Aficamten

2025年5月13日，生物制药公司Cytokinetics宣布，其新药Aficamten的Ⅲ期临床试验MAPLE-HCM已达到主要终点，结果显示，与标准β受体阻滞剂美托洛尔相比，Aficamten显著改善了梗阻性肥厚型心肌病(HCM)患者的峰值摄氧量(pVO2)。该药被行业媒体Evaluate列为2025年的十款潜在重磅疗法之一。【关于Aficamten】Aficamten是一种心肌肌球蛋白抑制剂，是一种新型药物，旨在减少每个心动周期中活性肌动蛋白-肌球蛋白横桥的数量，从而抑制与肥厚型心肌病相关的心肌收缩过度。在临床前模型中，该药物通过在独特且选择性的变构结合位点直接与心肌肌球蛋白结合来降低心肌收缩力，从而阻止肌球蛋白进入产生力的状态。【临床研究效果显著】这项随机、双盲、活性对照MAPLE-HCM试验(ClinicalTrials.gov注册号：NCT05767346)纳入了175例有症状的肥厚型心肌病和左心室流出道阻塞患者（纽约心脏协会心功能分级II或III级；堪萨斯城心肌病问卷临床总结评分在35至90分之间）。筛选时，试验参与者的静息左心室流出道梯度(LVOT-G)为30 mmHg或更高和/或瓦尔萨尔瓦指压后LVOT-G为50 mmHg或更高，左心室射血分数至少为60%，呼吸交换率至少为1.05，且峰值摄氧量(pVO2)低于预测值的100%。患者按1:1的比例随机分配接受Aficamten或美托洛尔治疗。主要终点是通过心肺运动测试测量的从基线到第24周的pVO2变化。研究结果表明，该试验达到了其主要终点，证明了Aficamten在提高峰值运动能力方面优于美托洛尔。此外，安全性数据分析显示，与美托洛尔相比，Aficamten具有更佳的疗效。此前，上市申请基于3期SEQUOIA-HCM试验(ClinicalTrials.gov 标识符:NCT05186818)，该项研究纳入了282名患有症状性肥厚型心肌病和左心室流出道阻塞的成年人。结果显示，与安慰剂相比，Aficamten治疗24周显著提高了运动能力，与基线相比，Aficamten治疗的患者通过心肺运动试验(CPET)测得的最大摄氧量(pVO2)增加了1.8 ml/kg/min，而安慰剂治疗的患者为0.0mL/kg/min(1.74mL/kg/min[1.04-2.44]；p=0.000002)。在所有10个预先指定的次要终点，包括Valsalva左心室流出道(LVOT)梯度、纽约心脏协会(NYHA)功能分级、堪萨斯城心肌病临床综合评分(KCCQ-CSS)、LVOT梯度< 30 mmHg的比例(分别在第12周和第24周)、符合间隔缩小治疗指南的持续时间(SRT)和第24周CPET期间的总工作量，均观察到统计学显著改善。SEQUOIA-HCM试验的进一步分析表明，Aficamten治疗与心脏重塑以及心脏结构、功能和生物标志物的改善有关，且不会对收缩功能产生负面影响。这些结果首次证明Aficamten可作为单药疗法，为梗阻性肥厚型心肌病患者带来具有临床意义的改善，重要的是，MAPLE-HCM的阳性结果为这种潜在新药与现有标准治疗方案相比的益处提供了重要的背景信息。【展望】FDA目前正在审查Aficamten用于治疗梗阻性肥厚型心肌病(HCM)的新药申请，预计将于2025年12月26日做出监管决定。同时，该药物也正在接受欧洲和中国的监管审查。此外，Aficamten还有几项临床试验，分别是3期ACACIA-HCM临床试验，比较了Aficamten作为单药治疗阻塞性HCM患者的效果；针对患有阻塞性HCM的儿科人群进行的CEDAR-HCM临床试验；针对HCM患者进行的FOREST-HCM开放标签扩展临床研究。除了HCM，Cytokinetics还在开发心肌激活剂omecamtiv mecarbil，用于治疗射血分数严重降低(HFrEF)的心力衰竭患者；CK-586，一种作用机制不同于Aficamten的心脏肌球蛋白抑制剂，用于治疗射血分数保留的心力衰竭(HFpEF)；以及CK-089，一种快速骨骼肌肌钙蛋白激活剂(FSTA)，用于治疗特定类型的肌营养不良症。参考来源：[1] Cytokinetics官网[2] Cytokinetics announces positive topline results from MAPLE-HCM. News release. Cytokinetics. May 13, 2025.[3] Cytokinetics announces FDA acceptance of New Drug Application for aficamten for the treatment of obstructive hypertrophic cardiomyopathy. News release. Cytokinetics. December 2, 2024.药事纵横投稿须知：稿费已上调，欢迎投稿

Two New Analyses from SEQUOIA-HCM on Effect of Aficamten Between Patients with Mild and Moderate-to-Severe Symptoms, and Across Geographic Regions HEOR Analyses of Real-World Data Reveal Disparities in Outcomes In Females and Older Patients with Non-Obstructive HCM SOUTH SAN FRANCISCO, Calif., May 18, 2025 (GLOBE NEWSWIRE) -- Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that additional data arising from two analyses from SEQUOIA-HCM, (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), and results from a real-world analysis related to non-obstructive HCM were presented at the European Society of Cardiology Heart Failure 2025 Congress. The results from an analysis of the efficacy of aficamten in patients with obstructive HCM and mild symptoms in SEQUOIA-HCM were also simultaneously published in The European Heart Journal.1 “These analyses from SEQUOIA-HCM demonstrate that the effect of aficamten on exercise capacity, symptoms, hemodynamics and cardiac biomarkers is consistent in patients with obstructive HCM regardless of baseline symptom severity and geographic region,” said Stephen Heitner, M.D., Vice President, Head of Clinical Research. “These findings are informative as we continue to explore the potential application of aficamten across a range of patient phenotypes in obstructive HCM.” Effect of Aficamten in Patients with Mild Symptoms and Moderate-to-Severe Symptoms Data from an additional analysis from SEQUOIA-HCM related to the effect of aficamten in patients with mild symptoms were presented in a Late Breaking Clinical Trial session and simultaneously published in The European Heart Journal. Patients in SEQUOIA-HCM (n=282) were divided into two groups according to baseline symptom severity: mild symptoms, defined as New York Heart Association (NYHA) Functional Class II and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) ≥80 (n=118; 62 randomized to aficamten), and moderate-to-severe symptoms defined as NYHA Functional Class II/III/IV and KCCQ-CSS <80 (n=150; 71 randomized to aficamten). The effect of aficamten on the primary endpoint of change from baseline to Week 24 in peak oxygen uptake (pVO2) was similar between symptom groups (1.6 and 1.8 mL/kg/min in mild and moderate-to-severe symptom groups respectively; interaction p=0.8). While both groups experienced improvements in KCCQ-CSS, the magnitude of improvement was greater in the moderate-to-severe symptom group compared to the mild symptom group (interaction p=0.02) as expected given the lower baseline KCCQ-CSS score. At the end of the treatment period, 54% of patients with mild symptoms and 36% of patients with moderate-to-severe symptoms were asymptomatic. Additionally, more than half of patients in both groups had an improvement of at least one NYHA Functional Class (interaction p=0.6). Improvements in resting and Valsalva left ventricular outflow tract (LVOT) gradients and NT-proBNP also did not differ significantly between the two groups (all interaction p≥0.3). The safety and tolerability profile of aficamten was similar to placebo in both subgroups. These data indicate that, in SEQUOIA-HCM, the effect of aficamten was observed independent of baseline symptom burden in patients with obstructive HCM. Effect of Aficamten in Patients with Obstructive HCM Consistent Across Geographic Regions Data from an additional analysis from SEQUOIA-HCM evaluating geographical differences in the effect of aficamten were presented in a Late Breaking Clinical Trial session. Participants from SEQUOIA-HCM (n=282) were classified into three geographic regions: Europe, including Israel (n=142; 50%), North America (n=94; 33%) and China (n=46; 16%). At baseline, patients in Europe and North America were on average older, with a higher BMI, lower LVOT gradients, lower KCCQ-CSS and were more likely to have comorbidities than those in China. A greater proportion of patients in North America were NYHA Functional Class III/IV compared to Europe and China. Peak VO2, Valsalva LVOT gradient, NT-proBNP and hs-cardiac troponin I were similar across geographical regions. The distribution of doses of aficamten was similar across regions. The effect of aficamten on the primary endpoint of change in pVO2 and all secondary endpoints was consistent, with no significant differences across regions (all interaction p>0.15). The incidence of serious adverse events was similar in the aficamten and placebo groups across regions, and occurrences of left ventricular ejection fraction (LVEF) <50% were infrequent. These results demonstrate that in SEQUOIA-HCM, while there were regional differences in patient baseline characteristics, the dosing, safety profile and effect of aficamten was consistent across the geographic regions studied. Analyses of Real-World Data Reveal Association Between Age, Sex and Cardiovascular Outcomes in Patients with Non-Obstructive HCM Data presented from a health economics and outcomes research (HEOR) analysis evaluated the association between age, sex and cardiovascular outcomes in patients with non-obstructive HCM. This retrospective cohort study included adult patients diagnosed with non-obstructive HCM from January 1, 2013 to December 31, 2021 using real-world data from Optum Market Clarity database. Of the 9,842 patients included, 46.2% were female, 53.8% were male and the age distribution was as follows: 24.2% were ages 55 to 64 years, 22.1% were ages 75 or older, 22.1% were ages 65 to 74, 19.9% were ages 40 to 54 and 11.7% were ages 18 to 39. Female patients had increased rates of stroke (risk ratio [RR] 1.32), heart failure (RR 1.22), cardiovascular hospitalization (RR 1.23) and cardiovascular rehospitalization (RR 1.15) compared to male patients (all p<0.01). However, female patients were less likely to have atrial fibrillation (RR 0.83) and ventricular tachycardia (RR 0.69) (p<0.001). Compared to patients aged 75 years or older, younger patients were less likely to have atrial fibrillation, stroke, heart failure, cardiovascular hospitalization and cardiovascular rehospitalization (all p<0.001). All-cause mortality was significantly greater in female patients compared to male patients (p=0.002). Patients aged 75 years or older had the highest all-cause mortality (16.6%; p<0.001), followed by patients aged 65 to 74 (8.3%), 55 to 64 (3.5%), 40 to 54 (3.1%) and 18 to 39 years (1.4%). These findings highlight disparities in morbidity and survival among females and older patients with non-obstructive HCM, emphasizing the potential role for novel treatments to help reduce the clinical burden. About Aficamten Aficamten is an investigational selective, small molecule cardiac myosin inhibitor discovered following an extensive chemical optimization program that was conducted with careful attention to therapeutic index and pharmacokinetic properties.2 Aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with HCM. In preclinical models, aficamten reduced myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state. The development program for aficamten is assessing its potential as a treatment that improves exercise capacity as measured by peak oxygen uptake (pVO2) and relieves symptoms in patients with HCM. Aficamten was evaluated in SEQUOIA-HCM, a positive pivotal Phase 3 clinical trial in patients symptomatic obstructive hypertrophic cardiomyopathy (HCM). Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic HCM from the U.S. Food & Drug Administration (FDA) and for the treatment of symptomatic obstructive HCM from the National Medical Products Administration (NMPA) in China. Aficamten is also currently being evaluated in ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients with non-obstructive HCM; CEDAR-HCM, a clinical trial of aficamten in a pediatric population with obstructive HCM; and FOREST-HCM, an open-label extension clinical study of aficamten in patients with HCM. This communication contains a summary of new data related to the clinical development of aficamten presented at the European Society of Cardiology Heart Failure 2025 Congress. Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Aficamten is currently under regulatory review in the U.S, where the FDA is reviewing a New Drug Application (NDA) for aficamten with a Prescription Drug User Fee Act (PDUFA) target action date of December 26, 2025. Additionally, the European Medicines Agency (EMA) is reviewing a Marketing Authorization Application (MAA) for aficamten, and The Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) is reviewing an NDA for aficamten with Priority Review. About Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. This ultimately limits the heart’s pumping function, resulting in reduced exercise capacity and symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. HCM is the most common monogenic inherited cardiovascular disorder, with approximately 280,000 patients diagnosed, however, there are an estimated 400,000-800,000 additional patients who remain undiagnosed in the U.S.3,4,5 Two-thirds of patients with HCM have obstructive HCM (oHCM), where the thickening of the cardiac muscle leads to left ventricular outflow tract (LVOT) obstruction, while one-third have non-obstructive HCM (nHCM), where blood flow isn’t impacted, but the heart muscle is still thickened. People with HCM are at high risk of also developing cardiovascular complications including atrial fibrillation, stroke and mitral valve disease.6 People with HCM are at risk for potentially fatal ventricular arrhythmias and it is one of the leading causes of sudden cardiac death in younger people or athletes.7 A subset of patients with HCM are at high risk of progressive disease leading to dilated cardiomyopathy and heart failure necessitating cardiac transplantation. About Cytokinetics Cytokinetics is a specialty cardiovascular biopharmaceutical company, building on its over 25 years of pioneering scientific innovations in muscle biology to advance a pipeline of potential new medicines for patients suffering from diseases of cardiac muscle dysfunction. Cytokinetics is readying for potential regulatory approvals and commercialization of aficamten, a cardiac myosin inhibitor following positive results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial in patients with obstructive hypertrophic cardiomyopathy (HCM). Aficamten is also being evaluated in additional clinical trials enrolling patients with obstructive and non-obstructive HCM. Cytokinetics is also developing omecamtiv mecarbil, a cardiac myosin activator, in patients with heart failure with severely reduced ejection fraction (HFrEF), CK-586, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten, for the potential treatment of heart failure with preserved ejection fraction (HFpEF) and CK-089, a fast skeletal muscle troponin activator with potential therapeutic application to a specific type of muscular dystrophy and other conditions of impaired skeletal muscle function. For additional information about Cytokinetics, visit www.cytokinetics.com and follow us on X, LinkedIn, Facebook and YouTube. Forward-Looking Statements This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics disclaims any intent or obligation to update these forward-looking statements and claims the protection of the Act’s Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements express or implied relating to the properties, treatment effect or potential benefits of aficamten or any of our other drug candidates or our ability to obtain regulatory approval for aficamten for the treatment of obstructive hypertrophic cardiomyopathy or any other indication from FDA or any other regulatory body in the United States or abroad by any particular date, if ever. Such statements are based on management’s current expectations, but actual results may differ materially due to various risks and uncertainties, including, but not limited to the risks related to Cytokinetics’ business outlines in Cytokinetics’ filings with the Securities and Exchange Commission. Forward-looking statements are not guarantees of future performance, and Cytokinetics’ actual results of operations, financial condition and liquidity, and the development of the industry in which it operates, may differ materially from the forward-looking statements contained in this press release. Any forward-looking statements that Cytokinetics makes in this press release speak only as of the date of this press release. Cytokinetics assumes no obligation to update its forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. CYTOKINETICS® and the CYTOKINETICS and C-shaped logo are registered trademarks of Cytokinetics in the U.S. and certain other countries. Contact: Cytokinetics Diane Weiser Senior Vice President, Corporate Affairs (415) 290-7757 References: Source: Cytokinetics, Incorporated