Asia-Inclusive Global Development of Enpatoran: Results of an Ethno-Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial.

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.