Medivir AB, Box 1086, 141 22, Huddinge, Sweden.
J Transl Med. 2018 May 9;16(1):125. doi: 10.1186/s12967-018-1497-4.
Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man.
The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3-30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg.
MIV-711 was a potent inhibitor of human cathepsin K (K: 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data.
MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011.
组织蛋白酶 K 是一种有吸引力的治疗靶点，可用于治疗骨吸收过度的疾病，如骨质疏松症和骨关节炎（OA）。本文描述了强效和选择性组织蛋白酶 K 抑制剂 MIV-711 的体外和食蟹猴的药理学特征，并基于人体单次剂量临床研究评估了向人体的转化。
使用重组酶测定和分化的人破骨细胞评估 MIV-711 的效力和选择性。单次给予健康食蟹猴 MIV-711（3-30 μmol/kg，po）。单次给药实验后测量 MIV-711 的血浆水平和骨吸收生物标志物 CTX-I，重复给药实验后测量尿 CTX-I、NTX-I 和 CTX-II 生物标志物水平。在人体健康受试者中，评估 MIV-711 的安全性、药代动力学和药效学（血清 CTX-I），剂量范围为 20 至 600mg。
MIV-711 是一种强效的人组织蛋白酶 K 抑制剂（K：0.98 nmol/L），对其他人类组织蛋白酶具有超过 1300 倍的选择性。MIV-711 以 43 nmol/L 的 IC 值抑制人破骨细胞介导的骨吸收。MIV-711 以剂量依赖性方式降低猴子的血浆 CTX-I 水平，在最低点时降低高达 57%。CTX-I 的效果与 MIV-711 的血浆暴露呈线性相关，而疗效持续时间超过了血浆暴露时间。重复口服 MIV-711 还降低了尿中骨吸收生物标志物 CTX-I（93%）、NTX-I（71%）和软骨降解生物标志物 CTX-II（71%）的水平。MIV-711 在健康受试者中单次递增剂量给药时安全且耐受良好。MIV-711 以剂量依赖性方式降低血清 CTX-I 水平，在最低点时降低高达 79%。当与相应的猴子数据进行比较时，人类中 MIV-711 暴露与这些生物标志物的关系几乎相同。
MIV-711 是一种强效且选择性的组织蛋白酶 K 抑制剂，对猴子和人类的骨和软骨降解生物标志物具有剂量依赖性作用。总之，MIV-711 有望用于治疗人类骨和软骨相关疾病，如 OA。
试验注册 EudraCT 编号 2011-003024-12，于 2011 年 6 月 22 日注册。
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