背景:普利多匹定是一种高度选择性的sigma-1受体(S1R)激动剂,正在开发中用于治疗亨廷顿氏病(HD)和肌萎缩性侧索硬化症(ALS)。普利多匹定激活S1R可增强对神经元功能和存活至关重要但在神经退行性疾病中受损的细胞过程。人脑正电子发射断层扫描(PET)成像研究表明,在45毫克每日两次(bid)的治疗剂量下,普利多匹定选择性地和稳健地占据S1R。我们进行了浓度-QTc(C-QTc)分析,以评估普利多匹定对QT间期的影响,并研究其心脏安全性。
方法:使用PRIDE-HD的数据进行C-QTc分析,一项2期安慰剂对照试验,评估HD患者在52周内接受4种普利多匹定剂量(45,67.5,90,112.5mgbid)或安慰剂.在402例HD患者中同时测定了三份心电图(ECG)和血浆药物浓度。评估了普利多匹定对Fridericia校正的QT间期(QTcF)的影响。心脏相关的不良事件(AE)从PRIDE-HD单独分析和从三个双盲的汇总安全性数据,普利多匹定治疗HD的安慰剂对照试验(HART,MermaiHD,和PRIDE-HD)。
结果:观察到普利多匹定对Fridericia校正的QT间期(ΔQTcF)从基线的变化的浓度依赖性作用,斜率为0.012ms(ms)/ng/mL(90%置信区间(CI),0.0109-0.0127)。在45mgbid的治疗剂量下,预测的安慰剂校正的ΔQTcF(ΔΔQTcF)为6.6ms(上限90%CI,8.0ms),低于关注水平,与临床无关。对来自三个HD试验的汇总安全性数据的分析表明,在45mgbid下,普利多匹定与心脏相关的AE频率与安慰剂组相似.在任何普利多匹定剂量下,没有患者达到500ms的QTcF,也没有患者经历过尖端扭转(TdP)。
结论:在45mgbid治疗剂量下,普利多匹定显示良好的心脏安全性,对QTc间期的影响低于关注水平,但与临床无关。
背景:PRIDE-HD(TV7820-CNS-20002)试验注册:ClinicalTrials.gov标识符,NCT02006472,EudraCT2013-001888-23;HART(ACR16C009)试验注册:ClinicalTrials.gov标识符,NCT00724048;MermaiHD(ACR16C008)试用注册:ClinicalTrials.gov标识符,NCT00665223,EudraCTNo.2007-004988-22.
BACKGROUND: Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington\'s disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine\'s activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine\'s effect on the QT interval and investigated its cardiac safety profile.
METHODS: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD).
RESULTS: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109-0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose.
CONCLUSIONS: At the 45 mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant.
BACKGROUND: PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.