Washington Editor

The FDA approved Rituxan (rituximab) for rheumatoid arthritis, broadening the therapeutic antibody’s label and potentially its revenue.

Long sold as a cancer therapy, its new indication specifies its combination with methotrexate to reduce signs and symptoms in moderate to severe adult rheumatoid arthritis patients who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. It received a priority review from the agency.

In the U.S., the drug is marketed by Genentech Inc. and Biogen Idec Inc., both of which noted that Rituxan is the first rheumatoid arthritis treatment that selectively targets CD20-positive B cells, a mechanism of action that could affect multiple pathways by which B cells are believed to contribute to the disease’s initiation and development.

Sunil Agarwal, Genentech’s associate group medical director, told BioWorld Today that Rituxan would fill an important void for patients who do not respond to anti-TNF therapy, those with the "highest unmet medical need."

That point was echoed by Amy Ryan, Biogen Idec’s director of public affairs, who noted that TNF treatment fails 30 percent to 40 percent of the estimated 1.5 million patients with moderate to severe RA. "It’s exciting news for that patient population," she told BioWorld Today.

Physicians can begin prescribing the drug for rheumatoid arthritis immediately, given its longstanding approval status, and a joint sales force of about 100 will begin taking it to the 4,100 U.S. rheumatologists as soon as next week.

Rituxan, discovered by Biogen Idec, first received FDA approval more than eight years ago for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma. In the last fiscal year, its total sales exceeded $1.8 billion. (See BioWorld Today, Feb. 17, 2006.)

Despite its clearance to move into another large market, at least one industry analyst, Jason Kantor of RBC Capital Markets, projected a conservative forecast in a research note. He estimated first-year rheumatoid arthritis sales of about $100 million, with near-term earnings likely to be offset by the added costs of a new sales force and Biogen Idec’s 40 percent profit share.

However, he also pointed out that the new indication would prove more favorable for Genentech, of South San Francisco, as it essentially paves the road for a second-generation anti-CD20 antibody that if approved would trigger more Rituxan revenue for Genentech, as Biogen Idec’s profit share would drop to 30 percent.

Calling the new indication "a modest near-term growth driver," Kantor noted that more data are needed for Rituxan "to garner a meaningful piece of the multibillion-dollar market opportunity." Underscoring his point, he said data for Orencia (abatacept, from Bristol Myers Squibb Co.) and Rituxan are "remarkably similar" in anti-TNF failure patients, but Orencia could win out among those patients because of Rituxan’s B-cell depletion and potential safety concerns.

Its label documents the "slight" increase in serious infections among Rituxan patients compared to those on placebo, Agarwal said, as well as the fact that 32 percent of Rituxan patients had infusion-related events within 24 hours of receiving the drug compared to 23 percent of placebo patients.

Nonetheless, Kantor said the approval marked an "important entry point" in autoimmunity, a space in which Rituxan has demonstrated efficacy and continues to be tested in advanced trials for lupus and multiple sclerosis. The rheumatoid arthritis approval "will likely increase off-label use in other autoimmune diseases," Kantor said.

Not long ago, he and others were concerned that Rituxan might not even get clearance in rheumatoid arthritis, worries that arose partly from safety concerns.

But the FDA based its decision on data from three randomized, double-blinded, placebo-controlled studies. Results of a pivotal Phase III trial called REFLEX showed that a significantly greater proportion of patients who received a single treatment course of two 1,000 mg infusions of Rituxan with a stable methotrexate dose achieved American College of Rheumatology (ACR) 20, 50 and 70 response rates compared to patients who received placebo and methotrexate. Importantly, Agarwal noted that the efficacy results were "durable" and observed for up to six months.

The study included patients with active rheumatoid arthritis who had an inadequate response or were intolerant to prior treatment with methotrexate and one or more TNF antagonist therapies such as Enbrel (etanercept, from Amgen Inc.), Humira (adalimumab, from Abbott Laboratories) and Remicade (infliximab, from Johnson & Johnson).

Last month, the FDA approved another label expansion for Rituxan’s use as a front-line combination agent in diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens in previously untreated patients. Biogen Idec is expected to file another supplemental biologics license application for Rituxan to treat indolent, front-line and maintenance non-Hodgkin’s lymphoma in the first half of this year.

Also going forward, the partners are jointly funding late-stage studies in additional autoimmune indications. Among them is a Phase III trial in earlier-stage rheumatoid arthritis, a Phase III study in extrarenal lupus, a Phase II trial in lupus nephritis, and studies in primary progressive multiple sclerosis and the relapsing-remitting form of the disease. In addition, the National Institutes of Health is sponsoring a Phase III trial testing Rituxan in patients with anca-associated vasculitis.

It was approved in the European Union under the trade name MabThera in June 1998, and is sold there and elsewhere in the world by F. Hoffmann-La Roche Ltd., save for Japan. There, Rituxan is co-marketed by Japanese companies. Roche, of Basel, Switzerland, filed for European approval in rheumatoid arthritis last fall.

For Biogen Idec, the next big company event is scheduled for next week when an FDA advisory committee meets to consider whether Tysabri (natalizumab) can return to the market as a treatment for multiple sclerosis. The FDA recently indicated that Biogen Idec and partner Elan Corp. plc, of Dublin, Ireland, can again dose the product as monotherapy in patients previously treated with Tysabri in prior clinical trials.

For Genentech, a coming milestone relates to Lucentis (ranibizumab), which is under FDA review for age-related macular degeneration. A decision is expected by the end of June, given its new priority review status, after which the drug is expected to quickly take hold of the wet AMD market.

On Wednesday, shares in Genentech (NYSE:DNA) lost 74 cents to close at $84.95, while Biogen Idec’s stock (NASDAQ:BIIB) slid 30 cents to $46.95.

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