Optimal treatment sequence for targeted immune modulators for the treatment of moderate to severe ulcerative colitis

BACKGROUND: Ulcerative colitis is a chronic immune-mediated inflammatory condition of the large intestine and rectum. Several targeted immune modulators (TIMs) have demonstrated effectiveness for the treatment of moderate to severe ulcerative colitis and are approved by the FDA. Patients may try multiple TIMs, and currently there are no biomarkers or prognostic factors to guide choice of treatment sequence. In 2020, the Institute for Clinical and Economic Review (ICER) conducted a review of TIMs for the treatment of ulcerative colitis as individual agents relative to conventional treatment but did not address the relative ranking of various treatment sequences to each other. OBJECTIVE: To extend the ICER framework to identify the optimal treatment sequence as informed by metrics such as maximizing incremental net health benefit (NHB), minimizing incremental total cost, or maximizing incremental quality-adjusted life-years (QALYs). METHODS: The model was developed as a Markov model with 8-week cycles over a lifetime time horizon from a US payer perspective, including only direct health care costs. Health states consisted of active moderate to severe ulcerative colitis, clinical response without achieving remission, clinical remission, and death. Efficacy of TIMs were informed by the ICER-conducted network meta-analysis. Up to 3 treatments were modeled in a sequence that consisted of 2 different TIMs followed by conventional treatment. Sequences were ranked according to each objective. NHB was calculated using a threshold of $150,000 per QALY gained. Probabilistic sensitivity analysis (PSA) was undertaken to estimate the probability of each sequence having the highest NHB rank under each objective. RESULTS: 21 possible sequences were evaluated in the base case. Two attempts at conventional treatment represented the lowest cost option and, while yielding the fewest QALYs, resulted in the highest NHB. None of the sequences had an incremental cost per QALY below $150,000 relative to 2 attempts with conventional treatment, so the resulting NHB was negative for all sequences. The sequence with the highest NHB was infliximab-dyyb followed by tofacitinib (-0.116). This regimen also had the lowest incremental costs ($37,266). For orally and subcutaneously administered TIMs, the sequence of golimumab-tofacitinib had the highest NHB (-0.344). Ustekinumab-vedolizumab was the top-ranked sequence as measured by QALY maximization (0.172 incremental QALYs) but also had the highest total incremental cost ($166,094). Results of the PSA were consistent with deterministic rankings for the top-ranking sequences but also showed that the top 2 or 3 regimens were often close together. CONCLUSIONS: Based on the results of this analysis, the optimal sequence of TIMs as measured by NHB and cost minimization was infliximab or biosimilars as first-line treatment, then moving to tofacitinib, adalimumab, or vedolizumab. Sequences that generated the most QALYs began with ustekinumab, followed by vedolizumab, tofacitinib, and adalimumab. DISCLOSURES: This study was based on an evidence synthesis and economic evaluation sponsored by the Institute for Clinical and Economic Review (ICER). Pandey and Fazioli are employees of ICER. Bloudek reports grants from ICER during the conduct of the study and personal fees from Astellas, Akcea, Dermira, GlaxoSmithKline, Sunovion, Seattle Genetics, and TerSera Therapeutics, outside the submitted work. Pandey reports grants from California Healthcare Foundation, Harvard Pilgrim Healthcare, Kaiser Foundation Health Plan Inc., and the Donoghue Foundation, during the conduct of the study, and other support from Aetna, America's Health Insurance Plans, Anthem, AbbVie, Alnylam, AstraZeneca, Biogen, Genentech/Roche, GlaxoSmithSline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, United Healthcare, HealthFirst, Pfizer, Boehringer-Ingelheim, uniQure, Evolve Pharmacy Solutions, and Humana, outside the submitted work. Fazioli reports grants from Arnold Ventures, California Healthcare Foundation, Harvard Pilgrim Healthcare, Kaiser Foundation Health Plan Inc., and The Donaghue Foundation, during the conduct of the study, and other support from Aetna, America's Health Insurance Plans, Anthem, AbbVie, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, United Healthcare, HealthFirst, Pfizer, Boehringer-lngelheim, uniQure, Evolve Phamacy Solutions, and Humana, outside the submitted work. Ollendorf reports grants from ICER, during the conduct of the study, along with other support from CEA Registry sponsors and personal fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Sunovion, University of Colorado, Center for Global Development, and Neurocrine, outside the submitted work. Carlson reports grants from ICER, during the conduct of the study, and personal fees from Allergan, outside the submitted work. The inputs and model framework that were leveraged for this analysis were presented as part of the ICER assessment of TIMs for the treatment of moderate to severe ulcerative colitis.