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

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.

Topical treatment with the Toll-like receptor agonist DIMS0150 has potential for lasting relief of symptoms in patients with chronic active ulcerative colitis by restoring glucocorticoid sensitivity.

BACKGROUND: Patients with chronic active ulcerative colitis (UC) are regarded as treatment failures and represent an area of high unmet medical need, as normally the only remaining option is colectomy. METHODS: We treated a total of eight chronic active severe UC outpatients with the immunomodulatory agent DIMS0150 as an add-on to current therapies. Seven patients received a single topical dose of 30 mg and one special case subject received three doses with 4 weeks between dosing occasions. All patients were classed as treatment failures and were elected for colectomy. Efficacy evaluation was determined in terms of colitis activity index, endoscopic improvement, and histologic disease activity assessed primarily at week 12 with a follow-up period of over 2 years. Glucocorticoid sensitivity was assayed by in vitro measurement of interleukin 6. RESULTS: All patients demonstrated a pronounced and rapid reduction in their colitis activity index within 1 week following a single intracolonic administration via colonoscope of the agent DIMS0150. Further improvements were evident at week 4, resulting in a clinical response rate for the single-dose treatment of 71%, with 43% in clinical remission. By week 12 the clinical response and remission rates had reached 82% and 71%, respectively. A follow-up period of over 2 years posttreatment indicated that all but one of the treated patients had avoided the need for colectomy, with the longest patient being in symptom-free remission for over 27 months. Treatment with DIMS0150 restored glucocorticoid sensitivity. CONCLUSIONS: DIMS0150 may have the potential to be an effective agent to treat chronic active UC patients with the prospect to avoid colectomy on a long-term basis and is currently the subject of a clinical phase III study (EudraCT number: 2011-003130-14).

Multigene analysis can discriminate between ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) and the irritable bowel syndrome (IBS) are heterogeneous disorders of the gastrointestinal tract and can profoundly affect the quality of life. Because many of the symptoms of IBD are similar to those of IBS, the former may be misdiagnosed. In addition, the 2 major forms of IBD, ulcerative colitis (UC) and Crohn's disease (CD), have overlapping nonspecific, pathologic features leading to difficulties in assessing colonic inflammation and hence the term IBD unclassified has been proposed. The aim of this study was to identify and assess the utility of a certain set of marker genes that could help to distinguish IBS from IBD, and further to discriminate between UC and CD. METHODS: Subtractive suppression hybridization was used to identify IBD-specific genes in colonic mucosal biopsy specimens. In quantitative polymerase chain reaction experiments, the differential expressions of identified genes then were analyzed using a classification algorithm and the possible clinical value of these marker genes was evaluated in a total of 301 patients in 3 stepwise studies. RESULTS: Seven marker genes were identified as differentially expressed in IBD, making it possible to discriminate between patients suffering from UC, CD, or IBS with area under the receiver-operating characteristic curves ranging from 0.915 to 0.999 (P < .0001) using the clinical diagnosis as gold standard. CONCLUSIONS: Expression profiling of relevant marker genes in colonic biopsy specimens from patients with IBD/IBS-like symptoms may enable swift and reliable determination of diagnosis, ultimately improving disease management.