Efficacy of Natalizumab Therapy in Patients of African Descent With Relapsing Multiple Sclerosis:  Analysis of AFFIRM and SENTINEL Data FREE

Patients with multiple sclerosis (MS) who are of African descent may experience a more aggressive disease course than patients who are of white race/ethnicity. Patients of African descent tend to have more frequent relapses, worse postrelapse recoveries, faster transition from relapsing remitting to secondary progressive MS, and more rapid accumulation of ambulatory disability.^1- 5 Genetic factors seem to at least partially influence susceptibility to MS and modify the disease course.^5- 7

In addition, the response to treatment with interferon beta-1a seems attenuated in this population.⁵ Clinically important differences may exist between patients of African descent and patients of white race/ethnicity with respect to treatment response. The apparently diminished treatment response in patients of African descent with MS could be due to differences in the natural history of the disease, including environmental and genetic factors, differential responses to treatment, or a combination of these variables.

In the pivotal Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trials, natalizumab was shown to be effective as monotherapy^8- 9 and in combination with interferon beta-1a¹⁰ in large diverse groups of patients with relapsing MS. The objectives of this meta-analysis were to assess the efficacy of natalizumab use in patients of African descent with relapsing MS who participated in these studies and to determine if the efficacy in this subgroup was comparable with that in the overall study population.

Patients of African descent who participated in the AFFIRM^8- 9 or SENTINEL¹⁰ trial were included in this post hoc analysis; the inclusion criteria for these phase 3 studies were previously published. In the AFFIRM trial, the study population was randomized 2:1 to receive natalizumab (300 mg) or placebo by intravenous infusion once every 4 weeks for up to 116 weeks. In the SENTINEL trial, the study population was randomized to receive natalizumab (300 mg) or placebo by intravenous infusion once every 4 weeks plus intramuscular interferon beta-1a (30 μg) once weekly for up to 116 weeks. Analyses were performed among patients of African descent who participated in these studies and who at screening identified their racial/ethnic origin as “black.”

To achieve adequate patient numbers for analysis, data from the 2 studies were combined. Hence, the placebo group consists of patients randomized to placebo in AFFIRM and to placebo plus intramuscular interferon beta-1a in SENTINEL, while the natalizumab-treated group consists of patients randomized to natalizumab monotherapy in AFFIRM and to natalizumab plus intramuscular interferon beta-1a in SENTINEL. “Study” was excluded as a stratification factor for analyses because sample sizes were too small to investigate differences in results between the 2 trials.

Treatment effects on the following efficacy end points at 2 years were assessed: annualized relapse rate (ARR), time from first dose to first relapse, number of new or enlarged T2-weighted lesions, number of gadolinium-enhancing lesions, changes in T1-weighted and T2-weighted lesion volumes, change in Expanded Disability Status Scale (EDSS) score from baseline, and time from first dose to sustained disability progression (defined as a ≥1.0-point increase in EDSS from a baseline EDSS of ≥1.0 or a ≥1.5-point increase in EDSS from a baseline EDSS of 0, sustained for 12 weeks or 24 weeks). Magnetic resonance imaging measurements were assessed at the Central MRI Analysis Center at the Institute of Neurology, University College London, London, England.^8,10

The following statistical analysis methods were used for each end point. The statistical models included the same covariates as were used in the previous analyses. The ARR was analyzed using Poisson regression with overdispersion adjusted for the number of relapses in the year before study enrollment, baseline EDSS (≤3.5 vs >3.5), presence of gadolinium-enhancing lesions at baseline, and age (<40 vs ≥40 years). The time from first dose to first relapse was analyzed using a Cox proportional hazards model adjusted for the number of relapses in the year before study enrollment. A rank-based analysis of covariance was used to compare changes in T2-weighted and T1-weighted lesion volume over 2 years, number of new or enlarged T2-weighted lesions over 2 years, number of gadolinium-enhancing lesions at 2 years, and change in EDSS from baseline at 2 years. Each model was adjusted for the corresponding baseline value. Missing data were not imputed. The time from first dose to sustained (12 week and 24 week) disability progression was analyzed using a Cox proportional hazards model adjusted for baseline EDSS and age (<40 vs ≥40 years).

One of us (A.L.P.) performed the statistical analysis using commercially available software (SAS Institute Inc, Cary, North Carolina). Biogen Idec provided files containing all data described herein to the UCSF Multiple Sclerosis Center. Another of us (B.A.C.C.) verified the results by performing a replication statistical analysis with this data set using a different software program (STATA, version 9.0; StataCorp LP, College Station, Texas).

Forty-nine patients of African descent participated in either study: 6 patients from the AFFIRM study and 22 patients from the SENTINEL study were in the placebo arms, and 4 patients from the AFFIRM study and 17 patients from the SENTINEL study were in the natalizumab-treated arms. Of 49 patients, 36 patients (73%) completed the studies; 13 patients (27%) withdrew (7 from the placebo arm and 6 from the natalizumab-treated arm). Two patients (1 from each treatment arm) discontinued the study drug but completed the study follow-up. Demographic and baseline disease characteristics are given in Table 1. Overall, the 2 study arms were fairly well matched at baseline, but some slight imbalances caused by randomization were not stratified by race/ethnicity. Patients in the placebo arm showed a trend toward more relapses in the year before study enrollment than participants in the natalizumab-treated arm. Placebo patients also had a higher median baseline T1-weighted hypointense lesion volume. Because important baseline factors were included in the statistical models to assess treatment effect, all inferences were adjusted for baseline imbalances.

Natalizumab therapy significantly reduced the ARR over 2 years compared with placebo. The unadjusted ARR was 63% lower in the natalizumab-treated group (0.80 vs 0.30, P = .01). After adjusting for baseline covariates, the treatment effect remained significant (Figure 1A). Natalizumab therapy also significantly reduced the risk of first relapse by 68% over 2 years compared with placebo (Figure 1B).

Natalizumab therapy had a significant effect on magnetic resonance imaging outcomes over 2 years in patients of African descent (Table 2). Natalizumab use significantly reduced the mean number of new or enlarged T2-weighted lesions over 2 years by 90% and the mean number of gadolinium-enhancing lesions at 2 years by 79% compared with placebo. Natalizumab therapy also significantly reduced changes in T2-weighted and T1-weighted lesion volume over 2 years compared with placebo (Figure 2).

In Table 3, the relative effects of natalizumab use on relapses and magnetic resonance imaging outcomes in participants of African descent vs non-African descent are compared among the present study, AFFIRM, and SENTINEL. Similar results were found when the participants of non-African descent were restricted to those of white race/ethnicity (data not shown).

Statistically significant benefits of natalizumab use on disability were not found in this data set. The mean (median) changes in EDSS at 2 years were 0.03 (0.0) for natalizumab and 0.60 (0.50) for placebo (P = .22). The estimated hazard ratios were 0.789 (95% confidence interval, 0.283-2.199; P = .65) for time to 12-week sustained disability progression and 0.578 (95% confidence interval, 0.105-3.170; P = .53) for time to 24-week sustained disability progression. The large confidence intervals and nonsignificant P values do not allow any definite conclusions about an effect on disability over 2 years and are anticipated owing to the small sample size.

One patient in the natalizumab-treated group was persistently positive for antinatalizumab antibodies during the course of treatment. This patient experienced disability progression (at 12 weeks and at 24 week), had the largest change in EDSS at 2 years (3.0 points), and demonstrated the most relapses (n = 4), gadolinium-enhancing lesions (n = 3), and new or enlarged T2-weighted lesions (n = 10) among patients of African descent in the natalizumab-treated group over 2 years.

Among 49 patients, 100% (28 of 28) of placebo and 95% (20 of 21) of natalizumab-treated patients reported at least 1 adverse event. Blurred vision was reported by 29% (6 of 21) of natalizumab-treated patients vs no placebo patients. Table 4 gives adverse events experienced by at least 5 patients in either study group. The overall incidence of adverse events among this subpopulation was similar to that among the overall study populations.^8- 10

Patients of African descent typically exhibit a more aggressive course of MS characterized by rapid progression of disability, more frequent relapses, and worse postrelapse recoveries. Little research on treatment in this population has been reported. The limited available data suggest that this patient population does not seem to respond to treatment with interferon beta as robustly as their counterparts of white race/ethnicity; however, it is unclear whether the observed reduced response is due to a treatment effect or differences in the natural history of the disease.⁵

A limitation of the present study is that race/ethnicity was self-identified. Patients of African descent with MS in the United States and Europe are often an admixed population, and genetic determination of the extent of admixture could not be used in this study because DNA was not collected from the study participants. The extent of African-origin HLA DNA and the presence of the null mutation of HLA -DRB5 are associated with more severe disability outcomes in African Americans with MS.^4,6 Therefore, it is possible that these genetic factors are uncontrolled confounders in our study and could bias the observations if they were disproportionately represented in the placebo group.

The present post hoc analysis included patients with MS of African descent who participated in the pivotal AFFIRM and SENTINEL trials. The pooling of data in this meta-analysis allowed for adequate numbers for assessment, and the inclusion of data from the SENTINEL trial seemed reasonable, especially because patients of African descent might be less responsive to treatment with interferon beta-1a.⁵ However, assuming that interferon beta-1a has at least some efficacy in patients of African descent, the inclusion of many patients who were actively receiving interferon beta-1a in the placebo group would be expected to attenuate the differences between the placebo and natalizumab-treated groups and could result in underestimation of the effect of natalizumab use on disease activity in this data set. To our knowledge, this is the first study to examine and demonstrate efficacy of an MS disease–modifying therapy among this population in the context of placebo-controlled trials.

This analysis demonstrated statistically significant reductions in relapses and magnetic resonance imaging lesion activity with natalizumab treatment. Although analyses of disability progression did not show statistically significant differences between the placebo and natalizumab-treated groups (possibly owing to the small sample size), the positive trend seen for change from baseline in EDSS, along with a similar effect on time to sustained disability progression, is encouraging and should be explored further. Because patients of African descent tend to have more severe disease and may be less responsive to interferon treatment, the findings from this study are relevant to clinicians who treat patients with MS.

In clinical practice, natalizumab is used primarily as a second-line therapy in patients who have had ongoing disease activity, despite treatment with interferons or glatiramer acetate, or in patients who cannot tolerate these medications. The results of the present study provide supporting evidence that natalizumab has beneficial effects in patients of African descent with MS. We believe that this information will be clinically helpful for neurologists who are contemplating the use of natalizumab in this patient population. Studying the effects of medications among patients of different racial/ethnic backgrounds raises ethical and technical challenges. Despite these challenges, the authors recommend further research with the goal of characterizing the efficacy of natalizumab treatment, as well as other disease-modifying therapies, in patients from various racial/ethnic backgrounds.

Correspondence: Bruce A. C. Cree, MD, PhD, MCR, UCSF Multiple Sclerosis Center, University of California, San Francisco, 350 Parnassus Ave, Ste 908, San Francisco, CA 94117 (bruce.cree@ucsf.edu).

Accepted for Publication: December 16, 2010.

Author Contributions:Study concept and design: Cree, Tornatore, Pace, and Cha. Acquisition of data: Cree. Analysis and interpretation of data: Cree, Stuart, Tornatore, Jeffery, Pace, and Cha. Drafting of the manuscript: Cree, Tornatore, Jeffery, Pace, and Cha. Critical revision of the manuscript for important intellectual content: Cree, Stuart, Tornatore, Jeffery, Pace, and Cha. Statistical analysis: Cree and Pace. Obtained funding: Cree. Administrative, technical, and material support: Jeffery and Cha. Study supervision: Tornatore, Jeffery, and Cha.

Financial Disclosure: This study was sponsored by Biogen Idec and by Elan Drug Technologies. Dr Cree has received honoraria from Biogen Idec, Elan Drug Technologies, and Teva Neurosciences for educational or consulting activities; has received grant support from BioMS/Lilly, EMD Serono, and Genentech; and is supported by grants from the National Institutes of Health and the National Multiple Sclerosis Society. Dr Stuart is a consultant or speaker for and has received research support from Biogen Idec. Dr Tornatore has received honoraria for speaking and consulting with Biogen Idec and Teva Neurosciences and has received grant support from Biogen Idec. Dr Jeffery has received honoraria for speaking and consulting with Biogen Idec, Bayer, Teva Neurosciences, EMD Serono, Pfizer, and GlaxoSmithKline and receives research support from Biogen Idec, Bayer, Teva Neurosciences, Serono, and Pfizer.

Additional Contributions: Katherine L. Hauswirth, RN, MSN, provided editorial support in the development of the manuscript. We wish to acknowledge the patients who participated in the AFFIRM and SENTINEL trials.