Fulcrum Therapeutics Inc (FULC) 2025 Q1 法說會逐字稿

Good morning and Welcome to Fulcrum Therapeutics first quarter 2025 financial results and business update conference call. (Operator Instructions). This call is being webcast live and can be accessed on investors section of Fulcrum website at www.fulcrumtx.com and it's being recorded.

早安，歡迎參加 Fulcrum Therapeutics 2025 年第一季財務業績和業務更新電話會議。（操作員指令）。本次電話會議正在進行網路直播，可透過 Fulcrum 網站 www.fulcrumtx.com 的投資者專區訪問，會議內容正在進行錄音。

Please be reminded that remarks during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 may include statements about the company's future expectations and plans, clinical development timelines, and financial projections.

請注意，本次電話會議中的言論可能包含《1995 年私人證券訴訟改革法案》所定義的前瞻性陳述，其中可能包括有關公司未來預期和計劃、臨床開發時間表和財務預測的陳述。

While these forward-looking statements represent Fulcrum's view as of today, this should not be relied upon as representing the company's views in the future. Fulcrum may update these statements in the future, but it's not taking on an obligation to do so. Please refer to Fulcrum's most recent filings, the Securities and Exchange Commission, for discussions of certain risks and uncertainties associated with the company's business.

雖然這些前瞻性陳述代表了 Fulcrum 目前的觀點，但不應將其視為代表公司未來的觀點。Fulcrum 將來可能會更新這些聲明，但沒有義務這樣做。請參閱 Fulcrum 向美國證券交易委員會提交的最新文件，以了解與公司業務相關的某些風險和不確定性的討論。

Leading the call today will be Alex C. Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer. After providing updates on the company's key programs, there'll be a brief Q&A in which the bulk management team will be available for questions. With that, it is my pleasure to send the call over to Alex.

今天主持電話會議的將是 Fulcrum 執行長兼總裁 Alex C. Sapir。與 Alex 一起參加電話會議的還有財務長 Alan Musso。在介紹公司主要專案的最新情況後，將有一個簡短的問答環節，批量管理團隊將回答您的問題。我很高興將電話轉接給亞歷克斯。

Thank you, Olivia, and good morning, everyone, and thanks for joining us today. So before jumping into the updates for the quarter, I just wanted to take a moment to welcome Dae Gon Ha, the newest member of the Fulcrum management team, as our Senior Vice President, Head of Strategy and Business Development.

謝謝你，奧莉維亞，大家早安，謝謝你們今天加入我們。因此，在介紹本季的最新情況之前，我想花點時間歡迎 Fulcrum 管理團隊的最新成員 Dae Gon Ha 擔任我們的高級副總裁、策略和業務發展主管。

Now Dae Gon is no stranger to Fulcrum nor to the sickle cell space. For the past five years, Dea Gon was an equity research analyst at the banking firm Steeple covering Fulcrum. Dea Gon, whose first day with the company is today, will be focused on overall corporate strategy and business development here at Fulcrum as we continue our efforts in sickle cell disease and other benign hematological conditions.

現在，Dae Gon 對 Fulcrum 和鐮狀細胞領域並不陌生。過去五年來，Dea Gon 一直擔任 Steeple 銀行的股票研究分析師，負責 Fulcrum 的研究。今天是 Dea Gon 加入公司的第一天，他將專注於 Fulcrum 的整體企業策略和業務發展，我們將繼續致力於治療鐮狀細胞疾病和其他良性血液疾病。

So now let's turn to the updates for the quarter. The past several months have been an exciting period for Fulcrum as we've continued to make good progress with our lead program Pociredir , which is currently enrolling in a phase 1b trial, a trial that we call Pioneer for the treatment of sickle cell disease, an inherited blood disorder afflicting approximately 100,000 people in the US and approximately 4.4 million people worldwide.

現在讓我們來看看本季的更新。過去幾個月對 Fulcrum 來說是令人興奮的時期，因為我們的主導項目 Pociredir 繼續取得良好進展，該項目目前正在進行 1b 期試驗，我們稱該試驗為“先鋒”，用於治療鐮狀細胞病，這是一種遺傳性血液病，困擾著美國約 10 萬人和全球約 440 萬人。

I am pleased to announce that we've completed enrollment in the 12 mg cohort cohort 3, with a total of 16 patients enrolled and plan to share results of this cohort in early Q3. These data will include key baseline, patient characteristics, adverse events, magnitude of HBF induction, and changes in other important hematological parameters measured throughout the study.

我很高興地宣布，我們已經完成了 12 毫克隊列第 3 組的招募，共有 16 名患者入組，併計劃在第三季度初分享該隊列的結果。這些數據將包括關鍵基線、患者特徵、不良事件、HBF 誘導的程度以及整個研究過程中測量的其他重要血液學參數的變化。

Let me spend a bit of time providing some details on these 16 patients. The majority of these patients have come from sites in the US, with the remainder coming from a single site in South Africa. Their median fetal hemoglobin level at the start of the study was 7.7%, with a mean value of 7.6%. To date, no patients have discontinued from the study, and we continue to see greater than 90% adherence to the once a day oral drug regimen.

請容許我花一點時間來介紹這 16 名患者的詳細資訊。這些患者大多來自美國的站點，其餘則來自南非的一個站點。研究開始時他們的胎兒血紅素水準中位數為 7.7%，平均值為 7.6%。到目前為止，還沒有患者停止研究，而且我們繼續看到超過 90% 的患者堅持每天一次的口服藥物治療方案。

Furthermore, we're pleased to report that the data monitoring committee for the Pioneer study, after reviewing interim data from the 12 mg cohort, recommended that we continue the study as planned with the initiation of the 20 mg cohort cohort 4, which is now underway and currently screening patients. We remain on track with our plans to report data from cohort 4, the 20 mg cohort, by the end of 2025.

此外，我們很高興地報告，先鋒研究的數據監測委員會在審查了 12 毫克組的中期數據後，建議我們按計劃繼續進行研究，並啟動 20 毫克組第 4 組，該組目前正在進行篩選。我們仍按計畫在 2025 年底前報告第 4 組（即 20 毫克組）的數據。

And we continue to believe that inducing fetal hemoglobin is the optimal strategy for treating sickle cell disease. Evidence for this approach continues to grow as highlighted by not only the recently approved gene therapies, but recent data analysis showing that even modest increases in fetal hemoglobin correlate to reduced disease severity.

我們仍然相信誘導胎兒血紅蛋白是治療鐮狀細胞疾病的最佳策略。這種方法的證據不斷增加，不僅最近批准的基因療法強調了這一點，而且最近的數據分析表明，即使胎兒血紅蛋白的適度增加也與疾病嚴重程度的降低有關。

Specifically, a recent data analysis that was presented at as last December shows that for every 1% increase in HBF, there was a 4% to 8% reduction in Vaso-Occlusive Crisis or VOCs. These VOCs occur when sickled red blood cells prevent oxygenated blood from getting to the tissues, resulting in debilitating pain, often requiring hospitalization or visits to the emergency room.

具體來說，去年 12 月發布的最新數據分析表明，HBF 每增加 1%，血管閉塞危像或 VOC 就會減少 4% 至 8%。當鐮狀紅血球阻止含氧血液進入組織時，就會產生這些揮發性有機化合物 (VOC)，導致劇烈疼痛，通常需要住院或在急診室就診。

Additionally, fetal hemoglobin levels in the mid 20% range have shown in your abolition of these VOCs that I spoke about. Based on Pociredir mechanism of action and the data that we have previously disclosed, we believe that Pociredir has the potential to provide a differentiated therapeutic option for people living with sickle cell disease.

此外，20% 中間範圍內的胎兒血紅蛋白水平已表明您消除了我所說的這些 VOC。基於Pociredir的作用機制和我們先前揭露的數據，我們相信Pociredir有潛力為鐮狀細胞疾病患者提供差異化的治療選擇。

And we look forward to providing important clinical data this year to further validate our potentially transformative approach with Pociredir. At the upcoming European Hematology Association Meeting, or EHAF for short, which is being held in June in Milan, we have two abstracts that have been accepted for poster presentation.

我們期待今年提供重要的臨床數據，以進一步驗證我們使用 Pociredir 的潛在變革方法。在即將於 6 月在米蘭舉行的歐洲血液學會會議（簡稱 EHAF）上，我們有兩篇摘要已被接受進行海報展示。

Those abstracts include preclinical target engagement and reversibility of gene expression data with Pociredir, as well as clinical data from our previously completed phase one healthy volunteer study. Now beyond Pociredir, we continue to advance our earlier stage development program for the potential treatment of inherited aplastic anemias.

這些摘要包括 Pociredir 的臨床前標靶參與和基因表現數據的可逆性，以及我們先前完成的第一階段健康志願者研究的臨床數據。現在，除了 Pociredir 之外，我們還將繼續推進我們早期的開發計劃，以尋找治療遺傳性再生障礙性貧血的方法。

Such as Diamond-Blackfan Anemia or DBA, Shwachman-Diamond Syndrome, and Fanconi anemia. We plan to submit an IND for DBA in the fourth quarter of this year. And with that overview, I will now turn it over to our Chief Financial Officer Alan Musso to run through the financials. Over to you, Alan.

例如 Diamond-Blackfan 貧血症或 DBA、Shwachman-Diamond 症候群和 Fanconi 貧血症。我們計劃在今年第四季提交 DBA 的 IND。有了這些概述，我現在將把時間交給我們的財務長艾倫·穆索 (Alan Musso) 來介紹財務狀況。交給你了，艾倫。

Thanks, Alex. I'll now go over our results for the quarter ended March 31, 2025. Our research and development expenses were $13.4 million for the first quarter of 2025 compared to $19.8 million for the first quarter of 2024.

謝謝，亞歷克斯。我現在將回顧截至 2025 年 3 月 31 日的季度業績。2025 年第一季我們的研發費用為 1,340 萬美元，而 2024 年第一季為 1,980 萬美元。

The decrease of $6.4 million was due to the discontinuation of our losmapimod program and the global development cost sharing reimbursement under the Sanofi collaboration, partially offset by increased costs related to the advancement of the phase 1b pioneer trial of pociredir.

減少 640 萬美元是由於我們停止了 losmapimod 項目，以及與賽諾菲合作下的全球開發成本分攤報銷，但部分被與 pociredir 1b 期先驅試驗的推進相關的成本增加所抵消。

The general administrative expenses were $7 million for the first quarter of 2025 compared to $10.1 million for the first quarter of 2024. $3.1 million decrease, primarily due to decreased employee compensation costs as a result of the reduction in workforce implemented in the third quarter of 2024.

2025 年第一季的一般管理費用為 700 萬美元，而 2024 年第一季為 1,010 萬美元。減少 310 萬美元，主要原因是 2024 年第三季實施裁員導致員工薪資成本下降。

Net loss was $17.7 million for the first quarter of 2025 compared to a net loss of $26.9 million for the first quarter of 2024. And turning to the balance sheet, we ended the first quarter of 2025 with cash equivalent, and marketable securities of $226.6 million compared to $241 million as of December 31, 2024. The $14.4 million decrease is primarily due to cash used to fund the operating activities.

2025 年第一季淨虧損為 1,770 萬美元，而 2024 年第一季淨虧損為 2,690 萬美元。談到資產負債表，截至 2025 年第一季度，我們的現金等價物和有價證券為 2.266 億美元，截至 2024 年 12 月 31 日為 2.41 億美元。1,440 萬美元的減少主要是由於用於資助經營活動的現金。

And finally turning to cash guidance based on our current operating plans, we continue to expect that our existing cash equivalents and marketable securities will be sufficient to fund our operating requirements into at least 2027. And with that, I'll turn the call over back to you Alex.

最後，根據我們目前的營運計劃，轉向現金指導，我們繼續預計我們現有的現金等價物和有價證券將足以滿足我們至少到 2027 年的營運需求。說完這些，我將把電話轉回給你，亞歷克斯。

That's great. Thanks, Alan. So to conclude, Fulcrum is off to a solid start in 2025, and we're very much looking forward to delivering two important data releases this year with the Pioneer trial. So with that overview of the business and the financials that Alan went over, Olivia, let's go ahead and open it up for questions.

那太棒了。謝謝，艾倫。總而言之，Fulcrum 在 2025 年取得了良好的開端，我們非常期待今年透過先鋒試驗發布兩項重要數據。奧利維亞，艾倫概述了業務和財務狀況，現在我們可以開始提問了。

(Operator Instructions). First question coming from the line of Joseph Schwartz with Leerink Partners, sir your line is now open.

（操作員指令）。第一題來自 Leerink Partners 的 Joseph Schwartz，先生，您的路線現已開放。

Great, thanks so much. Congrats on all the progress and hi to Dae Gon. Look forward to working together again. I was wondering if you could talk some more about the quantum of data you expect to report from the 12 mg cohort of Pioneer mid-year.

太好了，非常感謝。恭喜你所取得的所有進步，並向 Dae Gon 問好。期待再次合作。我想知道您是否可以再多談談您預計在年中報告的先鋒 12 毫克隊列的數據量。

What range of follow-up duration do you anticipate we'll see for the 16 patients who've been enrolled, and will we get any data on the markers of homolysis in addition to fetal hemoglobin data for these patients?

對於已入選的 16 名患者，您預計我們將進行多長的追蹤時間？除了胎兒血紅蛋白數據外，我們還會獲得有關這些患者的同源性溶解標記物的任何數據嗎？

Yeah, great question, Joe, thanks for asking it to answer that, I will turn that answer over to Iain Fraser, our Head of development who is actually was in the room, but it wasn't introduced at the outset of the call.

是的，喬，這個問題問得很好，謝謝你提出這個問題，我會把答案交給我們的開發主管伊恩·弗雷澤，他當時就在房間裡，但在通話開始時並沒有提出這個問題。

Yeah, thanks, Alice. Maybe for the first, the second part of your question, Joe markers of hemolysis, yes, we'll be providing hematological parameters, the blood counts, bilirubins, and so on, as indicators of hemolysis. With respect to the first part of your question, we will have all the data for all16 patients on the treatment.

是的，謝謝，愛麗絲。也許對於您問題的第一部分、第二部分，喬，溶血標記物，是的，我們將提供血液學參數、血球計數、膽紅素等作為溶血的指標。關於您問題的第一部分，我們將擁有所有接受治療的 16 名患者的所有數據。

Phase of the study, so that's the three-month treatment duration and then a subset of the patients with the four week follow up after that. There probably will not be all 16 for the full four weeks based on the data cut, but we will have a subset of those patients.

研究階段，即三個月的治療期，然後對一部分患者進行四週的追蹤。根據數據截斷，整整四周可能不會有全部 16 名患者，但我們將擁有其中的一部分患者。

Great, thanks. That's super helpful. And then, I guess, does the observed dosing provide you with a specific data on the number of doses that patients are receiving real time, and do you happen to have any of that data handy that you can share with us?

太好了，謝謝。這非常有幫助。然後，我想，觀察到的劑量是否為您提供了患者即時接受的劑量數量的具體數據，並且您是否恰好有任何可以與我們分享的數據？

Yeah, Joe, is this sort of related to the 90% adherence number that we referenced in our opening remarks?

是的，喬，這與我們在開場白中提到的 90% 的遵守率有關嗎？

Yeah, I'm just, yeah, I guess any, is there any more colour that you can provide on, the timing of the doses? Are they all within the prescribed time frame and I guess how many doses have occurred to date?

是的，我只是，是的，我想，您能提供更多關於劑量時間的資訊嗎？它們是否都在規定的時間範圍內？我猜到目前為止已經注射了多少劑？

Yeah, it's a it's it's a great question, Joe. I appreciate you asking it so let me give up maybe a little bit of background. So just for everybody that's on the call, it is an oral once daily dosing and the way that we're able to capture the adherence rates is not through the more traditional kind of pill counts at the end of the month where the patient comes in and gets their next bottle.

是的，喬，這個問題問得真好。感謝你提出這個問題，我先簡單介紹一下背景。因此，對於每個值班的人來說，這都是每天口服一次的劑量，我們能夠捕捉到依從率的方式不是通過更傳統的在月底計數藥丸的方式，即病人來拿下一瓶藥。

It's really using this AI tool that we mentioned and that is listed in our investor presentation AI cure and this is something where the actual patient has to sort of. Register themselves on this AI tool show that they've actually put the drug in their mouth, have swallowed it. They then have to open their mouth to show that the that the drug is gone and then and then we get reports.

它確實使用了我們提到的這個 AI 工具，並且在我們的投資者演示 AI 治療中列出，這是實際患者必須做的事情。在這個人工智慧工具上註冊表明他們確實將毒品放入嘴裡併吞下。然後他們必須開口表明藥物已經消失，然後我們才會收到報告。

I wouldn't necessarily say on a real-time basis, but we get them in a very sort of timely manner as. Do the as do the sites as well and so that's really where that where that 90% that's where that 90% number is coming from, not really from the more traditional ways that people measure adherence to drug around pill counts, anything else you want to add to that?

我不一定會說是即時的，但我們會以非常及時的方式獲得它們。這些網站也是這樣嗎？這才是 90% 這個數字的真正來源，而不是人們根據藥丸數量來衡量藥物依從性的更傳統方式，您還有什麼要補充的嗎？

No, other than that, the patient selects the time of day that they want to take their medication, and the app will remind them at that time, so everything's built around that, time of day that that they're taking it, and that gets captured as well.

不，除此之外，患者選擇他們想要服藥的時間，應用程式會在那個時間提醒他們，所以一切都是圍繞這一點構建的，他們服藥的時間，也會被記錄下來。

Yeah, and we, so we certainly can capture that joe, assuming that they're using the tool which we know they are in. Greater than 90% of cases so we can actually determine are they actually taking it exactly at 8 o'clock every day for the full 84 days or not I don't have that data handy and I'm not, we haven't really discussed whether that's something that we'll be presenting when we share the data in early Q3. Does that answer your question?

是的，所以我們當然可以抓住那個喬，假設他們使用我們知道他們所使用的工具。超過 90% 的病例，因此我們實際上可以確定他們是否真的在整整 84 天內每天 8 點準時服藥，我手頭沒有這些數據，我們還沒有真正討論過在第三季度初分享數據時是否會展示這些數據。這回答了你的問題嗎？

Yeah, that's excellent. We're looking forward to your updates this year. Thanks for the inputs.

是的，太棒了。我們期待您今年的更新。感謝您的意見。

Yeah, thanks so much, Joe, for the questions.

是的，非常感謝喬提出的問題。

Thank you. Our next question coming from line of Matthew Biegler with Oppenheimer, you let us know.

謝謝。我們的下一個問題來自 Oppenheimer 的 Matthew Biegler，請告訴我們。

Oh great. Hey everyone, I'll send my congrats as well. Thanks for the updated color here. The baseline HBF is a bit higher, I think at 7% than we anticipated given like the severity of disease for these patients at entry. So number one, do you think you've gotten a representative sample of the broader demographic you're going to be trying to treat here when we do get the data and number two.

哦，太好了。大家好，我也向你們表示祝賀。感謝這裡更新的顏色。考慮到這些患者入院時的病情嚴重程度，我認為基線 HBF 比我們預期的要高一些，為 7%。那麼第一，當我們獲得數據時，您是否認為您已經獲得了一個具有代表性的更廣泛人群的樣本，並且您將嘗試在這裡進行處理？第二，

Do you think poster should work equally well or perhaps even better in patients with higher baseline HPF?

您是否認為海報對於具有較高基線 HPF 的患者應該具有同樣好的效果，甚至更好？

Yeah, great question, Joe. Sorry, great question, Matt. Thanks for asking them. Yeah, let me maybe just comment a little bit on your first sort of comment that it was a little bit sort of higher than many people had had expected. I think that what we were hearing in our normal course of conversations with investors is that because this was a more severe patient population, I think some were worried that, you were seeing.

是的，喬，問得好。抱歉，馬特，問得好。謝謝你詢問他們。是的，讓我對你的第一個評論做一點評論，它比很多人預期的要高一點。我認為，我們在與投資者的正常對話中聽到的是，由於這是一個更嚴重的患者群體，我認為有些人對此感到擔憂。

A baseline fetal hemoglobin in the very sort of low single digits, and if they are in the very low single digits, it's going to be very sort of difficult to get them, to a number that that people can get excited about. So I think when we saw what the baselines were at, 7.7% for the median and the mean value.

基線胎兒血紅素處於非常低的個位數，如果處於非常低的個位數，那麼將很難將其調至令人興奮的數字。所以我認為當我們看到基線時，中位數和平均值是 7.7%。

7.6% we thought it was important to sort of share that with folks because again I think many people were thinking that boy these baseline fetal hemoglobin levels could be extremely low given the severity of the patients that were enrolling and then maybe in answer to your other two questions, let me turn that one over to Iain.

7.6% 我們認為與大家分享這一點很重要，因為我再次認為很多人都認為，考慮到入組患者的嚴重程度，這些基線胎兒血紅蛋白水平可能非常低，然後也許在回答你的另外兩個問題時，讓我把這個問題交給伊恩。

Yeah, I would think Matt, that that in the General population with larger numbers, those that have the more severe phenotype will tend to have lower baseline fetal hemoglobins. We have a small sample size here, at the moment and spans a range of those baselines.

是的，馬特，我認為在數量較大的一般人群中，那些具有更嚴重表型的人往往會具有較低的基線胎兒血紅蛋白。目前，我們這裡的樣本量很小，涵蓋了一系列基線。

I don't think there's anything unexpected around that, and as Alex said, we thought it was helpful to provide that additional bit of colour, leading into the data readout. With respect to your other question about, responsiveness, I think at the moment, we don't have any reason to believe that your baseline level of HBF in and of itself determines your response to [Boeria].

我認為這並沒有什麼意外，正如亞歷克斯所說，我們認為提供額外的色彩以引導數據讀數是有幫助的。關於你的另一個問題，關於反應能力，我認為目前，我們沒有任何理由相信你的 HBF 基線水平本身決定了你對[波埃里亞]。

And we've certainly seen from the initial 16 patients in all that that some at the low end had a pretty robust induction of HBF in response to drug. I think what is fair to say is that if you're starting very low, where you eventually max out at steady state on therapy may be. At a lower absolute fetal hemoglobin than if you were starting at a higher level, but I think we need the fuller data set to be able to comment further on that.

我們確實從最初的 16 名患者中看到，一些低端患者在藥物反應中出現了相當強烈的 HBF 誘導。我認為公平地說，如果你的起點很低，那麼最終你的治療可能會達到最大的穩定狀態。與從較高水平開始時相比，絕對胎兒血紅蛋白較低，但我認為我們需要更完整的數據集才能對此進行進一步評論。

Okay, awesome. That makes a lot of sense. If I could just maybe squeeze one quick one minute on the guide going from, I guess mid-year to early 3Q, is that just kind of the nuts and bolts of the execution of the clinical trial, or you actually want to get more follow up on, potential disease modification and points, such like that. Thank you very much.

好的，太棒了。這很有道理。如果我可以花一分鐘時間快速講解一下從年中到第三季度初的指南，這是否只是臨床試驗執行的具體細節，或者您實際上想要獲得更多的後續信息、潛在的疾病修改和要點，諸如此類。非常感謝。

Yeah, Matt, I think it was really just more the execution of the trial. We thought that obviously having more patients versus less patients would be better. The fact that we've enrolled 16 and as Iian said, we'll have the full treatment data for all of those 16 patients at the at the end of Q3. So that, sorry, at the beginning of Q3. So that was really, I think the reason that we tighten that guidance, but still that guidance has always been in the sort of mid, mid-year range.

是的，馬特，我認為這實際上只是審判的執行。我們認為，顯然病人越多越好，病人越少越好。事實上，我們已經招募了 16 名患者，正如 Iian 所說，我們將在第三季末獲得這 16 名患者的完整治療數據。抱歉，這是在第三季開始時。所以我認為這確實是我們收緊指導的原因，但該指導仍然一直處於年中範圍內。

Thank you. Our next question coming from the line of [at work and help with coffee summer] your line is now open.

謝謝。我們的下一個問題來自[在工作和夏天幫忙喝咖啡]您的線路現已開放。

Great thank you. Thank you very much for taking the call and I apologize, I'm bouncing a little bit between calls today, but I just want to get a sense for and I apologize if this was asked, but what is, what's a win for you guys from the 12 week data?

非常感謝。非常感謝您接聽電話，我很抱歉，今天我在通話之間有點猶豫，但我只是想了解一下，如果有人問到這個問題，我很抱歉，但是從 12 週的數據來看，你們的勝利是什麼？

Obviously we saw somewhere around 10% there's going to be some differences in terms of the patients who are enrolled maybe the baseline, he will be different, but what are you guys really focused on from that data set to know that this is, working? And in the ballpark you're looking for.

顯然，我們看到大約 10% 的差異，就入組的患者而言，也許是基線，他會有所不同，但你們真正關注的是該數據集的什麼，以知道這是有效的？並且就在您尋找的範圍內。

Yeah, thanks for the question, Ted. I'll start and then I'll turn it over to Iain for any you know additional color as we've said in the past and as we said in our opening remarks, I think that any increase in fetal hemoglobin is beneficial to the patients and even something as small as a 1% increase can lead to a 4% of anywhere from a 4% to 8% reduction in VOCs.

是的，謝謝你的提問，泰德。我先開始，然後我會把它交給 Iain，以便您提供任何額外的信息，正如我們過去所說的那樣，正如我們在開場白中所說的那樣，我認為胎兒血紅蛋白的任何增加都對患者有益，即使像 1% 這樣小的增加也可以導致 VOC 減少 4% 到 8%。

We also know that based on Drugs that have been approved for the treatment of sickle cell, VOC reduction somewhere in the sort of 25% to 50% range is considered clinically meaningful for the patients and that has been the basis of approval. So where you sort of net out in that 4% to 8% range, you could easily have single digit, absolute single digit increases in fetal hemoglobin.

我們也知道，根據已獲準用於治療鐮狀細胞疾病的藥物，VOC 減少 25% 至 50% 左右被認為對患者俱有臨床意義，這也是獲得批准的基礎。因此，當您的淨值在 4% 到 8% 的範圍內時，胎兒血紅素很容易出現個位數、絕對個位數的增長。

Compared to where the patients were at baseline and that can be clinically meaningful, certainly for the patients. Once you get to that 25% range, that's really where it becomes transformative for patients. Maybe let me stop there and see what additional colour Iain wants to add.

與患者基線時的情況相比，這具有臨床意義，當然對於患者而言。一旦達到 25% 的範圍，對患者來說這才是真正的轉變。也許我應該停在那裡看看伊恩想要添加什麼顏色。

So I think Ted, you alluded to what we had seen before and we're looking to see with, as we broaden the numbers of patients in the cohort, that we reaffirm that magnitude of induction and as Alex said, the mid-single digit percent increases in in fetal hemoglobin are expected to be clinically meaningful.

所以我認為，泰德，你提到了我們之前看到的情況，我們希望看到，隨著我們擴大隊列中的患者數量，我們重申誘導的程度，正如亞歷克斯所說，胎兒血紅蛋白的中等個位數百分比增加預計具有臨床意義。

Great. Excellent. Thanks and thanks guys. It really makes a lot of sense. Look forward to the data

偉大的。出色的。謝謝大家。這確實很有道理。期待數據

Yeah, thanks.

是的，謝謝。

Thank you. Our next question coming from the line of Kristen Kluska with Cantor Fitzgerald, your line is now open.

謝謝。我們的下一個問題來自 Cantor Fitzgerald 的 Kristen Kluska，您的線路現已開放。

Hi, good morning, everybody. Very encouraging to see you ended up with 16 patients in this cohort, and that enrollment overall seems to be going a lot faster than a lot of us expected. How much of this, in your opinion, could just be attributed to the loss of Oxbryta and different dynamics or how much of it is attributed to getting more sites on board?

大家好，早安。非常高興地看到您最終在這個隊列中招募了 16 名患者，並且總體而言，招募速度似乎比我們許多人預期的要快得多。您認為，這在多大程度上可以歸因於 Oxbryta 的損失和不同的動態，或者在多大程度上可以歸因於更多網站的加入？

Yeah, Kristen, it's Alex. Thanks for the question. I think it's a combination of both, and when you say getting sites on board, I think what we have now is we've got the right sites on board and what I mean by right sites is these are sites that we know tend to treat older patients that maybe have more severe disease.

是的，克莉絲汀，我是亞歷克斯。謝謝你的提問。我認為這是兩者的結合，當你說讓站點加入時，我認為我們現在擁有的是，我們已經擁有了正確的站點，我所說的正確站點是指我們知道這些站點傾向於治療可能患有更嚴重疾病的老年患者。

Either 4 VOCs over a 12-month period of time or two VOCs over a six-month period of time. So these patients do tend to be more severe. So I think that, part of that is driven by the fact that we've got the right sites on board. I think part of it is also driven by the fact that Voxelotor is no longer available and obviously the patients that were on.

12 個月內檢測出 4 種 VOC，或 6 個月內檢測出 2 種 VOC。所以這些患者的病情確實往往更為嚴重。所以我認為，部分原因是我們已經選擇了正確的網站。我認為部分原因也是由於 Voxelotor 不再可用，顯然之前服用該藥物的患者也受到影響。

Voxelotor obviously were very interested in actively managing their disease. So once they had to go off, I think that many of those patients were going back to their physicians and saying, what else is what else is available. And then I would say that the third factor is just kind of overall excitement.

Voxelotor 顯然對積極管理他們的疾病非常感興趣。因此，一旦他們必須停藥，我想很多病人都會回到他們的醫生那裡，問他們還能有什麼其他的方法。然後我想說，第三個因素就是整體的興奮感。

And momentum around fetal hemoglobin induction as really what we believe is the path forward to really potentially see transformative treatment options for these patients and with us being very much sort of at the forefront and leading that charge.

我們真正相信，胎兒血紅蛋白誘導的發展勢頭是真正有可能為這些患者帶來變革性治療選擇的途徑，而我們在這方面處於領先地位。

Physicians get excited about the drug, they start, get excited about the trial, they start the patient, they hear, positive sentiments from their patients and that just sort of feeds even greater success and greater enrollment into the, in, into the study Iain anything you want to add there?

醫生對這種藥物感到興奮，他們開始對試驗感到興奮，他們開始治療患者，他們聽到患者的積極情緒，而這只會帶來更大的成功和更多的人參與研究，伊恩，您還有什麼要補充的嗎？

Well, the only additional bit of colour would be, I think we've articulated previously how getting some of these sites that are best matched to this patient population takes a long time to get those sites up and running, and there is that lag phase.

好吧，唯一需要補充的是，我想我們之前已經解釋過，如何讓一些網站與這些患者群體最匹配，需要很長時間才能讓這些網站啟動並運行，並且有一個滯後階段。

And I think what we're seeing is that lag phase being overcome, those sites being activated with the right sites being able to recruit the patients and that's really helped with the recruitment in the study.

我認為，我們看到的是滯後階段被克服，這些站點被激活，正確的站點能夠招募患者，這對研究中的招募確實有幫助。

Okay thanks and I know you're you talked about that you don't currently have reason to believe that baseline levels will determine your responses but has there been any work or research done to understand why certain patient populations may present as more severe and why these patients don't respond to other therapies that are part of your inclusion exclusion criteria.

好的，謝謝，我知道您說過，您目前沒有理由相信基線水平將決定您的反應，但是是否有任何工作或研究來了解為什麼某些患者群體可能表現得更嚴重，以及為什麼這些患者對屬於納入排除標準的其他療法沒有反應。

And I think ultimately where I'm trying to go with my question. If you're able to show response in a population that's already deemed to be quite severe and tougher to treat with any intervention, how does that help us understand how the data can translate potentially to a more traditional all-comer's population.

我想最終我會透過我的問題來說明這一點。如果您能夠在已經被認為病情相當嚴重且難以透過任何干預措施治療的人群中顯示出反應，那麼這將如何幫助我們理解數據如何潛在地轉化為更傳統的所有人群。

Iain you want to take that?

伊恩，你想拿走那個嗎？

Yeah, that, that's a great question. I think there are lots of components there, Kristen, on the one hand, the, relationship between, the underlying genetics and the severity manifestations of the disease. And it, and HPF is obviously a big contributor to that, but there are other components related to that as well. And then secondly is the aspect of responsiveness to therapy as being able to provide benefit to those patients.

是的，這是一個很好的問題。克莉絲汀，我認為這裡有很多因素，一方面是潛在遺傳因素和疾病嚴重程度表現之間的關係。而且，HPF 顯然是其中的重要貢獻者，但也有其他與此相關的因素。其次是治療反應方面，它能夠為患者帶來益處。

And I think that's going to be different for different therapies. Different therapies will have different. Reasons for responsiveness or non-responsiveness. I think as we move through our clinical program, those are things that we're going to be looking for. Are there key issues that we can tease out as determining responsiveness or not, and translating to benefits.

我認為不同的療法會有所不同。不同的治療方法會有所不同。響應或不響應的原因。我認為，隨著我們臨床計畫的推進，這些都是我們要尋找的東西。我們是否可以找出決定回應能力與否並轉化為利益的關鍵問題。

So I think that's an important piece of it. With respect to the translatability to the less severe patient population, we do have data from the initial 16 patients in the study, who were less clinically severe at the outset, and while we don't have really clinical data because it's a short study, we do have their HBF responses and those, as I think everyone knows, have been very encouraging.

所以我認為這是其中很重要的一部分。關於對病情較輕的患者群體的可轉化性，我們確實有研究中最初 16 名患者的數據，這些患者一開始的臨床病情較輕，雖然由於這是一項短期研究，我們沒有真正的臨床數據，但我們確實有他們的 HBF 反應，我想大家都知道，這些反應非常令人鼓舞。

So we certainly expect to see that responsiveness there and even at the high end of baseline fetal hemoglobin, small increments, even on top of relatively high baselines are clearly associated with benefit as well. So we would expect to see that translate to.

因此，我們當然希望看到那裡的反應性，甚至在胎兒血紅蛋白基線的高端，小的增量，即使在相對較高的基線之上，也明顯與益處相關。因此我們希望看到這一點得到轉化。

Thanks Alex and Iain.

感謝 Alex 和 Iain。

Yeah, thanks, Kristen. Next question, operator.

是的，謝謝，克里斯汀。下一個問題，接線生。

Thank you. And as reminded to ask a question, please press 11. Our next question coming from the line of Gregory Renzo with RBC Capital Markets. The line is now open.

謝謝。提醒您提問，請按 11。我們的下一個問題來自加拿大皇家銀行資本市場的 Gregory Renzo。該線路現已開通。

Good Morning Alex and team. It's Ani on for Greg. Thanks for the updates this quarter and for taking our questions. Just a couple from us first, given the shifts at the FDA, how are you thinking about the impact to Pay's broader developments such as on endpoint selection, HBF as a surrogate marker, which I know you've talked about before, and even the overall development timelines? What's your take on the current set up with regulators? And then just quickly in your deck you note novel HBF inducers in your discovery pipeline. Could you share how you're thinking about differentiating from other mechanisms in the landscape such as wis degraders, DNM-T1 inhibitors, etc. to bring that novelty? Thanks so much.

早上好，亞歷克斯和團隊。格雷格 (Greg) 的 Ani 表演。感謝您本季的更新以及回答我們的問題。首先我們想問幾個問題，鑑於 FDA 的變化，您如何看待對 Pay 更廣泛發展的影響，例如終點選擇、HBF 作為替代標記（我知道您之前談過），甚至整體開發時間表？您對目前的監管機構有何看法？然後，您可以在您的簡報中快速記錄您發現流程中的新型 HBF 誘導劑。您能否分享一下您如何考慮將其與景觀中的其他機制（例如 wis 降解劑、DNM-T1 抑制劑等）區分開來，以帶來這種新穎性？非常感謝。

Yeah, two really good questions, and I appreciate you asking them maybe to answer those, let me turn this over to Iain.

是的，這是兩個非常好的問題，我很感謝你提出這些問題，也許為了回答這些問題，讓我把這個問題交給伊恩。

Yeah, and I think what we'll be doing as we've articulated previously is that at the end of the 20 mg cohort, at the end of the phase 1 study, we'll be interacting with the FDA in the end of phase one interaction. And I think that'll be our opportunity to get a gauge on their thinking as we discuss plans for the next study there.

是的，我認為我們將要做的，正如我們之前所闡述的那樣，在 20 毫克組結束時，即在第一階段研究結束時，我們將在第一階段互動結束時與 FDA 進行互動。我認為這將是我們討論下一項研究計劃時了解他們想法的機會。

So that, so that's an upcoming interaction which is planned and which we expect will occur at the end of the 20 mg cohort. With respect to the other HPF inducers, I think we're looking more broadly and agnostically at compounds that are able to induce HPF.

所以，這是即將發生的相互作用，這是計劃中的，我們預計它將發生在 20 毫克隊列結束時。關於其他 HPF 誘導劑，我認為我們正在更廣泛、更不可知地研究能夠誘導 HPF 的化合物。

I think it's early days in the clinic for some of the other inducers that have just entered the clinic in the last year or so, including, as you mentioned, which degrades and the Which ZBTB 7A degrader from BMS and GSK's DNMT1 inhibitor. We don't have any clinical data from those as yet, but we'll be monitoring those closely and looking for alternative ways of inducing HBF.

我認為對於去年左右剛進入臨床的一些其他誘導劑來說，臨床還處於早期階段，包括您提到的降解劑和 BMS 的 ZBTB 7A 降解劑以及 GSK 的 DNMT1 抑制劑。目前我們還沒有任何臨床數據，但我們將密切監測並尋找誘導 HBF 的替代方法。

Great, thanks so much

太好了，非常感謝

Thanks Anish

謝謝 Anish

Thank you. And I'm showing no further questions in the and Queue at this time and this concludes today's conference call. Thank you all for your participation, and you may now disconnect.

謝謝。目前，隊列中沒有其他問題，今天的電話會議到此結束。感謝大家的參與，現在您可以斷開連線了。