Jan. 2, 2003
Laurie Barclay, MD
The monoclonal antibody natalizumab reduces relapses of multiple sclerosis (MS) and increases rates of clinical remission for patients with Crohn's disease, according to the results of two studies reported in the Jan. 2 issue of the New England Journal of Medicine.
"Natalizumab is an alpha-4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with MS," write David H. Miller, MD, and colleagues from the International Natalizumab MS Trial Group.
In this double-blind, controlled trial, 213 patients with relapsing-remitting or relapsing secondary progressive MS were randomized to receive either 3 mg/kg or 6 mg/kg intravenous natalizumab or placebo every 28 days for six months.
After treatment, the mean number of new lesions on gadolinium-enhanced magnetic resonance imaging was 9.6 in the placebo group, 0.7 in the 3 mg/kg natalizumab group (P < .001), and 1.1 in the 6 mg/kg natalizumab group (P < .001 compared with placebo). These numbers were significant for both groups of MS patients.
Clinical relapses during the six-month treatment period occurred in 27 of 71 patients receiving placebo, in 13 of 68 patients receiving 3 mg/kg natalizumab (P = .02), and in 14 of 74 patients receiving 6 mg/kg natalizumab (P = .02).
Although well-being on a visual analogue scale was slightly worse after treatment in the placebo group (mean decrease, 1.38 mm on a 100 mm scale), it was better in the 3 mg/kg natalizumab group (mean increase, 9.49 mm) and in the 6 mg/kg natalizumab group (mean increase, 6.21 mm). Adverse events (such as headache or infection) were similar in all groups.
"Natalizumab had beneficial effects on clinical and imaging outcomes in patients with relapsing MS. Therapy was well tolerated during the six month trial," the authors write, acknowledging the need for longer-term data. "The effect of natalizumab on the progression of disability and its effect in direct comparison with existing therapies are not yet known."
Early studies have shown that the glycoprotein alpha-4 beta-1 integrin may play a role in the pathogenesis of MS. The glycoprotein is expressed on the surface of lymphocytes and monocytes and probably mediates the migration of these cells to the brain causing inflammation. It may also play a role in regulating immune cell activation, another hallmark of MS.
Other studies have shown that the same glycoprotein plays a role in Crohn's disease using a similar mechanism in the gut.
In a separate double-blind study by Subrata Ghosh, MD, and colleagues from the Natalizumab Pan-European Study Group, 248 patients with moderate to severe Crohn's disease were randomized to treatment with two infusions of placebo four weeks apart, one infusion of 3 mg/kg natalizumab followed by placebo, two infusions of 3 mg/kg natalizumab, or two infusions of 6 mg/kg natalizumab.
Both groups receiving two infusions of natalizumab had higher remission rates than the placebo group at multiple time points, although the group receiving two infusions of 6 mg/kg natalizumab did not have a significantly higher rate of remission at the week six primary end point than did the placebo group.
Rates of response, defined as a reduction of at least 70 points on the Crohn's Disease Activity Index, were significantly higher in the natalizumab groups, and ranged from 44% to 71% at week six in the group receiving two infusions of 3 mg/kg. All natalizumab groups improved in quality of life scores, and those receiving two infusions of natalizumab improved in C-reactive protein levels. Rates of adverse events were similar in all groups.
"On the basis of our short-term study, the efficacy of natalizumab for reducing signs and symptoms of Crohn's disease appears to be at least similar to that of the tumor necrosis factor alpha-inhibitor infliximab," the authors write. "Although our findings provide evidence of the efficacy and tolerability of natalizumab-mediated inhibition of alpha-4 integrin in the short-term treatment of moderate-to-severe Crohn's disease, the longer-term benefit and safety of this treatment and its value relative to other therapies for this condition remain to be defined."
Elan Pharmaceuticals, maker of natalizumab, sponsored these studies and has financial arrangements with some of the study authors.
In an accompanying editorial, Ulrich H. von Andrian, MD, PhD, and Britta Engelhardt, PhD, review the molecular biology of this new therapeutic and provide perspective on future developments and other autoimmune diseases that may likely benefit.
"The alpha-integrins have also been implicated in other inflammatory conditions such as ulcerative colitis, rheumatoid arthritis, insulitis, vaculitis, atherosclerosis, and asthma. Treatment with alpha-integrin antagonists may lead to improvement in at least some of these diseases," they write.
N Engl J Med. 2003;348(1):15-23, 24-32, 68-72
Reviewed by Charlotte E. Grayson, MD
Laurie Barclay, MD is a staff writer with WebMD.
Medscape Medical News 2003.
© 2003 Medscape