Tocilizumab plus prednisolone was twice as effective as placebo plus prednisolone at inducing complete remission in patients with giant cell arteritis (GCA), and four times as effective at producing relapse-free survival in a small, phase 2, randomized, double-blind, placebo-controlled trial. Patients in the tocilizumab group also were able to stop glucocorticoids 12 weeks sooner than those in the control group, researchers report in an article published online March 4 in the Lancet.
The Roche-funded single-center study was the first published randomized controlled trial of tocilizumab in patients with GCA, note Peter M. Villiger, MD, and colleagues at the University of Bern, Switzerland. Tocilizumab is a humanized monoclonal antibody against the interleukin 6 receptor and is approved for the treatment of moderate to severe rheumatoid arthritis in adults and for the treatment of juvenile idiopathic arthritis.
The researchers randomly assigned 30 patients who met the 1990 American College of Rheumatology GCA criteria to intravenous treatment with either tocilizumab (20 patients; 8 mg/kg) or placebo (10 patients), given every 4 weeks for 52 weeks. Patients in both groups received oral prednisolone, starting at 1 mg/kg/day and tapering to 0 mg.
The primary study outcome was complete remission of GCA signs and symptoms at a prednisolone dose of 0.1 mg/kg/day at week 12, with normal erythrocyte sedimentation rate and C-reactive protein. Secondary endpoints included relapse-free survival at week 52, time to first relapse, and cumulative prednisolone dose. The study was powered to detect a risk difference of 60%.
At week 12, the researchers observed complete remissions in 17 (85%) tocilizumab patients vs four (40%) placebo patients (risk difference 45%; P = .0301). At week 52, relapse-free survival was observed in 17 (85%) tocilizumab patients vs two (20%) placebo patients (risk difference, 65%; P = .0010).
One goal of the study was to provide a safer alternative to the long-term glucocorticoids currently used to reduce the risk for vascular complications associated with GCA. To that end, the researchers reduced prednisolone rapidly and according to body weight, starting at 1 mg/kg/day and tapered by 0.1 mg/kg/day until week 8, then by 0.05 mg/kg each week to 0.1 mg/kg by week 12, and then dropping by 1 mg/day each month until reaching 0 mg. Minor relapses were treated by increasing the previous prednisolone dose by 10 mg/day for 2 weeks and then tapering. Major relapses were treated by repeating glucocorticoid induction.
The authors write, "Glucocorticoids could be rapidly tapered and discontinued by 36 weeks after the initiation of tocilizumab treatment. As a consequence, the cumulative prednisolone doses were reduced." The mean time to stopping prednisolone was 38 weeks in the tocilizumab group vs 50 weeks in the placebo group, for cumulative steroid doses of 43 mg/kg vs 110 mg/kg (P = .0005).
There were serious adverse events in seven (35%) tocilizumab patients vs five (50%) placebo patients. These were mainly gastrointestinal events in the tocilizumab group and cardiovascular and metabolic complications in the placebo patients.
Eric Matteson, MD, who is chair of the Division of Rheumatology at the Mayo Clinic, Rochester, Minnesota, and was not involved in the study, told Medscape Medical News, "This study gives very encouraging results about tocilizumab as steroid-sparing therapy for GCA. It does provide promising information for a phase 3 study. A phase 3 study is currently underway, called the GiACTA study. The last patient will complete follow-up in early April, and thereafter we should be learning results." The GiACTA study, sponsored by Hoffman LaRoche, includes 250 patients.
Other biologicals in either planned or ongoing early clinical studies in GCA include abatacept, ustekinumab, sirukumab, and gevokizumab. A trial of infliximab in GCA was terminated early because of a lack of efficacy. Dr Matteson said that results from an abatacept study reported at the 2015 American College of Rheumatology meeting suggest that the drug, which prevents T-cell activation by binding to CD80 and CD86, does appear to have efficacy in reducing GCA relapse rate and steroid burden. "It is a smaller study than the GiACTA trial, and it is uncertain where abatacept will fit in as a potential steroid-sparing agent for treatment of GCA," Dr Matteson said.
Dr Matteson added, "Currently, it appears to me that anti-interleukin 6 agents hold the most immediate promise as potential steroid-sparing agents."
Meanwhile, several of the biologicals being studied for GCA are already on the market for other conditions, mainly rheumatoid arthritis, but methotrexate is the only conventional alternative to glucocorticoids.
Dr Matteson cautioned, "Until we see the results from the GiACTA study, methotrexate is the only other agent which may have some modest benefit for management of GCA, but the effects are quite small, and I don't prescribe methotrexate very often for GCA. I think the study data will tell us which patients (new patients, and/or relapsing patients) are the best candidates for a biologic agent. What is clear is that virtually all patients with GCA suffer steroid-related side effects, and that additional treatments are very much needed."
The study was funded by Roche and the University of Bern. The authors and Dr Matteson have disclosed no relevant financial relationships.
Lancet. Published online March 4, 2016. Abstract
Tocilizumab
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