Sheffield Dermatology Research, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK.
Sheffield Children's Hospital Clinical Research Facility, Sheffield, UK.
Br J Dermatol. 2021 May;184(5):857-870. doi: 10.1111/bjd.19460. Epub 2020 Oct 9.
Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking.
To report the pharmacokinetic profile and long-term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD.
Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose dupilumab 2 or 4 mg kg followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score.
Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg , 61-77 mg L ; 4 mg kg , 143-181 mg L ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg , 47%; 4 mg kg , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively.
These safety and efficacy results support the use of dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.
年龄为 6 岁至<12 岁的重度特应性皮炎（AD）患儿的治疗选择有限。在一项为期 16 周、随机、安慰剂对照、III 期临床试验中，抑制白细胞介素（IL）-4/IL-13 信号的单克隆抗体度普利尤单抗显著改善了患儿的体征和症状，且安全性良好；但缺乏长期安全性和疗效数据。
报告度普利尤单抗在患有重度 AD 的 6 岁至<12 岁儿童中的药代动力学特征以及长期安全性和疗效。
重度 AD 患儿（年龄≥6 岁至<12 岁）参与了一项全球性、多中心、IIa 期、开放标签、递增剂量、序贯队列研究和随后的开放标签扩展（OLE）研究。患儿接受单剂量 2 或 4 mg/kg 的度普利尤单抗治疗，随后进行 8 周的药代动力学采样，然后每周接受 2 或 4 mg/kg 的治疗，持续 4 周（IIa 期），随后采用相同的每周方案（OLE）。主要终点为度普利尤单抗浓度-时间曲线和治疗中出现的不良事件（TEAEs）；次要评估包括湿疹面积和严重程度指数（EASI）和瘙痒峰值数字评定量表（PP-NRS）评分。
38 例患儿中，37 例完成了 IIa 期研究，33 例继续进入 OLE 期。度普利尤单抗浓度的特征是非线性、靶向介导的药代动力学（第 24-48 周的平均血清浓度：2 mg/kg，61-77 mg/L；4 mg/kg，143-181 mg/L）。TEAEs 多为轻至中度和一过性，均未导致治疗中断。最常见的 TEAEs 是鼻咽炎（2 mg/kg，47%；4 mg/kg，56%）和 AD 恶化（分别为 29%和 13%）。单剂量度普利尤单抗可迅速改善 AD，在第 52 周时进一步改善。第 2 周（IIa 期）时，EASI 和 PP-NRS 平均改善了-37%/-33%和-17%/-20%，第 52 周（OLE 期）时，EASI 和 PP-NRS 平均改善了-92%/-84%和-70%/-58%。
这些安全性和疗效结果支持将度普利尤单抗作为一种连续的长期治疗药物，用于治疗 6 岁至<12 岁的重度 AD 患儿。
