Analysis Of Phase III Study Showed Rituxan® Plus Methotrexate Reduced Joint Damage In Rheumatoid Arthritis Patients Who Respond Inadequately To TNF Antagonist Therapies
Findings on Mean Change in Genant-Modified Sharp Score in Patients with Moderate-to-Severe RA Presented at Leading Rheumatology Meeting
SOUTH SAN FRANCISCO, Calif. and CAMBRIDGE, Mass. - June 22, 2006 - Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) today announced positive results from an analysis of REFLEX, a Phase III clinical study of Rituxan® (Rituximab) in patients with rheumatoid arthritis (RA) who have had an inadequate response to previous treatment with one or more tumor necrosis factor (TNF) antagonist therapies. The findings showed that treatment with Rituxan in combination with a stable dose of methotrexate (MTX) reduced joint erosion and joint space narrowing at 56 weeks, compared to placebo and MTX. These are the first data to measure the progression of joint damage in this difficult-to-treat patient population. Results were presented for the first time today at a rheumatology meeting in Amsterdam, Netherlands.
Rituxan, the first and only CD20-positive B-cell-targeted therapy for RA, was recently approved by the U.S. Food and Drug Administration for use in combination with MTX for reducing signs and symptoms in adult patients with moderately-to-severely active RA who have had an inadequate response to one or more TNF antagonist therapies.
In this analysis at 56 weeks, patients treated with Rituxan and MTX displayed the following improvements, compared to patients who received placebo and MTX:
* The mean change in the composite Genant-modified Sharp score, which assesses progression of both joint erosion and joint space narrowing, was lower among Rituxan-treated patients than placebo-treated patients (1.00 versus 2.31, respectively; p = 0.0046).
* Mean changes in the erosion score (0.59 versus 1.32; p= 0.0114) and joint space narrowing score (0.41 versus 0.99; p=0.0006) were lower among Rituxan-treated patients than placebo-treated patients.
* A higher proportion of Rituxan-treated patients showed no additional erosion, compared to patients who received placebo (61 percent versus 52 percent, respectively; p = 0.0445).
“These data suggest that even the most difficult-to-treat RA patients who have not responded to prior TNF therapy may be able to reduce joint erosion and narrowing following treatment with Rituxan and methotrexate,” said Edward Keystone, M.D., University of Toronto, Canada. “Considering joint destruction leads to deformity and disability, it is imperative to continue researching potential approaches to address this debilitating process.”
In the multi-center, double-blind, placebo-controlled REFLEX study, patients were randomized to receive either a single treatment course of two infusions of Rituxan (1000 mg on days one and 15) or placebo, in combination with a stable dose of MTX and followed through 24 weeks. Following week 24, patients with active RA that had either demonstrated a response to an initial treatment course of Rituxan or had initially received placebo, were eligible for a subsequent or initial course of Rituxan treatment, respectively, and were followed through 56 weeks. X-rays of the hands and feet were taken at the start of the study and at weeks 24 and 56, and assessed using the Genant-modified Sharp method. Of the 520 total patients in the study, this analysis evaluated X-rays from 277 of the 311 Rituxan-treated patients and 186 of the 209 placebo-treated patients.
In the primary REFLEX study, the most frequently reported adverse events that occurred with Rituxan through 24 weeks were primarily infusion-associated. Serious adverse events occurred in 7 percent of patients receiving Rituxan and MTX compared to 10 percent in patients receiving placebo and MTX. Less than 1 percent of acute infusion reactions were serious. The incidence of serious infections was 2 percent in Rituxan-treated patients and 1 percent in placebo-treated patients. The companies are committed to monitoring long-term safety of Rituxan.
About Radiographic Analysis of Joint Structural Damage
Data on the progression of joint structural damage are obtained by taking X-rays of specific joints (typically in the hands and feet) before treatment and at various points after treatment has been initiated. The Genant-modified Sharp method focuses on 14 specific sites for evidence of bone erosion and 13 sites for narrowing of the joint space - both key measures of ongoing structural damage to the joints.
Erosion scores are assigned to each of the specified sites, with 0 representing “no erosion” and 3.5 representing “destruction of the joint.” Joint space narrowing scores are assigned to each of the specified sites, with 0 representing “no narrowing” and 4 representing “total loss of the joint space.” Increases in the scores indicate the extent of additional erosion, joint space narrowing or overall structural damage (both scores combined) that have occurred since treatment began.
About the Role of B-cells in Rheumatoid Arthritis
While RA has traditionally been considered a T-cell-mediated disease, newer 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
RA is a debilitating autoimmune disease that affects more than two million Americans1 and hinders the daily activities of sufferers. The damage that occurs in RA is a result of the immune system attacking joint tissue, causing painful chronic inflammation, often resulting in 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 and eyes.
Rituxan Safety Profile
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 percent of Rituxan-treated RA patients developed human anti-chimeric antibodies (HACA), this was not associated with loss of clinical response or additional safety observations.
The majority of patients experiencing an infusion-related reaction will do so during 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.
Rituxan is a therapeutic antibody that targets and selectively depletes CD20-positive B-cells without targeting stem cells or existing plasma cells. In RA patients who respond inadequately to TNF antagonist therapy, 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 MabThera® 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. On March 30, 2006, the companies also announced the submission of a sBLA to the FDA for the use of Rituxan, for the first-line treatment of patients (previously untreated) with low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma in combination with CVP (cyclophosphamide, vincristine and prednisone) or CHOP chemotherapy or following CVP chemotherapy for patients who achieved a response of stable disease or better.
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. For a copy of the Rituxan full prescribing information, including Boxed Warning, please call 1-800-821-8590 or visit http://www.gene.com.
Founded 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics for significant unmet medical needs. A considerable number of the currently approved biotechnology products originated from or are based on Genentech science.
Genentech manufactures and commercializes multiple biotechnology products and licenses several additional products to other companies. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit www.gene.com.
About Biogen Idec
Biogen Idec creates new standards of care in oncology, neurology and immunology. As a global leader in the development, manufacturing, and commercialization of novel therapies, Biogen Idec transforms scientific discoveries into advances in human healthcare. For product labeling, press releases and additional information about the company, please visit www.biogenidec.com.
The statement made in this press release relating to the potential of Rituxan plus methotrexate to reduce joint erosion and narrowing is forward-looking. Such statement is a prediction and involves risks and uncertainties such that the actual result may differ materially. Among other things, Rituxan as a potential treatment could be affected by unexpected safety, efficacy or manufacturing issues, the need for additional clinical studies, additional time requirements for data analysis, sBLA preparation or decision-making, FDA actions or delays, failure to receive FDA approval, competition, reimbursement, pricing, the ability to supply product or a product withdrawal.
Please also refer to Genentech’s and Biogen Idec’s periodic reports filed with the Securities and Exchange Commission. Genentech and Biogen Idec disclaim, and do not undertake, any obligation to update or revise the forward-looking statement in this press release.
1 American College of Rheumatology. “Rheumatoid Arthritis.”, www.rheumatology.org/public/factsheets/ra_new.asp?aud=pat, accessed 1/13/06.
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