Saturday, Oct 17, 2009
South San Francisco, Calif. -- October 17, 2009 --Genentech, Inc. a wholly-owned member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), and Biogen Idec (Nasdaq: BIIB) announced today that the companies received a Complete Response from the U.S. Food and Drug Administration (FDA) for a supplemental Biologics License Application (sBLA) for Rituxan® (rituximab) 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.
The FDA has indicated that they do not believe an approval for Rituxan (in people with RA who have not previously received MTX or those who were MTX inadequate responders) can be supported at this time due to the rare risk of progessive multifocal leukeoencephalopathy (PML) in light of the number of effective RA treatments currently available to patients in earlier stages of the disease. 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 Rituxan is rare (as of today, three reports out of approximately 100,000 patients), there are no known reliable PML treatments.
The FDA approved an additional sBLA submission today 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. The prescribing information will now include language 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 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.
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 Rituxan in certain blood cancers remain unchanged. Additionally, the companies remain committed to their development programs for other anti-CD20 molecules in both oncology and immunology.
"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, M.D., executive vice president, Global Development and chief medical officer, Genentech. "We are encouraged by the FDA's decision to support retreatment for people in later stages of RA and continue to believe that Rituxan is effective in this setting."
"In more than eight large studies conducted, Rituxan has demonstrated that it can improve the symptoms of RA, an often debilitating disease," said David Hagerty, M.D., vice president and chief medical officer, Rheumatology, Biogen Idec. "Patients living with moderate-to-severe RA who have limited treatment options continue to benefit from Rituxan."
Both applications 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.
About the Studies
Rituxan retreatment in TNF-IR Patients
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. In the study, 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.
Effect of Rituxan on Structural Damage
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. Following year two of treatment, 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.
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.
Rituxan plus MTX in DMARD-IR Patients
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.
The 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. No new or unexpected safety signals were observed in these clinical 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. The use of Rituxan in patients with RA who have not had prior inadequate response to one or more TNF-antagonists is not recommended at this time.
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. It was also approved in the European Union under the trade name MabThera® in June 1998. Rituxan is also approved for the treatment of NHL for the following:
Rituxan therapy does involve risks. Life-threatening side effects related to Rituxan therapy include infusion reactions and kidney and skin problems, and progressive multifocal leukoencephalopathy (PML, a rare condition that causes nerve damage within the brain). Serious side effects have occurred in patients treated with Rituxan including hepatitis B virus infections with related serious liver problems, other viral infections, heart problems, kidney failure, and stomach and bowel problems.
The most common adverse reactions observed in Rituxan-treated patients include fever, chills and shakes, itching, hives, cough, sneezing, and throat irritation or tightness. These usually occur within 24 hours after the first infusion. Other common side effects include headache, nausea, upper respiratory tract infection, and aching joints.
For additional safety information, please see the full prescribing information, including Boxed WARNINGS and Medication Guide, at 1-800-821-8590 or visit http://www.gene.com.
Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics to treat patients with serious or life-threatening medical conditions. The company, a wholly-owned member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.
About Biogen Idec
Biogen Idec creates new standards of care in therapeutic areas with high unmet medical needs. Biogen Idec is a global leader in the discovery, development, manufacturing, and commercialization of innovative therapies. Patients in more than 90 countries benefit from Biogen Idec's significant products that address diseases such as lymphoma, multiple sclerosis, and rheumatoid arthritis. For product labeling, press releases and additional information about the company, please visit http://www.biogenidec.com.