Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS.
Standard clinical endpoints in multiple sclerosis (MS) studies, such as disability progression defined by the expanded disability status scale (EDSS) and annualized relapse rate, may not fully reflect all aspects of therapeutic benefit experienced by patients. Pivotal studies showed that natalizumab is effective both as monotherapy (AFFIRM study) and in combination with interferon beta-1a (IFNβ-1a) (SENTINEL study) in patients with relapsing MS. We present AFFIRM and SENTINEL data demonstrating the efficacy of natalizumab on prespecified tertiary endpoints, including extent of confirmed change in EDSS score from baseline, time to sustained progression to EDSS milestone scores, hospitalizations, corticosteroid use, and time to confirmed progression of cognitive deficits. Natalizumab significantly reduced changes in EDSS scores (P < 0.001) and proportion of patients progressing to an EDSS score ≥4.0 (P < 0.001) and ≥6.0 (P = 0.002) compared with placebo. Natalizumab + IFNβ-1a significantly reduced changes in EDSS scores compared with placebo + IFNβ-1a (P = 0.011). Based on 0.5 standard deviation change in paced auditory serial addition test-3 score, natalizumab treatment reduced the risk of confirmed progression of cognitive deficits by 43% compared with placebo (HR 0.57 [95% CI 0.37, 0.89], P = 0.013); however, no significant difference between groups was seen in SENTINEL. Natalizumab, both as monotherapy and in combination with IFNβ-1a, significantly reduced the annualized rate of MS-related hospitalizations (by 64 and 61%, respectively) and the annualized rate of relapses severe enough to require steroid treatment (by 69 and 61%, respectively) compared with placebo and placebo + IFNβ-1a (P < 0.001). These analyses underline beneficial effects of natalizumab therapy in relapsing MS patients.
Jacobs Neurological Institute, Buffalo, NY 14203-1126, USA. bguttman@thejni.org
Bianca
B
Weinstock-Guttman
Steven L
SL
Galetta
Gavin
G
Giovannoni
Eva
E
Havrdova
Michael
M
Hutchinson
Ludwig
L
Kappos
Paul W
PW
O'Connor
J Theodore
JT
Phillips
Chris
C
Polman
William H
WH
Stuart
Frances
F
Lynn
Christophe
C
Hotermans
D000328:Adult; D000704:Analysis of Variance; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications / Q000188:drug therapy*; D000069442:Natalizumab; D009483:Neuropsychological Tests; D016016:Proportional Hazards Models; D013256:Steroids / Q000627:therapeutic use; D013997:Time Factors
D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D000069442:Natalizumab; D013256:Steroids; D016899:Interferon-beta