Systemic Lupus Erythematosus
Abstract 500: Tocilizumab (Humanized Anti IL-6 Receptor Monoclonal Antibody) In Patients With Systemic Lupus Erythematosus (SLE): Safety, Tolerability And Preliminary Efficacy
Authors: Gabor G. Illei1, Cheryl Yarboro2, Yuko Shirota3, Edward Tackey2, Larissa Lapteva3, Thomas Fleisher4, James Balow5, Peter Lipsky2. 1NIDCR, NIH, Bethesda, MD; 2NIAMS, Bethesda, MD; 3NIDCR, Bethesda, MD; 4CC, Bethesda, MD; 5NIDDK, Bethesda, MD
Background: What cytokine(s) should be targeted in SLE? In rheumatoid arthritis, biologics targeting IL-6 are on track to obtain FDA approval. Multiple cytokines, including interferon, TNFalpha, IL-10 and IL-6 play a role in the inflammation that characterizes SLE. IL-6 has multiple actions on the immune system, augmenting both B and T cell function. Blocking IL-6 has had benefit in murine lupus. This Phase I clinical trial studied an anti-IL-6 receptor monoclonal antibody.
Methods: A humanized anti-IL-6 receptor monoclonal antibody, toclizumab, was studied in an early dose-finding trial of 3 doses (infusions every 2 weeks for 12 weeks), followed by 8 weeks of observation. Sixteen SLE patients were enrolled and 15 completed treatment.
Results: The dose of prednisone varied from 0 to 15 mg/day. There was biologic effect, with a decrease in acute phase reactants, and a decrease in immunoglobulin and anti-dsDNA. Paradoxically, complement levels decreased. Swollen joint counts decreased. SLEDAI and SLAM scores decreased.
However, there were significant safety issues, including bacterial infection in 2, herpes zoster keratitis in one, and Grade 3 neutropenia in 2 patients.
Conclusions: Anti-IL-6 had both biologic and clinical efficacy in a dose finding study in 15 SLE patients.
Editorial Comment: Early phase I biologic trials need to establish an effective, but safe, dose and the best dosing regimen. This trial is both very positive, in terms of finding both clinical efficacy (consistently, given that 2 disease activity scales, SLEDAI and SLAM improved) and biologic effect (decrease in immunoglobulin and anti-dsDNA) but also raises safety concerns, in that there were bacterial infections, zoster and Grade 3 neutropenia – in a sample size of 15!
Complement levels decreased, but this is not necessarily “bad news”. Many SLE patients have high complement levels, because complement is an acute phase reactant. Thus, the decrease in complement is consistent with the decrease in other acute phase reactants seen in this trial.
This phase I trial will hopefully be followed by Phase II trials that might identify whether the infections and neutropenia seen exceed that which would be tolerable in sick SLE patients in need of biologic treatment.