January 2, 2003
Promising results from an early-phase clinical trial of the monoclonal antibody natalizumab (Antegren®; Biogen Inc., Cambridge MA and Elan Corporation, PLC, Dublin) in relapsing forms of MS were recently published:
Promising results from an early-phase clinical trial of the monoclonal antibody natalizumab (Antegren®; Biogen Inc., Cambridge MA and Elan Corporation, PLC, Dublin) have now been published, showing that the drug caused a reduction in accumulation of new enhancing lesions detected by magnetic resonance imaging (MRI) and a reduction in relapses of MS. These findings were originally reported at the 17th Congress of the European Committee on Treatment and Research in MS, in Dublin on September 15, 2001. David H. Miller, MD (Institute of Neurology, Queen Square, London) and colleagues in the International Natalizumab MS Trial Group now have published their findings in the January 2, 2003 issue of The New England Journal of Medicine (2003;348:15-23).
Antegren is a molecule designed to interfere with movement of potentially damaging immune cells from the bloodstream, across the “blood-brain barrier,” and into the brain and spinal cord. This monoclonal antibody blocks this movement by attaching to alpha 4-integrin, a protein on the surface of immune T cells which enables them to bind to and pass through the blood-brain barrier. Antegren was initially developed by Elan and is now being co-developed by Elan and Biogen. Early animal studies demonstrated that the antibody could be effective, and early toxicity studies suggested that it was safe to pursue in a larger clinical trial.
Two hundred and thirteen individuals with relapsing-remitting MS or secondary progressive MS with relapses were studied at 26 clinical centers in the U.S., United Kingdom and Canada. Individuals were given one of two doses of Antegren (3 or 6 mg per kilogram of body weight) or inactive placebo, delivered by infusion into the vein (intravenous) once every four weeks, for six months. The trial was double-blinded, meaning that neither physicians nor study participants knew who was on placebo and who was on experimental treatment.
The primary goal of the study was to evaluate safety and to determine the drug’s impact on accumulation of new “enhancing” MRI lesions. Secondary goals included evaluation of Antegren’s impact on MS relapses and progression of disability. Self-reports of participants’ well-being were also evaluated.
According to published results, Antegren significantly reduced the accumulation of new lesions detected by gadolinium-enhanced MRI. An average of 9.6 new lesions were seen in the placebo group, and 0.7 and 1.1 new lesions seen in the low- and high-dose Antegren groups, respectively. Relapses were also reduced: 27 placebo-treated patients experienced relapses during the six-month treatment period, compared with 13 and 14 relapses in the low- and high-dose Antegren groups. When treatment was stopped, new MRI-detected lesions and relapses reappeared. No changes in measures of disability were detected in any of the groups during the study. Subjects treated with placebo reported a slight worsening in well-being, while both Antegren treatment groups reported improvements.
Antegren was relatively well tolerated. The most common side effects included headache, weakness, urinary tract infection and an overall trend to increased rate of infection. Those treated with Antegren also showed more gastroenteritis, rash, urinary urgency, back pain and infrequent allergic-type reactions.
This short-term clinical trial showed promising results for an agent
that appears to have a highly specific – and different – mode of action
than currently available treatments. This study demonstrates that targeting
movement of immune cells into the central nervous system is a reasonable
approach to treatment of MS. Longer-term, controlled trials involving greater
numbers of individuals are required to determine whether Antegren can safely
benefit those with MS. Such studies of Antegren are underway, alone and
in combination with Avonex® (interferon beta-1a) in persons with relapsing-remitting
MS. Further information about those trials is available on the National
MS Society’s Web site in the section on Clinical Trials.
© 2003 The National Multiple Sclerosis Society