Pfizer Global Research and Development, New London, CT, USA.
Best Pract Res Clin Rheumatol. 2010 Aug;24(4):513-26. doi: 10.1016/j.berh.2010.02.003.
CP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) molecules. The molecular pathways through which the JAK moieties function are described along with the clinical mechanisms associated with their inhibition. Animal models of JAK inhibition are reviewed as a background for the possible inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is described, and the Phase IIA and IIB trials are reviewed in some detail. These trials were dose-ranging and showed a general dose response with relatively robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 6-week trial in which CP-690,550 was given as monotherapy was associated with highly efficacious responses at the mid and higher twice-daily dose ranges employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was administered in combination with methotrexate showed ACR20 responses, which were also statistically significant versus placebo interventions. CP-690,550 treatment was associated with side effects, which included headache and nausea. Infections were more common versus placebo as were elevations in transaminase enzymes when administered in combination with methotrexate, and increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Decreases in haemoglobin and white blood cell (WBC) counts were also observed along with small increases in serum creatinine. Occasional significant decreases of haemoglobin (>2 g dl(-1)) were observed, although decreases of WBC to less than 1000 per mm(3) were not seen. Plans for long-term follow-up of the described trials are described along with the features of five presently ongoing Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future directions include completion and publication of these trials along with study of JAK inhibition for other indications.
CP-690,550 是一种口服活性且选择性的 Janus 激酶（JAK）分子抑制剂。本文描述了 JAK 部分发挥作用的分子途径，以及与其抑制相关的临床机制。还回顾了 JAK 抑制的动物模型，作为 JAK 可能在人类中被抑制的背景。描述了 CP-690,550 在人类中的药代动力学，并详细回顾了 IIA 期和 IIB 期临床试验。这些试验是剂量范围试验，表现出与相对较强的美国风湿病学会 20 项（ACR20）反应一致的一般剂量反应。一项为期 6 周的 CP-690,550 单药治疗的概念验证试验，在使用的中高每日两次剂量范围内，具有高度有效的反应。随后进行了一项为期 24 周的剂量范围试验，其中 CP-690,550 与甲氨蝶呤联合给药，结果显示 ACR20 反应，与安慰剂干预相比也具有统计学意义。CP-690,550 治疗与副作用相关，包括头痛和恶心。与安慰剂相比，感染更为常见，当与甲氨蝶呤联合给药时，转氨酶升高，以及低密度脂蛋白（LDL）和高密度脂蛋白（HDL）胆固醇升高。还观察到血红蛋白和白细胞（WBC）计数下降，以及血清肌酐略有升高。偶尔也观察到血红蛋白显著下降（>2 g dl(-1)），尽管 WBC 降至每立方毫米 1000 以下的情况并未出现。描述了正在进行的五项 CP-690,550 酪氨酸激酶（JAK）抑制剂 III 期临床试验的长期随访计划，以及这些试验的特征。未来的方向包括完成和发表这些试验，以及研究 JAK 抑制的其他适应症。
