依奇珠单抗治疗中重度斑块状银屑病的 3 期临床试验。

Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis.

机构信息

From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).

出版信息

N Engl J Med. 2016 Jul 28;375(4):345-56. doi: 10.1056/NEJMoa1512711. Epub 2016 Jun 8.

DOI:10.1056/NEJMoa1512711

PMID:27299809

Abstract

BACKGROUND

Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1.

METHODS

We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12.

RESULTS

In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease.

CONCLUSIONS

In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).

摘要

背景

两项 3 期临床试验（UNCOVER-2 和 UNCOVER-3）显示，在 12 周的治疗期间，白细胞介素-17A 的单克隆抗体 ixekizumab 在治疗中重度银屑病方面优于安慰剂和依那西普。我们报告了来自 UNCOVER-2 和 UNCOVER-3 试验的 60 周数据，以及来自第三个 3 期试验 UNCOVER-1 的 12 周和 60 周数据。

方法

我们随机分配 1296 名 UNCOVER-1 试验患者、1224 名 UNCOVER-2 试验患者和 1346 名 UNCOVER-3 试验患者接受安慰剂（安慰剂组）、160mg 起始剂量后每 2 周 80mg 的 ixekizumab（2 周给药组）或 160mg 起始剂量后每 4 周 80mg 的 ixekizumab（4 周给药组）皮下注射。UNCOVER-2 和 UNCOVER-3 试验中的额外队列被随机分配接受每周两次 50mg 的依那西普。在 UNCOVER-3 试验的第 12 周，患者进入长期扩展期，在此期间他们接受每 4 周 80mg 的 ixekizumab 治疗至第 60 周；在 UNCOVER-1 和 UNCOVER-2 试验的第 12 周，对 ixekizumab 有反应的患者（定义为静态医生整体评估[sPGA]评分为 0[清除]或 1[最小银屑病]）被重新随机分配接受安慰剂、每 4 周 80mg 的 ixekizumab 或每 12 周 80mg 的 ixekizumab 治疗至第 60 周。主要终点是第 12 周时 sPGA 评分为 0 或 1 的患者百分比和从基线到银屑病面积和严重程度指数（PASI 75）减少 75%或更多的患者百分比。

结果

在 UNCOVER-1 试验中，患者对 ixekizumab 的反应优于安慰剂；在 2 周给药组中，81.8%的患者 sPGA 评分为 0 或 1，89.1%的患者 PASI 75 反应；在 4 周给药组中，相应的比例分别为 76.4%和 82.6%；在安慰剂组中，比例分别为 3.2%和 3.9%（所有与安慰剂比较的 ixekizumab 的差异均<0.001）。在 UNCOVER-1 和 UNCOVER-2 试验中，在第 12 周随机重新分配接受每 4 周 80mg 的 ixekizumab、每 12 周 80mg 的 ixekizumab 或安慰剂的患者中，分别有 73.8%、39.0%和 7.0%的患者保持 sPGA 评分为 0 或 1。UNCOVER-3 试验中的患者接受 ixekizumab 的连续治疗，从第 0 周到第 60 周，至少有 73%的患者 sPGA 评分为 0 或 1，至少有 80%的患者 PASI 75 反应。在使用 ixekizumab 期间报告的不良反应包括中性粒细胞减少症、真菌感染和炎症性肠病。

结论

在三项涉及银屑病患者的 3 期试验中，ixekizumab 的治疗效果持续至 60 周。与任何治疗一样，需要权衡不良反应的风险与益处。ixekizumab 治疗 60 周以上的疗效和安全性尚不清楚。（由礼来公司资助；UNCOVER-1、UNCOVER-2 和 UNCOVER-3 临床试验.gov 编号分别为 NCT01474512、NCT01597245 和 NCT01646177）。