阿昔替尼治疗 3802 例中度至重度特应性皮炎患者的综合安全性更新：来自 5200 多名患者长达 4 年暴露期的数据。

IF 8.6 1区医学 Q1 DERMATOLOGY

American Journal of Clinical Dermatology Pub Date : 2024-06-18 DOI:10.1007/s40257-024-00869-w

Eric L. Simpson, Jonathan I. Silverberg, Audrey Nosbaum, Kevin Winthrop, Emma Guttman-Yassky, Karin M. Hoffmeister, Alexander Egeberg, Hernan Valdez, Haiyun Fan, Saleem A. Farooqui, Gary Chan, Justine Alderfer, William Romero, Kanti Chittuluru

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Farooqui, Gary Chan, Justine Alderfer, William Romero, Kanti Chittuluru","doi":"10.1007/s40257-024-00869-w","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile.</p><h3>Objective</h3><p>We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program.</p><h3>Methods</h3><p>Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed.</p><h3>Results</h3><p>Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 10<sup>3</sup>/mm<sup>3</sup> before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7‒25.4] vs 6.7 [5.8‒7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6‒6.0] vs 0.1 [0.0‒0.4]), non-melanoma skin cancer (2.4 [0.6‒6.1] vs 0.2 [0.1‒0.4]), lymphopenia (3.5 [1.3‒7.6] vs 0.1 [0.0‒0.3]), and venous thromboembolism (1.7 [0.4‒5.1] vs 0.1 [0.0‒0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4‒1.6]) vs never-smokers (0.0 [0.0‒0.1]).</p><h3>Conclusions</h3><p>This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.]</p><h3>Clinical Trial Registration</h3><p>NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. 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引用次数: 0

摘要

背景：阿昔替尼是一种口服、每日一次的 Janus 激酶 1 选择性抑制剂，对中重度特应性皮炎疗效显著，且长期安全性可控：阿罗西替尼是一种口服、每日一次的 Janus 激酶 1 选择性抑制剂，对中重度特应性皮炎疗效显著，且具有可控的长期安全性：我们的目的是根据JADE临床开发项目中对中重度特应性皮炎患者最长近4年的现有数据，提供阿罗西替尼最新的长期安全性综合结果：分析包括3802例患者（暴露：5213.9患者年），这些患者来自II期单药研究（NCT02780167）和III期研究JADE MONO-1（NCT03349060）、JADE MONO-2（NCT03575871）、JADE TEEN（NCT03796676）、JADE COMPARE（NCT03720470）、JADE DARE（NCT04345367；仅 200 毫克）、JADE REGIMEN（NCT03627767）和 JADE EXTEND（NCT03422822；数据截止日期 2021 年 9 月 25 日）。接受一种或多种剂量阿罗西替尼200毫克或100毫克治疗的患者的数据被汇集到一致剂量队列（患者在合格的母研究和/或长期研究中被分配接受相同剂量的阿罗西替尼治疗）或可变剂量队列（患者接受开放标签阿罗西替尼200毫克治疗；应答者被随机分配到阿罗西替尼200毫克、100毫克或安慰剂，然后可接受阿罗西替尼200毫克加局部皮质类固醇治疗）。对特别关注的不良事件发生率进行了评估。对带状疱疹和严重感染的风险因素进行了Cox回归分析：总体而言，这项对阿罗西替尼暴露时间最长达 4 年的长期数据进行的安全性分析表明，与之前报告的风险概况相比没有发生任何变化。使用一致剂量的阿罗西替尼 200 毫克和 100 毫克时，最常见的严重感染（根据《监管活动医学字典》首选术语）是带状疱疹（0.5% 和 0.2%）、肺炎（两种剂量均为 0.2%）和单纯疱疹（两种剂量均为 0.1%）。带状疱疹的风险因素包括带状疱疹病史、阿昔替尼 200 毫克剂量、年龄≥ 65 岁、发病前绝对淋巴细胞计数为 3/mm3，以及居住在亚洲。对于严重感染，体重大于 100 千克是一个风险因素。老年患者（年龄≥65岁）与年轻患者（年龄在18岁至60岁之间）相比，使用阿罗西替尼200毫克和100毫克一致剂量的发病率/100患者年（95%置信区间）更高：本次安全性更新显示，阿罗西替尼的安全性表现一致，没有出现新的安全性信号，并继续证明阿罗西替尼在中重度特应性皮炎患者中具有可控的长期安全性。特定不良事件的风险在某些患者人群中较高，尤其是年龄≥65岁的患者。[临床试验注册：NCT02780167；研究开始日期：2016 年 4 月；主要完成日期：2017 年 3 月；研究完成日期：2017 年 4 月。NCT03349060；研究开始日期：2017 年 12 月 7 日；研究完成日期：2019 年 3 月 26 日。NCT03575871；研究开始日期：2018 年 6 月 29 日；研究完成日期：2019 年 8 月 13 日。NCT03720470；研究开始日期：2018 年 10 月 29 日；主要完成日期：2019 年 12 月 27 日；研究完成日期：2020 年 3 月 6 日。NCT03796676；研究开始日期：2019 年 2 月 18 日；研究完成日期：2020 年 4 月 8 日。NCT03627767；研究开始日期：2018 年 6 月 11 日；主要完成日期：2020 年 9 月 2 日；研究完成日期：2020 年 10 月 7 日。NCT04345367；研究开始日期：2020 年 6 月 11 日；主要完成日期：2020 年 12 月 16 日；研究完成日期：2021 年 7 月 13 日。NCT03422822；研究开始日期：2018 年 3 月 8 日；研究完成日期：进行中（预计完成日期：2026 年 1 月 31 日）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Integrated Safety Update of Abrocitinib in 3802 Patients with Moderate-to-Severe Atopic Dermatitis: Data from More than 5200 Patient-Years with Up to 4 Years of Exposure

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Integrated Safety Update of Abrocitinib in 3802 Patients with Moderate-to-Severe Atopic Dermatitis: Data from More than 5200 Patient-Years with Up to 4 Years of Exposure

Background

Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile.

Objective

We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program.

Methods

Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed.

Results

Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 10³/mm³ before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7‒25.4] vs 6.7 [5.8‒7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6‒6.0] vs 0.1 [0.0‒0.4]), non-melanoma skin cancer (2.4 [0.6‒6.1] vs 0.2 [0.1‒0.4]), lymphopenia (3.5 [1.3‒7.6] vs 0.1 [0.0‒0.3]), and venous thromboembolism (1.7 [0.4‒5.1] vs 0.1 [0.0‒0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4‒1.6]) vs never-smokers (0.0 [0.0‒0.1]).

Conclusions

This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.]

Clinical Trial Registration

NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. NCT03422822; study start date: 8 March, 2018; study completion date: ongoing (estimated completion date: 31 January, 2026).

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来源期刊

American Journal of Clinical Dermatology 医学-皮肤病学

CiteScore

15.20

自引率

2.70%

发文量

审稿时长

>12 weeks

期刊介绍： The American Journal of Clinical Dermatology is dedicated to evidence-based therapy and effective patient management in dermatology. It publishes critical review articles and clinically focused original research covering comprehensive aspects of dermatological conditions. The journal enhances visibility and educational value through features like Key Points summaries, plain language summaries, and various digital elements, ensuring accessibility and depth for a diverse readership.