Rituxan approval to mark a new era of B-cell targeted therapies of autoimmune disease?

DailyUpdates March 1^st, 2006: Genentech and Biogen Idec announced yesterday (press release) that the FDA has approved Rituxan (Rituximab) in combination with methotrexate to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Approved by the FDA in November 1997, Rituxan was the first therapeutic antibody approved for treating cancer in the US. A supplemental Biological License Application (sBLA) was approved for Rituxan in April 2001, adding several new uses related to B-cell non-Hodgkin's lymphoma. To date, more than 250,000 patients worldwide have been treated with Rituxan. Sales of Rituxan have grown impressively over the past seven years. The growth rate is now slowing and future growth is expected to come from new indications.

REFLEX, a Phase III clinical study of Rituxan in rheumatoid arthritis, met its primary endpoint and underpins the FDA’s approval. Analysts believe that additional approval for the treatment of rheumatoid arthritis will add a further $375 million to the global sales for this product. Rituxan is also being evaluated in Phase II/III clinical trials for primary progressive and relapsed remitting multiple sclerosis, ANCA-associated vasculitis, systemic lupus erythematosus.

REFLEX showed that a significantly greater proportion of patients who received a single treatment course of two infusions of Rituxan with a stable dose of methotrexate achieved American College of Rheumatology (ACR) 20, 50 and 70 response rates compared to patients who received placebo and methotrexate. The study included patients with active rheumatoid arthritis who had an inadequate response or were intolerant to prior treatment with one or more TNF antagonist therapies and current methotrexate therapy.

At 24 weeks, patients receiving Rituxan displayed clinically and statistically significant improvements in rheumatoid arthritis signs and symptoms, including pain and disability. In patients receiving Rituxan ACR 20, ACR 50 and ACR 70 was achieved by 51%, 27% and 12% of patients (compared to 18%, 5% and 1% of placebo treated patients).

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 methotrexate compared to 10% in patients receiving placebo and methotrexate. 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.

Rituxan is the first treatment for rheumatoid arthritis that selectively targets 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 rheumatoid arthritis.

Yesterday’s news is good for Rituxan and rheumatoid arthritis patients alike; it also establishes a clear proof of concept for the development of other B cell-targeted therapies for the treatment of rheumatoid arthritis, other autoimmune disorders.

Another B-cell target that has considerable promise is BAFF (also known as BLyS). This target is fully evaluated in our recent report BAFF & APRIL: Emerging Targets for autoimmune disease & Cancer Therapeutics - Proof of concept, indications and development activity

BAFF plays a key part in the control of B-cell biology in secondary lymphatic organs. In particular BAFF stimulates the maturation and survival of B-cells within germinal centers of the spleen, other lymphatic organs and lymph nodes.

There is particularly good evidence to support a role of BAFF in the etiology of rheumatoid arthritis, and especially in a subset of patients with synovial germinal centers. BAFF is able to promote the production of rheumatoid factor while its blockade is able to prevent the progression of an animal model of disease. Blockade is also able to reduce IgG release by human synovial tissue suggestive of clinical efficacy. In patients, articular BAFF levels are increased, and convincingly, Human Genome Science’s phase II study of the neutralizing anti-BAFF monoclonal antibody LymphoStat-B revealed an ACR 20 response in 35% of patients as compared to 16% in controls. ZymoGenetics is also targeting BAFF for the treatment of rheumatoid arthritis.

One particular advantage of blocking BAFF and/or APRIL for the treatment of rheumatoid arthritis is that this approach may improve both the efficacy and safety of TNF blocking drugs. One risk associated with TNF therapies is the development of lymphoma but since targeting the BAFF family appears to be an approach to this cancer, a therapeutic such that blocks BAFF is appealing in a combination therapy.

Hopefully yesterday’s news on Rituxan will mark the start of a new era in the treatment of autoimmune disease.