Fulcrum Therapeutics Inc (FULC) 2023 Q2 法說會逐字稿

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

早上好，歡迎參加 Fulcrum Therapeutics 2023 年第二季度財務業績和業務更新電話會議。 （操作員說明）。此次電話會議正在 Fulcrum 網站 www.fulcrumtx.com 的投資者部分進行網絡直播並進行錄音。

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, including the clinical hold on FTX-6058, clinical development time lines and financial projections. 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 is not taking on an obligation to do so.

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。這些可能包括有關公司未來預期和計劃的陳述，包括FTX-6058 的臨床擱置、臨床試驗開發時間表和財務預測。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，但不承擔這樣做的義務。

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.

請參閱 Fulcrum 最近向美國證券交易委員會提交的文件，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 today are Dr. Iain Fraser, Interim Chief Medical Officer; and Greg Tourangeau, Fulcrum's Principal Accounting Officer.

今天的電話會議將由 Fulcrum 首席執行官兼總裁 Alex Sapir 主持。今天與 Alex 一起參加電話會議的是臨時首席醫療官 Iain Fraser 博士；以及 Fulcrum 首席會計官 Greg Tourangeau。

After providing updates on our key programs, there will be a brief Q&A in which Alex, Iain and Greg will be available to answer your questions.

在提供我們的關鍵計劃的最新信息後，將會有一個簡短的問答，其中 Alex、Iain 和 Greg 將回答您的問題。

With that, it is my pleasure to turn the call over to Alex. Please go ahead.

至此，我很高興將電話轉給亞歷克斯。請繼續。

Thank you, operator, and thanks to all of you for taking time to join us today. It's truly an honor for me to have the opportunity to lead Fulcrum at this important time and to build on the company's strong foundation as we work towards advancing our pipeline and delivering on our commitment to improve the lives of patients with rare genetic diseases.

謝謝您，接線員，也感謝大家今天抽出時間加入我們。我真的很榮幸有機會在這個重要時刻領導 Fulcrum，並在我們努力推進我們的產品線並兌現改善罕見遺傳病患者生活的承諾的同時，在公司的堅實基礎上再接再厲。

So what I'd like to do this morning is to provide a brief update on our 2 key programs, losmapimod for Facioscapulohumeral Muscular Dystrophy or FSHD for short and FTX-6058 for sickle cell disease. After that, I'll provide a couple of corporate updates and then turn it over to Greg for financial highlights. And after Greg, we'll open it up for questions.

因此，今天早上我想做的是簡要介紹我們的 2 個關鍵項目：用於治療面肩肱型肌營養不良症（簡稱 FSHD）的 losmapimod 和用於治療鐮狀細胞病的 FTX-6058。之後，我將提供一些公司最新情況，然後將其交給格雷格以獲取財務摘要。在格雷格之後，我們將開放提問。

So let's start with losmapimod, our most advanced program. As a quick reminder, losmapimod, a selective p38 alpha/beta MAP kinase inhibitor is currently in Phase III development for the treatment of FSHD, a form of muscular dystrophy with an estimated patient population of 30,000 in the U.S.

讓我們從我們最先進的程序 losmapimod 開始。快速提醒一下，losmapimod 是一種選擇性 p38 α/β MAP 激酶抑製劑，目前正處於治療 FSHD 的 III 期開發中，FSHD 是一種肌肉營養不良症，在美國估計有 30,000 名患者。

Now FSHD is characterized by relentless and accumulating loss of muscle function over many years, resulting in the inability to perform daily life activities like putting away the dishes or listing a cup of coffee, activities that you and I take for granted.

現在，FSHD 的特點是多年來肌肉功能不斷累積喪失，導致無法進行日常生活活動，例如收起碗碟或列出一杯咖啡，這些您我認為理所當然的活動。

Now even more [sobering] is the fact that these patients have no approved treatment options for their disease. These are the factors that drove us to embark on this journey to find options for these patients that had none. So in June of 2022, we initiated our Phase III trial for losmapimod, which we call the REACH study.

現在更[發人深省]的是，這些患者的疾病沒有經過批准的治療方案。這些因素促使我們踏上這段旅程，為這些沒有選擇的患者尋找選擇。因此，我們於 2022 年 6 月啟動了 Losmapimod 的 III 期試驗，我們稱之為 REACH 研究。

Let me give a bit of background on REACH. It's 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 reachable workspace or RWS, a quantitative measure of upper extremity range of motion and function that specifically evaluate shoulder and arm mobility using 3D motion sensor technology.

讓我介紹一下 REACH 的一些背景知識。這是一項為期 48 週的試驗，旨在在美國和美國以外地區進行註冊。地理。該研究的主要終點是可達工作空間或 RWS 相對於基線的變化，這是上肢運動範圍和功能的定量測量，專門使用 3D 運動傳感器技術評估肩部和手臂的活動能力。

Now preserving this upper extremity function is critical for these patients to maintain their independence and their ability to perform some of these activities of daily living that I talked about earlier.

現在，保留這種上肢功能對於這些患者保持獨立性和執行我之前談到的一些日常生活活動的能力至關重要。

As part of this study, we'll also be looking at some other important secondary endpoints like muscle fat infiltration or MFI, which is an important marker of disease pathology as well as self-supported quality of life measures and health care utilization questionnaires that will really help inform our thinking on our payer strategy as we prepare for a commercial launch.

作為這項研究的一部分，我們還將研究一些其他重要的次要終點，例如肌肉脂肪浸潤或 MFI（這是疾病病理學的重要標誌）以及自我支持的生活質量測量和醫療保健利用調查問卷，這些在我們準備商業發佈時，確實有助於我們對付款人策略的思考。

I'm really excited to share that screening in the REACH study has now closed, and we expect enrollment to complete later this quarter. And with this being a 48-week study, we plan to report top line data in the fourth quarter of 2024. For us and more importantly, for the patients, this brings us one step closer to delivering the first-ever FDA-approved therapy for patients with FSHD.

我非常高興地告訴大家，REACH 研究的篩選現已結束，我們預計註冊工作將在本季度晚些時候完成。這是一項為期48 週的研究，我們計劃在2024 年第四季度報告主要數據。對於我們來說，更重要的是對於患者來說，這使我們離提供有史以來第一個FDA 批准的療法又近了一步對於 FSHD 患者。

Let me now move on to 6058. 6058 is our oral HbF inducer for the potential treatment of patients with sickle cell disease. As previously announced, we received a clinical hold letter from FDA on February 24th and at that point, immediately suspended dosing and paused enrollment in the Phase Ib trial for 6058.

現在讓我談談 6058。6058 是我們的口服 HbF 誘導劑，用於治療鐮狀細胞病患者。正如之前宣布的，我們於 2 月 24 日收到了 FDA 的臨床暫停函，當時我們立即暫停了 6058 的給藥並暫停了 Ib 期試驗的入組。

In the initial feedback provided by FDA, they stated that the hold was related to preclinical data that we submitted in April, October and December of 2022 as well as other nonclinical and clinical evidence of hematological malignancies observed with other PRC2 inhibitors.

在FDA 提供的初步反饋中，他們表示，暫停與我們在2022 年4 月、10 月和12 月提交的臨床前數據以及使用其他PRC2 抑製劑觀察到的血液惡性腫瘤的其他非臨床和臨床證據有關。

In order for us to restart the Phase Ib study, the agency has requested that Fulcrum further define the patient population where the potential benefit of continued treatment with 6058 outweighs potential risk.

為了讓我們重新啟動 Ib 期研究，該機構要求 Fulcrum 進一步定義繼續使用 6058 治療的潛在益處超過潛在風險的患者群體。

I do think it's important to mention that at this stage, the FDA has not requested any additional preclinical or clinical data as a prerequisite to restarting the Phase Ib study in patients. Based on preliminary clinical data that we obtained prior to the clinical hold, 6058 has demonstrated dose-dependent increases in total fetal hemoglobin or HbF of a magnitude that we believe has the potential to lead to a meaningful improvement in disease severity.

我認為值得一提的是，現階段 FDA 並未要求任何額外的臨床前或臨床數據作為在患者中重新啟動 Ib 期研究的先決條件。根據我們在臨床暫停前獲得的初步臨床數據，6058 已證明胎兒總血紅蛋白或 HbF 呈劑量依賴性增加，我們相信這種增加有可能導致疾病嚴重程度出現有意義的改善。

We believe that 6058 as an oral HbF inducer has the potential to provide a differentiated therapeutic option for patients living with sickle cell disease and that the clinical and preclinical data generated to date demonstrate a favorable benefit risk profile.

我們相信 6058 作為口服 HbF 誘導劑有可能為鐮狀細胞病患者提供差異化​​的治療選擇，並且迄今為止產生的臨床和臨床前數據證明了良好的獲益風險狀況。

Overall, our interactions with FDA have been productive and collaborative, and we look forward to continuing our interactions as we work towards resolving the clinical hold as quickly as possible. I will provide an update once we have more clarity on the regulatory path forward, and I intend to provide specifics regarding this more narrowly-defined patient population once we have agreement with FDA.

總的來說，我們與 FDA 的互動是富有成效和協作的，我們期待繼續我們的互動，努力盡快解決臨床擱置問題。一旦我們對未來的監管路徑有了更清晰的了解，我將提供最新信息，並且一旦我們與 FDA 達成協議，我打算提供有關這一更狹窄定義的患者群體的具體信息。

So that covers the updates on our 2 key clinical programs. Before turning it over to Greg, let me give a quick update on 2 other important topics. As we remain committed to delivering groundbreaking therapies for underserved communities, in July of this year, we obtained an exclusive global license from CAMP4 Therapeutics to acquire intellectual property arising from CAMP4's preclinical research program in Diamond-Blackfan Anemia or DBA for short.

這涵蓋了我們兩個關鍵臨床項目的更新。在將其交給格雷格之前，讓我快速介紹一下其他兩個重要主題的最新情況。由於我們仍然致力於為服務不足的社區提供突破性的治療方法，今年7 月，我們獲得了CAMP4 Therapeutics 的全球獨家許可，以獲取CAMP4 的Diamond-Blackfan 貧血（簡稱DBA）臨床前研究項目所產生的知識產權。

Under the terms of this agreement, Fulcrum will research investigational oral compounds for the potential treatment of DBA, a congenital rare blood disorder that affects an estimated 5,000 individuals worldwide.

根據該協議的條款，Fulcrum 將研究用於 DBA 潛在治療的研究性口服化合物，DBA 是一種先天性罕見血液疾病，影響全球約 5,000 人。

Our agreement with CAMP4 further strengthens our discovery pipeline, and we are excited to expand on CAMP4's foundational preclinical work, which we believe has potential broad applications and a unique opportunity for growth.

我們與 CAMP4 的協議進一步加強了我們的發現渠道，我們很高興能夠擴展 CAMP4 的基礎臨床前工作，我們相信這具有潛在的廣泛應用和獨特的增長機會。

Additionally, solidifying our leadership team is one of my key priorities, and I am pleased to announce the appointment of Alan Musso, to the position of Chief Financial Officer effective August 7.

此外，鞏固我們的領導團隊是我的首要任務之一，我很高興地宣布任命 Alan Musso 擔任首席財務官，該職位於 8 月 7 日生效。

I have known Alan for some time now and thus have firsthand knowledge of his financial acumen, his keen strategic insights on a range of complex financial decisions [that face] a company of our size, and most importantly, his character.

我認識艾倫已經有一段時間了，因此對他的財務敏銳度、他對我們這種規模的公司所面臨的一系列複雜財務決策的敏銳戰略洞察力有第一手的了解，最重要的是，他的性格。

His leadership experience within the biopharma industry will be invaluable as the company enters its next stage of development. Welcome aboard, Alan. And so with that, let me turn it over to Greg to give an update on our financials. Greg?

隨著公司進入下一發展階段，他在生物製藥行業的領導經驗將非常寶貴。歡迎加入，艾倫。因此，讓我將其轉交給格雷格，以提供有關我們財務狀況的最新信息。格雷格？

Thanks, Alex. We ended June 30, 2023, with cash, cash equivalents and marketable securities of $278.2 million as compared to [$203.9] million as of December 31, 2022. We continue to operate from a strong financial position, and we expect our cash, cash equivalents and marketable securities to fund our operating expenses into mid-2025. This projection assumes a timely resolution of the FTX-6058 clinical hold.

謝謝，亞歷克斯。截至2023 年6 月30 日，我們的現金、現金等價物和有價證券為2.782 億美元，而截至2022 年12 月31 日為2.039 億美元。我們繼續以強勁的財務狀況運營，我們預計我們的現金、現金等價物和有價證券，為我們到 2025 年中期的運營支出提供資金。該預測假設 FTX-6058 臨床擱置問題得到及時解決。

Collaboration revenue was $0.9 million for the second quarter of 2023 as compared to $1.9 million for the second quarter of 2022. Research and development expenses were $17.8 million for the second quarter of 2023 as compared to $25 million for the second quarter of 2022.

2023 年第二季度的合作收入為 90 萬美元，而 2022 年第二季度為 190 萬美元。2023 年第二季度的研發費用為 1,780 萬美元，而 2022 年第二季度為 2,500 萬美元。

The decrease of $7.2 million was primarily attributable to a $5 million milestone due to GSK that we achieved during the second quarter of 2022 upon the initiation of REACH as well as decreased costs as a result of the clinical hold for FTX-6058.

減少 720 萬美元的主要原因是，我們在 2022 年第二季度 REACH 啟動後，由於葛蘭素史克 (GSK) 實現了 500 萬美元的里程碑，以及 FTX-6058 臨床擱置導致的成本降低。

General and administrative expenses were $10.3 million for the second quarter of 2023 as compared to $11.1 million for the second quarter of 2022. The decrease of $0.8 million was primarily due to decreased professional services costs.

2023 年第二季度的一般及管理費用為 1,030 萬美元，而 2022 年第二季度為 1,110 萬美元。減少 80 萬美元主要是由於專業服務成本減少。

Net loss was $23.8 million for the second quarter of 2023 as compared to $34.1 million for the second quarter of 2022. And with that, let me turn it back over to Alex.

2023 年第二季度的淨虧損為 2380 萬美元，而 2022 年第二季度的淨虧損為 3410 萬美元。因此，讓我把它轉回給 Alex。

That's great. Thanks, Greg. And with that overview, operator, let's go ahead and open it up for questions.

那太棒了。謝謝，格雷格。有了這個概述，操作員，讓我們繼續提出問題。

(Operator Instructions) Our first question comes from Dae Gon Ha with Stifel.

（操作員說明）我們的第一個問題來自 Stifel 的 Dae Gon Ha。

This is Benazir on for Dae Gon. Can you hear me okay?

這是貝娜齊爾（Benazir）代表大貢（Dae Gon）出場。你能聽到我說話嗎？

We cannot hear you.

我們聽不到你的聲音。

Hello.

你好。

Yes. Go ahead again.

是的。再繼續吧。

This is Benazir on for Dae Gon. Can you hear me?

這是貝娜齊爾（Benazir）代表大貢（Dae Gon）出場。你能聽到我嗎？

Yes. Operator, maybe let's move on to the next question, and then we can come back to Dae Gon and his colleagues there. It's just too difficult to hear them.

是的。接線員，也許我們可以繼續下一個問題，然後我們可以回到 Dae Gon 和他的同事那裡。聽到他們的聲音太困難了。

The next question comes from Joseph Schwartz with Leerink Partners.

下一個問題來自 Leerink Partners 的 Joseph Schwartz。

Can you hear me okay?

你能聽到我說話嗎？

Yes, loud and clear. Thanks, Joe.

是的，響亮而清晰。謝謝，喬。

Congrats on the progress. I was hoping you could expand a bit on a comment that I heard regarding the FDA, the FDA has not asked for any more preclinical data in order to get off of hold, just given you are doing some more non-tox preclinical studies. Does that suggest that really the key to getting off of hold lies solely on the ability to define a patient population where there's an attractive risk benefit relationship. Can you help us -- can you just explain this concept a little bit more?

祝賀取得的進展。我希望你能對我聽到的關於 FDA 的評論進行一些擴展，FDA 沒有要求任何更多的臨床前數據來擺脫困境，只是考慮到你正在做一些更多的非毒性臨床前研究。這是否表明擺脫困境的關鍵僅僅在於確定具有有吸引力的風險收益關係的患者群體的能力。你能幫助我們嗎——你能多解釋一下這個概念嗎？

Yes, absolutely, Joe, and thanks for asking the question. I'll start off and then I'll turn it over to Iain to provide a bit more insight. So you're absolutely right. The FDA has not requested any additional preclinical or clinical data prior to restarting our Phase Ib study in patients. What they have requested is some additional, what I would define as, pharmacology data before moving into healthy volunteers. So with that sort of broader overview, let me just turn it over to Iain, and he can go into a little bit more detail.

是的，當然，喬，感謝您提出這個問題。我將開始，然後將其交給 Iain 以提供更多見解。所以你是完全正確的。在重新啟動我們的 Ib 期患者研究之前，FDA 並未要求提供任何額外的臨床前或臨床數據。他們要求的是一些額外的，我將其定義為，在進入健康志願者之前的藥理學數據。因此，有了這種更廣泛的概述，讓我把它交給伊恩，他可以更詳細地介紹一下。

Yes. Thanks, Alex. I think it's just important to make that differentiation between the 2 aspects of the hold and the 2 aspects of the clinical program. The one around the patients with sickle cell disease in the Ib study, and as Alex has said, the request there is around defining the appropriate patient population.

是的。謝謝，亞歷克斯。我認為區分保留的兩個方面和臨床計劃的兩個方面非常重要。 Ib 研究中圍繞鐮狀細胞病患者的研究，正如 Alex 所說，那裡的要求是圍繞定義適當的患者群體。

The second piece is around getting back into healthy volunteers. Obviously, we've studied a number of them already, over 80, in our initial clinical evaluations, but there's still additional work that's traditionally done in healthy volunteers at this stage of the drug development program. And as part of that, there's a preclinical pharmacology study to evaluate the target engagement after a short number of doses in order to provide reassurance that giving a small number of doses to healthy volunteers is not associated with any long-term alterations.

第二部分是關於恢復健康的志願者。顯然，在我們的初步臨床評估中，我們已經研究了其中的一些，超過 80 個，但在藥物開發項目的這個階段，仍然有傳統上在健康志願者中完成的額外工作。作為其中的一部分，有一項臨床前藥理學研究來評估短期劑量後的目標參與度，以便確保給健康志願者提供少量劑量不會與任何長期改變相關。

So that's the work that's ongoing, but it's specifically for the healthy volunteer population. And as we've said before, the healthy volunteer population is a nice to have as part of the drug development program, but it's not an absolute requirement and our priority is very much around getting back into the patient population for the Ib.

這就是正在進行的工作，但它是專門針對健康的志願者群體的。正如我們之前所說，健康的志願者群體作為藥物開發計劃的一部分是一件好事，但這並不是絕對的要求，我們的首要任務是回到 Ib 患者群體中。

The next question comes from Edward Tenthoff with Piper Sandler.

下一個問題來自愛德華·滕托夫和派珀·桑德勒。

And just 2 questions, if I may. Firstly, welcome aboard, Alan. So with respect to the question, so you'll go back into healthy volunteers first most likely, is that true? And can you define what would be a long-term follow-up there? And how quickly do you think you could get back into sickle cell patients?

如果可以的話，只有兩個問題。首先，歡迎加入，艾倫。所以關於這個問題，你最有可能首先回到健康的志願者身上，這是真的嗎？您能否定義長期後續行動是什麼？您認為多久才能回到鐮狀細胞病患者身上？

And then I just wanted to follow up. Is there anything specific that needs to be done with losmapimod and REACH other than just executing on the trial to report the data late next year.

然後我只想跟進。除了明年年底執行試驗以報告數據之外，還需要對 Losmapimod 和 REACH 進行哪些具體操作？

Yes, it's great. Let me turn it over to Iain for the first question, then I'm happy to take the second question there, Ed. Thanks for asking both.

是的這很好。讓我把第一個問題交給伊恩，然後我很樂意回答第二個問題，艾德。感謝您同時詢問。

Yes. Thanks, Alex. And to be clear, the healthy volunteers and those (inaudible) are not linked in any way in terms of getting back into the clinic. The healthy volunteer studies that are typically done at this stage are things like a radiolabeled ADME study, which is a single dose study or a formulation switch study, again, typically a single-dose crossover type study that are supportive for the overall program, they're not required.

是的。謝謝，亞歷克斯。需要明確的是，健康志願者和那些（聽不清）在返回診所方面沒有任何联系。通常在這個階段進行的健康志願者研究是放射性標記的 ADME 研究，這是一項單劑量研究或配方轉換研究，同樣，通常是支持整個計劃的單劑量交叉類型研究，他們不需要。

And so again, our priority is to get back into the patients. There's not a requirement that there'd be any healthy volunteer studies initiated first. It's getting back into the patients and then the healthy volunteer studies will proceed in parallel as necessary. And if there are any issues in getting back into healthy volunteers, those types of studies can be done in the patient population, if needed. So it's not a requirement.

同樣，我們的首要任務是回到患者身邊。並不要求首先啟動任何健康的志願者研究。它會回到患者身上，然後健康志願者研究將根據需要並行進行。如果在恢復健康志願者方面存在任何問題，如果需要，可以在患者群體中進行此類研究。所以這不是一個要求。

Helpful clarification.

有用的澄清。

That's great. Ed, this is Alex. In terms of your second question, yes, we had announced in our earlier comments. We're delighted that screening has closed. This is a study that has enrolled very quickly. We would expect enrollment to close sometime later this quarter. So if you add 48 weeks to that, which is the duration of the study. That would put us out until sometime in the fourth quarter of next year to release top line and what you would see during that top line release -- would essentially be what you would expect to see will provide patient disposition, the balance between the [two arms]. We'll be providing the primary endpoint as well as the secondary endpoints, we'll report out on safety. And we are -- we would expect to see similar improvement that we saw in the ReDUX4 study across all of those key primary and secondary endpoints. So we're certainly looking forward to that day.

那太棒了。艾德，這是亞歷克斯。關於你的第二個問題，是的，我們在之前的評論中已經宣布了。我們很高興篩選已經結束。這是一項註冊速度非常快的研究。我們預計註冊將在本季度晚些時候的某個時候結束。如果再加上 48 週，這就是研究的持續時間。這將使我們要等到明年第四季度的某個時候才能發布頂線，而您在頂線發布期間會看到的內容基本上就是您期望看到的內容，它將提供患者的處置，[兩者之間的平衡]武器]。我們將提供主要終點和次要終點，我們將報告安全性。我們希望在所有這些關鍵的主要和次要終點上看到與我們在 ReDUX4 研究中看到的類似的改進。所以我們當然期待那一天的到來。

The next question comes from Dae Gon Ha with Stifel.

下一個問題來自 Dae Gon Ha 和 Stifel。

This is Benazir on for Dae Gon. Can you guys hear me now?

這是貝娜齊爾（Benazir）代表大貢（Dae Gon）出場。你們現在能聽到我說話嗎？

Yes, much better. Thank you so much.

是的，好多了。太感謝了。

Great. So one of our questions was, have there been any additional discussions with the FDA regarding DUX4 as a biomarker in FSHD and if DUX4 like data occurs in REACH with minimal effect on DUX4 composite score, but like a noteworthy benefit in a reachable workspace, how would they interpret that? And what about the EMA feedback as well?

偉大的。因此，我們的問題之一是，是否與FDA 就DUX4 作為FSHD 的生物標誌物進行了任何其他討論，以及如果REACH 中出現類似DUX4 的數據，對DUX4 綜合評分的影響最小，但就像在可到達的工作空間中具有顯著的好處一樣，如何他們會解釋嗎？ EMA 的反饋又如何呢？

Yes. Great question. I think to answer that, let me turn that 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. That has not been a topic of discussion with the regulators. The focus is on the endpoints as defined for the REACH study, which for the primary endpoint is obviously the reachable workspace and not the biomarker. The biomarker is not being evaluated in the REACH study at all. And that, as I said, has not been a topic of discussion.

是的。這尚未成為監管機構討論的話題。重點是 REACH 研究定義的終點，主要終點顯然是可到達的工作空間，而不是生物標誌物。 REACH 研究中根本沒有對該生物標誌物進行評估。正如我所說，這並不是討論的話題。

The next question comes from Matthew Biegler with OPCO.

下一個問題來自 OPCO 的 Matthew Biegler。

This is Matt Hagood on for Matt. I wanted to ask, just given the variability inherent in FSHD, could you talk about what gives you confidence that, that 1-year time line in the FSHD study will be long enough to make a meaningful impact on outcomes.

我是馬特·哈古德（Matt Hagood）為馬特代言。我想問的是，考慮到 FSHD 固有的變異性，您能否談談是什麼讓您相信 FSHD 研究的 1 年時間線將足夠長，足以對結果產生有意義的影響。

Yes. Iain?

是的。伊恩？

Yes. Thanks, Matt. So you're correct that there is heterogeneity in FSHD. I think that's pretty well described. We're very much encouraged by the data from the ReDUX4 Phase II study in 80 patients on the reachable workspace, which did show a nominally statistically significant difference between losmapimod and placebo in that study. So I think we're encouraged by that as we move into a larger number of patients 230 in the REACH study and the powering in that study is based on the observed effect seen in the ReDUX4 Phase II study.

是的。謝謝，馬特。所以你說 FSHD 存在異質性是正確的。我認為這描述得很好。我們對 ReDUX4 II 期研究的數據感到非常鼓舞，該研究對 80 名患者進行了可達工作空間，該數據確實顯示了該研究中 losmapimod 和安慰劑之間名義上的統計學顯著差異。因此，我認為，當我們在 REACH 研究中進入更多患者 230 名患者時，我們對此感到鼓舞，並且該研究的動力是基於 ReDUX4 II 期研究中觀察到的效果。

So that's with respect to the primary. And then one of the secondary endpoints in the REACH study is an MRI-based endpoint, which because it is a whole-body MRI assessment accounts for the heterogeneity at least across different muscles in any given patient and [samples] the muscles broadly across each patient. So I think that's helpful in that it's a more integrated evaluation. It's not focused purely on the upper extremity, which the reachable workspace does.

這就是關於初級的。 REACH 研究的次要終點之一是基於MRI 的終點，因為它是全身MRI 評估，至少解釋了任何特定患者不同肌肉之間的異質性，並且對每個患者的肌肉進行了廣泛的[採樣] 。病人。所以我認為這是有幫助的，因為這是一個更加綜合的評估。它並不像可到達的工作區那樣純粹關注上肢。

(Operator Instructions) The next question is from Judah Frommer with Credit Suisse.

（操作員說明）下一個問題來自瑞士信貸銀行的 Judah Frommer。

Congrats on the progress. Maybe just to put a finer point on the updates we can expect in sickle cell. I guess if all goes as planned, what would be the next update we would hear related to patients? And what would be the next update we would hear related to healthy volunteers? Just trying to figure out if those would come at the same time and which would come first?

祝賀取得的進展。也許只是為了更好地說明我們在鐮狀細胞中可以期待的更新。我想如果一切按計劃進行，我們聽到的與患者相關的下一個更新會是什麼？我們會聽到的與健康志願者相關的下一個更新是什麼？只是想弄清楚這些是否會同時出現以及哪個會先出現？

Yes. Great question, Judah. Thanks for asking. Let me sort of set the stage a little bit in terms of our thoughts on when we would expect to come off clinical hold, and then I'll turn it over to Iain to get more specifically into the questions that you posed.

是的。好問題，猶大。謝謝你的詢問。讓我就我們預計何時結束臨床擱置的想法做一些準備，然後我將把它交給伊恩，以更具體地討論你提出的問題。

So when the hold first came out at the end of February, I think it was around the beginning of March that we had guided to that it would take at least a minimum of 6 months in order to reach resolution with FDA. So that sort of puts us out until the September time frame.

因此，當 2 月底首次取消暫停時，我認為大約是在 3 月初，我們已指導至少需要 6 個月的時間才能與 FDA 達成解決方案。因此，這讓我們不得不推遲到 9 月份的時間範圍內。

So I would expect that we would be able to share with everybody the resolution that has been reached in the path forward with the FDA sometime probably in the fourth quarter of this year or possibly even the first quarter of next year. As I mentioned, the conversations with FDA continue to go well. I would define them as productive and very collaborative. But as many of you know, it's just -- there's a process when engaging with the FDA, and that process simply takes time.

因此，我希望我們能夠與大家分享在前進道路上與 FDA 達成的決議，可能是在今年第四季度，甚至可能是明年第一季度。正如我提到的，與 FDA 的對話繼續順利。我將他們定義為富有成效且協作性很強的人。但正如你們許多人所知，與 FDA 合作有一個過程，而這個過程只是需要時間。

And then once we get off hold, obviously, one of our key priorities as an organization is to reinitiate that Phase Ib study, begin dosing patients again with the 12-milligram, ideally 10 patients and then move to the 20. And our belief is that we'll continue to see these dose-dependent increases in HbF that we've been so happy with prior to the hold.

然後，一旦我們擺脫困境，顯然，我們作為一個組織的關鍵優先事項之一是重新啟動Ib 期研究，開始再次給患者服用12 毫克，最好是10 名患者，然後轉向20 名患者。我們的信念是我們將繼續看到 HbF 的劑量依賴性增加，在暫停之前我們對此感到非常滿意。

I think it's probably a little bit premature at this stage to guide when we would be able to report out either data from healthy volunteers or data from the other 2 cohorts the 12-milligram and the 20-milligram cohort that I mentioned in the Phase Ib study. But I don't know, Iain, if you have anything else you'd want to share.

我認為現階段指導我們何時能夠報告來自健康志願者的數據或來自其他兩個隊列（我在 Ib 階段提到的 12 毫克和 20 毫克隊列）的數據可能有點為時過早學習。但我不知道，伊恩，你是否還有什麼想分享的。

No. Just to reemphasize what I mentioned earlier in response to a question that the 2 populations, the healthy volunteer and the sickle cell patients are really quite distinct in terms of what is required to get back to those populations and that our primary focus is around getting back to the sickle cell patients until we'll announce when we've achieved agreements on that and we're moving forward with the study in the patient population for the healthy volunteers. It will likely be whatever the next healthy volunteer study happens to be, and that's likely what will be announced. But they're not linked, and they're not sequenced.

不。只是再次強調我之前在回答一個問題時提到的內容，即健康志願者和鐮狀細胞患者這兩個人群在返回這些人群所需的條件方面確實非常不同，而且我們的主要關注點是回到鐮狀細胞患者身上，直到我們就此達成協議時宣布，並且我們正在推進針對健康志願者的患者群體的研究。下一次健康志願者研究可能會是什麼，這很可能就是將要宣布的內容。但它們沒有聯繫，也沒有排序。

This concludes the question-and-answer portion of the call. I will now turn the call back over to Fulcrum's CEO, Alex for closing remarks. Alex?

通話的問答部分到此結束。我現在將把電話轉回 Fulcrum 的首席執行官 Alex 進行結束語。亞歷克斯？

That's great. Thanks, Michelle. So overall, I would say I'm very encouraged by the continued progress in the first half of 2023 and with our strong cash position out until mid-2025, we, as a team, look forward to executing on many of the key priorities for our 2 clinical programs in the months ahead.

那太棒了。謝謝，米歇爾。因此，總的來說，我想說，我對 2023 年上半年的持續進展感到非常鼓舞，並且我們在 2025 年中期之前擁有強勁的現金狀況，作為一個團隊，我們期待執行許多關鍵優先事項我們未來幾個月的2 個臨床項目。

And finally, let me just take this opportunity to express my sincere appreciation and gratitude to my fellow Fulcrum teammates, to the physicians we work with, to advance our clinical studies and finally, and most importantly, to the patients and their families. It's the efforts of this collective group of people that each day brings us one step closer to treating the root cause of genetically-defined rare diseases and bringing transformative therapies to patients.

最後，讓我藉此機會向我的 Fulcrum 隊友、與我們一起工作的醫生、推進我們的臨床研究以及最後最重要的患者及其家人表達我真誠的讚賞和感謝。正是這一群人的共同努力，讓我們每天都離治療基因罕見病的根本原因、為患者帶來變革性療法更近了一步。

So thanks again, everyone, for joining us on the call this morning. I look forward to seeing many of you at some of the upcoming fall investor conferences. Have a great rest of the day. Thanks.

再次感謝大家今天早上加入我們的電話會議。我期待在即將舉行的秋季投資者會議上見到你們中的許多人。祝你這一天好好休息。謝謝。

This concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。