Abstract Details

Title Pharmacodynamic Biomarkers of Interferon ß-1a: Assessment in Patients Receiving Long-Term Treatment with Subcutaneous Interferon ß-1a

Topic Multiple Sclerosis

Presentation(s) P13 - Poster Session 13 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-007

Objective Evaluate candidate biomarkers for their potential as pharmacodynamic markers in long-term scIFNβ-1a administration in a large patient cohort.

Background Several pharmacodynamic biomarkers have been described in patients treated with interferon (IFN) β. While some biomarkers are well established i.e. neopterin, 2’5’-oligoadenylate synthetase (2’5’OAS), and Myxovirus protein A (MxA), there is little evidence for the use of soluble TNF related apoptosis inducing ligand (TRAIL), interferon-γ inducible protein (IP-10) and interleukin-1 receptor antagonist (IL-1RA) as pharmacodynamic markers upon subcutaneous (sc) IFNβ-1a administration on long-term treatment.

Design/Methods Biomarkers (neopterin, 2’5’OAS, TRAIL, IP-10, IL-1RA) were measured in serum samples using validated assays. Serum samples were collected at baseline (month [M] 0), M6, M12, M18 and M24 from 448 REFLEX trial patients with clinically isolated syndrome (CIS) who received scIFNβ-1a 44μg administered once (ow) or three times weekly (tiw), or placebo. Whole-blood MxA gene expression was measured at M0 and M24. In the extension trial, REFLEXION, 302 patients with CIS or who converted to multiple sclerosis (MS) were followed up to 5 years; neopterin, IP-10 and TRAIL serum levels were analyzed every 6 months. The pharmacodynamic effect of each biomarker was tested following scIFNβ-1a administration using linear mixed effect models with biomarker expression as the independent variable, biomarker expression at M0, treatment arm, gender and time as fixed effects, and subject as a random effect.

Results All investigated biomarkers were significantly up-regulated 1.5-4 fold in response to scIFNβ-1a treatment versus M0. For each biomarker, upregulation versus M0 was maintained over the 5-year monitoring period and dose-dependent. No changes were observed in placebo patients; the greatest changes were observed with scIFNβ-1a 44μg tiw, and intermediate changes were observed with scIFNβ-1a 44μg ow.

Conclusions Neopterin, 2’5’OAS, MxA, IL-1RA and - on long-term treatment - TRAIL and IP-10 were confirmed as pharmacodynamic markers associated with scIFNβ-1a treatment.

Authors/Disclosures
Mark S. Freedman, MD, F�鶹��ýӳ�� (University of Ottawa) PRESENTER	Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion(Janssen/J&J). Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BiogenIdec. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS/Celgene. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Inc. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion (Janssen/J&J). Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer Healthcare. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BiogenIdec. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRI Bio. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Magenta Therapeutics. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Freedman has received research support from Sanofi Genzyme.
	No disclosure on file
	No disclosure on file
Yann Hyvert, PhD (Merck Healthcare KGaA)	Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany. An immediate family member of Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany.
	No disclosure on file
	No disclosure on file
Fernando Dangond, MD, F�鶹��ýӳ��	Dr. Dangond has received personal compensation in the range of $1,000,000+ for serving as a Head, Global Clinical Development (employee for 12 years) with EMD Serono.

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