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Keywords:

  • first-in-human study;
  • interleukin-6;
  • monoclonal antibody;
  • pharmacokinetics;
  • sirukumab

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Interleukin (IL)-6 is a cytokine known for pleiotropic and pro-inflammatory functions. IL-6 is involved in various disease processes including lupus erythematosus, rheumatoid arthritis, insulin resistance and malignancy.

• Anti-IL-6 receptor therapy has recently been demonstrated to be effective in the treatment of patients with rheumatoid arthritis.

WHAT THIS STUDY ADDS

• Sirukumab, a human monoclonal antibody against soluble IL-6, has been found to bind to human IL-6 with high affinity and specificity and thus suppress the biological activity of IL-6. Preclinical studies have demonstrated the safety of sirukumab in cynomolgus monkeys, a toxicologically relevant animal species, following repeated intravenous and subcutaneous administrations.

• This study shows that sirukumab has desirable pharmacokinetic characteristics (linear pharmacokinetics with long half-life), a low incidence of immunogenicity and a well-tolerated safety profile in healthy subjects, supporting further development of sirukumab as a potentially valuable therapeutic agent.

AIMS To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects.

METHODS Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg−1 in a dose-escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab.

RESULTS Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both Cmax and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V1), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V2) were 0.364 l day−1, 3.28 l, 0.588 l day−1 and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose–response relationship was observed. No subjects were positive for antibodies to sirukumab.

CONCLUSIONS Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg−1 in healthy subjects.