Development and Validation of Clinical Scoring Tool to Predict Outcomes of Treatment With Vedolizumab in Patients With Ulcerative Colitis

Abstract

Background & aims: We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).

Methods: We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017.

Results: Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.

Conclusions: We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

Keywords: Biologic; Personalized Medicine; Prognostic Factor; Response to Treatment.

Conflict of interest statement

Conflicts of interest

These authors disclose the following: Parambir S. Dulai and the University of California, San Diego hold a provisional patent for the prediction modeling outlined herein. Parambir S. Dulai reports consulting for Takeda, Janssen, Pfizer, and AbbVie; travel support from Takeda and Janssen; and grant support from Takeda, Pfizer, Janssen, and AbbVie. Siddharth Singh reports research support from AbbVie and Pfizer; consulting for Pfizer, AbbVie, Takeda, and AMAG Pharmaceuticals; and career development awards from the American College of Gastroenterology and Crohn’s and Colitis Foundation. Niels Vande Casteele reports consulting for Takeda and Janssen. Joseph Meserve reports travel support from Takeda. Jenna L. Koliani-Pace reports travel support from Takeda. Brigid S. Boland reports research support from Takeda and Janssen; and consulting for AbbVie and Prometheus. John T. Chang reports grant support from Takeda. David Faleck reports travel support from Takeda. Robert Hirten reports speaking or advisory boards for Takeda and Janssen. Ryan Ungaro reports service as a consultant or advisory board member for Takeda, Pfizer, and Janssen. Dana Lukin reports consulting for AbbVie, Janssen, and Salix. Keith Sultan reports speaking engagement for AbbVie; research support for Takeda, Celgene, Hoffmann-La Roche, Gilead, and Pfizer. David Hudesman reports consulting for AbbVie, Takeda, Janssen, and Pfizer. Shannon Chang reports consulting for Oshi. Eugenia Shmidt reports travel support from Takeda. Arun Swaminath reports fellowship support from Janssen, AbbVie, and Pfizer; and grant support from Pfizer. Maria Rosario reports being an employee of Takeda Pharmaceuticals U.S.A., Inc. Vipul Jairath reports consulting fees from AbbVie, Janssen, Takeda, Sandoz, Ferring, Pfizer, GlaxoSmithKline, Robarts Clinical Trials, Eli Lilly, and Arena; and speaker fees from Takeda, Ferring, Janssen, and Shire. Leonardo Guizzetti reports being an employee of Robarts Clinical Trials. Brian G. Feagan reports grant support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Roche, Genentech, Johnson & Johnson, Janssen, Millennium, Pfizer, Receptos, Tillotts, and UCB; service as a consultant or advisory board member for AbbVie, ActoGeniX, Akros, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Baxter Healthcare Corp, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, enGene, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, GiCare Pharma, Gilead, Given Imaging, GlaxoSmithKline, Inception IBD Inc, Ironwood Pharmaceuticals, Johnson & Johnson, Janssen, Japan Tobacco, Kyowa Hakko Kirin Co Ltd, Lexicon, Lilly, Lycera Biotech, Merck, Mesoblast Ltd, Millennium, Nektar, Nestlé, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics & Diagnostics, Protagonist, Receptos, Salix, Shire, Sigmoid Pharma, Synergy Pharmaceuticals Inc, Takeda, Teva Pharmaceutical Industries Ltd, TiGenix, Tillotts, UCB, Vertex Pharmaceuticals, VHsquared Ltd, Warner Chilcott, Wyeth, Zealand Pharma, and Zyngenia. Corey A. Siegel reports service as a consultant or advisory board member for AbbVie, Amgen, Celgene, Lilly, Janssen, Sandoz, Pfizer, Prometheus, Sebela, and Takeda; speaker for AbbVie, Janssen, Pfizer, and Takeda; grant support from the Crohn’s and Colitis Foundation, AHRQ (1R01HS021747–01), AbbVie, Janssen, Pfizer, and Takeda; intellectual property for MiTest Health, LLC, and ColonaryConcepts, LLC; and equity interest for MiTest Health and Colonary Concepts. Bo Shen reports consulting for Janssen, Salix, AbbVie, Takeda, Theravance, and Robarts Clinical Trials. Sunanda Kane reports consulting for AbbVie, Merck, Spherix Health, Seres Pharmaceuticals, and Samsung Bioepis. Edward V. Loftus Jr reports consulting for Janssen, Takeda, AbbVie, UCB, Amgen, Pfizer, Salix, Mesoblast, Eli Lilly, Celgene, and CVS Caremark; and research support from Janssen, Takeda, AbbVie, UCB, Amgen, Pfizer, Genentech, Gilead, Receptos, Celgene, MedImmune, Seres Therapeutics, and Robarts Clinical Trials. William J. Sandborn reports personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Novo Nordisk, Mesoblast Inc, Shire, Ardelyx Inc, Actavis, Seattle Genetics, MedImmune (AstraZeneca), ActoGeniX NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adheron Therapeutics, Immune Pharmaceuticals, Celgene, and Arena Pharmaceuticals; personal fees from Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and University of Western Ontario (owner of Robarts Clinical Trials); grants and personal fees from Prometheus Laboratories, AbbVie, Gilead Sciences, Boehringer Ingelheim, Amgen, Takeda, Atlantic Pharmaceuticals, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Pfizer, Nutrition Science Partners, Receptos, and Amgen; grants, personal fees, and nonfinancial support from Janssen; and grants from the Broad Foundation, American College of Gastroenterology, and Exact Sciences. Bruce E. Sands reports consulting/advisory board or honoraria from 4D Pharma, AbbVie, Allergan Sales, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Capella BioScience, Celgene, EnGene, Ferring, Gilead, Janssen, Lilly, Lyndra, MedImmune, Oppilan Pharma, Otsuka, Palatin Technologies, Pfizer, Progenity, Rheos Pharmaceuticals, Seres Therapeutics, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma R&D, Inc., TiGenix, Vivelix Pharmaceuticals, and WebMD. Jean-Frederic Colombel reports service as a consultant or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Arena Pharmaceuticals, Celgene Corporation, Celltrion, Enterome, Eli Lilly, Ferring Pharmaceuticals, Genentech, Janssen and Janssen, Medimmune, Merck & Co, Nextbiotix, Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Development & Commercialization, Inc, Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, Theradiag; speaker for AbbVie, Ferring, Takeda, and Celgene Corporation; stock options for Intestinal Biotech Development and Genefit; and research grants from AbbVie, Takeda, Janssen, and Janssen. Karen Lasch and Charlie Cao report being employees of Takeda Pharmaceuticals USA, Inc. The remaining authors disclose no conflicts.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Prognostic CDST with stratified treatment outcomes in the VICTORY cohort.

Figure 2.

Prognostic CDST with stratified VDZ concentrations in the GEMINI 1 trial. Three-group statistical comparisons at each time point done using nonparametric testing (Kruskal-Wallis). *P < .05, **P < .01, ***P < .001. aAll values in the table are median VDZ concentration (interquartile range) (μg/mL); postdose concentration was measured 2 hours after dosing. bLow probability; ≤26 points in the CDST model at baseline. cIntermediate probability; >26 to ≤32 points in the CDST model at baseline. dHigh probability; >32 points in the CDST model at baseline. PK, pharmacokinetics.

Figure 3.

Changes in (A) partial Mayo score and (B) fecal calprotectin in the GEMINI 1 trial cohort stratified by CDST. Statistical comparisons at each time point for partial Mayo score was done by ANOVA with type I error controlled based on a closed test procedure; fecal calprotectin statistical analysis was done using nonparametric testing (Kruskal-Wallis). *P < .05, **P < .01, ***P < .001 for both. aAll values in the table are least-squares (LS) mean partial Mayo score (PMS) (with standard error in parentheses). bLow probability; ≤26 points in the CDST model at baseline. cIntermediate probability; >26 to ≤32 points in the CDST model at baseline. dHigh probability; >32 points in the CDST model at baseline. eAll values in the table are median percent change in fecal calprotectin (interquartile range).