Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis.
BACKGROUND
Natalizumab, a humanized monoclonal IgG4 antibody, is an alpha4-integrin antagonist, which inhibits the migration of inflammatory cells into the central nervous system, a key pathogenic mechanism in multiple sclerosis (MS). In a six month, phase II clinical trial of patients with relapsing MS, natalizumab significantly reduced the formation of new gadolinium-enhanced (Gd+) lesions and the number of clinical relapses.


OBJECTIVE
To investigate the relationship of historical relapse rate and new Gd + lesion number with subsequent MS disease activity and natalizumab treatment in the phase II study.


METHODS
Patients who participated in the phase II study were stratified into subgroups according to: (i) the number of relapses in the two years prior to entry into the study: 2 relapses (n = 108), 3 relapses (n =57), and >3 relapses (n =48); (ii) the number of new Gd + lesions at baseline (Month 0): 0 (n = 129), 1-2 (n =50), and >2 (n =33). Relapses and new Gd + lesions during the treatment phase of the trial were determined and compared for each subgroup.


RESULTS
Both the prestudy relapse rate and number of new Gd + lesions at baseline were related to the subsequent risk of a relapse; baseline number of Gd + lesions was related to the likelihood of subsequent new Gd + lesion formation. There was a lower proportion of subjects with an on-study relapse and fewer new Gd + lesions in all natalizumab-treated subgroups when compared with their placebo counterpart; the difference was most apparent in the subgroups of patients with >3 relapses in the two years prior to study entry and >2 new Gd -- lesions at Month 0.


CONCLUSIONS
There was a lower proportion of subjects with an on-study relapse in natalizumab-treated patients, particularly in those with a more active disease at study entry. Larger ongoing phase III studies will allow more definitive investigation of these preliminary subgroup findings.
O'Connor
Paul
P
Division of Neurology, St. Michael's Hospital, 30 Bond Street, Suite 3007S Shuter Wing, Toronto, Ontario, Canada. oconnorp@smh.toronto.on.ca
Miller
David
D
Riester
Katherine
K
Yang
Minhua
M
Panzara
Michael
M
Dalton
Catherine
C
Miszkiel
Katherine
K
Khan
Omar
O
Rice
George
G
Sheremata
William
W
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000069442:Natalizumab; D055502:Secondary Prevention; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab