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ANTEGREN: The New Drug Treatment for Multiple Sclerosis
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Antegren, a humanized monoclonal antibody, is one of the first in a new class of potential therapeutics known as alpha 4 integrin inhibitors that are designed to prevent migration of inflammatory cells from blood vessels to sites of inflammation. Monoclonal antibodies are synthesized in pure form from a single clone of cells in the laboratory. These antibodies can be made in large quantities and have a specific affinity for nearly any target molecule of interest.
Antegren binds to cell surface receptors known as alpha-4-beta 1 (VLA-4) and alpha-4-beta-7 integrins. These receptors help white blood cells, particularly T lymphocytes and eosinophils, move from the inside of blood vessels out into the tissues of the body at sites of inflammation, where these cells then participate in the inflammatory process. Blocking these receptors with Antegren prevents the cells from contributing to inflammation by preventing their migration and subsequent activation.
Elan Corporation, plc and Biogen, Inc. are collaborating on the development, manufacture and marketing of Antegren for use in inflammatory conditions such as Crohn’s disease and multiple sclerosis (MS).
Antegren was discovered in Elan’s research facilities in South San Francisco. Data on Antegren have been reported in peer-reviewed literature and at international meetings over the past few years. In 1992, Elan scientists first described a role for alpha-4 integrin in an animal model of MS. (Yednock et al., Nature, vol. 356, pp. 63-66.)
In 1995, an extension of the early findings demonstrating prevention of demyelination in a guinea pig model was presented in the Journal of Neuroimmunology. (Kent et.al., Journal of Neuroimmunology, vol. 58, pp. 1-10.)
An extension of the guinea pig model into a more chronic phase of the disease was presented in the October, 1996 issue of Neurology. (Keszthelyi et al., Neurology, vol. 47, pp. 1053-1059.)
The description of Antegren as a humanized antibody was presented in 1997 in Human Antibodies. (Leger et al., Human Antibodies, vol. 8, pp. 3-16.)
Tubridy et.al. (Neurology, August 1999) studied the effect of Antegren on active lesions with magnetic resonance imaging (MRI) in multiple sclerosis patients. This study concluded that “short-term treatment with monoclonal antibody against alpha 4 integrin results in a significant reduction in the number of new active lesions on MRI.” In addition, two abstracts reporting encouraging data on Antegren in Crohn’s disease in ulcerative colitis were presented at the American Gastroenterological Association Digestive Disease Week meetings in Miami, Florida in May 1999.
More recently, results from a Phase 2 study of Antegren in Crohn’s disease were presented at the May 2001 annual meeting of the American Gastroenterological Association Digestive Disease Week. Antegren demonstrated promising results on multiple endpoints. This Phase 2 study (CD 202) enrolled 248 moderate-severely active patients with Crohn’s disease (Crohn’s Disease Activity Index (CDAI) score 220-450). The randomized, double-blind, placebo-controlled, parallel group study was conducted across eight countries at 35 sites. The patients were randomized to one of four treatment groups: a single 3 mg/kg Antegren infusion; two 3 mg/kg Antegren infusions at a 4-week interval; two 6 mg/kg Antegren infusions at a 4-week interval; or placebo. Patients were followed for 12 weeks following the first infusion and were assessed using the CDAI and changes in quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (“IBDQ”).
A statistically significant difference in clinical response (decrease of >70 points in CDAI) was noted as early as week two and was maintained through week 12 with a maximal response of 71% in the 3mg/kg dose group versus 38% in the placebo group. Remission, defined as a CDAI score of <150, was achieved by 44% of patients in the 3 mg/kg dose group versus 27% in the placebo group. There was also a statistically significant difference in the change from baseline IBDQ score in patients receiving two infusions of Antegren as compared to those receiving placebo at both week 6 and week 12.
Overall, Antegren was well tolerated with the most common adverse events being headache and abdominal pain. There were no notable differences among treatment groups in the number of patients reporting side effects.
In addition to its potential as a treatment for Crohn’s disease, Antegren has also been evaluated in a Phase 2 multiple sclerosis (MS) study. Results of the Phase 2 study were presented in September 2001, at the annual meeting of the European Congress on Treatment and Research in Multiple Sclerosis (ECTRIMS).
The trial was a Phase 2, double-blind, placebo-controlled trial of 213 MS patients at 26 sites in the U.S., Canada, and the U.K. Patients received either of two Antegren 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 Antegren for 6 months had fewer new gadolinium-enhancing lesions than patients treated with placebo. In the placebo group (n=71), the cumulative mean number of new enhancing lesions during the treatment period was 9.6, whereas the Antegren 3 mg/kg group (n=68) had a mean of 0.7 new lesions and the Antegren 6 mg/kg group (n=74) had accumulated a mean of 1.1 lesions during the same period.
Secondary endpoints in the study included the change in the MSFC (MS Functional Composite) and in the EDSS (Expanded Disability Status Score) over the treatment phase. There were no changes seen in these parameters in either the placebo or treatment groups over the 6 months of treatment.
The number of MS relapses over the treatment period—one of the pre-specified clinical endpoints in the trial—was also reduced, with 38% of the placebo group compared to 19% in the Antegren groups experiencing relapse.
Antegren was generally well tolerated in the study. The most common adverse events in the study were headache, asthenia, and urinary tract infections. Certain adverse events occurred more commonly with Antegren compared to placebo, such as gastroenteritis, rash, urinary urgency, back pain, and fever. Additionally, serious adverse events included infrequent hypersensitivity-like reactions.
Elan and Biogen announced in December 2001 that Phase 3 studies of Antegren in both MS and Crohn’s disease were underway. Biogen and Elan are collaborating on two trials in MS. The AFFIRM (Antegren 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 Antegren is effective in slowing the rate of clinical relapses. The second trial, known as SENTINEL (safety and efficacy of Antegren in combination with Avonex® (interferon beta-1a) in subjects 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 will be one of the largest conducted in MS, is designed to determine whether the treatment of MS with Antegren 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 two Phase 3 clinical trials in Crohn’s disease. The first Phase 3 trial, the largest to be conducted in Crohn’s disease, is a randomized, multi-center, placebo-controlled, double blind study of approximately 850 patients, which is designed to measure both the response and the ability to induce remission in patients at week 10 of administration of Antegren. The second randomized, multi-center, placebo-controlled, double blind Phase 3 trial of approximately 300 patients is designed to evaluate the effect of Antegren on the duration of response and remission in patients with Crohn’s disease.
Resource: Elan
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