Gastrointestinal disorders like UC can dramatically affect the quality of life , and involves a life-long clinical management of the disease focusing on the induction and maintenance of remission. GCS remain the treatment of choice of initial therapy but about a third of the patients will fail to respond and further management requires a comprehensive understanding of the patients and the potential risks and benefits of further interventions making the disease course difficult to manage. The aim of the treatment with DIMS0150 is to help the patients remain in the group of easier manageable UC patients by restoring their steroid sensitivity.
The mechanisms behind steroid resistance are complex and numerous cytokines have been implicated as important factors. For example, Xystrakis and colleagues.  could show that by restoring otherwise deficient levels of IL-10 in steroid resistant asthmatics greatly improved their steroid responsiveness. In a more recent study performed with PBMCs derived from steroid resistant UC patients, the authors could demonstrate that addition of IL-10 to the PMBCs enhanced steroid sensitivity, whereas neutralizing IL-10 through addition of specific antibodies reduced steroid sensitivity .
Similar clinical observations have been demonstrated using type I interferons. For example, steroid resistant UC patients receiving daily intravenous injections of natural IFN-β experienced a rapid improvement of clinical symptoms . The ability of type I interferons to modulate steroid sensitivity gained further support from studies performed in steroid resistant asthmatics where treatment with IFN-α dramatically improved symptoms allowing their steroid dose to be tapered .
We could show that the TLR9 agonist DIMS0150 acts as an immunomodulatory compound by inducing IL-10, IL-6, type I interferons and IP-10 in vitro, the same cytokines/chemokines implied to be important in regaining steroid sensitivity. The induction of IP-10 in vivo in the phase IIa study correlates well with the in vitro IP-10 analysis suggesting that treatment with DIMS0150 is likely to induce the same steroid enhancing cytokines as previously recorded.
The biomarker CD163 belongs to a superfamily of cysteine-rich scavenger receptors (SRCR), several of which are involved in the innate immune response . CD163 is described to mediate anti-inflammatory effects  and its expression is strongly induced by anti-inflammatory mediators and GCS [20, 42]. Interestingly, some of these anti-inflammatory mediators that up-regulate CD163 on mRNA level in monocytes and macrophages are IL-6 and IL-10 [43–45], both of which are shown to be induced by DIMS0150.
Thrombospondin-1 belongs functionally to a group of diverse multidomain counteradhesive proteins influencing endothelial cell behaviour [46–48]. It could be shown that TSP-1 expression correlates with IL-10 expression in colon cancer with significant lower mean vessel counts suggesting that IL-10 stimulates expression of angiostatic factors as TSP-1 , linking also the second biomarker to a cytokine induced by DIMS0150. The identification of these marker genes and their relation to DIMS0150 induced cytokines are considered important factors in understanding how DIMS0150 restores steroid sensitivity.
To assess the clinical utility of CD163, TSP-1 and IL-1RII as predictors of clinical response, a PoC phase IIa study in steroid refractory or steroid dependent UC patients on concomitant steroid treatment was performed and the results compared to those of the steroid sensitivity marker IL-6. Although this study was somewhat limited in size, it was nevertheless deemed sufficiently large enough to provide a robust assessment of the biomarkers. We hypothesized that DIMS0150 should enhance steroid sensitivity leading to improvements of symptoms and a reduced disease activity score and that prior analysis using the biomarker genes should enable a prediction of clinical response. The clinical outcome of the study showed that approximately half of the DIMS0150 treated patients (10 of 22) responded to the treatment and that this observation was very much in line with the biomarker data obtained at the time of screening. Both IL-6 and CD163 analysis strongly suggested the presence of two groups of patients being included in the study. One group demonstrated a clear picture of steroid resistance and the other showed a steroid response similar to healthy volunteers. Patients with a reduced response to steroids as determined by CD163, TSP-1 or IL-6 were statistically more likely to respond to the DIMS0150 treatment. The predictive potential of the biomarkers could be illustrated by classification analysis of the expression data compared to clinical response or non-response following DIMS0150 treatment. All three markers demonstrated a high potential as surrogate markers for a DIMS0150 response with CD163 and TSP-1 being slightly more sensitive than IL-6 because of their ability to demonstrate the steroid re-sensitizing effect of DIMS0150. As expected, the combination of all three markers gave the best result with an AUC of 0.98. This equates to a correct prediction of clinical response in 90% (9/10) of patients classified as being steroid refractory according to the biomarker assay. Conversely, 91% (10/11) of patients whose steroid sensitivity was comparable to healthy controls failed to respond to DIMS0150 treatment. A possible interpretation would be, patients classified with the biomarkers as steroid refractory are indeed steroid refractory patients. By contrast, patients that show no difference to healthy could be inferred as steroid dependent. The validity of these interpretations can only be properly tested through additional clinical studies where subjects are included using the clinical definitions of steroid resistance and dependence as given in the ECCO guidelines .
Regarding the special case patient who received three doses of DIMS0150, the biomarker assay confirmed that the patient was steroid refractory at time of first dosing and classified as a potential responder to DIMS0150. Upon treatment with DIMS0150, a pronounced clinical response could be observed with the patient in complete remission at week 12. Further biomarker analysis at week 12 demonstrated that the patient most likely had regained steroid sensitivity that could be confirmed by treating an upcoming relapse successfully with GCS. While we have consistently recorded a steroid re-sensitizing effect for DIMS0150 in vitro, these in vivo data provide for the first time, evidence for a shift to improved steroid sensitivity in a steroid unresponsive patient following DIMS0150 treatment.
Based on these promising data, a placebo-controlled, multiple dose, double-blind, randomized phase III clinical study (NCT01493960) is currently on-going to assess the efficacy and safety of DIMS0150 as an add-on to current practice in chronic active treatment refractory UC patients.
This study will also provide a unique opportunity to gain further evidence for the observed in vivo shift in steroid sensitivity following DIMS0150 treatment and controlled steroid tapering combined with a long follow-up phase will gather information about reaching and length of steroid-free remission.