Cytokinetics Inc (CYTK) 2024 Q3 法說會逐字稿

Good afternoon, and welcome to Cytokinetics' third-quarter 2024 conference call. At this time, I would like to inform you that this call is being recorded and that all participants are in a listen-only mode. (Operator Instructions)

下午好，歡迎參加 Cytokinetics 2024 年第三季電話會議。目前，我想通知您，本次通話正在錄音，所有參與者都處於只聽模式。（操作員指令）

I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please go ahead.

現在我將電話轉給 Cytokinetics 公司事務資深副總裁 Diane Weiser。請繼續。

Good afternoon, and thanks for joining us on the call today.

下午好，感謝您今天的電話會議。

Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Fady Malik, EVP of R&D, will provide updates related to the clinical development program for aficamten. Andrew Callos, EVP and Chief Commercial Officer, will address commercial readiness activities for aficamten.

總裁兼執行長羅伯特布魯姆 (Robert Blum) 將首先介紹本季的情況和最新發展情況。研發執行副總裁 Fady Malik 將提供有關 aficamten 臨床開發計劃的最新資訊。執行副總裁兼商務長 Andrew Callos 將負責 Aficamten 的商業準備活動。

Stuart Kupfer, SVP and Chief Medical Officer, will provide updates regarding omecamtiv mecarbil, CK-586, and our earlier-stage development pipeline. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the third quarter. And finally, Robert will review our corporate development strategies and review expected upcoming milestones.

高級副總裁兼首席醫療官 Stuart Kupfer 將提供有關 omecamtiv mecarbil、CK-586 和我們早期開發管道的最新進展。執行副總裁兼財務長 Sung Lee 將提供第三季的財務概覽。最後，羅伯特將回顧我們的公司發展策略並回顧預期的未來里程碑。

Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Our actual results might differ materially from those projected in these forward-looking statements.

請注意，以下討論的部分內容（包括我們對問題的回答）包含與未來事件和表現而非歷史事實相關的陳述，並構成前瞻性陳述。我們的實際結果可能與這些前瞻性陳述中的預測有重大差異。

Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our third-quarter 2024 financial results filed on Form 8-K that was furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call.

有關可能導致我們的實際結果與這些前瞻性陳述存在重大差異的因素的其他資訊包含在我們向美國證券交易委員會提交的文件中，包括我們今天向美國證券交易委員會提交的 8-K 表上的 2024 年第三季度財務業績當前報告。我們不承擔本次電話會議後更新任何前瞻性聲明的義務。

And now, I will turn the call over to Robert.

現在，我將電話轉給羅伯特。

Thank you, Diane and thanks to all for joining us today. As we communicated just a few weeks ago at our Investor and Analyst Day, we made significant progress across our pipeline in the third quarter.

謝謝你，黛安，也謝謝大家今天的到來。正如我們幾週前在投資者與分析師日上所傳達的那樣，我們在第三季度取得了重大進展。

Most importantly, we completed the rolling submission and submitted our new drug application to the FDA for aficamten. This is an exciting milestone for Cytokinetics as well as the physician and patient communities and it brings us one step closer to hopefully bringing aficamten to patients suffering from obstructive HCM. It reflects a tremendous amount of work from our colleagues for which we're especially grateful.

最重要的是，我們完成了滾動提交，並向 FDA 提交了阿菲坎滕的新藥申請。這對於 Cytokinetics 以及醫生和患者群體來說都是一個激動人心的里程碑，它使我們距離為患有阻塞性 HCM 的患者提供 aficamten 的希望更近了一步。這體現了我們同事們的大量工作，對此我們特別表示感謝。

While we have requested priority review of the submission, our base case is standard review. The next step will be the expected announcement of filing acceptance and assigned PDUFA date.

雖然我們已要求對提交的內容進行優先審查，但我們的基本情況是標準審查。下一步將是預期的申請受理公告和指定的 PDUFA 日期。

During Q3, we also supported CORXEL, formerly Ji Xing, in filing the NDA in China for aficamten for obstructive HCM, which we're pleased to announce today was recently accepted for filing.

在第三季度，我們也支持 CORXEL（前身為吉星）在中國提交了用於治療阻塞性 HCM 的阿菲坎汀的 NDA，我們今天很高興地宣布，該申請最近已被接受提交。

Meanwhile, our commercial preparations for the potential approval and launch of aficamten in the United States are dialing up according to plan. As Andrew will elaborate, we're executing prelaunch activities, including recently launching an HCM disease awareness campaign for health care professionals.

同時，我們為阿法坎汀在美國獲得批准和上市所做的商業準備正在按計劃進行。正如安德魯所詳細說明的，我們正在執行預發布活動，包括最近針對醫療保健專業人士發起的 HCM 疾病宣傳活動。

In addition, we selected third-party external partners to support education, distribution and patient support, altogether forming a bespoke patient experience. And we refined sales territory configurations as well as sales training and recruiting programs in the United States, while we also concurrently hired our initial geographic and functional team leaders in Europe.

此外，我們也選擇了第三方外部合作夥伴來支持教育、分銷和病患支持，共同形成客製化的病患體驗。我們完善了美國的銷售區域配置以及銷售培訓和招聘計劃，同時也在歐洲聘請了最初的地理和職能團隊領導人。

During the quarter, we continued to present and publish additional data from SEQUOIA-HCM, further strengthening the evidence supporting its potential next-in-class safety and efficacy profile. As Fady will elaborate, the additional analyses show that treatment with aficamten is associated with improvements in exercise capacity, gradients, symptoms, biomarkers, cardiac structure and function as well as favorable cardiac remodeling.

在本季度，我們繼續展示和發布來自 SEQUOIA-HCM 的更多數據，進一步加強了支持其潛在的同類安全性和有效性的證據。正如 Fady 所詳細闡述的，額外的分析表明，使用阿菲坎特治療與運動能力、梯度、症狀、生物標記、心臟結構和功能的改善以及有利的心臟重塑有關。

Together, these analyses expand in meaningful ways on the overall profile of aficamten and are enabling of the positioning that we foresee for a next-in-class cardiac myosin inhibitor that we believe can expand the category and activate broader adoption.

總的來說，這些分析對阿菲坎汀的整體概況進行了有意義的擴展，並且使我們能夠預見其作為下一代心臟肌球蛋白抑制劑的定位，我們相信這可以擴大該類別並激活更廣泛的應用。

Beyond aficamten, we prepared to start two new clinical trials from within our emerging specialty cardiology franchise, COMET-HCF, the confirmatory Phase III clinical trial of omecamtiv mecarbil and AMBER-HFpEF, the Phase II clinical trial of CK-586.

除了阿菲坎頓 (aficamten) 之外，我們還準備在我們新興的專業心臟病學特許經營權內啟動兩項新的臨床試驗，即 COMET-HCF、omecamtiv mecarbil 的確認性 III 期臨床試驗和 AMBER-HFpEF、CK-586 的 II 期臨床試驗。

As Stuart will share, each of omecamtiv mecarbil and CK-586 offers an opportunity to expand our specialty cardiology franchise by targeting underserved populations at opposite ends of the spectrum of heart failure, those with severely reduced ejection fraction and those with supernormal ejection fraction.

正如 Stuart (Stuart) 所說，omecamtiv mecarbil 和 CK-586 均提供了擴大我們專科心臟病學特許經營權的機會，透過針對心臟衰竭譜兩端的服務不足的人群，即射血分數嚴重降低的人群和射血分數。

Finally, while our specialty cardiology franchise remains our top priority, our research dedicated to novel muscle-directed therapies has continued within our labs in South San Francisco and our long-standing innovation in muscle biology continues with another promising drug candidate called CK-089, readying to begin a first-in-human study.

最後，雖然我們的專業心臟病學特許經營權仍然是我們的首要任務，但我們對新型肌肉導向療法的研究仍在南舊金山的實驗室內繼續進行，我們在肌肉生物學領域的長期創新也繼續進行，另一種有前途的候選藥物 CK-089 已準備好開始首次人體研究。

CK-089 is a fast skeletal muscle troponin activator, which we believe may have potential therapeutic application to a specific type of muscular dystrophy. You'll be hearing more about how we have applied lessons learned with prior fast skeletal troponin activators to our next level plans for CK-089 as it will soon begin clinical development in this fourth quarter.

CK-089 是一種快速骨骼肌肌鈣蛋白激活劑，我們相信它可能對特定類型的肌肉營養不良症具有潛在的治療作用。您將會聽到更多關於我們如何將從先前的快速骨骼肌鈣蛋白激活劑中獲得的經驗教訓應用到 CK-089 的下一階段計劃中的信息，因為它將很快在第四季度開始臨床開發。

Where we stand today at Cytokinetics is a reflection of thoughtful planning, strategic positioning and prudent capital deployment, all in service of realizing the full potential of our muscle biology platform. We are not a company expecting to simply build for the success of a single drug candidate.

我們今天在 Cytokinetics 所處的地位反映了深思熟慮的規劃、策略定位和審慎的資本配置，所有這些都是為了充分發揮我們肌肉生物學平台的潛力。我們不是一家僅僅期望單一候選藥物成功的公司。

Instead, we're focused on building momentum across our pipeline and planning for our future by prosecuting a portfolio of multiple muscle-directed drug candidates designed to address diseases of high unmet need. By doing so we hope to impact the lives of both patients as well as return meaningful value to shareholders in enduring ways.

相反，我們專注於在整個產品線中建立勢頭，並透過起訴多個肌肉導向候選藥物組合來規劃我們的未來，這些藥物旨在解決高度未滿足的疾病需求。透過這樣做，我們希望影響患者的生活，並以持久的方式為股東帶來有意義的價值。

With that, I'll turn the call over to Fady, please.

說完這些，我將把電話轉給 Fady。

Thanks, Robert. In the third quarter, we presented additional data from SEQUOIA-HCM and FOREST-HCM at three medical congresses: the European Society of Cardiology Congress, the Hypertrophic Cardiomyopathy Society Scientific Sessions and the Heart Failure Society of America Annual Scientific Meeting.

謝謝，羅伯特。第三季度，我們在三個醫學大會上展示了更多來自 SEQUOIA-HCM 和 FOREST-HCM 的數據：歐洲心臟病學會大會、肥厚型心肌病學會科學會議和美國心臟衰竭學會年度科學會議。

These pre-specified analyses build on the primary results presented and published earlier this year to dig deeper into the profile of aficamten. The depth and volume of these analyses is truly extraordinary with 8 presentations, five being late breakers, plus five simultaneous publications in leading cardiac journals. Each of these analyses exceeded our best case expectations for aficamten and gives us confidence in the opportunity for aficamten to address a significant unmet need in obstructive HCM.

這些預先指定的分析以今年稍早提出和發布的主要結果為基礎，深入挖掘了阿菲坎滕的概況。這些分析的深度和數量確實非同尋常，共有 8 篇演講，其中 5 篇是最新突破，另外還有 5 篇同時在領先的心臟期刊上發表。這些分析中的每一項都超出了我們對阿菲卡姆滕的最佳預期，並使我們相信阿菲卡姆滕有機會解決阻塞性 HCM 中未滿足的重大需求。

Key amongst the additional data from SEQUOIA-HCM are findings that show that aficamten may be associated with favorable cardiac remodeling and improvements in several measures of cardiac structure and function. Together, these data show that aficamten appears to change the architecture of the heart and has potential to be disease-modifying, something that's key to changing the trajectory of HCM.

SEQUOIA-HCM 的附加數據中的關鍵發現表明，阿菲卡汀可能與有利的心臟重塑以及心臟結構和功能的多項指標的改善有關。總之，這些數據表明，阿菲卡汀似乎可以改變心臟的結構，並具有改變疾病的潛力，這是改變 HCM 軌蹟的關鍵。

Other analyses from SEQUOIA-HCM presented during the quarter showed that treatment with aficamten improved patients' symptoms, quality of life and cardiac biomarkers. Furthermore, a responder analysis showed aficamten was associated with broad clinical efficacy as the majority of patients who received aficamten in SEQUOIA-HCM achieved one or more clinically relevant outcome.

本季度公佈的 SEQUOIA-HCM 的其他分析表明，使用阿菲坎特治療可改善患者的症狀、生活品質和心臟生物標記。此外，反應者分析表明，阿菲卡汀具有廣泛的臨床療效，因為大多數在 SEQUOIA-HCM 中接受阿菲卡汀治療的患者都獲得了一個或多個臨床相關的結果。

One of the 4 pre-specified outcomes was a complete hemodynamic response, defined as having a resting LVOT gradient of less than 30 and a Valsalva LVOT gradient of less than 50, which was achieved by 2/3 of patients in SEQUOIA-HCM. These data were complemented by findings from an integrated safety analysis that pulled data from REDWOOD-HCM, SEQUOIA-HCM and FOREST-HCM and reinforced the safety profile of aficamten.

4 個預先指定的結果之一是完全的血流動力學反應，定義為靜止 LVOT 梯度小於 30 且 Valsalva LVOT 梯度小於 50，SEQUOIA-HCM 中的 2/3 患者達到了這一水平。這些數據得到了綜合安全分析結果的補充，該分析提取了 REDWOOD-HCM、SEQUOIA-HCM 和 FOREST-HCM 的數據並強化了 aficamten 的安全性。

Finally, an analysis of open-label data from FOREST-HCM showed that the majority of patients who attempted withdrawal of standard of care medications at the discretion of an investigator were successful with some patients achieving monotherapy, suggesting there's a potential for aficamten to be tolerated and effective as monotherapy in patients with oHCM. This hypothesis is being explored further in the MAPLE-HCM trial, which I'll address in a moment.

最後，對 FOREST-HCM 的開放標籤數據的分析表明，大多數患者在研究人員的建議下嘗試停用標準治療藥物，並取得了成功，有些患者實現了單一治療，這表明阿菲坎汀作為 oHCM 患者的單一療法具有耐受性和有效性。MAPLE-HCM 試驗正在進一步探討這個假設，稍後我將解釋。

Five of the recent publications were recently assembled collectively in the November 5 issue of the Journal of American College of Cardiology, nearly an entire issue devoted to aficamten.

最近發表的五篇論文被集中刊登在 11 月 5 日的《美國心臟病學會雜誌》上，幾乎整整一期都是關於心臟病學愛好者的。

As we continue to curate the data from SEQUOIA-HCM, each subsequent analysis elaborates on the primary results from SEQUOIA-HCM to reinforce the effect of aficamten on clinical outcomes, symptom burden, cardiac biomarkers and cardiac structure and function. Together, this large and growing body of evidence paints a clear picture of the relevance of aficamten to clinical practice as a next-in-class cardiac myosin inhibitor and potentially the cardiac myosin inhibitor of choice for both physicians and patients.

隨著我們繼續整理 SEQUOIA-HCM 的數據，每個後續分析都會詳細闡述來自 SEQUOIA-HCM 的主要結果，以強化阿菲卡汀對臨床結果、症狀負擔、心臟生物標記以及心臟結構和功能的影響。總之，不斷增長的大量證據清楚地表明了阿菲坎汀作為下一代心臟肌球蛋白抑制劑與臨床實踐的相關性，並且可能成為醫生和患者的首選心臟肌球蛋白抑制劑。

All of these clinical work streams also continue to be supported by our medical affairs organization. During the quarter, our field medical teams met with health care professionals, including many HCM KOLs, hospital and IDN leadership and formulary decision-makers to discuss and educate about the results from SEQUOIA-HCM.

所有這些臨床工作流程也繼續得到我們醫療事務組織的支持。在本季度，我們的現場醫療團隊會見了醫療保健專業人士，包括許多 HCM KOL、醫院和 IDN 領導以及處方決策者，以討論和宣傳 SEQUOIA-HCM 的結果。

Now moving to the ongoing clinical trials program for aficamten. We're pleased to report that during the third quarter, we completed enrollment in MAPLE-HCM. Through the rest of this year, we will continue conducting this important trial and we expect to share results from MAPLE-HCM in the first half of 2025, ahead of when we hope to launch aficamten commercially.

現在轉向正在進行的 aficamten 臨床試驗計劃。我們很高興地報告，在第三季度，我們完成了 MAPLE-HCM 的註冊。今年剩餘時間，我們將繼續進行這項重要的試驗，並預計在 2025 年上半年分享 MAPLE-HCM 的結果，屆時我們希望能夠提前推出 aficamten。

If positive, MAPLE-HCM represents the first potential label expansion opportunity for aficamten with results that may provide the rationale to position it as first-line therapy in practice guidelines.

如果結果為陽性，MAPLE-HCM 代表 aficamten 的第一個潛在標籤擴展機會，其結果可能為將其定位為實踐指南中的一線治療提供理由。

During the quarter, we also continued enrollment in ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in patients with symptomatic non-obstructive HCM. We now have activated over 90 sites in 13 countries, ensuring that the results from ACACIA-HCM will be representative of a broad and diverse study population.

在本季度，我們也繼續參與 ACACIA-HCM，這是針對有症狀的非阻塞性 HCM 患者進行阿菲坎汀的關鍵 III 期臨床試驗。目前，我們已經在 13 個國家/地區啟動了 90 多個站點，確保 ACACIA-HCM 的結果能夠代表廣泛而多樣化的研究人群。

Enrollment is brisk and we expect to continue to activate new sites and enroll patients at existing and new sites through this year and into next year towards our goal of completing enrollment in 2025.

報名工作進展順利，我們預計今年和明年將繼續啟動新站點，並在現有站點和新站點招募患者，以實現 2025 年完成報名的目標。

Additionally, we continued conduct of CEDAR-HCM, evaluating a pediatric population of patients with symptomatic oHCM as well as an additional Phase I study of aficamten in healthy Japanese and Caucasian participants that may support development of aficamten in Japan.

此外，我們繼續進行 CEDAR-HCM 研究，評估有症狀的 oHCM 兒科患者群體，以及在健康的日本和高加索參與者中進行 aficamten 的附加 I 期研究，這可能支持 aficamten 在日本的發展。

Altogether, I'm proud of the substantial progress we made across the clinical development program for aficamten in the third quarter.

總而言之，我為第三季阿菲坎頓臨床開發計畫的重大進展感到自豪。

Now I'll turn it over to Andrew.

現在我將把話題交給安德魯。

Thanks, Fady. In the third quarter, we continued our commercial readiness activities for the potential approval and launch of aficamten in the US. We were pleased to launch HCM Beyond the Heart, an unbranded disease awareness campaign for health care professionals. The campaign was born out of market research and real-world feedback from cardiologists, nurses and patients and highlights the story of 5 individuals living with HCM to illuminate the multidimensional struggle faced daily by people living with HCM.

謝謝，法迪。第三季度，我們繼續進行商業準備活動，為 aficamten 在美國獲得批准和上市做準備。我們很高興推出「HCM Beyond the Heart」——一項針對醫療保健專業人士的非品牌疾病宣傳活動。該活動源於市場研究和來自心臟病專家、護理師和患者的真實回饋，重點介紹了 5 名 HCM 患者的故事，以闡明 HCM 患者每天面臨的多維度掙扎。

We are planning to showcase this campaign at the upcoming AHA scientific session in Chicago next week and we plan to launch a similar patient focus unbranded awareness campaign in first quarter 2025. The launch of HCM Beyond the Heart also marked the first deployment of our omnichannel digital communication strategies, which has successfully validated our investment in planning and set the stage for broader digital engagement to come ahead of and through the time of potential approval and launch in 2025.

我們計劃在下週於芝加哥舉行的 AHA 科學會議上展示這項活動，並計劃在 2025 年第一季啟動類似的以患者為中心的無品牌宣傳活動。HCM Beyond the Heart 的推出也標誌著我們全通路數位通訊策略的首次部署，這成功驗證了我們在規劃方面的投資，並為 2025 年潛在批准和推出之前和期間更廣泛的數位參與奠定了基礎。

During the third quarter, we selected third-party external partners for our bespoke patient experience, which we believe is a key element of differentiation for our potential commercial launch. We also made significant progress towards solidifying our promotional launch campaign.

在第三季度，我們選擇了第三方外部合作夥伴來提供客製化的患者體驗，我們相信這是我們潛在商業發布的差異化關鍵因素。我們在鞏固促銷活動方面也取得了重大進展。

Additionally, we advanced our sales force preparations, including finalizing our customer call list and establishing the geographic boundaries for our planned sales territories. We have also designed a robust recruiting plan, training curriculum to be approximately 125 to 150 reps we expect to bring on board. While we do not plan to hire sales reps until closer to launch next year, we already have hundreds of qualified candidates in our pipeline prior to going out into the marketplace to recruit.

此外，我們也推進了銷售團隊的準備工作，包括確定客戶電話清單和確定計畫銷售區域的地理邊界。我們也設計了完善的招募計畫和培訓課程，預計招募約 125 至 150 名代表。雖然我們計劃在明年產品發布前招募銷售代表，但在進入市場招聘之前，我們已經擁有數百名合格的候選人。

From the payer side, we continued pre-approval information exchange with key payers and made progress in developing our payer value dossier for both US and ex-US payers. Our HEOR team was also active in presenting and publishing research highlighting the unmet need in HCM, the associated cost burden given current treatment and the potential value of aficamten in HCM.

從付款人方面，我們繼續與主要付款人進行預核准資訊交換，並在為美國和美國以外付款人制定付款人價值檔案方面取得了進展。我們的 HEOR 團隊也積極展示和發表研究成果，強調 HCM 中未滿足的需求、當前治療帶來的相關費用負擔以及阿菲坎特在 HCM 中的潛在價值。

Moving on to commercial readiness activities in Europe. Our plan is to prioritize major markets and gate hiring and capital deployment alongside regulatory and reimbursement milestones at a country level. During the third quarter, we designed our distribution model, refined regulatory and labeling strategies, established country launch sequencing, engage with European key opinion leaders and progress development of HTA dossier while continuing engaging with key HTAs for early scientific advice.

繼續進行歐洲的商業準備活動。我們的計劃是優先考慮主要市場和登機口招聘以及資本部署，以及國家層面的監管和報銷里程碑。在第三季度，我們設計了分銷模式，完善了監管和標籤策略，確定了國家發布順序，與歐洲關鍵意見領袖進行了接觸，並推進了 HTA 檔案的開發，同時繼續與關鍵 HTA 合作以獲得早期科學建議。

We also established our initial go-to-market plan for Germany, which is expected to be the first country where we launched aficamten in Europe. We now have a head of Europe in place and are recruiting for key country leadership in the U.K. and France as well as functional leadership roles for European operations, again, alongside gated investment.

我們還制定了針對德國的初步市場進入計劃，預計德國將成為我們在歐洲推出 aficamten 的第一個國家。我們現在已經任命了一位歐洲區負責人，並正在招募英國和法國主要國家的領導人以及負責歐洲業務的職能領導職位，同樣，還有門控投資。

As we get closer to the potential approval of launch of aficamten, our commercial readiness activities are continuing to ramp up. Importantly, what we're building today for aficamten will enable synergies with future potential commercial launches across our specialty cardiology franchise. Shared resources, systems, commercial infrastructure and sales organization will facilitate enhanced efficiencies and effectiveness with each specialty cardiology launch.

隨著我們越來越接近 aficamten 的潛在上市批准，我們的商業準備活動正在繼續加緊。重要的是，我們今天為 aficamten 所建構的將與我們專業心臟病學特許經營未來潛在的商業發布產生協同效應。共享的資源、系統、商業基礎設施和銷售組織將促進每項專業心臟病學服務的推出提高效率和效力。

With that, I will turn the call over to Stuart.

說完這些，我將把電話轉給史都華。

Thanks Andrew. I'll start with CK-586, our next cardiac myosin inhibitor for the potential treatment of a subset of patients with heart failure with preserved ejection fraction or HFpEF and hypercontractility.

謝謝安德魯。我首先要介紹的是 CK-586，這是我們的下一款​​心臟肌球蛋白抑制劑，用於治療射血分數保留或 HFpEF 和收縮性亢進的心臟衰竭亞組患者。

During the quarter, we presented the full data from the Phase I study of CK-586 at the American College of Clinical Pharmacology, which showed that CK-586 was safe and well tolerated. No serious adverse events were observed and no study-stopping criteria were met.

本季度，我們在美國臨床藥理學會公佈了 CK-586 I 期研究的全部數據，該數據表明 CK-586 是安全且耐受性良好的數據。未觀察到嚴重不良事件，且未符合研究停止標準。

The half-life of CK-586 was observed to be between 14 to 17 hours. CK-586 demonstrated dose proportional exposure and a PK/PD relationship for left ventricular ejection fraction that appeared shallow and predictable. At the highest single dose of 600 milligrams, the mean decrease in ejection fraction was less than 5%.

CK-586 的半衰期為 14 至 17 小時之間。CK-586 顯示出與劑量成比例的暴露和左心室射血分數的 PK/PD 關係，這種關係似乎較淺且可預測。在最高單劑量600毫克時，射血分數平均下降不到5%。

Together, these data demonstrate pharmacologic properties that may enable once-daily fixed dose administration. Because the data from this Phase I study were supportive of advancing the Phase II, we began start-up activities for AMBER-HFpEF, which is a Phase II clinical trial of CK-586 in patients with symptomatic HFpEF with ejection fraction of at least 60% designed to evaluate the safety, tolerability and pharmacodynamic profile of CK-586 compared to placebo. We're pleased to share that we're on track to start AMBER-HFpEF before the end of the year.

總之，這些數據證明了可能實現每日一次固定劑量給藥的藥理特性。由於此 I 期研究的數據支持推進 II 期研究，我們開始了 AMBER-HFpEF 的啟動活動，這是 CK-586 對射血分數至少為 60% 的症狀性 HFpEF 患者進行的 II 期臨床試驗，旨在評估 CK-586 與安慰劑相比的安全性、耐受性和藥效學特徵。我們很高興地告訴大家，我們將在今年年底前啟動 AMBER-HFpEF。

Next, let's move to omecamtiv mecarbil, our cardiac myosin activator for the potential treatment of a subset of patients with heart failure with severely reduced ejection fraction. During the quarter, we conducted study start-up activities for COMET-HF, the confirmatory Phase III clinical trial assessing the efficacy and safety of omecamtiv mecarbil in 1,800 patients with symptomatic heart failure with severely reduced ejection fraction less than 30%.

接下來，讓我們討論一下 omecamtiv mecarbil，這是我們的心臟肌球蛋白活化劑，用於治療射血分數嚴重降低的一組心臟衰竭患者。在本季度，我們進行了 COMET-HF 的研究啟動活動，這是一項確認性 III 期臨床試驗，旨在評估 omecamtiv mecarbil 對 1,800 名射血分數嚴重降低至低於 30% 的症狀性心臟衰竭患者的療效和安全性。

COMET-HF is designed with pragmatic features to improve efficiency of study conduct and reduce patient burden. We expect to begin this trial during this fourth quarter. Heart failure with reduced ejection fraction or HFrEF represents about half of the population of heart failure.

COMET-HF 採用實用功能設計，可提高研究效率並減輕患者負擔。我們預計將於第四季開始此項試驗。射血分數降低或HFrEF的心臟衰竭約佔心臟衰竭人口的一半。

Drilling down further, estimates point to a large and growing population of patients with high-risk heart failure and severely reduced ejection fraction below 30%. These are patients who have recurrent heart failure events. They may have limiting use of guideline-directed medical therapy due to poor tolerability and have very elevated NT-proBNP consistent with severe heart failure. Despite the use of SGLT2 inhibitors, there's a large residual risk of cardiovascular events in this subset of patients with HFrEF.

進一步深入研究發現，患有高風險心臟衰竭且射血分數嚴重降低（低於 30%）的患者數量正在增加。這些是患有復發性心臟衰竭的患者。由於耐受性差，他們可能限制使用指南指導的藥物治療，並且 NT-proBNP 水平非常高，與嚴重的心臟衰竭相符。儘管使用了 SGLT2 抑制劑，但這組 HFrEF 患者仍有很大的心血管事件殘留風險。

In GALACTIC-HF, this subset of patients with severely reduced ejection fraction experienced a substantially greater treatment benefit with omecamtiv mecarbil.

在 GALACTIC-HF 中，這群射血分數嚴重降低的患者在使用 omecamtiv mecarbil 治療後獲得了顯著的治療益處。

Whereas omecamtiv mecarbil is targeting patients with heart failure and severely reduced ejection fraction, CK-586 is designed to address patients with super and normal ejection fraction at the opposite end of the spectrum of heart failure. These patients also have high unmet need and despite advances in care with SGLT2 inhibitors, have a poor prognosis following heart failure hospitalization.

omecamtiv mecarbil 針對的是患有心臟衰竭和射血分數嚴重降低的患者，而 CK-586 則旨在治療處於心臟衰竭譜另一端的射血分數超高和正常的患者。這些患者還有很大的未滿足需求，儘管 SGLT2 抑制劑的治療取得了進展，但心臟衰竭住院後的預後仍然不佳。

While the pathophysiology of these 2 heart failure populations is different, medical need for both patient subgroups remains high despite guideline-directed medical therapy with markedly increased risk of cardiovascular mortality and hospitalization for acute decompensated heart failure. Both omecamtiv mecarbil and CK-586 represent opportunities to expand our specialty cardiology franchise into these populations at either end of the heart failure spectrum.

雖然這兩類心臟衰竭患者的病理生理學不同，儘管接受了指南指導的藥物治療，但這兩類患者亞群的醫療需求仍然很高，並且心血管死亡和因急性失代償性心臟衰竭住院的風險顯著增加。omecamtiv mecarbil 和 CK-586 都代表著將我們的專業心臟病學特許經營權擴展到心臟衰竭譜兩端的人群中的機會。

Now looking beyond our specialty cardiology franchise, as Robert mentioned, we're pleased to be renewing our neuromuscular pipeline with a novel drug candidate arising from our research called CK-089. CK-089 is a fast skeletal muscle troponin activator or FSTA, designed to amplify skeletal muscle response to nerve input, extending time to fatigue and increasing muscle force and power with potential therapeutic application to a specific type of muscular dystrophy.

正如羅伯特所提到的，現在，除了我們的專業心臟病學特許經營權之外，我們很高興能夠利用我們研究中產生的一種名為 CK-089 的新型候選藥物來更新我們的神經肌肉管線。CK-089 是一種快速骨骼肌肌鈣蛋白激活劑或 FSTA，旨在增強骨骼肌對神經輸入的反應，延長疲勞時間並增加肌肉力量和力量，具有治療特定類型的肌肉營養不良症的潛在治療作用。

Having completed IND-enabling studies, we expect to start a first-in-human Phase I study of CK-089 in healthy subjects soon. We look forward to sharing more details of our plans to reinvigorate our neuromuscular development activities as informed by prior learnings very soon. What this means is that by the end of this year, we will have one or more drug candidates in each phase of clinical development from Phase I to Phase III, which conveys the richness of our pipeline in muscle-directed therapies.

在完成 IND 支持研究後，我們預計很快就會在健康受試者中啟動 CK-089 的首次人體 I 期研究。我們期待很快分享更多有關根據先前經驗重振神經肌肉發育活動的計劃細節。這意味著到今年年底，我們將在從 I 期到 III 期的臨床開發每個階段擁有一種或多種候選藥物，這表明我們在肌肉導向治療方面的產品線非常豐富。

And with that, I will pass it over to Sung.

現在我將把麥克風交給宋。

Thanks, Stuart. We're pleased to report our third quarter of 2024 financial results.

謝謝，斯圖爾特。我們很高興地報告 2024 年第三季的財務表現。

Starting with the balance sheet. We finished the third quarter of 2024 with approximately $1.3 billion in cash, cash equivalents and investments compared to $1.4 billion at the end of the second quarter of 2024. Cash, cash equivalents and investments declined by approximately $81 million during the third quarter of 2024.

從資產負債表開始。截至 2024 年第三季度，我們的現金、現金等價物和投資約為 13 億美元，而 2024 年第二季末為 14 億美元。2024 年第三季度，現金、現金等價物和投資減少約 8,100 萬美元。

Moving on to the income statement. Total revenues in the third quarter of 2024 were $0.5 million compared to $0.4 million for the same period in 2023.

繼續看損益表。2024 年第三季總營收為 50 萬美元，而 2023 年同期為 40 萬美元。

R&D expenses in the third quarter of 2024 were $84.6 million compared to $82.5 million for the same period in 2023. The increase was primarily driven by higher personnel-related expenses to progress our pipeline, partially offset by the completion of clinical trials in 2023.

2024 年第三季的研發費用為 8,460 萬美元，而 2023 年同期為 8,250 萬美元。成長的主要原因是為推進我們的產品線而增加的人員相關費用，但 2023 年完成的臨床試驗部分抵消了這一增長。

G&A expenses in the third quarter of 2024 were $56.7 million compared to $40.1 million for the same period in 2023. The increase was primarily driven by investments toward commercial readiness and personnel-related expenses.

2024 年第三季的 G&A 費用為 5,670 萬美元，而 2023 年同期為 4,010 萬美元。成長主要源自於商業準備和人員相關費用的投資。

Net loss for the second quarter of 2024 was $160.5 million or $1.36 per share basic and diluted compared to a net loss of $129.4 million or $1.35 per share basic and diluted for the same period in 2023.

2024 年第二季淨虧損為 1.605 億美元，即基本和攤薄每股虧損 1.36 美元，而 2023 年同期淨虧損為 1.294 億美元，即基本和攤薄每股虧損 1.35 美元。

Turning to the financial guidance for 2024. We are reiterating all aspects of our prior guidance, which can be found in our press release. As we head towards the end of 2024, our balance sheet remains an asset and positions us well to prepare for the potential launch of aficamten, advance our earlier and later-stage pipeline and invest in our proven muscle biology platform.

談到2024年的財務指引。我們重申我們之前指導的所有方面，可以在我們的新聞稿中找到。隨著我們接近 2024 年底，我們的資產負債表仍然是一項資產，並使我們能夠為 aficamten 的潛在推出做好準備，推進我們早期和後期的管道，並投資於我們成熟的肌肉生物學平台。

We stand to realize synergies from the commercial and R&D investments as our potential future medicines and development activities can all leverage the infrastructure and capabilities that we are creating today and in the years to follow. We believe these capital allocation priorities can enable us to become a leader in specialty cardiology with multiple medicines, delivering benefit for patients and sustainable growth for investors.

我們將實現商業和研發投資的協同效應，因為我們未來的潛在藥品和開發活動都可以利用我們今天和未來幾年正在創建的基礎設施和能力。我們相信，這些資本配置優先事項可以使我們成為擁有多種藥物的專業心臟病學領導者，為患者帶來利益並為投資者帶來可持續成長。

With that, I'll hand it back over to Robert.

說完這些，我就交還給羅伯特。

Thank you, Sung. The third quarter indeed was marked by important achievements, continuing a year marked by substantial progress. By this time next year, we expect that our company will look quite different and we're building our infrastructure and capabilities to ensure our successes in the years to come.

謝謝你，宋。第三季確實取得了重要成就，延續了長足進步的一年。到明年這個時候，我們預計公司將會煥然一新，我們正在建立基礎設施和能力，以確保未來幾年的成功。

To that end, during the quarter, we further strengthened our executive leadership team with the addition of Brett Pletcher, who joined as EVP, Chief Legal Officer, in August. Brett is a seasoned attorney and industry executive with deep experience developing operational reach and capacity and providing practical legal advice, having spent 17 years at Gilead, 13 of those as General Counsel. We're fortunate to have Brett join our team as we look ahead to the next important chapters for Cytokinetics and increased scope and scale as we mature corporate development.

為此，我們在本季度進一步加強了我們的執行領導團隊，並於 8 月任命 Brett Pletcher 擔任執行副總裁兼首席法律長。布雷特是一位經驗豐富的律師和行業高管，在拓展營運範圍和能力以及提供實用的法律建議方面擁有豐富的經驗，曾在吉利德工作 17 年，其中 13 年擔任總法律顧問。我們很榮幸 Brett 加入我們的團隊，我們期待著 Cytokinetics 的下一個重要篇章以及隨著公司發展的成熟而擴大範圍和規模。

Cytokinetics is well funded and well positioned for future successes. As we advance towards the potential approval and launch of aficamten in the United States with global launches hopefully to follow, we're approaching an important inflection point for our company. As we look ahead to that point and beyond, we're laying the groundwork for our Vision 2030 and sustain growth and enduring future successes as a premier specialty cardiology company.

Cytokinetics 資金充足，為未來的成功做好了準備。隨著我們逐步獲得美國政府的批准並推出 aficamten，並有望隨後在全球推出，我們公司正在迎來一個重要的轉折點。展望這一天及以後，我們正在為「2030 願景」奠定基礎，並作為一家頂尖的專業心臟病學公司保持成長並取得持久的未來成功。

As you've heard, this business remains anchored in aficamten for the potential treatment of HCM, followed by omecamtiv mecarbil for the potential treatment of heart failure with severely reduced ejection fraction and then CK-586 for the potential treatment of heart failure with preserved ejection fraction. This franchise design is intentional with common features across these patient populations and the prescribers that treat them, including a limited distribution model, few or ineffective available therapies and high unmet patient need.

正如您所聽到的，這項業務仍然以用於治療 HCM 的 aficamten 為支柱，其次是用於治療射血分數嚴重降低的心臟衰竭的 omecamtiv mecarbil，然後是用於治療射血分數保留的心臟衰竭的 CK-586。這種特許經營設計是有意為之，針對這些患者群體和治療他們的處方人員的特點，包括有限的分銷模式、可用的治療方法很少或無效以及未滿足的患者需求很高。

Each of these underscore potential for higher return on investment and provide us the ability to realize R&D and commercial synergies. To achieve these objectives, we're committed to investing wisely and maintaining a strong financial foundation to enable both forward motion as well as velocity. Looking back at the quarter, I'm proud of the tremendous progress we've made towards achieving our vision.

這些都強調了更高投資回報的潛力，並為我們提供了實現研發和商業綜效的能力。為了實現這些目標，我們致力於明智投資並保持強大的財務基礎，以推動前進並加快速度。回顧本季度，我為我們在實現願景方面取得的巨大進展感到自豪。

Now I'll recap our upcoming milestones. For aficamten, we expect to continue advancing our go-to-market strategies and prepare to launch aficamten in the United States in 2025, of course, subject to FDA approval. We expect to submit an MAA to the EMA in Q4 2024 and coordinate with CORXEL to support the planned launch of aficamten in China in 2025, pending approval.

現在我將回顧我們即將實現的里程碑。對於阿菲卡汀，我們預計將繼續推進我們的市場進入策略，並準備在 2025 年在美國推出阿菲卡汀，當然，這需獲得 FDA 的批准。我們預計將於 2024 年第四季向 EMA 提交 MAA，並與 CORXEL 協調以支援 aficamten 計劃於 2025 年在中國上市（待批准）。

We expect to complete conduct of MAPLE-HCM and share results in the first half of 2025. We expect to continue enrollment in ACACIA-HCM through 2024 with objective to complete enrollment in 2025. And we expect to continue enrollment in CEDAR-HCM as well as the Phase I study of aficamten in Japanese and Caucasian participants. And for omecamtiv mecarbil, we expect to start COMET-HF, the confirmatory Phase III clinical trial in this Q4 2024. For CK-586, we expect to start AMBER-HFpEF, the Phase II clinical trial also in this Q4 2024.

我們預計將在 2025 年上半年完成 MAPLE-HCM 的實施並分享結果。我們預計將持續招生到 2024 年，目標是在 2025 年完成招生。我們希望繼續參與 CEDAR-HCM 以及針對日本和高加索人群的 aficamten 第一階段研究。對於 omecamtiv mecarbil，我們預計將於 2024 年第四季啟動確認性 III 期臨床試驗 COMET-HF。對於 CK-586，我們預計也將在 2024 年第四季啟動 II 期臨床試驗 AMBER-HFpEF。

And for earlier clinical development, preclinical development and ongoing research, we expect to initiate clinical development of CK-089 by starting a Phase I study in healthy volunteers in this fourth quarter and we expect to continue ongoing preclinical development and research activities directed to additional muscle biology-focused programs through this year.

對於早期臨床開發、臨床前開發和正在進行的研究，我們預計將在第四季度對健康志願者進行 I 期研究，啟動 CK-089 的臨床開發，並預計將在今年繼續開展針對其他肌肉生物學重點項目的臨床前開發和研究活動。

Operator, with that, we can now please open the call up to questions.

接線員，好了，我們現在可以開始提問了。

(Operator Instructions) Akash Tewari, Jefferies.

(操作員指示) Akash Tewari，Jefferies。

This is Phoebe on for Akash. Looking at the SEQUOIA data, it seems like the largest magnitude of LVEF reductions were seen in hypercontractile patients with LVEF greater than 75. If you had a mechanism that could show gradient relief benefits without affecting LVEF, first, would it be considered and would it be clinically useful for patients with severe hypercontractility? And second, would you still expect to see a benefit on pVO2?

這是 Phoebe 為 Akash 主持的節目。從 SEQUOIA 數據來看，LVEF 下降幅度最大的似乎是 LVEF 大於 75 的高收縮性患者。如果您有一種可以在不影響 LVEF 的情況下顯示梯度緩解益處的機制，首先，它會被考慮嗎？其次，您還期望看到 pVO2 帶來的好處嗎？

Thank you. I'll ask Fady to respond to that, please.

謝謝。請 Fady 對此作出回應。

Yes. I think the underlying point that you made is that this is a disease of hypercontractility. And in some cases and in most cases, it leads to obstruction as well. Having an ejection fraction of 80% is just not normal. It's not normal even in people that have -- that don't have hypertrophic cardiomyopathy.

是的。我認為您提出的潛在觀點是，這是一種收縮性亢進疾病。在某些情況下，甚至在大多數情況下，它也會導致阻塞。射血分數達到 80% 是不正常的。即使對於沒有肥厚型心肌病變的人來說，這也是不正常的。

And so we think one of the targets in treating this disease is to both reduce the contractility to more normal levels so that the tissue remodeling, the myofibril disarray, the cardiac wall stresses can all begin to decline as well as to reduce the gradient. And so I don't know if just treating obstruction by itself is sufficient.

因此，我們認為治療這種疾病的目標之一是將收縮力降低到更正常的水平，以便組織重塑、肌原纖維混亂、心臟壁應力都可以開始下降並降低梯度。所以我不知道僅治療阻塞本身是否足夠。

You can do that with septal reduction therapy for instance and that does result in substantial improvement in patients' symptoms. But often, they go on to develop nonobstructive HCM and issues over time as their disease progresses. So I don't believe that just treating, but not decreasing the hypercontractility is potentially a therapeutic benefit.

例如，您可以透過鼻中隔縮小療法來實現這一點，而這確實可以顯著改善患者的症狀。但通常，隨著病情的進展，他們會發展為非阻塞性 HCM，並且隨著時間的推移而出現問題。所以我不認為僅僅治療而不降低收縮性過度就可能具有治療效果。

Tess Romero, JPMorgan.

摩根大通的泰斯羅梅羅 (Tess Romero)。

So on the Phase III MAPLE-HCM trial in patients with symptomatic oHCM, how confident are you in a positive trial here? And specifically, could you walk us through the magnitude of change for aficamten over metoprolol you need to hit a p-value that is significant? And relatedly, what can you tell us on how the patients that enrolled jived with your expectations?

那麼，對於針對有症狀的 oHCM 患者進行的 III 期 MAPLE-HCM 試驗，您對該試驗的積極結果有多大信心？具體來說，您能否向我們介紹一下阿菲坎特相對於美托洛爾的變化幅度，以達到顯著的 p 值？與此相關的是，您能告訴我們入組的患者是否符合您的期望嗎？

Good questions. Obviously, as we approach the readout of MAPLE-HCM expected next year, we believe that this study will play an important role in consideration and adoption of aficamten, hopefully also in line with evolving guidelines. And the study MAPLE-HCM was specifically designed, if anything, perhaps as would be accelerating what would otherwise be potentially a Phase IV study and could enable label expansion.

好問題。顯然，隨著我們接近預計明年的 MAPLE-HCM 讀數，我們相信這項研究將在考慮和採用 aficamten 方面發揮重要作用，希望也符合不斷發展的指導方針。MAPLE-HCM 研究是經過專門設計的，如果有的話，也許可以加速原本可能進入 IV 期的研究，並可以實現標籤擴展。

I'll ask Fady to speak to how we designed the study and how we feel about the patients that were enrolled.

我會請法迪談談我們如何設計這項研究，以及我們對參與研究的患者的感受。

Yes. I think this has been a study that has been very highly welcomed by the investigator community is answering an important question for them. In terms of enrolling patients, we've done very well, I think, in enrolling patients who meet the target, have meaningful symptoms, have meaningful reduction in their exercise capacity and in whom initiating treatment with aficamten or metoprolol we'll be able to assess which -- what is the magnitude of benefit for each of those therapies and how they compare.

是的。我認為這項研究受到了研究者們的高度歡迎，它解答了他們一個重要的問題。在招募患者方面，我認為我們做得非常好，我們招募了符合目標、有顯著症狀、運動能力顯著下降且開始使用阿菲坎特或美托洛爾治療的患者，我們將能夠評估每種療法的益處程度以及它們之間的比較。

So we think for several reasons that aficamten has already shown benefit on top of beta blockers. And so these are patients that -- who were symptomatic and given beta blockers, had inadequate response to treatment and subsequently responded to aficamten.

因此，我們認為，出於多種原因，阿非卡坦已顯示出比β受體阻斷劑更佳的益處。這些患者有症狀並服用β受體阻斷劑，對治療的反應不足，隨後對阿菲坎汀有反應。

On the SEQUOIA, we had patients on aficamten, not on beta blockers. We had beta blocker patients, not on any other therapy. And I think that gave us a window into what we expect to see here, which I think is the results will be consistent with the hypothesis of this trial.

在 SEQUOIA 上，我們讓患者服用阿非卡坦，而不是β受體阻斷劑。我們接受的是β受體阻斷劑治療的患者，並沒有接受其他治療。我認為這為我們了解我們期望看到的結果提供了一個窗口，我認為結果將與這次試驗的假設一致。

I'm not going to speculate really on what is meaningful or how big of a change we're looking for. We have powered the trial somewhat conservatively with looking at a delta-Peak VO2 of about 2 with decent power to show anything down to probably 1.5 in terms of change in Peak VO2, which covers the region where SEQUOIA was positive as well. So I think we're adequately powered and we look forward to the results.

我不會真正猜測什麼是有意義的，或者我們正在尋求多大的改變。我們對試驗進行了較為保守的觀察，發現峰值攝氧量 delta-Peak VO2 大約為 2，並且有相當好的功率可以顯示峰值攝氧量的變化，最低可達 1.5，這也涵蓋了 SEQUOIA 呈陽性的區域。所以我認為我們有足夠的力量，我們期待結果。

Salim Syed, Mizuho.

瑞穗的薩利姆賽義德 (Salim Syed)。

I guess one for me on MAPLE as well. Assuming you guys actually get the results you want here, could you just maybe give us your thoughts on getting those results published and into treatment guidelines? Like how often does the committee meet and when that could potentially happen? Could it happen prior to the supplementary approval?

我想 MAPLE 上也有一個適合我。假設你們確實得到了想要的結果，能否告訴我們關於將這些結果發表並納入治療指南的想法？例如，委員會多久開一次會，什麼時候可能開會？這可能發生在補充批准之前嗎？

Yes. So obviously, we can't commit for what others will be doing, but the guidelines are updated in a continuous way and regularly, not just once a year. And as you've seen already in this year, we've been aggressive about ensuring that data go quickly from presentation to publication.

是的。因此顯然，我們不能承諾其他人會做什麼，但是指南會持續定期更新，而不僅僅是每年一次。正如您今年所看到的，我們一直積極確保數據從呈現到發布的整個過程能夠快速進行。

I think we've had a quite uncommon number of presentations and publications this year, underscoring how closely we're working with the academic community to make sure these data get properly peer reviewed and published for consideration. So that won't change next year.

我認為我們今年的演講和出版物數量相當不尋常，強調了我們與學術界的密切合作，以確保這些數據得到適當的同行評審和發表以供審議。所以明年情況不會改變。

Could you -- you think you can get it done prior to the actual approval? Because I think the threshold is publication, correct?

您認為您可以在實際批准之前完成此事嗎？因為我認為門檻就是出版，對嗎？

Well, for consideration of guidelines you're saying?

那麼，您說的是考慮指導方針嗎？

Yes, correct. Yes.

是的，正確。是的。

I would think that that makes a big difference. And it's certainly our goal to get it published as soon as possible next year. I don't think we should be ahead of even having the data committing to whether that would be ahead of potential approval. But knowing that this is our objective, I think you should assume we'll continue to be very aggressive.

我認為這會帶來很大的不同。我們的目標當然是明年盡快出版它。我認為，我們不應該提前獲得數據，而應該先承諾是否會提前獲得批准。但知道這是我們的目標，我想你應該認為我們會繼續積極。

Roanna Ruiz, Leerink Partners.

Roanna Ruiz，Leerink Partners。

This is Nik Gasic on for Roanna. Maybe first on MAPLE -- maybe ask a different way. I guess, looking ahead to the results for afi relative to metoprolol next year, I guess, what could the Peak VO2 improvement with afi look like in this study relative to what you saw in SEQUOIA previously? And then I guess, like what's the outlook on the time line of possible guideline adoption for using afi in earlier lines of therapy if the MAPLE data are positive?

這是 Nik Gasic，代表 Roanna 演出。也許首先在 MAPLE 上 — — 也許可以用不同的方式詢問。我想，展望明年 afi 與美托洛爾相關的結果，我想，相對於您之前在 SEQUOIA 中看到的，本次研究中 afi 的峰值攝氧量改善情況會是什麼樣的？然後我想，如果 MAPLE 數據是正面的，那麼在早期治療中使用 afi 的可能指南採用的時間線前景如何？

I feel like we might have just answered that, but maybe I'll turn to Fady and see if there's anything more he might want to add.

我覺得我們可能剛剛回答了這個問題，但也許我會轉向 Fady 看看他是否還有什麼要補充的。

Yes. I mean I just will reiterate in SEQUOIA, we had 1.74 mL/kilo/minute improvement in patients not on beta blockers. That effect was modestly bigger. So we're kind of in that range of Peak VO2 improvement. Prior publications of metoprolol use in HCM showed that metoprolol doesn't increase Peak VO2.

是的。我的意思是，我只想在 SEQUOIA 中重申，未服用 β 受體阻斷劑的患者病情改善了 1.74 毫升/公斤/分鐘。這種影響稍微大一些。因此我們處於峰值攝氧量的改善範圍內。先前關於美托洛爾在 HCM 中的應用的出版物顯示，美托洛爾不會增加峰值攝氧量。

And so you can guess that if we're in the same ballpark, we might see something in that range. This is a smaller study than SEQUOIA was. We're treating patients whom are slightly less symptomatic because we wanted to sort of expand the aperture to naive patients and newer patients. So the exact effect size is a little tricky to handicap, but I don't think the exact effect size is really what's important. What's important is that there is a meaningfully different and better effect of aficamten to improve exercise function and symptoms than metoprolol does in these patients. So that should guide its use in therapy.

因此你可以猜到，如果我們處於同一水平，我們可能會看到該範圍內的一些東西。這項研究比 SEQUOIA 規模小。我們正在治療症狀較輕微的患者，因為我們想將治療範圍擴大到初治患者和新患者。因此，確切的效果大小對於預測來說有點棘手，但我不認為確切的效果大小才是真正重要的。重要的是，阿菲坎特在改善這些患者的運動功能和症狀方面比美托洛爾具有明顯不同的、更好的效果。所以這應該可以指導其在治療中的使用。

As to the guidelines, I mean, this -- we'll present this. We'll get it published, I think, fairly rapidly. The guideline committees, they don't publish their meeting schedules, they don't publish their timing of updating guidelines, but they are aware that this is a fast-moving field and that they do need to be timely and sort of considering the evidence and revising their guidelines. So leave it at that.

至於指導方針，我的意思是，這個——我們將會提出這個。我想我們會很快將其發佈。指南委員會不會公佈會議日程，也不會公佈更新指南的時間，但他們意識到這是一個快速發展的領域，他們確實需要及時考慮證據並修改指南。那就這樣吧。

Got it. And then maybe if I may, could you comment about how you're thinking about the European launch dynamics for afi if it's approved? And I guess any learnings that you could apply based on what you're seeing from the competitor launch throughout Europe?

知道了。然後如果可以的話，您能否評論一下如果 afi 獲得批准，您如何看待其在歐洲的發布動態？我想，根據您從整個歐洲競爭對手的發布情況中看到的情況，您可以學到什麼嗎？

So we're really just taking one question per analyst right now, but I suspect you'll get your question answered as we go through what looks to be a very long list of folks who want to ask questions. We'll come back to that.

因此，我們現在實際上只針對每位分析師回答一個問題，但我想，當我們瀏覽一份很長的想要提問的人的名單時，你的問題就會得到答案。我們稍後會討論這個問題。

Operator, if we could move to the next one please.

接線員，請我們轉到下一個。

Jason Zemansky, BofA.

美國銀行的 Jason Zemansky。

This is Cameron Bozdog on for Jason. Congrats on the quarter. So in terms of leveraging afi's profile to warrant a potential pricing premium, I guess, what factors are likely to be critical here? Is it going to be efficacy, safety, the administrative profile? Or I guess, in other words, do you think less frequent LVEF reductions below 50% in SEQUOIA versus EXPLORER is enough to warrant a pricing premium? Or would you need to see the safety benefit reflected in the monitoring protocols or the label to establish a basis for a premium here?

我是 Cameron Bozdog，為 Jason 主持節目。恭喜本季取得佳績。因此，就利用 afi 的形象來確保潛在的定價溢價而言，我猜，哪些因素可能至關重要？它是功效、安全性還是管理概況？或者我猜，換句話說，您是否認為 SEQUOIA 與 EXPLORER 相比，LVEF 降低至 50% 以下的頻率較低，足以保證溢價？或者您需要看到監控協議或標籤中反映的安全效益，作為加價的基礎？

So first off, your question is kind of presupposing that there'll be a pricing premium and we haven't spoken to that, but instead, we've referred to pricing within a relative same ZIP code. But maybe I'll ask Andrew to comment, if he will, on what we believe is ultimately going to translate to wider adoption for a next-in-class therapeutic in this category.

首先，您的問題有點假設會有價格溢價，而我們還沒有談到這一點，而是提到了相對相同郵遞區號內的定價。但如果可以的話，我可能會請安德魯就我們認為最終將導致該類別的下一代治療方法得到更廣泛採用的因素發表評論。

Sure. So I think Robert answered the pricing and I'm assuming you're asking about US pricing where we have the ability to set the price. But in the US, we'll be in the proximity of what the established price for the market is.

當然。所以我認為羅伯特回答了定價問題，我假設你問的是美國的定價，我們有能力設定價格。但在美國，我們的價格將接近市場既定的價格。

In terms of uptake of payers based on price, we're certainly going to be working and have already been with commercial payers. We're working on medical exception through Medicare payers. I think we addressed IRA challenges, which is an industry challenge, not unique to us. And that's how we'll get access that we believe will be within parity of competition. So we've really been taking that out of the equation and focusing on educating, promoting and uptake as well as supporting patients.

在基於價格的付款人的接受度方面，我們肯定會開展工作，並且已經與商業付款人合作了。我們正在透過醫療保險支付方處理醫療例外問題。我認為我們解決了 IRA 挑戰，這是一個行業挑戰，並非我們獨有的。這就是我們獲得准入的方式，我們相信這將在競爭中處於同等水平。因此，我們確實已經將其從考慮範圍中剔除，並專注於教育、推廣、吸收以及支持患者。

So the market research we've done underscores the importance of risk mitigation and ultimately how that can translate to hopefully more physicians prescribing a cardiac myosin inhibitor for more patients. And we do hope that if approved, aficamten could be accompanied by a risk mitigation profile that fits with next-in-class objectives.

因此，我們所做的市場調查強調了降低風險的重要性，以及最終如何轉化為希望更多的醫生為更多的患者開立心臟肌球蛋白抑制劑。我們確實希望，如果獲得批准，aficamten 可以附帶符合下一類目標的風險緩解措施。

Sean McCutcheon from Raymond James.

雷蒙德詹姆斯 (Raymond James) 的肖恩麥卡琴 (Sean McCutcheon)。

On CK-586, can you speak to the lessons that you took from the EMBARK results? How are the target patients in AMBER meaningfully similar or different in your estimation from EMBARK? And what pharmacologic properties do you view as the most valuable provided the mechanism proves out in the subsegment of HFpEF patients?

關於 CK-586，您能談談您從 EMBARK 結果中學到的教訓嗎？您估計 AMBER 中的目標患者與 EMBARK 中的目標患者有何有意義的相似或不同？如果該機制在 HFpEF 患者的子群體中得到證實，您認為哪些藥理特性最有價值？

Sure. So that's a good question for Stuart maybe to pick up on and Fady, if he wants to add anything.

當然。所以這對史都華來說是個好問題，如果法迪想補充什麼的話，或許可以回答。

Sure. Thanks for the question. So first of all, we're very encouraged with the potential benefit in this population with CK-586 in large part from the data we observed in nonobstructive HCM with aficamten. So -- and similar results were observed with mavacamten and nonobstructive HCM in terms of the pharmacodynamic improvement, symptomatic improvement. But the EMBARK data do inform and encourage a potential benefit of CK-586 in this population of HFpEF patients with hypercontractility.

當然。謝謝你的提問。首先，我們對 CK-586 對該族群的潛在益處感到非常鼓舞，這很大程度上來自於我們在非阻塞性 HCM 中使用阿菲坎特所觀察到的數據。因此—在藥效學改善和症狀改善方面，mavacamten 和非阻塞性 HCM 觀察到了相似的結果。但 EMBARK 數據確實顯示並證明了 CK-586 對患有高收縮性的 HFpEF 患者群體具有潛在益處。

Now we are enriching a population, of course, with an ejection fraction of at least 60%. We have a lot to learn in terms of the potential dosing range that may be effective and safe and tolerable. And so this first inpatient study will help us characterize the pharmacodynamic benefits.

現在我們正在豐富一個群體，當然，其射血分數至少為 60%。在可能有效、安全且可耐受的潛在劑量範圍方面，我們還有很多需要學習。因此，這項首次住院研究將幫助我們描述藥效學益處。

We'll be measuring cardiac biomarkers such as NT-proBNP, cardiac troponin and as well, of course, of evaluating ejection fraction. And what we observed, I think, very favorably in our Phase I study was a very shallow exposure response profile with respect to only small incremental decreases of ejection fraction with increasing doses of CK-586.

我們將測量心臟生物標記，例如 NT-proBNP、心臟肌鈣蛋白，當然還有評估射血分數。我認為，我們在第一階段研究中觀察到的結果非常有利，那就是暴露反應曲線非常淺，即隨著 CK-586 劑量的增加，射血分數僅有小幅遞減。

So I'm not going to go into a lot of speculation about comparing study designs or the data from EMBARK, but the data we've accumulated so far are very encouraging with CK-586 as well as aficamten in nonobstructive HCM. And so we're quite optimistic and look forward to this Phase II trial.

因此，我不會對比較研究設計或 EMBARK 的數據進行大量猜測，但迄今為止我們累積的數據對於 CK-586 以及非阻塞性 HCM 中的 aficamten 非常令人鼓舞。因此我們非常樂觀並期待第二階段的試驗。

The EMBARK study was not a large study and therefore, there's still a lot to be learned from testing a cardiac myosin inhibitor in a larger, longer study. So our goal will be to do a proper development program for CK-586 to inform CK-586.

EMBARK 研究並不是一項大規模研究，因此，透過在更大規模、更長期的研究中測試心臟肌球蛋白抑制劑，仍有許多東西需要學習。因此我們的目標是製定適當的 CK-586 開發計劃，以告知 CK-586。

We have -- I just want to add, I'm sorry, Robert, that we -- this is a placebo-controlled trial. And so it's going to be a much more rigorous assessment of the cardiac myosin inhibitor in this population with HFpEF and hypercontractility as opposed to EMBARK.

我們有——我只想補充一下，抱歉，羅伯特，我們——這是一項安慰劑對照試驗。因此，與 EMBARK 相比，我們將對患有 HFpEF 和高收縮性的人群中的心臟肌球蛋白抑制劑進行更嚴格的評估。

Yes. Thank you, Stuart.

是的。謝謝你，斯圖爾特。

Paul Choi, Goldman Sachs.

高盛的保羅·崔（Paul Choi）。

I just want to return to the subject of MAPLE and with regard to any sort of clinical efficacy bar that has been potentially discussed with payers as they think about potential guideline changes there. And have they provided any feedback to you or any sort of physician community commentary on sort of what would be considered clinically meaningful here versus [metoprolol] as to drive guideline changes here?

我只想回到 MAPLE 的話題上，並討論任何類型的臨床療效標準，因為他們正在考慮潛在的指導方針變化，所以他們可能會與付款人討論該問題。他們是否曾向您提供任何回饋或任何形式的醫生社群評論，說明與 [美托洛爾] 相比，什麼具有臨床意義，從而推動指南的改變？

Yes. So I'll ask Andrew to comment, but I think it would be premature for us to be talking about MAPLE with payers before we have data from MAPLE and before we have even an approval potentially based on SEQUOIA. But we are gathering insights into how payers think about these things in a general sense.

是的。因此我會請安德魯發表評論，但我認為，在我們獲得 MAPLE 數據之前，甚至在我們獲得基於 SEQUOIA 的批准之前，與付款人討論 MAPLE 還為時過早。但我們正在收集關於付款人對這些事情的總體看法。

So maybe Andrew, if you could comment, please?

那麼也許安德魯，你可以發表評論嗎？

Certainly, yes. So as Robert had mentioned, our focus right now with payers is based on SEQUOIA. Strategically, we're discussing options in terms of how you then start to work MAPLE into payer conversations as well as value arguments, both in the US as well as Europe.

當然是的。正如羅伯特所提到的，我們目前對付款人的關注點是基於 SEQUOIA。從戰略上講，我們正在討論如何將 MAPLE 融入美國和歐洲的付款人對話和價值論點中的選擇。

The value for MAPLE from a physician point of view really does 2 things. It expands physician population. There is a subset of physicians who are more apathetic to treating with new agents and are okay with beta blockers as is because they don't really have experience with CMI. So when you show a head-to-head relative to what they're using today, that certainly releases additional physicians. So it expands the market.

從醫生的角度來看，MAPLE 的價值其實有兩點。它擴大了醫生數量。有一部分醫生對於使用新藥物治療不太感興趣，並且只接受β受體阻斷劑，因為他們實際上沒有 CMI 經驗。因此，當您展示與他們今天所使用方法的對比時，肯定會釋放更多的醫生。因此它擴大了市場。

And then when you look at preference share, when you have a secondary study that has within the range of similar results is what we're expecting, then that kind of is a validation for that primary study, which then further enhances share. So it should work with -- from guidelines, it should work with market expansion, it should help with share preference and certainly is going to help with value arguments in the US and in Europe. But we're not talking to payers at the moment about MAPLE.

然後，當您查看偏好份額時，如果您進行的二次研究的結果與我們預期的相似，那麼這對研究來說是一種驗證，從而進一步提高了份額。因此，從指導方針來看，它應該與市場擴張相配合，它應該有助於股票偏好，並且肯定有助於美國和歐洲的價值論點。但我們目前還沒有與付款人討論 MAPLE 事宜。

Jason Butler, Citizens JMP.

傑森‧巴特勒 (Jason Butler)，公民 JMP。

Just a quick one on 089. You guys have a long history with this class. Can you, at a high level, just tell us how 089 differs from the prior candidates?

關於 089，我只想簡單說一下。你們與這個班級有著悠久的歷史。您能否從整體上告訴我們 089 與之前的候選人有何不同？

Yes. So 089 comes from a very different chemical scaffold and for which I'll ask Fady to comment in a moment. But please understand that we've applied learnings to our interest as relates to 089 and in particular, you'll hear more about how we're developing it going forward, underscoring that we're not going to be pursuing the development of 089 in ALS, but rather in a muscular dystrophy and in fact, a rare form of disease where we think it may play a potential role.

是的。因此，089 來自一個非常不同的化學支架，稍後我會請 Fady 對此發表評論。但請理解，我們已將所學知識應用於與 089 相關的興趣，特別是，您將聽到更多有關我們如何進一步開發它的信息，強調我們不會在 ALS 中追求 089 的開發，而是在肌肉萎縮症中，事實上，這是一種罕見的疾病，我們認為它可能發揮潛在的作用。

Fady, do you want to comment on how it may differ from prior fast skeletal compounds?

Fady，你想評論一下它與之前的快速骨骼化合物有何不同嗎？

Yes. I mean CK-089 is a third molecule and we -- each iteration have come to a molecule that is more potent, has better pharmaceutical properties. It's a challenging target and we think 089 kind of maximizes the efficacy that we can pull out of this mechanism of action, at least in preclinical models and is better suited in terms of its physical properties for doing dosing and dose ranging and so forth. So still early days.

是的。我的意思是 CK-089 是第三種分子，我們每次迭代都會得到一個更有效、具有更好藥用特性的分子。這是一個具有挑戰性的目標，我們認為 089 可以最大限度地發揮這種作用機制的功效，至少在臨床前模型中是如此，而且其物理特性更適合進行劑量和劑量範圍等。因此還處於早期階段。

We have some very interesting and promising preclinical data and we'll be looking to see if we can translate that going forward into the clinic.

我們有一些非常有趣且有前景的臨床前數據，我們將研究是否可以將其轉化為臨床應用。

The world has evolved quite a bit around skeletal muscle since we were advancing 2 prior compounds. And we're borrowing from those learnings, too, in terms of how we think about skeletal muscle force, power, endurance, fatigue and muscle function. And we do believe that CK-089 has an opportunity to establish a position where some others have been building value for shareholders. And again, you'll hear more about our plans as we roll forward into Phase I and hopefully beyond.

自從我們改進了兩種先前的化合物以來，世界已經圍繞著骨骼肌發生了相當大的進化。我們也藉鑒了這些經驗，來思考骨骼肌的力量、耐力、疲勞和肌肉功能。我們確實相信，CK-089 有機會在其他公司為股東創造價值的地方確立自己的地位。再說一次，隨著我們進入第一階段，甚至更長時間，你們將會聽到更多關於我們計劃的資訊。

Charles Duncan, Cantor Fitzgerald.

查爾斯鄧肯、康托菲茨傑拉德。

This is [Zia] on for Charles. So we just have one for omecamtiv mecarbil. As you near initiation for COMET-HF, what is your view on its competitive position within the heart failure market, specifically as other treatments for heart failure with reduced ejection fraction continue to develop?

這是 [Zia] 為查爾斯主持的。因此我們只有一個 omecamtiv mecarbil。隨著 COMET-HF 即將啟動，您如何看待它在心臟衰竭市場中的競爭地位，特別是隨著其他治療射血分數降低的心臟衰竭的療法不斷發展？

Thank you. An excellent question. I think it warrants being answered by both Fady and Stuart as well as Andrew may have a perspective on that and I'll ask our team to comment. Starting with Fady, please.

謝謝。一個很好的問題。我認為這個問題值得 Fady 和 Stuart 以及 Andrew 回答，他們可能對此有自己的看法，我會請我們的團隊發表評論。請從 Fady 開始。

Well, sure. I think in the population that we plan to study omecamtiv mecarbil in people with severely reduced ejection fraction and really severe heart failure, there are a few new options. Many of the drugs that are developed lower blood pressure. They can be challenging to use in these patients because they impact kidney function. And they don't address the core element of why these patients are so symptomatic at this point in their disease process, which is their cardiac function has deteriorated substantially and is now severely reduced.

嗯，當然了。我認為，在我們計劃研究 omecamtiv mecarbil 對射血分數嚴重降低和嚴重心臟衰竭患者的治療人群中，有一些新的選擇。許多已開發的藥物可以降低血壓。它們對這些患者的使用可能具有挑戰性，因為它們會影響腎功能。他們並沒有解決為什麼這些患者在疾病發展的這個階段會出現如此明顯的症狀的核心問題，即他們的心臟功能已經大大惡化，現在嚴重下降。

So I think omecamtiv has sort of a unique place in terms of being used in this area and it's conceptually easy to understand why it would benefit these patients, easy to explain to patients why you would use it. And so I think the enthusiasm that we have been met with as we announced the initiation of this trial rather announced the intent to conduct COMET in the heart failure community has been quite large.

因此，我認為 omecamtiv 在該領域的應用具有獨特的地位，並且從概念上很容易理解為什麼它會對這些患者有益，也很容易向患者解釋為什麼要使用它。因此我認為，當我們宣布啟動這項試驗，或宣布打算在心臟衰竭社群中進行 COMET 時，我們所受到的熱情是相當大的。

I get e-mails weekly, frankly, from investigators that are interested in participating, are grateful that we're continuing to develop omecamtiv mecarbil because it really fills an unmet need for them in terms of what do they do next when the sort of foundational treatments for heart failures are not working.

坦白說，我每週都會收到有興趣參與的研究人員的電子郵件，他們感謝我們繼續開發 omecamtiv mecarbil，因為它確實滿足了他們尚未滿足的需求，即當心臟衰竭的基礎治療不起作用時，他們下一步該怎麼做。

Stuart, anything to add from the clinical perspective before we ask Andrew to comment commercially?

斯圖爾特，在我們請安德魯發表商業評論之前，從臨床角度還有什麼要補充的嗎？

Just add that, as Fady said, these patients are running out of options. And if you look at the profile of risk in this population, there is a marked inflection point at the threshold of (technical difficulty) 30% ejection fraction. The risk of mortality and acute decompensated heart failure goes up dramatically with ejection fraction of less than 30%. And as Fady was mentioning, these patients are running out of options. They really don't have options withdrawing guideline-directed medical therapy and heading towards end-stage heart failure.

還要補充一點，正如法迪所說，這些病人已經沒有選擇了。如果你觀察一下該族群的風險狀況，你會發現在射血分數（技術難度）30% 的閾值處有一個明顯的拐點。射血分數低於 30% 時，死亡和急性失代償性心臟衰竭的風險急劇增加。正如法迪所提到的，這些病人已經沒有選擇了。他們真的沒有選擇，只能停止指導性藥物治療，走向末期心臟衰竭。

And again, what we observed in GALACTIC-HF was that this was a population not only with the highest risk of major heart failure events and mortality, this is a population in which omecamtiv mecarbil benefited the most. And so there's sort of an alignment of the stars here and we think this is a population that could truly benefit from omecamtiv mecarbil.

而且，我們在 GALACTIC-HF 中觀察到的是，這個群體不僅是發生重大心臟衰竭事件和死亡風險最高的群體，也是 omecamtiv mecarbil 受益最大的群體。因此，這裡存在某種星星的排列，我們認為這個群體可以真正從 omecamtiv mecarbil 中受益。

Thank you, Stuart. Andrew?

謝謝你，斯圖爾特。安德魯？

Sure. From a market positioning point of view, so there's a couple of considerations. One, when we look at kind of future competitive environment as well as what's on the market today and the guideline-directed medical therapy, kind of quad therapy, our expectation will be completely generic at that point.

當然。從市場定位的角度來看，有幾點考量。首先，當我們審視未來的競爭環境以及當今市場的情況和指南指導的藥物治療、四聯療法時，我們的預期將完全是通用的。

We also look at what is in the pipeline. So we're pretty confident in terms of very clear positioning for omecamtiv mecarbil, especially when you consider the clinical arguments that were just described. This patient population also has challenges with hypotension or renal dysfunction or hyperkalemia, where we're expecting omecamtiv will continue to show a neutral effect on those side effects that are associated with guideline-directed therapy.

我們也會關注正在進行的事情。因此，我們對 omecamtiv mecarbil 的明確定位非常有信心，尤其是當您考慮到剛剛描述的臨床論點時。該患者族群也面臨低血壓、腎功能障礙或高血鉀等挑戰，我們預期奧美拉唑將繼續對與指引指導治療相關的副作用表現出中性作用。

There's a strong health economic argument as well. And then with little treatment options, we're expecting kind of premium pricing as well as the fact that this will lay on top of our existing specialty cardiovascular franchise, our field force, our headquarter-based employees, so very little add from a cost basis as well.

還有強有力的健康經濟論點。由於治療選擇很少，我們預計價格會比較高，而且這將建立在我們現有的專業心血管特許經營權、我們的現場人員、我們總部的員工之上，因此從成本基礎來看，增加的幅度也很小。

So a really clear economic argument, really clear business case, really clear clinical argument as well as looking at the future competitive set from a positioning point of view. And that's why we're moving forward with omecamtiv from a commercial point of view.

因此，這是一個真正清晰的經濟論點、真正清晰的商業案例、真正清晰的臨床論據，同時也是從定位的角度看待未來的競爭力。這就是我們從商業角度推進 omecamtiv 的原因。

That makes a lot of sense --

這很有道理--

I'm really pleased that -- sure, I just want to comment, I'm really pleased that we're hearing from more investors and equity research analysts about our strategy for omecamtiv mecarbil and people are doing their work on this. I'll suggest that I think it's an opportunity to realize the kind of synergies we've been talking about around our specialty cardiology model and it would be a mistake to believe that we're targeting a population for which there are good alternatives because they are really not.

我真的很高興 - 當然，我只是想評論一下，我真的很高興我們從更多的投資者和股票研究分析師那裡聽到了關於我們對 omecamtiv mecarbil 的戰略的意見，而且人們正在為此開展工作。我認為這是一個機會來實現我們一直在談論的圍繞專業心臟病學模式的協同效應，如果認為我們針對的人群有很好的替代方案，那就錯了，因為事實上並沒有很好的替代方案。

And we do believe we have a positioning as well as a profile for omecamtiv mecarbil, if positive in this confirmatory study that can translate into a meaningful opportunity. So looking forward to updating you more -- and more on that. Operator, next question please.

我們確實相信，我們對 omecamtiv mecarbil 有一個定位和概況，如果這項確認研究的結果呈陽性，那麼這將轉化為一個有意義的機會。因此，我期待著向您提供更多關於此方面的最新消息。接線員，請問下一個問題。

Srikripa Devarakonda, Truist Securities.

Srikripa Devarakonda，Truist Securities。

I have a question on MAPLE as well. I think, Fady, you talked about getting imaging data in MAPLE that might suggest a difference in cardiac remodeling. I was wondering if 6 months -- you think 6 months is enough to demonstrate the difference? I think you've mentioned that it's the start of showing the difference. And do you think long-term data from FOREST would add to that? Or would you need to show longer data from MAPLE?

我也有關於 MAPLE 的問題。我認為，Fady，您談到了在 MAPLE 中獲得的成像數據可能表明心臟重塑的差異。我想知道 6 個月——您認為 6 個月是否足以顯示差異？我想你已經提到過，這是顯示差異的開始。您認為 FOREST 的長期數據會增加這一點嗎？或者您需要顯示來自 MAPLE 的更長的數據？

Well, let me put it differently, a little bit differently. Already with SEQUOIA, for instance, we've presented data that 6 months, you start to see changes in terms of reduction of LV mass and left atrial size that reflect positive changes in cardiac structure. So 6 months is enough. Those changes may increase over time, which means you need longer follow-up.

嗯，讓我換個說法，稍微不一樣。例如，透過 SEQUOIA，我們已經展示了 6 個月的數據，您開始看到左心室質量和左心房大小的減少，這反映了心臟結構的積極變化。所以6個月就夠了。這些變化可能會隨著時間的推移而增加，這意味著您需要更長的後續追蹤。

But I think what we'll see and I hope we'll see with MAPLE is that with beta blockers, you don't see any of those changes over 6 months. So the process doesn't even start. It doesn't -- it doesn't get underway. There's not really any mechanistic reason to believe that you will see it in those patients. And so if you haven't started in 6 months, there's no reason to believe that somehow much longer treatment with that particular modality is going to lead to the same sort of changes that we'll demonstrate over time with aficamten.

但我認為我們會看到並且我希望我們會看到，透過 MAPLE 使用的 β 受體阻斷劑，在 6 個月內你不會看到任何變化。因此該過程根本就未開始。它沒有——它沒有開始。確實沒有任何機械原因可以相信你會在這些病人身上看到它。因此，如果您在 6 個月內還沒有開始治療，那麼就沒有理由相信採用該特定方式進行更長時間的治療會導致我們在使用 aficamten 時隨時間推移所展示的相同類型的變化。

Got it. So I think the point I was trying to get to is, would this help from a reimbursement perspective that this is not just the exercise capacity, but also the cardiac remodeling that you see at 6 months?

知道了。所以我認為我想要表達的觀點是，從報銷的角度來看，這是否有幫助？

Andrew, do you want to take that? I mean, I know from a physician perspective and we just had -- frankly, had a call on this, this morning with our steering committee. They're all interested in how to demonstrate that early -- earlier use of this mechanism of action may change the course of people's disease progression. And so there's really strong interest in the physician community of that question. And it's difficult to show and likely payers may feel differently. It's hard to know, but I think it's an important question to ultimately answer.

安德魯，你想拿走那個嗎？我的意思是，從醫生的角度來看，我們剛剛——坦率地說，今天早上我們與指導委員會就此事進行了通話。他們都對如何證明早期使用這種作用機制可能會改變人們的疾病進展過程感興趣。因此，醫生群體對這個問題非常感興趣。而且這很難證明，而且可能的付款人可能會有不同的感受。這個問題很難回答，但我認為這是一個最終需要回答的重要問題。

Thanks for the question. I think ultimately, the more data that we can add to arguments for payers, MAPLE certainly starts to add to that argument. SEQUOIA clearly adds to that argument. Having outcomes data. So right now we're focused on linking Peak VO2 to outcomes, secondaries like New York Heart Class and KCCQ, they all resonate very well with payers. This added to that certainly should help that argument. So we haven't broached the subject with payers yet. But again, I think additional evidence is always helpful.

謝謝你的提問。我認為，最終，我們為付款人論點提供的數據越多，MAPLE 肯定就會開始為該論點提供支持。SEQUOIA 顯然支持了這個論點。擁有結果數據。所以現在我們專注於將峰值攝氧量與結果聯繫起來，紐約心臟課程和 KCCQ 等次要項目都與付款人產生了很好的共鳴。除此之外，這無疑應該有助於這個論點。所以我們還沒有與付款人討論這個問題。但我再次認為，額外的證據總是有幫助的。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B.Riley Securities。

Congrats on a strong third quarter. So for the CK-586 HFpEF Phase II trial, 12-week treatment period, what would be your expectation for functional improvement given what you've seen in the nHCM patients in REDWOOD? And are you able to quantify beyond, obviously, the proBNP information you'll get? Or should we just wait for the MYK-224 AURORA study data early next year to understand what good looks like in a placebo-controlled manner? And also thinking how this stacks up relative to the GLP-1 drugs being increasingly used in HFpEF?

恭喜第三季業績強勁。那麼對於 CK-586 HFpEF II 期試驗的 12 週治療期，根據您在 REDWOOD 的 nHCM 患者中看到的情況，您對功能改善的期望是什麼？顯然，您能夠量化您所獲得的 proBNP 資訊嗎？或者我們應該等待明年初的 MYK-224 AURORA 研究數據來了解以安慰劑對照的方式看起來是什麼樣的？並且思考這與在 HFpEF 中越來越多使用的 GLP-1 藥物相比如何？

Let me start. I'll ask Stuart to comment. But I think just I'll make the point that in our nHCM study in REDWOOD, the nHCM cohort, that was 10 weeks of treatment and that seemed adequate to see meaningful biomarker signals and some symptom improvement. So I think that here, we have just similar chance of seeing that in these patients.

讓我開始吧。我會請史都華發表評論。但我想我要指出的是，在我們在 REDWOOD 的 nHCM 研究中，nHCM 隊列經過了 10 週的治療，似乎足以看到有意義的生物標記信號和一些症狀改善。因此我認為，我們在這些患者身上看到這種情況的機會是相似的。

This is more of a dose-finding trial. By the time we got to the nonobstructive HCM cohort in REDWOOD, we already had a pretty good sense of doses. But I think, again, the duration of this trial should allow for us to get a sense of how this drug impacts patients' symptoms and other measures of cardiac function and structure.

這更像是一次劑量探索試驗。當我們到達 REDWOOD 的非阻塞性 HCM 隊列時，我們已經對劑量有了相當好的了解。但我認為，這次試驗的持續時間應該可以讓我們了解這種藥物如何影響患者的症狀以及心臟功能和結構的其他指標。

As to the use of GLP-1, Stuart, do you want to comment on how we're thinking about that in this population?

至於 GLP-1 的使用，斯圖爾特，您想評論我們如何看待這一人群嗎？

I'm sorry, I didn't quite get the question, Fady. So --

抱歉，法迪，我沒太明白你的問題。所以--

I guess Mayank was asking in -- how GLP-1s are now being used in HFpEF? How are we incorporating the change in therapy and our consideration of our plans going forward?

我猜 Mayank 想問的是——GLP-1 現在在 HFpEF 中是如何應用的？我們如何將治療的改變與未來計劃的考慮結合起來？

Well, the way we think about this is that these are different mechanisms of action. And there has been -- there is some evidence of some benefit for GLP-1 receptor agonist in HFpEF. It's not completely clear at this point how much is related to weight reduction or some other potential mechanism.

嗯，我們的想法是，這些都是不同的作用機制。並且有證據顯示 GLP-1 受體激動劑對 HFpEF 有一定益處。目前還不完全清楚其中有多少是與減肥或其他潛在機制有關。

But I think the point is that this population is one at high risk of adverse cardiovascular outcomes. And what we've seen in -- certainly in patients with HFrEF is that addition of new mechanism of action that address different pathways result in incremental risk reduction for adverse heart failure outcomes. And so we anticipate the same with the mechanism of action for CK-586 cardiac myosin inhibition, again, analogous to what we've seen so far in patients with nonobstructive HCM.

但我認為關鍵在於，這類族群發生心血管不良後果的風險很高。我們在 HFrEF 患者中看到的是，增加針對不同途徑的新的作用機制可以逐步降低不良心力衰竭後果的風險。因此，我們預期 CK-586 心臟肌球蛋白抑制的作用機制也會出現同樣的情況，這與我們迄今為止在非阻塞性 HCM 患者中看到的情況類似。

So there's no reason why these mechanisms shouldn't be complementary. So we don't see that as competitive, but I think you got an answer.

所以沒有理由說這些機制不應該是互補的。因此我們認為這不具有競爭力，但我認為你已經得到了答案。

But I think there's a lot to be appreciated about the spectrum or continuum of heart failure from severely reduced EF to supernormal EF. And I do believe the way we're positioning is different. One shouldn't think that all drugs are going to be equally across that spectrum, including GLP-1s.

但我認為，從射血分數 (EF) 嚴重降低到射血分數 (EF) 超常，心臟衰竭的範圍或連續性有很多值得了解的地方。我確實認為我們的定位方式不同。我們不應該認為所有藥物，包括 GLP-1，都會有相同的效果。

Yes. Remember, GLP-1s are applied in obese people. Not everybody with HFpEF is obese. So there are clearly segments of the HFpEF population that are not going to be helped by GLP-1s just because they're not going to need or it would be adverse to give them a lot of weight loss. And patients with high ejection fraction likewise, we will try to avoid people with metabolic syndrome and obesity as a means of carving out a phenotype that we think is responsive to this mechanism of action.

是的。請記住，GLP-1 適用於肥胖者。並非所有患有 HFpEF 的人都是肥胖的。因此，顯然 HFpEF 族群中的一些人不會從 GLP-1 中得到幫助，因為他們不需要大量減肥，或者 GLP-1 對他們的體重減輕不利。同樣，對於射血分數高的患者，我們會盡量避免患有代謝症候群和肥胖症的患者，以便形成我們認為對這種作用機制有反應的表型。

Thank you. Operator, next question please.

謝謝。接線員，請問下一個問題。

Yasmeen Rahimi from Piper Sandler.

派珀·桑德勒 (Piper Sandler) 樂隊的 Yasmeen Rahimi。

It's so wonderful, this is the first call in two years that we did not bring up the word in the Q&A of REMS. So it's nice to see that. And nor am I going to ask a question on that. Okay. So I'm going to -- I feel pretty good about not talking about that anymore.

太棒了，這是兩年來我們第一次在 REMS 的問答環節中沒有提及這個詞。我很高興看到這一點。我也不會就此提出問題。好的。所以我要──我覺得不再談論這件事了。

But would love to continue the dialogue on MAPLE. I think ultimately, what maybe we need your help on is to understand what is the size of the obstructive market that fails beta blocker or even gets worse on beta blocker? And what kind of cost analyses could you potentially put together to kind of make the argument of down the line of aficamten being positioned as first line? But maybe to the extent you could educate us on the size of the market if MAPLE shows superiority, would greatly appreciate and I'll jump back into the queue.

但很想繼續關於 MAPLE 的對話。我認為最終我們可能需要您的幫助來了解服用 β 受體阻斷劑無效或服用 β 受體阻斷劑後病情惡化的阻塞性市場規模有多大？您可以將哪些類型的成本分析放在一起，以證明 aficamten 被定位為第一線？但如果 MAPLE 表現出優勢的話，也許您可以向我們介紹市場的規模，我將不勝感激，並重新回到隊列中。

Thank you. Andrew, you've done some good work around market segmentation. Do you want to tackle that?

謝謝。安德魯，你在市場區隔方面做得很好。你想解決這個問題嗎？

Sure. Good question. So from a beta blocker point of view, at least in our -- this is not from claims data or a large data source from market research, we do know that about 25% of patients experience contraindication to beta blocker, at least what over 100 or so physicians told us and maybe about 80% to 90% have unwanted side effects. So certainly, it's not a agent that patients love to take from what we've heard.

當然。好問題。因此從β受體阻斷劑的角度來看，至少在我們看來——這不是來自索賠數據或來自市場研究的大型數據源，我們確實知道大約 25% 的患者對β受體阻滯劑有禁忌症，至少超過 100 名醫生告訴我們這是如此，並且大約 80% 到 90% 的患者有不良副作用。所以從我們所聽到的來看，這肯定不是患者喜歡服用的藥物。

When we look at those that fail beta blockers and kind of the value argument, I think our overall -- it's hard to create a value argument around a low-cost generic. I think the value argument has to get elevated to a higher level. Things like KCCQ, New York Heart Class, what actually does change outcomes as does Peak VO2 change outcomes, hard outcomes, outcomes like hospitalization, death, et cetera. If you have a lower New York Heart Class or a better Peak VO2, then certainly you have better outcomes, avoiding septal reduction therapy or surgery, the associated comorbidities associated with HCM.

當我們研究那些對β受體阻斷劑不起作用的藥物以及某種價值論點時，我認為總體而言——很難圍繞低成本仿製藥創建價值論點。我認為價值論點必須提升到更高的水準。諸如 KCCQ、紐約心臟課程等，實際上確實會改變結果，峰值攝氧量也會改變結果、硬性結果、住院、死亡等結果。如果您的紐約心臟等級較低或峰值攝氧量較高，那麼您肯定會獲得更好的治療效果，可以避免間隔縮小治療或手術以及與 HCM 相關的合併症。

So these are the kinds of value arguments that we really look at making. I don't think that a failure of a beta blocker will really help from that regard. I think where it does help, what I alluded to earlier, it creates additional evidence. It creates evidence against what a standard of care is for many physicians and gets them to rethink potentially therapy. So it opens up the market. It's not a larger population, obviously, it's still oHCM, but it is a larger market opportunity and therefore, larger market penetration.

所以這些是我們真正想要提出的價值論點。我認為β受體阻斷劑的失效不會在這方面有真正的幫助作用。我認為它確實有幫助，正如我之前提到的，它提供了額外的證據。它為許多醫生的護理標準提供了證據，並讓他們重新考慮潛在的治療方法。因此它開拓了市場。顯然，這不是一個更大的人口，它仍然是 oHCM，但它是一個更大的市場機會，因此，市場滲透率也更大。

I think a lot of the questions we're getting today relate to MAPLE and I assume that means that a lot of the analysts are refining their models to understand what MAPLE could mean in terms of opening the market to yet broader adoption. And I appreciate that while I'll underscore and as Andrew is pointing out, it's the body of evidence that I think creates a tipping point around which cardiologists activated perhaps outside of centers of excellence may ultimately feel more comfortable prescribing aficamten if approved.

我認為我們今天收到的許多問題都與 MAPLE 有關，我認為這意味著許多分析師正在改進他們的模型以了解 MAPLE 在開放市場並獲得更廣泛採用方面的意義。我很感激這一點，儘管我會強調，正如安德魯指出的那樣，我認為這是大量證據，它創造了一個臨界點，如果獲得批准，那麼在卓越中心之外的心臟病專家最終可能會更願意開出阿菲坎汀。

We think that's going to make a big difference. So it contributes to velocity of commercial launch. It contributes to what will be the expansion of the category beyond where it's currently perhaps entrenched in centers of excellence. We've talked about the concentration of prescribers and we do believe that MAPLE can make a meaningful difference in terms of adding to the evidence to support the use of cardiac myosin inhibitors. And that's where I think it will enable better diffusion of this innovation broader into the marketplace. Operator, next question, please.

我們認為這將會產生重大影響。因此它有助於加快商業發布的速度。它有助於將該類別擴展到目前可能紮根於卓越中心的領域之外。我們已經討論了處方者的集中度，我們確實相信 MAPLE 可以在增加支持使用心臟肌球蛋白抑制劑的證據方面發揮有意義的作用。我認為這將使這項創新能夠更好地在市場上得到更廣泛的傳播。接線員，請問下一個問題。

Rohan Mathur, Oppenheimer.

羅漢·馬圖爾，奧本海默。

This is Rohan on for Leland Gershell. On aficamten, just as you think about implications from the ongoing launch of a cardiac myosin inhibitor, what sort of steps of the commercial process would you expect the incumbent therapy to maybe catalyze in terms of growing market awareness and helping an uptake and eventual payer coverage once aficamten is potentially available?

這是 Rohan 代替 Leland Gershell 上場。關於阿菲坎汀，正如您思考正在推出的心臟肌球蛋白抑制劑的影響一樣，您認為現有療法可能在商業化過程中催化哪些步驟，以提升市場認知度並幫助阿菲坎汀在可能上市後被接受並最終實現付款人覆蓋？

Yes. So we've done a lot of work around what a next-in-class opportunity can mean for category expansion, broader penetration, activating cardiologists who might not be currently yet prescribing a cardiac myosin inhibitor. We think it has a lot to do with things that we've been talking about in terms of next-in-class profile. It's not just about safety and efficacy. It's about ease of use and convenience. It's about the patient experience.

是的。因此，我們圍繞著下一代機會對類別擴展、更廣泛的滲透、激活可能尚未開出心臟肌球蛋白抑制劑的心臟病專家的意義進行了大量工作。我們認為這與我們一直在談論的下一代產品概況有很大關係。這不僅僅關乎安全性和有效性。它與易用性和便利性有關。這是關於病人的體驗。

And maybe, Andrew, you can talk a bit more about these things.

也許，安德魯，你可以多談談這些事情。

Sure. So really, when you're the second agent, I think we can -- a disease that has a new therapy that hasn't had a targeted therapy. So we're doing our own disease awareness campaign. We rolled out a disease awareness campaign in HCPs not long ago and with patients in early Q1, I think many of us in the US have seen direct-to-consumer TV advertising for the category. There's broader disease awareness now. There's patient organizations.

當然。所以實際上，當你是第二種藥物時，我認為我們可以——一種尚未有針對性治療的疾病得到新的治療。因此我們正在進行自己的疾病宣傳活動。不久前，我們在第一季初向 HCP 和患者推出了一項疾病宣傳活動，我想美國很多人都看過該類別的直接面向消費者的電視廣告。現在人們對疾病的認識更加廣泛了。有患者組織。

So all these things create awareness by payers. They see these things out in the marketplace by physicians. It gets patients in the physician offices talking about maybe additional treatment options. So the increased awareness certainly should have an increased market opportunity for us where we're not fighting awareness of disease. We're educating more on aficamten and the unique properties as well as the areas of differentiation.

所有這些都會提高付款人的意識。他們在市場上看到醫生們會做這樣的事。它讓醫生辦公室裡的患者討論可能的額外治療選擇。因此，在我們不再與疾病意識奮鬥的情況下，意識的提高無疑會為我們帶來更多的市場機會。我們正在對 aficamten 及其獨特屬性以及差異化領域進行更多的教育。

And I am showing no further questions from our phone lines. I'd now like to turn the conference back over to President and CEO, Robert Blum, for any closing remarks.

我沒有從電話線提出其他問題。現在，我想將會議交還給總裁兼執行長羅伯特布魯姆 (Robert Blum)，請他作最後發言。

Thank you. I want to thank all the participants on our call today for your continued support and interest in Cytokinetics. Obviously, a lot to cover today. We've had a very busy year.

謝謝。我要感謝今天參加電話會議的所有參與者對 Cytokinetics 的持續支持和關注。顯然，今天要講的內容很多。我們度過了非常忙碌的一年。

Q3 was a good quarter in terms of progress against our goals. If you haven't already, I would encourage you to listen in on the investor event that's archived on our website. We went into some great detail around our strategies, not just as it relates to aficamten and oHCM, but also nHCM and how that creates a through line to our specialty cardiology franchise anchored with both omecamtiv and CK-586.

從實現我們目標的進展來看，第三季表現良好。如果您還沒有，我鼓勵您收聽我們網站上存檔的投資者活動。我們詳細介紹了我們的策略，不僅涉及 aficamten 和 oHCM，還涉及 nHCM，以及如何透過 omecamtiv 和 CK-586 為我們的專科心臟病學特許經營打造一條貫穿線。

And what you heard today speaks to not just progress around those programs, but also in research and earlier development and how that's all enveloped in a company that's being prudent with regard to capital investment deployment and efficiencies that could create commercial synergies.

您今天所聽到的不僅說明了這些項目的進展，還說明了研究和早期開發方面的進展，以及如何將這一切都包含在一家在資本投資部署和效率方面保持審慎的公司中，從而可以創造商業協同效應。

As I mentioned, our goal is not simply to launch aficamten next year, but to do so in a way that's differentiated and could be enabling of us to set the table for the franchise that we've been talking about.

正如我所提到的，我們的目標不僅僅是明年推出 aficamten，而且要以一種差異化的方式推出，並使我們能夠為我們一直在談論的特許經營奠定基礎。

I want to again thank everybody for your interest in what we're doing, your attention on this call. We look forward to keeping you up-to-date through the remainder of the year. And with that, operator, we can conclude the call, please.

我想再次感謝大家對我們所做的事情的興趣和對這次電話會議的關注。我們期待在今年餘下的時間為您提供最新資訊。接線員，我們現在可以結束通話了。

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

謝謝。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。