Fulcrum Therapeutics Inc (FULC) 2023 Q3 法說會逐字稿

Good morning, and welcome to Fulcrum Therapeutics Third Quarter 2023 Financial Results and Business Update Conference Call. (Operator Instruction] This call is being webcast live on the Investors section of Fulcrum's website at www.fulcrumtx.com and is being recorded.

早安，歡迎參加 Fulcrum Therapeutics 2023 年第三季財務業績和業務更新電話會議。 （操作員說明）本次電話會議正在 Fulcrum 網站 www.fulcrumtx.com 的投資者部分進行網路直播並進行錄音。

Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development time lines and financial projections. While these forward-looking statements represent Fulcrum views 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 is not taking on any obligation to do so. Please refer to Fulcrum's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

請注意，本次電話會議期間發表的言論可能包含 1995 年《私人證券訴訟改革法案》含義內的前瞻性陳述。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。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 可能會在未來更新這些聲明，但不承擔任何這樣做的義務。請參閱 Fulcrum 最近向美國證券交易委員會提交的文件，以了解與該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 Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer; and Dr. Iain Fraser, Interim Chief Medical Officer. After providing updates on our key programs, there will be a brief Q&A in which Alex, Alan and Iain will be available to answer your questions. With that, it's my pleasure to turn the call over to Alex. Sir, you may begin.

今天的電話會議將由 Fulcrum 執行長兼總裁 Alex Sapir 主持。與 Alex 一起參加電話會議的還有財務長 Alan Musso；和臨時首席醫療官 Iain Fraser 博士。在提供我們的關鍵計劃的最新資訊後，將會有一個簡短的問答，其中 Alex、Alan 和 Iain 將回答您的問題。至此，我很高興將電話轉給亞歷克斯。先生，您可以開始了。

That's great. Thanks, [Towanda], and thanks to all of you for joining us today. We are pleased with the progress that we've made in the Third Quarter of 2023, advancing our 2 clinical assets, losmapimod and pociredir. In addition, we remain well capitalized with a cash position of $257 million as of September 30 and have extended our cash runway into 2026, through our strategic review and budget process only on our essential priorities.

那太棒了。謝謝，[Towanda]，也謝謝大家今天加入我們。我們對 2023 年第三季的進展感到高興，推進了我們的 2 種臨床資產 losmapimod 和 pociredir。此外，截至 9 月 30 日，我們的資本充足，現金部位為 2.57 億美元，並透過僅針對我們的基本優先事項的策略審查和預算流程，將我們的現金跑道延長至 2026 年。

So what I'd like to do this morning is to provide an update on our 2 key programs, losmapimod for facioscapulohumeral muscular dystrophy or FSHD, and pociredir previously referred to as FTX-6058 for sickle cell disease, after which I'll turn it over to Alan for some financial highlights.

所以今天早上我想做的是提供我們兩個關鍵項目的最新信息，用於治療面肩肱型肌肉營養不良症或FSHD 的losmapimod，以及用於治療鐮狀細胞病的pociredir（之前稱為FTX- 6058），之後我將把它轉過來請艾倫了解一些財務要點。

So let's start with our most advanced program, losmapimod. Just as a quick reminder, losmapimod is a selective p38 alpha/beta MAP kinase inhibitor and is currently in Phase III development for the treatment of FSHD for which there are currently no approved treatment options. FSHD is a form of muscular dystrophy with an estimated patient population of 30,000 in the U.S. alone. The disease is characterized by a slow and progressive loss of muscle function over many years, resulting in significant impairment of upper extremity function and mobility. As a result, many patients are unable to perform many of the life's daily activities that we all take for granted, like reaching for a cup of coffee in the kitchen cabinet, brushing your teeth, feeding one's self and even practicing good hygiene.

讓我們從最先進的程式 losmapimod 開始。快速提醒一下，losmapimod 是一種選擇性 p38 α/β MAP 激酶抑制劑，目前正處於治療 FSHD 的 III 期開發中，目前尚無核准的治療方案。 FSHD 是一種肌肉營養不良症，光在美國估計就有 30,000 名患者。此疾病的特徵是多年來肌肉功能緩慢且進行性喪失，導致上肢功能和活動能力顯著受損。因此，許多患者無法進行許多我們認為理所當然的日常活動，例如在廚房櫃子裡喝杯咖啡、刷牙、自己吃飯，甚至保持良好的衛生習慣。

These critical factors and our insights on the genetic underpinnings of FSHD drove us to identify and develop a safe and effective treatment option with the potential to slow disease progression for these patients. In September of this year, we completed enrollment in REACH, our global Phase III trial for losmapimod, which we initiated in June of 2022. We believe that the rapid pace of enrollment of the 260 patients into the trial is a real testament to the high unmet need of this rare disease. We are on track to report top line in the Fourth Quarter of 2024, which will bring us one step closer to delivering the first-ever FDA-approved therapy for FSHD.

這些關鍵因素以及我們對 FSHD 遺傳基礎的見解促使我們確定並開發一種安全有效的治療方案，有可能減緩這些患者的疾病進展。今年 9 月，我們完成了 REACH 的入組，這是我們於 2022 年 6 月啟動的洛斯馬莫德全球 III 期試驗。我們相信，260 名患者入組試驗的快速速度真正證明了該試驗的高這種罕見疾病的需求未被滿足。我們預計在 2024 年第四季報告營收，這將使我們距離推出首個經 FDA 批准的 FSHD 療法又更近了一步。

Now let me just give quick reminder to everybody about REACH. REACH is a 48-week trial intended to be registration enabling both in the U.S. and in ex U.S. geographies. The primary endpoint for the study is the change from baseline in the relative surface area or RSA score, which is a quantitative assessment of reachable workspace or RWS. This is a measure of upper extremity range of motion and function that specifically evaluates shoulder and arm mobility using 3D motion sensor technology. Preserving this upper extremity function is critical for patients to maintain their independence and their ability to perform some of these activities of daily limiting that I spoke about earlier.

現在讓我快速提醒大家有關 REACH 的資訊。 REACH 是一項為期 48 週的試驗，旨在在美國和美國以外的地區註冊。研究的主要終點是相對表面積或 RSA 評分相對於基線的變化，這是對可達工作空間或 RWS 的定量評估。這是上肢運動範圍和功能的衡量標準，專門使用 3D 運動感測器技術評估肩部和手臂的活動能力。保留這種上肢功能對於患者保持獨立性和執行我之前提到的一些日常限制活動的能力至關重要。

As part of this study, we'll also be looking at other key secondary endpoints like muscle fat infiltration or MFI, which is an important marker of disease pathology measured by whole body MRI as well as reported quality of life measures and health care utilization questionnaires that will help inform our thinking on our payer strategy as we begin preparing for a commercial launch here in the U.S. We are pleased to have reached. There is no pun intended there, this critical milestone, and we look forward to sharing with everyone top line results in the Fourth Quarter of next year.

作為這項研究的一部分，我們還將關注其他關鍵的次要終點，例如肌肉脂肪浸潤或 MFI，這是透過全身 MRI 以及報告的生活品質測量和醫療保健利用問卷測量的疾病病理學的重要標誌當我們開始準備在美國進行商業發佈時，這將有助於我們對付款人策略的思考。我們很高興能夠達成這項協議。這是一個重要的里程碑，沒有雙關語的意思，我們期待與大家分享明年第四季的頂線結果。

So let me now move on to pociredir, our oral fetal hemoglobin inducer, or HPF for short for the potential treatment of patients with sickle cell disease. In August 2023, the FDA lifted the clinical hold on our investigational new drug application for pociredir for the potential treatment of sickle cell disease. Our interactions with the FDA were productive and collaborative throughout the hold, and we're pleased to have aligned on a revised inclusion, exclusion criteria that targets a more severe patient population for this Phase Ib study. I think it's also important to note that there were no changes in the protocol-defined dose escalation scheme or the 3-month treatment duration.

現在讓我談談 pociredir，我們的口服胎兒血紅蛋白誘導劑（簡稱 HPF），用於鐮狀細胞疾病患者的潛在治療。 2023 年 8 月，FDA 取消了對 pociredir 用於鐮狀細胞疾病潛在治療的新藥研究申請的臨床擱置。在整個擱置期間，我們與 FDA 的互動是富有成效和協作的，我們很高興能夠就修訂後的納入、排除標準達成一致，該標準針對這項 Ib 期研究的更嚴重的患者群體。我認為還需要注意的是，方案定義的劑量遞增方案或 3 個月的治療持續時間沒有變化。

We are working hard to resume enrollment in the Phase Ib study at the 12-milligram dose followed by the 20-milligram dose of pociredir. Each of these dose cohorts are scheduled to enroll 10 patients. We are reactivating current sites as well as identifying new sites in the U.S. and ex-U.S. that are excited to participate. Now as many of you know, activating new sites takes time, given the contracting and IRB approval process. I think once we have a few months of enrollment under our belt, we'll be in a far better position to estimate when we would expect to have results of the 12 and the 20-milligram to share with everyone.

我們正在努力恢復 Ib 期研究的註冊，先服用 12 毫克劑量的 pociredir，然後服用 20 毫克劑量。每個劑量組計劃招募 10 名患者。我們正在重新啟動現有站點，並在美國和美國以外地區尋找新站點。很高興參加。現在，正如你們許多人所知，鑑於合約和 IRB 批准流程，啟動新站點需要時間。我認為，一旦我們進行了幾個月的註冊，我們就能更好地估計何時能與大家分享 12 毫克和 20 毫克的結果。

I just want to take a minute and talk about why we're so excited about pociredir given the fact that this is only in a Phase Ib study. So data that we obtained prior to the clinical hold demonstrated that pociredir increased total fetal hemoglobin of a magnitude that could translate into a meaningful improvement in disease severity. Specifically, after only 42 days of treatment, we observed up to a 10 percentage point increase in fetal hemoglobin from baseline or total fetal hemoglobin of approximately 25%.

我只想花一點時間談談為什麼我們對 pociredir 如此興奮，因為這只處於 Ib 期研究中。因此，我們在臨床試驗之前獲得的數據表明，pociredir 增加了胎兒總血紅蛋白的數量，這可以轉化為疾病嚴重程度的有意義的改善。具體來說，僅經過 42 天的治療，我們就觀察到胎兒血紅素較基線增加了 10 個百分點，胎兒總血紅素增加了約 25%。

We believe that as an oral HbF inducer, we believe that pociredir has the potential to provide a differentiated therapeutic option for patients living with sickle cell disease. Addressing the significant unmet need in sickle cell remains a key priority for us, and we look forward to providing further updates on our progress. So with that clinical update, I'll now turn it over to Alan, our Chief Financial Officer, who will provide an update on our financials. Alan has been a great addition to the team since joining in August, and he will be invaluable as we move into the next phase of growth and continue to advance our mission of delivering these transformative therapies.

我們相信，作為一種口服 HbF 誘導劑，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。解決鐮狀細胞方面未滿足的重大需求仍然是我們的首要任務，我們期待提供有關我們進展的進一步更新。因此，透過臨床更新，我現在將其移交給我們的財務長艾倫，他將提供我們財務狀況的最新資訊。自從八月加入以來，艾倫一直是團隊的重要補充，當我們進入下一階段的成長並繼續推進我們提供這些變革性療法的使命時，他將發揮不可估量的作用。

So Alan, over to you.

艾倫，交給你了。

Thank you, Alex. Let me start with our cash position. We ended September 30, 2023, with cash, cash equivalents and marketable securities of $257.1 million. And during the Third Quarter, our net cash burn was $21.1 million. We continue to operate from a strong financial position. And based on our recent operating results and current projections, we now expect our cash runway to extend into 2026. An update from our prior guidance of mid-2025.

謝謝你，亞歷克斯。讓我從我們的現金狀況開始。截至 2023 年 9 月 30 日，我們的現金、現金等價物及有價證券為 2.571 億美元。第三季度，我們的淨現金消耗為 2,110 萬美元。我們繼續以強勁的財務狀況營運。根據我們最近的經營業績和目前的預測，我們現在預計我們的現金跑道將延長至 2026 年。這是我們之前 2025 年中期指導的更新。

In the Third Quarter of 2023, our collaboration revenue was $0.8 million, that compares to $1.2 million for the Third Quarter of 2022. Our research and development expenses were $18.2 million for the Third Quarter of 2023 compared to $15.4 million for the Third Quarter of 2022. The increase of $2.8 million was primarily due to increased costs associated with the advancement of our Phase III REACH trial, including the completion of enrollment during September of 2023. Our general and administrative expenses were $10 million for the Third Quarter of 2023 as compared to $9.7 million for the Third Quarter of 2022. The increase of $0.3 million was primarily due to increased facilities, professional services and software costs. Our net loss was $24 million for the Third Quarter of 2023, and that compares to $23.7 million for the Third Quarter of 2022.

2023 年第三季度，我們的合作收入為 80 萬美元，而 2022 年第三季為 120 萬美元。2023 年第三季我們的研發費用為 1820 萬美元，而 2022 年第三季為 1540 萬美元增加280 萬美元主要是由於推進III 期REACH 試驗相關的成本增加，包括2023 年9 月期間完成的入組。與2023 年第三季相比，我們的一般和管理費用為1000 萬美元。2022 年第三季為970 萬美元。增加30 萬美元主要是因為設施、專業服務和軟體成本增加。 2023 年第三季我們的淨虧損為 2,400 萬美元，而 2022 年第三季的淨虧損為 2,370 萬美元。

And with that, let me turn it back over to Alex.

接下來，讓我把它轉回給亞歷克斯。

Great. Thanks, Alan, and again, great to have you on the team. So [Towanda], let's go ahead and open it up for questions.

偉大的。謝謝艾倫，再次感謝你加入我們的團隊。 [Towanda]，讓我們繼續提問。

(Operator Instructions) Our first question comes from the line of Corrine Jenkins with Goldman Sachs.

（操作員說明）我們的第一個問題來自高盛的科琳·詹金斯 (Corrine Jenkins)。

This is Craig on for Corinne. So I had one specifically related to pociredir. And I guess with that Phase Ib study, what do you guys hope to see in order to consider moving forward the program? And based on that, what do you think you need to show from a risk-benefit point of view in order to get the FDA to maybe reconsider the current patient population you're evaluating the agent to maybe a broader one?

這是為科琳代言的克雷格。所以我有一個與 pociredir 專門相關的。我想透過 Ib 期研究，你們希望看到什麼才能考慮推進該計劃？基於此，您認為您需要從風險效益的角度展示什麼，以便讓 FDA 重新考慮您正在評估該藥物的當前患者群體，或許是更廣泛的患者群體？

Yes. It's great. Thanks for the question, Craig. And let me turn that over to Iain Fraser, our Chief Medical Officer. Iain has really been instrumental in driving those conversations with the FDA. So I think he's probably best equipped to answer that question.

是的。這很棒。謝謝你的提問，克雷格。讓我把這個問題交給我們的首席醫療官伊恩·弗雷澤 (Iain Fraser)。伊恩在推動與 FDA 的對話方面確實發揮了重要作用。所以我認為他可能最有能力回答這個問題。

Yes. Thanks, Alex, and thanks for the question. As Alex mentioned earlier, at the 12-milligram dose that we've studied to date, which was only a partial cohort, essentially only 3 patients and the longest duration of 42 days. So just 6 weeks halfway into the treatment period, we were seeing rises of around 10 percentage points in the fetal hemoglobin.

是的。謝謝亞歷克斯，也謝謝你的提問。正如 Alex 之前提到的，我們迄今為止研究的 12 毫克劑量只是部分隊列，基本上只有 3 名患者，最長持續時間為 42 天。因此，僅在治療期過半的 6 週，我們就看到胎兒血紅蛋白上升了約 10 個百分點。

Obviously, it depends where your baseline HbF starts out as to where you end up and there was at least one patient there started out at about 15%, relatively high and reached 25%, which we believe and I think backed by the literature that once you enter the high 20% range of total HbF that you significantly impact the symptoms of sickle cell disease. So that's the range that I think will be most convincing to REACH. And I think what we're trying to demonstrate with this is with the 12-milligram dose as we extend the duration of dosing out to the full 3 months how much higher do we get the field hemoglobin to rise and across the entire cohort at different baseline fetal hemoglobin, how high do each of those individuals reach.

顯然，這取決於您的基線HbF 從哪裡開始到最終的結果，至少有一名患者一開始HbF 約為15%，相對較高，後來達到25%，我們相信這一點，並且我認為這一點得到了文獻的支持，曾經當您進入總 HbF 的 20% 高範圍時，您會顯著影響鐮狀細胞疾病的症狀。所以這是我認為最有說服力的 REACH 範圍。我認為我們試圖用這個來證明 12 毫克劑量，當我們將給藥持續時間延長到整整 3 個月時，我們可以使整個隊列的現場血紅蛋白在不同的時間升高多少。胎兒血紅蛋白基線，每個人達到的高度。

So that's our intent. That's the target towards which we are shooting. And as we've articulated previously, based on our earlier healthy volunteer data, we believe that there is even further incremental efficacy to be gained as we go up from 12 milligrams to the next dose around 20 milligrams, and we fully expect that, that will outperform even the 12-milligram dose. So that's the directionality that we expect, that's the region of total HbF that we think will be significantly transformative, and that's what the data we'll be looking for as we start to dose in this cohort.

這就是我們的意圖。這就是我們射擊的目標。正如我們之前所闡明的，根據我們早期的健康志願者數據，我們相信，當我們從 12 毫克增加到下一劑量 20 毫克左右時，會獲得進一步的增量療效，並且我們完全期望，甚至會優於12 毫克劑量。這就是我們期望的方向性，這就是我們認為將具有重大變革性的總 HbF 區域，這就是我們在該隊列中開始給藥時要尋找的數據。

Yes. And then, Craig, this is Alex. Let me just sort of answer specifically your question about what do you feel like we need to show to the FDA to expand the patient population beyond where we are today. I think the -- obviously, the FDA looks at everything from a risk benefit perspective. And right now, we've shown some benefit, albeit in a very small number of patients. So if we're able to achieve what Iain spoke about, we'll take that information back to the FDA and have what we believe is a very sort of thoughtful discussion armed with much more data to show how this drug can benefit patients. And from there, we believe that over the long run, we will be able to expand that patient population.

是的。然後，克雷格，這是亞歷克斯。讓我具體回答一下您的問題，即您認為我們需要向 FDA 展示什麼，才能將患者群體擴大到超越今天的水平。我認為，顯然，FDA 從風險收益的角度看待一切。目前，我們已經顯示出一些益處，儘管只針對極少數患者。因此，如果我們能夠實現伊恩所說的目標，我們會將這些資訊帶回 FDA，並進行我們認為是非常深思熟慮的討論，並配備更多數據來展示這種藥物如何使患者受益。從那時起，我們相信從長遠來看，我們將能夠擴大患者群體。

I think what's important to remember is that there's been a lot of talk recently over the past couple of weeks with the Vertex CRISPR cell and gene therapy compound as well as bluebird. And I think that if you look at the level of fetal hemoglobin that they're able to get up to in the 30s, we do believe that with -- based on what we've been able to show prior to the whole, we believe that with 3 months of dosing with the 12-milligram and potentially 3 months of dosing with the 20-milligram, we may be able to get up to similar levels. And I think that's very, very exciting for the sickle cell community and for the patients specifically.

我認為重要的是要記住，過去幾週有很多關於 Vertex CRISPR 細胞和基因治療化合物以及藍鳥的討論。我認為，如果你看看他們在 30 多歲時能夠達到的胎兒血紅蛋白水平，我們確實相信——基於我們在整體之前能夠展示的內容，我們相信服用12 毫克的藥物3 個月，以及可能服用20毫克的藥物3 個月，我們也許能夠達到類似的水平。我認為這對鐮狀細胞界和患者來說非常非常令人興奮。

Our next question comes from the line of Dae Go Ha with Stifel.

我們的下一個問題來自 Dae Go Ha 和 Stifel 的對話。

This is Benazir on for Dae Go. Just a couple on pociredir. How challenging has it been to refine some of the prior trial sites? To participate in the trial at this point, can you share some color on that? And what are some of the questions that they're having about the clinical hold and how they can feel more comfortable about drug safety? And then a follow-up to that is we know that you're not exactly sure about one you're going to have data on pociredir, but is it more or like going to be midyear or year-end or somewhere in between, if not at a conference, maybe just a presentation for the company?

這是貝娜齊爾 (Benazir) 在大高 (Dae Go) 上的表現。 pociredir 上只有一對。完善之前的一些試驗站點有何挑戰性？現在參加試驗，能分享一些資訊嗎？他們對臨床保留有哪些疑問以及如何對藥物安全性感到更加放心？然後，我們知道您不太確定您將在 pociredir 上獲得數據，但它是否更像是年中或年底或介於兩者之間的某個時間，如果不是在會議上，也許只是為公司做一次演示？

Yes, that's great. Thanks. Let me start and then Iain, please feel free to jump in if I miss anything. So yes, so just as a quick reminder, we had 7 sites in the Phase Ib study prior to the initiation of the hold. And it's just as a reminder, that was an all-comer study. So our plan specific, and they were all U.S. sites, our plans, specifically in the U.S. is to double the number of sites, specifically in the U.S. as well as to look outside of the U.S. as well. And we feel that we need to go to a greater number of sites simply because we have a more narrowly defined inclusion/exclusion criteria.

是的，那太好了。謝謝。讓我開始吧，然後伊恩，如果我錯過了什麼，請隨時加入。所以，是的，簡單提醒一下，在暫停啟動之前，我們有 7 個研究中心處於 Ib 期研究中。這只是提醒一下，這是一項全民研究。因此，我們的計劃是具體的，而且它們都是美國站點，我們的計劃，特別是在美國，是將站點數量增加一倍，特別是在美國，同時也將目光投向美國以外的地區。我們認為我們需要訪問更多的網站，只是因為我們有更狹窄的納入/排除標準。

So it will be a more difficult trial to enroll than we have in the past. I think what we've been hearing from physicians, and I'd like Iain to comment on this as well. But I think what we've been hearing from physicians is the benefits that this drug as an oral HbF inducer can provide to patients, right?

因此，入學將比過去更加困難。我想我們已經從醫生那裡聽到了，我也希望伊恩對此發表評論。但我認為我們從醫生那裡聽到的是這種藥物作為口服 HbF 誘導劑可以為患者帶來的好處，對嗎？

We've been able to show up until now that with 6 weeks of dosing at a 12-milligram dose, we can get patients to total fetal hemoglobin levels of 25. And I think that's I think that's really exciting for the -- I think that's really exciting for the sites and the physicians that are going to participate in this study. And I think it's also very exciting for the patients as well. I think in terms of when we think we'll be able to show that, I think right now, our focus has really been on engaging with the centers.

到目前為止，我們已經能夠證明，透過 12 毫克劑量的 6 週給藥，我們可以使患者的胎兒總血紅蛋白水平達到 25。我認為這對 - 我認為這真的很令人興奮對於將要參與這項研究的研究中心和醫生來說，這確實令人興奮。我認為這對患者來說也非常令人興奮。我認為，就我們認為何時能夠證明這一點而言，我認為現在我們的重點實際上是與這些中心合作。

Once we have those centers stood up, we've got a couple of IRBs that have already approved it. We have one site that is ready to start receiving drug. And we're also doing a lot with the sickle cell community in and around those sites to really sort of educate the community about this very, very interesting study that the center is now participating in.

一旦我們讓這些中心成立，我們就有幾個 IRB 批准了它。我們有一個站點已準備好開始接收藥物。我們也與這些地點及其周圍的鐮狀細胞社區做了很多工作，以真正教育社區有關該中心現在正在參與的這項非常非常有趣的研究。

So that's really been our focus. I think at this point, Benazir, I think if I was to give you sort of any indication. The only thing I would know with great certainty is that -- that indication or that guidance would be incorrect. So I think give us a couple of months -- let us get a couple of months of patient enrollment under our belt. As I've said in the past. And I think at that point, we'll be in a much better position to provide more specific guidance that I feel more comfortable about. So anything else you think around the centers, Iain?

這確實是我們的重點。我想在這一點上，貝娜齊爾，我想我是否可以給你任何指示。我唯一可以肯定的是──那個指示或那個指導是不正確的。所以我想給我們幾個月的時間——讓我們進行幾個月的病患登記。正如我過去所說的。我認為到那時，我們將能夠更好地提供我覺得更舒服的更具體的指導。那麼你對這些中心還有什麼想法嗎，伊恩？

Yes. Thanks, Alex. I can provide a little bit of color around the types of sites themselves. And as Alex alluded to earlier, it was an all-comer study. And so we were at a number of sites that started out essentially as pediatric sites. And because of the way that sickle cell disease care is administered, a lot of the pediatric sites hold on to their older patients as they go into adulthood because they don't have great partners to transfer those patients to. And so we had a number of those sites within the study originally.

是的。謝謝，亞歷克斯。我可以為網站本身的類型提供一些顏色。正如亞歷克斯之前提到的，這是一項全民研究。因此，我們訪問了許多最初是兒科網站的網站。由於鐮狀細胞疾病護理的管理方式，許多兒科中心在老年患者進入成年後仍保留著他們，因為他們沒有好的合作夥伴可以將這些患者轉移到那裡。因此，我們最初的研究中有很多這樣的網站。

Those are obviously somewhat younger patients overall, less treatment experienced and less severe impact of disease, just given the duration that they've experienced. And what we're finding as we go out is that the number of those sites feel that they don't have quite the level of severity or previous treatment experience that we might need for the protocol. And so those are sites that are not continuing, but some of them clearly still do have those patients.

整體而言，這些患者顯然比較年輕，經歷過的治療較少，疾病影響也較輕，僅考慮到他們經歷的持續時間。當我們走出去時，我們發現這些站點的數量認為它們的嚴重程度或先前的治療經驗不符合我們的方案可能需要的水平。因此，這些網站不再繼續存在，但其中一些顯然仍然有這些患者。

So that's been one experience, and then we've also broadened our net and are looking at a number of sites that treat exclusively adults that obviously do have many of these more severely impacted patients. And so we are bringing them into the fold as well. So we're casting a wide net. We've noticed those subtleties of the patient populations at the different sites. And we're meeting with lots of investigators.

這就是一次經歷，然後我們也擴大了我們的網絡，並正在尋找一些專門治療成人的網站，這些網站顯然確實有許多受影響更嚴重的患者。因此，我們也將它們納入其中。所以我們正在廣泛撒網。我們注意到不同地點患者群體的這些微妙之處。我們正在會見很多調查人員。

Our next question comes from the line of Joseph Schwartz with SVB Leerink.

我們的下一個問題來自 Joseph Schwartz 與 SVB Leerink 的對話。

It's Joe Schwartz from Leerink Partners. I was wondering if you could talk some more about how the new inclusion criteria negotiated with the FDA could influence the profile of disease severity? Which will be reflected in the future cohorts for the Phase Ib for pociredir? And do you think that pociredir will still be able to generate an increase in hemoglobin which is sufficient for generating a clinical benefit in patients with more severe disease? I guess I'm wondering if you think the patients in future cohorts will have as much of an opportunity to reach the 20% range you referenced earlier if they're starting out at lower baseline levels compared to those who were treated previously?

我是 Leerink Partners 的 Joe Schwartz。我想知道您是否可以多談談與 FDA 協商的新納入標準如何影響疾病嚴重程度？哪些將反映在 pociredir 的 Ib 期未來隊列中？您認為 pociredir 是否仍能增加血紅素，足以為患有更嚴重疾病的患者帶來臨床益處？我想我想知道，如果未來隊列中的患者與之前接受治療的患者相比，他們的基線水平較低，他們是否有機會達到您之前提到的 20% 範圍？

Yes. Great question. I think to answer that, let me turn that one over to Iain.

是的。很好的問題。我想回答這個問題，讓我把這個問題交給伊恩。

Yes, absolutely. And it's one that we've given a lot of thought to, and I think it will be interesting to see the data as it rolls out. I think I'd make a couple of comments about it. One is in the 16 patients that we've treated thus far in the Ib study as a pretty high rate of baseline fetal hemoglobin. And while we don't have full 3 months data in all of them, the initial trajectory of increase in HbF is pretty consistent across all of those. So it didn't seem as though it was higher a steeper rate at the higher baseline HbF and the low ones appear to be responding just as well. So that's the first point.

是的，一點沒錯。我們對此進行了很多思考，我認為隨著數據的推出，看到這些數據將會很有趣。我想我應該對此發表一些評論。其中之一是我們迄今為止在 Ib 研究中治療的 16 名患者，其基線胎兒血紅蛋白水平相當高。雖然我們沒有所有這些數據的完整 3 個月數據，但 HbF 的初始成長軌跡在所有這些數據中都非常一致。因此，在較高基線 HbF 下，似乎並沒有出現較高的較陡峭的速率，而較低的 HbF 似乎也有同樣的反應。這是第一點。

The second point is, I think the mechanism of action being distinct from that of HU has some advantages in this respect. Obviously, we'll need to demonstrate that as we move into the more severely impacted patients, but it's not operating through a stress erythropoiesis-type response, which HU is. There's some discussion about whether that mechanism might be susceptible to depletion of stem cells or fatigue in the marrow or whatever description you want to append to it. So I think the differentiated mechanism of action acting through alterations in gene transcription are likely to be successful in that more severely impacted patient population, but we'll get the patients in and we'll have to demonstrate that in the clinic, and that's our expectation.

第二點是，我認為與HU不同的作用機制在這方面有一些優勢。顯然，當我們進入受影響更嚴重的患者時，我們需要證明這一點，但它並不是透過應激性紅血球生成型反應來運作，而 HU 是這樣的。有一些討論是關於該機制是否容易受到幹細胞耗盡或骨髓疲勞的影響，或者您想附加的任何描述。因此，我認為透過改變基因轉錄發揮作用的差異化作用機制可能會在受影響更嚴重的患者群體中取得成功，但我們會讓患者參與進來，我們必須在臨床上證明這一點，這就是我們的期待。

Interesting. And then could you just walk us through the calculus you employed to develop the estimate that your inclusion criteria for pociredir covers 7,500 to 10,000 sickle saltation in the United States. And I'm just wondering how confident you are in that estimate as you engage with the sites now? And what do you expect the screen failure rate for patients to be going forward?

有趣的。然後您能否向我們介紹您使用的微積分來估計您的 pociredir 納入標準涵蓋了美國的 7,500 到 10,000 次鐮狀跳躍。我只是想知道，當您現在與這些網站互動時，您對這一估計有多大信心？您預計患者的篩檢失敗率未來會是多少？

Yes, maybe as it relates to the screen failure rate, I'll ask Iain to answer that. But yes, let me give a bit of color, Joe, in terms of how we got to that number. I think what's important to remember in looking at the inclusion/exclusion criteria. These are people that have either tried or failed on some of these advanced therapies or for whatever reason, don't have access to the advanced therapies, voxelotor and crizanlizumab because of the simple fact that they don't have proper insurance or their co-pays are too high.

是的，也許因為它與螢幕故障率有關，我會請伊恩來回答這個問題。但是，是的，喬，讓我稍微說明一下我們是如何達到這個數字的。我認為在考慮納入/排除標準時要記住什麼很重要。這些人要么嘗試過某些先進療法，要么失敗了，或者出於某種原因，無法獲得先進療法、voxelotor 和 crizanlizumab，原因很簡單，他們沒有適當的保險或他們的合作夥伴。薪水太高了。

So let me give you some high-level numbers. We know that from 2019, when both vox and criz launched through 2022, both of those products -- each generated about 10,000 prescriptions. We know that about 25% of those prescriptions never converted to a patient start. And our assumption there is that those patients simply didn't have proper insurance cover or didn't have access to the drug due to payer-related issues.

因此，讓我給您一些高級數字。我們知道，從 2019 年 vox 和 Criz 推出到 2022 年，這兩種產品都產生了約 10,000 個處方。我們知道，大約 25% 的處方從未轉化為患者開始使用。我們的假設是，這些患者根本沒有適當的保險，或者由於付款人相關問題而無法獲得藥物。

What we also know is that during the first year, you sold about 30% discontinuation rate with vox, we don't actually have specific numbers for crizanlizumab discontinuation rates in the first year. But you could always -- you could assume that it's probably similar to vox, maybe a little bit higher because it does require sort of infusions at an infusion center.

我們也知道，在第一年，vox 的停藥率約為 30%，我們實際上沒有第一年 crizanlizumab 停藥率的具體數字。但你總是可以——你可以假設它可能與 vox 類似，也許更高一點，因為它確實需要在輸液中心進行某種輸液。

So sort of doing all of that math gets you to around sort of 75 to 10,000 patients. Where that number may be overestimated is the fact that not all of those patients meet the patient severity criteria, but where that number may be an underestimate is the fact that it doesn't include any prescriptions in 2023. We only have prescriptions through 2022. So sort of taking all of those numbers into consideration that's how we sort of arrived at the 75 to 10,000 patients in the U.S. that meet that inclusion/exclusion criteria, which represents about 7.5% to 10% of the total 100,000 patient population. Did you want to address your second question?

因此，進行所有這些數學運算後，您就可以了解大約 75 到 10,000 名患者。這個數字可能被高估的事實是，並非所有這些患者都符合患者嚴重程度標準，但該數字可能被低估的事實是，它不包括 2023 年的任何處方。我們只有 2022 年之前的處方。因此，考慮到所有這些數字，我們就得出了美國符合納入/排除標準的75 至10,000 名患者的情況，約佔100,000 名患者總數的7.5% 至10%。您想解決第二個問題嗎？

Yes. So this is Iain. We haven't projected a screen fail rate at this point. I can tell you that for the initial phase of the study, where we recruited 16 patients, that screen fail rate was a little over 50%. So it was a relatively high screen fail rate at that point. And we're sort of carrying that forward at the moment even though patient population is likely to be more severe. We have more experience with the sites and -- with the education of the sites around the protocol and so expect to be able to help with patient selection in that fashion.

是的。這就是伊恩。目前我們還沒有預測螢幕故障率。我可以告訴你，在研究的初始階段，我們招募了 16 位患者，篩檢失敗率略高於 50%。所以當時螢幕故障率相對較高。儘管患者人數可能會更加嚴重，但我們目前正在推進這項計劃。我們對這些網站以及圍繞協議的網站教育有更多的經驗，因此希望能夠以這種方式幫助患者選擇。

Our next question comes from the line of Edward Tenthoff with Piper Sandler.

我們的下一個問題來自愛德華·滕托夫（Edward Tenthoff）和派珀·桑德勒（Piper Sandler）的對話。

So no one ever asked a question on poor little losmapimod. So I guess I'll be the one to ask it. With all of the -- with the data coming in the back half of next year, what are some of the commercial prep that you're doing? And as you kind of project out here, what's the calculus between keeping it and launching it yourself, partnering it, maybe partnering it overseas? Just update us on sort of where you head is on that?

所以沒有人問過關於可憐的小洛斯馬莫德的問題。所以我想我會是問這個問題的人。考慮到明年下半年的數據，你們正在做哪些商業準備？當你在這裡進行專案時，保留它與自己啟動它、合作它、也許與海外合作之間的計算是什麼？請告訴我們您對此的最新進展？

Yes, absolutely. Thanks so much for the question, Ted, and I appreciate you asking a question on losmapimod. Thank you. So yes. So just as a quick reminder, we would have -- we plan to have top line results in the Fourth Quarter. We would then file the NDA sometime in early 2025 for an approval sometime in 2026. We've been very clear that we believe that we can launch this drug quite successfully in the U.S. with a fairly sort of modest commercial infrastructure, while at the same time, looking for partners ex U.S. and we will begin the process of sort of standing up that commercial organization at the end of this year, beginning of next year, starting with our first kind of key hire, which would be that -- which would be that Chief Commercial Officer.

是的，一點沒錯。非常感謝您提出這個問題，Ted，我也很感謝您提出有關 Losmapimod 的問題。謝謝。所以是的。因此，作為一個快速提醒，我們計劃在第四季度獲得頂線結果。然後，我們將在2025 年初的某個時候提交NDA，以便在2026 年的某個時候獲得批准。我們非常清楚，我們相信我們可以在美國相當成功地推出這種藥物，憑藉相當適度的商業基礎設施，同時到時候，尋找美國以外的合作夥伴，我們將在今年年底、明年初開始建立該商業組織的過程，從我們的第一種關鍵招聘開始，這將是——這將是擔任首席商務官。

And I think one of the reasons that we're so excited about our ability to be able to do this ourselves is a fairly sort of concentrated market. It's a fairly small number of neuromuscular specialists that treat these patients with FSHD. They're very, very well organized from a patient efficacy standpoint, and we have an excellent relationship with the FSHD Society.

我認為我們對自己能夠做到這一點感到如此興奮的原因之一是市場相當集中。治療這些 FSHD 患者的神經肌肉專家數量相當少。從患者療效的角度來看，他們組織得非常非常好，而且我們與 FSHD 協會有著良好的關係。

And the fact that there are currently no treatment options and the drug that's probably the closest behind us is probably 2 to 3 years, Roche's product, that's a Myostatin inhibitor. It's 2 to 3 years behind us. we believe that we really do have an opportunity to be successful with this launch in the U.S., doing it ourselves and then the ability to help a tremendous number of patients in the U.S. as well as working collaboratively with a partner ex U.S. to help patients around the world.

事實上，目前還沒有治療選擇，最接近我們的藥物可能是 2 到 3 年，羅氏的產品，這是一種肌肉生長抑制素抑制劑。比我們落後了2到3年。我們相信，我們確實有機會在美國成功推出這項產品，我們自己做，然後有能力幫助美國的大量患者，並與美國以外的合作夥伴合作，幫助周圍的患者世界。

That's super helpful. And I do think it will garner more attention as we get into the New Year. So thanks for the update.

這非常有幫助。我確實認為，隨著新年的到來，它會引起更多關注。感謝您的更新。

Our next question comes from the line of Matthew Biegler with Oppenheimer & Company.

我們的下一個問題來自奧本海默公司的馬修‧比格勒 (Matthew Biegler)。

I will also jump on the FSHD bandwagon here. I wanted to ask maybe about some different scenarios for REACH 3. And specifically, if you saw a path forward if the study doesn't hit or maybe narrowly misses the reachable workspace end point? Like do you think the biomarker endpoint might be sufficient, I guess, taking a page out of Sarepta's playbook and what we've seen now over the last couple of weeks. What -- kind of what are your thoughts there?

我也將在這裡加入 FSHD 潮流。我想問 REACH 3 的一些不同場景。具體來說，如果研究沒有達到或可能差點錯過可到達的工作空間終點，您是否看到了前進的道路？就像你認為生物標記終點可能就足夠了一樣，我想，借鑒 Sarepta 的劇本以及我們在過去幾週所看到的內容。你有什麼想法？

Yes. Great question Matt. Let me turn that one over to Iain.

是的。好問題馬特。讓我把這個交給伊恩。

Yes. Thanks, Matt. So just to be clear, in terms of biomarkers in REACH, we are not evaluating the [DUX4 transcript] which was evaluated in the Phase II study is that's not really a feasible clinical trial measure to make. What we do, however, are a number of secondary endpoints that are different than the reachable workspace endpoint. And those include the MRI endpoints, which I guess could be considered a biomarker, which evaluates the accumulation of fat in muscle tissue that still has -- what looks like normal contractile muscle in dispersed with fat.

是的。謝謝，馬特。因此，需要明確的是，就 REACH 中的生物標記而言，我們沒有評估 II 期研究中評估的 [DUX4 轉錄物]，因為這並不是真正可行的臨床試驗措施。然而，我們所做的是許多與可到達工作區端點不同的輔助端點。其中包括 MRI 終點，我想它可以被認為是一種生物標記物，它評估肌肉組織中脂肪的積累，但仍然存在——看起來像分散有脂肪的正常收縮肌肉。

And so that we also showed in the Phase II study as for the reachable workspace, that you've got a stabilization of that fat accumulation relative to the placebos and showed an increase. So we think that, that's clearly an important secondary endpoint. We also have an evaluation of dynamometry, so conventional muscle strength testing, which we're evaluating. We have some patient-reported outcomes that reflect on both patient global impression of change, but also some specific questions related to FSHD itself. And so there are a number of those secondaries that I think will be important to consider irrespective of what happens to the primary endpoint.

因此，我們也在第二階段研究中表明，對於可到達的工作空間，相對於安慰劑，脂肪積累穩定並顯示出增加。所以我們認為，這顯然是一個重要的次要終點。我們也對測力法進行評估，即我們正在評估的傳統肌肉力量測試。我們有一些患者報告的結果，這些結果既反映了患者對變化的整體印象，也反映了與 FSHD 本身相關的一些具體問題。因此，我認為無論主要終點發生什麼情況，都需要考慮許多次要終點。

But if as you articulate the primary misses narrowly, I think having all of those secondaries trending in a favorable direction towards losmapimod over placebo will be extraordinarily helpful and persuasive in that context.

但如果你狹隘地闡明主要的失誤，我認為在這種情況下，讓所有這些次要因素都朝著洛斯馬莫德而不是安慰劑的有利方向發展將是非常有幫助和有說服力的。

Yes. And Matthew, this is Alex. The only other thing I would add to what Iain said is going back to something I said earlier regarding pociredir and how the FDA looks at everything from a risk benefit perspective. I think what's also important to note is that when we file our NDA with the FDA, we will have over 3,600 patients in our patient safety database. And this has been shown to be a very, very safe drug. And so I think that -- that is a really important sort of piece of information that the FDA will look at as it considers the safety and efficacy data in totality and decides whether to approve this drug or not for patients for which they had not.

是的。馬修，這是亞歷克斯。我要對 Iain 所說的話補充的唯一一件事是回到我之前所說的有關 pociredir 的內容以及 FDA 如何從風險收益的角度看待一切。我認為還需要注意的是，當我們向 FDA 提交 NDA 時，我們的病患安全資料庫中將有超過 3,600 名患者。這已被證明是一種非常非常安全的藥物。所以我認為，這是 FDA 會考慮的一條非常重要的訊息，因為它會整體考慮安全性和有效性數據，並決定是否批准這種藥物用於尚未批准的患者。

We have a follow-up from the line of Dae Gon Ha with Stifel.

我們有來自 Dae Gon Ha 和 Stifel 的後續作品。

Just one more question from us. For FSHD, can you remind us of the powering for REACH and the assumptions that went into it for the mutual workspace? Given that it's a mobility test, how should we think about it in the context again of the recent [Embark] trial failure and what read-through for the powering assumptions for REACH?

我們還有一個問題。對於 FSHD，您能否提醒我們 REACH 的動力以及共同工作空間的假設？鑑於這是一項移動性測試，我們應該如何在最近 [Embark] 試驗失敗的背景下思考它，以及對 REACH 的動力假設進行哪些解讀？

Yes. Great question. Let me turn that over to Iain.

是的。很好的問題。讓我把這個交給伊恩。

Yes. So REACH was powered based on the observed data from ReDUX4 from the Phase II study. And you may recall that was an 80-patient study, 40 in each arm. And essentially, what we took was the change from baseline to the treatment effect losmapimod minus placebo on the reachable workspace, and also assess the variability in the measurement in that particular cohort and then applied it to the power calculations for the REACH study.

是的。因此，REACH 的發展是基於第二階段研究中 ReDUX4 的觀察數據。您可能還記得那是一項有 80 名患者參與的研究，每組 40 名患者。本質上，我們採取的是從基線到可到達工作空間上洛斯馬莫德減去安慰劑的治療效果的變化，並評估該特定隊列中測量的變異性，然後將其應用於REACH 研究的功效計算。

The REACH study was originally powered on a total enrollment of 230 patients with an expectation that 210 of them would be FSHD type 1 and 20 of them would be type 2 and that's a reflection of the relative epidemiology of type 1 versus type 2. Type 1 is overwhelmingly the most prevalent, 95% or so of that. The ReDUX4 study enrolled only type 1s and so even though we are enrolling some type 2s in the REACH study, we powered the study on only the type 1. So the study was powered on an expectation of 210 type 1 patients in the REACH study, and that gave us a power of 93% or 94% using the magnitude of change and the standard deviation from ReDUX4.

REACH 研究最初總共招募了 230 名患者，預計其中 210 名患者為 1 型 FSHD，其中 20 名患者為 2 型，這反映了 1 型與 2 型的相對流行病學。1 型 絕大多數是最普遍的，佔其中的95% 左右。 ReDUX4 研究僅招募了1 型患者，因此即使我們在REACH 研究中招募了一些2 型患者，我們也僅針對1 型患者開展了該研究。因此，該研究的開展是基於REACH 研究中預計有210 名1 型患者的參與，使用變化幅度和 ReDUX4 的標準差，我們得到了 93% 或 94% 的功效。

As it turns out, when we cut off screening for the REACH study based on what we thought the screen fail rate was going to be in order to reach those 230 patients the screen fail rate dropped down, and we ended up enrolling a number of more patients. And so at the end of the day, the total enrollment was 260 instead of 230, and of that 260 there were 18 FSHD type 2s. So we now have 242 FSHD 1.

事實證明，當我們根據我們的預期篩檢失敗率來終止 REACH 研究的篩檢，以便涵蓋這 230 名患者時，篩檢失敗率下降了，我們最終招募了更多患者患者。因此，最終註冊人數為 260 人，而不是 230 人，其中 260 人中有 18 名 FSHD 2 型。所以我們現在有 242 個 FSHD 1。

So 242 versus the original powering around 210, so that bumps the power up into -- over 95% using the same assumptions from ReDUX4.

因此，與 ReDUX4 中相同的假設相比，原始功率為 242 左右，功率約為 210，因此將功率提高到超過 95%。

So that was an inadvertent over enrollment. That wasn't our intention. But was a reflection of the enthusiasm at the sites and the fact that the sites have gotten better at screening the patients until the screen fail rate dropped down. And so that's where we stand based on our actual enrollment now in REACH.

所以這是一次無意的過度招生。那不是我們的意圖。但這反映了這些網站的熱情，以及這些網站在篩檢患者方面做得更好，直到篩檢失敗率下降。這就是我們目前在 REACH 中的實際註冊情況。

Ladies and gentlemen, this concludes the question and answer portion of the call. I would now like to turn the call back over to Fulcrum's CEO, Alex for closing remarks.

女士們、先生們，電話問答部分到此結束。現在我想將電話轉回 Fulcrum 的執行長 Alex 進行結束語。

Thanks, [Towanda]. So just to quickly wrap up, we remain, as we always have, deeply committed to treating the root cause of genetically defined rare diseases and bringing these transformative therapies to patients.

謝謝，[托旺達]。因此，為了快速結束，我們仍然一如既往地堅定致力於治療基因罕見疾病的根本原因，並將這些變革性療法帶給患者。

Before we conclude today's call, as I always like to do, I'd just like to extend my sincere appreciation and gratitude to my fellow Fulcrum teammates to the physicians we work with to advance our clinical trials and finally and most importantly, to the patients who participate in our clinical trials as well as their families. Without them, we would not be able to achieve our goals as a company. Thanks again, everyone, who joined the meeting -- who joined the call this morning. Please stay safe and healthy.

在我們結束今天的電話會議之前，正如我一直喜歡做的那樣，我想向我的 Fulcrum 隊友、與我們合作推進臨床試驗的醫生，以及最後也是最重要的向患者表示衷心的讚賞和感謝參與我們臨床試驗的人及其家人。沒有他們，我們將無法實現公司的目標。再次感謝今天早上參加會議的所有人。請保持安全和健康。

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

女士們、先生們，今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。