Tocilizumab Approved for the Treatment of Systemic Juvenile Idiopathic Arthritis
May 18, 2011
On April 15, 2011, the USA FDA approved tocilizumab (TCZ), with or without concomitant methotrexate (MTX) for the treatment of systemic juvenile idiopathic arthritis.
SJIA, the rarest type of Juvenile Idiopathic Arthritis (JIA), affects only ten percent of children with JIA but accounts for nearly two-thirds of all childhood arthritis mortality. Whether this sub form of JIA is autoimmune or autoinflammatory in nature, specific targeting of inflammatory cytokines is an appealing approach in the management of this disease. TCZ, a humanized monoclonal antibody previously approved for the treatment of rheumatoid arthritis in adults, binds the soluble- and membrane-bound IL-6 receptor, thereby inhibiting the biological effects of IL-6.
The Data
The double-blind, placebo controlled randomized controlled phase III TENDER trial, upon which FDA approval was based, followed one open-label and one placebo-controlled trial in Japan (where the drug originated), as well as an open label single dose trial in Europe.
The first part of this five-year ongoing multinational study examined safety and efficiency of intravenously administered tocilizumab in 112 children with active SJIA for twelve weeks. The primary endpoint of this portion of the study was the proportion of subjects achieving at least JIA ACR30 response plus absence of fever at week 12.
Children aged 2-17 were randomized to receive placebo or tocilizumab at 2 different doses based on body weight. The doses used in this study were based on pK modeling in children in earlier studies, and differed from the typical adult RA dose. TCZ was given IV every 2 weeks at doses of 12 mg/kg for children body weight <30 kg or 8 mg/kg for children body weight ≥30 kg. To be eligible for enrollment, study participants had to have active SJIA for at least six months and demonstrate intolerance or inadequate response to previous treatments. Patients were allowed to continue on stable doses of MTX, non-steroidal anti-inflammatories, or corticosteroids (maximum dose of 0.5 mg/kg/day). A significant portion of the study patients had failed prior anti-TNF and anti-IL-1 therapy. The average age of the study patients was 9.5 years with an average disease duration of 5 years. Most children presented with very active disease, including fevers in approximately half and an average of 19 swollen joints.
At 12 weeks, 85% of the participants receiving tocilizumab met the primary endpoint, compared with 24% percent of children receiving placebo. As a secondary endpoint, 85% and 71% percent of the children in the tocilizumab group achieved JIA ACR50 and 70 responses by week twelve, compared to only 11% and 8% of children who received placebo, respectively.
Safety
The most frequent side effects in the study included upper respiratory infections, headache, nasopharyngitis and diarrhea. The most commonly reported infections included pneumonia, gastroenteritis, chickenpox, and ear infections; these were more frequently seen in tocilizumab treated patients. Infusion reactions were reported in 16% percent of patients in the tocilizumab group and 5% of patients in the placebo group including two separate anaphylactic reactions in one tocilizumab treated patient, who eventually withdrew from the study. Five additional serious adverse events of pneumonia, septic arthritis, chickenpox, dehydration and Macrophage Activation Syndrome (MAS) were observed in tocilizumab treated patients. Grade 3 (<1.0 × 109/L) neutropenia was observed in 5 tocilizumab treated children, Grade 2 (2.5 – 5 × ULN) liver enzyme elevations (ALT) were observed in another 5 tocilizumab treated children and 4 tocilizumab treated children had elevation in total cholesterol ≥ 240 mg/dL, compared with only one patient in the placebo group.
Tocilizumab should be avoided in children with active acute or chronic infections, known history of elevated liver or lipid levels, and neutropenia. Special caution should be used in children with a history of serious infusion reactions to other biologic agents. The FDA label recommendation for lab monitoring in SJIA patients is neutrophils, platelets, ALT and AST at the time of the 2nd infusion and then every 2 to 4 weeks. The recommended lipid monitoring in SJIA patients is the same as in RA - 4 to 8 weeks following initiation of ACTEMRA therapy, then at approximately 24 week intervals.
Supply, Administration, and Cost
According to the package insert, the recommended dosing for tocilizumab in SJIA patients less than 30 kg weight is 12 mg/kg and in those greater than 30 kg weight is 8 mg/kg IV at 2 week intervals. The drug is supplied in single use vials containing 80 mg, 200 mg, and 400 mg.
The Bottom Line
Tocilizumab is the first FDA approved drug for the treatment of active SJIA. The drug demonstrated a significant clinical response and a tolerable safety profile within the first 12 weeks of an ongoing five-year multinational trial. The long-term safety and efficacy profile of tocilizumab in SJIA is still being established.
Hotline Author: Andreas Reiff, M.D., Professor of Pediatrics, USC Keck School of Medicine, Head, Division of Rheumatology Children’s Hospital Los Angeles
Hotline Editors: Arthur Kavanaugh, MD, and Eric Ruderman, MD
Disclosures: Dr. Reiff : Consultant and speaker for Amgen, Abbott, Genentech, Pfizer. Dr. Ruderman: Consultant for Amgen, Abbott, Pfizer, and UCB. Dr. Kavanaugh: Research studies for Roche, Genentech.
In addition to review by the editors, this Hotline has been reviewed by all members of the ACR Executive Committee, Communications and Marketing Committee and Drug Safety Committee.
The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author(s) and does not represent a position statement of the American College of Rheumatology.
