Abstract：
BACKGROUND: 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 (Cmax) ranged from 5.3 to 63.0 μg/mL, median Tmax ranged from 3.0 to 7.0 days, mean terminal half-life (t1/2z) ranged from 2.39 to 7.43 days, and mean apparent volume (Vz/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.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov Identifier NCT06161090 (29 November, 2023), NCT04893941 (15 May, 2021).
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 (Cmax) ranged from 5.3 to 63.0 μg/mL, median Tmax ranged from 3.0 to 7.0 days, mean terminal half-life (t1/2z) ranged from 2.39 to 7.43 days, and mean apparent volume (Vz/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.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov Identifier NCT06161090 (29 November, 2023), NCT04893941 (15 May, 2021).
摘要：
背景：Stapokibart,一种新型人源化抗白细胞介素（IL）-4受体α单克隆抗体，抑制IL-4和IL-13的信号传导，这是特应性皮炎（AD）2型炎症的关键驱动因素。本研究旨在评估安全性，耐受性,药代动力学（PK），和Stapokibart的药效学（PD）在一个随机的，双盲,安慰剂对照单次递增剂量（SAD）研究和多次递增剂量（MAD）研究。
方法：SAD研究在一个中心招募了33名年龄在18-65岁的健康男性成年人。MAD研究在七个中心招募了39名年龄在18-70岁的中度至重度AD患者。登记的受试者被随机分配到皮下(SC)剂量的stapokibart(75-600mg)或安慰剂。测定血清胸腺和活化调节趋化因子(TARC)和总免疫球蛋白E(IgE)作为stapokibart的PD生物标志物。
结果:在初次给药后,在健康志愿者和患有AD的受试者中观察到类似的PK特征。Stapokibart在两种类型的受试者中均表现出非线性药代动力学。单剂量后,平均最大血清浓度（Cmax）范围为5.3至63.0μg/mL，Tmax中位数为3.0至7.0天，平均终末半衰期（t1/2z）范围为2.39至7.43天，健康受试者的平均表观体积（Vz/F）为3.64至6.73L。在每2周施用三个剂量的300mg的stapokibart之后,患有AD的受试者的平均AUC累积比为2.29。第43天的中位血清总IgE和TARC水平从基线下降14.9-25.2％和48.6-77.0％，分别,在接受三剂stapokibart的AD受试者中。无受试者出现≥3级不良事件(AE)或严重AE或因AE而终止研究。Stapokibart组和安慰剂组之间的AE的发生率相似。
结论：Stapokibart显示良好的药代动力学，药效学,安全,SAD和MAD研究中的耐受性。基于这些结果,已经在中重度AD患者中进行了stapokibart的II期和III期试验.
背景：ClinicalTrials.gov标识符NCT06161090（11月29日，2023),NCT04893941(5月15日，2021)。
方法：SAD研究在一个中心招募了33名年龄在18-65岁的健康男性成年人。MAD研究在七个中心招募了39名年龄在18-70岁的中度至重度AD患者。登记的受试者被随机分配到皮下(SC)剂量的stapokibart(75-600mg)或安慰剂。测定血清胸腺和活化调节趋化因子(TARC)和总免疫球蛋白E(IgE)作为stapokibart的PD生物标志物。
结果:在初次给药后,在健康志愿者和患有AD的受试者中观察到类似的PK特征。Stapokibart在两种类型的受试者中均表现出非线性药代动力学。单剂量后,平均最大血清浓度（Cmax）范围为5.3至63.0μg/mL，Tmax中位数为3.0至7.0天，平均终末半衰期（t1/2z）范围为2.39至7.43天，健康受试者的平均表观体积（Vz/F）为3.64至6.73L。在每2周施用三个剂量的300mg的stapokibart之后,患有AD的受试者的平均AUC累积比为2.29。第43天的中位血清总IgE和TARC水平从基线下降14.9-25.2％和48.6-77.0％，分别,在接受三剂stapokibart的AD受试者中。无受试者出现≥3级不良事件(AE)或严重AE或因AE而终止研究。Stapokibart组和安慰剂组之间的AE的发生率相似。
结论：Stapokibart显示良好的药代动力学，药效学,安全,SAD和MAD研究中的耐受性。基于这些结果,已经在中重度AD患者中进行了stapokibart的II期和III期试验.
背景：ClinicalTrials.gov标识符NCT06161090（11月29日，2023),NCT04893941(5月15日，2021)。
