Fulcrum Therapeutics Inc (FULC) 2023 Q4 法說會逐字稿

Good morning, and welcome to Fulcrum Therapeutics' fourth-quarter and full-year 2023 financial results and business update conference call. (Operator Instructions) 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 的第四季度和 2023 年全年財務業績和業務更新電話會議。（操作員說明）本次電話會議正在進行網路直播，可以在 Fulcrum 網站 www.fulcrumtx.com 的投資者部分進行觀看，並且正在錄音。

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

請注意，本次電話會議期間發表的言論可能包含 1995 年《私人安全訴訟改革法案》含義內的前瞻性聲明。這些可能包括有關公司未來預期、計劃、臨床開發時間表和財務預測的聲明。

While these forward-looking statements presents Fulcrum's view 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 it's not taking on an obligation to do so. Please refer to Fulcrum's most recent filing with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

雖然這些前瞻性陳述代表了 Fulcrum 目前的觀點，但不應依賴它們代表公司未來的觀點。Fulcrum 可能會在未來更新這些聲明，但它不承擔這樣做的義務。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. Ian Frazier, Interim Chief Medical Officer. After providing updates on our key programs, there will be a brief Q&A in which Alex, Alan, and Ian will be available to answer your questions.

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 Ian Frazier 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 Ian 將回答您的問題。

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

至此，我很高興將電話轉給亞歷克斯。

That's great. Thanks, Valerie. And thanks to all of you for joining us today. 2023 was a year in which we both completed enrollment in our Phase 3 REACH trial for losmapimod for facioscapulohumeral muscular dystrophy or FSHD for short and resolve the clinical hold for pociredir, which allowed us to resume clinical testing in patients with sickle cell disease.

那太棒了。謝謝，瓦萊麗。感謝大家今天加入我們。 2023 年，我們完成了losmapimod 治療面肩肱型肌肉營養不良症（簡稱FSHD）的3 期REACH 試驗的入組，並解決了pociredir 的臨床擱置問題，這使我們能夠恢復鐮狀細胞病患者的臨床測試。

In the fourth quarter, we continued to drive forward our two key clinical programs and advance our preclinical pipeline. And with our cash runway that extends into 2026, I do believe that we are well positioned to execute our corporate objectives and deliver on key milestones in 2024 and beyond. So at this point, let me go a bit deeper and elaborate on the progress we've made toward our goal of delivering transformative therapies to improve the lives of patients with rare genetic diseases.

第四季度，我們繼續推進兩個重點臨床項目並推進臨床前管線。憑藉我們延伸至 2026 年的現金跑道，我確實相信我們有能力執行我們的企業目標並在 2024 年及以後實現關鍵里程碑。因此，在這一點上，讓我更深入地闡述我們在實現提供變革性療法以改善罕見遺傳疾病患者生活的目標方面所取得的進展。

Let's start with our most advanced program, losmapimod, which is an oral small molecule p38 alpha-beta MAP kinase inhibitor currently in Phase 3 development for the treatment of FSHD.

讓我們從我們最先進的項目 losmapimod 開始，它是一種口服小分子 p38 α-β MAP 激酶抑製劑，目前處於 FSHD 治療的 3 期開發階段。

Now FSHD is a rare form of muscular dystrophy with an estimated US prevalent patient population of 30,000. FSHD is characterized by a slow but relentless loss of muscle function year after year, resulting in significant impairment of upper extremity muscle function and mobility.

現在，FSHD 是一種罕見的肌肉營養不良症，估計美國患病人數為 30,000 人。FSHD 的特徵是肌肉功能年復一年緩慢但持續喪失，導致上肢肌肉功能和活動能力顯著受損。

As a result, many patients are unable to perform daily life activities that you and I take for granted, such as reaching for a cup of coffee, reaching for a cup in the kitchen cabinet, brushing your teeth, feeding yourself, even practicing good hygiene. And about 20% of patients ultimately become wheelchair bound.

結果，許多患者無法進行你我認為理所當然的日常生活活動，例如伸手去拿一杯咖啡、伸手去廚房櫃子裡的杯子、刷牙、自己吃飯，甚至保持良好的衛生習慣。大約 20% 的患者最終只能坐輪椅。

Despite the high unmet need, there are currently no approved treatment options for these patients. So in our quest to bring hope for these patients, in September of last year, we completed enrollment in our global Phase 3 trial for losmapimod with a total of 260 patients enrolled in the trial.

儘管需求未被滿足，但目前尚無針對這些患者的核准治療方案。因此，為了給這些患者帶來希望，去年 9 月，我們完成了 Losmapimod 全球 3 期試驗的入組，共有 260 名患者入組。

The trial initiated in June 2022 and 15 months later, we had surpassed our enrollment expectations, which we believe is a real testament to the high unmet need for this rare disease. We are on track to report top-line data in the fourth quarter of 2024, which will bring us one step closer to delivering the first-ever FDA-approved therapy for FSHD patients.

該試驗於 2022 年 6 月啟動，15 個月後，我們的入組人數超出了預期，我們認為這真正證明了這種罕見疾病的需求尚未得到滿足。我們預計在 2024 年第四季報告主要數據，這將使我們距離為 FSHD 患者提供首個 FDA 批准的治療方法又更近了一步。

So just a quick reminder of some of the details around the Phase 3 study, which we call REACH. REACH is a 48-week trial intended to be registration enabling both in the US and in ex-US geographies. The primary endpoint for REACH is a change from baseline in the relative surface area or RSA, which is a quantitative assessment of reachable workspace.

快速提醒一下有關第三階段研究（我們稱之為 REACH）的一些細節。REACH 是一項為期 48 週的試驗，旨在在美國和美國以外進行註冊。REACH 的主要終點是相對表面積或 RSA 相對於基線的變化，這是對可達工作空間的定量評估。

RSA is an objective measure of upper extremity range of motion and muscle function that specifically evaluates shoulder and arm mobility using 3D motion sensor technology. In our Phase 2 study, losmapimod demonstrated a 10% change in the RSA score relative to placebo at 48 weeks. And based on interactions with FDA, we are currently assessing the extent to which a change in the RSA score is considered meaningful to patients.

RSA 是上肢運動範圍和肌肉功能的客觀測量方法，專門使用 3D 運動感測器技術評估肩部和手臂的活動能力。在我們的 2 期研究中，48 週時，losmapimod 的 RSA 評分相對於安慰劑有 10% 的變化。根據與 FDA 的互動，我們目前正在評估 RSA 評分的變化對患者有意義的程度。

Additionally, key secondary endpoints include muscle fat infiltration or MFI, which is an important marker of disease pathology measured by whole-body MRI, shoulder dynamometry, as well as self-reported quality-of-life measures that will help inform our thinking on our payer strategy as we begin preparing for our commercial launch here in the US.

此外，關鍵的次要終點包括肌肉脂肪浸潤或MFI，這是透過全身MRI、肩部測力以及自我報告的生活品質測量來測量的疾病病理學的重要標誌，這些測量將有助於我們思考我們的健康狀況。

Now turning to pociredir, our oral HbF inducer for the potential treatment of patients with sickle cell disease or SCD for short. Sickle cell is a lifelong inherited blood disorder that severely impacts quality of life for approximately 100,000 people in the US and approximately 4.4 million people worldwide.

現在轉向 pociredir，我們的口服 HbF 誘導劑，用於治療鐮狀細胞疾病或簡稱 SCD 患者。鐮狀細胞疾病是一種終生遺傳性血液疾病，嚴重影響美國約 10 萬人和全球約 440 萬人的生活品質。

Historically, the standard of treatment for sickle cell disease has involved blood transfusions, pain medications, and hydroxyurea, focusing primarily on symptom relief. And while exciting scientific progress has enabled the advancement and more recently the approval of gene-editing therapeutic approaches, we believe there remains a high unmet need for safe and accessible therapeutic options that are broadly protective of sickle cell symptomatology. As a first-in-class oral small molecule HbF inducer, we believe pociredir has the potential to address a critical unmet need for patients.

從歷史上看，鐮狀細胞疾病的治療標準涉及輸血、止痛藥和羥基脲，主要著重於緩解症狀。儘管令人興奮的科學進步推動了基因編輯治療方法的進步，並在最近獲得了批准，但我們認為，對廣泛保護鐮狀細胞症狀的安全且易於使用的治療方案的需求仍然存在很大的未滿足的需求。作為一流的口服小分子 HbF 誘導劑，我們相信 pociredir 有潛力解決患者未滿足的關鍵需求。

And just as a quick reminder, in August of 2023, the FDA lifted the clinical hold for pociredir. And I think it's also really important to note that there were no changes either in the protocol defined-dose escalation scheme or three-month treatment duration. Clinical trial sites have now been activated, and others have been selected and are going through the necessary steps for site activation in order to be ready for patient recruitment for the Phase 1b study we call PIONEER.

順便提醒一下，2023 年 8 月，FDA 取消了對 pociredir 的臨床擱置。我認為還需要注意的是，方案規定的劑量遞增方案或三個月的治療持續時間都沒有變化，這一點也非常重要。臨床試驗站點現已激活，其他站點也已選定，正在執行站點激活的必要步驟，以便為我們稱為 PIONEER 的 1b 期研究招募患者做好準備。

Based on the revised inclusion-exclusion criteria, we will be enrolling patients with high disease severity. Cohort 3 of the PIONEER study will evaluate pociredir at the 12-milligram once-daily dose followed by Cohort 4 at the 20-milligram once-daily dose. Both cohorts are expected to enroll approximately 10 patients each. And we look forward to providing specific guidance on readout of the 12-milligram and 20-milligram cohort as we have additional sites activated and a good basis to project enrollment trajectory.

根據修訂後的納入-排除標準，我們將招募疾病嚴重程度較高的患者。PIONEER 研究的第 3 組將評估 12 毫克每日一次劑量的 pociredir，隨後第 4 組將評估 20 毫克每日一次劑量的 pociredir。兩個隊列預計各招募約 10 名患者。我們期待為 12 毫克和 20 毫克隊列的讀數提供具體指導，因為我們已激活其他站點並為預測註冊軌跡奠定了良好的基礎。

We're looking forward to building on the encouraging clinical data obtained prior to the clinical hold, which demonstrated that pociredir increased total HbF of a magnitude that could translate into a meaningful improvement in disease severity. More specifically, after only 42 days of treatment, we observed up to a 10-percentage point increase in HbF from baseline or total HbF of approximately 25%.

我們期待以臨床暫停前獲得的令人鼓舞的臨床數據為基礎，這些數據表明 pociredir 使總 HbF 增加了一定程度，可以轉化為疾病嚴重程度的有意義的改善。更具體地說，僅經過 42 天的治療，我們就觀察到 HbF 較基線增加了 10 個百分點，或總 HbF 增加了約 25%。

We believe that pociredir as an oral HbF inducer has the potential to provide a differentiated therapeutic option for people living with sickle cell disease. Addressing the significant unmet need in the sickle cell community remains a key priority for us, and we are excited to build on this momentum in the years ahead.

我們相信 pociredir 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。解決鐮狀細胞群體中未滿足的重大需求仍然是我們的首要任務，我們很高興在未來幾年繼續保持這一勢頭。

So that's the clinical update. For the financial update, let me turn it over to Alan Musso, our Chief Financial Officer, who will walk you through some of the numbers. Alan, over to you.

這就是臨床更新。對於財務更新，讓我將其交給我們的財務長艾倫·穆索（Alan Musso），他將向您介紹一些數字。艾倫，交給你了。

Thanks, Alex. I'll now go over our results for the fourth quarter and full year ended December 31, 2023, beginning with the results for the quarter. Collaboration revenue was $0.9 million for the fourth quarter of 2023 compared to $0.7 million for the same period in 2022. Our research and development expenses were $19 million for the fourth quarter of 2023 compared to $18.6 million for the same period in 2022. The increase of $0.4 million was primarily due to higher personnel costs.

謝謝，亞歷克斯。我現在將回顧截至 2023 年 12 月 31 日的第四季和全年業績，從本季業績開始。2023 年第四季的協作收入為 90 萬美元，而 2022 年同期為 70 萬美元。2023 年第四季我們的研發費用為 1,900 萬美元，而 2022 年同期為 1,860 萬美元。增加 40 萬美元主要是因為人員成本增加。

General and administrative expenses were $9.9 million for the fourth quarter of 2023 compared to $10.1 million for the same period in 2022. The decrease of $0.2 million was primarily due to lower professional service costs. And for the fourth quarter of 2023, Fulcrum reported a net loss of $24.8 million compared to $26.1 million for the same period in 2022.

2023 年第四季的一般及管理費用為 990 萬美元，而 2022 年同期為 1,010 萬美元。減少 20 萬美元主要是因為專業服務成本降低。Fulcrum 報告 2023 年第四季淨虧損為 2,480 萬美元，而 2022 年同期淨虧損為 2,610 萬美元。

I'll now review the results for the year ended December 31, 2023. Collaboration revenue was $2.8 million for the year ended December 31, 2023, compared to $6.3 million for the same period in 2022. The lower collaboration revenue during 2023 was attributable to the completion of activities under our collaboration agreement with Acceleron, which terminated in October 2022, and due to a decrease in revenues under our collaboration agreement with MyoKardia as we completed our research services during the fourth quarter of 2023.

我現在將回顧截至 2023 年 12 月 31 日的年度業績。截至 2023 年 12 月 31 日止年度，合作收入為 280 萬美元，而 2022 年同期為 630 萬美元。2023 年合作收入較低的原因是我們與Acceleron 的合作協議項下的活動已完成（該協議於2022 年10 月終止），以及由於我們在2023 年第四季度完成了研究服務，因此我們與MyoKardia的合作協議項下的收入減少。

Our research and development expenses were $71.8 million for the year ended December 31, 2023, compared to $76.8 million in 2022. The decrease in 2023 was primarily attributable to a $5 million milestone obligation incurred upon the initiation of the REACH clinical trial in the second quarter of 2022 under our license agreement with GlaxoSmithKline. Our general and administrative expenses were $41.7 million for each of the years ended December 31, 2023, and 2022. The net loss was $97.3 million for the year ended December 31, 2023, compared to $109.9 million in 2022.

截至 2023 年 12 月 31 日止年度，我們的研發費用為 7,180 萬美元，而 2022 年為 7,680 萬美元。2023 年的下降主要歸因於根據我們與葛蘭素史克的許可協議於 2022 年第二季度啟動 REACH 臨床試驗而產生的 500 萬美元的里程碑義務。截至 2023 年 12 月 31 日及 2022 年 12 月 31 日止的年度，我們的一般及管理費用均為 4,170 萬美元。截至 2023 年 12 月 31 日止年度的淨虧損為 9,730 萬美元，而 2022 年為 1.099 億美元。

And now turning to the balance sheet, we ended 2023 with cash, cash equivalents, and marketable securities of $236.2 million compared to $202.9 million as of December 31, 2022. This increase in our cash position is primarily due to net proceeds from our January 2023 equity offering of $117.3 million, partially offset by our net cash used in operating activities in 2023. And during the fourth quarter of 2023, our cash burn was $20.9 million. We continue to operate from a strong financial position with a cash runway into 2026.

現在看資產負債表，截至 2023 年，我們的現金、現金等價物和有價證券為 2.362 億美元，而截至 2022 年 12 月 31 日為 2.029 億美元。我們現金部位的增加主要是因為我們 2023 年 1 月發行股票的淨收益為 1.173 億美元，部分被我們 2023 年經營活動所使用的淨現金所抵銷。2023 年第四季度，我們的現金消耗為 2,090 萬美元。到 2026 年，我們將繼續保持強勁的財務狀況和現金跑道。

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

接下來，讓我把電話轉回給亞歷克斯。

Great. Thanks so much, Alan. So as all of you can see, we are well positioned for a very exciting 2024 and are encouraged by the progress across our two clinical programs, losmapimod, which has the potential for -- which has first-in-market potential for patients with FSHD; and pociredir, which has best-in-class potential for patients living with sickle cell disease.

偉大的。非常感謝，艾倫。因此，正如大家所看到的，我們已準備好迎接非常激動人心的2024 年，並對我們的兩個臨床項目losmapimod 所取得的進展感到鼓舞，該項目有潛力為FSHD 患者提供市場上的首個潛力;和 pociredir，它對鐮狀細胞疾病患者俱有同類最佳的潛力。

So at this point, Valerie, let's go ahead and open it up for questions.

所以現在，瓦萊麗，讓我們繼續提問。

(Operator Instructions) Matthew Biegler, Oppenheimer.

（操作員說明）Matthew Biegler，Oppenheimer。

Hey. Good morning, guys. I just wanted to maybe tack on something you said about on the regulatory side of the coin here for losmapimod. Can you just walk us through your interactions with the FDA and where you are with discussions on the clinical benefit for reachable workspace, and I guess what you'll need to show in REACH to make them happy? Thanks.

嘿。早上好傢伙。我只是想補充一下您所說的有關洛斯馬莫德監管方面的內容。您能否向我們介紹一下您與 FDA 的互動以及您對可達工作空間的臨床益處的討論，我想您需要在 REACH 中展示什麼才能讓他們滿意？謝謝。

Yes, thanks so much, Matt, for the question and let me let me just say a couple of things. I will turn it over to Ian to go in a bit more detail. So the REACH study is a very well-powered study with the 260 patients that we had enrolled. We've got a 96% powering on that study. And we believe that that study has the potential to be registration enabling based on our interactions to date with FDA. But I think more specifically to answer your question around reachable workspace, let me turn that one over to Ian.

是的，非常感謝馬特提出這個問題，讓我簡單說幾句話。我會將其交給 Ian，讓其了解更多細節。因此，REACH 研究是一項非常有力的研究，我們招募了 260 名患者。我們對此研究的支持率為 96%。我們相信，根據我們迄今為止與 FDA 的互動，該研究有可能獲得註冊。但我想更具體地回答您有關可達工作空間的問題，讓我把這個問題交給 Ian。

Yes. Thanks, Alex, and thanks, Matt. So obviously, there are no drugs approved for FSHD. And so there's no precedent in the regulatory sphere for an endpoint. However, we have had a number of productive and indeed ongoing discussions with FDA involving both the review division, which is in neurology, as well as the core division. And we are executing on a plan that we've agreed upon with them that we believe will establish the clinical meaningfulness of the reachable workspace.

是的。謝謝，亞歷克斯，謝謝，馬特。顯然，目前還沒有批准用於 FSHD 的藥物。因此，端點的監管領域沒有先例。然而，我們與 FDA 進行了許多富有成效且持續的討論，涉及神經病學審查部門以及核心部門。我們正在執行與他們商定的一項計劃，我們相信該計劃將確立可及工作空間的臨床意義。

Specifically, there are a couple of components to that. First is that we are generating additional data from observational studies in FSHD. So this is not involving any treatment with losmapimod but observing these patients as requested by the agency to identify what is for them the most appropriate measures of change in upper extremity function. And this is achieved through evaluating items on patient-reported outcomes. The next step will be to apply those back to the REACH data themselves in order to derive what is the clinically meaningful threshold for reachable workspace.

具體來說，有幾個組成部分。首先，我們正在從 FSHD 的觀察性研究中產生更多數據。因此，這不涉及洛斯馬莫德的任何治療，而是按照該機構的要求觀察這些患者，以確定對他們來說上肢功能變化最合適的措施。這是透過評估患者報告的結果項目來實現的。下一步將是將這些應用回 REACH 資料本身，以便得出可到達工作空間的有臨床意義的閾值。

And then secondly, we are conducting a number of exit interviews of patients that have gone through the REACH study. And this will help to enhance our understanding as well as FDA's understanding of what a change in RWS means for them. And our expectation is that at the very latest, these data would all be available at the time of NDA submission. And of course, ultimately, FDA will also ultimately make the final determination as to what is considered clinically meaningful considering the totality of evidence.

其次，我們正在對已經完成 REACH 研究的患者進行一些退出訪談。這將有助於增強我們以及 FDA 對 RWS 變化對他們的意義。我們的期望是，最晚，這些數據將在提交新藥申請時全部可用。當然，最終 FDA 也將考慮到全部證據，最終決定什麼被認為具有臨床意義。

Okay, okay. So effectively, we can say that there needs to be a little bit more validation work done on the RWS assay, is that a fair characterization?

好吧好吧。因此，我們可以說，RWS 測定需要進行更多的驗證工作，這是一個公平的表徵嗎？

I think that the validation work on the instrument itself in terms of the test-retest capabilities, the training process that goes into it, the provision of the technical pieces of it, all of that has been done, and it's really quite satisfactory. I think it's the last remaining pieces around that the clinical meaningfulness and what is considered minimally clinically significant change.

我認為儀器本身的驗證工作，包括重測能力、訓練過程、技術部分的提供，所有這些都已經完成，而且確實非常令人滿意。我認為這是圍繞臨床意義和被認為是最低臨床顯著變化的最後剩下的部分。

Understood. Thanks a lot.

明白了。多謝。

Corinne Johnson, Goldman Sachs.

科琳·約翰遜，高盛。

Good morning. This is Craig on for Corinne. I guess one for us, how familiar are physicians with the reachable workspace endpoint? And can you describe some of your physician education efforts that you're planning once you have the data?

早安.這是為科琳代言的克雷格。我想對我們來說，醫生對可到達的工作空間端點有多熟悉？您能否描述一下您在獲得數據後計劃開展的一些醫生教育工作？

Great question, Craig, and thanks for asking that. I'll start, and then I'll certainly turn it over to Ian if he has any others. So I would say that reachable workspace is not a standard instrument that neuromuscular specialists currently use when evaluating their patients with FSHD. It is somewhat of a novel instrument. And so in terms of the answer to your question about what we're doing from an educational standpoint, really, train them on what reachable workspace is and what a change in reachable workspace actually means.

很好的問題，克雷格，感謝您提出這個問題。我會開始，然後如果伊恩還有其他的話，我一定會交給他。因此，我想說，可達工作空間並不是神經肌肉專家目前在評估 FSHD 患者時使用的標準工具。這在某種程度上是一種新穎的樂器。因此，就您從教育角度來看我們正在做什麼的問題的答案而言，實際上，培訓他們什麼是可達工作空間以及可達工作空間的變化實際上意味著什麼。

We're doing a number of programs throughout the year. We've got a program in two weeks at the at the MDA conference, a CME program in which we're actually spending a lot of time with the physicians that have signed up for that program. And we walk them through what is reachable workspace? What is a normal baseline for patients? And what does the change in reachable workspace actually mean?

我們全年都會開展許多項目。我們在兩週後的 MDA 會議上製定了一個計劃，這是一個 CME 計劃，在該計劃中，我們實際上花了很多時間與已簽約該計劃的醫生在一起。我們引導他們了解什麼是可達工作空間？患者的正常基線是多少？可到達工作空間的變化實際上意味著什麼？

The clinical meaningfulness of that change, going back to the first question that Matt asked, will ultimately be sort of determined once we have the REACH data. But there's a number of activities that we're doing this year and in 2025 to really educate physicians on reachable workspace so that when the data does come out, they've got some context for those results.

回到 Matt 提出的第一個問題，一旦我們獲得 REACH 數據，這項變更的臨床意義將最終得到確定。但是，我們今年和 2025 年將開展許多活動，真正讓醫生了解可到達的工作空間，以便當數據出來時，他們能夠了解這些結果的一些背景資訊。

Ian, anything you would add?

伊恩，你還有什麼要補充的嗎？

No, the only thing I would add perhaps is obviously all of the investigators in our clinical studies, both the ReDUX4 Phase 2 as well as REACH in Phase 3, we are very well familiar with it now because of their participation in the study, and they obviously speak to their colleagues as well. So I think there's some level of dissemination to the clinical trials themselves. And then additionally, as Alex said, we have some CME programs designed to inform and educate physicians around that.

不，我唯一要補充的可能是我們臨床研究中的所有研究人員，包括 ReDUX4 2 期和 REACH 3 期，我們現在非常熟悉它，因為他們參與了這項研究，並且顯然他們也會與同事交談。所以我認為臨床試驗本身有一定程度的傳播。此外，正如 Alex 所說，我們有一些 CME 項目，旨在為醫生提供相關資訊和教育。

Got it. Thank you very much.

知道了。非常感謝。

Thanks, Greg.

謝謝，格雷格。

Joseph Schwartz, Leerink Partners.

約瑟夫‧施瓦茨，Leerink Partners。

Hi, good morning. Andrea Park dialing in for, Joe. Thank you for taking our questions. The first one is on losmapimod. Given reachable workspace is in a standard instrument, now how can physicians measure benefit in the real world if they don't have access to the tools? Are there other metrics that could track with reachable workspace or clinically meaningful benefits? And I have a follow up. Thank you.

早安.安德里亞·帕克（Andrea Park）撥通電話，喬。感謝您接受我們的提問。第一個是losmapimod。鑑於可到達的工作空間位於標準儀器中，那麼如果醫生無法使用這些工具，他們如何衡量現實世界中的益處呢？是否有其他指標可以追蹤可達的工作空間或具有臨床意義的益處？我有一個後續行動。謝謝。

Okay, that's great. Yes, I think -- thanks for So much for the question. I think to answer that, let me turn that over to Ian, our Chief Medical Officer.

好的，太好了。是的，我想——非常感謝您提出這個問題。我想回答這個問題，讓我把這個問題交給我們的首席醫療官伊恩。

I think the advantage of the reachable workspace is that it provides a quantitative assessment that the treating physicians typically use in a more qualitative sense to understand how their patients are doing. So it allows us to put some numbers around those qualitative terms. And since there haven't been any therapies that alter the course of the disease available to date, there's really been no need to do that. All the therapy is symptomatic to this point. So it's really adding a little bit of quantitative measures around the more qualitative sense in the clinic.

我認為可及的工作空間的優點是它提供了定量評估，治療醫生通常在更定性的意義上使用該評估來了解患者的情況。因此，它使我們能夠在這些定性術語周圍添加一些數字。由於迄今為止還沒有任何可以改變疾病進程的療法，因此實際上沒有必要這樣做。到目前為止，所有的治療都是針對症狀的。因此，它實際上是在臨床中圍繞更定性的意義添加了一些定量措施。

I think the important pieces to point out here are, number one, that reachable workspace has been shown previously, prior to Fulcrum's involvement, that FSHD patients exhibit a decline in their reachable workspace over time. That's in a small natural history study that was published several years ago, and that's consistent with clinical observations around measuring muscle strength by more traditional measures like dynamometry, for example.

我認為這裡要指出的重要一點是，第一，在 Fulcrum 參與之前，先前已經表明，FSHD 患者的可到達工作空間隨著時間的推移而下降。這是幾年前發表的一項小型自然史研究中的結果，這與透過測力等更傳統的方法測量肌肉力量的臨床觀察結果是一致的。

We know that in addition, the reachable workspace correlates with instruments, patient-reported outcome instruments, such as the [neurological] upper extremity questionnaire and that work has been published. And we've also shown from our Phase 2 data the correlation between the reachable workspace and the shoulder at the dynamometry. And it's the shoulder at the dynamometry because obviously, reachable workspace is focused on the upper extremity and the shoulder and that there's major muscle component of that.

此外，我們知道，可到達的工作空間與儀器、患者報告的結果儀器（例如[神經學]上肢問卷）相關，並且該工作已發表。我們也根據第二階段的數據顯示了可到達工作空間與測力時肩膀之間的相關性。測力計中的肩膀是因為顯然，可到達的工作空間集中在上肢和肩膀上，並且其中有主要的肌肉成分。

So there are correlations that have been observed in the reachable workspace. And as I say, probably most importantly, it's that documentation of the decline experienced by these patients. And that's what the patients report. It's this inevitable decline over time. And that's something that the treating physicians and caregivers also report. And so there's consistency in the measure from that respect as well.

因此，在可達工作空間中觀察到了相關性。正如我所說，可能最重要的是這些患者所經歷的衰退的記錄。這就是患者的報告。隨著時間的推移，這是不可避免的衰退。治療醫生和護理人員也報告了這一點。因此，從這方面來看，衡量標準也具有一致性。

Okay, got it. Thank you. And then my second question is on pociredir. I know that baseline characteristics like HbF can play a role in how much HbF you can achieve. So would it be possible to provide patient baseline characteristics ahead of your next update that we can better contextualize and appreciate the data when they're released? Thank you very much.

好，知道了。謝謝。我的第二個問題是關於 pociredir 的。我知道 HbF 等基線特徵會影響您能達到多少 HbF。那麼，是否有可能在下次更新之前提供患者基線特徵，以便我們在數據發佈時更好地了解數據並對其進行評估？非常感謝。

Yes, this is Ian again. So maybe I can just add that we do have in our corporate presentation on the web the data from the initial 16 patients that were enrolled in the study that includes a plot of their HbF, and it includes the baseline fetal hemoglobin that they went in with. The comment that I would make there is that there was a range of baseline HbF, and I think speaking from memory, it was about 3% at the low end and just under 20% at the at the high end. And we know that in the sickle cell patient population in general, it's around 5% to 10% of the average baseline.

是的，這又是伊恩。所以也許我可以補充一點，我們在網路上的公司演示中確實有來自最初 16 名參與研究的患者的數據，其中包括他們的 HbF 曲線圖，以及他們參與研究時的基線胎兒血紅蛋白。我要評論的是，HbF 基線有一個範圍，我認為從記憶來看，低端約為 3%，高端略低於 20%。我們知道，在一般鐮狀細胞患者群體中，這一比例約為平均基線的 5% 至 10%。

So we've seen to date a pretty wide spread across baseline HbFs. And while we don't have three-month data in all of those patients, certainly the initial slope of the increase in HbF across all of those baselines look pretty similar. So it didn't appear that those that were starting out higher had a lower response or vice versa.

因此，迄今為止，我們已經看到基線 HbF 的分佈相當廣泛。雖然我們沒有所有這些患者的三個月數據，但所有這些基線的 HbF 增加的初始斜率肯定看起來非常相似。因此，那些起點較高的人的反應似乎並不較低，反之亦然。

I think where -- the critical piece of this is where did the patients end up with after three months. It looks like from the 6-milligram data that we have, which is the highest dose that's gone out to three months, may not even be plateauing fully at the three-month mark. And so that will obviously need to be evaluated further as we move through the process. But we will -- once we have the data around the fetal hemoglobin, we will reveal those baseline HbFs as well because it is an important component.

我認為最關鍵的是三個月後患者最終去了哪裡。從我們掌握的 6 毫克數據來看，這是三個月以來的最高劑量，但在三個月後可能還沒有完全達到穩定水平。因此，在我們完成整個過程時，顯然需要進一步評估。但一旦我們獲得了胎兒血紅蛋白的數據，我們就會揭示那些基線 HbF，因為它是一個重要的組成部分。

Dae Gon Ha, Stifel.

大貢河，斯蒂菲爾。

Good morning. Thanks for taking our questions, and congrats on the progress. Three questions, if I may. One, Alex, have you guys actually started some pre-commercialization work with the payers specifically? I think there was quite a bit of questions around physicians and their comfort as well as the regulators, but how do payers feel about the reachable workspace and the magnitude you showed so far?

早安.感謝您提出我們的問題，並祝賀我們的進展。如果可以的話，我問三個問題。第一，亞歷克斯，你們真的已經開始專門與付款人進行一些預商業化工作了嗎？我認為圍繞著醫生及其舒適度以及監管機構存在很多問題，但是付款人對可到達的工作空間以及迄今為止所表現出的規模有何感想？

Second, sticking with losmapimod, the 10% change you detected in ReDUX4, I was wondering if you could go into a little bit more on the test-retest variability you mentioned to an earlier question. Any other evidence you can point to that kind of gives us some comfort around your Phase 3 REACH powering? And then I've got a follow up on the pociredir story.

其次，堅持使用 losmapimod，也就是您在 ReDUX4 中檢測到的 10% 變化，我想知道您是否可以進一步討論您在先前的問題中提到的重測變異性。您能指出的任何其他證據可以讓我們對您的第 3 階段 REACH 供電感到放心嗎？然後我對 pociredir 的故事進行了後續報導。

Okay, great. Yes, why don't I -- I'll take question one, and then I'll turn question number two over to over to Ian. And then we'll come back to you for question number three.

好的，太好了。是的，為什麼我不——我將回答第一個問題，然後我將第二個問題交給伊恩。然後我們會再回答您的第三個問題。

Thanks, Dae Gon. I think, really -- a really good question. So yes, we have done some initial payer work, both in the US as well as ex-US. And I don't remember the specifics of the study that we did, but I think it was around 10 payers that we had spoken to and shared with them the target product profile and shared with them the results of the ReDUX4 study. And they obviously were well aware that there were no available treatment options for these patients.

謝謝，大袞。我認為，確實是一個非常好的問題。所以，是的，我們已經在美國和美國以外完成了一些初始付款人工作。我不記得我們所做的研究的具體內容，但我認為我們與大約 10 個付款人交談並與他們分享了目標產品概況，並與他們分享了 ReDUX4 研究的結果。他們顯然很清楚這些患者沒有可用的治療選擇。

The objective of the work that we did was really to try to understand their thoughts around pricing. And what we heard loud and clear from those payers is that they would expect that when this drug gets approved and comes to market that it would command rare disease type pricing such as in the hundreds of thousands of dollars.

我們所做工作的目的實際上是嘗試了解他們對定價的想法。我們從這些付款人那裡清楚地聽到的是，他們預計當這種藥物獲得批准並上市時，它將獲得罕見疾病類型的定價，例如數十萬美元。

I think probably a really good comp to look at would be the pricing that Biogen has with SKYCLARYS. SKYCLARYS targets Friedreich's ataxia. Again, neuromuscular disease, not a lot of mortality, but high morbidity, so very, very similar to what we see with FSHD. The biggest difference between FA and FSHD is the prevalent population. FSHD is about four times the size.

我認為，百健 (Biogen) 與 SKYCLARYS 的定價可能是一個非常值得關注的比較。SKYCLARYS 針對弗里德賴希的共濟失調症。再次強調，神經肌肉疾病的死亡率並不高，但發病率很高，與我們在 FSHD 中看到的情況非常非常相似。FA 和 FSHD 之間最大的區別在於流行人群。FSHD 的大小約為其四倍。

So the payer work that we've done, albeit somewhat limited to date, really been around pricing. And the feedback that we've heard from payers is that they would expect this as the first entrant in a rare disease to be priced in the hundreds of thousands of dollars similar to other rare disease therapies.

因此，我們所做的付款人工作雖然迄今為止有所限制，但實際上是圍繞定價進行的。我們從付款人那裡聽到的反饋是，他們希望這是一種罕見疾病的第一個進入者，其定價與其他罕見疾病療法類似，為數十萬美元。

I will say, Dae Gon, the other thing that we're also doing -- well, this hasn't been confirmed with payers. I think our instinct is that payers will require a confirmed genetic test of FSHD before approving the product. And as of right now, because there are no treatment options for patients with FSHD, very little genetic testing is done. And of the genetic testing that is done, it's clunky in that it takes a lot of time to get these genetic tests back. They're expensive. Sometimes, the insurance company will pay for it. Sometimes, they won't.

我想說的是，Dae Gon，我們也在做的另一件事——嗯，這還沒有得到付款人的證實。我認為我們的直覺是，付款人在批准產品之前需要對 FSHD 進行確認的基因測試。截至目前，由於 FSHD 患者沒有治療選擇，因此很少進行基因檢測。對於已完成的基因測試來說，它很笨重，因為需要花費大量時間才能恢復這些基因測試。它們很貴。有時，保險公司會支付費用。有時，他們不會。

So that's an area that we're going to spend a lot of time on in 2024 and 2025 to really streamline that process of genetic testing because right now, it is not as efficient as we feel like it needs to be at the time that we launch, given our instinctive assumption that payers will require confirmed genetic testing before agreeing to approve the drug.

因此，我們將在 2024 年和 2025 年在這個領域花費大量時間，以真正簡化基因檢測流程，因為目前，它的效率並不像我們認為的那樣高效。同意批准該藥物之前需要經過確認的基因檢測。

So on the second question, Ian, maybe I'll turn that one over to you.

那麼，關於第二個問題，伊恩，也許我會把這個問題交給你。

Yes, sure. So briefly, just to recap the ReDUX4 reachable workspace data, as you indicated, showed that 10-percentage-point treatment effect difference that was derived from a repeated measures model that was used to assess that endpoint, and that is the same model that will be used for the REACH study.

是的，當然。簡而言之，正如您所指出的，回顧 ReDUX4 可到達工作區數據，顯示 10 個百分點的治療效果差異源自於用於評估該終點的重複測量模型，並且該模型將用於 REACH 研究。

And just to recap, that includes evaluations at baseline week 4, week 12, 24, 36, and 48. So it's not just a single comparison of the week 48 out to the baseline value. So it incorporates all of those measures over time. And the treatment effect difference on an RSA unit score was about 0.05 with a baseline reachable workspace score in those patients of 0.54 to 0.53. That's five quadrants. So the theoretical max, there would be 1.25 just to contextualize that.

回顧一下，這包括基線第 4 週、第 12 週、第 24 週、第 36 週和第 48 週的評估。因此，這不僅僅是第 48 週與基線值的單次比較。因此，隨著時間的推移，它將納入所有這些措施。RSA 單位評分的治療效果差異約為 0.05，這些患者的基線可達工作空間評分為 0.54 至 0.53。那是五個像限。因此，理論上的最大值為 1.25，只是為了說明這一點。

So those are the data points that were used to power the Phase 3 REACH study. 230 patients originally projected, and 260 finally enrolled in that study. With respect to the test-retest, so we do have that. I don't have that number in front of me, and we can circle back to you with that. That's in the published literature that certainly can confirm that aspect outside of the ReDUX4 study. The variability in the change from baseline in reachable workspace, that standard deviation went into the power calculations for the REACH study. And so we are incorporating not just the treatment effect size but also the variability from that in ReDUX4.

這些是用來支持第三階段 REACH 研究的數據點。最初預計有 230 名患者參加研究，最終有 260 名患者參加。關於重測，我們確實有。我面前沒有這個號碼，我們可以用這個號碼回電給您。已發表的文獻肯定可以在 ReDUX4 研究之外證實這一點。可到達工作空間相對於基線變化的變異性，即標準差，已納入 REACH 研究的功效計算中。因此，我們不僅考慮了治療效果的大小，也考慮了 ReDUX4 中治療效果的變異性。

Okay. I appreciate the color there. Switching gears to pociredir, Alex, on the site activation, it seems like you're making some progress on certain sites that have already been activated, but you're also going out to activate more. Just wondering, for those that you're working on now, what are some pushes and pulls you're hearing from them before they can get on board? And sort of separate to that is what piece of data are you looking to collect to further expand the TAM of pociredir longer term? Thanks so much, guys.

好的。我很欣賞那裡的顏色。Alex，在網站啟動方面切換到 pociredir，看起來您在某些已啟動的網站上取得了一些進展，但您也將出去啟動更多網站。只是想知道，對於那些你現在正在工作的人來說，在他們加入之前，你從他們那裡聽到了哪些推動和拉動？與此不同的是，您希望收集哪些數據來進一步擴展 pociredir 的長期 TAM？非常感謝，夥計們。

Yes, great question, Dae Gon. Thanks for asking those. Yes, I think the -- or actually, let me back up a little bit. So at the ASH meeting, we had an opportunity to probably interact on a one-on-one basis with maybe 30 of the top thought leaders in sickle cell.

是的，很好的問題，大坤。謝謝你問這些。是的，我認為——或者實際上，讓我稍微備份一下。因此，在 ASH 會議上，我們有機會與大約 30 位鐮狀細胞疾病領域的頂尖思想領袖進行一對一的互動。

And I think while there were a minority of physicians that said that they weren't interested in participating in this study, primarily because of the fact that it is a small study and it's a new site and it's going to take nine months to get that site up and running and they may only be able to give us sort of one to two patients, they said, for the time being, we're going to sit on the sidelines. Then come back to us once you are ready to enroll in a larger sort of Phase 2/3 study.

我認為，雖然有少數醫生表示他們對參與這項研究不感興趣，主要是因為這是一項小型研究，而且是一個新站點，需要九個月的時間才能獲得結果他們說，站點已啟動並正在運行，他們可能只能為我們提供一到兩名患者，目前我們將袖手旁觀。當您準備好參加更大規模的 2/3 階段研究時，請回來與我們聯繫。

So the sites that we're talking to right now are all sites that have expressed an interest, and a lot of those are many of those physicians that we spoke to at ASH. I would say the majority of those physicians that we spoke to were very interested in the potential that pociredir could bring to their patients.

因此，我們現在正在交談的網站都是表示有興趣的網站，其中許多是我們在 ASH 交談過的醫生。我想說，我們採訪過的大多數醫生都對 pociredir 為患者帶來的潛力非常感興趣。

So all the sites that we're talking with right now, we've sort of screened out all those that are no longer interested. And so we essentially have identified a series of sites that are very interested in participating. And essentially, we're just going through getting the IRBs to approve it, getting the contracts through.

因此，我們現在正在談論的所有網站，我們都篩選掉了所有不再感興趣的網站。因此，我們基本上已經確定了一系列非常有興趣參與的網站。本質上，我們只是讓IRB批准它，讓合約通過。

And the second question -- second part of that question, Dae Gon?

第二個問題－問題的第二部分，Dae Gon？

Yeah, with regards to the trial -- the PIONEER trial, I mean, your long-term goal is to eventually expand the TAM, right, given the high severity of disease right now? So what kind of data are you looking to collect in PIONEER before you can look to expand that?

是的，關於試驗——PIONEER 試驗，我的意思是，考慮到目前疾病的嚴重程度，你們的長期目標是最終擴大 TAM，對吧？那麼，在擴展資料之前，您希望在 PIONEER 中收集什麼樣的資料呢？

Yeah, great question. And I think some of that has to do with conversations that we've had with the agency to date, and Ian has been intimately involved in those conversations. Maybe I'll turn that one over to Ian.

是的，很好的問題。我認為其中一些與我們迄今為止與該機構進行的對話有關，伊恩一直密切參與這些對話。也許我會把這個交給伊恩。

Yeah, absolutely, Alex. It is clear that the agency thinks of this in terms of risk and benefits. And they articulated that certainly in terms of their dealings with the gene therapy approaches in particular, which we know are associated with pretty significant risks, including malignancy, with the black box warning going to the Bluebird product. However, they feel that they understand the upside and the benefits of those therapies much better than they do with something like pociredir, which is still in early development.

是的，絕對是，亞歷克斯。顯然，該機構從風險和利益的角度考慮了這一點。他們明確表達了這一點，特別是在處理基因治療方法方面，我們知道基因治療方法與相當大的風險有關，包括惡性腫瘤，藍鳥產品帶有黑框警告。然而，他們認為自己比 pociredir 等療法更了解這些療法的優點和好處，後者仍處於早期開發階段。

So I think the initial approach here is in the context of the PIONEER study. This three-month study is really to articulate fully at doses that we think are likely to be therapeutic, which are the 12-milligram and potentially the 20-milligram once-daily doses, what sort of fetal hemoglobin inductions we can see in those patients.

所以我認為這裡最初的方法是在 PIONEER 研究的背景下進行的。這項為期三個月的研究實際上是為了充分闡明我們認為可能具有治療作用的劑量，即每天一次的12 毫克劑量和可能的20 毫克劑量，我們可以在這些患者中看到什麼樣的胎兒血紅蛋白誘導。

And I think really demonstrating that and based on our initial experience at the 12-milligram dose, which only went up to six weeks or so, we feel that there -- patients will be able to reach that high 20%, maybe even low 30% range where the disease becomes transformative. And so it's really filling out the efficacy side, at least in the first instance, on HbF before being able to go back to the agency and a, to relax some of the inclusion-exclusion criteria in the first instance; and b, to extend the dosing beyond the three months, which is the context of the current trial.

我認為真正證明了這一點，根據我們在 12 毫克劑量方面的初步經驗（僅持續了六週左右），我們認為患者將能夠達到高 20%，甚至低 30%疾病發生轉變的百分比範圍。因此，至少在第一個例子中，它實際上是在滿足 HbF 的功效方面，然後才能返回到該機構，並且首先放寬一些納入排除標準； b，將給藥時間延長至三個月以上，這是目前試驗的背景。

Excellent. Thank you very much, guys.

出色的。非常感謝你們。

Thanks, Dae Gon.

謝謝，大袞。

Thank you. 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?

謝謝。通話的問答部分到此結束。現在，我將把電話轉回 Fulcrum 的執行長 Alex，讓其結束語。亞歷克斯？

Thanks so much, Valerie. And I guess just to wrap up, as you can see from our progress that we've made and our plans for 2024, we remain deeply committed to treat the root causes of genetically defined rare diseases and bring in these transformative therapies to patients.

非常感謝，瓦萊麗。我想總結一下，正如您從我們所取得的進展和 2024 年的計劃中看到的那樣，我們仍然堅定地致力於治療基因定義的罕見疾病的根本原因，並將這些變革性療法帶給患者。

And before we conclude today's call, as I always do, I would like to extend 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. Thanks again to everyone who joined this morning, and please stay safe and healthy. Thanks so much.

在我們結束今天的電話會議之前，像往常一樣，我想向我的 Fulcrum 隊友、與我們合作推進臨床研究的醫生，以及最後也是最重要的向患者和患者致以誠摯的讚賞和感謝。家人。再次感謝今天早上加入的所有人，請保持安全和健康。非常感謝。

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.

謝謝。女士們、先生們，今天的會議到此結束。感謝大家的參與。您現在可以斷開連線。祝你有美好的一天。