Abstract：
Enpatoran is a novel, highly selective, and potent dual toll-like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia-inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno-bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single-center, open-label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non-Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non-Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach.
摘要：
Enpatoran是一部小说,高度选择性,和有效的双重toll样受体（TLR）7和TLR8抑制剂目前正在开发中，用于治疗包括系统性红斑狼疮（SLE）在内的自身免疫性疾病，皮肤红斑狼疮（CLE），和肌炎。正在进行的II期研究（WILLOW;NCT05162586）正在对活动性SLE或CLE患者进行24周的评估，目前正在招募。根据国际协调会议E5和E17原则，支持WILLOW作为亚洲包容性多区域临床试验（MRCT）的发展。我们根据临床药代动力学（PK）评估了种族对enpatoran的敏感性，药效学（PD），和来自民族桥接研究的安全性数据(NCT04880213)，辅以相关定量PK，PD,和疾病轨迹建模(DTM)结果，和药物代谢/疾病知识。单中心,开放标签，按体重匹配的白人和日本受试者的顺序剂量组研究，高度,和性别证明了亚洲人与亚洲人的PK和PD特性相当非亚裔（白人和其他）受试者的单次100、200和300mg口服给药剂量。DTM表明亚洲人与亚洲人的SLE疾病轨迹没有显着差异。非亚洲人。醛氧化酶（AOX）被认为是一个关键的贡献者，以enpatoran代谢，根据AOX代谢的市售药物的体外和临床PK数据，文献综述表明AOX功能没有相关的种族差异，支持居民种族敏感性低的结论。一起来看,包括WILLOW在内的MRCTs中纳入亚裔患者的情况是基于证据Totality方法.
