Objectives: The anti-IL-6 receptor antibody tocilizumab inhibits signaling of IL-6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. The AMBITION study evaluated tocilizumab monotherapy efficacy and safety vs. methotrexate in patients with active RA, who had not previously failed methotrexate/biologics treatment.
Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomized 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at Week 24.
Results: The intent-to-treat analysis demonstrated that tocilizumab was superior to methotrexate treatment with a higher ACR20 response (69.9 vs. 52.5%; P<0.0001), and DAS28<2.6 rate (33.6 vs. 12.1%) at Week 24. Mean high sensitivity C-reactive protein (hsCRP) was within the normal range from Week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events (AEs) with tocilizumab was 3.8% vs. methotrexate, 2.8% (p=0.50), and of serious infections, 1.4% vs. 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs. 0.4%) and increased total cholesterol ≥240 mg/dL (13.2% vs. 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs. 2.5%), respectively.
Conclusion: Tocilizumab monotherapy is superior to methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favorable benefit-risk, in patients who have not previously failed methotrexate or biologics treatment.