Amy Pace

Anti-JC Virus Antibodies: Implications for PML Risk Stratification

A study was undertaken to establish an enzyme‐linked immunosorbent assay (ELISA) to detect JC virus (JCV)‐specific antibodies in multiple sclerosis (MS) patients, and to evaluate its potential utility for identifying patients at higher or lower risk (ie, risk stratification) of developing progressive multifocal leukoencephalopathy (PML).

Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study

BACKGROUND The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. METHODS Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. FINDINGS 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. INTERPRETATION Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

Anti–JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy

The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti–JC virus (JCV) antibodies. We analyzed whether anti‐JCV antibody levels, measured as index, may further define PML risk in seropositive patients.

Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis

Background: Validated measures of sustained improvements in neurological function have not been established for multiple sclerosis (MS) clinical studies. Objective: To evaluate sustained Expanded Disability Status Scale (EDSS) change as a potential indicator of neurological improvement and as an outcome measure in MS clinical studies. Methods: Analyses were performed on patients (n = 620) from the pivotal natalizumab study AFFIRM with baseline EDSS scores ≥2.0. Cumulative probabilities of neurological improvement, defined as a 1.0-point decrease in EDSS score sustained for ≥12 weeks, were estimated by Kaplan–Meier analysis. A Cox proportional hazards model identified associated baseline factors and examined treatment effects. Results: Sustained improvement (as well as sustained worsening) in neurological disability was seen in AFFIRM patients. Sustained EDSS changes correlated well with quality of life measurements (SF36 and VAS). Natalizumab increased the cumulative probability of improvement over 2 years by 69% versus placebo (HR = 1.69; 95% CI 1.16–2.45; p = 0.006). Sensitivity analyses showed consistent benefits of natalizumab with variations in improvement magnitude and duration, and baseline disease activity. Conclusion: These analyses demonstrate that sustained EDSS improvement is an additional measure that is sensitive to treatment effects over 2 years and correlates with quality of life. Further research is warranted to validate its use as an MS study clinical outcome.

Effect of neutralizing antibodies on biomarker responses to interferon beta The INSIGHT study

Background: Interferon beta (IFNβ) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNβ therapies. Biomarkers of the IFNβ response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNβ bioactivity. Methods: In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (≤8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNβ-1a, subcutaneous (SC) IFNβ-1a, or IFNβ-1b. Results: Treatment with IM IFNβ-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFNβ-1a 22 μg, 44 μg, and IFNβ-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb−)/NAb-negative (NAb−) patients (all p < 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers ≥100 TRU compared with BAb−/NAb− patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. Conclusions: These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.

Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a

Background: Findings from a small clinical study suggested that statins may counteract the therapeutic effects of interferon beta (IFNβ) in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFNβ-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of statins on efficacy of IFNβ. SENTINEL was a prospective trial of patients with RRMS treated with natalizumab (Tysabri®, Biogen Idec, Inc., Cambridge, MA) plus IM IFNβ-1a (Avonex®, Biogen Idec, Inc.) 30 μg compared with placebo plus IM IFNβ-1a 30 μg. Clinical and MRI outcomes in patients treated with IM IFNβ-1a only (no-statins group, n = 542) were compared with those of patients taking IM IFNβ-1a and statins at doses used to treat hyperlipidemia (statins group, n = 40). Results: No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-hyperintense lesions (p = 0.802) at 2 years. More patients in the statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the no-statins group. Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes. Conclusions: Statin therapy does not appear to affect clinical effects of IM interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.

Comparison of the Timed 25-Foot and the 100-Meter Walk as Performance Measures in Multiple Sclerosis

Background. Ambulation impairment is a major component of physical disability in multiple sclerosis (MS) and a major target of rehabilitation programs. Outcome measures commonly used to evaluate walking capacities suffer from several limitations. Objectives. To define and validate a new test that would overcome the limitations of current gait evaluations in MS and ultimately better correlate with the maximum walking distance (MWD). Methods. The authors developed the Timed 100-Meter Walk Test (T100MW), which was compared with the Timed 25-Foot Walk Test (T25FW). For the T100MW, the subject is invited to walk 100 m as fast as he/she can. In MS patients and healthy control volunteers, the authors measured the test–retest and interrater intraclass correlation coefficient. Spearman rank correlations were obtained between the T25FW, the T100MW, the Expanded Disability Status Scale (EDSS), and the MWD. The coefficient of variation, Bland–Altman plots, the coefficient of determination, and the area under the receiver operator characteristic curve were measured. The mean walking speed (MWS) was compared between the 2 tests. Results. A total of 141 MS patients and 104 healthy control volunteers were assessed. Minor differences favoring the T100MW over the T25FW were observed. Interestingly, the authors demonstrated a paradoxically higher MWS on a long (T100MW) rather than on a short distance walk test (T25FW). Conclusion. The T25FW and T100MW displayed subtle differences of reproducibility, variability, and correlation with MWD favoring the T100MW. The maximum walking speed of MS patients may be poorly estimated by the T25FW since MS patients were shown to walk faster over a longer distance.

Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate.

BACKGROUND In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0-3) with the recommended DMF dosage (240 mg twice daily). METHODS Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks. RESULTS The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing and related symptoms was 5% in the placebo group and 37% in the DMF group. Most GI and flushing events were of mild or moderate severity and resolved during the study. The events were temporally associated with the use of diverse symptomatic therapies (efficacy not assessed) and infrequently led to DMF discontinuation. CONCLUSIONS This integrated analysis indicates that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.

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

BACKGROUND Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (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]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important. OBJECTIVE To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS. DESIGN Post hoc analysis. SETTING Academic research. PATIENTS Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. MAIN OUTCOME MEASURE Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial. RESULTS Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group, P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91, P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52, P = .008). CONCLUSION Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

Natalizumab reduces relapse clinical severity and improves relapse recovery in MS

OBJECTIVES Compare relapse clinical severity, post-relapse residual disability, and the probability of confirmed complete recovery from relapse between patients who relapsed during natalizumab (n=183/627 [29%]) and placebo (n=176/315 [56%]) treatments in the AFFIRM trial. METHODS In this post-hoc analysis, relapse clinical severity and residual disability were defined by change in Expanded Disability Status Scale (EDSS) score occurring between pre-relapse and at-relapse assessment and between pre-relapse and post-relapse assessment, respectively. Patients were considered completely recovered from relapse when their post-relapse EDSS score was less than or equal to their pre-relapse EDSS score, and this was maintained for 12 or 24 weeks. RESULTS At relapse, an increase in EDSS score of ≥0.5 points occurred in 71% of natalizumab and 84% of placebo patients (P=0.0088); an increase of ≥1.0 point occurred in 49% of natalizumab and 61% of placebo patients (P=0.0349) (mean increase in EDSS at relapse: natalizumab=0.77; placebo=1.09; P=0.0044). After relapse, residual disability of ≥0.5 EDSS points remained in 31% of natalizumab and 45% of placebo patients (P=0.0136) (mean post-relapse residual EDSS increase: natalizumab=0.06; placebo=0.28; P=0.0170). In patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, natalizumab increased the probability of 12-week confirmed complete recovery from relapse by 55% (hazard ratio [HR]=1.554; P=0.0161) and 67% (HR=1.673; P=0.0319) compared to placebo, respectively. CONCLUSIONS In AFFIRM, natalizumab treatment decreased the clinical severity of relapses and improved recovery from disability induced by relapses. These beneficial effects would limit the step-wise accumulation of disability.