SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany.
Probity Medical Research, Waterloo, ON, Canada.
Lancet. 2017 Jul 15;390(10091):276-288. doi: 10.1016/S0140-6736(17)31279-5. Epub 2017 Jun 6.
Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis.
We did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing.
reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death.
In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis.
Merck & Co.
替拉珠单抗是一种高亲和力的人源化 IgG1κ 抗体，靶向白细胞介素 23p19，是慢性斑块型银屑病治疗策略的新进展。先前的研究表明，白细胞介素 23p19 的抑制作用可改善临床症状。我们进行了两项 3 期临床试验，以评估替拉珠单抗与安慰剂和依那西普相比，在治疗慢性斑块型银屑病方面是否更具优势。
我们进行了两项三项、平行组、双盲、随机对照研究，即 reSURFACE 1（在澳大利亚、加拿大、日本、英国和美国的 118 个地点进行）和 reSURFACE 2（在欧洲、以色列和美国的 132 个地点进行）。年龄在 18 岁及以上的中重度慢性斑块型银屑病（受累体表面积≥10%，医生总体评估[PGA]评分≥3，银屑病面积和严重程度指数[PASI]评分≥12）患者被随机（通过交互式语音和网络响应系统）分配至替拉珠单抗 200mg、替拉珠单抗 100mg 或安慰剂（2:2:1）组，或替拉珠单抗 200mg、替拉珠单抗 100mg、安慰剂或依那西普 50mg（2:2:1:2）组。通过区域分层，并按体重（≤90kg 或>90kg）和既往生物制剂治疗银屑病的情况进行分层，进行随机分组。研究者、参与者和研究人员对分组情况均不知情，直到研究完成才公开。分配的药物在外观和包装上完全相同。替拉珠单抗在第 1 部分的第 0 周和第 4 周以及第 2 部分的第 16 周进行皮下注射（第 12 周和第 16 周，将安慰剂组中重新分配至替拉珠单抗组的患者纳入治疗）；依那西普在 reSURFACE 2 的第 1 部分每周两次，第 2 部分每周一次。主要终点是第 12 周 PASI75 应答率和 PGA 缓解率（评分较基线降低≥2 级且评分≤0 或 1）。在所有参与者治疗人群中评估安全性，在全分析集评估疗效。这两项试验均在 ClinicalTrials.gov 上注册，编号为 NCT01722331（reSURFACE 1）和 NCT01729754（reSURFACE 2）。这些研究已经完成，但正在进行扩展研究。
reSURFACE 1 于 2012 年 12 月 10 日至 2015 年 10 月 28 日进行，reSURFACE 2 于 2013 年 2 月 12 日至 2015 年 9 月 28 日进行。在 reSURFACE 1 中，772 例患者被随机分配，替拉珠单抗 200mg 组 308 例，替拉珠单抗 100mg 组 309 例，安慰剂组 155 例。在第 12 周，替拉珠单抗 200mg 组 192 例（62%）和替拉珠单抗 100mg 组 197 例（64%）患者达到 PASI75，安慰剂组 9 例（6%）（替拉珠单抗 200mg 和 100mg 组与安慰剂组相比，p<0.0001）。替拉珠单抗 200mg 组 182 例（59%）和替拉珠单抗 100mg 组 179 例（58%）患者达到 PGA 缓解，安慰剂组 11 例（7%）（替拉珠单抗 200mg 和 100mg 组与安慰剂组相比，p<0.0001）。在 reSURFACE 2 中，1090 例患者被随机分配，替拉珠单抗 200mg 组 314 例，替拉珠单抗 100mg 组 307 例，安慰剂组 156 例，依那西普组 313 例。在第 12 周，替拉珠单抗 200mg 组 206 例（66%）和替拉珠单抗 100mg 组 188 例（61%）患者达到 PASI75，安慰剂组 9 例（6%）和依那西普组 151 例（48%）（替拉珠单抗 200mg 和 100mg 组与安慰剂组相比，p<0.0001；替拉珠单抗 200mg 与依那西普相比，p<0.0001，替拉珠单抗 100mg 与依那西普相比，p=0.0010）。替拉珠单抗 200mg 组 186 例（59%）和替拉珠单抗 100mg 组 168 例（59%）[校正后]患者达到 PGA 缓解，安慰剂组 7 例（4%）和依那西普组 149 例（48%）（替拉珠单抗 200mg 和 100mg 组与安慰剂组相比，p<0.0001；替拉珠单抗 200mg 与依那西普相比，p=0.0031，替拉珠单抗 100mg 与依那西普相比，p=0.0663）。在两项试验中，所有组的严重不良事件均相似且发生率较低。reSURFACE 2 中有 1 例患者死亡，发生在替拉珠单抗 100mg 组，患者患有酒精性心肌病和脂肪性肝炎，死因无法确定。
在两项 3 期临床试验中，替拉珠单抗 200mg 和 100mg 与安慰剂和依那西普相比，在治疗中重度慢性斑块型银屑病方面具有疗效，且耐受性良好。
默克公司。
