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FDA Approves Rituxan (Rituximab), the First Targeted B-Cell Therapy for Treatment of Moderate-to-Severe Rheumatoid Arthritis

Only Therapy to Show Improvement in Signs and Symptoms Through 24 Weeks Following One Treatment Course

SOUTH SAN FRANCISCO, C.A., and CAMBRIDGE, M.A. -- March 1, 2006 -- Genentech, Inc. and Biogen Idec, Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved, following Priority Review, the therapeutic antibody RituxanŽ (rituximab) in combination with methotrexate (MTX) to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.

Rituxan is the first treatment for RA that selectively targets immune cells known as CD20-positive B-cells. Through this unique mechanism of action, Rituxan may affect multiple pathways by which B-cells are believed to contribute to the initiation and development of RA.

"The FDA approval of Rituxan for RA provides an important new treatment approach for patients who do not respond adequately to TNF antagonist therapy," said Stephen Paget, M.D., chairman, professor of medicine and physician-in-chief at the department of medicine, division of rheumatology, at the Hospital for Special Surgery in New York. "In clinical trials, Rituxan demonstrated significant improvement in joint pain, inflammation and physical function from a single course of therapy in this difficult-to-treat patient population."

Clinical Study Results for Rituxan in RA
The FDA based its approval decision for Rituxan for RA on data from three randomized, double-blind, placebo-controlled studies of patients with active RA. Results of the pivotal Phase III trial known as REFLEX showed that a significantly greater proportion of patients who received a single treatment course of two infusions of Rituxan (1000 mg on days one and 15) with a stable dose of MTX achieved American College of Rheumatology (ACR) 20, 50 and 70 response rates compared to patients who received placebo and MTX. The study included patients with active RA who had an inadequate response or were intolerant to prior treatment with one or more TNF antagonist therapies and current MTX therapy.

At 24 weeks, patients receiving Rituxan displayed clinically and statistically significant improvements in RA signs and symptoms, including pain and disability. In patients receiving Rituxan:

- 51% achieved ACR 20, the primary endpoint of the study, versus 18% of placebo patients
- 27% achieved ACR 50, versus 5% of placebo patients
- 12% achieved ACR 70, versus 1% of placebo patients

Rituxan was also shown to reduce biologic markers of inflammation.

In REFLEX, the most frequently reported adverse events that occurred with Rituxan were primarily infusion-associated. Serious adverse events occurred in 7% of patients receiving Rituxan and MTX compared to 10% in patients receiving placebo and MTX. Less than 1% of acute infusion reactions were serious. The incidence of serious infections was 2% in Rituxan-treated patients and 1% in placebo-treated patients. The companies are committed to monitoring long-term safety of Rituxan.

"The FDA approval of Rituxan for RA marks an important milestone in our ongoing efforts to advance the understanding of B-cell-mediated autoimmune diseases," said Hal Barron, M.D., Genentech's senior vice president, Development and chief medical officer. "This milestone, coupled with the additional new indication for Rituxan in diffuse large B-cell lymphoma, further establishes the companies at the forefront of novel B-cell research."

"Today marks a significant milestone in Biogen Idec and Genentech's commitment to delivering first-in-class, innovative therapies for patients with significant unmet medical needs," said Burt Adelman, MD, executive vice president, development, Biogen Idec.

About ACR Response
ACR 20, ACR 50 and ACR 70 responses indicate a 20, 50 and 70% improvement in the number of swollen and tender joints, respectively, as well as a 20, 50 and 70% improvement compared with baseline in three of five disease-activity measures: patient assessment, physician assessment, pain scale, Health Assessment Questionnaire and the value for one acute phase reactant (erythrocyte sedimentation rate or C-reactive protein).

About the Role of B-cells
While RA has traditionally been considered a T-cell-mediated disease, new research suggests that other immune cells called B-cells may play multiple roles in the initiation and development of RA, including:

- Presentation of antigens (substances capable of triggering an immune response), which may contribute significantly to T-cell responses
- Production of antibodies that trigger an immune attack against a person's own cells or tissues (autoantibodies) and perpetuate the disease process
- Production of chemical signal molecules (cytokines) known to promote inflammation and joint damage

About RA
RA is a debilitating autoimmune disease that affects more than two million Americans(1) and hinders the daily activities of sufferers. RA occurs when the immune system inappropriately attacks joint tissue, causing painful chronic inflammation and irreversible destruction of cartilage, tendons and bones, often resulting in disability. Common RA symptoms include inflammation of the joints, swelling, fatigue, stiffness and pain. Additionally, since RA is a systemic disease, it can have effects in other tissues such as the lungs, eyes and bone marrow.

Rituxan Safety Profile
The safety profile of Rituxan has been established in more than 730,000 patient exposures over a period of 8 years.

In general, the adverse events observed in patients with RA were similar in type to those seen in patients with non-Hodgkin's lymphoma (NHL). The most common adverse events observed in patients treated with Rituxan for RA in clinical trials were infusion reactions and infections. No significant change in average immunoglobulin levels was observed in Rituxan-treated patients in clinical trials. There was no increase in hematologic malignancies, demyelinating events or risk of opportunistic infections (including tuberculosis) in Rituxan-treated patients over 24 weeks of treatment. Although 5% of Rituxan-treated patients developed human anti-chimeric antibodies (HACA), this was not associated with loss of clinical response or additional safety observations.

The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to: flu-like illness, fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema, hypotension and hypoxia. These symptoms vary in severity and generally are reversible with medical intervention.

Severe infusion reactions have been reported in patients treated with Rituxan, some with fatal outcomes in patients with NHL. These severe reactions typically occur during the first infusion. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. Patients who develop clinically significant infusion reactions should have their Rituxan infusion discontinued and receive medical treatment.

Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of tumor lysis syndrome following treatment with Rituxan. Severe mucocutaneous skin reactions, some with fatal outcome, have been reported in association with Rituxan treatment. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving Rituxan in combination with chemotherapy for diffuse large B-cell (DLBCL), CD20-positive, non-Hodgkin's lymphoma.

Other serious or potentially life-threatening adverse reactions that have been reported following Rituxan therapy include Hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, and cardiac arrhythmias.

About Rituxan
Rituxan is a therapeutic antibody that targets and selectively depletes CD20-positive B-cells without targeting stem cells or existing plasma cells. In patients with RA, Rituxan is given as two 1000 mg IV infusions separated by two weeks, in combination with MTX. It is recommended to administer the steroid methylprednisolone 100 mg IV 30 minutes prior to each infusion.

In addition to RA, Rituxan is being studied in other autoimmune diseases with significant unmet medical needs, including systemic lupus erythematosus, lupus nephritis, multiple sclerosis and ANCA-associated vasculitis.

Rituxan, discovered by Biogen Idec, received FDA approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma. It was also approved in the European Union under the trade name MabTheraŽ in June 1998. In addition, Rituxan received FDA approval in February 2006 for the treatment of DLBCL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens in previously untreated patients.

Genentech and Biogen Idec co-market Rituxan in the United States, and Roche markets MabThera in the rest of the world, except Japan, where Rituxan is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd. Rituxan is the top-selling oncology therapeutic in the United States with more than 730,000 patient exposures worldwide.


SOURCE: Genentech, Inc.

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