Rituximab (Rituxan) plus methotrexate combo denied approval for rheumatoid arthritis treatment

Rituximab (Rituxan), a blood cancer drug from Genentech, Inc and Biogen Idec has been denied approval for treating patients with rheumatoid arthritis (RA) who no longer respond to treatment with a disease modifying antirheumatic drug (DMARD), including methotrexate (MTX).

Rituximab (Rituxan) cannot be approved for treating people with with RA who have not previously received methotrexate (MTX) or those who were MTX inadequate responders due to the rare risk of progessive multifocal leukeoencephalopathy (PML).

A number of effective RA treatments currently available to patients in earlier stages of the disease risk progressive multifocal leukeoencephalopathy (PML).

PML is a usually fatal brain disease caused by the reactivation of a common virus called the JC virus.

Although the incidence of PML in RA patients treated with rituximab (Rituxan) is rare (as of today, three reports out of approximately 100,000 patients), there are no known reliable PML treatments.

“We are committed to patient safety and understand the Agency`s decision, given the uncertainty regarding the risk of PML, and we will discuss next steps with the FDA to determine an appropriate path forward,” said Hal Barron, MD, executive vice president, Global Development and chief medical officer,Genentech.

Genentech, which is currently controlled by Roche, and Biogen Idec received a Complete Response from the U.S. Food and Drug Administration (FDA) for a supplemental Biologics License Application (sBLA) for rituximab (Rituxan) plus methotrexate (MTX) in patients with moderately-to-severely active rheumatoid arthritis (RA) who no longer respond to treatment with a disease modifying antirheumatic drug (DMARD), including MTX.

US FDA, however, approved an additional sBLA submission from the companies to include updated safety and efficacy data in the label that provides guidance on how later-stage
patients, those who have inadequately responded to tumor necrosis factor (TNF)-antagonist therapies, can be retreated with Rituxan.

Rituximab (Rituxan) prescribing information will now include that subsequent courses of the standard Rituxan regimen (two doses at 1000 mg each) can be administered every 24 weeks
or based on clinical evaluation.

Subsequent courses of Rituximab (Rituxan) should not be administered sooner than 16 weeks. Rituxan`s ability to improve physical function and slow joint damage for up to two years as demonstrated in clinical studies has also been added.

Rituximab (Rituxan) was approved for patients with moderately-to-severely active RA who have inadequately responded to one or more tumor necrosis factor (TNF)-antagonist therapies in 2006.

The current indications for Rituximab (Rituxan) in certain blood cancers remain unchanged.

Genentech and Biogen Idec’s sBLs included data from five Rituxan Phase III RA studies: SUNRISE,REFLEX, SERENE, IMAGE and MIRROR, in addition to long-term safety data from the
overall RA clinical trial experience.

SUNRISE was the first randomized, double-blind, placebo-controlled study assessing controlled retreatment with Rituxan in moderately-to-severely active RA patients who had an inadequate response to previous treatment with at least one TNF-antagonist.

Patients received one course of Rituxan at the 1000 mg dose plus MTX and were then randomized at week 24 to received treatment with either Rituxan plus MTX or placebo plus MTX.

At 48 weeks of the 318 patients retreated with a second course of Rituxan, 54 percent achieved an ACR20 response compared to 45 percent of the 157 patients who received one course of Rituxan and were retreated with placebo.

In addition, among the week 24 ACR20 responders, a significantly greater proportion of patients who received two courses of Rituxan maintained the response at 48 weeks, compared to patients who received one course of Rituxan.

REFLEX was a randomized, double-blind, placebo-controlled study that evaluated a course of Rituxan in 517 patients who had an inadequate response to TNF-antagonists

The study showed that Rituxan was effective in improving signs and symptoms in these patients and was the basis for Rituxan`s first approval for RA in 2006. This study has also shown at one year that Rituxan treatment slowed the progression of structural damage in RA in patients who are TNF-IR and led to an FDA approval in 2008. Slowing of progression of structural damage in the majority of these RA patients has been maintained at two years.

More patients receiving Rituxan plus MTX, had no progression of structural damage than in year one (68 percent vs. 60 percent), and the majority (87 percent) of the patients who had no progression of structural damage in year one also experienced no progression in the second year, following year two of treatment.

While, IMAGE was a randomized, double-blind, placebo-controlled study that evaluated the effect of placebo plus MTX compared to two doses of Rituxan plus MTX in patients with moderately-to-severely active RA who had not received prior MTX treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both Rituxan dose groups and were higher than in the placebo group.

SERENE was a 24-week placebo-controlled study that evaluated Rituxan in 509 DMARD-IR patients who had an inadequate response to treatment with MTX. Patients in the study treated with a single course of two infusions of Rituxan in combination with a stable dose of MTX showed a statistically significant higher ACR20 response rate compared to patients who received placebo in combination with MTX.

MIRROR investigated the efficacy and safety profile of three fixed treatment regimens of Rituxan in combination with MTX in 378 patients with active RA. Two courses of each of the three regimens were given to patients in the study 24 weeks apart. The randomized, double-blind, international study showed that patients in all three Rituxan treatment groups had similar ACR responses at 48 weeks.

Safety profile of Rituxan in the SUNRISE, REFLEX, SERENE, IMAGE and MIRROR studies was consistent with other trials in RA patients. The rates of serious infections and acute infusion reactions were similar to previous trials.

While the efficacy of Rituxan was supported in four controlled trials in patients with RA
with prior inadequate responses to non-biologic DMARDs, and in a controlled trial in MTX-naïve patients, a favorable risk-benefit relationship has not yet been established in these populations.

Rituxan is a therapeutic antibody that binds to a particular protein, the CD20 antigen found on the surface of malignant cells as well as normal B-cells. In non-Hodgkin`s lymphoma (NHL) and autoimmune disorders such as RA, Rituxan works with the body`s own immune system to eliminate marked CD20-positive B-cells. Stem cells (B-cell progenitors, those cells that give rise to B-cells) in bone marrow do not have the CD20 protein. Therefore, B-cells regenerate after Rituxan treatment and return to normal levels in about 12 months for most patients.

Rituxan, discovered by Biogen Idec, first received FDA approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent. Rituxan was also approved in the European Union under the trade name MabThera in June 1998.

Rituxan received FDA approval for rheumatoid arthritis in February 2006.

Genentech and Biogen Idec co-market Rituxan in the U.S., and Roche markets MabThera in the rest of the world, except Japan, where Rituxan is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd.

Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics. Genentech, a wholly-owned member of the Roche Group, has headquarters in South San Francisco, California.

Biogen Idec addresses diseases such as lymphoma, multiple sclerosis, and rheumatoid arthritis.