司他泊巴特在健康志愿者和成人特应性皮炎受试者中的药代动力学、药效学、安全性及耐受性
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Stapokibart in Healthy Volunteers and Adult Subjects with Atopic Dermatitis.
作者信息
Zhang Libo, Zhang Weilong, Xu Yufeng, Dong Lihou, Sun Yunjuan, Jia Yingmin, Li Zhichuan, Chen Bo, Hou Jie, Zhang Jianzhong
机构信息
Keymed Biosciences (Chengdu) Co., Ltd, Chengdu, 610219, Sichuan, China.
United-Power Pharma Tech Co., Ltd., Beijing, 102206, China.
出版信息
Adv Ther. 2024 Jul;41(7):2953-2965. doi: 10.1007/s12325-024-02887-w. Epub 2024 Jun 4.
INTRODUCTION
Stapokibart, a novel humanized anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits the signaling of IL-4 and IL-13, which are key drivers of type 2 inflammation in atopic dermatitis (AD). This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of stapokibart in a randomized, double-blind, placebo-controlled single ascending dose (SAD) study and a multiple ascending dose (MAD) study.
METHODS
The SAD study enrolled 33 healthy male adults aged 18-65 years at a single center. The MAD study enrolled 39 patients with moderate-to-severe AD aged 18-70 years at seven centers. Enrolled subjects were randomized to subcutaneous (SC) doses of stapokibart (75-600 mg) or placebo. Serum thymus and activation-regulated chemokine (TARC) and total immunoglobulin E (IgE) were measured as PD biomarkers for stapokibart.
RESULTS
Similar PK characteristics were observed in healthy volunteers and subjects with AD after the initial administration. Stapokibart exhibited non-linear pharmacokinetics in both types of subjects. Following single doses, the mean maximum serum concentration (C) ranged from 5.3 to 63.0 μg/mL, median T ranged from 3.0 to 7.0 days, mean terminal half-life (t) ranged from 2.39 to 7.43 days, and mean apparent volume (V/F) ranged from 3.64 to 6.73 L in healthy subjects. The mean AUC accumulation ratio was 2.29 in subjects with AD after three doses of stapokibart 300 mg administered every 2 weeks. The median serum total IgE and TARC levels on day 43 decreased from baseline by 14.9-25.2% and 48.6-77.0%, respectively, among subjects with AD receiving three doses of stapokibart. No subjects developed grade ≥ 3 adverse events (AEs) or serious AEs or discontinued the study because of AEs. The incidence of AEs was similar between stapokibart and placebo groups.
CONCLUSION
Stapokibart showed favorable pharmacokinetics, pharmacodynamics, safety, and tolerability in the SAD and MAD studies. Based on these results, phase II and phase III trials of stapokibart have been performed in subjects with moderate-to-severe AD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT06161090 (29 November, 2023), NCT04893941 (15 May, 2021).
简介
Stapokibart是一种新型人源化抗白细胞介素（IL）-4受体α单克隆抗体，可抑制IL-4和IL-13的信号传导，这两种细胞因子是特应性皮炎（AD）中2型炎症的关键驱动因素。本研究旨在通过一项随机、双盲、安慰剂对照的单剂量递增（SAD）研究和多剂量递增（MAD）研究，评估Stapokibart的安全性、耐受性、药代动力学（PK）和药效学（PD）。
方法
SAD研究在一个中心招募了33名年龄在18至65岁之间的健康成年男性。MAD研究在7个中心招募了39名年龄在18至70岁之间的中重度AD患者。入选的受试者被随机分配接受皮下（SC）剂量的Stapokibart（75 - 600mg）或安慰剂。血清胸腺和活化调节趋化因子（TARC）以及总免疫球蛋白E（IgE）被作为Stapokibart的PD生物标志物进行测量。
结果
首次给药后，在健康志愿者和AD受试者中观察到相似的PK特征。Stapokibart在这两类受试者中均表现出非线性药代动力学。单次给药后，健康受试者的平均最大血清浓度（C）范围为5.3至63.0μg/mL，中位T范围为3.0至7.0天，平均末端半衰期（t）范围为2.39至7.43天，平均表观容积（V/F）范围为3.64至6.73L。在每2周给予300mg Stapokibart三剂的AD受试者中，平均AUC累积比值为2.29。在接受三剂Stapokibart的AD受试者中，第43天的血清总IgE和TARC水平中位数分别较基线下降了14.9 - 25.2%和48.6 - 77.0%。没有受试者发生≥3级不良事件（AE）或严重AE，也没有受试者因AE而停止研究。Stapokibart组和安慰剂组的AE发生率相似。
结论
在SAD和MAD研究中，Stapokibart显示出良好的药代动力学、药效学、安全性和耐受性。基于这些结果，已在中重度AD受试者中开展了Stapokibart的II期和III期试验。
试验注册
ClinicalTrials.gov标识符NCT06161090（2023年11月29日），NCT04893941（2021年5月15日）。
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