2024玛伐凯泰治疗梗阻性肥厚型心肌病总结.docx

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1、2024玛伐凯泰治疗梗阻性肥厚型心肌病总结玛伐凯泰(mavacamten )是一种首创的、有口服活性的、选择性心 肌肌球蛋白变构调节剂，目前已被美国食品和药物管理局(FDA )批 准用于治疗心功能NYHA II- III级的症状性梗阻性肥厚型心肌病 (OHCM )成人患者，以改善功能能力和症状。II期和III期临床试验 已证实，玛伐凯泰具有良好的耐受性，左室流出道压力梯度降低，运 动耐力和症状改善，并与生物标志物等其他临床相关参数的改善相 关。除此之外，影像学相关研究还显示，玛伐凯泰治疗有利于心脏重 塑。近日，EUR /E4/?丁，发表的综述回顾了已完成和正在进行的玛 伐凯泰治疗症状性OHCM

2、患者的相关数据，本文整理了十大要点。Clinical studiesPre-clinical dataHypercontractile LVLVOT obstruction symptomsTargeted molecular approachMyosin inhibitorsMavacamtenBasic scienceContractility Compliance EnergeticsLV hypertrophyj Disarray.Myocardial fibrosisPhase 3 clinical trialsIn obstructiveHCMEPLORER-HCMGain of

3、functionMHY7 mutationsOff state uOn stateHCMsarcomereHCM sarcomerewith allostericmyosin inhibitionVALOR-HCMImproved symptomsand exercise performanceRelief of LVOT gradientImproved QOLI LA sizeE/e，IV cavity sizeI NT ProBNP and HsThTReduced need forseptal reduction therapiesln nnuctl ODYSSEY-HCM (Ongo

4、ing)图1 OHCM的治疗途径(中心图)注：左上.血流动力学结果，左室流出道梗阻及与左心室肥厚相关的症状；左下.约40%的患者发现了基因变异；中QHCM患者的肌球蛋白-肌动蛋白交叉桥连接过多，玛伐凯泰可使其正常化；右上.OHCM小鼠和猪模型的临床前观察数据；右下.玛伐凯泰治疗OHCM的两项安慰剂对照临床试验十大要点一览1 .肥厚型心肌病（HCM ）是一种由心肌肌节功能障碍引起的疾病，可 导致过多的肌球蛋白-肌动蛋白交叉桥连接和钙敏感性增加。2 .玛伐凯泰是一种可逆的肌球蛋白抑制剂，靶向HCM的核心病理生理机制。其可减少能够与肌动蛋白有效相互作用的肌球蛋白头的数量。因此，可通过降低肌节的过度活

5、动，减少左心室流出道（LVoT ）梗阻， 降低左心室充盈压力。Myosin Inhibitors: Mechanism of ActionS*rcnrNormal contractility EffectIVe relaxationHCM PathoPhySiOlOgy Ibo many actin-myosin crossbridges engagedHCM S*rcom*r with WUvac*mtnAttenuated hypercontractility Improved relaxation Improved energeticsHyperrantractilityImpaired

6、 relaxationAltered myocardial energetics图2玛伐凯泰治疗HCM的基本原理3 .在体内，玛伐凯泰可被CYP2C19和CYP3A4广泛代谢，具有较高的药物相互作用倾向，且具有很长的半衰期（6-23天）。4 .PIONEER-HCM 期试验显示，玛伐凯泰的获益具有剂量依赖性， 其可以浓度依赖性方式降低左心室射血分数（LVEF ）。当血药浓度在 350 - 695 ng/mL时,可减少LVOT梗阻，LVEF均 50%o在研究 中，大多数不良事件为轻-中度，且与研究药物无关，耐受性较好。PIONEER-OLE开放标签延长试验中期分析显示，在48周时，玛伐凯 泰治疗

7、患者的LVOT梗阻、NYHA分级和NT-proBNP血清浓度持续 持久降低，使用堪萨斯城心肌病问卷（KCCQ ）评估的患者报告的症 状也有所改善。重要的是，所有患者的LVEF均保持在50%以上。3 年时的额外随访显示，玛伐凯泰治疗与心血管血流动力学、症状和生 活质量的持续改善相关。一项使用人工智能增强型心电图（AI-ECG ）监测疾病状态的分析显示, 玛伐凯泰治疗或可改善心电图形态。表1玛伐凯泰试验的特点及相关结局Title (reference)PIONEER HCMiCEXPLORER HCM3437VALOR-ACH43DesignOpen-label Non-randomizedDou

8、ble-blind randomizedDouble-blindRandomizedN21251112Duration (weeks)123016NYHA classll/lllll/llllll/IVDose (mgday)2-2015-152.5-15Primary endpointChange in post-exercise LVOT gradientExercise capacity symptom burdenContinued eligibility for SRTOUTCOMESI LVOT gradientsImproved exercise capacity and ven

9、tilatory efficiency! NYHA classI NRS dyspnoea scoreImproved health status1 LVOT gradients Improved exercise capacityI NYHA classI NT-proBNP and hs-cTnl Improved diastolic function1 eligibility for SRTI LVOT gradientsI NYHA classI NT-proBNP and hs-cTnlImproved health statushsTnl, high-sensitivity car

10、diac Troponin I; LVOT. left ventricular outflow tract N. patient number NYHA. New York Heart Association; NT-proBNP. N-terminal pro-B-type natriuretic peptide： NRS1 numerical rating scale; SRT1 septal reduction therapy.5 .EXPL0RER-HCM III期试验是迄今为止在OHCM患者中探究玛伐 凯泰的规模最大的安慰剂对照试验。研究显示，玛伐凯泰可显著改善 LVOT梗阻，且与运

11、动耐力、症状负担、Valsalva梯度、健康状况和 B型钠尿肽（BNP ）水平改善相关。与安慰剂相比，玛伐凯泰组患者 的严重不良事件发生率相当（分别为9%和8% ）。WeeksWeeks- Mavacamten - Placebo图3基线时和治疗30周后的LVOT梯度注：A.静止时的梯度；B. Valsalva梯度；C.运动后梯度6 .EXPL0RER-HCM二次分析显示，在未使用受体阻滞剂的患者中， 玛伐凯泰对运动耐力和NYHA分级的影响更大，但其在改善LVoT梗 阻和BNP水平方面的疗效与是否应用受体阻滞剂无关。表2 Explorer-HCm二次分析结果AnalysisKey result

12、sBeta-Nocker subgroup analysis MavacamtentS effects on primary endpoint (pVO2 and NYHA class)EXPLORER-HCM36: N = 251 (BB: n= 189; no BB: n = 62) EXPLORER-LTE53 were greater in patients not receiving background BB than receiving cohort of MAVA-LTE (NCT03723655) N = 231 (BB: n = 175; no BB: n = 56) th

13、em Less improvements in pVO2 with mavacamten vs. placebo in patients on BB Mavacamten showed greater benefits vs. placebo in LVOT gradient reduction. NYHA class, and NT-proBNP levels, irrespective of BB use Mavacamten benefits maintained in MAVA-LTE with or without BB Mavacamten improvements in VENC

14、O2 slope similar with and withoutBBCMR subgroup study48 Reductions in LV mass index greater with mavacamten vs. placebo;N = 35P .0001) Change in LV mass index correlated positively with change in hsTnlEchocardiographic parameters37 Complete resolution of mitral valve SAM in 81% of patients onN = 251

15、mavacamten vs. 34% on placebo (P .0001) Complete resolution of mitral regurgitation. Nine per cent in mavacamten vs. no patients on placebo (P .001) Mavacamten improved diastolic function vs. placebo, including septalEJe9t and lateral Eet and LAVI (all P .0001) Mavacamten significantly reduced LV wall mass and LV thickness index (consistent with CMR)Health status analysis50 51 Improvements in KCCQ greater with mavacamten than placebo;n