Predictive nature of IgM anti-α-glucose serum biomarker for relapse activity and EDSS progression in CIS patients: a BENEFIT study analysis

M S Freedman, C Metzig, L Kappos, C H Polman, G Edan, H-P Hartung, D H Miller, X Montalban, J Yarden, L Spector, E Fire, N Dotan, S Schwenke, V Lanius, R Sandbrink, C Pohl, M S Freedman, C Metzig, L Kappos, C H Polman, G Edan, H-P Hartung, D H Miller, X Montalban, J Yarden, L Spector, E Fire, N Dotan, S Schwenke, V Lanius, R Sandbrink, C Pohl

Abstract

Background: Higher serum levels of at least one of a panel of four α-glucose IgM antibodies (gMS-Classifier1) in clinically isolated syndrome (CIS) patients are associated with imminent early relapse within 2 years.

Objective: The objective of this study was to determine the prognostic value of gMS-Classifier1 in a large study cohort of CIS patients.

Methods: The BEtaseron(®) in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) 5-year study was designed to evaluate the impact of early versus delayed interferon-β-1b (IFNβ-1b; Betaseron(®)) treatment in patients with a first event suggestive of multiple sclerosis (MS). Patients (n = 258, 61% of total) with a minimum of 2 ml baseline serum were eligible for the biomarker study. gMS-Classifier1 antibodies' panel (anti-GAGA2, anti-GAGA3, anti-GAGA4 and anti-GAGA6) levels were measured blinded to clinical data. Subjects were classified as either 'positive' or 'negative' according to a classification rule.

Results: gMS-Classifier1 was not predictive for the time to clinically definite MS or time to MS according to the revised McDonald's criteria, but did significantly predict an increased risk for confirmed disability progression (log-rank test: p = 0.012).

Conclusions: We could not confirm previous results that gMS-Classifier1 can predict early conversion to MS in CIS. However, raised titres of these antibodies may predict early disability progression in this patient population.

Conflict of interest statement

Conflict of interest statement: MS Freedman is a consultant/advisory board member for Bayer HealthCare, Glycominds, Biogen Idec, Celgene, Merck Serono, Novartis, Sanofi-Aventis and Teva Neuroscience. He serves on steering committees for Bayer HealthCare, Merck Serono, Celgene, Biogen Idec, Novartis and Sanofi-Aventis.

L Kappos discloses that the University Hospital Basel has received research support from Bayer HealthCare, Biogen Idec, GlaxoSmithKline, Merck Serono, Novartis Pharmaceuticals, Sanofi-Aventis, Teva Pharmaceuticals, and Wyeth Pharmaceuticals. L Kappos has been principal investigator, member, or chair of steering committees or advisory boards in MS clinical trials sponsored by Abbott Laboratories, Bayer HealthCare, Bayhill, Berlex, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Centocor, Eisai, Genzyme, GlaxoSmithKline, Immune Response, Medicinova, Neurocrine, Novartis Pharmaceuticals, Sanofi-Aventis, Merck Serono, Roche, Teva Pharmaceuticals, UCB Pharma, and Wyeth, and has received lecture fees from one or more of these companies. Payments and consultancy fees have been exclusively used for the support of research activities.

C Polman has received consulting fees from Biogen Idec, Bayer HealthCare, Teva, Serono, Novartis, GlaxoSmithKline, UCB, AstraZeneca, Roche, and Antisense Therapeutics; lecture fees from Biogen Idec, Bayer HealthCare, Novartis, and Teva; grant support from Biogen Idec, Bayer HealthCare, GlaxoSmithKline, Novartis, Serono, and Teva.

G Edan received personal compensation for serving on an advisory board for BENEFIT, has received honoraria for consultation or research grants from Merck Serono, Biogen Idec, Teva-Aventis, LFB.

H-P Hartung has received honoraria and consultancy fees from, and participated as an investigator in phase 2 and 3 trials for, Biogen Idec, Bayer Vital, Bayer HealthCare, Genzyme, Merck Serono, Novartis and Teva Pharmaceuticals. H-P Hartung has received research grant support from Biogen Idec, Bayer Schering Pharma, Merck Serono, Teva Pharmaceuticals with approval by the rector of HHU.

DH Miller has received grant support from Biogen Idec, Novartis and GlaxoSmithKline for performance of MRI analyses in clinical trials, as well as honoraria for advisory or consultancy work, lectures, and related travel expenses from Biogen Idec, Bayer HealthCare, Novartis and GlaxoSmithKline.

X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer HealthCare, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall.

C Metzig, V Lanius, C Pohl, R Sandbrink, and S Schwenke are salaried employees of Bayer Pharma AG.

J Yarden, L Spector, E Fire, and N Dotan are salaried employees of Glycominds and hold stock options from Glycominds.

Figures

Figure 1.
Figure 1.
Kaplan–Meier curves for gMS-Classifier1 positive versus negative patients with respect to (A) time to clinically definite multiple sclerosis, (B) time to McDonald MS and (C) time to confirmed Expanded Disability Status Scale (EDSS) progression. *Log-rank test p-value for comparison of gMS-Classifier1 groups with respect to time-to-event variables. Analyses performed using sera set A.

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