A New and More Successful Means of Treating Multiple Sclerosis
Abstract & Commentary
Synopsis: Treatment with natalizumab, an antibody to a4 integrin, led to fewer inflammatory brain lesions and fewer relapses in patients with relapsing multiple sclerosis.
Source: Miller DH, et al. N Engl J Med. 2003;348:15-23.
In patients with multiple sclerosis, inflammatory lesions appear to arise from an autoimmune response involving lymphocytes and monocytes. The glycoprotein a4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an antibody against a4 integrin that reduced the development of brain lesions in experimental models in a preliminary study of patients with multiple sclerosis.
In a randomized, double-blind trial, Miller and colleagues randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the 6-month treatment period. Clinical outcomes included relapses and self-reported well-being.
There were marked reductions in the mean number of new lesions in both treatment groups—9.6% in the placebo group, as compared to 0.7% in the group given 3 mg of natalizumab per kilogram (P = 0.001) and 1.1% in the group given 6 mg per kilogram (P < 0.001). Twenty-seven patients in the placebo group had relapses as compared to 13 in the group given 3 mg per kilogram (P = 0.02) and 14 in the group given 6 mg per kilogram (P = 0.02). The placebo group reported a slight worsening in well-being, whereas the groups receiving natalizumab reported improvement.
Comment by Ralph R. Hall, MD, FACP
Safety and tolerability is an important aspect of new trials such as this. In this study, similar numbers of patients in each group had adverse events during treatment. Eleven serious events occurred in 7 patients in the placebo group, 5 serious events in 5 patients in patients receiving the 3-mg dose and 4 events occurred in 3 patients in the group receiving 6 mg. Four of these events were considered to be immune-mediated and related to the study drug. One subject receiving natalizumab had an anaphylactoid reaction, which was rapidly reversed with antihistamines and corticosteroids.
It is of note that the reductions in the formation of lesions was approximately 90% in both the 3- and 6-mg doses of natalizumab and was thus greater than the reduction of 50-80% reported with beta-interferons and of approximately 30% with glatiramer acetate. Further, the patients receiving natalizumab had improved feeling of well-being and did not experience the flu-like symptoms and painful injection sites that are experienced with the interferons.
Binding antibodies against the natalizumab developed in 11% of the patients. It is not known whether this will affect more continuous treatment.
In the same issue of this edition of the New England Journal of Medicine, Ghosh and colleagues report the use of natalizumab for the treatment of active Crohn’s disease. Natalilzumab increased the rates of clinical remissions and improved the quality of life.1 This study found that natalizumab significantly lowered the levels of C-reactive protein, an acute phase reactant whose measurement is used to quantify generalized inflammation. (Both the multiple sclerosis and the Crohn’s disease studies were funded by Elan Pharmaceuticals and Biogen.)
These reports are encouraging, but, as usual, longer studies are in order. There are still the concerns of whether the autoimmune response in multiple sclerosis is the primary cause of the disease or an epiphenomenon of another disease process. Our treatments directed at the autoimmune process, therefore, may not be as effective as targeting the initiating event.
Dr. Hall is Emeritus
Professor of Medicine at University of Missouri-Kansas City School of Medicine.
Reference
1. Ghosh S, et al. N Engl J Med. 2003;348:24-32.
Treatment with natalizumab, an antibody to a4 integrin, led to fewer inflammatory brain lesions and fewer relapses in patients with relapsing multiple sclerosis.
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