Pharmacokinetics, pharmacodynamics and tolerability of HL2351, a hybrid Fc-fused human Interleukin-1 receptor antagonist, in healthy subjects

抄録

Background

HL2351 is a novel recombinant protein formed by the fusion of hIL-1Ra into an antibody derived Fc developed to treat autoimmune or autoinflammatory diseases including rheumatoid arthritis and cryopyrin-associated periodic syndromes. This study aimed to evaluate the tolerability, pharmacokinetics, pharmacodynamics of HL2351 after a single subcutaneous (SC) administration for the first time in humans.

Methods

A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted in healthy subjects, who randomly received a single SC administration of HL2351 or its matching placebo in a ratio of 8:2 at 1, 2, 4, 8 and 12 mg/kg. All subjects in active-controlled group received a single SC administration of anakinra at 100 mg. Serial serum samples were collected up to 672 hours post-dose for pharmacokinetic analysis of HL2351. Anti-HL2351 antibodies were determined before and 29 days after HL2351 treatment. Furthermore, serial peripheral blood mononuclear cell samples were collected and treated with IL-1ß to express IL-6, inhibition of which was the pharmacodynamic marker. Tolerability was assessed throughout the study based on physical examination, clinical laboratory and serum cytokine (IL-6, IL-8, C3, TNF-α and IFN-γ) tests.

Results

A total of 58 subjects were enrolled and completed the study. After a single SC administration of HL2351, the maximum plasma concentration was observed 24 to 72 hours post-dose and HL2351 was eliminated following a monoexponential behavior with a much longer half-life than anakinra (27.21-45.28 vs. 3.97 hour). Serum concentration of HL2351 increased dose-proportionally. Anti-HL2351 antibodies were not detected in any subject treated with HL2351. The inhibition of IL-6 expression widely varied, showing no clear trend before and after HL2351, placebo, anakinra. Neither serious adverse events nor clinically significant changes in tolerability parameters were noted.

Conclusion

Single SC administration of HL2351 was well tolerated and showed linear pharmacokinetic characteristics at doses up to 12 mg/kg in healthy subjects. The terminal half-life HL2351 was >9 times greater than that of anakinra. HL2351 can be further developed as a useful treatment option for patients with autoimmune or autoinflammatory diseases.