Hoffmann-La Roche Inc (NUTLEY, New Jersey) announced that the US FDA has issued a complete response letter for the Biologics License Application (BLA) for Actemra^® (tocilizumab), the first humanized interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody studied for the treatment of adults with moderate-to-severe rheumatoid arthritis (RA). The FDA has requested additional documentation related to the manufacturing of the drug and certain other outstanding components such as final labeling. The additional information requested for approval does not involve safety or efficacy issues, nor do any additional studies need to be conducted as a prerequisite for approval of Actemra.

The BLA that Roche submitted to the agency on November 26, 2007 is based on results from five international phase III studies, which enrolled >4000 patients in 41 countries. The drug was compared with disease-modifying antirheumatic drug (DMARD) monotherapies. Findings demonstrated that Acterma used as monotherapy or in combination with DMARDs, such as methotrexate, significantly reduced the signs and symptoms of RA as measured by ACR (as well as achieving disease activity score remission) regardless of previous therapy or disease severity. Furthermore, patients who had previously failed anti-TNF treatments also showed significant improvement in signs and symptoms of RA after treatment with the drug. On July 29, 2008, the Arthritis Advisory Committee of the FDA voted 10-1 to recommend approval of Actemra, which has also been filed with the European authorities and other world authorities. If approved, the therapy will be the first and only medication to specifically target IL-6 in patients with RA.

Four phase III studies are completed and have reported meeting their primary endpoints. The fifth phase III study, the LITHE trial evaluating Actemra in RA, is an ongoing 2-year study, which is expected to report complete data evaluating the effects of the drug on the inhibition of structural joint damage in 2009. Actemra is generally well tolerated and its overall safety profile is consistent across all global clinical studies. Serious adverse reactions reported in clinical studies include serious infections, gastrointestinal perforations, and hypersensitivity reactions including anaphylaxis; the most common adverse reactions reported were upper respiratory tract infection, nasopharyngitis, headache, and hypertension. Increases in liver enzymes ALT and AST were seen in some patients; these increases were generally mild and reversible, with no evidence of hepatic injuries or any observed impact on liver function. Laboratory changes, including increases in lipids (total cholesterol, LDL, HDL, triglycerides) and decreases in neutrophils and platelets, were seen in some patients without association with clinical outcomes. Treatments, such as Actemra, that suppress the immune system may cause an increase in the risk of malignancies.

Actemra is part of a codevelopment agreement with Chugai Pharmaceuticals Co in Japan, which launched the therapy in June 2005 for the treatment of Castleman's disease. In April 2008, additional indications for RA, juvenile idiopathic arthritis, and systemic-onset juvenile idiopathic arthritis were also approved in Japan.

Also for the treatment of RA, Roche is also developing ocrelizumab, a humanized anti-CD20 antibody, currently in phase III study.