Identifying the Optimal Treatment Sequence for Ustekinumab in Treatment Algorithms for Advanced Therapies in Ulcerative Colitis

Introduction: Ustekinumab (UST) is a monoclonal antibody against interleukin-12/23 approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults. With the paucity of data on biologic sequencing in UC, information on when best to initiate UST treatment is limited. The objective of this study was to identify the optimal position of UST in the treatment of UC. Methods: A hybrid model with decision tree for induction and a Markov cohort model for maintenance was developed to assess clinical efficacy of UST therapy when used 1st, 2nd, or 3rd line. The treatment basket for 1st and 2nd line was represented by infliximab (33%), adalimumab (33%), and vedolizumab (33%), and 3rd line was comprised of vedolizumab (50%) and tofacitinib (50%). Patients moved to next line of treatment upon loss of response, and those failing the first 3 lines of advanced therapy moved to conventional treatment (e.g., aminosalicylates and/or immunosuppressants, corticosteroids). The model estimated time spent in remission, response, active UC (Mayo score 6-12), surgery, and death over 1, 3 and 5 years. Transition probabilities for remission, response and surgery were derived from randomized controlled trials, network meta-analysis, and the literature. Results: Time spent in remission or response was highest when UST was used 1st line, with patients spending on average 8.5 (71%), 23.1 (64%) and 32.2 (54%) months in remission or response over 1, 3 and 5 years, respectively. UST used 2nd line was next best, with patients spending on average 7.9 (66%), 14.5 (40%) and 17.5 (29%) months in remission or response over 1, 3 and 5 years, respectively. When UST was used 3rd line, patients spent on average 7.6 (63%), 13.8 (38.5%) and 16.7 (28%) months in remission or response over 1, 3 and 5 years, respectively. Consequently, using UST 1st vs 2nd line (or 1st vs 3rd line) reduced time spent in active UC by 0.6 (0.9), 8.3 (9) and 13.8 (14.5) months over 1, 3 and 5 years, respectively, and surgery was postponed. Conclusion: Based on this analysis, initiating UST as a 1st-line advanced therapy for UC resulted in more favorable patient outcomes. Specifically, this treatment algorithm demonstrated the greatest potential benefit (increasing with longer time horizon) in terms of time spent in remission or response and postponing surgery. Future research is required to generate long-term clinical data to confirm these results.Figure 1.: A. Clinical outcomes compared by biologic therapy. B. Multivariable logistic regression models. Raw outcome data: clinical remission 24 months (67/105 infliximab, 44/112 adalimumab, 42/71 vedolizumab), clinical and endoscopic remission 24 months (45/91, 36/110, 29/62), clinical remission 48 months (28/55, 20/64, 8/16), clinical and endoscopic remission 48 months (18/48, 10/54, 7/16). Denominators vary due to patients with limited follow-up time or no endoscopic data. *Significant at threshold p<0.0125. †Due to a reduced number of outcomes, only the first 4 covariates were included to limit model overfitting. Abbreviations: OR = odds ratio, CI = confidence interval.