Shakeri-Nejad Kasra, Aslanis Vassilios, Veldandi Uday Kiran, Mooney Louise, Pezous Nicole, Brendani Bruno, Juan Axel, Allison Mark, Perry Robert, Legangneux Eric
Novartis Pharma AG, Basel, Switzerland.
Novartis Pharma AG, Basel, Switzerland.
Clin Ther. 2015 Nov 1;37(11):2489-2505.e2. doi: 10.1016/j.clinthera.2015.09.006. Epub 2015 Oct 27.
The International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects.
The study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days -1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated.
Of the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for ΔΔQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum ΔΔQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure.
The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.
国际协调会议E14指南要求，对于所有具有全身生物利用度的新型非抗心律失常药物，需在一项临床全面QT研究中进行强化心脏安全性评估，该研究通常在健康受试者中开展。这项全面QT研究调查了治疗剂量（2毫克）和超治疗剂量（10毫克）的西苯莫德（BAF312）对健康受试者心脏复极化的影响。
该研究为随机、双盲、平行组、安慰剂和莫西沙星对照的多次口服给药研究。符合条件的受试者被随机分为3组，分别接受西苯莫德（在18天内滴定至2毫克和10毫克）、安慰剂（第-1天至18天）或莫西沙星400毫克（第10天和第18天）。在预定时间点，从给药前1小时至给药后24小时记录的动态心电图中提取三份心电图，记录时间为基线期以及治疗评估第10天和第18天。主要药效学变量是稳态条件下时间匹配、安慰剂校正、基线调整后的平均QTcF（ΔΔQTcF）。此外，还评估了西苯莫德及其主要循环代谢物M3和代谢物M5的药代动力学参数。
在304名入组受试者中，281名（92.4%）纳入药效学分析，270名（88.8%）完成研究。在所有预先定义的治疗时间点，西苯莫德两个剂量的ΔΔQTcF双侧90%置信区间（CI）上限均在10毫秒（ms）的监管阈值内，且无任何剂量相关效应。治疗剂量和超治疗剂量的双侧90%CI最高观察上限分别为9.8毫秒和9.6毫秒，均在给药后3小时观察到。未观察到治疗中出现的QTc值>480毫秒，且QTc较基线增加>60毫秒的情况。通过对心脏复极化进行个体化心率校正（QTcI）也得到了类似结果。在两个治疗评估日，400毫克莫西沙星给药后最大ΔΔQTcF>5毫秒，证明了检测的有效性。所选超治疗剂量产生的暴露量（Cmax和AUC）比治疗剂量高约5倍，被认为适合研究西苯莫德在预期最大治疗暴露量的数倍剂量下对QT/QTc的影响。
研究结果提供了证据，表明西苯莫德与QT延长相关的显著致心律失常潜力无关。
