Biomarkers can predict potential clinical responders to DIMS0150 a toll-like receptor 9 agonist in ulcerative colitis patients.

Alexander W Gielen,Nikolai V Kuznetsov,Ragnar Befrits,Robert Lofberg,Oliver D Von Stein,Petra Von Stein,Arezou Zargari,Eugen Musch

doi:10.1186/1471-230x-14-79

Abstract

BackgroundGlucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 not only induces production of key anti-inflammatory cytokines as IL-10 but interestingly also enhances steroid sensitivity in steroid refractory UC patients. We investigated, in the context of a clinical study, whether a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment.MethodsIn a non-interventional pilot study, blood from steroid refractory UC patients and healthy volunteers was taken and thirty-four previously described steroid response genes were analysed by real time PCR analysis. To establish clinical utility of the identified biomarkers, a placebo controlled, randomized, double blinded study in active steroid dependent and steroid resistant UC patients on concomitant steroid therapies was used (EudraCT number: 2006-001846-15).ResultsWe identified three potential biomarkers CD163, TSP-1 and IL-1RII whose response to steroids was significantly enhanced when DIMS0150 was applied. Thirty-four subjects were randomized to receive a single rectal administration of placebo or 30 mg of DIMS0150. Blood derived PBMCs were obtained prior to dosing and assayed for evidence of a steroid enhancing effect following steroid incubation in the presence of DIMS0150. Comparison to established steroid sensitivity marker IL-6 confirmed that clinical responders are steroid refractory UC patients. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of the patients.ConclusionUsing specific steroid response biomarkers, GCS refractory UC patients most likely to benefit from DIMS0150 treatment could be identified and illustrates the usefulness of a personalized treatment approach.

Highlights

Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will fail to respond and progress to a more severe and difficult to manage disease state
The drug functions as an immunomodulator by activating the Toll-Like Receptor 9 (TLR9) present in immune cells such as B-cells, macrophages and plasmacytoid dendritic cells that are found in abundance on mucosal surfaces such as the colonic mucosa
DIMS0150 induces cytokines having a role in steroid sensitivity DIMS0150 is a fully synthetic oligodeoxynucleotide and its mode of action is thought to be triggered by the interaction with TLR9, which stimulates the production of specific chemokines and cytokines from mucosal immune cells, such as B-cells, macrophages and plasmacytoid dendritic cells (pDCs)

Summary

Introduction

Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 induces production of key anti-inflammatory cytokines as IL-10 but interestingly enhances steroid sensitivity in steroid refractory UC patients. Ulcerative colitis (UC) is a disease characterised by chronic inflammation of the rectal and colonic mucosa. The drug functions as an immunomodulator by activating the Toll-Like Receptor 9 (TLR9) present in immune cells such as B-cells, macrophages and plasmacytoid dendritic cells (pDCs) that are found in abundance on mucosal surfaces such as the colonic mucosa. Activation of TLR9 by DIMS0150 results in the local production of potent anti-inflammatory cytokines such as IL-10 and type I interferons that have interestingly been shown to increase steroid sensitivity in cells derived from steroidresistant UC patients [7] and human monocytes [8]

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