而我們正在談論的是，它是關於嘗試改善紅血球健康全面的。所以我們確實從這個角度來看，它們是截然不同的

And Chris, I mean that last point is the one that I would just emphasize is that I know folks are trying to make comparisons, but in so many ways, they're incomparable because of the profound difference in the mechanisms. And you'll hear a lot from us because we continue to be emboldened by this by the data that we see very consistently that the benefits of power of pyruvate kinase activation really do go beyond hemoglobin. So we'll await the data. Fortunately, we don't have to wait that long. Energize T is coming midyear, but I think above oral and the other dimensions, hemoglobin and the like, that's really the big headline for this mechanism is it's ultimately about red blood cell health.

克里斯，我的意思是，我要強調的最後一點是，我知道人們正在嘗試進行比較，但在很多方面，由於機制的深刻差異，它們是無法比較的。您會從我們這裡聽到很多訊息，因為我們不斷看到的數據讓我們更加大膽，丙酮酸激酶活化能力的好處確實超越了血紅蛋白。所以我們將等待數據。幸運的是，我們不必等那麼久。Energize T 將於年中推出，但我認為除了口腔和其他維度、血紅蛋白等之外，這確實是該機制的大標題，因為它最終與紅血球健康有關。

Thank you. One moment for our next question. Our next question comes from the line of Danielle Brill with Raymond James. Your line is now open.

謝謝。請稍等一下我們的下一個問題。我們的下一個問題來自丹妮爾·布里爾和雷蒙德·詹姆斯的對話。您的線路現已開通。

Hi, guys. Good morning. Thanks so much for the questions. Unusual. We have a question on powering assumptions for aggregate, key on, like Chris said, we know it's not apples to apples, but when you look at this pattern that their mean hemoglobin increase was about 1.5 grams and they achieved I think, around a 40% response rate. And on your primary endpoint with this context, what are your internal expectation for how mitapivat will perform? And I also have a follow-up.

嗨，大家好。早安.非常感謝您的提問。異常。我們有一個關於總體假設的動力問題，關鍵是，就像克里斯說的那樣，我們知道這不是同類，但是當你看到這個模式時，他們的平均血紅蛋白增加了大約1.5 克，我認為他們實現了大約40 克。 ％ 反應速度。在這種情況下，您的主要終點是，您對 mitapivat 的表現有何內部期望？我還有一個後續行動。

Thanks for the question. So in regards to our powering assumptions, we haven't spoken about these, but we have, of course, studied all of the programs in front of us, which includes our own internal programs in which we took a very similar development approach for thalassemia as we had for PKD in regards to the hemoglobin increase that you mentioned. So we don't have from a transfusion dependent perspective, we don't believe you necessarily need to increase hemoglobin on top of making trends to impact people reduce their transfusions. This is truly a different approach because people when they get transfused, their hemoglobin goes down over time. So what we are trying to do here is basically avoiding that people their hemoglobin decreases back to a transfusion trigger, which then would trigger a transfusion. And it comes down again to that different mechanism of action, if you're like stimulating out red blood cells, ultimately your or you're going to increase the hemoglobin versus what we are trying to do about keeping the red blood cells happier and healthier, thereby reducing hemolysis is a completely different way of actually trying to avoid transfusions.

謝謝你的提問。因此，就我們的動力假設而言，我們還沒有談論這些，但我們當然研究了我們面前的所有計劃，其中包括我們自己的內部計劃，其中我們對地中海貧血症採取了非常相似的開發方法正如我們對PKD 所做的那樣，關於您提到的血紅蛋白增加。因此，從輸血依賴的角度來看，我們認為除了影響人們減少輸血的趨勢之外，您不一定需要增加血紅素。這確實是一種不同的方法，因為人們在輸血時，他們的血紅蛋白會隨著時間的推移而下降。因此，我們在這裡試圖做的基本上是避免人們的血紅蛋白下降回到輸血觸發點，從而觸發輸血。這又歸結為不同的作用機制，如果你想刺激紅血球，最終你或你會增加血紅蛋白，而不是我們試圖讓紅血球更快樂和更健康，從而減少溶血是實際上嘗試避免輸血的完全不同的方式。

Thanks. That's helpful. And that actually on a perfect segue for my follow-up. Do you have data on Avon, the potential of mitapivat for extending the half-life of healthy red blood cells.

謝謝。這很有幫助。這其實是我後續行動的完美延續。您是否有雅芳（Avon）的數據，米塔皮瓦（mitapivat）延長健康紅血球半衰期的潛力？

So we in the context of you mean healthy volunteers, red blood cells

所以我們在你的上下文中指的是健康志願者，紅血球

or likely extending the lifespan of transfused blood.

或可能延長輸血的壽命。

So yes, so this is something that is extremely difficult to come to measure in the context of a transfusion setting as everything is kind of mixed. So it would require very, very calm, unique experience to be able to tease apart those types of red blood cells that are available. So we're not planning on doing that right now for our transfusion dependent patients.

所以，是的，在輸血環境中這是很難測量的，因為一切都是混合的。因此，需要非常非常冷靜、獨特的經驗才能區分出可用的紅血球類型。因此，我們現在不打算為依賴輸血的患者這樣做。

Got it. Thanks. And thanks again for the questions.

知道了。謝謝。再次感謝您的提問。

Thank you.

謝謝。

And our next question comes from the line of Gregory Renza with RBC Capital Markets. Your line is now open.

我們的下一個問題來自加拿大皇家銀行資本市場部的格雷戈里·倫扎 (Gregory Renza)。您的線路現已開通。

Hey, good morning, Brian and team. Congrats on all the progress and thanks for taking my questions. Brian, you certainly speak to the multibillion dollar opportunity available with the PK activation and your portfolio. Just curious if you could then maybe just elaborate a little bit on that, maybe provide some of that inputs or assumptions that you using to get to that characteristic, whether it's with respect to mitapivat and the ramp of indications or the broader portfolio? And maybe I'll just layer in my second question and with respect to the landscape in PKR activation, perhaps have you. And Sarah can just read a little bit about maybe the differences with mitapivat versus others, especially have a pivotal test. Certainly, you've mentioned I believe you have the body of data. But when you think about some of the nuances upon PK activation or evidence of selectivity, maybe just help us understand the differences between mitapivat and the landscape. Thanks so much.

嘿，早上好，布萊恩和團隊。恭喜所有進展並感謝您提出我的問題。Brian，您確實談到了 PK 活化和您的投資組合帶來的數十億美元的機會。只是好奇您是否可以對此進行一些詳細說明，也許提供一些您用來獲得該特徵的輸入或假設，無論是關於 mitapivat 和適應症的增加還是更廣泛的投資組合？也許我會提出我的第二個問題，關於公正黨激活的情況，也許你有。莎拉可以讀一點關於 mitapivat 與其他藥物的差異，特別是有一個關鍵的測試。當然，您提到我相信您擁有大量數據。但是，當您考慮 PK 活化或選擇性證據時的一些細微差別時，也許可以幫助我們理解 mitapivat 和景觀之間的差異。非常感謝。

Yes. Thanks, Greg. So I'll get started on your first question about the multi-billion dollar opportunity or opportunities that I referenced in my prepared comments that really comes from the fact that we're rapidly progressing in our pipeline, moving from clear ultra rare with PKD. into successively larger prevalent diseases. Some of those diseases, I think are a well characterized in terms of opportunity, sickle cell, for sure. There's been a lot of interest in a lot of therapeutic development focus. And here we're talking about moving from 3 to 8,000 patients across the U.S. and EU five in the case of PKD., jumping to just in the U.S. alone, 100,000 patients with sickle cell disease. But it's more than that. I mean, as we've already discussed this morning, we had this really exciting opportunity relatively near term with a potential launch next year in thalassemia, which is a prevalence step up in the case of the U.S. from PKD sickle cell I just mentioned. And then even after that, with our other PKR activator AG nine four six moving into low risk MDS. The great news about all this is we're moving in the right direction in terms of prevalence, and that is allowing us to enter into very compelling commercial opportunities and it also allows us to navigate through the appropriate pricing dynamics as we go forward. But we are very excited, most importantly, with the fact that as we advance our pipeline and as we've already noted, we have two back-to-back launch potentials with calcemia next year, followed by sickle cell disease in 2026. And then sorry, you want to pick up with the next question.

是的。謝謝，格雷格。因此，我將開始回答你的第一個問題，即我在準備好的評論中提到的一個或多個數十億美元的機會，這些機會實際上來自於我們的管道正在迅速取得進展，從明顯的超罕見的PKD 轉變。逐漸演變成更大的流行疾病。我認為其中一些疾病在機會方面具有明確的特徵，當然，鐮狀細胞疾病。人們對許多治療開發焦點很感興趣。在這裡，我們討論的是美國和歐盟的 PKD 患者數量從 3 名增加到 8,000 名，僅在美國就有 10 萬名鐮狀細胞疾病患者。但還不止於此。我的意思是，正如我們今天早上已經討論過的那樣，我們在近期內獲得了這個非常令人興奮的機會，明年可能會推出針對地中海貧血的藥物，就美國而言，地中海貧血是我剛才提到的PKD 鐮狀細胞病患病率上升的一個階段。即使在那之後，我們的另一個 PKR 活化劑 AG 九四六也進入了低風險 MDS。關於這一切的好消息是，我們在流行方面正朝著正確的方向前進，這使我們能夠進入非常引人注目的商業機會，也使我們能夠在前進的過程中通過適當的定價動態。但最重要的是，我們感到非常興奮，因為隨著我們的產品線不斷推進，正如我們已經指出的那樣，我們有兩個連續推出的潛力，分別是明年的鈣血症藥物和2026 年的鐮狀細胞病藥物。抱歉，您想回答下一個問題。

Sure. So in regard PKR2 activation and the differences between mitapivat and some other PKR activator. So we indeed probably stimulate T K a different ticket item enzymes amongst which the PKR., which is important for the red blood cell. But then also Pecem two is important, and we understand more and more of the relevance that the relevance of this specific IDO enzyme in the context of the diseases that we are studying. And as you know, calcemia sickle-cell disease MDS, there is different components to these diseases in which stimulation of Pecem two may be relevant as it is expressed in immature red blood cells. It is expressed in other tissues that are also touched by these diseases. We are planning to further study this clinically as well as specifically in sickle cell disease in the kidney. As we know, kidney is such an important organ in the context of sickle cell disease and many patients suffer from kidney disease. And we believe that Pecem two may have an added advantage there in regards to how that compares to other PK activator, specifically about what if that is some day, this is the drug that home, it's to be format drug. They always spoke about being a PKR, selective agents in regards to how they translate into other enzymes and enzymes. They have not spoken about that. It just highlights that there's selectivity message.

當然。因此，關於 PKR2 活化以及 mitapivat 和其他一些 PKR 活化劑之間的差異。因此，我們確實可能會刺激 T K 一種不同的酶，其中包括 PKR，它對紅血球很重要。但 Pecem 2 也很重要，我們越來越了解這種特定 IDO 酶與我們正在研究的疾病的相關性。如您所知，鈣血症鐮狀細胞疾病 MDS，這些疾病有不同的組成部分，其中 Pecem 2 的刺激可能與之相關，因為它在未成熟的紅血球中表達。它在其他也受這些疾病影響的組織中表達。我們計劃在臨床上進一步研究這一點，特別是在腎臟鐮狀細胞疾病方面。眾所周知，腎臟是鐮狀細胞疾病中非常重要的器官，許多患者患有腎臟疾病。我們相信，與其他 PK 活化劑相比，Pecem 2 可能有額外的優勢，特別是如果有一天，這是一種回家的藥物，它將成為一種格式藥物。他們總是談論如何成為 PKR，即如何轉化為其他酵素和酵素的選擇性試劑。他們還沒有談論過這一點。它只是強調存在選擇性訊息。

Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open as for the on for Salveen.

謝謝。我們的下一個問題來自 Salveen Richter 與高盛的對話。您通往 Salveen 的路線現已開通。

Thanks so much for taking your question on just one on sickle cell, could you just discuss where you see power kind of fitting into the current commercial landscape just broadly? And then can you also speak to the commercial or the enrollment progression and any physician feedback you've gotten so far. Thanks so much.

非常感謝您提出鐮狀細胞的問題，您能否簡單討論一下您認為權力在哪裡廣泛地適應當前的商業格局？然後您還可以談談廣告或註冊進度以及您迄今為止收到的任何醫生回饋嗎？非常感謝。

Sure. And maybe I will just start and then quickly turn it over to Satya and then Sarah can pick up on the enrollment aspects. I mean, the fundamental premise of what we're driving towards with sickle cell disease is we believe that mitapivat pilocarpine has the potential to be what we refer to as foundational therapy. This is a very different mechanism of action. As we've talked about very unique from currently available options. We're increasingly convinced that the benefits on making the red blood cells healthier, really position it as such and then the fact that this is an oral treatment only adds to that potential. But I'll let Steve speak a little bit more about not just how we're thinking about sickle cell disease, but the bridge as we go from PKD. two energy to Dallas, Caemi and then the sickle cell.

當然。也許我會開始，然後快速將其移交給薩蒂亞，然後莎拉可以接手註冊方面的事宜。我的意思是，我們推動鐮狀細胞疾病治療的基本前提是我們相信米塔皮瓦毛果芸香鹼有潛力成為我們所說的基礎療法。這是一種非常不同的作用機轉。正如我們所討論的，目前可用的選項非常獨特。我們越來越相信，讓紅血球更健康的好處確實如此，而這是一種口服治療的事實只會增加這種潛力。但我會讓 Steve 多談談我們如何看待鐮狀細胞疾病，以及我們擺脫 PKD 的橋樑。兩個能量到達拉斯，卡米，然後是鐮狀細胞。

Thanks, Brian. I'll start with sickle cell disease for us. But as you said, we have a very important milestone with the policymakers launch ahead of that, which we believe will be an important point from growing the commercial capabilities, executing on the telephony launch and after that, capitalizing on our sickle cell disease.

謝謝，布萊恩。我將從鐮狀細胞疾病開始。但正如你所說，我們有一個非常重要的里程碑，政策制定者在此之前推出，我們相信這將是增強商業能力、執行電話推出以及之後利用我們的鐮狀細胞疾病的一個重要點。

When we think about sickle cell disease, Brian mentioned that and I mentioned that already the prevalence of the disease is 100,000 patients in the U.S., which is a significant step up from where we are today with PK deficiency is a disease where patients are diagnosed and the burden of disease is well-characterized at the moment. The adult patient population with sickle cell disease has very limited treatment options available. They are either improving hemoglobin levels, which is the case a brighter for our improving DUCs. And based on the Phase two data and the target product profile we have for by recurrent for loans, we believe that we'll be very well-positioned with fiber kind to provide a treatment option, which will bring benefits to physicians, patients and ultimately payers as well by improving hemoglobin, reducing VOCs and ultimately improving the way our patients feel and function. And that's going to be at a unique value proposition if we were to deliver on that profile.

當我們想到鐮狀細胞疾病時，Brian 提到過這一點，我也提到過，在美國，這種疾病的盛行率已經有10 萬名患者，這與我們今天的情況相比是一個顯著的進步，PK 缺乏症是一種患者被診斷出來並接受治療的疾病。疾病負擔目前已被充分錶徵。患有鐮狀細胞疾病的成年患者群體的可用治療選擇非常有限。它們要么正在改善血紅蛋白水平，對於我們改善的 DUC 來說，這種情況更加明顯。根據第二階段的數據和我們透過經常性貸款獲得的目標產品概況，我們相信我們將在纖維種類方面處於非常有利的地位，以提供治療選擇，這將為醫生、患者帶來好處，並最終通過改善血紅蛋白、減少揮發性有機化合物並最終改善患者的感覺和功能方式，也為付款人提供了幫助。如果我們要實現這一目標，這將是一個獨特的價值主張。

So we are very excited about that opportunity to come. But before we get to sickle cell disease, we are very excited to progress with our launch preparation for thalassemia as well. Afterwards, though the results from the energize R&D during the year we have definitely our press the button and are actively preparing fertility near launch to come in 2025, Senor to sickle cell disease. I think the policymakers launch will be a meaningfully differentiated in terms of market characteristics that compare to PKD. And that will position us well for adoption of fire behind assuming approval in 2025, including again, these patients are diagnosed. It's 6,000 diagnosed patients in the U.S. with the leukemia and well-established ICD-10 codes, a stronger concentration of the prescriber base. And all of these elements gives us confidence on our ability to commercialize the product and drive adoption at launch and similar to sickle cell disease. There's a better understanding of the thalassemia unmet need across both the transfusion dependence and also the non-transfusion dependent patients as well. So we are gearing up and getting ready to commercial organization to go launch into lithium in 2025, potentially followed by back-to-back launches in sickle cell disease in 20.

因此，我們對這個機會的到來感到非常興奮。但在我們討論鐮狀細胞疾病之前，我們非常高興能夠在地中海貧血的上市準備工作中取得進展。之後，儘管今年的研發成果令人振奮，但我們確實已按下按鈕，並正在積極準備 2025 年推出的生育功能，以預防鐮狀細胞疾病。我認為，與 PKD 相比，政策制定者推出的產品在市場特徵方面將具有顯著的差異化。假設 2025 年獲得批准，這將使我們為火的採用做好準備，包括再次診斷這些患者。美國有 6,000 名確診患有白血病的患者，擁有完善的 ICD-10 代碼，處方者基礎更加集中。所有這些因素都讓我們對產品商業化和在推出時推動採用的能力充滿信心，就像鐮狀細胞疾病一樣。人們對輸血依賴性和非輸血依賴性患者的地中海貧血未滿足的需求有了更好的了解。因此，我們正在做好準備，讓商業組織在 2025 年推出鋰產品，隨後可能在 20 年連續推出鐮狀細胞疾病產品。

Yes. And so I was just going to say that's great set. And I think everybody consents or excitement about what we have in front of us. And I was just going to ask Sarah to make a comment about the progress with rise up Phase three for sickle cell factory

是的。所以我想說這是很棒的一套。我認為每個人都同意或對我們面前的事情感到興奮。我只是想請莎拉對鐮狀細胞工廠第三階段的進展發表評論

because we are equally excited to move towards those launches. So we are heavily focused on our Phase three enrollment. Of course, right now, the the trial is progressing as we are anticipating. There's a lot of enthusiasm, both within our teams and of course, on the by the investigators as well. And so everything is on track to deliver to the milestone that we have set out for this year.

因為我們同樣對這些發布感到興奮。因此，我們非常關注第三階段的招生。當然，目前審判正在按照我們的預期進行。我們的團隊內部，當然還有調查人員，都充滿了熱情。因此，一切都步入正軌，以實現我們今年設定的里程碑。

Thank you so much.

太感謝了。

Thank you very much. Question comes from the line of Tessa Romero with JPMorgan. Your line is now open.

非常感謝。問題來自泰莎·羅梅羅 (Tessa Romero) 與摩根大通的關係。您的線路現已開通。

Great. Good morning, Brian and team. Thank you for taking our question, so we can give a little bit to commercial PKD. And do you still think that PKD could be a 200 to 150 million peak opportunity here in the US? And if so, how long do you think it could take you to get there? And then my second question is, and we know that you're moving 89, 46 forward in lower-risk MDS, but we were curious and have you formally de-prioritized the program in sickle cell disease as we hadn't heard anything on this in a while? And can you confirm if that's the case or not? And thanks so much for taking your questions.

偉大的。早上好，布萊恩和球隊。感謝您提出我們的問題，因此我們可以為商業 PKD 提供一點幫助。您是否仍認為 PKD 在美國可能是 2 億至 1.5 億美元的高峰機會？如果是這樣，您認為需要多長時間才能到達那裡？然後我的第二個問題是，我們知道你們在低風險 MDS 方面正在推進 89、46，但我們很好奇，你們是否正式取消了鐮狀細胞疾病計畫的優先順序，因為我們沒有聽到任何消息一會兒這個？你能否證實是否屬實？非常感謝您提出問題。

Thanks a lot has actually the second question. We can handle that very quickly, which is no. And we have not de-prioritized anything with AG. nine or six. I think we're inspired by the potential. And at the right time, we'll provide updates about the progress, not just in our pursuit of low risk MDS, but also where we stand with respect to sickle cell disease.

非常感謝，其實有第二個問題。我們可以很快處理這個問題，但事實並非如此。我們並沒有降低 AG 的任何優先順序。九個或六個。我認為我們受到了潛力的啟發。在適當的時候，我們將提供有關進展的最新信息，不僅是我們追求低風險 MDS 的進展，而且還包括我們在鐮狀細胞病方面的進展。

Cecilia, do you want to comment on the first one we have today and

塞西莉亞，你想對我們今天的第一個評論發表評論嗎？

thanks for the question. So we definitely remain excited about the opportunity and PKD., and we continue to expect those peak sales of $200 million to $225 million for the U.S. We continue to make progress each quarter and we're learning and I said I said it is helping also fit those capabilities for our launch, and we think it's going to be slow and steady, continuing to see the trends we've seen in 2023 for the next few years. But we do stick around maintain our peak of $220 million to $225 million , the

謝謝你的提問。因此，我們對這個機會和 PKD 絕對感到興奮。我們繼續預計美國的銷售額將達到 2 億至 2.25 億美元。我們每個季度都會繼續取得進展，我們正在學習，我說過我說這也有幫助為我們的發布配備這些功能，我們認為這將是緩慢而穩定的，在接下來的幾年裡繼續看到我們在2023 年看到的趨勢。但我們確實堅持維持了2.2億美元到2.25億美元的峰值，

I mean with PKD., and we've talked about this previously, but the in the deep commercial experience, the books that I have across multiple rare disease launches. This one-stop, it's a challenge. It is ultra rare. It's diagnostically intensive. There's long lead times for patients. So slow and steady is the right phrase. What we're continued to be inspired by each quarter is that persistency, which is something we saw relatively early with the launch of Paracon and PKD. that is a really important feature as we think about chronic rare disease launches to come that are in our sights. And so we'll we'll take the slow and steady path, and we're going to continue to expect that going forward. But the way pirate kind is performing is what we believe really puts us in a position of strength as we approach energize sorry, kissing energized as we approach our senior as well as sickle cell beyond that.

我的意思是 PKD，我們之前已經討論過這個問題，但是在深入的商業經驗中，我擁有的關於多種罕見疾病的書籍。這個一站式，是個挑戰。這是極為罕見的。這是診斷密集型的。患者的交貨時間很長。所以緩慢而穩定是正確的短語。每個季度我們繼續受到的啟發是這種堅持，這是我們在 Paracon 和 PKD 推出時相對較早看到的。當我們考慮即將推出的慢性罕見疾病時，這是一個非常重要的特徵。因此，我們將採取緩慢而穩定的道路，並且我們將繼續期待這種情況的發展。但我們相信，海盜的表演方式真正讓我們處於強勢地位，當我們接近活力抱歉時，當我們接近我們的高級以及鐮狀細胞時，接吻充滿活力。

Okay, thanks so much for taking our questions, Youbet's.

好的，非常感謝 Youbet 提出我們的問題。

Thanks a lot.

多謝。

Thank you. Our next question comes from the line of Greg Harrison with Bank of America. Your line is now open.

謝謝。我們的下一個問題來自美國銀行的格雷格·哈里森 (Greg Harrison)。您的線路現已開通。

Good morning and thanks for taking the question. I also just wanted to follow-up on AG. nine four six, how are you thinking just generally in development of about development and potentially overlapping indications with mitapivat if there could be improvement? And for example, in sickle cell, like you've discussed or or even calcemia? And what would you need to see from nine, four, six in order to make that decision?

早上好，感謝您提出問題。我也只想跟進AG。九四六，您對發展以及與 mitapivat 潛在重疊的適應症的整體發展有何看法（如果可以改進的話）？例如，在鐮狀細胞中，就像您所討論的，甚至是鈣血症？為了做出這個決定，你需要從九、四、六中看到什麼？

Yes, I'll start and then Sarah can jump in. First of all, Greg, I hope we're in that position where we have multiple indications just as we have right now with the PyroCarbon, one of the key advantages of it geos that having a really a leading PK activation franchises. We have not one but two products that we're developing and that allows us to have different economics, different pricing dynamics across the indications and between the products. I think there's a wide enough space for us right now, given where we are in the development program with AG. nine, four six that we can tailor the appropriate target product profiles, whether it's for sickle cell disease or for low-risk MDS.

是的，我先開始，然後莎拉可以加入。首先，格雷格，我希望我們處於這樣的位置，我們有多種跡象，就像我們現在的 PyroCarbon 一樣，它的關鍵優勢之一是擁有真正領先的 PK 激活特許經營權。我們正在開發的不是一種而是兩種產品，這使我們能夠在不同的適應症和產品之間擁有不同的經濟學和不同的定價動態。我認為，考慮到我們與 AG 的開發計劃目前所處的階段，我們現在有足夠廣闊的空間。九、四、六，我們可以客製化適當的目標產品概況，無論是針對鐮狀細胞疾病或低風險 MDS。

In the case of lower-risk MDS, as I think folks know, we just reported out last year very encouraging proof of concept from our Phase IIa study. And we're in the process right now of making enhancements in the design so we can pursue Phase IIb. I feel very good about the work the team has done, and that will be the next step. And as I mentioned before, at the right time, we'll also report out the progress on sickle cell disease, anything you want to answer and just high level?

就低風險 MDS 而言，我想大家都知道，我們去年剛剛報告了 IIa 期研究的非常令人鼓舞的概念證明。我們現在正在改進設計，以便我們可以進行 IIb 階段。我對團隊所做的工作感到非常滿意，這將是下一步的工作。正如我之前提到的，在適當的時候，我們也會報告鐮狀細胞疾病的進展，您想回答什麼問題嗎？

I think what you can express expect from development is that we always strive to design our trials to meet multiple stakeholders their needs, meaning we take our target product profile very seriously. So that is something that for nine for six, it's the same. We take very seriously and we incorporate we will be incorporating patient voice into regular regulatory feedback, obviously as well.

我認為您可以表達對開發的期望是，我們始終努力設計我們的試驗以滿足多個利害關係人的需求，這意味著我們非常重視我們的目標產品概況。所以這對九對六來說是一樣的。我們非常重視，我們顯然也將把患者的聲音納入定期監管回饋中。

We are a great example of that is in the case of sickle cell disease, a point that we're very proud of that. Our geos is we have deeply involved the community. In fact, Sara and I attended the conference last year where we won an award from the community about how carefully and thoughtfully. We involved sickle cell disease warriors and caregivers in how we think about designing the trials recruiting for the trials and ultimately what the commercial profile should look like and we'll do the same thing with AG. nine four six.

鐮狀細胞疾病就是一個很好的例子，我們對此感到非常自豪。我們的地理定位是我們深入參與社區。事實上，Sara 和我去年參加了會議，我們獲得了社區頒發的獎項，表彰我們的細心和周到。我們讓鐮狀細胞疾病戰士和護理人員參與如何設計試驗、招募試驗人員以及最終商業概況應該是什麼樣子，我們將與 AG 做同樣的事情。九四六。

Great. Thanks for taking the questions.

偉大的。感謝您提出問題。

You've got. Great. Thanks.

你有。偉大的。謝謝。

Thank you. And our last question will come from the line of David Round with TD Cowen. Your line is now open.

謝謝。我們的最後一個問題將來自 David Round 和 TD Cowen 的對話。您的線路現已開通。

Hi, guys. This is David on for Mark. Thanks for taking my questions. I have to kind of follow-up question one on Erik's question earlier was the difference in the primary endpoint between mitapivat and powder sets for the transfusion dependent patients, something that was recommended to you by regulatory authorities or was it more of an internal choice? And then my second question is turning to the design of the Phase IIb in MDS. And do you plan to test multiple dose levels of 89 for six? And any color on the enrollment criteria versus what regulatory hot in the COMMANDS trial would be would be great. Thank you.

嗨，大家好。這是大衛替馬克代言。感謝您回答我的問題。我必須對埃里克之前的問題提出一個後續問題，即對於輸血依賴患者來說，米塔皮瓦和粉劑組之間的主要終點有何差異，這是監管機構向您推薦的，還是更多的是內部選擇？然後我的第二個問題是轉向 MDS IIb 期的設計。您是否計劃對六人測試 89 的多個劑量等級？註冊標準上的任何顏色與命令試驗中的監管熱點都會很棒。謝謝。

Thank you. Thanks, Dhivya. So in regards to the first question, primary endpoint, yes, indeed, we do, as I just mentioned on the previous question as well, we do our development in collaboration with regularly with regulators. So we take feedback from the regulators very seriously and tried to come. It really incorporate the feedback as best as we can. And so that's how we ended up settling for the 50% endpoints in a rolling 12 week period interval, which we indeed truly believe is a more dynamic endpoint and really reflects the real-world experience of a patient. So this is where it's always very good and we're always very grateful to be able to have those conversations because I do think incorporating feedback from multiple stakeholders always leads to better design choice. So and so that's that on the primary endpoint.

謝謝。謝謝，迪維亞。因此，關於第一個問題，主要終點，是的，確實，我們確實這樣做，正如我剛剛在上一個問題中提到的那樣，我們定期與監管機構合作進行開發。因此，我們非常重視監管機構的回饋，並盡力做到這一點。它確實盡可能地融合了回饋。這就是我們最終在 12 週滾動間隔內確定 50% 終點的方式，我們確實相信這是一個更具動態的終點，並且真正反映了患者的真實體驗。因此，這總是非常好的地方，我們總是非常感激能夠進行這些對話，因為我確實認為整合多個利害關係人的回饋總是會帶來更好的設計選擇。這就是主要終點。

And then in regards to your question for MDS Phase IIb, yes, the Phase IIb is indeed on in our multiple doses that we are testing, we are going to test higher doses than we originally anticipated just because we have learned from our Phase two A. that MDS patients overall have lower exposure to same amount of drug than other other patient populations and healthy volunteers. So we are incorporating those learnings into our Phase IIb.

然後關於你對 MDS IIb 期的問題，是的，IIb 期確實在我們正在測試的多個劑量中正在進行，我們將測試比我們最初預期更高的劑量，因為我們從第二階段 A 中學到了教訓. MDS 患者總體上比其他患者群體和健康志願者接觸相同劑量的藥物的情況要少。因此，我們正在將這些經驗教訓納入我們的 IIb 階段。

And in regards to our inclusion criteria, we have not come and we haven't presented the trialing progress post or anything like that yet, but you can expect this population to be relatively similar to how our population was in the Phase two A. However, we will be focusing on transfusion patients with transfusion burden. It will also be a broad broad MDS population just like we allowed in the IIa and we are not excluding perceived population like specific mutations or things like that.

至於我們的納入標準，我們還沒有來，我們還沒有提交試驗進度帖子或類似的東西，但你可以預期這個人群與我們在第二階段 A 的人群相對相似。但是，我們將重點關注有輸血負擔的輸血患者。這也將是一個廣泛的 MDS 人群，就像我們在 IIa 中所允許的那樣，我們並不排除諸如特定突變或類似情況的感知人群。

Thank you.

謝謝。

Thank you. I would now like to hand the conference back over to Mr. Brian Goff for closing remarks.

謝謝。現在我想將會議交回給 Brian Goff 先生致閉幕詞。

All right. Thanks a lot, Norma, and thank you very much, everyone, for participating in today's call. Very good questions, which we very much appreciate. As you heard today, our team is great conviction in our potential to deliver transformative new therapies to patients and significant long-term value to shareholders. And we really look forward to speaking with all of you again, soon. So thanks a lot.

好的。非常感謝諾瑪，也非常感謝大家參加今天的電話會議。非常好的問題，我們非常感謝。正如您今天所聽到的，我們的團隊堅信我們有潛力為患者提供變革性的新療法，並為股東帶來巨大的長期價值。我們真誠地期待很快再次與你們所有人交談。非常感謝。

This concludes today's conference call. Thank you for your participation. You may now disconnect, and everyone have a wonderful day.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接，每個人都有美好的一天。