Scientific information about Antegren
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 II 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 II study (CD 202) enrolled 244 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 38 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 74% in the 3mg/kg dose group versus 38% in the
placebo group. Remission, defined as a CDAI score of <150, was achieved by 46%
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.
Elan and Biogen met with the FDA in mid May to discuss the Phase III Crohn�s
disease studies, which are designed to assess both the short-term treatment of active Crohn�s disease and to assess the long-term durability of responses with Antegren.
In addition to its potential as a treatment for Crohn�s disease, Antegren has also been evaluated in a Phase II multiple sclerosis (MS) study. Results of the Phase II 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 II, 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 that 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 0.6 new lesions and the Antegren 6 mg/kg group (n=74) had accumulated a mean of 1.2 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 34 relapses in the placebogroup compared to 19 in the Antegren 3mg/kg group and 14 in the Antegren 6 mg/kg group.
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.
Based on the positive Phase II findings in MS and Crohn�s disease, Elan and Biogen intend to move this compound into Phase III studies in both indications by the end of 2001. The companies are planning to start two Phase III studies in MS, studying Antegren as a monotherapy, as well as in combination with Biogen�s Avonex� (Interferon beta-1a).