A phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis
A phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis
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DOI：
10.1002/art.34339
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发表时间：
2012-06-01
影响因子：
--
通讯作者：
Tak, Paul P.
中科院分区：
文献类型：
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作者：
Krausz, Sarah;Boumans, Maria J. H.;Tak, Paul P.
目的观察甲磺酸阿吡莫德口服治疗类风湿关节炎（RA）的安全性、耐受性、药代动力学和疗效。方法我们进行了一项IIa期、随机、双盲、安慰剂对照的概念验证研究，阿吡莫德联合甲氨蝶呤治疗29例活动性RA患者（阿吡莫德治疗与安慰剂治疗患者的比例为3：1），分3个阶段。患者接受阿吡莫德100 mg/天或安慰剂4周（第1阶段）或8周（第2阶段）。在第3阶段，患者接受阿吡莫德100 mg每日两次或安慰剂治疗8周，可选延长4周。在整个过程中评估临床应答（28个关节的疾病活动性评分[DAS 28]和美国风湿病学会[ACR]标准）;对基线和第29天（第1和2阶段）或第57天（第3阶段）收集的滑膜组织样本进行细胞标志物和细胞因子染色，用于免疫组织化学分析。结果在第1、2阶段仅观察到轻度不良事件，而在第3阶段，所有患者均出现头痛和/或恶心。在阿吡莫德治疗的患者（100 mg/天）中，与基线相比，第29天和第57天的DAS 28有小幅但显著的降低。在第29天，仅6%的患者达到ACR 20应答，在第57天，仅25%的患者达到ACR 20应答，与安慰剂组应答者的百分比相似。增加剂量（100 mg，每日两次）并未改善临床疗效。与临床结果一致，阿吡莫德对滑膜生物标志物的表达没有影响。重要的是，我们也没有观察到阿吡莫德对滑膜IL-12和IL-23表达的影响。结论我们的结果不支持阿吡莫德抑制IL-12/IL-23能够诱导RA的稳健临床改善的观点。
Objective To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA). Methods We performed a phase IIa, randomized, double-blind, placebo-controlled proof-of-concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod-treated to placebo-treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis. Results While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod-treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression. Conclusion Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.