"Actemra^®," a Humanized Anti-Human IL-6 Receptor Monoclonal Antibody,
Filed for Rheumatoid Arthritis in the United States

November 21, 2007 (Tokyo) - Chugai Pharmaceutical Co., Ltd. [Head Office: Chuo-ku, Tokyo; President Osamu Nagayama (hereafter, "Chugai")] and F. Hoffmann-La Roche Ltd. (hereafter "Roche") [Head Office: Basel, Switzerland. Chairman and CEO: Franz B. Humer] announced today the submission of a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) seeking approval to market the humanized anti-human IL-6 (interleukin-6) receptor monoclonal antibody, Actemra^® [generic name: tocilizumab (genetical recombination)] to reduce the signs and symptoms in adults with moderate to severe rheumatoid arthritis.

Actemra^®, created by Chugai in collaboration with Osaka University, utilizes genetic recombinant technology to produce monoclonal antibody from mouse anti-IL-6 receptor monoclonal antibody. It works by inhibiting IL-6 biological activity through competitively blocking the binding of IL-6 to its receptor.

In Japan, Actemra^® was launched in June 2005 by Chugai, as an orphan drug for Castleman's disease, following approval in April, the same year.  Subsequently, it was filed for the additional indications of rheumatoid arthritis and systemic onset juvenile idiopathic arthritis in April 2006.

Outside of Japan, five phase III clinical trials, including extension studies in rheumatoid arthritis are going on in 40 countries involving more than 4,000 patients worldwide under co-development between Chugai and Roche. The BLA submission to the FDA is based on results and extension studies from four out of five of these trials, and the interim analysis of the remaining ongoing trial.

Rheumatoid arthritis is a systemic inflammatory disease in which the cause is unknown. The main symptoms are multiple joint inflammation and progressive joint damage. Millions of patients are suffering from the pain and debilitating effects of the disease In the United States.

A Marketing Authorisation Application (MAA) for the product will be filed with the European Medicines Agency (EMEA) in early December.
 
[Reference]

- Outline of five phase III clinical trials

1. OPTION Study
Objective:
To investigate Actemra's efficacy and safety for rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment.

Method:
This is a double-blinded trial evaluating 623 patients with moderate to severe active rheumatoid arthritis despite long term treatment with methotrexate (MTX). Patients were allocated to receive Actemra 4mg/kg, Actemra 8mg/kg, or placebo every four weeks (intravenous infusion), in combination with weekly MTX.

Results:
ACR response rates were used to determine the anti-rheumatic efficacy, and at the end of the 24 weeks (or at the last observation), Actemra group achieved statistically significantly higher response rates versus placebo.

2. TOWARD Study
Objective:
To investigate Actemra's efficacy and safety for rheumatoid arthritis patients with inadequate response to DMARDs treatment.

Method:
This is a double-blinded trial evaluating 1,216 patients with moderate to severe active rheumatoid arthritis despite treatment with DMARDs. Patients were allocated to receive Actemra 8mg/kg, or placebo every four weeks (intravenous infusion), in combination with traditional DMARDs.

Results:
ACR response rates were used to determine the anti-rheumatic efficacy, and at the end of the 24 weeks (or at the last observation), Actemra group achieved statistically significantly higher response rates versus placebo.

3. RADIATE Study
Objective:
To investigate Actemra's efficacy and safety for rheumatoid arthritis patients with inadequate response to an anti-tumor necrosis factor (anti-TNF) agent.

Method:
This is a double-blinded trial evaluating 498 patients with moderate to severe active rheumatoid arthritis despite treatment with anti-TNF agent. Patients were allocated to receive Actemra 4mg/kg, Actemra 8mg/kg, or placebo every four weeks (intravenous infusion), in combination with weekly MTX.

4. AMBITION Study
Objective:
To investigate efficacy and safety of Actemra monotherapy versus methotrexate in rheumatoid arthritis patients.

Method:
This is a double-blinded trial evaluating 673 patients with moderate to severe active rheumatoid arthritis. Patients were allocated to receive Actemra 8mg/kg every four weeks (intravenous infusion) plus weekly MTX placebo, or Actemra placebo very four weeks plus weekly MTX.

5. LITHE Study
Objective:
To investigate Actemra's efficacy with respect to prevention of joint damage, and safety for rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment.

Method:
This is a double-blinded trial evaluating 1,170 patients with moderate to severe active rheumatoid arthritis despite treatment with methotrexate (MTX). Patients were allocated to receive Actemra 4mg/kg, Actemra 8mg/kg, or placebo every four weeks (intravenous infusion), in combination with weekly MTX.

* LITHE study is ongoing, while the interim analysis is included in the submission data.

- Safety profile
The overall safety profile observed in the global studies of Actemra is consistent and Actemra is generally well tolerated. The serious adverse events reported in ACTEMRA global clinical studies included serious infections and hypersensitivity reactions including a few cases of anaphylaxis. The most common adverse events reported in clinical studies were upper respiratory tract infection, nasopharyngitis, headache, hypertension and transient increases in liver function tests (ALT and AST) were seen in some patients. These increases were generally mild and reversible, with no hepatic injuries or any observed impact on liver function.