Multiple sclerosis - natalizumab
While the precise causes of multiple sclerosis remain unknown, various processes are implicated in the formation of the inflammatory brain lesions that give rise to the symptoms. The lesions appear to result from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein α-4 integrin is expressed on the surface of these cells, and it is critical in the adhesion of the cells to the vascular endothelium, and migration into the parenchyma.
Biogen is developing the humanised monoclonal antibody natalizumab, first discovered by Elan, which is an α-4 integrin antagonist that has been shown to reduce the development in brain lesions in experimental models.
To determine the effect of natalizumab against α-4 integrin and the resulting activity on MRI lesion activity in MS patients, a randomised, double blind, placebo-controlled trial was carried out on 72 patients with active relapsing remitting or 428+secondary progressive multiple sclerosis.1
The patients were given two intravenous infusions of natalizumab or placebo four weeks apart, and were followed up for 24 weeks afterwards with serial MRI and clinical assessment. Those given the monoclonal antibody were shown to have significantly fewer new active lesions - 1.8 on average, compared with 3.6 for those given placebo - and 1.6 versus 3.3 new enhancing lesions. There was no significant difference in the number of new active or enhancing lesions in the second 12 weeks of the study.
A further, longer term, randomised, double blind trial has been carried out in a total of 213 patients.2 The subjects, all of whom had relapsing remitting or relapsing secondary progressive multiple sclerosis, were given 3 or 6mg/kg natalizumab or placebo every 28 days for six months. There were marked reductions in the mean number of new lesions in both groups of patients given the active, with 9.6 per patient in those given placebo, 0.7 in those given the lower dose, and 1.1 in the higher dosage group. A total of 27 of the 71 patients given placebo had relapses, compared with 13 of the 68 in the 3mg group and 14 of the 74 in the 6mg group.
Phase III trials of the antibody in MS patients continue. It is also being investigated as a potential treatment for Crohn's disease, where α4 integrins are one of the mediators of the migration of leukocytes from the circulation into the parenchyma, and their activation within inflammatory sites.3