Merck KGaA, Darmstadt, Germany

Author Of 1 Presentation

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0323 - Effect of neutralizing antibodies on pharmacodynamic biomarkers of subcutaneous interferon β-1a in REFLEX and REFLEXION (ID 959)

Speakers
Presentation Number
P0323
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Several pharmacodynamic (PD) biomarkers have been described in patients (pts) with multiple sclerosis (MS) treated with interferon β (IFNβ), each with variable degrees of evidence. Non-responders to IFNβ often produce neutralizing antibodies (NAbs), which are expected to diminish PD biomarker response to treatment (tx). In the REFLEX and REFLEXION trials, around 15% of subcutaneous (sc) IFNβ-1a treated pts developed NAbs.

Objectives

To evaluate the effect of NAbs on candidate pharmacodynamic biomarkers of long-term scIFNβ-1a therapy in a large pt cohort.

Methods

Biomarkers (neopterin, 2’5’-oligoadenylate synthetase [2’5’OAS], soluble TNF-related apoptosis-inducing ligand [TRAIL], interferon-γ inducible protein [IP-10], interleukin-1 receptor antagonist [IL-1RA]) were measured in serum samples using validated assays with appropriate quality standards applied. Samples from 448 clinically isolated syndrome (CIS) pts who received scIFNβ-1a 44 μg once (ow) or three (tiw) times weekly, or placebo (PBO) in REFLEX were collected at baseline (month[M]0), M6, M12, M18, M24. Whole-blood Myxovirus protein A (MxA) gene expression measured at M0, M24. In the extension trial, REFLEXION, 302 pts with CIS or who converted to MS were followed up to 5 yrs; neopterin, IP-10, TRAIL serum levels analysed every 6 months. The PD effect of each biomarker was tested upon scIFNβ-1a tx using linear mixed effect models (independent variable:biomarker expression; fixed effects:baseline biomarker expression, tx arm, gender, time; random effect:subject). Serum NAb levels were analyzed in pts from REFLEX and REFLEXION; PD data stratified by pt NAb status (NAb-positive[≥20 neutralizing units/mL]/NAb-negative).

Results

In REFLEX (M0-24) and REFLEXION (M24-60), levels of all assessed biomarkers in NAb-positive pts were similar to those measured for PBO in REFLEX. In NAb-negative pts, all biomarkers were significantly upregulated in response to scIFNβ-1a tx vs M0 of REFLEX. No changes were seen in PBO pts. The greatest changes were observed with scIFNβ-1a tiw; intermediate changes with scIFNβ-1a ow. In REFLEXION, a modest dose-dependent biomarker response to scIFNβ-1a tx was observed.

Conclusions

It is known that classical IFN-responsive PD genes do not predict clinical response to IFNβ. In this study, PD biomarkers were upregulated by scIFNβ-1a in the 85% of pts NAb-negative. Reduced PD biomarker expression in NAb-positive pts was consistent with the concept that NAbs reduce PD activity of scIFNβ-1a.

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