Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine
Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine
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DOI：
10.1016/j.yrtph.2019.05.013
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发表时间：
2019-08-01
影响因子：
3.4
通讯作者：
Monticello, Thomas M.
中科院分区：
文献类型：
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作者：
Bussiere, Jeanine L.;Davies, Rhian;Monticello, Thomas M.
降钙素基因相关肽(CGRP)及其受体在偏头痛的病理生理过程中起重要作用。因此，降钙素基因相关肽受体的单抗拮抗剂埃伦单抗，每月一次，剂量为70或140毫克，已被批准用于成人偏头痛的预防治疗。由于埃伦单抗的物种特异性，食蟹猴被用于药理学、药代动力学和毒理学研究，以支持临床计划。埃伦单抗在体外对血小板无影响(通过结合、激活或吞噬实验)。对人体组织的埃伦单抗特异染色没有显示任何脱靶结合。在食蟹猴的心血管安全药理学研究中或在体外的人类离体冠状动脉中，没有埃罗单抗相关的发现。在食蟹猴身上进行的重复剂量毒理学研究，剂量水平高达225毫克/公斤(1个月)或高达150毫克/公斤(最长6个月)，每周两次皮下注射(SC)，没有证据表明埃伦单抗介导的不良毒性。在加强的食蟹猴出生前发育研究中，对怀孕、胚胎-胎儿或出生后的生长和发育没有影响。在出生后3个月的婴儿中，根据可测量的血清浓度，有证据表明埃伦单抗的胎盘转移。母体和发育未观察到效应水平(NOEL)是所测试的最高剂量(50 mg/kg SC Q2W)。总体而言，这些非临床数据表明，到目前为止还没有值得关注的安全信号，并在动物观察到的安全剂量和临床剂量水平之间提供了足够的暴露范围。
Calcitonin gene-related peptide (CGRP) and its receptor have been implicated as a key mediator in the pathophysiology of migraine. Thus, erenumab, a monoclonal antibody antagonist of the CGRP receptor, administered as a once monthly dose of 70 or 140 mg has been approved for the preventive treatment of migraine in adults. Due to the species specificity of erenumab, the cynomolgus monkey was used in the pharmacology, pharmacokinetics, and toxicology studies to support the clinical program. There were no effects of erenumab on platelets in vitro (by binding, activation or phagocytosis assays). Specific staining of human tissues with erenumab did not indicated any off-target binding. There were no erenumab-related findings in a cardiovascular safety pharmacology study in cynomolgus monkeys or in vitro in human isolated coronary arteries. Repeat-dose toxicology studies conducted in cynomolgus monkeys at dose levels up to 225 mg/kg (1 month) or up to 150 mg/kg (up to 6 months) with twice weekly subcutaneous (SC) doses showed no evidence of erenumab-mediated adverse toxicity. There were no effects on pregnancy, embryo-fetal or postnatal growth and development in an enhanced pre-postnatal development study in the cynomolgus monkey. There was evidence of placental transfer of erenumab based on measurable serum concentrations in the infants up to 3 months post birth. The maternal and developmental no-observed-effect level (NOEL) was the highest dose tested (50 mg/kg SC Q2W). These nonclinical data in total indicate no safety signal of concern to date and provide adequate margins of exposure between the observed safe doses in animals and clinical dose levels.