Dr. McBride, Ms Jiang, and Drs. Abbas, Morimoto, Li, Maciuca, Townsend, and Kennedy may own stock or stock options in F. Hoffmann-La Roche Ltd., the parent company of Genentech, Inc., as part of their general employment compensation.
Systemic Lupus Erythematosus
Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I, placebo-controlled, double-blind, dose-escalation study†
Article first published online: 27 OCT 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 11, pages 3666–3676, November 2012
How to Cite
McBride, J. M., Jiang, J., Abbas, A. R., Morimoto, A., Li, J., Maciuca, R., Townsend, M., Wallace, D. J., Kennedy, W. P. and Drappa, J. (2012), Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I, placebo-controlled, double-blind, dose-escalation study. Arthritis & Rheumatism, 64: 3666–3676. doi: 10.1002/art.34632
ClinicalTrials.gov identifier: NCT00541749.
- Issue published online: 27 OCT 2012
- Article first published online: 27 OCT 2012
- Accepted manuscript online: 25 JUL 2012 09:55AM EST
- Manuscript Accepted: 10 JUL 2012
- Manuscript Received: 17 MAR 2011
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 IFNα, 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, IFN-inducible proteins, and autoantibodies.
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.
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.
The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.