当抗TNFα制剂失效后，还有其他方案治疗克罗恩病吗？

来源：医学界消化频道

翻译及述评：上海交通大学医学院附属瑞金医院消化科  顾于蓓  孙培君

应用Ustekinumab对克罗恩病患者进行静脉注射诱导缓解治疗和皮下注射维持缓解治疗中药代动力学和应答效应的关系研究：UNITI-1、UNITI-2和IM-UNITI临床试验研究结果

背景：阐明针对CD患者的UNITI-1、UNITI-2 静脉注射诱导缓解研究和IM-UNITI维持缓解研究中Ustekinumab（UST）的药代动力学和应答反应结果。

方法：从上述三项III期双盲对照研究中获得中重度CD患者的药代动力学、有效性和安全性数据。在前两项诱导缓解研究中：UNITI-1研究纳入了741例抗TNF制剂治疗失败的患者，UNITI-2研究纳入了628例传统治疗疗效欠佳的患者（包括未使用过抗TNF制剂的患者）。在其后的IM-UNITI维持缓解研究中纳入的受试者均为完成UNITI-1和UNITI-2研究的患者。在诱导研究中受试者均接受一次静脉注射治疗，受试者分为三组：一组是治疗剂量为130 mg的UST静脉注射，另一组治疗剂量根据患者体重来进行分层（约为6 mg/kg,其中体重≤55kg的患者为260 mg UST，体重＞55 kg但≤85 kg的患者为390 mg UST，体重＞85kg的患者为520 mg UST），第三组为安慰剂组。在上述两项研究中产生有效应答的受试者共计397例，这部分患者此后被进一步纳入IM-UNITI皮下注射的维持缓解研究，并被随机分为三组，第一组为每12周接受皮下注射UST 90 mg治疗，第二组为每8周接受UST 90 mg治疗，第三组为接受安慰剂治疗。在所有研究的不同时间点采集受试者的血样标本来检测UST的血清药物浓度和免疫原性。而后通过CDAI和CRP来评估临床疗效，并研究UST的血清药物浓度与疗效之间的相关性。研究还评估了不良事件（诸如感染、严重感染和严重不良反应）的发生率。

结果：UST的血清药物浓度与药物剂量相关，并且在两项诱导缓解研究中受试者的药物浓度未见差异。治疗剂量为130 mg组和 约6 mg/kg组的药物中位峰浓度分别为41.9 ug/ml和126.1 ug/ml。在8周诱导治疗结束后上述两组的药物中位峰浓度分别为2.1 ug/ml和6.4 ug/ml。在维持治疗开始后受试者的血药浓度达到稳定：每8周接受UST 90 mg治疗组的药物中位谷浓度持续稳定在1.97-2.24 ug/ml，该谷浓度较每12周接受UST 90 mg治疗组三倍增高（每12周接受UST 90 mg治疗组药物中位谷浓度为0.61-0.76 ug/ml）。通过药物耐受性分析可得1年内抗UST抗体发生率为2.3%。在诱导缓解与维持缓解研究中发现血清UST浓度与患者的疾病缓解率呈正相关（见图1），并与CRP水平呈负相关。在所有研究中均未发现血清UST浓度与感染率、严重感染率和严重不良反应率相关。

结论：在UNITI-1、UNITI-2 静脉注射诱导缓解研究和IM-UNITI皮下注射维持缓解研究中均提示血清UST药物浓度与疗效呈正相关。在所有研究中均未观察到全身系统性应用UST与感染、严重感染和严重不良反应这些不良事件相关。

图1

述评：自1998年第一个生物制剂（英夫利昔单抗）问世后，生物制剂以其优异的抗炎作用与较小的不良反应几乎在克罗恩病的治疗历史中奠定了里程碑式的意义。然而在近20年的使用过程中，生物制剂继发性失效这一重要问题被逐渐显现：部分患者在使用生物制剂一段时间后，体内开始逐渐出现抗抗体并导致药物疗效欠佳。许多患者与家属都较为担心在应用生物制剂不久后地将来可能面临这样的尴尬情况。目前应对继发性失效的措施主要包括：1.联合应用免疫抑制剂，2.生物制剂的转换治疗（包括同种类型生物制剂相互间转换和不同类型生物制剂间的相互转换）。Ustekinumab（UST）是一种全新类型的生物制剂，其有别于其他抗TNF制剂的生物制剂，UST的治疗靶点为抗Il-12/IL-23的p40亚基，从而抑制下游的炎症信号通路。当2016年美国消化疾病周中公布了UST的III期临床试验研究结果后受到了全球广泛关注，它几乎为抗TNF制剂的继发性失效问题找到了一个强有力的解决方案；同时也增加了克罗恩病患者有效治疗手段的选择。我们热切期待UST投入临床应用，为克罗恩病患者带来福音。

（上海瑞金医院消化内科 顾于蓓 孙培君）

Abstract

Background: PK & exposure-response (ER) data of ustekinumab (UST) from UNITI-1,UNITI-2 IV induction studies; & IM-UNITI maintenance study in Crohn' disease (CD) were evaluated. 

Methods: PK, efficacy & safety data were obtained from three Phase 3, doubleblind, PBO-controlled trials in patients (pts) with moderate-severe CD. These included 2 induction studies which enrolled 741 tumor necrosis factor (TNF) antagonist-failure pts (UNITI-1), 628 TNF conventional therapy-refractory (including TNF antagonist-naïve) pts(UNITI-2), & the subsequent maintenance study (IM-UNITI) which enrolled pts who completed the induction studies. Participants in the induction studies received a single IV induction treatment with UST 130 mg, tiered doses by weight approximating 6 mg/kg UST (~ 6 mg/kg: 260 mg for pts £55 kg, 390 mg for pts >55 kg & £85 kg, & 520 mg for pts >85 kg), or PBO at week 0. UST responders from the IV induction studies comprised the primary study population (n=397) & were randomly assigned to receive SC UST 90 mg q12w, UST 90 mg q8w, or PBO. Blood samples were collected at various time points during these 3 studies for evaluation of serum UST concentrations & immunogenicity. Clinic efficacy outcomes were based on CDAI score. C-reactive protein (CRP) level was also evaluated as an efficacy measure. The relationships between serum UST concentrations & efficacy, as well as incidence of selected safety events including infections, serious infection & serious adverse events (SAE) were evaluated. 

Results: Serum UST concentrations over time were proportional to dose & were similar between UNITI-1 and UNITI-2 pts. Based on pooled data, median peak serum UST concentrations were 41.9 µg/mL & 126.1 µg/mL for the 130 mg & ~6 mg/kg dose groups, respectively. At the end of induction (week 8), median UST concentrations were 2.1 µg/mL & 6.4 µg/mL for these dose groups, respectively. Steadystate was reached by the start of the second SC maintenance dose. Median steady-state trough serum UST concentrations over time in the UST q8w group (1.97 to 2.24 µg/mL) were 3-fold higher than in the q12w group (0.61 to 0.76 µg/mL). The incidence of antibodies to UST through 1 year was 2.3% using a drug-tolerant assay. During induction & maintenance, serum UST concentrations were positively associated with the proportions of pts achieving remission (Figure 1), and inversely related to CRP levels. There was no relationship between serum UST concentrations & the incidence of infections, serious infections or SAEs following induction or maintenance treatment with UST. 

Conclusions: Serum USTconcentrations were dose-proportional & a positive E-R relationship for efficacy was observed  during UST IV induction & SC maintenance treatment of pts with CD. No associations were observed between systemic UST exposure & selected safety events across the nduction &maintenance studies.

作者简介

顾于蓓，医学博士

上海瑞金医院消化内科，主治医师

长期从事难治性炎症性肠病诊治工作

2014年赴CCF进修

现任中国医师协会肛肠分会炎症性肠病组委员

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