S1579 Potential Role of Biomarkers in Approved and Investigational Drugs for Crohn’s Disease: Step Towards Personalized Medicine

Introduction: Crohn’s disease (CD) can affect any segment of the gastrointestinal tract and has an unpredictable disease course. Further, the clinical trajectory of CD varies widely, and monitoring often requires invasive tests. We aim to analyze trial designs of approved and investigational drugs along with literature on personalized medicine (PM) to explore role of predictive tools such as biomarkers in treatment response assessment. Methods: We extracted CD treatment-related data from 3 sources: Food and Drug Administration (FDA) package inserts, ClinicalTrials.gov (CTG), and PubMed. FDA labels were reviewed to evaluate trial designs of approved drugs since 1998 and CTG for ongoing phase III trials of investigational drugs. PubMed search was conducted using terms “Crohn’s disease” AND “personalized medicine”. Results: We evaluated 18 PM studies in CD, of which 4 had predictive biomarker assessments. Two of these studies assessed inflammatory markers i.e. brazikumab showing higher response in patients with increased IL 22 (51% vs 42%) or C-reactive protein (21% vs 18%), and adalimumab showing increased response in higher mTNF(+) immune cells (92% vs 15%). Response to adalimumab was also evaluated with TREM-1 expression, however this was not predictive of endoscopic (P = 0.53) or clinical (P = 0.79) remission. A recent study found ileal microvillar length (>1.7 µm) to be predictive of response to both vedolizumab and ustekinumab (P = 0.02). Next, we reviewed CD trial designs of both approved and investigational drugs. Study designs of initially approved drugs targeted patients unresponsive to conventional therapies, and later expanded to include those failing biologics. On CTG review of drug development efforts, we found 46 ongoing phase III clinical trials registered for CD treatment, of which 15 were addressing PM. It was noted that while translational studies suggested a potential for biomarkers, none of the subsequent phase 3 trials of approved or investigational drugs utilized them to predict clinical response or further assess their utility. Conclusion: We found that multiple translational studies are suggesting potential of inflammatory markers, gene expression and even ileal microvillar length in predicting drug response in CD. Though a growing number of therapies have been approved, there were no CD predictive biomarker driven response assessments in phase 3 trials. There is need for more research on biomarkers in CD drug development to improve personalized treatment decisions and clinical outcomes.