Results from study of Rituxan in rheumatoid arthritis show promise

Genentech, Inc., Biogen Idec and Roche have announced that the New England Journal of Medicine published the results of a Phase IIa study showing that two doses of Rituxan® (Rituximab), administered two weeks apart, improved symptoms in patients with moderate-to-severe rheumatoid arthritis (RA) for up to 48 weeks when combined with methotrexate (MTX), compared to MTX alone. Preliminary findings from this study, first presented at the 2002 and 2003 meetings of the American College of Rheumatology (ACR), included both a primary analysis of patients at week 24 and an exploratory analysis at week 48.

The randomized, double-blind, placebo-controlled study demonstrated that patients with moderate-to-severe RA receiving the combination of Rituxan with MTX and a brief course of corticosteroids produced higher ACR 20, 50 and 70 responses than with MTX alone. A subsequent exploratory analysis also demonstrated that responses were sustained for up to 48 weeks. Rituxan is a therapeutic antibody that selectively depletes B-cells (or B-lymphocytes), which may play a key role in the inflammatory cascade of the disease.

"The study provides support for the concept that B-lymphocytes play a central role in rheumatoid arthritis and suggests that B-lymphocyte targeted therapy has potential," said Professor Jonathan Edwards, M.D., University College of London, United Kingdom, lead investigator for the study.

Key Results
In the study, investigators administered patients with two infusions of Rituxan on day one and day 15 and followed patients for up to 104 weeks to assess the response of Rituxan alone or in combination with MTX or cyclophosphamide (CTX) compared to MTX alone (control arm). The primary efficacy results at 24 weeks showed that the proportion of patients reaching the primary endpoint of improving by at least 50 percent in disease scores (ACR 50) was significantly greater in the Rituxan- combination-treated groups compared with patients in the control arm of the study.

Response rates at 24 weeks, when using Rituxan in combination with MTX, included:

• 73 percent (29/40) of patients experienced ACR 20 (vs. 38 percent, or 15/40, on control)
• 43 percent (17/40) experienced ACR 50 (vs. 13 percent, or 5/40)
• 23 percent (9/40) experienced ACR 70 (vs. 5 percent, or 2/40)

Exploratory analyses assessing improvement signs and symptoms were also performed at week 48. In a preliminary analysis presented at the 2003 ACR meeting, similar response rates were maintained in the Rituxan plus MTX group for up to 48 weeks without further Rituxan treatment. Response rates included:

• 65 percent (26/40) experienced ACR 20 (vs. 20 percent, or 8/40, on control)
• 35 percent (14/40) experienced ACR 50 (vs. 5 percent, or 2/40)
• 15 percent (6/40) experienced ACR 70 (vs. 0 percent)

"These data in RA are the first in our ongoing efforts to understand the role that B-cells may play in a wide range of immunological or autoimmune diseases such as lupus and multiple sclerosis," said Hal Barron, M.D., Genentech senior vice president of Development and Chief Medical Officer. "We are committed to understanding the underlying mechanisms by which these diseases progress to help provide potential new therapies for patients and physicians."

"RA affects over two million Americans, and despite recent advances in therapy, many patients do not respond or respond inadequately to current treatments," said Burt Adelman, M.D., executive vice president, Development, Biogen Idec. "By selectively targeting B-cells, Rituxan may offer an entirely new approach to treating RA."

About the Study
The study included 161 patients from 11 countries with moderate-to-severe, active, long-standing RA (mean duration 10.4 years) who had previously failed one to five disease-modifying anti-rheumatic drugs (DMARDs) and responded inadequately to MTX at the time of entering the study. Participants in the 24-week, four-arm, placebo-controlled trial were randomized into one of four treatment groups: methotrexate (MTX) alone; Rituxan alone; Rituxan in combination with cyclophosphamide; and Rituxan in combination with MTX. Each group also received a 17-day course of corticosteroids. Rituxan was infused intravenously on days one and 15 of the study -- no further treatment with Rituxan was given.

According to the investigators, the study's safety results indicate that all three Rituxan regimens had similar levels and type of adverse events compared to MTX-alone arm. Peripheral blood immunoglobulin levels remained within the normal range throughout the treatment cycle. Most adverse events were reported during the initial 15 days, and many were associated with the first infusion of Rituxan. Overall, the infusion reactions were less frequent and severe than those observed in studies with non-Hodgkin's lymphoma (NHL) patients. The majority of events were mild-to-moderate in severity. They included transient hypo- and hypertension, cough, pruritus and rash. At week 48, the incidence and types of events, including infections, were evenly balanced between all groups. During the period of week 24 to week 48, a total of four additional serious adverse events were reported. These included two serious infections (arytenoiditis, infection of the cartilage in the back of the wind pipe, in the Rituxan+CTX group and viral gastroenteritis in the Rituxan-alone group). The other events were goitre (Rituxan-alone) and replacement of a renal stent (Rituxan+MTX).

Ongoing Studies
Based on results from this study, the companies initiated global randomized studies evaluating Rituxan in the treatment of RA, including a pivotal Phase III study known as REFLEX, for patients who have had an inadequate response to tumor necrosis factor (TNF) inhibitor therapies and a Phase IIb dose optimization study, known as DANCER, for patients with disease-modifying anti-rheumatic drugs (DMARD) failure. DANCER has completed enrollment. Both studies have a primary endpoint of ACR 20 at 24 weeks.

Also based on results from this Phase IIa study, as well as other small investigator-sponsored studies in various autoimmune-mediated diseases, the companies have committed to advancing Rituxan into clinical development for other immunology indications.

About RA and B-Cells
RA is a debilitating autoimmune disease that affects more than two million Americans and hinders the daily activities of sufferers(1). RA occurs when the body's own immune system inappropriately attacks joint tissue and causes chronic inflammation that destroys healthy tissue and damage within the joints. Symptoms include inflammation of the joints, swelling, 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.

Both genetics and environmental factors play a role in RA, and there is no known cure. Treatments include a variety of steroidal and non-steroidal anti-inflammatory drugs, immunosuppressive agents, disease-modifying anti-rheumatic drugs (DMARDs), and biologics. However, many patients continue to have an inadequate response to treatment.

The role of immune dysfunction in RA has predominantly focused on T-cells. However, the evidence from this study reinforces the importance of B-cells in the pathogenesis of RA. B-cells secrete inflammatory cytokines directly or act as antigen presenting cells, leading to the production of inflammatory cytokines. In addition, B-cells are responsible for the production of auto-antibodies such as rheumatoid factor, which is a prognostic factor for aggressive RA.

About Rituxan
Rituxan is a therapeutic antibody that selectively targets B-cells, which are thought to play a key role in the inflammatory cascade of RA -- a series of reactions inflaming the synovia (joint fluid) and leading to the cartilage loss and bone erosion that is characteristic of the disease. Genentech, Biogen Idec and Roche continue to investigate Rituxan's impact on the inflammatory cascade of RA.

Rituxan received initial U.S. Food and Drug Administration (FDA) approval in November 1997 for the treatment of relapsed or refractory low-grade or follicular, CD20 positive, B-cell NHL. It also was approved in the European Union (EU) under the trade name MabThera® in June 1998. Genentech and Biogen Idec co-market Rituxan in the United States and Roche markets Rituxan in the rest of the world, except Japan, where Rituxan is co-marketed with Zenyaku Kogyo Co. Ltd. There have been more than 370,000 patient exposures of Rituxan to date worldwide.

Rituxan Safety Profile in NHL
In NHL patients, the majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to: flu-like fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema, and hypotension. These symptoms vary in severity and generally are reversible with medical intervention. In rare instances, severe and fatal infusion-related reactions have occurred, nearly all of which have been associated with the first Rituxan infusion. These events appear as manifestations of an infusion-related complex and include hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and tumor lysis syndrome. Patients who develop clinically significant infusion-related cardiopulmonary events should have their Rituxan infusion discontinued and receive medical treatment.

In rare instances, severe mucocutaneous skin reactions have occurred that may be associated with Rituxan therapy. Many of these reactions have been described as paraneoplastic pemphigus and are known to be associated with various B-cell lymphomas, particularly NHL and chronic lymphocytic leukemia. Patients who develop a severe mucocutaneous skin reaction should have Rituxan discontinued and receive appropriate medical treatment, including a skin biopsy to guide therapy.