Journal
JOURNAL OF NEUROLOGY
Volume 259, Issue 5, Pages 898-905Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00415-011-6275-7
Keywords
Multiple sclerosis; Natalizumab; Outcomes; Cognitive function; Hospitalization; Corticosteroids
Categories
Funding
- Czech Ministry of Education [MSM 0021620849]
- Biogen Idec Inc.
- Biogen Idec
- Teva Neurosciences
- EMD Serono
- Pfizer
- Novartis
- Acorda
- National MS Society
- National Institutes of Health
- Shire
- Bayer Schering HealthCare
- Elan
- FivePrime
- Genzyme
- GlaxoSmithKline
- GW Pharma
- Ironwood
- Merck Serono
- Protein Discovery Laboratories
- sanofi-aventis
- Teva
- Vertex Pharmaceuticals
- UCB Pharma
- Teva Aventis
- Merz
- Actelion
- Advanacell
- Allozyne
- BaroFold
- Bayer HealthCare Pharmaceuticals
- Bayer Schering Pharma
- Bayhill
- BioMarin
- CLC Behring
- Genmab
- GeNeuro SA
- Genmark
- Lilly
- MediciNova
- Novo Nordisk
- Peptimmune
- Santhera
- Roche
- UCB
- Wyeth
- Swiss MS Society
- Swiss National Research Foundation
- European Union
- Gianni Rubatto Research Foundation
- Roche Research Foundation
- Bayer
- Genentech
- Antisense Therapeutics
- Schering AG
- Bayer Schering
- Novartis Research Foundation
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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 (IFN beta-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 a parts per thousand yen4.0 (P < 0.001) and a parts per thousand yen6.0 (P = 0.002) compared with placebo. Natalizumab + IFN beta-1a significantly reduced changes in EDSS scores compared with placebo + IFN beta-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 IFN beta-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 + IFN beta-1a (P < 0.001). These analyses underline beneficial effects of natalizumab therapy in relapsing MS patients.
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