Fulcrum Therapeutics, Inc. (FULC) 2026 Q1 法說會逐字稿

Good morning, and welcome to Fulcrum Therapeutics first quarter 2026 financial results and business update conference call. Currently, all participants are in a listen-only mode. This call is being webcast live and can be accessed on the Investors section of Fulcrum's website at www.fulcrumtx.com and is being recorded.

早安，歡迎參加 Fulcrum Therapeutics 2026 年第一季財務業績與業務最新進展電話會議。目前所有與會者皆處於僅收聽模式。本次電話會議將進行線上即時網路直播，可於 Fulcrum 官網 www.fulcrumtx.com 的「投資人」專區收看，並將被錄音。

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

提醒各位，本次電話會議中的發言可能包含《1995 年私人證券訴訟改革法》所界定的前瞻性陳述，可能包括關於公司未來預期與計畫、臨床開發時程以及財務預測的陳述。儘管這些前瞻性陳述代表 Fulcrum 截至今日的觀點，但不應被依賴為公司未來的觀點。Fulcrum 未來可能更新這些陳述，但不承擔必須更新之義務。請參閱 Fulcrum 最近向美國證券交易委員會（SEC）提交的文件，其中討論了與公司業務相關的若干風險與不確定性。

Leading the call today will be Alex Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer; and Dr. Iain Fraser, Senior Vice President, Clinical Development. After providing updates on the company's key programs, there will be a brief Q&A in which the Fulcrum management team will be available for questions.

今天主持電話會議的是 Fulcrum 執行長兼總裁 Alex Sapir。與 Alex 一同出席的還有財務長 Alan Musso，以及臨床開發資深副總裁 Iain Fraser 醫師。在公司重點專案更新後，將進行簡短的問答環節，Fulcrum 管理團隊將回答提問。

With that, it's my pleasure to turn the call over to Alex.

接下來，很高興把電話會議交給 Alex。

That's great. Thanks, Shannon, and good morning, everyone. We appreciate you all joining us today. The first quarter of 2026 was an important and exciting period for Fulcrum, highlighted by the positive clinical data we reported from the Phase 1B PIONEER trial of pociredir in sickle cell disease.

太好了。謝謝 Shannon，大家早安。感謝各位今天加入我們。2026 年第一季對 Fulcrum 而言是重要且令人振奮的一段期間，亮點是我們公布了 pociredir 在鐮狀細胞疾病（sickle cell disease）之第 1B 期 PIONEER 試驗的正向臨床數據。

Now as a reminder, sickle cell disease is a serious genetic blood disorder with a significant unmet need affecting approximately 120,000 patients in the United States and millions more globally. Patients with sickle cell disease face a substantial disease burden, including chronic pain and fatigue as well as serious complications such as vaso-occlusive crises, stroke and progressive end organ damage, all of which result in a substantial reduction in life expectancy of over 20 years.

提醒一下，鐮狀細胞疾病是一種嚴重的遺傳性血液疾病，存在顯著未被滿足的醫療需求；在美國約影響 12 萬名患者，全球則影響數百萬人。鐮狀細胞疾病患者承受沉重的疾病負擔，包括慢性疼痛與疲勞，以及血管阻塞危象（vaso-occlusive crises）、中風與進行性終末器官損傷等嚴重併發症，這些都會使預期壽命大幅縮短超過 20 年。

Now we have known for decades that increasing levels of fetal hemoglobin, or HbF, in patients with sickle cell disease leads to improvements in anemia and reductions in vaso-occlusive pain crises. And so it was for that reason that we were so pleased with the data that we reported in February, demonstrating that after only 12 weeks of treatment, 20 milligrams of pociredir taken once daily demonstrated a robust and clinically meaningful increase in HbF from 7.1% at baseline to 19.3% at week 12, along with improvements in markers of hemolysis and improvements in anemia.

數十年來我們已知，提高鐮狀細胞疾病患者的胎兒血紅素（fetal hemoglobin，HbF）水平，可改善貧血並降低血管阻塞性疼痛危象。因此，我們在 2 月公布的數據令我們非常振奮：僅治療 12 週後，每日一次口服 20 毫克的 pociredir 使 HbF 由基線 7.1% 顯著且具臨床意義地提升至第 12 週的 19.3%，同時改善溶血指標並改善貧血。

We also observed continued progression toward pan-cellular expression of HbF, which we believe is critical for achieving meaningful clinical benefit. And importantly, we saw a reduction in the number of VOCs we would have expected in this severe patient population with 7 of the 12 patients experiencing no VOCs during the 12-week treatment period.

我們也觀察到 HbF 持續朝向全細胞（pan-cellular）表現的方向進展，我們相信這對達成具意義的臨床效益至關重要。更重要的是，在這個病情嚴重的患者族群中，我們看到血管阻塞危象（VOC）的發生次數低於預期；12 名患者中有 7 名在 12 週治療期間未出現任何 VOC。

And importantly, pociredir has continued to be generally well tolerated with no treatment-related serious adverse events reported to date. And so taken together, these data reinforce our conviction in pociredir's potential to address the underlying biology of sickle cell disease and support our belief that pociredir has the potential to represent a differentiated once-daily oral treatment option for patients.

同樣重要的是，截至目前為止，pociredir 整體耐受性仍良好，未通報任何與治療相關的嚴重不良事件。綜合而言，這些數據強化了我們對 pociredir 有潛力針對鐮狀細胞疾病根本生物學機制的信心，並支持我們相信 pociredir 有潛力成為具差異化、每日一次口服的治療選項，造福患者。

Now during the quarter, we also initiated an open-label long-term dosing trial for patients in the PIONEER study, and we recently enrolled our first patient in this new study. All patients in this long-term dosing study previously completed 12 weeks of treatment as part of the PIONEER trial therefore, we expect to provide a distinct -- we expect the study to provide a distinct data set, offering important insights into long-term safety, durability of response, and the effects of reinitiating treatment with pociredir.

本季期間，我們也啟動了針對 PIONEER 研究患者的開放標籤長期給藥試驗，並且近期已納入首位患者。所有參與此長期給藥研究的患者先前皆已完成 PIONEER 試驗中的 12 週治療；因此，我們預期該研究將提供一套獨特的資料集，帶來關於長期安全性、反應持久性，以及重新開始使用 pociredir 治療之影響的重要洞見。

We also continue to support initiatives aimed at improving the care journey for people living with sickle cell disease, including our recent collaboration with MedicAlert and the Sickle Cell Disease Association of America, or SCDAA, to help improve access to patient-specific care information in the emergency department setting.

我們也持續支持旨在改善鐮狀細胞疾病患者照護旅程的倡議，包括近期與 MedicAlert 以及美國鐮狀細胞疾病協會（Sickle Cell Disease Association of America，SCDAA）的合作，以協助在急診環境中提升取得患者個別化照護資訊的可近性。

Looking ahead, we are now focused on the next stage of clinical development for pociredir, and we expect to provide an update in the design of our next trial later this quarter following our upcoming end-of-phase meeting with the FDA and receipt of the final meeting minutes. Pending FDA feedback from that end-of-phase meeting, we plan to initiate a potential registration-enabling trial in the second half of 2026.

展望未來，我們目前聚焦於 pociredir 臨床開發的下一階段。我們預期在本季稍晚、於即將與 FDA 召開期末會議（end-of-phase meeting）並收到最終會議紀要後，更新下一項試驗的設計。視該期末會議中 FDA 的回饋而定，我們計畫於 2026 年下半年啟動一項可能具註冊支持（registration-enabling）性的試驗。

And so with a strong balance sheet that provides cash runway into 2029, we are well positioned to advance pociredir through the next phase of clinical development.

憑藉可支撐至 2029 年的強勁資產負債表與現金續航力（cash runway），我們具備良好條件推進 pociredir 進入下一階段的臨床開發。

Now before turning it over to Alan, I want to cover the two other important corporate updates. First, I want to welcome Josh Lehrer to our Board of Directors. Josh brings to Fulcrum a deep experience and passion for sickle cell disease as well as a strong track record in advancing transformative therapies in this space, including his role in the development and approval of Oxbryta. We are honored to have Josh join Fulcrum at this important stage.

在交給 Alan 之前，我想說明另外兩項重要的公司最新進展。首先，歡迎 Josh Lehrer 加入我們的董事會。Josh 對鐮狀細胞疾病具備深厚經驗與熱忱，並在推動此領域具變革性的療法方面擁有卓越紀錄，包括他在 Oxbryta 的開發與核准過程中所扮演的角色。我們很榮幸在這個重要階段迎來 Josh 加入 Fulcrum。

And secondly, I would also like to thank Alan for his years of dedication and leadership as he looks towards retirement later in the year. Alan has played a critical role in strengthening our balance sheet and instilling financial discipline across the organization, and we are grateful for his continued commitment to Fulcrum as he remains in his role until a successor is named to ensure a smooth transition.

第二，我也要感謝 Alan 多年來的投入與領導，他預計於今年稍晚退休。Alan 在強化我們的資產負債表、並在全公司建立財務紀律方面扮演關鍵角色；我們也感謝他持續對 Fulcrum 的承諾，他將在找到接任者之前持續留任，以確保順利交接。

And so with that, let me turn it over to Alan to review our financial results. And again, Alan, thanks for all you've done for Fulcrum.

那麼接下來，我把時間交給 Alan 來回顧我們的財務結果。再次感謝你為 Fulcrum 所做的一切，Alan。

Thanks, Alex, and thank you for the kind words. It's been a privilege to be part of Fulcrum's progress, and I'm proud of what we've accomplished together. With the impressive results from the PIONEER trial, a talented and motivated team, and a strong capital base, the company is well positioned to deliver transformative therapy for sickle cell patients. I look forward to continue working with the team over the coming months and ensuring a successful transition.

謝謝你，Alex，也謝謝你的美言。能參與 Fulcrum 的進展是一種榮幸，我也為我們共同完成的成果感到自豪。憑藉 PIONEER 試驗令人印象深刻的結果、一支才華洋溢且充滿動力的團隊，以及強健的資本基礎，公司已具備良好條件為鐮狀細胞患者帶來具變革性的療法。我期待在接下來幾個月持續與團隊合作，並確保交接順利成功。

And with that, I'll now go over our results for the first quarter ended March 31, '26. Research and development expenses were $14.1 million for the first quarter of 2026 compared to $13.4 million for the first quarter of 2025. The increase of $700,000 was primarily driven by higher employee compensation costs, including $400,000 of increased stock-based compensation expense.

接下來我將說明截至 2026 年 3 月 31 日止第一季的業績。2026 年第一季研發費用為 1,410 萬美元，較 2025 年第一季的 1,340 萬美元增加。增加的 70 萬美元主要由較高的員工薪酬成本所帶動，其中包括增加 40 萬美元的以股份為基礎之薪酬費用。

General and administrative expenses were $8.1 million for the first quarter of 2026 compared to $7 million for the first quarter of 2025. The increase of $1.1 million was primarily driven by higher employee compensation costs, including $300,000 of increased stock-based compensation expense as well as higher professional services costs. The net loss (sic – see press release, "loss from operations") was $22.2 million for the first quarter of 2026 compared to a net loss (sic – see press release, "loss from operations") of $20.4 million for the first quarter of 2025.

2026 年第一季一般及行政費用為 810 萬美元，較 2025 年第一季的 700 萬美元增加。增加的 110 萬美元主要由較高的員工薪酬成本所帶動，其中包括增加 30 萬美元的以股份為基礎之薪酬費用，以及較高的專業服務成本。2026 年第一季淨損（原文註記：sic – 見新聞稿「營運損失」）為 2,220 萬美元，較 2025 年第一季淨損（原文註記：sic – 見新聞稿「營運損失」）2,040 萬美元增加。

Now turning to the balance sheet. We ended the first quarter of 2026 with cash, cash equivalents, and marketable securities of $333.3 million compared to $352.3 million as of December 31, 2025. The $19 million decrease was primarily due to cash used to fund our operating activities. And based on our current plans, we expect our existing cash, cash equivalents and marketable securities will be sufficient to fund our operating requirements into 2029, providing runway to advance pociredir through the next phase of clinical development.

接著看資產負債表。2026 年第一季末，我們的現金、約當現金及有價證券為 3.333 億美元，較 2025 年 12 月 31 日的 3.523 億美元下降。減少的 1,900 萬美元主要由用於支應營運活動的現金所致。基於我們目前的計畫，我們預期現有的現金、約當現金及有價證券將足以支應我們至 2029 年的營運需求，提供推進 pociredir 進入下一階段臨床開發的資金續航力。

And with that, I'll turn it back over to you, Alex.

那麼，我把時間交還給你，Alex。

That's great. Thanks so much, Alan. So Fulcrum has reached an important inflection point. With the positive clinical data from our PIONEER trial, reinforcing our conviction in pociredir's potential in sickle cell disease. We are focused on the next stage of development and look forward to providing an update on our plans following our upcoming end-of-phase meeting with the FDA. And with a strong balance sheet and a dedicated team, we believe we are well positioned to advance pociredir through the next phase of clinical development.

太好了。非常感謝你，Alan。因此，Fulcrum 已經到達一個重要的轉折點。PIONEER 試驗的正向臨床數據進一步強化了我們對 pociredir 在鐮狀細胞疾病中潛力的信心。我們正專注於下一階段的開發，並期待在即將與 FDA 召開期末會議（end-of-phase meeting）後，就我們的計畫提供最新進展。此外，憑藉強健的資產負債表與投入的團隊，我們相信自己已具備良好條件，能推進 pociredir 進入下一階段的臨床開發。

And so with those brief remarks, Shannon, why don't we go ahead and open up the line for questions.

那麼，以上是簡短的說明。Shannon，我們現在就開放電話線進行提問吧。

Joe Schwartz, Leerink Partners.

Joe Schwartz，Leerink Partners。

Alan, congrats on your upcoming retirement, and thanks for your excellent stewardship of the company over the years.

Alan，恭喜你即將退休，也感謝你多年來對公司卓越的領導與管理。

Alex, as you reflect on the experience gained through PIONEER, what are the most important things you've learned that you might not have fully appreciated going in? And how will those lessons shape your Phase 3 design and execution?

Alex，回顧你們在 PIONEER 中累積的經驗，你認為最重要、且在進入試驗前可能沒有完全意識到的收穫是什麼？這些經驗將如何影響你們第三期試驗的設計與執行？

Yeah. It's a great question, Joe. And I may start, and I'll also turn it over to Iain to see if he wants to add anything. I mean, I think the one thing that I've really learned from PIONEER and talking with a lot of the investigators and hearing from those investigators, the conversations that they've had with their patients is that there continues to be a continued high, high, high unmet need in this patient population, especially in the severe patient population that we studied in the PIONEER trial and the severe patient population that we would expect to continue in our next phase of clinical development. I would say that's learning number one.

是的。這是個很好的問題，Joe。我先回答，之後也會請 Iain 看看是否要補充。我認為我從 PIONEER、以及與許多研究者交流、聽他們分享與病患對話內容中學到的一點是：在這個病患族群中仍然存在非常、非常、非常高的未被滿足醫療需求，尤其是在我們於 PIONEER 試驗中研究的重症病患族群，以及我們預期在下一階段臨床開發中仍會延續的重症族群。我會說這是第一個收穫。

I would say learning number two is that there is such a strong connection between fetal hemoglobin and reduction in VOCs. And we've known this for a long time, but spending time as much as I have with people like Marty Steinberg, who has spent decades researching the underlying biology of fetal hemoglobin. He says it just so succinctly and he's just so simple in his explanation in that if you can increase fetal hemoglobin, you're going to see a reduction in VOC, you're going to see an improvement in anemia because of an increase in total hemoglobin because you're seeing less hemolysis.

第二個收穫是：胎兒血紅蛋白（HbF）與 VOC 減少之間有非常強的連結。我們早就知道這點，但我花了很多時間與像 Marty Steinberg 這樣的人交流——他花了數十年研究胎兒血紅蛋白的基礎生物學。他的說法非常精煉、解釋也很簡單：如果你能提高胎兒血紅蛋白，就會看到 VOC 的降低；也會看到貧血改善，因為總血紅蛋白上升，因為溶血減少。

And so I think it's really -- to me, Joe, it's those two things taken together, one related to the unmet need of the patient population and secondarily is what we think is a very, very profound and robust induction of fetal hemoglobin. That's really, I think, what continues to motivate me and make me excited for the next phase of this asset's journey along the clinical development timeline.

所以我認為，對我來說，Joe，這兩點合在一起——一是與病患族群的未被滿足需求相關，二是我們認為胎兒血紅蛋白有非常、非常顯著且強勁的誘導效果——這正是持續驅動我、也讓我對這項資產在臨床開發時程中下一階段的旅程感到興奮的原因。

Iain, you've obviously been pretty deeply involved with PIONEER as well. Anything you would want to add to that?

Iain，你顯然也很深入參與 PIONEER。你還有什麼想補充的嗎？

I think you captured it very well, Alex. It's the severity of the disease and the manifestations experienced by these patients coupled with the really high unmet need in terms of available therapies for the patients. And I think on a daily basis, we continue to be reminded of that.

我認為你總結得很好，Alex。就是疾病的嚴重性與這些病患所經歷的各種表現，再加上就現有可用治療而言非常高的未被滿足需求。我想我們每天都不斷被提醒這一點。

Okay. Great. Thanks. And then as you approach discussions with the FDA, what level of evidence do you think they might require in order to consider HbF as a reasonably likely surrogate endpoint for accelerated approval? And how do you plan to position what you've seen efficacy and safety-wise for pociredir so far in terms of that clinical profile to support your case?

好的。很好。謝謝。接著，當你們準備與 FDA 討論時，你認為他們可能需要什麼程度的證據，才會考慮將 HbF 作為加速核准（accelerated approval）中「合理可能」的替代終點（surrogate endpoint）？另外，你們打算如何就目前為止在 pociredir 的療效與安全性所見，來定位其臨床特徵，以支持你們的論點？

Yeah. It's a great question, Joe. And obviously, Iain has been very, very deep in those preparation for our upcoming meeting. So I think to answer that, let me turn that one over to Iain.

是的。這是個很好的問題，Joe。而且很明顯 Iain 在為我們即將到來的會議做準備方面投入得非常、非常深。所以為了回答這題，我把它交給 Iain。

Yeah. Thanks, Alex. Thanks, Joe. I think there's really substantial published literature that demonstrates the association between higher HbF levels and improved clinical outcomes in sickle cell disease. And as we've discussed previously and again, today, that biological relationship is really a key part of the underlying rationale for our program overall.

好的，謝謝，Alex。謝謝你，Joe。我認為已有相當大量的已發表文獻顯示：較高的 HbF 水準與鐮狀細胞疾病中較佳的臨床結果之間存在關聯。正如我們先前以及今天再次討論的，這個生物學關係確實是我們整體計畫背後基本原理的關鍵部分。

Of course, the role that HbF could play in terms of the regulatory framework is one that is going to be a topic of discussion with regulators to understand their perspective on the appropriate path forward. Our focus remains on designing a robust study that can meaningfully demonstrate clinical benefit, and we hope to align with the regulators on the optimal strategy around that.

當然，HbF 在法規框架中可能扮演的角色，將會是我們與監管機關討論的主題之一，以了解他們對於適當前進路徑的看法。我們的重點仍是設計一項穩健的研究，能夠有意義地證明臨床效益；我們也希望能與監管機關就此達成一致，找出最佳策略。

Anupam Rama, JPMorgan.

Anupam Rama，JPMorgan。

Alan, best wishes on the retirement, man. So at the Sickle Cell Disease Research Symposium, will there be any new analysis that will be presented relative to the 1Q corporate update for PIONEER?

Alan，祝你退休一切順利。那麼在鐮狀細胞疾病研究研討會（Sickle Cell Disease Research Symposium）上，是否會相較於 PIONEER 第一季公司更新（1Q corporate update）呈現任何新的分析？

And I know -- second question, I know that the first patients have been dosed in the OLE portion of the Phase 1B. What portion of the patients from PIONEER went to the OLE? And could we see that update maybe around ASH?

另外第二個問題，我知道在第一期 B（Phase 1B）的 OLE 部分已經有首批病患完成給藥。PIONEER 中有多少比例的病患進入了 OLE？我們是否可能在 ASH 左右看到更新？

Yeah. Maybe let me -- I'll answer the second question, and then Iain, I can turn it over to you to answer the first question. Yes. So we have enrolled our first patient in this open-label long-term dosing for pociredir. Right now, Anupam, we're targeting the 17 US-based patients that were enrolled in either Cohort 3b and that was the 12-milligram cohort, or Cohort 4, which was the 20-milligram cohort.

是的。也許我先回答第二個問題，然後 Iain，我再把第一個問題交給你。是的，我們已在這項針對 pociredir 的開放標籤長期給藥（open-label long-term dosing）中納入第一位病患。目前，Anupam，我們的目標是 17 位美國受試者，他們先前在 Cohort 3b（12 毫克劑量組）或 Cohort 4（20 毫克劑量組）中入組。

And so right now, really, our focus has really been on getting those sites activated. Unfortunately, this is not your sort of traditional OLE study where patients roll right over. This is considered a new study. And so it has to go through the same mechanics of any new protocol that gets introduced to an institution. So that obviously takes a bit of time.

因此目前，我們的重點其實是在啟動這些研究中心。不幸的是，這不是那種傳統的 OLE 研究、病患可以直接無縫銜接進入的模式。這被視為一項新的研究，因此必須走完任何新方案在機構導入時所需的相同流程。這顯然需要一些時間。

I think it's a little difficult to project when we would have patients of those 17 patients enrolled in this open-label long-term dosing for pociredir. We don't think we'll get all of them. Some may be lost to follow-up, some may be in other clinical trials. But I think given what we've heard from investigators in terms of the interest level in going back on therapy, we should expect to see a decent number of that 17.

我覺得要預測這 17 位病患何時能完成入組、進入這項針對 pociredir 的開放標籤長期給藥研究，有點困難。我們不認為能全部納入。有些可能失訪，有些可能參與其他臨床試驗。但根據我們從研究者那裡聽到的、病患對重新接受治療的興趣程度，我們應該會看到這 17 人中有相當數量參與。

If you ask me to try to predict, is ASH possible? I'd say it's probably going to be sometime in 2027 before we would have a critical mass of patients enrolled in order to be able to see a duration of therapy that is going to be a meaningful interesting and new data point. We've seen what happens to this therapy when patients are dosed for 12 weeks.

如果你要我預測 ASH 是否有可能，我會說：可能要到 2027 年某個時間點，我們才會累積到足夠的入組人數，能觀察到具有意義、且有趣的新數據點所需的治療期間。我們已經看過病患接受 12 週給藥時這項治療的表現。

I think what's going to be really interesting is what happens when patients are dosed for longer 24 weeks or 6 months. And so that would probably be the first data set that we would share with folks. And so more than likely, that probably would happen sometime in 2027 as opposed to ASH 2026.

我認為真正有趣的是：當病患接受更長時間的給藥——24 週或 6 個月——會發生什麼。因此，那大概會是我們第一個會對外分享的資料集。更有可能是在 2027 年某個時間點，而不是 ASH 2026。

There is a second question.

還有第二個問題。

Yes. This is Iain. I can handle that one. So we've indicated that we expect to provide a fulsome reporting of the entire PIONEER study at a medical conference later this year. We have not provided details on that as yet. As we indicated in the press release, the FSCDR symposium oral abstract will include previously disclosed clinical data.

是的。我是 Iain。我來回答那題。我們已表示，預期會在今年稍晚的一場醫學會議上，對整個 PIONEER 研究做完整（fulsome）的報告。我們目前尚未提供相關細節。如同我們在新聞稿中所述，FSCDR 研討會的口頭摘要將包含先前已披露的臨床數據。

Kristen Kluska, Cantor.

Kristen Kluska，Cantor。

Let me also add my congrats to Alan for a great career in biotech and pharma, including the accomplishments at Fulcrum. The first question I had for you was just on broadly understanding the latest views coming from FDA. I know there's been several workshops, including at ASH. I know the team has met with some thought leaders in Washington, DC. So bigger picture without specifically honing in on Fulcrum's path forward, what's the latest you've been hearing from these thought leaders about how they're thinking about sickle cell disease as an indication, the unmet need, and just receptiveness to hearing about new drug classes?

我也想向 Alan 表達祝賀，恭喜你在生技與製藥領域的精彩職涯，包括在 Fulcrum 的各項成就。我第一個問題是，想更廣泛地了解 FDA 近期釋出的觀點。我知道已經有好幾場研討會，包括在 ASH 期間；也知道團隊在華盛頓特區與一些意見領袖會面。從更宏觀的角度、先不特別聚焦 Fulcrum 的前進路徑，你最近從這些意見領袖那裡聽到的最新看法是什麼？他們如何看待鐮狀細胞疾病這個適應症、未被滿足需求，以及對於聽取新藥物類別的接受度？

Yeah. It's a great question, Kristen. And I'll start, and Iain, you may want to add some thoughts as well. And I'll sort of -- I'll break the question up into two pieces. What are we hearing and what are we doing with folks on the Hill? And then what are we hearing and seeing at the FDA?

是的。這是個很好的問題，Kristen。我先回答，Iain 你也可以再補充一些想法。我會把這個問題大致拆成兩個部分：我們在國會山莊那邊聽到什麼、以及我們和山上的人士在做什麼；然後是我們在 FDA 那邊聽到與看到什麼？

I think what we -- and I personally have been spending a lot of time in Washington, DC. Kristen is referencing a very interesting program that she attended in which we provided a congressional briefing to staffers of Senators and Congressmen just several weeks ago in Washington, DC, where we really talked about the unmet need. We had a couple of patients talk about their journey, and it was a standing room only. And towards certain parts of the meeting, there were very few dry eyes in the house.

我想我們——而且我個人最近花了很多時間在華盛頓特區。Kristen 提到她參加了一個非常有意思的活動；就在幾週前在華盛頓特區，我們向參議員與眾議員的幕僚做了一場國會簡報，重點談到未被滿足的醫療需求。我們也請了幾位病患分享他們的歷程，現場座無虛席。而在會議某些段落，幾乎沒有人不落淚。

And so I think that what the politicians understand is that sickle cell continues to be a disease with very high unmet need with shortened life expectancy of 20 years, not to mention during their time here, experiencing very debilitating pain crises, and organ damage, leg ulcers, I could go on and on.

因此我認為政治人物理解到的是：鐮狀細胞疾病仍然是一種未被滿足醫療需求非常高的疾病，預期壽命縮短 20 年；更不用說在他們的人生期間，還會經歷非常折磨人的疼痛危象、器官損傷、腿部潰瘍等等，我可以一直列下去。

And so I think that it's important that the senators and congressmen on the Sickle Cell Disease Caucus, on the Rare Disease Caucus, and on the Doc Caucus, they understand that and can help sort of lend their support in terms of how high the unmet need is in this patient population. So I'd say that's, I would say, on the -- more on the Hill side.

所以我認為很重要的是，鐮狀細胞疾病國會小組（Sickle Cell Disease Caucus）、罕見疾病國會小組（Rare Disease Caucus）以及醫師國會小組（Doc Caucus）的參議員與眾議員能理解這點，並在支持這個病患族群未被滿足需求之高方面提供協助。我想這部分比較偏向國會山莊那一側。

I think on the FDA side, I would point you to Agios' recent press release that showed that they will be moving forward with filing an sNDA in the coming months for sickle cell disease with mitapivat. And we think that what that shows is an understanding of how high the unmet need is and potentially some regulatory flexibility to try to get drugs to patients as quickly as we can.

我想在 FDA 這一側，我會請你參考 Agios 最近的新聞稿，內容顯示他們將在未來幾個月推進 mitapivat 用於鐮狀細胞疾病的 sNDA 申請。我們認為這顯示主管機關理解未被滿足需求之高，並可能在法規上具備一定彈性，讓藥物能盡快送到病患手上。

These drugs obviously have to be not only effective, but they need to be safe. And so we're obviously very excited and looking forward to engaging with the FDA in our upcoming end-of-phase meeting.

當然，這些藥物不僅要有效，也必須安全。因此我們非常期待，並且很期待在即將到來的期末會議（end-of-phase meeting）與 FDA 互動。

Iain, anything you would want to add to that?

Iain，你有什麼想補充的嗎？

No, I think you've covered the key points really well, Alex. Given the severity of the disease and the unmet need, I think the recent progress in the sickle cell disease landscape is very encouraging for the field, and we look forward to moving forward our program with pociredir.

沒有，我覺得你已經把重點講得很完整了，Alex。考量到疾病的嚴重性與未被滿足的需求，我認為近期鐮狀細胞疾病領域的進展對整個領域非常令人鼓舞，我們也期待推進我們的 pociredir 計畫。

Thank you. And then my other question is just focusing in a little bit more on the open-label extension. Obviously, you want to understand the longer-term impacts on both safety and efficacy. But I'm curious if there are any endpoints in particular, you're really trying to understand the longer-term efficacy. So are there certain endpoints that maybe take a little bit longer for the benefits to occur where a trial longer than 12 weeks potentially might give you some insight?

謝謝。那我另一個問題是更聚焦在開放標籤延伸試驗（open-label extension）。顯然你們想了解安全性與有效性的長期影響。但我好奇的是，在長期有效性方面，有沒有特別想了解的終點？也就是說，是否有些終點可能需要更久才會出現效益，因此超過 12 週的試驗可能會提供一些洞見？

Yeah. Kristen, that's a great question. I think to answer that, I will turn that one over to Iain, who has been deeply involved in the design as well as the execution of the open-label long-term dosing study that -- for which we've enrolled our first patient. Iain?

是的。Kristen，這是個很好的問題。要回答這題，我想把問題交給 Iain；他深度參與了這項開放標籤長期給藥研究的設計與執行——我們也已經納入了第一位受試者。Iain？

Yeah. Thanks, Alex, and thanks, Kristen. So as we've indicated before, at the 12-week treatment duration with pociredir, the HbF levels are starting to flatten out, but we don't believe they've reached their peak level at that point. And so one of the outcomes of the study that we'll be very much interested in is to see the progression beyond that 12-week mark.

好的，謝謝 Alex，也謝謝 Kristen。如同我們先前提到的，在使用 pociredir 治療 12 週時，HbF 水平開始趨於平緩，但我們不認為那時已達到峰值。因此，本研究我們非常感興趣的一個結果，是觀察超過 12 週之後的變化趨勢。

And then downstream of the HbF, as we've seen with other hematological markers, markers of hemolysis in particular, but also the increase in total hemoglobin that we've seen. Those are probably not maxed out either at that point. And with a longer duration of increased HbF, we would expect to see further improvements in those markers. So I think it's looking at how that response plays out over a longer treatment period.

接著在 HbF 的下游，如同我們在其他血液學指標所看到的，特別是溶血指標，以及我們觀察到的總血紅素上升；這些在那個時間點可能也尚未達到最大值。隨著 HbF 在更長期間維持升高，我們預期這些指標會進一步改善。所以我認為重點在於觀察這個反應在更長治療期間如何展開。

Having said that, I think it is important, and Alex alluded to this earlier, that these patients have been off pociredir for some time. So it's not the traditional open-label extension, where they roll over immediately into that. So they'll be starting from a new baseline. But it's the extended dosing duration in particular that we're interested in tracking.

不過我也要說，這點很重要——Alex 先前也提到——這些病患已經停用 pociredir 一段時間。因此這不是傳統那種立即銜接的開放標籤延伸試驗（roll over）。他們會從新的基線開始。但我們特別有興趣追蹤的是延長給藥期間本身。

Corinne Johnson, Goldman Sachs.

Corinne Johnson，高盛。

Congratulations to Alan as well from all of us in terms of the retirement. Maybe a question for us on just kind of the competitive landscape and evolving treatment landscape in sickle cell disease. I guess, could you help us think through the role you expect pociredir to play, particularly if there's more kind of oral medications that come to market over the next couple of years?

也代表我們大家恭喜 Alan 退休。我的問題可能是關於鐮狀細胞疾病的競爭格局與治療版圖的演變。你們能否協助我們思考一下，你們預期 pociredir 會扮演什麼角色，特別是在未來幾年可能會有更多口服藥物上市的情況下？

Sure, absolutely. I'll start and then, Iain, you may want to add some additional points that I maybe leave off. So yeah, I think the way we think about this, Kristen (sic – Corinne), is there's sort of oral -- and it's interesting. This market is one that I think will grow exponentially over the next 5 to 10 years. If you look at just the sheer number of drugs in development for the treatment of sickle cell disease.

當然可以。我先回答，然後 Iain 你也可以補充一些我可能漏掉的重點。所以是的，我們看待這件事的方式，Kristen（口誤——Corinne），是口服——而且很有意思。我認為這個市場在未來 5 到 10 年會呈指數型成長，如果你看看目前正在開發、用於治療鐮狀細胞疾病的藥物數量就知道。

This is a market -- a very large market that has been underserved for years and years. And so I think the way that we see this market evolving is very much towards the oral treatment options. And there's really -- to us, we think about this as sort of two different approaches. One is sort of operating downstream on the mature red blood cells like the PK activators do.

這是一個——非常大的市場，多年來一直被忽視、服務不足。因此我們認為這個市場的演變方向會非常明顯地走向口服治療選項。對我們而言，基本上可分成兩種不同的策略：一種是像 PK 活化劑那樣，作用在下游、針對成熟紅血球。

And the second is operating more upstream when those red blood cells are being formed in the bone marrow and ensuring that those red blood cells have enough fetal hemoglobin as they're being formed because once those red blood cells have enough fetal hemoglobin and are formed and do get spit out of the bone marrow, those red blood cells cannot and will not sickle. They maintain their salt flexible shape, thereby preventing vaso-occlusive crises. They have a lifespan of about 120 days versus a 30-day lifespan for a sickled hemoglobin.

第二種則是更上游地作用，在紅血球於骨髓形成時介入，確保紅血球在形成過程中具有足夠的胎兒血紅素；因為一旦紅血球在形成時就有足夠的胎兒血紅素，並且從骨髓釋放到周邊血液後，這些紅血球就不會、也不能發生鐮化。它們會維持柔韌的形狀，從而預防血管阻塞危象。其壽命約 120 天，相較之下，鐮化血紅素的紅血球壽命約 30 天。

And so for us, we think that really attacking the upstream underlying cause of the disease as we're doing with pociredir, we believe that that will ultimately be the treatment of choice as we look over the next 5 to 10 years as this market evolves.

因此對我們來說，像我們以 pociredir 所做的那樣，真正去攻擊疾病上游的根本原因，我們相信隨著未來 5 到 10 年市場演變，這最終會成為首選治療方式。

Now where we are in relation to some of those other fetal hemoglobin inducers, conservatively, we believe that we have about a 24-month head start over the next closest competitor, and that next closest oral HbF inducer would be BMS' product, BMS-986 (sic – BMS-986470), which is a WIZ, a dual degrader WIZ and ZBTB7A or LRF for sort.

至於我們相對於其他胎兒血紅素誘導劑的位置，保守估計，我們認為相較於下一個最接近的競爭者，我們大約領先 24 個月；而下一個最接近的口服 HbF 誘導劑會是 BMS 的產品 BMS-986（口誤——BMS-986470），它是一種 WIZ 的雙重降解劑（dual degrader），同時針對 WIZ 與 ZBTB7A（或簡稱 LRF）。

So they'll be -- they're currently in the clinic in a Phase 1 study, and they expect to announce the results of that Phase 1 study sometime in -- I think it's the first quarter, the first half of 2027. So we'll be well underway, we believe, with our Phase 3 study, while the next closest competitor, BMS is reporting out their Phase 1 study results in 2027.

所以他們——目前正在進行一期臨床研究，並預期在——我想是 2027 年第一季或上半年——公布該一期研究結果。屆時我們相信，我們的三期研究將已經進行得相當深入，而最接近的競爭者 BMS 則是在 2027 年才會公布他們的一期結果。

And so maintaining that two-year head start so that when we come to market, we could have this market essentially without other oral HbF competitors, we believe that that's an important consideration that we want to make sure that we maintain that 24-month head start.

因此維持這個兩年的領先優勢，讓我們在上市時基本上能在沒有其他口服 HbF 競品的情況下進入市場；我們認為這是一個重要考量，我們也希望確保能維持這 24 個月的領先。

Iain, anything else you would want to add about the competitive landscape and how we see this market evolving over time?

Iain，關於競爭格局以及我們如何看待這個市場隨時間演變，你還有什麼想補充的嗎？

I think you mentioned the key points, Alex. I think the focus of the PK activators is on the increases in total hemoglobin resulting from a decrease in hemolysis and agree that the HbF mechanism, I think, has emerged as a more central, more upstream mechanism to address more widely manifestations of sickle cell disease. I think we're seeing that reflected in the interest in the clinic in sponsors that are bringing forward oral HbF inducers.

我認為你已經提到關鍵重點了，Alex。我想 PK 活化劑的重點在於透過降低溶血來提升總血紅素；我也同意 HbF 機制似乎已成為更核心、更上游的機制，能更廣泛地處理鐮狀細胞疾病的各種表現。我們也看到這點反映在臨床上的興趣上：有越來越多贊助方在推進口服 HbF 誘導劑。

James Condulis, Stifel.

James Condulis，Stifel。

I'll add my congrats as well, Alan. Maybe just one sort of kind of on the competitive landscape and all these regulatory dynamics. Novo recently hit on a VOC endpoint. And just curious if you think that changes anything at all as it relates to the potential regulatory path for you. And if the drug were to be approved on VOCs, does that sort of change what the FDA may be open to approving as it relates to endpoints that are not a VOC endpoint? Just curious your perspectives there.

Alan，我也要向你致上祝賀。想請教一個關於競爭格局以及這些監管動態的問題。Novo 最近在 VOC 終點上達標。想請問你是否認為這會對你們潛在的監管路徑帶來任何改變。以及如果該藥物是以 VOC 作為終點而獲批，這是否會改變 FDA 對於核准非 VOC 終點的態度或可能性？想聽聽你們的看法。

Yeah. James, great question. Maybe just to orient everybody, they did have a co-primary total hemoglobin and VOCs, and they hit on that. It was a 27% reduction in vaso-occlusive crisis. So very similar to the percent reduction in VOCs that we saw with another product that's currently approved and generally not widely used, a product called L-Glutamine that saw a 25% reduction in VOCs.

是的。James，問得很好。先幫大家簡單對齊一下背景：他們的共同主要終點是總血紅蛋白與 VOC，而他們達標了。血管阻塞危機（vaso-occlusive crisis）降低了 27%。這與另一個目前已獲批、但一般並未被廣泛使用的產品所看到的 VOC 降幅非常相近；那個產品叫 L-麩醯胺酸（L-Glutamine），其 VOC 降幅為 25%。

So I wanted just to make sure that everybody was on the call was oriented to specifically what James was talking about. Iain, maybe I'll have you sort of take the heart of James's question, which is really around if there's any potential sort of read-through with pociredir and our path forward.

所以我只是想確保所有與會者都清楚 James 具體在談什麼。Iain，也許我請你來回答 James 問題的核心，也就是這是否對 pociredir 以及我們後續路徑有任何可推論的影響。

Iain?

Iain？

Yeah. I think the fact that VOCs is an important clinical endpoint, I think, remains the case. I don't think there's any change in that. I think as we've discussed before, the literature associating increases in fetal hemoglobin with reductions in VOCs certainly remains the case.

是的。我認為 VOC 是一個重要的臨床終點，這點依然成立。我不認為這方面有任何改變。正如我們之前討論過的，文獻中將胎兒血紅蛋白（HbF）增加與 VOC 減少連結起來的證據，仍然是成立的。

And given the magnitude of HbF induction that we've seen in the PIONEER study to date, both at the 12 and the 20-milligram doses, we would expect that that would translate into a VOC benefit. And I think that remains an important clinical endpoint.

而且，基於我們迄今在 PIONEER 研究中看到的 HbF 誘導幅度，無論是 12 毫克或 20 毫克劑量，我們預期這會轉化為 VOC 的臨床獲益。我認為這仍然是一個重要的臨床終點。

Matthew Biegler, OpCo.

Matthew Biegler，OpCo。

Congrats to you, Alan, as well. Maybe just piggybacking on some of the -- an earlier comment that you made, Alex. I'm thinking about maybe potential future combination strategies here. And you mentioned PKR activators and some of the other, quote-unquote, downstream treatments, where you guys are more upstream and maybe that makes logical sense. So it sounds to me like maybe there might be a better partner for you than hydroxyurea. Have you given any thoughts to that?

也恭喜你，Alan。延續你先前的一些評論，Alex。我在想未來可能的聯合治療策略。你提到 PKR 活化劑以及其他一些所謂「下游」治療，而你們更偏「上游」，這在邏輯上似乎合理。所以聽起來，對你們而言，可能會有比羥基脲（hydroxyurea）更好的合作夥伴。你們有思考過這點嗎？

Yeah. It's a really good question, Matt. And Iain, I may turn this over to you, but I think just maybe just a couple of initial thoughts. So hydroxyurea has been approved now for -- coming over 40 years. It is clearly the mainstay. I think that patients at times aren't crazy about it. It doesn't have a great sort of adherence to drug because of some of the side effects associated with it.

是的，Matt，這是個非常好的問題。Iain，我可能把這題交給你，不過我先說幾點初步想法。羥基脲已獲批超過 40 年，顯然是治療的基石。不過患者有時並不太喜歡它；由於一些相關副作用，用藥依從性並不理想。

But despite that, it is very much the mainstay. And so I think our long-term development strategy has always been to figure out a path forward for us to be used in combination with hydroxyurea. We don't believe that that will be part of the design that we will reach agreement on with the FDA as part of our upcoming end-of-phase meeting with them. But we do see that as an important part of the ongoing clinical development program for pociredir.

但即便如此，它仍然是非常重要的基石療法。因此，我們的長期開發策略一直是找出一條路徑，讓我們能與羥基脲聯合使用。我們不認為這會成為我們即將與 FDA 進行期末（end-of-phase）會議、並達成一致的試驗設計的一部分；但我們確實認為，這會是 pociredir 持續臨床開發計畫中很重要的一環。

Yeah. I think, Iain, maybe if you want to take kind of maybe just beyond HU, -- is there the idea of possibly combining an HbF inducer with potentially a PK activator or potentially operating on different mechanisms and potentially seeing greater efficacy than either one could achieve on their own?

是的。我想，Iain，也許你可以談談超越 HU 之外的部分——是否有可能把 HbF 誘導劑與 PK 活化劑聯合，或是透過不同機制作用，從而看到比任何單一療法更高的療效？

Yeah, absolutely. We've certainly seen that in other fields, and that certainly remains a potential in this disease, which has so many manifestations that are so severe. I think as we think of those, however, our primary objective at the moment really is to generate an interpretable data set with pociredir that will support its registration. And I think understanding in the context of monotherapy is really the first step in that journey, so that we really have a full understanding of that and that we could then give serious consideration to how do we evaluate potential combination therapies down the road.

是的，完全有可能。我們在其他領域確實看過這種情況，而在這個疾病中也仍然存在這樣的潛力；這個疾病有非常多且非常嚴重的表現。不過，當我們思考這些可能性時，我們目前的首要目標其實是產生一套可解讀的 pociredir 數據集，以支持其註冊申請。我認為先在單藥治療（monotherapy）的情境下理解它，是這段旅程的第一步，如此我們才能真正全面理解，並在未來認真評估如何檢驗潛在的聯合療法。

Yeah. I think that's well said, Iain.

是的。我覺得你說得很好，Iain。

Gregory Renza, Truist Securities.

Gregory Renza，Truist Securities。

And also let me add my congratulations to Alan on his service at Fulcrum and in the industry. Alex, I know, of course, that the focus is on pociredir, but I'm just curious when you see the time being right to potentially advance or nominate some of the discovery programs and think about the novel HbF inducers that you may have in the library.

我也要祝賀 Alan 在 Fulcrum 以及在整個產業中的服務。Alex，我知道焦點當然是在 pociredir，但我想請教，你認為什麼時候會是合適的時點，去推進或提名一些探索性研發（discovery）專案，並思考你們資料庫中可能有的新型 HbF 誘導劑？

And then maybe secondarily, as we think about the FDA meetings upcoming, can you just give us an update on the engagement plans with respect to EMA and the global development?

另外，關於即將與 FDA 的會議，能否也請你更新一下與 EMA 的互動規劃，以及全球開發策略？

Sure. I'll take the first question, and Iain, I'll turn the second question over -- actually, Iain, why don't you -- if you want -- do you want to take the second question first?

當然。我先回答第一個問題，第二個問題我交給 Iain——其實 Iain，你要不要先回答第二個問題？

Yeah, yeah. Happy to do that. Thanks, Greg. So as we've indicated before, the context of a registrational sickle cell disease study is likely to be a global study. And we've indicated that we will be interacting with EMA later this year as part of that process. So that's certainly the first step on looking more globally and getting additional feedback on the program.

好，好。我很樂意。謝謝你，Greg。正如我們之前所提到的，作為註冊性（registrational）的鐮狀細胞疾病研究，其情境很可能會是一項全球性研究。我們也表示過，作為該流程的一部分，我們將在今年稍晚與 EMA 互動。這當然是朝更全球化方向、並就該計畫取得更多回饋的第一步。

Yeah, it's great. And then yeah, I think, Greg, in terms of your first question, our discovery efforts, so we're a company of about 60, 65 people. We've got 20, 25 people focused entirely on discovery. And then within their discovery work, they are focused entirely on developing the second, third, and fourth generation oral HbF inducer.

很好。然後，Greg，關於你的第一個問題，也就是我們的探索性研發工作：我們公司大約有 60 到 65 人，其中有 20 到 25 人完全專注於探索性研發。而在他們的探索性研發工作中，他們完全聚焦於開發第二代、第三代與第四代的口服 HbF 誘導劑。

And so that has really been our key area of focus because we -- again, going back to something that I said earlier, we do believe that this is a market that ultimately will be dominated by oral fetal hemoglobin inducers because of the reasons that I mentioned earlier. And so we're thinking about how can we develop a product that potentially could cannibalize pociredir once it eventually hits the market.

因此，這一直是我們的核心聚焦領域，因為——回到我先前提到的一點——我們確實相信，基於我之前提到的原因，這個市場最終將由口服胎兒血紅蛋白誘導劑所主導。因此，我們在思考的是：我們如何開發一個產品，在未來一旦 pociredir 上市後，可能會反過來侵蝕（cannibalize）pociredir 的市場。

I think at this point, it's a little bit premature, Greg, to kind of estimate when we would start seeing things coming out of our discovery efforts and conducting those IND-enabling studies. But I will say that in the coming years, what we believe we will see is a number of new INDs almost entirely focused on trying to come out with an even better oral HbF inducer than what we currently have with pociredir, given how we see this market evolving over the next 5 to 10 years.

我認為在這個時間點，Greg，要去估計我們何時會開始看到探索性研發成果、並啟動那些 IND 申請前（IND-enabling）的研究，可能還有點太早。不過我想說的是，在未來幾年，我們相信會看到多個新的 IND，而這些幾乎都會聚焦於：在我們看待未來 5 到 10 年市場演變的前提下，嘗試推出一個比我們目前的 pociredir 更好的口服 HbF 誘導劑。

Thank you. And I'm currently showing no further questions at this time. Thank you, everyone, for your participation on today's call. This does conclude the conference. Thank you, and you may now disconnect.

謝謝。目前我這邊顯示暫無其他提問。感謝各位參與今天的電話會議。本次會議到此結束。謝謝，您現在可以掛線。