Cytokinetics Inc (CYTK) 2022 Q4 法說會逐字稿

Good afternoon, and welcome, ladies and gentlemen, to Cytokinetics' Fourth Quarter 2022 Conference Call. At this time, I would like to inform you that this call is being recorded. (Operator Instructions) I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

下午好，女士們，先生們，歡迎來到 Cytokinetics 2022 年第四季度電話會議。此時，我想通知您，此通話正在錄音中。 （操作員說明）我現在將把電話轉給 Cytokinetics 的企業傳播和投資者關係高級副總裁 Diane Weiser。請繼續。

Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, who will begin with an overview of the quarter and recent developments. Fady Malik, EVP of R&D, will provide updates related to omecamtiv mecarbil and aficamten, as well as other drug candidates comprising our early clinical development pipeline. Andrew Callos, EVP and Chief Commercial Officer, will speak further about omecamtiv mecarbil and our specialty cardiology franchise strategy related to aficamten. Stuart Kupfer, SVP and Chief Medical Officer, will provide an update on reldesemtiv. Robert Wong, VP and Chief Accounting Officer, will provide a financial overview of the past quarter and Ching Jaw, SVP and Chief Financial Officer, will discuss our 2023 financial guidance and corporate development strategies. Finally, Robert Blum will provide closing comments and review expected key milestones for 2023.

下午好，感謝您今天加入我們的電話會議。總裁兼首席執行官 Robert Blum，他將首先概述本季度和最近的發展。研發部執行副總裁 Fady Malik 將提供與 omecamtiv mecarbil 和 aficamten 以及構成我們早期臨床開發管道的其他候選藥物相關的最新信息。執行副總裁兼首席商務官 Andrew Callos 將進一步談論 omecamtiv mecarbil 和我們與 aficamten 相關的專業心髒病學特許經營戰略。高級副總裁兼首席醫療官 Stuart Kupfer 將提供有關 reldesemtiv 的最新信息。副總裁兼首席會計官 Robert Wong 將提供上一季度的財務概覽，高級副總裁兼首席財務官 Ching Jaw 將討論我們的 2023 年財務指導和企業發展戰略。最後，羅伯特·布魯姆 (Robert Blum) 將提供結束語並回顧 2023 年預期的關鍵里程碑。

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. 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 fourth quarter 2022 financial results filed on Form 8-K and our Form 10-K, each of which were filed today. We undertake no obligation to update any forward-looking statements after this call.

請注意，以下討論的部分內容，包括我們對問題的回答，包含與未來事件和業績相關的陳述，而不是歷史事實，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預測的結果存在重大差異。有關可能導致我們的實際結果與這些前瞻性陳述中的結果存在重大差異的因素的更多信息包含在我們提交給美國證券交易委員會的文件中，包括我們在 8-K 表格和 10 表格中提交的關於我們 2022 年第四季度財務結果的當前報告- K，每一個都是今天提交的。我們沒有義務在此次電話會議後更新任何前瞻性陳述。

And now I will turn the call over to Robert.

現在我將把電話轉給羅伯特。

Thank you, Diane, and thanks to all for joining us on the call today. The fourth quarter of 2022 was productive across our pipeline with continued progress being made through the beginning of this year.

謝謝你，黛安，感謝大家今天加入我們的電話會議。 2022 年第四季度，我們的整個管道都富有成效，今年年初繼續取得進展。

Beginning with omecamtiv mecarbil, yesterday, we received a complete response letter from the FDA. The letter communicated that GALACTIC-HF is not sufficiently persuasive to establish substantial evidence of effectiveness for reducing the risk of heart failure events and cardiovascular death in adults with chronic heart failure with HFrEF in lieu of evidence from at least 2 adequate and well-controlled clinical investigations.

從 omecamtiv mecarbil 開始，昨天，我們收到了 FDA 的完整回复信。這封信表明，GALACTIC-HF 不足以證明有效降低 HFrEF 慢性心力衰竭成人患者心力衰竭事件和心血管死亡風險的實質性證據代替來自至少 2 個充分且控制良好的臨床試驗的證據調查。

FDA stated that results from an additional clinical trial of omecamtiv mecarbil are required to establish substantial evidence of effect for the treatment of HFrEF with benefits that outweigh the risks. As we stated in our call this morning, we expect to request a meeting with FDA in order to understand FDA's views regarding the CRL and what may be required to support potential approval of omecamtiv mecarbil in the United States. However, as mentioned this morning, we have no plans to conduct an additional clinical trial of omecamtiv mecarbil, and our focus remains on the development program for aficamten.

FDA 表示，需要 omecamtiv mecarbil 的額外臨床試驗結果來確定治療 HFrEF 的益處大於風險的實質性證據。正如我們今天早上在電話中所說，我們希望與 FDA 舉行會議，以了解 FDA 對 CRL 的看法，以及支持 omecamtiv mecarbil 在美國的潛在批准可能需要什麼。然而，正如今天上午所提到的，我們沒有計劃對 omecamtiv mecarbil 進行額外的臨床試驗，我們的重點仍然是 aficamten 的開發計劃。

While disappointing, this is a scenario for which we prepared. As Andrew will elaborate, in anticipation of this potential outcome, a substantial portion of our anticipated 2023 commercial spending and hiring was gated on the potential approval of omecamtiv mecarbil. Our commercial infrastructure has also been designed and developed with the ability to pivot to focus on aficamten in line with our specialty cardiovascular franchise strategy. Moreover, and in parallel, as you'll be hearing more from my colleagues, we will continue in 2023 to press forward with regulatory authorities to seek approvals for omecamtiv mecarbil in other countries and as may provide support to corporate development and business development activities.

雖然令人失望，但這是我們為之準備的場景。正如安德魯將詳細闡述的那樣，在預期這一潛在結果的情況下，我們預期的 2023 年商業支出和招聘的很大一部分取決於 omecamtiv mecarbil 的潛在批准。我們的商業基礎設施也經過設計和開發，能夠根據我們的專業心血管特許經營戰略專注於治療。此外，與此同時，隨著您從我的同事那裡聽到更多信息，我們將在 2023 年繼續與監管機構一起推動 omecamtiv mecarbil 在其他國家/地區獲得批准，並可能為企業發展和業務發展活動提供支持。

As mentioned previously, we believe in the science underlying omecamtiv mecarbil and the demonstrated clinical evidence to potentially benefit patients with advanced and worsening heart failure. With that said, however, we will not bet the company on omecamtiv mecarbil and ours is a broad pipeline on novel muscle biology-directed drug candidates. Cytokinetics is well positioned to press forward with aficamten as represents our next major opportunity to bring forward an important new medicine to serve patients in need.

如前所述，我們相信 omecamtiv mecarbil 的科學依據和已證明的臨床證據可能使晚期和惡化的心力衰竭患者受益。然而，話雖如此，我們不會將公司賭在 omecamtiv mecarbil 上，我們的公司擁有廣泛的新型肌肉生物學導向候選藥物管道。 Cytokinetics 已準備好與 aficamten 一起推進，因為它代表了我們提出重要新藥來為有需要的患者提供服務的下一個重大機會。

And to that end, in the fourth quarter, the development program for aficamten progressed in both obstructive and nonobstructive HCM. As Fady will explain, we're poised for an important year with data expected from Cohort 4 of REDWOOD-HCM in nHCM this coming weekend at the ACC scientific sessions in New Orleans and results from the pivotal Phase III trial, SEQUOIA-HCM later this year in Q4. Concurrently, we have plans to substantially expand the development program for aficamten by beginning 2 new Phase III clinical trials in 2023, one in OHCM with aficamten as monotherapy and 1 in nHCM.

為此，在第四季度，aficamten 的開發計劃在阻塞性和非阻塞性 HCM 方面取得了進展。正如 Fady 將解釋的那樣，我們準備迎接重要的一年，預計本週末在新奧爾良舉行的 ACC 科學會議上來自 nHCM 的 REDWOOD-HCM 隊列 4 的數據以及關鍵的 III 期試驗 SEQUOIA-HCM 的結果將於今年晚些時候公佈年第四季度。同時，我們計劃通過在 2023 年開始 2 項新的 III 期臨床試驗，一項在 OHCM 中以 aficamten 作為單一療法，一項在 nHCM 中，從而大幅擴展 aficamten 的開發計劃。

As Stuart will elaborate for reldesemtiv, patient enrollment continued in COURAGE-ALS following the first interim analysis that occurred last quarter, and we expect the data monitoring committee to conduct the second interim analysis for the ongoing trial in the second quarter of this year. We believe reldesemtiv can represent an entirely new pharmacology for ALS patients underserved by the lack of a muscle-directed therapy.

正如 Stuart 將為 reldesemtiv 詳細說明的那樣，在上個季度進行的第一次中期分析之後，COURAGE-ALS 的患者招募繼續進行，我們預計數據監測委員會將在今年第二季度對正在進行的試驗進行第二次中期分析。我們相信 reldesemtiv 可以代表一種全新的藥理學，適用於因缺乏肌肉導向療法而服務不足的 ALS 患者。

Entering 2023, Cytokinetics remains on strong financial footing with over 2 years of forward cash owing to our strategic and gated build of our commercial capabilities as well as our creative deal-making and prudent investment spending. We expect our burn rate in 2023 to be within a comparable range to 2022 despite our broadening of the clinical development program for aficamten, as well as our expanding and extending our early clinical development pipeline, as you'll also hear more during our call today.

進入 2023 年，由於我們對商業能力的戰略性和封閉式建設以及我們創造性的交易決策和審慎的投資支出，Cytokinetics 仍保持著強大的財務基礎，擁有超過 2 年的遠期現金。儘管我們擴大了 aficamten 的臨床開發計劃，並擴大和擴展了我們的早期臨床開發管道，但我們預計 2023 年的燒傷率將在與 2022 年相當的範圍內，因為您在今天的電話會議中也會聽到更多信息.

And despite the setback for omecamtiv mecarbil, our mission remains the same as it has been for 25 years now, to bring forward new medicines for patients with diseases of impaired muscle function and our convictions run as strong as ever.

儘管 omecamtiv mecarbil 遭遇挫折，但 25 年來我們的使命始終如一，即為患有肌肉功能受損疾病的患者開發新藥，我們的信念一如既往地堅定。

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

有了這個，我會把電話轉給 Fady。

Thanks, Robert. Before we move on to aficamten, I want to express my disappointment in this outcome for omecamtiv mecarbil and also share my gratitude to the many employees, investigators and patients, who contributed to the development program over the years. While we continue to work with FDA and assess the next steps for omecamtiv mecarbil, in the fourth quarter, the European Medicines Agency accepted the marketing application for omecamtiv mecarbil. And Ji Xing announced that the Center for Drug Evaluation of the National Medical Products Administration of the People's Republic of China accepted the NDA submission for omecamtiv mecarbil.

謝謝，羅伯特。在我們繼續討論 aficamten 之前，我想表達我對 omecamtiv mecarbil 這一結果的失望，並感謝多年來為開發計劃做出貢獻的許多員工、研究人員和患者。在我們繼續與 FDA 合作並評估 omecamtiv mecarbil 的後續步驟的同時，歐洲藥品管理局在第四季度接受了 omecamtiv mecarbil 的營銷申請。吉星宣布，國家藥品監督管理局藥品審評中心已受理奧美卡替莫卡必爾的新藥申請。

We'll continue to pursue international approvals for omecamtiv mecarbil as we assess its future for the program in the U.S.

我們將繼續尋求 omecamtiv mecarbil 的國際批准，因為我們評估其在美國的計劃的未來。

Moving on to aficamten. We made excellent progress in the fourth quarter with nearly 100 clinical trial sites opening to screening, enrollment increased substantially in SEQUOIA-HCM in the fourth quarter and into early 2023. We've now enrolled more than 2/3 of the targeted 270 patients and believe we're on track to complete enrollment in the second quarter, with results expected in the fourth quarter of the year.

繼續前進。我們在第四季度取得了很好的進展，近 100 個臨床試驗站點開放篩選，第四季度和 2023 年初 SEQUOIA-HCM 的註冊人數大幅增加。我們現在已經註冊了目標 270 名患者中的 2/3 以上，並且相信我們有望在第二季度完成註冊，預計將在今年第四季度取得結果。

During the quarter, we also completed enrollment in Cohort 4 of REDWOOD-HCM. We plan to share data from this cohort in nonobstructive HCM patients in a poster session at the American College of Cardiology Scientific Sessions this coming weekend, setting us up for advancement into a pivotal Phase III clinical trial in patients with nonobstructive nHCM in the second half of the year.

在本季度，我們還完成了 REDWOOD-HCM 隊列 4 的註冊。我們計劃在即將到來的周末美國心髒病學會科學會議的海報會議上分享非阻塞性 HCM 患者隊列的數據，為我們在下半年進入非阻塞性 nHCM 患者的關鍵 III 期臨床試驗做好準備那一年。

Related to REDWOOD-HCM, during the quarter, we were also pleased to announce the full results from cohorts 1 and 2 of REDWOOD-HCM were published in JACC, elaborating on its next-in-class profile.

與 REDWOOD-HCM 相關，在本季度，我們還高興地宣布 REDWOOD-HCM 第 1 組和第 2 組的全部結果已在 JACC 上發表，詳細闡述了其一流的概況。

In addition, with further preparations for our second Phase III clinical trial of aficamten as monotherapy compared to metoprolol in patients with obstructive HCM. We're calling the trial MAPLE-HCM, which stands for metoprolol versus aficamten in patients with left ventricular outflow tract obstruction on exercise capacity. The trial is expected to begin within the second quarter of this year. But in advance, I'd like to share a few key points about its design.

此外，我們正在為我們的第二個 III 期臨床試驗做進一步準備，將 aficamten 作為單一療法與美托洛爾相比，用於治療阻塞性 HCM 患者。我們將試驗稱為 MAPLE-HCM，它代表左心室流出道梗阻患者的美托洛爾與阿非卡坦對運動能力的影響。該試驗預計將在今年第二季度內開始。但在此之前，我想分享一些有關其設計的要點。

MAPLE-HCM is a Phase III multicenter, randomized, double-blind, active comparator trial in patients with symptomatic OHCM and elevated LVOT gradients. It is expected to enroll approximately 170 patients. The primary endpoint is change in peak VO2 assessed by CPET from baseline to week 24. Secondary endpoints include change in NYHA class, KCCQ, NT-proBNP and measures of structural remodeling. We look forward to sharing more details about the trial upon the opening of enrollment.

MAPLE-HCM 是針對有症狀的 OHCM 和 LVOT 梯度升高的患者的 III 期多中心、隨機、雙盲、主動比較試驗。預計將招募大約 170 名患者。主要終點是 CPET 評估的峰值 VO2 從基線到第 24 週的變化。次要終點包括 NYHA 等級、KCCQ、NT-proBNP 和結構重塑測量的變化。我們期待在開放註冊時分享有關試驗的更多詳細信息。

Looking to our earlier-stage pipeline, during the fourth quarter, we began a Phase I study of CK-136, our cardiac troponin activator in development for the potential treatment of patients with HFrEF and other types of heart failure, such as right ventricular failure resulting from impaired cardiac contractility. The advancement of CK-136 extends our cardiovascular franchise as it may provide differentiated effects for the potential treatment of these other forms of heart failure by employing an alternative mechanism of action within the sarcomere. We expect to share data from the Phase I trial in the second half of the year.

展望我們的早期管道，在第四季度，我們開始了 CK-136 的 I 期研究，CK-136 是我們正在開發的心肌肌鈣蛋白激活劑，用於治療 HFrEF 和其他類型的心力衰竭患者，例如右心室衰竭心肌收縮力受損所致。 CK-136 的進步擴展了我們的心血管專營權，因為它可以通過在肌節內採用替代作用機制，為這些其他形式的心力衰竭的潛在治療提供差異化的效果。我們預計將在今年下半年分享 I 期試驗的數據。

Additionally, more recently, we presented preclinical data related to a newer compound, CK4021586 or CK-586. It's another cardiac myosin inhibitor. CK-586 has a mechanism of action that's distinct from aficamten, and its advancement affords us the potential to explore the therapeutic application of cardiac myosin inhibition to treat certain types of heart failure with preserved ejection fraction where hypercontractility may play a role.

此外，最近，我們提供了與更新化合物 CK4021586 或 CK-586 相關的臨床前數據。它是另一種心肌肌球蛋白抑製劑。 CK-586 具有不同於 aficamten 的作用機制，它的進步使我們有可能探索心肌肌球蛋白抑制的治療應用，以治療某些類型的射血分數保留的心力衰竭，其中高收縮性可能發揮作用。

We look forward to advancing this compound into clinical development during this first half of the year.

我們期待在今年上半年將該化合物推進臨床開發。

Despite the CRL for omecamtiv mecarbil, we have 3 other cardiovascular drug candidates advancing in development, led by aficamten in the pivotal Phase III clinical trial, SEQUOIA-HCM. Our cardiovascular franchise emerging from our sarcomere-directed research continues to deliver on the promise of new potential medicines for patients.

儘管 omecamtiv mecarbil 已獲得 CRL，但我們還有其他 3 種心血管候選藥物正在開發中，由 aficamten 在關鍵的 III 期臨床試驗 SEQUOIA-HCM 中領導。我們的心血管專營權源於我們的肌節定向研究，繼續為患者提供新的潛在藥物的承諾。

With that, I will turn the call over to Andrew to speak about omecamtiv mecarbil and our specialty cardiology franchise strategy.

有了這個，我將把電話轉給安德魯來談論 omecamtiv mecarbil 和我們的專業心髒病學特許經營戰略。

Thanks, Fady. While we're disappointed by the complete response letter we received yesterday, this was a scenario for which we had planned and budgeted. As we've discussed, a substantial portion of our anticipated 2023 commercial spending and hiring was gated on the approval of omecamtiv mecarbil. As a result of our receiving a CRL, we will dial back on what would have been our commercial spending had FDA approved omecamtiv mecarbil.

謝謝，法迪。雖然我們對昨天收到的完整回复信感到失望，但這是我們已經計劃和預算的場景。正如我們所討論的，我們預期的 2023 年商業支出和招聘的很大一部分取決於 omecamtiv mecarbil 的批准。由於我們收到了 CRL，如果 FDA 批准了 omecamtiv mecarbil，我們將減少我們的商業支出。

With that said, the commercial readiness infrastructure that we have established was always developed with an eye toward a cardiovascular franchise strategy and the future launch of aficamten and additional cardiac muscle modulators. Over 90% of our commercial team has responsibilities that are not solely dedicated to omecamtiv mecarbil. Our parent team is predominantly the same team needed to support aficamten, so we have no plan for reductions in our workforce. We will also not be expanding our commercial organization in 2023, but instead shifting our focus on now preparing for the potential approval and launch of aficamten.

話雖如此，我們建立的商業準備基礎設施始終著眼於心血管特許經營戰略以及未來推出的 aficamten 和其他心肌調節劑。我們商業團隊中超過 90% 的人所承擔的責任不僅僅局限於 omecamtiv mecarbil。我們的母團隊主要是支持 aficamten 所需的同一團隊，因此我們沒有裁員計劃。我們也不會在 2023 年擴大我們的商業組織，而是將重點轉移到現在為可能批准和啟動 aficamten 做準備。

This is not the path we had hoped for, for our company and for patients with heart failure with reduced ejection fraction, but we are nimble and will pivot and now execute on this planned scenario.

對於我們公司和射血分數降低的心力衰竭患者而言，這不是我們所希望的道路，但我們很靈活，將轉向並現在執行這個計劃的方案。

In Q4, we continued commercial activities related to aficamten. Last quarter, we completed an initial go-to-market strategy for aficamten and progressed our commercial readiness plans. We are within the window in which much work needs to be done to prepare for potential global launches of aficamten across potentially multiple indications. Cardiac myosin inhibition is proving to be important for the treatment of patients with OHCM and we expect that will propel Cytokinetics to be a global specialty cardiovascular company, leading with aficamten and necessitating our important planning and executing in both 2023 and in 2024.

在第四季度，我們繼續與 aficamten 相關的商業活動。上個季度，我們完成了 aficamten 的初步上市戰略，並推進了我們的商業準備計劃。我們正處在一個窗口內，需要做很多工作來準備在可能的多種適應症下在全球範圍內推出 aficamten。心肌肌球蛋白抑制被證明對 OHCM 患者的治療很重要，我們預計這將推動 Cytokinetics 成為一家全球專業心血管公司，以 aficamten 領先，並需要我們在 2023 年和 2024 年進行重要的計劃和執行。

With that, I will turn the call over to Stuart to provide an update on reldesemtiv.

有了這個，我將把電話轉給 Stuart，以提供有關 reldesemtiv 的更新。

Thanks, Andrew. On the neuromuscular side, reldesemtiv remains a key late-stage program for our company. In the fourth quarter, we proceeded with patient enrollment in COURAGE-ALS with now over 450 patients enrolled to date or more than 3/4 of our target patient enrollment. We're on track to complete enrollment in the second quarter of 2023 and read out results in 2024.

謝謝，安德魯。在神經肌肉方面，reldesemtiv 仍然是我們公司的一個關鍵後期項目。在第四季度，我們繼續在 COURAGE-ALS 中進行患者入組，目前已有超過 450 名患者入組，占我們目標入組患者的 3/4 以上。我們有望在 2023 年第二季度完成註冊，並在 2024 年宣讀結果。

During the quarter, we announced the continuation of COURAGE-ALS following the first interim analysis for futility conducted by the Data Monitoring Committee, which reviewed unblinded data from the trial. We expect the second interim analysis to take place in the second quarter, which will also assess for futility as well as the option for a potential fixed increase in total sample size to augment the statistical power of the trial.

在本季度，我們宣布繼續進行 COURAGE-ALS，這是在數據監測委員會對試驗的非盲數據進行審查後對無效性進行的第一次中期分析之後。我們預計第二次中期分析將在第二季度進行，該分析還將評估無效性以及可能固定增加總樣本量以增強試驗統計功效的選項。

Also during the fourth quarter of 2022, we continued to enroll patients who completed COURAGE-ALS into COURAGE-ALS OLE or the open-label extension and we advanced plans for a managed access program for reldesemtiv to be available to patients, who have completed any of our previous ALS trials, including VITALITY-ALS, the Phase III clinical trial of tirasemtiv, and FORTITUDE-ALS, the Phase II clinical trial of reldesemtiv.

同樣在 2022 年第四季度，我們繼續將完成 COURAGE-ALS 的患者納入 COURAGE-ALS OLE 或開放標籤擴展，我們推進了 reldesemtiv 管理訪問計劃的計劃，以供已完成任何我們之前的 ALS 試驗包括 VITALITY-ALS（tirasemtiv 的 III 期臨床試驗）和 FORTITUDE-ALS（reldesemtiv 的 II 期臨床試驗）。

Finally, late last year, we were pleased to present data at the 33rd International Symposium on ALS/MND from an analysis of FORTITUDE-ALS, showing that patients' predicted survival risk score was strongly correlated with decline in ALSFRS-R and suggesting that the inclusion criteria selected for COURAGE-ALS will have the intended outcome of enriching for participants with more rapidly progressing disease, while minimizing but not excluding participants with more slowly progressing disease.

最後，去年年底，我們很高興地在第 33 屆肌萎縮側索硬化/運動神經病國際研討會上展示了對 FORTITUDE-ALS 的分析數據，表明患者的預測生存風險評分與 ALSFRS-R 的下降密切相關，並表明為 COURAGE-ALS 選擇的納入標準將具有豐富疾病進展較快參與者的預期結果，同時最大限度地減少但不排除疾病進展較慢的參與者。

And with that, I will turn it over to Robert Wang.

然後，我將把它交給 Robert Wang。

Thanks, Stuart. We ended the fourth quarter with approximately $830 million in cash and investments. Our revenue in Q4 2022 came primarily from Astellas to co-fund COURAGE-ALS. Our fourth quarter 2022 R&D expenses increased to $75 million from $43.5 million in the fourth quarter of 2021, primarily due to increases in spending for clinical development activities for SEQUOIA-HCM and COURAGE-ALS and for our other cardiac muscle inhibitor and early research programs.

謝謝，斯圖爾特。我們在第四季度結束時擁有約 8.3 億美元的現金和投資。我們在 2022 年第四季度的收入主要來自安斯泰來共同資助 COURAGE-ALS。我們 2022 年第四季度的研發費用從 2021 年第四季度的 4350 萬美元增加到 7500 萬美元，這主要是由於 SEQUOIA-HCM 和 COURAGE-ALS 的臨床開發活動以及我們其他心肌抑製劑和早期研究項目的支出增加。

Our fourth quarter 2022 G&A expenses were $54 million up from $33.8 million in Q4 2021 due primarily to higher outside service spending in anticipation of the potential commercial launch of omecamtiv mecarbil and our increase in personnel-related costs including stock-based compensation.

我們 2022 年第四季度的 G&A 費用為 5400 萬美元，高於 2021 年第四季度的 3380 萬美元，這主要是由於預期 omecamtiv mecarbil 的潛在商業發布導致外部服務支出增加，以及我們的人員相關成本增加，包括基於股票的薪酬。

And now Ching will review our financial outlook, 2023 guidance and corporate development strategies.

現在，Ching 將回顧我們的財務前景、2023 年指導方針和公司發展戰略。

Thanks, Robert. Today, we announced our financial guidance for 2023. The company anticipates revenue will be approximately $5 million, driven by Astellas reimbursement of the cost of COURAGE-ALS. In addition, we expect to receive $50 million in a milestone payment from Royalty Pharma upon the start of the pivotal Phase III clinical trial of aficamten in non-obstructive HCM.

謝謝，羅伯特。今天，我們公佈了 2023 年的財務指南。公司預計收入將約為 500 萬美元，這主要得益於 Astellas 報銷 COURAGE-ALS 的成本。此外，我們預計在非阻塞性 HCM 中的 aficamten 關鍵 III 期臨床試驗開始後，將從 Royalty Pharma 獲得 5000 萬美元的里程碑付款。

Operating expenses will be in the range of $420 million to $450 million and net cash utilization will be approximately $350 million to $375 million.

運營費用將在 4.2 億美元至 4.5 億美元之間，淨現金使用量將約為 3.5 億美元至 3.75 億美元。

Our current cash balance of approximately $830 million represents more than 2 years of forward cash based on our projected 2023 operating expenses and net cash utilization.

根據我們預計的 2023 年運營費用和淨現金利用率，我們目前的現金餘額約為 8.3 億美元，代表超過 2 年的遠期現金。

With our having received a CRL from the FDA, we will not incur a substantial portion of cost for what would have been our planned spending to launch omecamtiv mecarbil in the United States, a majority of which was purposefully gated on potential FDA approval. As Andrew mentioned earlier, related to omecamtiv mecarbil, we planned for the possibility of this scenario and have managed our spending judiciously by gating majority of this potential commercial spending to FDA approval. As a result, a significant majority of our commercial infrastructure can be redeployed to support potential global launch planning for aficamten.

由於我們已經收到了 FDA 的 CRL，我們將不會為我們在美國推出 omecamtiv mecarbil 的計劃支出承擔很大一部分成本，其中大部分是有意獲得 FDA 批准的。正如 Andrew 之前提到的，與 omecamtiv mecarbil 相關，我們計劃了這種情況的可能性，並通過將大部分潛在商業支出納入 FDA 批准來明智地管理我們的支出。因此，我們的大部分商業基礎設施都可以重新部署，以支持潛在的 aficamten 全球發布計劃。

Looking to other programs and spending this year, of our anticipated $150 million in clinical development spending in 2023, roughly 60% will be allocated to development program of aficamten.

看看今年的其他項目和支出，在我們預計 2023 年的 1.5 億美元臨床開發支出中，大約 60% 將分配給 aficamten 的開發項目。

As we have done in the past, we aim to end 2023 with more than 2 years of cash runway. We remain in a strong cash position, but as a testament to our goal of maintaining multiple levers for accessing capital, we are continuing to pursue additional business development and corporate development deals this year.

正如我們過去所做的那樣，我們的目標是到 2023 年結束時有超過 2 年的現金跑道。我們的現金狀況仍然強勁，但為了證明我們保持多種槓桿獲取資本的目標，我們今年將繼續尋求更多的業務發展和企業發展交易。

And with that, I'll turn the call back over to Robert Blum.

有了這個，我會把電話轉回給羅伯特布魯姆。

Thank you, Ching. While things didn't go the way we had hoped for omecamtiv mecarbil with our having received a CRL from FDA, 2022 was still a year of very meaningful progress with our company maturing and transforming. We are familiar with overcoming challenges at Cytokinetics. And as Andrew said, we planned for this scenario and we are prepared to maintain our momentum without pause. As we assess potential next steps for omecamtiv mecarbil in the United States, in 2023, our priority remains focused to aficamten, which is advancing in a broadening development program with several important near-term milestones this year.

謝謝你，清。雖然事情並沒有像我們希望的 omecamtiv mecarbil 那樣發展，我們已經收到了 FDA 的 CRL，但隨著我們公司的成熟和轉型，2022 年仍然是非常有意義的一年。我們熟悉如何在 Cytokinetics 克服挑戰。正如安德魯所說，我們為這種情況做好了計劃，我們準備毫不猶豫地保持我們的勢頭。當我們評估 omecamtiv mecarbil 在美國的潛在後續步驟時，2023 年，我們的優先事項仍然集中在 aficamten 上，它正在推進一個擴大的發展計劃，今年有幾個重要的近期里程碑。

We look forward to presenting important new data arising from REDWOOD-HCM in both non-obstructive and obstructive HCM this weekend at ACC and beginning 2 more Phase III clinical trials as part of the development program for aficamten. And in addition, we look forward to results from SEQUOIA-HCM later this year.

我們期待本週末在 ACC 上展示 REDWOOD-HCM 在非阻塞性和阻塞性 HCM 中產生的重要新數據，並作為 aficamten 開發計劃的一部分開始另外 2 項 III 期臨床試驗。此外，我們期待今年晚些時候 SEQUOIA-HCM 的結果。

In recent years, we have been looking to this next-in-class cardiac myosin inhibitor as the principal fulcrum on which we build our commercial business in the United States and internationally, and that has not changed with the recent FDA action.

近年來，我們一直將這種一流的心肌肌球蛋白抑製劑視為我們在美國和國際上開展商業業務的主要支點，這並沒有隨著 FDA 最近的行動而改變。

Reldesemtiv also represents a promising late-stage opportunity, and we also have plans in the coming year to expand and advance our early-stage pipeline to support our continued corporate development.

Reldesemtiv 也代表了一個有前途的後期機會，我們也有計劃在來年擴大和推進我們的早期管道，以支持我們持續的企業發展。

Our future remains bright and as always, we appreciate the support of our shareholders.

我們的未來依然光明，我們一如既往地感謝股東的支持。

Now I'll recap our upcoming milestones for 2023. For omecamtiv mecarbil, we expect to request a meeting with FDA to understand what may be required to support potential approval of omecamtiv mecarbil in the United States. And we expect to engage with EMA regarding the MAA for the treatment of HFrEF.

現在我將回顧一下我們即將到來的 2023 年里程碑。對於 omecamtiv mecarbil，我們希望請求與 FDA 舉行會議，以了解可能需要什麼來支持 omecamtiv mecarbil 在美國的潛在批准。我們希望與 EMA 就用於治療 HFrEF 的 MAA 進行接觸。

For aficamten, we expect to present data from cohort 4 of REDWOOD-HCM and data from 48 weeks of treatment with aficamten in FOREST-HCM at the American College of Cardiology 72nd Annual Scientific Session this weekend. And we expect to complete patient enrollment in SEQUOIA-HCM in Q2 2023, with results expected from that trial in Q4 2023.

對於 aficamten，我們預計將在本週末的美國心髒病學會第 72 屆年度科學會議上展示 REDWOOD-HCM 隊列 4 的數據和 FOREST-HCM 中 aficamten 治療 48 週的數據。我們預計將在 2023 年第二季度完成 SEQUOIA-HCM 的患者註冊，預計該試驗將於 2023 年第四季度獲得結果。

We expect to begin MAPLE-HCM, the second Phase III clinical trial of aficamten, as monotherapy in patients with obstructive HCM in Q2 2023, and we expect to begin a Phase III clinical trial of aficamten in nonobstructive HCM in the second half of 2023. And also, we expect to advance our U.S. go-to-market strategy for aficamten during 2023.

我們預計將於 2023 年第二季度開始 Aficamten 的第二個 III 期臨床試驗 MAPLE-HCM 作為阻塞性 HCM 患者的單一療法，我們預計將於 2023 年下半年開始非阻塞性 HCM 的 aficamten III 期臨床試驗。此外，我們預計將在 2023 年推進我們在美國的 aficamten 上市戰略。

For CK-136, we expect data from the Phase I study of CK-136 in the second half of 2023. For reldesemtiv, we expect the Data Monitoring Committee to conduct the second interim analysis from COURAGE-ALS in Q2 2023. We expect to complete patient enrollment in COURAGE-ALS also in Q2 2023, with results expected in 2024.

對於 CK-136，我們預計 CK-136 的 I 期研究數據將在 2023 年下半年獲得。對於 reldesemtiv，我們預計數據監測委員會將在 2023 年第二季度對 COURAGE-ALS 進行第二次中期分析。我們預計2023 年第二季度完成 COURAGE-ALS 患者登記，預計 2024 年取得結果。

And for our preclinical development and ongoing research, we expect to advance CK-586 into clinical development in the first half of this year.

對於我們的臨床前開發和正在進行的研究，我們預計將在今年上半年將 CK-586 推進到臨床開發。

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

接線員，有了這個，我們現在可以打開電話提問了。

(Operator Instructions) And our first question is from Yasmeen Rahimi with Piper Sandler.

（操作員說明）我們的第一個問題來自 Yasmeen Rahimi 和 Piper Sandler。

I'm deeply sorry for the outcome of omecamtiv. I guess my 1 question is directed to Fady in regards to SEQUOIA. Is there -- do you guys get notified if patients have any sort of ejection fraction drops or any safety signals that arise? And if you could comment on what you guys are seeing on the blinded basis? And then I'll jump back into the queue and respect your wishes of 1 question per person.

我對 omecamtiv 的結果深感抱歉。我想我的第一個問題是針對 Fady 關於 SEQUOIA 的。有沒有 - 如果患者有任何類型的射血分數下降或出現任何安全信號，你們會收到通知嗎？如果你能評論你們在盲法基礎上看到的東西？然後我會跳回隊列並尊重您每人 1 個問題的意願。

Thank you, Yasmin, for that. I can't really comment on emerging safety data. We -- I will tell you what we see, which is that we don't see ejection fractions that are dealt with by merely dose reduction. Those are taken care of by the IWRS system that dispenses drug. And in order to dispense drug, that sites have to enter in the site red ejection fraction. That's done by a cardiologist that's not part of the study team and is blinded to study treatment. But the -- so we don't get notified if EFs drops below 50%.

亞斯敏，謝謝你。我真的不能對新出現的安全數據發表評論。我們——我會告訴你我們所看到的，那就是我們沒有看到僅僅通過減少劑量來處理的射血分數。這些由分配藥物的 IWRS 系統負責。並且為了分配藥物，該部位必須進入該部位紅色射血分數。這是由不屬於研究團隊的心髒病專家完成的，並且對研究治療不知情。但是——所以如果 EF 低於 50%，我們不會收到通知。

If somebody's ejection fraction dropped below 40%, that would require a termination of treatment, and that would become a noted event to which we would become privy to. But I'm -- we're pleased with how things are going and maybe I should just put it that way.

如果某人的射血分數下降到 40% 以下，則需要終止治療，這將成為我們將知曉的著名事件。但我 - 我們對事情的進展感到滿意，也許我應該這樣說。

And our next question is from Joe Pantginis with H.C. Wainwright.

我們的下一個問題來自 H.C. 的 Joe Pantginis。溫賴特。

So curious, so Robert, this morning, you talked about how it's early to discuss in the iterative process with regard to omecamtiv in Japan and the EU potential there. I was just curious if you had any commentary about the approach that Ji Xing is taking and if there's any differentiation?

非常好奇，所以羅伯特，今天早上，你談到了在迭代過程中討論日本的 omecamtiv 和那裡的歐盟潛力是多麼的早。我只是想知道您是否對吉星所採取的方法有任何評論，是否有任何區別？

Yes. So I should allow Ji Xing to comment there in the driver's seat as it relates to the regulatory submission in China. But I think we've learned from the interactions with FDA as to how we might best position omecamtiv mecarbil in other jurisdictions. And I would not consider that what happened with FDA to necessarily close the door on any other countries, especially in light of the fact that we've taken different tact. Maybe that's the best way I could say it. Outside the United States, our strategies are different.

是的。所以我應該允許 Ji Xing 在駕駛員座位上發表評論，因為它與中國的監管提交有關。但我認為我們已經從與 FDA 的互動中了解到我們如何最好地在其他司法管轄區定位 omecamtiv mecarbil。而且我不認為 FDA 發生的事情必然會關閉任何其他國家的大門，特別是考慮到我們採取了不同的策略這一事實。也許這是我能說的最好的方式。在美國以外，我們的策略是不同的。

And our next question is from Jason Zemansky with Bank of America.

我們的下一個問題來自美國銀行的 Jason Zemansky。

Curious, as you think about a go-to-market strategy for aficamten. Any sense on how one could potentially operationalize the dosing monitoring, whether it's a focused echocardiogram or potentially either 4 weeks or 8 weeks, something to avoid kind of the 2-week potential monitoring that we see within the SEQUOIA Phase III design?

很好奇，當您考慮 aficamten 的上市策略時。關於如何潛在地實施劑量監測的任何意義，無論是聚焦超聲心動圖還是潛在的 4 週或 8 週，以避免我們在 SEQUOIA III 期設計中看到的那種 2 週潛在監測？

So as you probably can well appreciate, the way in which this drug may ultimately be labeled will be informed by how it was studied in clinical research, but I'll ask Fady to elaborate.

因此，正如您可能理解的那樣，這種藥物最終可能被標記的方式將取決於它在臨床研究中的研究方式，但我會請 Fady 詳細說明。

Yes. I mean I think, first of all, the echos can be done in a quite focused fashion. The only things you need to assess are the gradient and the ejection fraction. We do lots of other views and things like that in echocardiograms that can take longer. But it's really up for the -- up to the site to decide on how to implement that.

是的。我的意思是，我認為，首先，迴聲可以以非常集中的方式完成。您唯一需要評估的是梯度和射血分數。我們在超聲心動圖中做很多其他視圖和類似的事情可能需要更長的時間。但這真的取決於站點來決定如何實施它。

With regards to your question about dosing, I should be clear that as the -- every 2-week schedule we employed in SEQUOIA represents a minimum dosing interval. There's no penalty. There's no reason why you couldn't employ a longer dosing interval if that was the patient's preference or the physician's preference. What I would expect the label to reflect is that you wait at least 2 weeks before making a dosing change and it's up to the patient and the physician as to how long they want to wait after that.

關於你關於劑量的問題，我應該清楚，因為我們在 SEQUOIA 中採用的每 2 週的時間表代表一個最小劑量間隔。沒有罰款。如果這是患者的偏好或醫生的偏好，那麼您沒有理由不能採用更長的給藥間隔。我希望標籤反映的是，您至少要等待 2 週才能進行劑量更改，這取決於患者和醫生他們想要等待多長時間。

I think one of the things that we are optimistic about is that SEQUOIA will be enabling of patients to get to target dose rapidly and enabling of symptom relief rapidly. And I think that's ultimately going to play to our strategy, which would be speaking to how the category may ultimately expand in light of potential availability of aficamten. And I think Fady may have another comment to make.

我認為我們樂觀的事情之一是 SEQUOIA 將使患者能夠迅速達到目標劑量並迅速緩解症狀。我認為這最終將對我們的戰略產生影響，即根據 aficamten 的潛在可用性，該類別最終可能會如何擴展。我認為 Fady 可能還有其他意見要發表。

A follow-up. I mean, I think these patients obviously have lived with their symptoms for a long time. I don't think that necessarily detracts from how soon they would like to see relief from their symptoms. If you had a choice between spending weeks or months to get to feeling relief from something you have carried with you for many years versus a shorter period of time, I'm not sure why patients wouldn't select a shorter period of time, even as they maybe have been living with their disease for a long time.

跟進。我的意思是，我認為這些患者顯然已經帶著症狀生活了很長時間。我認為這不一定會影響他們希望多快看到症狀得到緩解。如果你可以選擇花數週或數月來從你多年來隨身攜帶的東西中獲得解脫，還是花更短的時間，我不確定為什麼患者不會選擇更短的時間，即使因為他們可能長期患有疾病。

So we think the more rapid titration that we've employed in SEQUOIA in terms of the dosing interval will be something that would be attractive to patients.

因此，我們認為我們在 SEQUOIA 中採用的更快速的滴定在給藥間隔方面將對患者有吸引力。

And our next question is from Srikripa Devarakonda with Truist Securities.

我們的下一個問題來自 Truist Securities 的 Srikripa Devarakonda。

This is Ishan. I'm on for Kripa. So with omecamtiv, you have said that you don't want to run another trial in U.S. So just wondering, what is the likelihood of you either divesting this asset to a company that already has a franchise in place or has the capital? And what is the threshold for you to want to do this?

這是伊山。我支持 Kripa。所以對於 omecamtiv，你說過你不想在美國進行另一次試驗。所以只是想知道，你將這項資產剝離給已經擁有特許經營權或擁有資本的公司的可能性有多大？你想要這樣做的門檻是什麼？

Yes. So a number of you have been posing that question. And we're just within 24 hours of having received a disappointing CRL, and how we might ultimately monetize omecamtiv mecarbil is not something for which we're yet ready to communicate publicly. What I will say is divesting omecamtiv mecarbil to be permitting of another company to run clinical trials would be something that we should consider. But I think we've got experience with other companies running clinical research for omecamtiv mecarbil, and I don't think that is something that we have high confidence as in the interest of science or patients.

是的。所以你們中的一些人一直在提出這個問題。我們距離收到令人失望的 CRL 僅不到 24 小時，而我們最終如何通過 omecamtiv mecarbil 獲利還不是我們準備公開交流的事情。我要說的是，剝離 omecamtiv mecarbil 以允許另一家公司進行臨床試驗將是我們應該考慮的事情。但我認為我們有與其他公司合作開展 omecamtiv mecarbil 臨床研究的經驗，我認為這不是我們對科學或患者的利益充滿信心的事情。

So what we may do instead is around partnering omecamtiv mecarbil. And I think that's where we've been leaning already. Already, we've been well engaged with other companies, who have appetite to partner around omecamtiv mecarbil. And that's something that I think is more likely going to be something that moves the needle for Cytokinetics.

所以我們可以做的是圍繞合作 omecamtiv mecarbil。我認為這就是我們一直在傾斜的地方。我們已經與其他有興趣圍繞 omecamtiv mecarbil 合作的公司進行了良好的合作。我認為這更有可能推動細胞動力學的發展。

And our next question is from Carter Gould with Barclays.

我們的下一個問題來自巴克萊銀行的卡特古爾德。

Looking forward to seeing you down in New Orleans this weekend. I guess that's a good segue to our question, which is, in the past, you've talked about the nonobstructive data being sort of a pilot for moving into HFrEF. And I guess how do you think now about the appropriate jumping off point for doing a study in HFpEF with 1 of the myosin activators, and I guess really how does 586's movement into the clinic, I guess, either complicate or complement that strategy?

期待本週末在新奧爾良見到您。我想這是我們問題的一個很好的轉折點，也就是，在過去，你曾談到非阻塞性數據是進入 HFrEF 的一種試點。我想您現在如何看待使用一種肌球蛋白激活劑在 HFpEF 中進行研究的合適起點，我猜想 586 進入臨床是如何使該策略複雜化或補充的？

Yes. So I'll start and turn it over to Fady. But our movement of 586 into the clinic underscores our enthusiasm for myosin inhibition in patients with HFpEF, who have hypercontractile ventricles. What you're seeing in nHCM, I should say, what we're seeing in nHCM and you'll see on Sunday, we believe augurs well for this mechanism in certain patients with HFpEF as will be now able to be explored with 586 as it moves forward. So I'll turn it over to Fady to speak to what in particular we see in nHCM as reads on those patients with HFpEF.

是的。所以我會開始並將它交給 Fady。但是我們將 586 帶入臨床強調了我們對具有過度收縮心室的 HFpEF 患者肌球蛋白抑制的熱情。你在 nHCM 中看到的，我應該說，我們在 nHCM 中看到的，你將在周日看到，我們相信這預示著某些 HFpEF 患者的這種機制現在可以用 586 進行探索它向前移動。因此，我將把它交給 Fady 來談談我們在 nHCM 中看到的特別是對 HFpEF 患者的解讀。

We laid this strategy out in 2018 at an R&D Day, which is that oHCM represents the vanguard of application for a cardiac myosin inhibitor with obvious extension to nHCM, but then nHCM provides a genetic model, if you will, of a more severe form of heart failure preserved ejection fraction. That is in the patients in whom that disease manifests as high ejection fraction, thickened ventricles. In many ways, frankly, you have difficulty distinguishing them from nHCM patients in absence of doing the genetics.

我們在 2018 年的研發日制定了這一戰略，即 oHCM 代表了心肌肌球蛋白抑製劑應用的先鋒，並明顯擴展到 nHCM，但如果你願意的話，nHCM 提供了一種更嚴重形式的遺傳模型心力衰竭保留射血分數。那是在這種疾病表現為射血分數高、心室增厚的患者中。在許多方面，坦率地說，如果不進行遺傳學研究，您很難將他們與 nHCM 患者區分開來。

And so we think of this as a natural progression of the development program and the entry of 586 into the clinic enables us to potentially use a different molecule in heart failure with preserved ejection fraction as maybe less complicated in terms of making it available in that population in the long term.

因此，我們認為這是開發計劃的自然進展，586 進入臨床使我們有可能在射血分數保持不變的心力衰竭中使用不同的分子，因為在該人群中使用它可能不那麼複雜在長期。

But you also asked about properties of 586, and while we can't be so specific yet, we do believe that 586 operates by a different mechanism than does aficamten and more of that and why and how that may afford a potential advantage, and that path will come over time.

但是您還詢問了 586 的屬性，雖然我們還不能說得那麼具體，但我們確實相信 586 的運作機制與 aficamten 不同，還有更多，以及為什麼以及如何提供潛在優勢，並且路徑會隨著時間的推移而出現。

And our next question is from Tessa Romero with JPMorgan.

我們的下一個問題來自摩根大通的 Tessa Romero。

One commercial question for me. Can you talk a little bit about your market intel and what are the attributes about aficamten's emerging profile that may be the most kind of needle moving for the physicians in the clinic here?

一個商業問題問我。你能談談你的市場情報嗎？關於 aficamten 的新興形像有哪些特點，這可能是這裡診所醫生最喜歡的針頭移動方式？

And what are the prescribing factors that are most important for physicians? And how much variability is there in the marketplace on that? Just kind of curious if you're hearing that there could be some differences among various segments of the marketplace of HCPs.

對醫生來說最重要的處方因素是什麼？市場上有多少可變性？如果您聽說 HCP 市場的各個部分之間可能存在一些差異，我會有點好奇。

Sure. So I'm going to ask Andrew to comment and I'll just start by saying that you won't hear us saying anything comparative aficamten versus mavacamten. We think BMS is doing a good job with mavacamten and setting the table nicely for that compound doing well in a select number of patients with oHCM, but we are doing market research around aficamten and where its profile may be enabling of an expansion of the category. And I'll ask Andrew to elaborate on that.

當然。所以我要請安德魯發表評論，我首先要說你不會聽到我們說任何比較 aficamten 和 mavacamten 的事情。我們認為 BMS 在 mavacamten 方面做得很好，並為該化合物在選定數量的 oHCM 患者中表現良好做好了準備，但我們正在圍繞 aficamten 進行市場研究，其概況可能會擴大該類別.我會請安德魯詳細說明。

Sure. Thanks, Robert, and thanks for the question. Probably the key differences that we're hoping or at least in terms of differentiation really comes down to healthcare utilization as well as the physician and patient experience, both starting and staying on aficamten should it get approved. So things like not having to worry about other products that a patient could take around drug-to-drug interactions or fetal toxicity for, say, a female of child-bearing years, the amount of Echos that could be required, the type of REMS programs. So these are real or could be real challenges and differences should 1 product have and require less utilization and resources from healthcare and less monitoring and kind of patient follow-up.

當然。謝謝，羅伯特，謝謝你提出這個問題。我們希望或至少在差異化方面的關鍵差異可能真正歸結為醫療保健利用以及醫生和患者的體驗，如果它獲得批准，開始和繼續使用 aficamten。因此，諸如對於育齡女性而言，不必擔心患者可能服用的其他產品會發生藥物間相互作用或胎兒毒性、可能需要的 Echo 量、REMS 的類型等問題程式。因此，如果 1 種產品具有並需要較少的醫療保健利用率和資源，以及較少的監測和患者隨訪，這些都是真實的或可能是真正的挑戰和差異。

So I think they are coming to be real issues in the marketplace potentially or differences, I should say, not issues. But obviously, we have to wait until Phase III and what our data would bear out to see if we can truly differentiate.

所以我認為它們可能會成為市場上的真正問題或差異，我應該說，而不是問題。但很明顯，我們必須等到第三階段以及我們的數據會證明什麼，才能看到我們是否能夠真正實現差異化。

Having a second cardiac myosin inhibitor in a category, not unlike we've seen in other therapeutic categories like pulmonary arterial hypertension for instance, is enabling of an expansion to patients who might not otherwise be receiving the first-in-class compound. And we've designed aficamten very much to be enabling of a broad therapeutic window, faster onset, faster reversibility were that to be required. And as such, that could be supportive of the use of aficamten, not just in certain HCM centers of excellence and certain patients, but rather in other patients who might stand to benefit as well and as would be prescribed by other cardiologists, too.

在一個類別中有第二種心肌肌球蛋白抑製劑，與我們在其他治療類別（例如肺動脈高壓）中看到的不同，能夠擴展到可能無法接受一流化合物的患者。我們設計的 aficamten 非常適合實現廣泛的治療窗口，更快的起效，更快的可逆性是所需要的。因此，這可能會支持使用 aficamten，不僅在某些 HCM 卓越中心和某些患者中，而且在其他可能受益的患者中，以及其他心髒病專家也會開出的處方中。

So our goal is ultimately to afford physicians and patients a choice with regard to a myosin inhibitor for their patients.

因此，我們的目標最終是為醫生和患者提供有關肌球蛋白抑製劑的選擇。

Our next question is from Dane Leone with Raymond James.

我們的下一個問題來自 Dane Leone 和 Raymond James。

Congrats on the progress heading into '23 now. Just maybe a few for me that have been topical for a lot of investors recently. Maybe if you could opine in terms of your discussions with the cardiovascular team over at the FDA and how explicit they have been in terms of endpoints for pivotal nonobstructive hypertrophic cardiomyopathy studies? Your peer, as is obvious, is using a KCCQ endpoint change from baseline event peak VO2, which has some similarities from the pivotal studies that have been done in obstructive.

祝賀現在進入'23的進展。對我來說，可能只有一些最近對很多投資者來說是熱門話題。也許你可以就你與 FDA 心血管團隊的討論發表意見，以及他們在關鍵的非阻塞性肥厚性心肌病研究的終點方面有多明確？很明顯，您的同行正在使用基線事件峰值 VO2 的 KCCQ 終點變化，這與阻塞性研究中所做的關鍵研究有一些相似之處。

But I'd be interested in your thoughts of kind of, one, what the hurdle is for a clinically meaningful change that the FDA team would review? And then secondly, if your experience kind of leads you down the same pathway of how to design that pivotal study. And then a real quick one after that. The enrollment for SEQUOIA is still ongoing. I think some people are asking right now, how close do you -- does your team think you're going to cut it in terms of having that top line data before year-end?

但是我對你的想法很感興趣，一個，FDA 團隊將審查的具有臨床意義的變化的障礙是什麼？其次，如果您的經驗有點引導您走上如何設計該關鍵研究的相同途徑。然後是一個真正的快速之後。 SEQUOIA 的招募仍在進行中。我想現在有些人在問，你有多接近 - 你的團隊認為你會在年底前獲得頂級數據方面削減它嗎？

So I'll answer the second part of your question and then ask Fady to answer the first part. We're pretty confident that we're moving towards completion of enrollment in SEQUOIA, to be confident that we'll see data in Q4. If you're asking if that's October versus November versus December, I think that we probably can't give you the resolution on that, that you're interested in, recognizing that the study is not yet concluded in enrollment. And some of those are things that relate to once it is concluded, how long might we need for database lock and what kind of outstanding queries might we still expect.

所以我會回答你問題的第二部分，然後讓 Fady 回答第一部分。我們非常有信心我們正在朝著完成 SEQUOIA 的註冊邁進，相信我們會在第四季度看到數據。如果你問的是 10 月還是 11 月還是 12 月，我認為我們可能無法就此給出你感興趣的解決方案，因為我們認識到該研究尚未在招生中結束。其中一些是與一旦結束、我們可能需要多長時間的數據庫鎖定以及我們仍可能期望有哪些未完成的查詢有關的事情。

We're obviously cleaning data as it's coming in. But I think we can confidently say Q4. I'm not sure I'm going to do any better than that right now.

我們顯然在清理數據。但我認為我們可以自信地說第四季度。我不確定我現在會做得更好。

Regarding endpoints in a pivotal Phase III study of nHCM, I think when we elaborate on that study, once it is underway, you'll see some similarities to the ongoing Phase III study with mavacamten, but also some notable distinctions based on aficamten has a different profile. But I'll ask Fady to comment on sort of what's clinically meaningful with regard to some of these end points.

關於 nHCM 關鍵 III 期研究的終點，我認為當我們詳細說明該研究時，一旦它開始，你會看到與正在進行的 mavacamten III 期研究有一些相似之處，但也有一些基於 aficamten 的顯著區別不同的配置文件。但我會請 Fady 就其中一些終點的臨床意義發表評論。

Well, I think the endpoints we can use in nHCM, in a lot of ways mirror what we'll use in oHCM, their function and their symptoms. They include peak VO2. They include KCCQ, they include NYHA class, and then secondarily think biomarkers and things that we've measured before. So conceptually, there's not I think a tremendous difference between the 2.

好吧，我認為我們可以在 nHCM 中使用的端點在很多方面反映了我們將在 oHCM 中使用的內容、它們的功能和症狀。它們包括峰值 VO2。它們包括 KCCQ，它們包括 NYHA 類，然後再考慮生物標誌物和我們之前測量過的東西。所以從概念上講，我認為兩者之間沒有巨大的區別。

I think in part, the question might be, what might you order first? And what might you focus on? And I think any of them are meaningful -- potentially meaningful and potentially approvable. KCCQ has been used to -- as an approvable endpoint in pivotal trials before. And obviously, we see the BMS design incorporates that into their primary endpoint and peak VO2 is what we're using in SEQUOIA.

我認為部分問題可能是，您可能首先訂購什麼？你會關注什麼？我認為它們中的任何一個都是有意義的——可能有意義並且可能會被批准。 KCCQ 以前曾被用作關鍵試驗中的可批准終點。顯然，我們看到 BMS 設計將其納入其主要終點，而峰值 VO2 正是我們在 SEQUOIA 中使用的。

It's a magnitude in general, people are looking for magnitudes that are up 5 points or more in the KCCQ that's a little arbitrary. I think you have to look at the whole distribution and ask is that driven -- if you were less than 5, but you had a substantial number of patients that had very large improvements, that's pretty meaningful for those patients. And if others don't respond [to it] as a treatment that is being given to improve patient symptoms, they can tell you whether they're feeling better and whether the treatment should be continued in them.

這是一個普遍的幅度，人們正在尋找 KCCQ 中上漲 5 點或更多的幅度，這有點武斷。我認為你必須查看整個分佈並詢問是否有驅動力——如果你少於 5 人，但你有大量患者有很大改善，這對這些患者來說非常有意義。如果其他人不響應 [對它] 作為改善患者症狀的治療，他們可以告訴你他們是否感覺好些以及是否應該繼續治療。

So we'll have those discussions with FDA. Ultimately, the results will inform how we approach potential discussions with FDA around expansion of a label for -- in nHCM.

所以我們將與 FDA 進行這些討論。最終，結果將告知我們如何處理與 FDA 圍繞擴展 nHCM 標籤的潛在討論。

My hope is that you'll see data in the poster on Sunday that will be revealing as to how aficamten may be received in nHCM. And again, I'll remind you, we're going to have a call with investors and analysts Monday morning to walk through those data as they were presented the day before. And that will inform how we might can -- elaborate on what would be a Phase III study design in connection with duration of treatment in time to end points.

我希望您能在周日的海報中看到數據，這些數據將揭示 nHCM 中如何接收 aficamten。再一次，我會提醒你，我們將在周一早上與投資者和分析師通電話，以瀏覽前一天提供的這些數據。這將告知我們如何做——詳細說明與治療持續時間到終點的時間相關的 III 期研究設計。

Our next question is from Jason Butler with JMP Securities.

我們的下一個問題來自 JMP 證券公司的 Jason Butler。

Just 1 on the upcoming reldesemtiv interim. Can you give us any more details in terms of the number of patients that you can add? Is it just 1 option? Or are there multiple options of adding different amounts of patients? And then any color on how long adding additional patients would add to the enrollment time lines?

在即將到來的 reldesemtiv 臨時計劃中只有 1 個。您能否就可以添加的患者數量向我們提供更多詳細信息？是只有1個選項嗎？或者是否有添加不同數量患者的多種選擇？然後，關於增加額外患者將增加入組時間線多長時間的任何顏色？

Yes. I'm going to ask Stuart, our Chief Medical Officer, to comment, but I'll mention that we haven't disclosed what is the specific number of patients that could be added. It's a single number, but maybe he can speak to how we're going to approach that.

是的。我要請我們的首席醫療官斯圖爾特發表評論，但我要提一下，我們還沒有透露可以增加的具體患者人數。這是一個單一的數字，但也許他可以談談我們將如何處理這個問題。

Thank you, Jason. It's a good question. By design, it's actually a fixed number of patients that would be upsized depending on the conditional power that's observed by the Data Monitoring Committee. And then essentially designing that way to mask sort of a magnitude of change in ALSFRS-R. So the -- essentially, it's binary, either upsizing or not.

謝謝你，傑森。這是個好問題。根據設計，它實際上是固定數量的患者，這些患者會根據數據監測委員會觀察到的條件功效而增加。然後基本上設計這種方式來掩蓋 ALSFRS-R 中的某種程度的變化。所以 - 本質上，它是二元的，無論是否擴大規模。

With respect to the time frame for continuing enrollment, I think that's sort of better discussed when -- if [the best] recommendation comes forward from the Data Monitoring Committee. But enrollment is going very well in COURAGE-ALS, and we don't expect a major delay in completing enrollment even if the trial is upsized.

關於繼續註冊的時間框架，我認為如果數據監控委員會提出 [最佳] 建議，則可以更好地討論這個問題。但 COURAGE-ALS 的招募進展順利，我們預計即使擴大試驗規模也不會嚴重延遲完成招募。

Maybe just to expand on that a little bit. I'll ask Fady to comment on how the Data Monitoring Committee is being guided.

也許只是為了擴大這一點。我將請 Fady 就數據監控委員會的指導方式發表評論。

Yes. So I think the interim analysis uses what's called a promising zone construct, which is either -- if you have a -- it's a construct trying to avoid what I term the near miss scenario. You've assumed a treatment effect, you power a study based on that assumption. The trial progresses and the treatment effect may be larger than you assume, which should certainly be a good scenario to be in. It could be a little less than you assumed. And if it's small enough, even it may be positive and clinically meaningful, you may no longer have the power to be confident you would end up with a positive study.

是的。所以我認為中期分析使用了所謂的有前途的區域構造，它要么是——如果你有——它是一個試圖避免我稱之為近乎錯過的場景的構造。你假設了治療效果，你根據該假設為研究提供動力。試驗的進展和治療效果可能比你想像的要大，這當然應該是一個很好的場景。它可能比你想像的要小一點。如果它足夠小，即使它可能是陽性的並且具有臨床意義，您可能不再有信心最終會獲得陽性研究。

So this is a onetime adjustment that the Data Monitoring Committee can make to a fixed size, fixed increment that would increase the power of the study. And the other scenario is there is a chance the study could stop for futility as well, if it looked like you really had no power at all to see a treatment benefit. So that's how I would describe the interim analysis in high-level terms.

因此，這是數據監控委員會可以對固定大小、固定增量進行的一次性調整，這將增加研究的功效。另一種情況是，如果您看起來真的根本沒有能力看到治療益處，那麼研究也有可能因無效而停止。這就是我用高層次術語描述中期分析的方式。

Most of those are possible outcomes, they may not be probable, but we thought it was important to lay them out there. There is an adaptive element, if you will, to the design and conduct of COURAGE-ALS as we think is our responsibility for this potentially being a first muscle-directed therapy in ALS.

其中大部分是可能的結果，它們可能不太可能，但我們認為將它們擺在那裡很重要。如果您願意的話，COURAGE-ALS 的設計和實施有一個適應性因素，我們認為這是我們的責任，因為這可能成為 ALS 中的第一個肌肉導向療法。

So we'll know soon enough what path we're going down. And more likely than not, we expect that the study will conclude enrollment without it either stopping early or being upsized in Q2.

所以我們很快就會知道我們要走的路是什麼。而且更有可能的是，我們預計該研究將結束招募，而不會在第二季度提前停止或擴大規模。

And our next question comes from Charles Duncan with Cantor Fitzgerald.

我們的下一個問題來自 Charles Duncan 和 Cantor Fitzgerald。

I, too, want to go off script off the afi script and ask a follow-up question on reldesemtiv. And I apologize upfront, it's probably a 3-part question. That is, first of all, with regard to that fixed increase in sample size, could you provide more color? Is it, call it, a 10% or 25%?

我也想脫離 afi 腳本並在 reldesemtiv 上問一個後續問題。我先道歉，這可能是一個由 3 部分組成的問題。也就是說，首先，關於固定增加的樣本量，你能提供更多的顏色嗎？是 10% 還是 25%？

Secondly, with regard to the ongoing OLE, do you have a sense of the rollover and persistence, and has Relyvrio impacted that.

其次，關於正在進行的 OLE，您是否了解過渡和持久性，Relyvrio 是否對此產生了影響。

And third, again, going to Relyvrio, is that, in some ways, changing or impacting the types of patients that are wanting to enroll in COURAGE-ALS?

第三，再一次，去 Relyvrio，是否在某種程度上改變或影響了想要參加 COURAGE-ALS 的患者類型？

I'm going to be turning to Stuart to answer these questions and anything Fady wants to add on top of that. We're not commenting on the number the patients that might be added. But to your question, is it 10% more, 25% more. Let me just say that it's not so many more that we don't expect that the study could still conclude enrollment this year, and therefore, we'd still expect results next year, if that helps you. It puts it into a ZIP code. Then I'll turn to Stuart, maybe to answer the other 2 questions.

我將求助於 Stuart 來回答這些問題以及 Fady 想補充的任何問題。我們不會評論可能增加的患者數量。但是對於你的問題，是多了 10%，還是多了 25%。我只想說，我們不希望這項研究今年仍能完成註冊，因此，我們仍然期待明年的結果，如果這對你有幫助的話。它將其放入郵政編碼。然後我會求助於斯圖爾特，也許會回答其他兩個問題。

Charles, thank you for your questions. With respect to the open-label extension, I think it's -- we can say that most of the patients are rolling over into the extension. So that study is going well. The impact of Relyvrio, not surprisingly, there has had some impact in terms of enrollment in North America. But we have a large portion of patients enrolling in Europe as well as Australia. So it really hasn't had a meaningful impact in terms of enrollment in the study.

查爾斯，謝謝你的問題。關於開放標籤擴展，我認為它是——我們可以說大多數患者都轉入了擴展。所以這項研究進展順利。 Relyvrio 的影響，毫不奇怪，在北美的招生方面產生了一些影響。但是我們有很大一部分患者在歐洲和澳大利亞註冊。因此，就參與研究而言，它確實沒有產生有意義的影響。

And furthermore, because this is now an approved therapy in North America, we are allowing patients even if they are treated with Relyvrio to enroll in the trial. So any approved therapy is permitted as background therapy in COURAGE-ALS.

此外，由於該療法現已在北美獲得批准，我們允許接受 Relyvrio 治療的患者參加試驗。因此，任何批准的療法都可以作為 COURAGE-ALS 的背景療法。

That's interesting. And then the last one in terms of enrollment that is being allowed. Is that what you just said?

那很有意思。然後是允許註冊的最後一個。是你剛才說的嗎？

That's right. They're allowed to enroll in the study if they're on Relyvrio. That's by -- incorporated by amendment. It is similar to we allow patients on [deravone] or patients on riluzole to participate.

這是正確的。如果他們在 Relyvrio 上，他們就可以參加這項研究。那是——通過修正案合併。這類似於我們允許使用 [deravone] 的患者或使用利魯唑的患者參與。

And our next question is from Justin Kim with Oppenheimer.

我們的下一個問題來自 Justin Kim 和 Oppenheimer。

So I think this morning covered a lot of ground across the pipeline, but just maybe a clarification in terms of the second MAPLE study for aficamten oHCM. Just wondering what type of blocking and tackling remains before initiating the study and if it's reasonable to expect the initiation after completion of enrollment for SEQUOIA?

所以我認為今天早上涵蓋了整個管道的很多內容，但也許只是對 aficamten oHCM 的第二次 MAPLE 研究進行了澄清。只是想知道在開始研究之前還剩下什麼類型的阻斷和處理，以及在完成 SEQUOIA 註冊後期望啟動是否合理？

Yes, I can comment on that. Thanks for the question. It's a complicated study to start from the point of view of drug supply and things, as we've said before. We are packaging and labeling and manufacturing 4 different supplies, an aficamten, a placebo for aficamten, the metoprolol and metoprolol for afi -- a placebo for metoprolol. So supply for this study is a bit more complicated than some of the other studies we've done. So that's one of the pieces of blocking and tackling we're taking care of.

是的，我可以對此發表評論。謝謝你的問題。正如我們之前所說，從藥物供應和事物的角度出發，這是一項複雜的研究。我們正在包裝、貼標籤和製造 4 種不同的用品，一種 aficamten，一種 aficamten 的安慰劑，美托洛爾和美托洛爾用於 afi——一種美托洛爾的安慰劑。因此，這項研究的供應比我們所做的其他一些研究要復雜一些。所以這是我們正在處理的阻止和解決問題之一。

In the meantime, we are embarking on startup activities at sites that include IRB submissions and contracts and negotiations, all those sorts of things. And as you mentioned, SEQUOIA is ongoing in terms of its enrollment and our preference, obviously, is not to compete against ourselves. So there's a bit of load management here that's ongoing. And I think we'll see the study start in the same time frame that we see SEQUOIA winding down in terms of enrollment.

與此同時，我們正在網站上開展啟動活動，包括 IRB 提交、合同和談判，所有這些事情。正如你所提到的，紅杉資本在其註冊方面正在進行中，我們的偏好顯然不是與我們自己競爭。因此，這裡正在進行一些負載管理。而且我認為我們會看到這項研究在我們看到 SEQUOIA 在註冊方面逐漸減少的同一時間框架內開始。

And our next question is from Salim Syed with Mizuho.

我們的下一個問題來自 Salim Syed 和 Mizuho。

I guess one for me on SEQUOIA. As folks start to pivot on handicapping this trial, does Cytokinetics have any data at all on peak VO2 change for aficamten even if from the OLE? Or is the powering here of 1.5 on peak VO2 changes based on what EXPLORER did? And mind you that was at 1.4 and that the notion is that aficamten is just a better product. And just quickly related to that, will you actually give us the baseline peak VO2 prior to read out, so we can handicap the trial?

我想在 SEQUOIA 上有一個適合我。隨著人們開始關注阻礙這項試驗，即使來自 OLE，Cytokinetics 是否有關於 aficamten 的峰值 VO2 變化的任何數據？還是 1.5 的峰值 VO2 功率根據 EXPLORER 的變化而變化？請注意，那是 1.4，這個概念是 aficamten 只是一個更好的產品。與此相關的是，您是否真的會在讀出之前給我們基線峰值 VO2，以便我們可以阻礙試驗？

Good questions. I'm going to ask Fady to answer them.

好問題。我要請 Fady 回答他們。

So Salim, I think you know probably that we haven't reported it and the protocols for REDWOOD and FOREST don't include exercise testing peak VO2 testing. So we don't have any data per se with that test in aficamten. 1.5 versus 1.4, I think that's just a matter we picked a round number and the powering was calculated in a way that gives us over 90% power to achieve that metric.

所以 Salim，我想你可能知道我們沒有報告它，REDWOOD 和 FOREST 的協議不包括運動測試峰值 VO2 測試。所以我們在 aficamten 中沒有關於該測試的任何數據。 1.5 與 1.4，我認為這只是我們選擇了一個整數的問題，並且功率的計算方式使我們有超過 90% 的功率來實現該指標。

So in terms of sheer number of patients enrolled, where SEQUOIA is somewhat larger than EXPLORER was, the p-value for the peak VO2 at 1.4 was less than 0.01. And so we should be quite well powered to see an improvement of 1.5, 1.4, even down to 1.0, which would represent, I think, in some ways what people think of as clinically meaningful with regards to peak VO2.

因此，就登記患者的絕對數量而言，SEQUOIA 比 EXPLORER 稍大，峰值 VO2 的 p 值在 1.4 時小於 0.01。因此，我們應該非常有能力看到 1.5、1.4 甚至下降到 1.0 的改善，我認為，這在某些方面代表了人們認為在峰值 VO2 方面具有臨床意義的東西。

So that's really what I can say about it now. I think we have a nice proof of concept in terms of how that endpoint can be impacted by a cardiac myosin inhibitor. And so that helps derisk, if you will, the primary endpoint of this trial.

所以這就是我現在能說的。我認為我們在心肌肌球蛋白抑製劑如何影響該終點方面有一個很好的概念證明。因此，如果您願意，這有助於降低該試驗的主要終點的風險。

Will you provide the baseline at some point, you think? Or...

您認為您會在某個時候提供基線嗎？或者...

Probably right before you see the primary outcome. But no, I don't think we'll be providing the baseline characteristics prior to the study's presentation.

可能就在您看到主要結果之前。但不，我認為我們不會在研究報告之前提供基線特徵。

And our next question is from Serge Belanger with Needham & Co.

我們的下一個問題來自 Needham & Co. 的 Serge Belanger。

Two questions on the aficamten Phase III program. First one on enrollment. So it looks like it's going to take about 14 to 15 months to enroll the 270 patients in the SEQUOIA trial. Just curious if you expect a similar pace of enrollment for the MAPLE study as well as the other Phase III trial in HCM, given that you can have 3 Phase III trials running concurrently?

關於 aficamten III 期計劃的兩個問題。第一個關於入學。因此，將 270 名患者納入 SEQUOIA 試驗似乎需要大約 14 到 15 個月的時間。只是好奇如果您可以同時進行 3 項 III 期試驗，您是否期望 MAPLE 研究以及 HCM 的其他 III 期試驗的註冊速度相似？

And then secondly, in terms of the regulatory strategy, should we expect that both the MAPLE and the nHCM Phase III trial to support separate sNDAs once they're complete?

其次，就監管策略而言，我們是否應該期望 MAPLE 和 nHCM III 期試驗一旦完成就支持單獨的 sNDA？

Yes. So I'll answer the second part first. Our registration strategy, the critical path is paved with SEQUOIA-HCM and we'll be submitting based on that in oHCM before MAPLE concludes. But you could imagine MAPLE would be the subject matter of a supplemental NDA following potential approval. And similarly, the Phase III study in nHCM, yes, to your question, again, would represent a separate submission as could be supportive of an expanded label in nHCM.

是的。所以我先回答第二部分。我們的註冊策略，關鍵路徑是用 SEQUOIA-HCM 鋪平的，我們將在 MAPLE 結束之前基於 oHCM 中的那個提交。但您可以想像，在獲得潛在批准後，MAPLE 將成為補充 NDA 的主題。同樣，nHCM 的 III 期研究，是的，對於你的問題，再次，將代表一個單獨的提交，因為它可以支持 nHCM 中的擴展標籤。

So all 3 of those being separate from a regulatory standpoint. What I should also mention is that our capabilities are such now that we would anticipate, unlike with omecamtiv mecarbil, where there is a significant time lag from a U.S. submission to a European one, in HCM, we're now equipped, we think, to be submitting more in parallel globally in order to be able to lend support for potential approvals, as would come internationally in more rapid succession.

因此，從監管的角度來看，所有這 3 個都是獨立的。我還應該提到的是，我們現在的能力是我們可以預期的，與 omecamtiv mecarbil 不同，在 HCM 中，從美國提交到歐洲提交存在明顯的時間滯後，我們現在已經配備，我們認為，在全球範圍內同時提交更多，以便能夠為潛在的批准提供支持，因為國際上會更快地連續提交。

So I'll turn now to Fady to address your first question regarding expected duration of enrollment in those second and third Phase III studies.

所以我現在請 Fady 來回答你關於第二和第三階段 III 研究的預期入學時間的第一個問題。

Yes. I think it's a question more related to the rate of enrollment, which I think we will -- these trials are a little different. So with regards to nHCM, the nHCM trial doesn't really compete for the same patients that MAPLE or SEQUOIA would enroll and we likely will be winding down enrollment in SEQUOIA before these 2 trials really get underway in terms of enrollment.

是的。我認為這是一個與入學率更相關的問題，我認為我們會——這些試驗有點不同。因此，關於 nHCM，nHCM 試驗並沒有真正競爭 MAPLE 或 SEQUOIA 將招募的相同患者，我們很可能會在這兩項試驗在招募方面真正開始之前逐漸減少 SEQUOIA 的招募。

So in terms of concurrent enrollment, MAPLE and nHCM don't compete against each other. The study population in MAPLE is a bit more flexible, if you will, in terms of what can be enrolled. And so it may help, I would say, continued enrollment at the pace that we've seen in SEQUOIA. And I think it's a little too early -- I mean, we've enrolled the nHCM cohort in REDWOOD quite briskly, and I'm optimistic we can do so in a Phase III trial as well. Hopefully, that answers your question.

因此，就並發註冊而言，MAPLE 和 nHCM 不會相互競爭。 MAPLE 的研究人群在可以註冊的方面更靈活一些。因此，我想說，這可能有助於以我們在 SEQUOIA 中看到的速度繼續招生。而且我認為現在還為時過早——我的意思是，我們已經非常迅速地在 REDWOOD 中招募了 nHCM 隊列，而且我很樂觀我們也可以在 III 期試驗中這樣做。希望這能回答您的問題。

And our next question is from Madhu Kumar with Goldman Sachs.

我們的下一個問題來自高盛的 Madhu Kumar。

I guess kind of following up on MAPLE-HCM, I'm kind of curious, how should we think about this trial and the potential kind of clinical impact and utility of aficamten if this trial is successful? What kind of white space in the obstructive HCM space do you think this drug -- this trial uniquely addresses? And I guess, kind of stepping back to some earlier data from last year about drug withdrawal, how do you think about that on the forward and the potential idea of monotherapy of aficamten and withdrawal of other therapies within the kind of formal clinical trial setting?

我想有點跟進 MAPLE-HCM，我有點好奇，我們應該如何考慮這項試驗以及如果這項試驗成功，aficamten 的潛在臨床影響和效用？您認為這種藥物在阻塞性 HCM 空間中有什麼樣的空白——該試驗獨特地解決了這個問題？我想，回到去年關於藥物戒斷的一些早期數據，你如何看待在正式臨床試驗環境中對阿非卡坦單藥治療和其他療法戒斷的前瞻性和潛在想法？

Yes. So your question has implications both for the clinical profile, but also the commercial profile. And maybe Fady can start talking about what could be the value of demonstrating effects of aficamten relative to metoprolol, but then Andrew should also comment.

是的。所以你的問題對臨床概況和商業概況都有影響。也許 Fady 可以開始談論證明 aficamten 相對於美托洛爾的作用的價值是什麼，但 Andrew 也應該發表評論。

The MAPLE-HCM study is something our investigators and steering committee members are really excited about. They view it as a critical question to have data, the support, if you will, using aficamten as first-line therapy. The real question is what benefits do you get from beta blockers as monotherapy? And in general, you do see reductions in gradient, improvement in symptoms, you don't see really any improvement in exercise capacity. And so how does that compare in a head-to-head study with aficamten as may eventually support at least from a scientific perspective, it's implementation as first-line therapy.

MAPLE-HCM 研究令我們的研究人員和指導委員會成員感到非常興奮。他們認為獲得數據和支持是一個關鍵問題，如果你願意的話，使用 aficamten 作為一線治療。真正的問題是你從 β 受體阻滯劑作為單一療法中得到什麼好處？總的來說，你確實看到了梯度下降、症狀改善，但你看不到運動能力有任何改善。那麼，在與 aficamten 的頭對頭研究中，這如何比較最終可能至少從科學的角度支持，它是作為一線治療的實施。

And the other thing is to look at how structural remodeling occurs in the context of beta blockade contrasted with cardiac myosin inhibition. So while that's not necessarily an approvable endpoint, it does speak to the differences in the way the 2 drugs may modify the course of the disease.

另一件事是研究在與心肌肌球蛋白抑制形成對比的 β 阻斷的情況下結構重塑是如何發生的。因此，雖然這不一定是一個可以批准的終點，但它確實說明了這兩種藥物可能改變疾病進程的方式的差異。

So I think the information is going to be very valuable to the HCM community as to how positioned this mechanism of action both in their practices, but also in their guidelines.

因此，我認為這些信息對於 HCM 社區將非常有價值，關於如何在他們的實踐和指南中定位這種行動機制。

The only thing maybe I'll add is around from a commercial perspective is that we certainly hear from patients and physicians that they would prefer to use a single product versus 2 products if they could, but they don't want to do that without evidence. That evidence not only supports informed utilization, but it could also support and inform guideline adjustments as well as the way payers think about what steps are required prior to say aficamten getting reimbursed.

我唯一要補充的是，從商業角度來看，我們肯定會從患者和醫生那裡聽到，如果可以的話，他們更願意使用一種產品而不是兩種產品，但他們不想在沒有證據的情況下這樣做.該證據不僅支持知情使用，而且還可以支持和告知指南調整，以及付款人考慮在獲得報銷之前需要採取哪些步驟的方式。

Does the patient need to step through? Does the patient have to have a requirement for multiple products? Could this remove a step for a patient? So it's those types of areas where a study like MAPLE could help further differentiate and inform both the prescriber and payor community.

患者是否需要跨步？患者是否必須對多種產品有需求？這可以為患者省去一個步驟嗎？因此，正是這些類型的領域，像 MAPLE 這樣的研究可以幫助進一步區分開處方者和付款人社區，並為他們提供信息。

You can well imagine payers would look at superiority versus metoprolol as enabling of a higher reference point for pricing. And that's something that we're mindful for too, as we think about how we might approach a go-to-market strategy for aficamten.

您完全可以想像，付款人會考慮與美托洛爾相比的優勢，因為它能夠為定價提供更高的參考點。這也是我們要注意的事情，因為我們考慮如何為 aficamten 制定上市戰略。

I'm showing no further questions at this time. I would now like to turn the conference back to Robert Blum for closing remarks.

我現在沒有進一步的問題。我現在想把會議轉回 Robert Blum 作閉幕詞。

Thanks, everyone, for joining us, not just on this call today, but also on the call this morning. I realize this call has gone over an hour, so we'll be brief in these concluding remarks. So I'll just simply say, that, yes, we are disappointed as it relates to the FDA action pertaining to omecamtiv mecarbil. But under every scenario, 2023 was always going to be a year about doubling down on aficamten and committing to a higher investment spending on aficamten and an expanded development program for aficamten.

感謝大家加入我們，不僅參加了今天的電話會議，還參加了今天早上的電話會議。我知道這次電話會議已經進行了一個多小時，所以我們將在這些結束語中進行簡短介紹。所以我只想簡單地說，是的，我們對 FDA 與 omecamtiv mecarbil 相關的行動感到失望。但在任何情況下，2023 年始終是加倍投入並承諾增加對 aficamten 的投資支出和擴大 aficamten 發展計劃的一年。

Not to say it's not also important for reldesemtiv and our early pipeline, but I do think we're aligned with shareholder expectations that aficamten represents an opportunity for which the return on investment should be predictably higher, and we recognize that, and that's where we're going to be focused.

並不是說這對 reldesemtiv 和我們的早期管道也不重要，但我確實認為我們符合股東的期望，即 aficamten 代表了一個機會，投資回報率應該可以預見地更高，我們認識到這一點，這就是我們的地方會很專注。

We're not going to be providing play-by-play with regard to omecamtiv and all of our interactions with regulatory authorities until such time as we have something material to talk about. And instead, you can anticipate in 2023 and starting with this weekend, we'll be talking a lot more about aficamten.

在我們有一些重要的事情要談之前，我們不會提供關於 omecamtiv 的逐個播放以及我們與監管機構的所有互動。相反，您可以預計到 2023 年，從本週末開始，我們將更多地討論 aficamten。

With that, I'll bring this call to a close. Thanks very much for your interest in what we're doing here at Cytokinetics and all the support, and we look forward to keeping you abreast of our progress this year.

至此，我將結束此次通話。非常感謝您對我們在 Cytokinetics 所做的工作感興趣以及所有的支持，我們期待著讓您了解我們今年的進展。

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

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。