Safety, tolerability, pharmacokinetics, and pharmacodynamics of a single orally administered dose of enpatoran in a phase i study of healthy japanese and caucasian participants

BackgroundEnpatoran, a novel, highly selective and potent dual toll-like receptor (TLR) 7 and TLR8 inhibitor, is in development for the treatment of autoimmune disorders including systemic and cutaneous lupus erythematosus. A first-in-human study in healthy participants has shown that enpatoran is well-tolerated and has a linear pharmacokinetic (PK) profile.ObjectivesTo compare the PK parameters, safety, and tolerability of single ascending oral doses of enpatoran in a Phase I study in Japanese and Caucasian participants, and to explore a potential PK/pharmacodynamic (PD) relationship.MethodsA single-centre, open-label, sequential dose group study enrolled healthy Japanese and Caucasian participants into three dose cohorts. Each Caucasian participant was matched by body weight (± 20%), height (± 15%) and sex to a Japanese participant. Participants received a single orally administered enpatoran dose of 100 mg, 200 mg, or 300 mg as a film-coated tablet under fasting conditions. PK parameters, (maximum plasma concentration [Cmax]; area under the plasma concentration–time curve (AUC) from time 0 to infinity [AUC0-inf]; AUC from time 0 to the last sampling time [AUC0-tlast]) determined using noncompartmental analysis, were estimated post-dose from Day 1–3. Safety was assessed from Day -1 to 8. PK (exposure) between the two ethnic groups was compared using an analysis of covariance (ANCOVA) model including ethnic group, natural log-transformed dose, and ethnic group by natural log dose interaction. Ex vivo secretion of cytokines (PD) under stimulated (using the TLR7/8 agonist, R848) and unstimulated conditions, was assessed pre- and post-dose. A panel of cytokines was analysed by multiplex immunoassay; IL-6 was considered the primary PD biomarker.ResultsThe study included 36 male participants (18 Japanese and 18 Caucasian) with a mean (± SD) age of 35.1 (± 10.8) years and mean (± SD) body mass index of 23.1 (± 2.1) kg/m2. Each dose group included six Japanese and six Caucasian participants. The geometric mean enpatoran plasma exposure parameters (Cmax, AUC0-inf, and AUC0-tlast) were consistent between the two ethnic groups for each dose level (Table 1) and indicated dose proportionality. ANCOVA modeling demonstrated comparable exposure between the two groups (geometric least square mean ratio [Japanese/Caucasian;90% CI] of Cmax: 0.9409 [0.7855–1.1270]; AUC0-inf: 0.8959 [0.7497–1.0704] and AUC0-tlast: 0.8963 [0.7511–1.0695]). Treatment-emergent adverse events (TEAEs) were observed in six Japanese (n = 0, 100 mg; n = 3, 200 mg; n = 3, 300 mg) and four Caucasian (n = 1, 100 mg; n = 0, 200 mg; n = 3, 300 mg) participants. There we no serious TEAEs; most were mild and not dose dependent. Treatment-related TEAEs were mild diarrhoea, mild flatulence, and moderate headache. There were no deaths, withdrawals, or early terminations due to TEAEs. Administering enpatoran effectively reduced ex vivo stimulated cytokine release, with maximal inhibition observed at 2 hours post-dose (IL-6: mean ≥99%). High inhibition levels were sustained through 24 hours in a dose-dependent manner (IL-6: mean ~76–97%). The pattern of cytokine release inhibition was consistent across doses and ethnic groups.Table 1.PK parameters in Japanese and Caucasian participants at the three enpatoran dose levelsParameter100 mg200 mg300 mgJapaneseCaucasianJapaneseCaucasianJapaneseCaucasianN = 6N = 6N = 6N = 6N = 6N = 6Cmax139175260245486490(ng/mL)AUC0-inf7749481910185028403330(h*ng/mL)AUC0-tlast7589311880183028103270(h*ng/mL)All values are Geometric mean.Cmax, maximum plasma concentration AUC0-inf, area under the plasma concentration–time curve (AUC) from time 0 to infinity; AUC0-tlast, AUC from time 0 to the last sampling time.ConclusionThere were no relevant ethnic differences in PK, PD, and safety between healthy Japanese and Caucasian participants across a range of single oral enpatoran doses, thus supporting the inclusion of Asian participants in future global Phase II studies.AcknowledgementsWe would like to thank those who took part in the study. This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), who funded medical writing support by Bioscript Stirling Ltd.Disclosure of InterestsSathej Gopalakrishnan Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Axel Krebs-Brown Employee of: Merck Healthcare KGaA, Marco Nogueira Filho Employee of: Merck Healthcare KGaA, Yoshihiro Kuroki Employee of: Merck Biopharma Co., Ltd., Angelika Bachmann Employee of: Merck Healthcare KGaA, Andreas Becker Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Frank Schippers Employee of: Merck Healthcare KGaA, Markus Fluck Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Özkan Yalkinoglu Employee of: Merck Healthcare KGaA, Lena Klopp-Schulze Employee of: Merck Healthcare KGaA