General Information

Actemra is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1 kappa. It binds specifically to IL-6 receptors. IL-6 is a pro-inflammatory cytokine produced by a variety of cell types, including T- and B-cells, lymphocytes, monocytes and fibroblasts.

Actemra us specifically indicated for the treatment of adult patients with moderately-to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Actemra is supplied as solution for intravenous infusion. Actemra may be used as monotherapy or concomitantly with methotrexate or other DMARDs. The recommended dose of Actemra for adults given once every 4 weeks as a 60-minute single intravenous drip infusion is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response.

Clinical Results

FDA Approval
The FDA approval of Actemra was based on five randomized, double-blind, multicenter studies. Actemra was administered intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).

Study One
This study evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 6 months prior to randomization, or who had not discontinued previous MTX treatment. The subjects received Actemra 8 mg/kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of Actemra patients who achieved an ACR20 response at Week 24. ACR20 was reached by 70% of the Actemra arm vs. 53% of the MTX alone arm.
Study Two
This ongoing 2-year study with a planned interim analysis at week 24 evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint at week 24 was the proportion of patients who achieved an ACR20 response. ACR20 was reached by 27% in the placebo/MTX arm, 51% in the Actemra 4mg/MTX arm and 56% in the Actemra 8 mg/MTX arm.
Study Three
This trial evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. ACR20 was reached by 27% of the placebo/MTX arm, 48% of the Actemra 4mg/MTX arm and 59% of the Actemra 8 mg/MTX arm.
Study Four
This study evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received Actemra 8 mg/kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. ACR20 was reached by 25% of the placebo/DMARDS arm and 61% of the Actemra/DMARDS arm.
Study Five
This study evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. ACR20 was reached by 10% of the placebo/MTX arm, 30% of the Actrmea 4mg/MTX arm and 50% of the Actemra 8 mg/MTX arm.

Ongoing Study Commitments

Genentech has agreed to conduct a pregnancy registry to evaluate pregnancy outcomes for women exposed to Actemra (tocilizumab) during pregnancy.
Protocol Submission: July 30, 2010
Study Completion Date: December 31, 2016
Final Report Submission:December 31, 2017

Genentech has agreed to conduct a long-term, observational study of patients who continue to be treated with tocilizumab in the open-label part of the treatment trials WA18695 and WA18696 to evaluate long-term serious risks of Actemra and to accrue safety data on at least 1000-1500 patients treated for 5 years.
Final Protocol Submission: December 17, 2009
Study Completion Date: June 30, 2013
Final Report Submission: June 30, 2014

Genentech has agreed to conduct a randomized, controlled trial to rule out a moderate increase in the risk of serious cardiovascular events with tocilizumab, e.g., stroke, non-fatal MI, cardiovascular death.
Final Protocol Submission: July 30, 2010
Study Completion Date: February 28,2018
Final Report Submission: February 28, 2019

Genentech has agreed to conduct a randomized trial to study the effects oftocilizumab on therapeutic vaccines. B cell-dependent antigens (e.g., pneumococcal polysaccharide vaccine) and T celldependent antigens (e.g., tetanus toxoid) will be evaluated.
Final Protocol Submission: April 30, 2010
Study Completion Date: October 31,2013
Final Report Submission: November 30,2012

Mechanism of Action

Actemra is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1 kappa subclass. It binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.