The efficacy of natalizumab in patients with relapsing multiple sclerosis: Subgroup analyses of AFFIRM and SENTINEL

Dept. of Neurology, St. Vincent's University Hospital, Dublin, Ireland.
Journal of Neurology (Impact Factor: 3.38). 04/2009; 256(3):405-15. DOI: 10.1007/s00415-009-0093-1
Source: PubMed


The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, > or = 3), Expanded Disability Status Scale score (< or = 3.5, > 3.5), number of T2 lesions (< 9, > or = 9), presence of gadolinium-enhancing (Gd+) lesions (0, > or = 1), age (< 40, > or = 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., > or = 2 relapses in the year before study entry and > or = 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: > or = 9 T2 lesions at baseline, > or = 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment. These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.

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Available from: Bianca Weinstock-Guttman,
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    • "In this subgroup, annualized relapse rate was reduced by 81% in the AFFIRM and by 76% in the SENTINEL trials, respectively (each P < 0.001).36 With respect to radiological outcome parameters, the mean number of new gadolinium enhancing lesions decreased by 84% in AFFIRM and by 96% in the SENTINEL trial (P < 0.001, respectively).36 Thus, current approval is supported by post hoc subgroup analyses of the two phase III clinical trials. "
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    ABSTRACT: Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08-3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.
    Journal of Central Nervous System Disease 04/2014; 6:41-49. DOI:10.4137/JCNSD.S14049
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    • "Moreover, our sample of patients is fully representative of the MS patient population treated with NTZ in southern Switzerland as all patients receiving NTZ in this region are treated at our site, and clinical and radiological characteristics of the patients included in the study were similar to remaining NTZ treated patients at our site (data not shown). Moreover, we postulate that our study population is well representative of a typical NTZ treated population as included patients experienced over 90% reduction of annualized relapse rate under NTZ treatment compared to the two years before NTZ initiation, which is in line with the known efficacy of NTZ in active MS patients [39,40]. A second limitation of this sub-analysis is represented by the lack of specific scales for assessment of mood disorders, even though the FAMS questionnaire includes items related to physiological wellness. "
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    ABSTRACT: De-escalating natalizumab (NTZ) to interferon beta 1b (IFN B 1B) is a possible treatment option in multiple sclerosis (MS) patients interrupting NTZ because of increased risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to evaluate satisfaction and adherence to treatment, behavioral and fatigue changes in patients switched to IFN B 1B compared to continued NTZ treatment. A 1 year, prospective, randomized, rater-blinded, parallel-group study. Nineteen relapsing remitting (RR) MS patients, randomly assigned to undergo either NTZ (n = 10) or IFN B 1B (n = 9) treatment, who had previously received NTZ for at least 12 months with disease stability and fearing or at risk for PML were included. Patients underwent behavioral and treatment assessments at baseline, after 24-week and 1 year follow-up. Behavioral assessment included measures of cognition, fatigue and quality of life. Treatment assessment included measures of satisfaction, persistence and adherence to treatment. Clinical-radiological disease activity and safety were also assessed. Baseline characteristics of patients were similar between groups except for Euro Quality Visual Analogue Scale, being higher in the NTZ group (p = 0.04). Within-group comparisons at the three time points, as well as interaction analysis of treatment effect over time did not show any statistically significant differences in behavioral or treatment assessments, but a coherent trend favoring NTZ over IFN B 1B. De-escalating NTZ to IFN B 1B is feasible and associated with overall good patient related outcome and persistently stable behavioral measures.
    BMC Neurology 02/2014; 14(1):38. DOI:10.1186/1471-2377-14-38 · 2.04 Impact Factor
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    • "Similarly, natalizumab reduced disability progression by 42% sustained at 12 weeks and by 54% sustained at 24 weeks [6], whereas fingolimod performed comparably to interferon (37% reduction sustained at 24 weeks with both) [23,24]. In a subgroup analysis of AFFIRM data, patients with very active MS (>2 relapses in previous year and Gd-enhancing lesions at baseline) had reductions of 81% in ARR, and 53% and 64% reduction in sustained (12 and 24 weeks, respectively) disability progression with natalizumab [25]. Equivalent figures for fingolimod were 63% and 22% [26]. "
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    ABSTRACT: Natalizumab, a highly specific alpha4-integrin antagonist, , has recently been registered across the Middle East and North Africa region. It improves clinical and magnetic resonance imaging (MRI) outcomes and reduces the rate of relapse and disability progression in relapsing-remitting multiple sclerosis (MS). Natalizumab is recommended for patients who fail first-line disease-modifying therapy or who have very active disease. Progressive multifocal leukoencephalopathy is a rare, serious adverse event associated with natalizumab.We aim to develop regional recommendations for the selection and monitoring of MS patients to be treated with natalizumab in order to guide local neurological societies. After a review of available literature, a group of neurologists with expertise in the management of MS met to discuss the evidence and develop regional recommendations to guide appropriate use of natalizumab in the region. Disease breakthrough is defined as either clinical (relapse or disability progression) or radiological activity (new T2 lesion or gadolinium-enhancing lesions on MRI), or a combination of both. Natalizumab is recommended as an escalation therapy in patients with breakthrough disease based on its established efficacy in Phase III studies. Several factors including prior immunosuppressant therapy, anti-John Cunningham virus (JCV) antibody status and patient choice will affect the selection of natalizumab. In highly active MS, natalizumab is considered as a first-line therapy for naive patients with disabling relapses in association with MRI activity. The anti-JCV antibody test is used to assess anti-JCV antibody status and identify the risk of PML. While seronegative patients should continue treatment with natalizumab, anti-JCV antibody testing every 6 months and annual MRI scans are recommended as part of patient monitoring. In seropositive patients, the expected benefits of natalizumab treatment have to be weighed against the risks of PML. Clinical vigilance and follow-up MRI scans remain the cornerstone of monitoring. After 2 years of natalizumab therapy, monitoring should include more frequent MRI scans (every 3-4 months) for seropositive patients, and the risk-benefit ratio should be reassessed and discussed with patients. Recommendations have been developed to guide neurologists in the Middle East and North Africa on patient selection for natalizumab treatment and monitoring.
    BMC Neurology 02/2014; 14(1):27. DOI:10.1186/1471-2377-14-27 · 2.04 Impact Factor
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