MECHANISMS OF RESPONSE TO INTERLEUKIN 12/23 BLOCKERS IN ULCERATIVE COLITS – TOWARDS PERSONALIZED MEDICINE

SUMMARY: Despite significant advances in the treatment of ulcerative colitis, still around 30% of patients fail to respond to all available treatments. These patients suffer from severe symptoms of bowel dysfunction. Many eventually need mutilating surgery with removal of complete colon. Ustekinumab, an IL 12/23 blocker with excellent safety profile, is the first drug from this class registered for of ulcerative colitis. Unfortunately, only one third of the patients respond completely, one third partially or loose response over time (partial responders/secondary non-responders) and one third do not respond at all (primary non-responders). Currently, the mechanisms of resistance to ustekinumab in ulcerative are not clear as the drug was introduced only recently. It is believed that primary non-response could be due to genetic variants or different expression profiles in inflamed colonic mucosa (pharmacogenomics). Understanding mechanisms of primary resistance is critical for optimal selection of patients who can benefit from this costly drug: Can we identify patients who are (un)likely to benefit from ustekinumab with genetic analysis in genes involved in IL 12/23 inflammatory pathway? Do primary non-responders have specific expression signature before or shortly after treatment in colonic mucosa? Partial response/secondary loss of response, however, could be due to insufficient exposure to the drug (pharmacokinetics). Identifying drug concentrations needed for disease control and understanding population pharmacokinetics is crucial for rational drug use: What drug concentrations are needed during induction of treatment? Can we use lower amount of the drug during maintenance? Do patients with more severe disease phenotype need higher drug exposure? Are drug concentrations in inflamed colonic mucosa more informative than serum drug concentrations? In this project we will address the above listed questions in a prospective real-life study. Thirty patients starting ustekinumab for active ulcerative colitis will be recruited. We will perform exposure-response analysis and identify ustekinumab concentrations needed for different levels of disease control. Apart from serum ustekinumab concentrations, we will also measure concentrations of the drug in inflamed colonic tissue mucosa. These findings will integrated in a population pharmacokinetic model. To explore the mechanisms of primary non-response we will also measure expression of inflammatory genes in colonic mucosa before and during treatment. Furthermore, we will explore whether genetic polymorphisms in these genes play a role in primary non-response. These findings will be integrated in future treatment algorithms of ulcerative colitis. Lastly, we will develop and validate dry blood spot assay for measurement of ustekinumab concentrations at home. This, combined with home measurement of inflammatory markers, C-reactive protein and fecal calprotectin, will be a valuable tool for telemedicine. Lastly, many new drugs which target IL 12/23 inflammatory pathway are in the pipelines of drug development. Because of this, understanding the mechanisms of ustekinumab response/failure, the first drug to target this inflammatory axis in ulcerative colitis, will have benefits that extend beyond the scope of this project.