P408. Prediction of clinical responders to treatment with DIMS0150 a Toll-Like Receptor 9 agonist in therapy refractory ulcerative colitis patients
O. von Stein1, E. Musch2, R. Löfberg3, N. Kuznetsov1, P. von Stein1, 1InDex Pharmaceuticals, Stockholm, Sweden, 2Marienhospital, Clinic of Colo-Proctology, Bottrop, Germany, 3IBD unit Sophiahemmet and the Dept of Medicine, Karolinska Institutet, Stockholm, Sweden
Background
Previous clinical studies suggest that local rectal administration of the Toll-Like Receptor 9 (TLR9) agonist in therapy refractory UC patients induced clinical response and remission. Clinical improvements were paralleled by a restoration of steroid sensitivity in vitro as determined by the use of specific biomarkers. The aim of the presented study was to determine whether patients mostly likely to benefit from DIMS0150 treatment could be identified through the use of these specific biomarkers.
Methods
We investigated, in the context of a randomized, placebo controlled clinical study, whether screening of a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment. Expression analysis of 34 steroid response genes were performed in vitro in peripheral blood mononuclear cells (PBMCs) derived from in 9 steroid refractory UC patients and compared to healthy volunteers. Clinical utility of the biomarkers was subsequently tested in a placebo controlled, randomized, double blinded study in active therapy resistant UC patients on concomitant steroid therapies.
Results
We identified two biomarkers CD163 and TSP1 whose response to steroids was significantly enhanced when DIMS0150 was applied in vitro. 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 sensitizing effect following steroid incubation in the presence of DIMS0150. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of those patients positive for both biomarkers. The clinical response rate in this positively identified group was impressive being over 80% for active at weeks 1 and 4 with a delta of over 50% to placebo. By contrast, patients with a negative outcome for the biomarkers had a response rate no different to placebo being 14% and 27% at weeks 1 and 4 respectively.
Conclusion
Using specific steroid response biomarkers, therapy refractory UC patients more likely to benefit from DIMS1050 treatment could be identified and illustrates the usefulness of a personalized treatment approach.