目的:MHV370是人Toll样受体(TLR)7和8的双重拮抗剂,在体外和体内抑制细胞因子和干扰素刺激的基因,并在小鼠狼疮模型中证明了疗效。这项首次针对人类的研究旨在评估安全性,耐受性,单剂量和多剂量MHV370在健康成人中的药代动力学和药效学,以及食物消耗对单剂量MHV370的影响。
方法:这是第一阶段,随机,安慰剂对照研究分三个部分进行。在A部分,参与者接受(3:1)单次递增剂量(SAD)1,3,10,20,40,80,160,320,640和1000mgMHV370或安慰剂.在B部分,参与者接受(3:1)多次递增剂量(MAD)25,50,100,200和400mgMHV370每日两次(b.i.d)或安慰剂,共14天.在C部分,参与者在禁食或进食条件下接受200mgMHV370的开放标签单剂量.安全,评价了药代动力学和药效学参数.
结果:MHV370耐受性良好,研究中未观察到安全信号。在评估的剂量范围内没有发生剂量限制性不良事件。MHV370的血浆浓度随着剂量的增加而增加(SAD为3-1000mg,平均[SD]最大血浆浓度范围为0.97[0.48]至1670[861.0]ng/mL,对于MAD为25-400mgb.i.d.在第1天的29.5[7.98]至759[325.0]ng/mL)。食物的摄取对MHV370的药代动力学没有相干影响。药效学数据表明,时间和剂量依赖性地抑制了TLR7介导的CD69在B细胞上的表达(从SAD160mg和MAD50mgb.i.d.开始,在给药后24小时抑制为100%),并且在离体刺激后TLR8介导的TNF释放(从SAD320mg和MAD100mgb.i.d.开始,在给药后24小时抑制>90%)。
结论:安全性,药代动力学和药效学数据支持MHV370在TLR7和TLR8过度激活导致的全身性自身免疫性疾病中的进一步发展.
OBJECTIVE: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and has demonstrated efficacy in murine models of lupus. This first-in-human
study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.
METHODS: This was a phase 1, randomised, placebo-controlled
study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.
RESULTS: MHV370 was well tolerated, and no safety signal was observed in the
study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).
CONCLUSIONS: The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.