Genentech and Biogen Idec Announce Top-Line Results from a Phase II/III Clinical Trial of Rituxan in Primary-Progressive Multiple Sclerosis

South San Francisco, Calif. and Cambridge, Mass. -- April 14, 2008 -- Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) today announced that a Phase II/III study of Rituxan® (rituximab) for primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period. Genentech and Biogen Idec will continue to analyze the study results and will submit the data for presentation at an upcoming medical meeting.

"We are disappointed in the outcome of the primary endpoint, but not surprised given the significant clinical challenges presented by PPMS," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. "There was some evidence of biologic activity, and we will continue to review all the data to better understand the role of B cells in MS."

"While the primary results are not what we had hoped, we continue to believe in the potential of B cell therapy for patients living with MS," said Michael Panzara, M.D., MPH, Vice President and Chief Medical Officer, Neurology Strategic Business Unit, Biogen Idec. "PPMS is widely considered a difficult form of MS to treat and historically no therapy has proven efficacy in this disease state."

About the Study
This Phase II/III randomized, double-blind, placebo-controlled, multi-center study was designed to evaluate the efficacy, safety and tolerability of four courses of Rituxan in patients with PPMS. A total of 439 patients from approximately 60 sites in the U.S. and Canada were randomized 2:1 to receive either four treatment courses of Rituxan six months apart or placebo. MRI evaluations were conducted at baseline, weeks 6, 48, 96 and 122.

Detailed safety data from the study is currently being evaluated. The incidence of overall adverse events was comparable between Rituxan and placebo treatment groups. Serious adverse events were 16.4 percent in the Rituxan arm versus 13.6 percent in the placebo arm, with an incidence of serious infections of 4.5 percent compared with <1.0 percent respectively. Infectious events reported in at least 10 percent of patients in either group included upper respiratory and urinary tract infections. Most infectious events in the Rituxan arm were reported as mild to moderate in severity, though events of greater severity were reported more frequently in patients receiving Rituxan. There were more infusion-related reactions with Rituxan, the majority of which were mild to moderate in severity. The companies continue to monitor the long-term safety of Rituxan treatment.

About MS and PPMS
MS is a chronic autoimmune disease where the body's immune system attacks the myelin sheath causing inflammation and destruction of this fatty, protective substance. The myelin sheath surrounds the body's nerve fibers in the central nervous system, which includes the brain, optic nerves and spinal cord. There are four generally accepted disease courses of MS with a wide variety of symptoms and variations of disease progression.

Symptoms of the disease vary from patient-to-patient. Neurological disability typically accumulates over time and may include weakness or fatigue; numbness or tingling; blurred vision, impaired color perception or visual loss; poor coordination of muscle movements; difficulty with bladder or bowel control; muscle stiffness (spasticity); speech problems and challenges with cognitive skills.

PPMS affects approximately 10 percent of the MS population and is evident by the slow and continuous progression of the disease. People with PPMS can experience plateaus in the progression of their disability, but generally do not experience distinct periods of relapse or remissions. The progressive nature of PPMS and severe debilitation associated with the disease can have a devastating impact on a patient's quality of life and ability to function.

About Rituxan
Rituxan, discovered by Biogen Idec, is a therapeutic antibody that first received Food and Drug Administration (FDA) approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B cell non-Hodgkin's lymphoma (NHL). It was also approved in the European Union under the trade name MabThera® in June 1998. In February 2006, Rituxan also received FDA approval in combination with methotrexate to reduce signs and symptoms and, in January 2008, to slow the progression of structural damage in adult patients with moderately-to-severely active RA who have had an inadequate response to one or more TNF-antagonist therapies. Rituxan is the first treatment for RA that selectively targets immune cells known as CD20-positive B cells. Rituxan does not target the entire immune system.

CD20 is not found on stem cells, pro-B cells (B cell precursors), normal plasma cells, or other normal tissues. Rituxan does not target plasma cells. These cells make antibodies that help fight infections.

Rituxan does not target stem cells in the bone marrow, and B cells can usually regenerate and gradually return to normal levels after treatment with Rituxan in about 12 months for most patients.

In addition, Rituxan received FDA approval in February 2006 for first-line treatment of previously-untreated patients with follicular NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy and in September 2006, also was approved for the treatment of non-progressing low-grade, CD20-positive, B cell NHL as a single agent, in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy, and for previously untreated diffuse large B cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemotherapy regimens.

Over the past ten years, there have been more than 1 million patient exposures to Rituxan.

Important Safety Information
Rituxan has been associated with fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions and progressive multifocal leukoencephalopathy (PML). Hepatitis B reactivation and cardiac arrhythmias and angina have also been observed. Patients should be closely observed for signs of infection if biologic agents and/or disease modifying anti-rheumatic drugs other than methotrexate are used concomitantly. Common adverse reactions (≥ 5%): hypertension, nausea, upper respiratory tract infection, arthralgia, pruritus, and pyrexia.

In addition to PPMS, for which there is currently no FDA-approved therapy, Rituxan is also being studied in other autoimmune diseases for significant unmet medical needs, including systemic lupus erythematosus, lupus nephritis and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis.

Genentech and Biogen Idec co-market Rituxan in the United States, and Roche markets MabThera in the rest of the world, except Japan, where Rituxan is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd. For a copy of the Rituxan full prescribing information, including Boxed Warning, please call 1-800-821-8590 or visit http://www.gene.com.

About Genentech
Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics for significant unmet medical needs. A considerable number of the currently approved biotechnology products originated from or are based on Genentech science. Genentech manufactures and commercializes multiple biotechnology products and licenses several additional products to other companies. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. 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. Founded in 1978, 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.

This press release contains a forward-looking statement regarding the potential of B cell therapy for patients living with MS. Such statement is a prediction and involves risks and uncertainties such that actual results may differ materially. Actual results may be affected by a number of factors including, but not limited to, unexpected safety, efficacy or manufacturing issues, the need for additional data or clinical studies, FDA actions or delays, failure to obtain or maintain FDA approval, competition, pricing, reimbursement, the ability to supply product, product withdrawals and new product approvals and launches, and intellectual property or contract rights. Please also refer to the risk factors described in Genentech and Biogen Idec's periodic reports filed with the Securities and Exchange Commission. Genentech and Biogen Idec disclaim, and do not undertake, any obligation to update or revise any forward-looking statements in this press release.

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Rituxan Shows Promise for MS

Cancer, Arthritis Drug May Help People With Multiple Sclerosis
By Salynn Boyles

WebMD Medical News Reviewed by Louise Chang, MD

Feb. 13 -- The novel cancer and rheumatoid arthritis drug Rituxan may prove to be a highly effective treatment for the most common form of multiple sclerosis, if results from a small, phase II trial are confirmed.

In the study, sponsored by the drug's manufacturers, patients with relapsing-remitting MS who were treated with a single course of Rituxan showed rapid reductions in the inflammatory brain lesions that are a hallmark of the disease.

And after nearly a year of follow-up, half as many patients treated with the drug had experienced clinically significant relapses as patients in the placebo arm of the study.

If the findings are confirmed in larger, phase III studies, the Rituxan research opens a new frontier for the study of the cause and treatment of MS, says lead author Stephen L. Hauser, MD, of the University of California, San Francisco (UCSF).

The study is published in the Feb. 14 issue of The New England Journal of Medicine.

"No matter what happens with Rituxan down the road, this represents a paradigm shift that has profound implications for our understanding of MS," he tells WebMD.

T Cells and B Cells
The leading treatments for MS target the T cells. The thinking has been that T-cell-mediated inflammation sends the immune system into overdrive, causing the body to attack itself.

MS occurs when this attack targets the protective insulation known as myelin, which protects nerve fibers of the central nervous system. Myelin helps nerve fibers transmit electrical signals.

Instead of targeting T cells, Rituxan targets specific immune cells called B cells.

Studies by the UCSF researchers and others suggest that B cells and related pathways play a key role in destroying myelin.

The study included 104 patients with relapsing-remitting multiple sclerosis treated with either two infusions of Rituxan separated by two weeks, considered one course of treatment, or placebo infusions.

The patients were followed for 48 weeks, and brain imaging was performed to look for areas of inflammatory lesions at weeks 4, 12, 16, 18, and 24.

The imaging revealed dramatic and very rapid improvements in these lesions.

By week 24, the Rituxan-treated patients showed 91% fewer lesions, compared with the placebo-treated patients, and the results were similar at week 48.

"What we found so stunning was not only that the drug worked, but that it worked almost immediately," Hauser says.

The patients who got Rituxan showed improvement in lesions with the first post-infusion MRI scan, taken just weeks after treatment ended.

"This could only have happened if the B cells themselves are the culprit and not the antibody," he says. "It sends us back to the lab to discover what it is about the B cell, independent of its impact on antibodies, that is at the center of what causes MS flares."

Rituxan Safety Concerns
Hauser says there were few treatment-related side effects among the patients in the study, but questions about the long-term safety of Rituxan remain.

Rituxan is approved for the treatment of non-Hodgkin's lymphoma (NHL) and rheumatoid arthritis.

Use of the drug has been linked to a rare but fatal brain infection known as progressive multifocal leukoencephalopathy (PML). But it is not clear if PML is caused by the drug or by the patients' underlying disease.

Until more is known and until Rituxan is approved for the treatment of MS, patients with multiple sclerosis should not use it, says John Richert, MD, the National Multiple Sclerosis Society's executive vice president for research and clinical programs.

"We really want to discourage off-label use," he tells WebMD. "We just don't know enough about its long-term safety."

But Richert agrees that the early findings offer the hope of a new direction in the study and treatment of MS.

"Within the limitations of what you would expect with a small trial of short duration, the (UCSF) results are very exciting," he says. "We are cautiously optimistic that the phase III trials will show the same degree of efficacy."

SOURCES:
Hauser, S.L., The New England Journal of Medicine, Feb. 14, 2008; vol 358: pp 676-688.
Stephen L. Hauser, MD, department of neurology, University of California, San Francisco.
John Richert, MD, executive vice president for research and clinical programs, National Multiple Sclerosis Society.
© 2008 WebMD, LLC. All rights reserved.

MabThera shows stable long-term arthritis safety

BARCELONA, June 13 (Reuters) - Roche Holding AG's (ROG.VX: Quote, Profile, Research) MabThera can deliver sustained benefits to rheumatoid arthritis patients and, significantly, its safety profile is unchanged even after multiple treatments, researchers said on Wednesday.

MabThera, already a top-selling cancer drug, is now also approved for use in rheumatoid arthritis and could be used in several other autoimmune diseases, such as lupus and multiple sclerosis.

It is likely to be given for longer periods in these conditions, raising concerns about potential side effects -- particularly infections, since the drug works by targeting B-cells in the immune system.

Data presented at the annual European Congress of Rheumatology, however, showed a low and unchanging rate of serious infections in patients receiving up to seven treatment courses at six- to 12-month intervals.

Follow-up results from a clinical study involving more than 1,000 patients also found the effectiveness of the drug in relieving symptoms was sustained or further improved with subsequent doses.

The data showed that after three courses of MabThera in patients who had an inadequate response to another class of biotech drugs, known as TNF inhibitors, the number achieving a 70-percent improvement in symptoms rose to 25 percent from 11 percent.

Edward Keystone, professor of medicine at the University of Toronto, who has worked with Roche in researching MabThera, said the long-term findings would allow physicians to make treatment decisions with confidence.

MabThera -- known as Rituxan in the United States, where it is sold by Genentech Inc. (DNA.N: Quote, Profile, Research) and Biogen Idec Inc. (BIIB.O: Quote, Profile, Research) -- is one of a number of new drugs for rheumatoid arthritis -- is one of a number of new drugs for rheumatoid arthritis recently approved or in late-stage development.

Roche believes worldwide sales of MabThera, already a blockbuster in cancer, could also eventually top $1 billion a year in rheumatoid arthritis and other autoimmune diseases.

The Swiss group has made rheumatoid arthritis a priority for the future and hopes it will become a major driver of the business in the years ahead.

Roche is also developing a second novel medicine for the crippling disease, called Actemra, which could get to market in 2008. Behind that, it has an antibody drug called ocrelizumab that is just entering final Phase III development.

((Reporting by Ben Hirschler; Editing by Louise Ireland; email: ben.hirschler@reuters.com; Reuters Messaging: ben.hirschler.reuters.com@reuters.net; +44 20 7542 5082)) Keywords: ARTHRITIS ROCHE/

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Cancer Drug Rituxan Cuts MS Flare-ups

Studies Show Multiple Sclerosis Patients Taking Rituxan Have Fewer Brain Lesions
By Charlene Laino

WebMD Medical News
Reviewed by Louise Chang, MD

May 1, 2007 (Boston) -- A drug that is already used to treat cancer and rheumatoid arthritis cut by more than half the chance that people with multiple sclerosis would have their symptoms flare up over a six-month period, researchers report.

In two early studies, people taking the drug, Rituxan, also had fewer areas of damage, or lesions, in their brain than those on placebo.

"We believe that if we can prevent these lesions, we can modify the course of this disease," says researcher Stephen Hauser, MD, chairman of neurology at the University of California, San Francisco, and president of the American Neurological Association.

If the research pans out, "this would be a very attractive and probably blockbuster therapy," he tells WebMD.

The research was presented at the American Academy of Neurology's 59th Annual Meeting.



How Rituxan Works
The exact cause of multiple sclerosis (MS) is unknown. But the disease is thought to be triggered by a malfunction in the immune system that prompts immune cells to attack the brain and/or spinal cord. The most common form of multiple sclerosis is a relapsing-remitting form in which relapses or "attacks" of worsening neurologic function appear, and then disappear, for months or years at a time.

Like many other drugs for MS, Rituxan targets the immune system to help calm the inflammation that scars nerves, leading to disease progression. But Rituxan homes in on the immune system in a brand new way, Hauser says.

The drug works by targeting cells in the immune system called B cells, which make antibodies that contribute to the disease process. B cells also secrete chemicals that can encourage inflammation, he says.

Though never compared head-to-head, the early research hints that the drug is twice as effective as drugs such as interferon that are now used to treat multiple sclerosis, he says.

Also, it's more convenient, requiring only two infusions every six months or so instead of the daily to weekly injections associated with current therapies, Hauser says.

Fewer Flare-ups in People on Rituxan
Both of the new studies involved people with the relapsing-remitting form of MS. In the first study, 69 people were given two one-hour infusions of Rituxan two weeks apart and 35 were given a placebo.

Over the next six months, 58% fewer people taking the drug had their symptoms flare up than those taking placebo: 14.5% of those on Rituxan experienced at least one relapse compared with 34.3% of those receiving a placebo.

Also, those on Rituxan had 91% fewer brain lesions seen on MRIs than those on placebo, Hauser says.

The second study, designed to look at the safety of the drug, showed "no unexpected problems," says researcher Amit Bar-Or, MD, of the Montreal Neurological Institute at McGill University in Montreal.

Twenty-six of 28 people were able to complete the 48-week study, in which they received two infusions of Rituxan two weeks apart and then another course six months later.

Most side effects were limited to mild to moderate reactions to the drug infusion, such as headaches and chills, Bar-Or tells WebMD. The two people who dropped out had infusion-related headaches.

Both studies were supported by Genentech Inc., and Biogen Idec., the companies that market the drug for certain types of lymphoma and for a moderate to severe form of rheumatoid arthritis in the U.S.

Safety a Concern
Gary Birnbaum, MD, director of the Multiple Sclerosis Treatment and Research Center in Golden Valley, Minn., says a big worry is a rare but rapidly fatal viral infection known as progressive multifocal leukoencephalopathy, or PML.

And while people on Rituxan appear to have fewer MS flare-ups, "we still don't know if it will actually stop disease progression," Birnbaum tells WebMD.

"These are important observations," Birnbaum says. "But we need longer trials to assess safety and effectiveness."

Immediate Drug Therapy Better Than Waiting
In a third study presented at the meeting, researchers reported that people who immediately start taking Betaseronat the first signs of MS are 41% less likely to have another attack over the next three years than those who delay treatment until they are diagnosed, as is currently done.

Betaseron is a brand of the interferon beta medications that are already used to treat people with relapsing-remitting MS. Other brands of interferon beta, which may reduce the frequency of relapses and delay disability, are Avonex and Rebif.

"I was one of those skeptics who told patients [who had one attack] we could wait," says researcher Mark S. Freedman, MD, director of the Multiple Sclerosis Unit at the University of Ottawa.

"But it turns out there is an 80% chance a person who has one attack will meet the criteria for MS by two years," he tells WebMD. "Immediate treatment can prevent or delay the chance of progression."

Freedman says it's possible that immediate treatment with the other interferon beta medications would provide the same benefit. "But it hasn't been shown."

SOURCES: American Academy of Neurology 59th Annual Meeting, Boston, April 29-May 5, 2007. Stephen Hauser, MD, chairman of neurology, University of California, San Francisco; president, American Neurological Association. Gary Birnbaum, MD, director, Multiple Sclerosis Treatment and Research Center, Golden Valley, Minn. Amit Bar-Or, MD, Montreal Neurological Institute, McGill University, Montreal. Mark S. Freedman, MD, director, Multiple Sclerosis Unit, University of Ottawa.

© 2007 WebMD, Inc. All rights reserved.

Insurer Ordered to Pay $40,000 for 'Off-Label' Use of Biologic Drug Rituxan

State insurance officials in New York have ordered a major health insurance provider to pay $40,000 to reimburse a young woman for “off-label’’ use of the world’s best-selling cancer treatment, biologic drug Rituxan.

It’s unclear what impact the ruling against United Healthcare will have, but it illuminates an increasingly-embattled corner of healthcare: When doctors decide to use costly biologics to treat conditions for which they have not been approved, are managed care providers required to pay?

Drugs like Rituxan, which the FDA has approved to treat non-Hodgkin's lymphoma and rheumatoid arthritis, are among the priciest on the market. But physicians and researchers have discovered that these biologics may be the most effective treatment for other intractable illnesses.

So, doctors try such “off-label” uses. Evidence suggests that Rituxan, for example, works on lupus, multiple sclerosis and the strain of Hodgkin’s disease that Jennifer McDonald had.

McDonald was first diagnosed with Hodgkin’s disease in 2004, when she was 17. After a standard chemotherapy treatment, the disease went into remission. When it recurred in 2005, her physician, Dr. Jennifer Pearce, turned to Rituxan, along with a new chemotherapy regimen.

Rituxan, a recombinant chimeric monoclonal antibody which binds to a key class of white blood cells, was developed jointly by Biogen-Idec Inc. of Cambridge, Mass. and Genentech Inc. of San Francisco. It had sales of $1.8 billion in the United States in 2005, more than any other cancer drug.

The new treatment worked for McDonald. But the young woman’s insurer refused to pay the $40,000 bill for the biologic, arguing that it wasn’t approved for use in treating Hodgkin’s disease, according to state records. McDonald, backed by Dr. Pearce and attorneys from the Albany Law School near her home in upstate New York, fought the denial.

The state insurance department turned to an expert panel to hear the appeal. Three doctors who specialize in treating cancer reviewed the medical literature and concluded that Rituxan was an appropriate treatment, “likely to be more beneficial than any other existing standard health service” to treat McDonald.

New York state officials told the Biologic Drug Report the ruling sets no immediate precedent beyond McDonald’s case, and it is unclear as to whether the decision will prompt the insurer to change any of its policies.

A United Healthcare representative sidestepped detailed questions, indicating only that “there are sometimes differing opinions" about whether a drug should be covered.

The law professor who helped represent McDonald, Prof. Joe Connors, said he wonders how many times life-saving therapies -- particularly costly biologics -- aren’t even tried following an initial rejection. “Many patients around the country might not had as zealous an advocate as Dr. Pearce and might choose to not prescribe it in the first place,’’ he said.

But with a number of biologics in clinical trials for possible future approval for additional indications, there are sure to be more battles ahead over whether managed care should pay for “off-label” uses of new therapies.

It’s an issue that’s of concern to many insurers, said Mohit M. Ghose, a spokesman for America's Health Insurance Plans, a trade group. “There’s a lot of conversation as to how these high-end cancer drugs and biotechnology drugs are handled."

-- by Matt Pacenza