中国健康志愿者中Toll样受体7（TLR 7）激动剂（RO7020531）的单

StephenW

Clin Transl Sci. 2020 Apr 8. doi: 10.1111/cts.12791. [Epub ahead of print]
A Single and Multiple Ascending Dose Study of Toll-Like Receptor 7 (TLR 7) Agonist (RO7020531) in Chinese Healthy Volunteers.
Luk A1, Jiang Q2, Glavini K3, Triyatni M3, Zhao N4, Racek T3, Zhu Y2, Grippo JF5.
Author information

1
    Phase 1, Clinical Trial Centre, The Chinese University of Hong Kong, Hong Kong SAR, China.
2
    Roche Innovation Center Shanghai, Shanghai, China.
3
    Roche Innovation Center, Basel, Switzerland.
4
    Roche Pharma Development Shanghai, Shanghai, China.
5
    Roche Innovation Center New York, New York, US.

Abstract

TLR7 agonists modulate broad spectrum immune activity and are evaluated in the treatment of human diseases including cancer and chronic viral infection. RO7020531, an oral prodrug of a TLR7 agonist, is in clinical development as part of a curative regimen against chronic hepatitis B. We report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO7020531 in Chinese healthy volunteers following single and multiple ascending doses (SAD & MAD). PK and PD samples were evaluated from four SAD cohorts and three MAD cohorts with 10 subjects each (8 active, 2 placebo). Safety and tolerability were monitored throughout the study. A total of 155 adverse events (AEs) were reported in 49 subjects. Fifty-one AEs in 18 subjects were assessed as treatment-related. Most of the AEs were mild; nine subjects experienced moderate AEs; there were no severe AEs. In two 150 mg MAD cohorts given every other day (QOD), 7 out of 20 subjects experienced pyrexia and were discontinued due to transient asymptomatic lymphopenia, which resolved 24-48 hours post-dose. The PK of the active metabolite, RO7011785, increased linearly with dose from 40mg to 170mg. There was no PK accumulation following QOD dosing. The PK profile is consistent with observations in white subjects in the global first-in-human study. Single and multiple doses of RO7020531 resulted in dose-dependent increases in TLR7 response markers at 100mg or above. Flu-like symptoms were associated with higher interferon-α levels. RO7020531 was safe and acceptably tolerated in Chinese healthy volunteers with a multiple 150 mg QOD dose regimen.

This article is protected by copyright. All rights reserved.
KEYWORDS:

China Phase I; Pharmacodynamics; Pharmacokinetics; Toll-like receptor 7 (TLR7)-specific agonist

PMID:
    32268000
DOI:
    10.1111/cts.12791

StephenW

临床翻译科学。 2020年4月8日。doi：10.1111 / cts.12791。 [Epub提前发行]
中国健康志愿者中Toll样受体7（TLR 7）激动剂（RO7020531）的单次和多次剂量研究。
陆克A1，姜Q2，格拉维尼K3，特里亚特尼M3，赵N4，赛克T3，朱Y2，格里波JF5。
作者信息

1个
    中国香港特别行政区香港中文大学临床试验中心第一阶段。
2
    上海罗氏创新中心，中国上海。
3
    瑞士巴塞尔罗氏创新中心。
4
    上海罗氏制药发展有限公司，中国上海。
5
    美国纽约罗氏创新中心，纽约。

抽象

TLR7激动剂可调节广谱免疫活性，并已在包括癌症和慢性病毒感染在内的人类疾病的治疗中进行了评估。作为针对慢性乙型肝炎的治疗方案的一部分，RO7020531是一种TLR7激动剂的口服药物，目前正在临床开发中。我们报告了RO7020531在单次和连续服用后在中国健康志愿者中的安全性，耐受性，药代动力学（PK）和药效学（PD）。多次上升剂量（SAD和MAD）。评估了来自四个SAD队列和三个MAD队列的PK和PD样本，每个队列有10名受试者（8名活跃患者，2名安慰剂）。在整个研究过程中对安全性和耐受性进行了监测。在49位受试者中，总共报告了155次不良事件（AE）。 18位受试者中的51位AE被评估为与治疗相关。大部分不良事件为轻度。 9名受试者经历了中度不良事件；没有严重的不良事件。每隔两天（QOD）进行两次150 mg MAD队列研究，每20名受试者中有7名出现发热，由于短暂的无症状淋巴细胞减少而停药，服药后24-48小时消失。活性代谢产物RO7011785的PK随剂量从40mg线性增加至170mg。 QOD给药后没有PK累积。 PK曲线与全球首次人类研究中白人受试者的观察结果一致。单剂和多剂RO7020531导致100mg或更高剂量的TLR7反应标记物剂量依赖性增加。流感样症状与较高的干扰素-α水平相关。 RO7020531在中国健康志愿者中采用150 mg QOD多次给药方案是安全的并且可以接受。

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关键字：

中国第一阶段；药效学；药代动力学； Toll样受体7（TLR7）特异性激动剂

PMID：
    32268000
DOI：
    10.1111 / cts.12791

StephenW

https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.12791