Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study.

Objective. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)–regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFN, were assessed in a phase I dose-escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFNinducible proteins, and autoantibodies. Methods. Patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN-inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab. Results. An acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose-limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN-inducible proteins or levels of anti–double-stranded DNA and anti– extractable nuclear antigen autoantibodies following treatment with rontalizumab. Conclusion. The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.