First-in-human study on tolerability, pharmacokinetics and pharmacodynamics of single and multiple escalating doses of XKH001, a recombinant humanized monoclonal antibody against IL-25 in healthy Chinese volunteers

BACKGROUND: XKH001 is a recombinant humanized IgG1 monoclonal antibody against IL-25 for the treatment of type 2 inflammatory diseases. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of XKH001 in humans for the first time. RESEARCH DESIGN AND METHODS: This clinical investigation adopted a randomized, double-blind, and placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) design. RESULTS: XKH001 was well tolerated in healthy Chinese subjects. Following repeated administration, XKH001 showed a slow absorption with a median Tmax of 4-7 days and a mean half-life (t1/2) of 22-25 days. The accumulation ratio ranged from 1.34 to 1.99. The exposure was mostly dose proportional, with a mean slope of 0.85-1.06. All subjects tested negative for ADA (except three subjects tested positive). The subjects who received 600 mg XKH001 in the MAD study showed a 78.2 ng/mL decrease in the total immunoglobulin E (IgE) level 85 days after the first administration, while the subjects who received matched placebo exhibited only an 8.6 ng/mL decrease. CONCLUSIONS: XKH001 showed favorable safety and pharmacokinetics profiles and a low immunogenicity in its first-in-human study. The data support its further clinical evaluation in patients with type 2 inflammatory diseases. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov (NCT05991661).