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How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data.

ABSTRACT: Ustekinumab is a fully human IgG1 monoclonal antibody that has been approved for the treatment of moderate to severe Crohn's disease, and more recently moderate to severe ulcerative colitis. It binds with high affinity to the p40 subunit of human interleukin-12 and 23. This mechanism of action prevents the bioactivity of both interleukins, thus precluding their interaction with the cell surface receptor protein. The pivotal clinical trials (UNITI-1, UNITI-2 and IM-UNITI) demonstrated its clinical efficacy and safety, in naïve patients and also in those previously exposed to immunosuppressants and/or biologics. There is now an extensive experience with its use worldwide, corroborating its favorable profile even in patients with refractory disease. However, the number of medical treatment options available in inflammatory bowel disease are still limited. Hence, we should prioritize the treatments that have a greater probability of response in an individual patient. Our aim was to review and summarize all the available literature regarding the potential predictors of response to ustekinumab that can increase the success rate with this therapy in clinical practice.

SUBMITTER: Gutierrez A

PROVIDER: S-EPMC7876229 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data.

Gutiérrez Ana A Rodríguez-Lago Iago I

Frontiers in medicine 20210128

Ustekinumab is a fully human IgG1 monoclonal antibody that has been approved for the treatment of moderate to severe Crohn's disease, and more recently moderate to severe ulcerative colitis. It binds with high affinity to the p40 subunit of human interleukin-12 and 23. This mechanism of action prevents the bioactivity of both interleukins, thus precluding their interaction with the cell surface receptor protein. The pivotal clinical trials (UNITI-1, UNITI-2 and IM-UNITI) demonstrated its clinica ...[more]

PMID: 33585530

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Project description:BackgroundReal-world data on clinical outcomes of ustekinumab in ulcerative colitis are lacking.ObjectiveTo assess short- and long-term clinical outcomes of ustekinumab in ulcerative colitis.MethodsAdult ulcerative colitis patients without previous colectomy starting ustekinumab treatment up until 11 December 2020 were identified through the Swedish Inflammatory Bowel Disease Register (SWIBREG). Prospectively recorded data were extracted from the SWIBREG. The primary outcome was persistence to ustekinumab 16 weeks after treatment initiation. Secondary outcomes included drug persistence beyond week 16, clinical remission (defined as a patient-reported Mayo rectal bleeding subscore = 0 and stool frequency subscore ≤1), biochemical remission (defined as faecal-calprotectin <250 μg/g) and changes in health-related quality of life (HRQoL), as measured by the Short Health Scale (SHS). Logistic regression was used to identify potential predictors of ustekinumab persistence at 16 weeks.ResultsOf the 133 patients with ulcerative colitis, only three were naïve to biologics and tofacitinib. The persistence rates of ustekinumab were 115/133 (86%) at 16 weeks and 89/133 (67%) at last follow-up, that is, after a median follow-up of 32 (interquartile range 19-56) weeks. The clinical remission rates were 17% at 16 weeks and 32% at the last follow-up. The corresponding rates for biochemical remission were 14% and 23%. The median faecal-calprotectin concentration decreased from 740 μg/g at baseline to 98 μg/g at the last follow-up (p < 0.01, n = 37). Improvement was seen in each dimension of the SHS between baseline and last follow-up (p < 0.01 for each dimension, n = 46). Male sex was associated with ustekinumab persistence at 16 weeks (adjusted odds ratio = 4.00, 95% confidence interval: 1.35-11.83).ConclusionIn this nationwide real-world cohort of ulcerative colitis patients with prior drug failures, including other biologics and tofacitinib, ustekinumab was associated with high drug persistence rates and improvements in clinical, biochemical and HRQoL measures.

Project description:PurposeUsing real-world data (RWD)-based trial simulation approach, we aim to simulate colorectal cancer (CRC) trials and examine both effectiveness and safety end points in different simulation scenarios.MethodsWe identified five phase III trials comparing new treatment regimens with an US Food and Drug Administration-approved first-line treatment in patients with metastatic CRC (ie, fluorouracil, leucovorin, and irinotecan) as the standard-of-care (SOC) control arm. Using Electronic Health Record-derived data from the OneFlorida network, we defined the study populations and outcome measures using the protocols from the original trials. Our design scenarios were (1) simulation of the SOC fluorouracil, leucovorin, and irinotecan arm and (2) comparative effectiveness research (CER) simulation of the control and experimental arms. For each scenario, we adjusted for random assignment, sampling, and dropout. We used overall survival (OS) and severe adverse events (SAEs) to measure effectiveness and safety.ResultsWe conducted CER simulations for two trials, and SOC simulations for three trials. The effect sizes of our simulated trials were stable across all simulation runs. Compared with the original trials, we observed longer OS and higher mean number of SAEs in both CER and SOC simulation. In the two CER simulations, hazard ratios associated with death from simulations were similar to that reported in the original trials. Consistent with the original trials, we found higher risk ratios of SAEs in the experiment arm, suggesting potentially higher toxicities from the new treatment regimen. We also observed similar SAE rates across all simulations compared with the original trials.ConclusionIn this study, we simulated five CRC trials, and tested two simulation scenarios with several different configurations demonstrated that our simulations can robustly generate effectiveness and safety outcomes comparable with the original trials using real-world data.

Dataset Information

How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data.

Publications

How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data.

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