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Open Access Research article

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

Nikolai V Kuznetsov1, Arezou Zargari1, Alexander W Gielen1, Oliver D von Stein1, Eugen Musch2, Ragnar Befrits3, Robert Lofberg4 and Petra von Stein1*

Author Affiliations

1 InDex Pharmaceuticals, Tomtebodavägen 23a, 171 77 Stockholm, Sweden

2 Clinic of Colo-Proctology and Intestine Center, Marienhospital, Bottrop, Germany

3 Gastroenterology and Hepatology Clinic, Karolinska University Hospital, Solna, Sweden

4 Department of Medicine, Karolinska Institutet and Stockholm Gastro Center, Stockholm, Sweden

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BMC Gastroenterology 2014, 14:79  doi:10.1186/1471-230X-14-79

Published: 23 April 2014

Abstract

Background

Glucocorticoids (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.

Methods

In 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).

Results

We 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.

Conclusion

Using 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.

Keywords:
Ulcerative colitis; Glucocorticosteroids; Steroid refractory; Biomarker; Companion diagnostics