A Controlled Trial of Natalizumab for Relapsing MS

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NEJM Volume 348:15-23 January 2, 2003 Number 1

A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

H. , M.D., A. Khan, M.D., A. Sheremata, M.D.,

Lance D. Blumhardt, M.D., P.A. Rice, M.D., Michele A. Libonati,

M.S., J. Willmer-Hulme, Ph.D., M. Dalton, M.B.,

A. Miszkiel, M.B., W. O'Connor, M.D., for the

International Natalizumab Multiple Sclerosis Trial Group

ABSTRACT

Background In patients with multiple sclerosis, inflammatory brain

lesions appear to arise from autoimmune responses involving activated

lymphocytes and monocytes. The glycoprotein 4 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 4 integrin antagonist that reduced the development of

brain lesions in experimental models and in a preliminary study of

patients with multiple sclerosis.

Methods In a randomized, double-blind trial, we 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 six-month

treatment period. Clinical outcomes included relapses and self-reported

well-being.

Results There were marked reductions in the mean number of new lesions

in both natalizumab groups: 9.6 per patient in the placebo group, as

compared with 0.7 in the group given 3 mg of natalizumab per kilogram

(P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram

(P<0.001). Twenty-seven patients in the placebo group had relapses, as

compared with 13 in the group given 3 mg of natalizumab per kilogram

(P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram

(P=0.02). The placebo group reported a slight worsening in well-being (a

mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the

natalizumab groups reported an improvement (mean increase of 9.49 mm in

the group given 3 mg of natalizumab per kilogram and 6.21 mm in the

group given 6 mg of natalizumab per kilogram).

Conclusions In a placebo-controlled trial, treatment with natalizumab

led to fewer inflammatory brain lesions and fewer relapses over a

six-month period in patients with relapsing multiple sclerosis.

Source Information

From the Institute of Neurology, London (D.H.M., C.M.D., K.A.M.); Wayne

State University School of Medicine, Detroit (O.A.K.); the University of

Miami School of Medicine, Miami (W.A.S.); University Hospital,

Nottingham, United Kingdom (L.D.B.); the London Multiple Sclerosis

Clinic, London, Ont., Canada (G.P.A.R.); Elan Pharmaceuticals, San

Francisco (M.A.L., A.J.W.-H.); and St. 's Hospital, University of

Toronto, Toronto (P.W.O.).

Address reprint requests to Dr. at the Department of

Neuroinflammation, Institute of Neurology, Queen Sq., London WC1N 3BG,

United Kingdom, or at d.miller@....