January 11, 2010 ( UPDATED January 13, 2010 ) — The US Food and Drug Administration (FDA) has approved tocilizumab intravenous infusion (Actemra, Roche) for the once-monthly treatment of moderately to severely active rheumatoid arthritis (RA) in adults who have had an inadequate response to 1 or more tumor necrosis factor antagonist therapies.
The first-in-class interleukin 6 receptor–inhibiting monoclonal antibody is the ninth biologic agent approved for the treatment of RA and may be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDS). It is expected to be available in the United States the week of January 18, 2010.
FDA approval was based on data from 5 multinational phase 3 clinical trials of more than 4000 patients, showing that tocilizumab therapy significantly decreased RA symptoms regardless of prior treatments.
Data from the RheumAtoiD ArthritIs Study in Anti-TNF FailurEs (RADIATE) trial showed that 50% and 30% of patients treated with methotrexate and tocilizumab 8 mg/kg and 4 mg/kg, respectively, achieved a 20% improvement in arthritis signs and symptoms (American College of Rheumatology [ACR] 20) at week 24 compared with 10% of those receiving methotrexate alone.
These findings were supported by data from the TOcilizumab Pivotal Trial in Methotrexate Inadequate respONders (OPTION) and TociLIzumab Safety and THE Prevention of Structural Joint Damage (LITHE) studies, in which the addition of tocilizumab 8 mg/kg and 4 mg/kg to methotrexate likewise significantly improved ACR20 rates at week 24 relative to methotrexate alone (59% and 48% vs 27%; 56% and 51% vs 27%). In the Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy (AMBITION) trial, 70% of patients receiving tocilizumab 8 mg/kg with methotrexate achieved ACR20 at week 24 compared with 53% of those receiving methotrexate alone.
The fifth study, Tocilizumab in cOmbination With traditional DMARD therapy (TOWARD), showed that the addition of tocilizumab 8 mg/kg to methotrexate or other DMARDS significantly improved ACR20 rates at week 24 compared with DMARDS alone (61% vs 25%).
"For many RA patients, treatment with existing therapies does not resolve the painful and debilitating symptoms of the disease," said Mark Genovese, MD, study investigator and professor of medicine and cochief of the Division of Immunology and Rheumatology at Stanford University Medical Center, California, in a company news release. "Data from the clinical development program clearly establish Actemra and its unique mechanism of action as an important new option for RA patients who experience continued disease symptoms despite treatment with existing therapies."
Recommended Dosage and Administration
The recommended starting dose for tocilizumab is 4 mg/kg administered once every 4 weeks as a 60-minute single drip infusion, followed by an increase to 8 mg/kg based on clinical response. Tocilizumab should not be used during active infection, including localized infections. Patients should be screened and treated for latent tuberculosis before initiation of therapy and monitored thereafter even in the absence of positive test results.
Because of the increased risk for infection, tocilizumab should not be used in combination with other biologic DMARDS, including tumor necrosis factor antagonists, interleukin 1 receptor antagonists, anti-CD20 monoclonal antibodies, and selective costimulation modulators.
Adverse Events and Safety Concerns
Adverse events most commonly reported in tocilizumab-treated patients include upper respiratory tract infection, nasopharyngitis, headache, high blood pressure, and liver enzyme elevations that were generally mild and reversible. Other laboratory changes, including increases in low-density lipoprotein cholesterol levels and decreased neutrophil and platelet counts, have also been observed and may require a decrease in dosage to 4 mg/kg. Serious adverse effects may include infection, gastrointestinal perforation, and hypersensitivity reactions, including anaphylaxis. As with other immunosuppressive therapies, tocilizumab may increase the risk for cancer.
Because of these and other safety concerns, the FDA is requiring the manufacturer to conduct a postmarketing clinical trial that will evaluate the long-term safety of tocilizumab therapy, particularly with respect to cardiovascular health. A risk evaluation and mitigation strategy will also be implemented to ensure proper drug usage and appropriate monitoring for hepatic and/or gastrointestinal adverse events.
"Physicians and patients need to be aware of the risk of serious adverse effects of Actemra and make informed decisions regarding its benefits and risks in the treatment of individual patients," noted Bob Rappaport, MD, director of the Division of Analgesics, Anesthetics and Rheumatology Products in the FDA's Center for Drug Evaluation and Research.
Tocilizumab previously was approved for the treatment of RA in the European Union and several other countries, including Mexico, India, Brazil, Switzerland, Australia, and Japan. Additional indications in Japan include Castleman's disease and juvenile idiopathic arthritis.
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