Biogen and Elan are collaborating on the development, manufacturing and commercialization of natalizumab, the first in a new class of compounds known as selective adhesion molecule inhibitors (SAM inhibitors). The findings published in the NEJM are based on a Phase II study conducted and analyzed by Elan and Biogen. The study was a double blind, placebo-controlled trial of 213 MS patients at 26 sites in the U.S., Canada and the U.K. Patients received either one of two natalizumab doses (3 mg/kg or 6 mg/kg) or placebo by intravenous infusion every 4 weeks for 6 months. Participants in the trial had either relapsing-remitting MS or secondary progressive MS.
The primary analysis was based on MRI scans and showed that patients treated with natalizumab for 6 months had up to 93 percent reduction in new gadolinium-enhancing lesions compared to patients treated with placebo. The reduction in lesions was seen as early as one month after the first infusion and was sustained during the treatment period. A mean of 9.6 new enhancing lesions developed during the treatment period in the placebo group (n= 71) versus 0.7 and 1.1 in the 3 mg/kg (n= 68) and 6 mg/kg groups (n=74), respectively.
There was a reduction of approximately 50% in the number of patients experiencing a relapse in the natalizumab groups compared to placebo – a tertiary endpoint of the study. In the study, 38% of the placebo treated patients (27/71) experienced one or more relapses, compared with only 19% of patients in either group treated with natalizumab (13/68 with 3mg/kg and 14/74 with 6mg/kg natalizumab respectively).
Natalizumab appeared to be well tolerated at both dose levels in this study. Certain adverse events occurred more commonly with natalizumab compared to placebo, such as infection, urinary tract infection, pharyngitis and rash. However, there were no significant differences between the treated groups and placebo. Additionally, serious adverse events included infrequent hypersensitivity-like reactions.
"The Phase II results were promising and demonstrated the ability of natalizumab to reduce MRI activity and the number of relapses. Because of these results, Phase III studies are underway to investigate the potential of natalizumab as a new treatment option for people with MS," said David Miller, M.D., lead author of the NEJM study and Professor of Neurology, Institute of Neurology, London, United Kingdom.
"There is a need for new types of therapies in the battle against MS. These data indicate that natalizumab may hold promise in MS, and the new clinical studies that are underway will help us determine if that promise is realized," said Stephen C. Reingold, Ph.D., Vice President of Research Programs, National Multiple Sclerosis Society.
"Patients' response to natalizumab was encouraging. With its unique mechanism of action, natalizumab represents a new class of therapies that could help in the treatment of MS," said J. Theodore Phillips, Jr., M.D., Ph.D., an investigator in the Phase II and Phase III trials, Texas Neurology, Baylor University Medical Center.
New Mechanism of Action
Natalizumab is the first in a new class of drugs known as SAM (selective adhesion molecule) inhibitors. In MS, immune cells migrate through the blood-brain barrier into the brain leading to inflammation and destruction of the myelin sheath (the insulation for the nerves) and eventual nerve cell death. In Crohn's disease, a similar process of inflammation occurs but in the gastrointestinal tract. Adhesion molecules on the surface of the immune cells play an important role in the migration of these cells. Natalizumab binds to a specific adhesion molecule on the immune cell surface known as alpha-4 integrin. By binding to alpha-4 integrin, natalizumab may inhibit immune cells from leaving the bloodstream and prevent them from migrating into the brain or the inflamed gut tissue and worsening the disease condition.
Phase III Trials in MS Fully Enrolled
Based on the promising findings in Phase II, Biogen and Elan have collaborated on two Phase III trials in MS which are both fully enrolled. The AFFIRM (natalizumab safety and efficacy in relapsing-remitting MS) trial is a two year, randomized, multi-center, placebo-controlled, double blind study of approximately 900 patients designed to determine whether natalizumab is effective in slowing the rate of disability in MS and reducing the rate of clinical relapses. The second trial, known as SENTINEL (safety and efficacy of natalizumab in combination with AVONEX® (Interferon beta-1a) in patients with relapsing-remitting MS), is a two year, randomized, multi-center, placebo-controlled, double blind study of approximately 1,200 patients. The SENTINEL trial, which is one of the largest conducted in MS, is designed to determine whether the treatment of MS with natalizumab in combination with AVONEX is more effective than AVONEX treatment alone in slowing the rate of disability in MS and in reducing the rate of clinical relapses.
Elan and Biogen are also conducting Phase III trials in Crohn's disease. There are two trials in Crohn's disease: ENACT-1 (Evaluation of Natalizumab in Active Crohn's Disease Trial - 1), the largest-ever study in Crohn's disease conducted to date, is now fully enrolled with more than 850 patients and will evaluate clinical response and ability to induce remission; ENACT-2 (Evaluation of Natalizumab As Continuous Therapy - 2) will evaluate duration of effect. Investigators expect ENACT-2 to be fully enrolled shortly.
About Biogen
Biogen is the world's oldest independent biotechnology company and a leader in biologics research, development and manufacturing. A pioneer in leading edge research in immunology, neurobiology and oncology, Biogen brings novel therapies to improve patients' lives around the world through its global marketing capabilities. For press releases and additional information about the company, please visit http://www.biogen.com.
About Elan
Natalizumab was discovered in Elan's research facilities in South San Francisco, and both Elan and Biogen have pioneered research into this novel pathway. Elan is focused on the discovery, development, manufacturing, selling and marketing of novel therapeutic products in neurology, pain management and autoimmune diseases. Elan shares trade on the New York, London and Dublin Stock Exchanges.
Safe Harbor/Forward Looking Statements
This press release contains forward-looking statements regarding the potential for ANTEGREN (natalizumab) as a therapeutic product. These statements are based on the companies' current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Drug development involves a high degree of risk. Success in early stage clinical trials does not ensure that later stage or larger scale clinical trials will be successful. For example, natalizumab may not show as promising a therapeutic effect or safety profile in later stage or larger scale clinical trials. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards. Problems or delays may arise during clinical trials or in the course of developing, testing or manufacturing natalizumab. For more detailed information on the risks and uncertainties associated with the companies drug development and other activities see the companies' periodic reports filed with the Securities and Exchange Commission. The companies do not undertake any obligation to publicly update any forward-looking statements.
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Journal
New England Journal of Medicine