First-in-human study on the pharmacokinetics, safety, and tolerability of single escalating doses and multiple doses of XT1061, a novel core protein allosteric modulator, in healthy Chinese subjects.

Objective: XT1061 is a newly developed oral small-molecule agent designed to promote the assembly of empty capsids devoid of pregenomic RNA, representing a potential therapeutic approach for chronic hepatitis B (CHB). This first-in-human trial aimed to assess the pharmacokinetic profile and tolerability of single ascending doses and multiple doses of XT1061 in healthy Chinese individuals. Methods: The Phase Ia clinical study consisted of two components: a double-blind, randomized, placebo-controlled, single-ascending-dose assessment conducted under fasting conditions across dose levels ranging from 12.5 mg to 600 mg-including a food-effect evaluation at 62.5 mg-followed by a multiple-dose regimen at 250 mg administered under fasting conditions. Results: XT1061 demonstrated good tolerability in healthy Chinese participants, with no notable difference in the incidence of adverse events between the XT1061 and placebo groups. Following administration, the median time to peak concentration ranged from 1.0 to 2.5 h, while the mean elimination half-life varied between 2.864 and 11.478 h. Systemic exposure exhibited an approximately dose-proportional increase. Steady-state concentrations were achieved within approximately 2 days of repeated dosing, with mean accumulation indices ranging from 1.043 to 1.333. Additionally, concomitant food intake reduced the peak plasma concentration by approximately 50%, although it had no significant impact on total systemic exposure, as measured by the area under the curve. Conclusion: These findings indicate that XT1061 possesses a favorable safety profile and predictable pharmacokinetics, providing a solid foundation for advancing into further clinical investigations to evaluate its efficacy and safety in patients with CHB. Clinical Trial Registration: [http://www.chinadrugtrials.org.cn/index.html], identifier [CTR20232071].