The safety of vedolizumab for ulcerative colitis and Crohn's disease

Abstract

Objective: Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab.

Design: Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model.

Results: In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy.

Conclusions: Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period.

Trial registration number: NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Keywords: INFLAMMATORY BOWEL DISEASE.

Conflict of interest statement

Competing interests: J-FC has served as consultant, advisory board member or speaker for AbbVie, ABScience, Amgen, Bristol-Myers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, MedImmune, Merck & Co, Millennium Pharmaceuticals, Neovacs, Nutrition Science Partners, Pfizer, Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB Pharma, Vertex, Dr August Wolff GmbH & Co. BES has served as a consultant for Abbott Immunology, AbbVie, Amgen, Astellas Pharma Global Development, AstraZeneca, Avaxia Biologics, Baxter Healthcare, Bracco Diagnostics, Bristol-Myers Squibb, Creative Educational Concepts, Curatio CME Institute/Axis Healthcare Communications, LLC, Dainippon Sumitomo Pharma, Dyax Corp, Elan Pharmaceuticals, Emmi Solutions, GlaxoSmithKline, Glaxo Wellcome, IMEDEX, Immune Pharmaceuticals, Janssen Biotech, Kyowa Hakko Kirin Pharma, Luitpold Pharmaceuticals, Mechanisms in Medicine, Pfizer, Prometheus Laboratories, PureTech Ventures, Sigmoid Pharma, Takeda Pharmaceuticals International Company, and Teva Pharmaceutical Industries; received financial support for research from Prometheus Laboratories, Pfizer, Janssen Biotech, Bristol-Myers Squibb, AbbVie, MedImmune; served as a speaker for Creative Educational Concepts; and is a shareholder of Avaxia Biologics. PR has served as a consultant for Bristol-Myers Squibb, Merck & Co, Abbott, Millennium/Takeda, Neovacs, Actogenics, Amgen, Pfizer, Falk Pharma, Tillotts, UCB Pharma; has received Grant/Research Support from Abbott, J&J, Genentech; and has received speaker fees from Centocor, Pfizer. WS has received financial support for research from Janssen, AbbVie, Pfizer, Amgen, Genentech; has received lecture fees from AbbVie, Takeda; and has served as a consultant to Janssen, AbbVie, Pfizer, Amgen, Genentech, Takeda. SD has served as a consultant, advisory board member, or review panel member for MSD, Schering Plough Corp, Abbott Laboratories, UCB, Ferring Pharmaceuticals, Cellerix, Takeda Pharmaceutical Company, Nycomed, Actelion, AstraZeneca, Danone Research, Chiesi, Novo Nordisk, Cosmo Technologies, Celltrion, Pharmacosmos, Alfa Wassermann, Genentech, Grunenthal, Pfizer, Tigenix, Vifor, Johnson and Johnson. GD'H has served as a consultant for Janssen Biologics, Takeda, Boehringer Ingelheim, Galapagos, Tillotts, Receptos, Salix, Setpoint, Versant, Mitsubishi, Prometheus; has received speaker fees from Takeda, Falk Pharma, Abbvie; and has served on an advisory board for GlaxoSmithKline, TEVA, Shire Pharmaceuticals. RP has served as a consultant, advisory board member or speaker for Abbott, Biogen/IDEC, Axcan Pharma, Bristol-Myers Squibb, Centocor, Chemocentryx, Ferring Pharmaceuticals, Genentech, Lippincott Williams & Wilkins, Medscape, Osiris Therapeutics, Novartis Pharmaceuticals, Genentech, Elan Pharmaceuticals, UCB; and has received research support from Abbott, UCB. EVL has received financial support for research from AbbVie, Janssen, UCB, Takeda, Pfizer, GlaxoSmithKline, Amgen, Bristol-Myers Squibb, Genentech, Robarts Clinical Trials, Gilead, Receptos; and has served as a consultant for AbbVie, Janssen, UCB, Takeda, Immune Pharmaceuticals, Celgene, MedImmune, Theradiag, Genentech, Seres Health, Sun Pharmaceuticals, Bristol-Myers Squibb. SS, IF, AP, CM are employees of Takeda Pharmaceuticals International, Cambridge, Massachusetts, USA. BA is an employee of Takeda Development Centre Europe, London, UK. BGF has received financial support for research from Abbott/AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma; has received lecture fees from Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma; served as a consultant for Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare, Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging, GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Hakko Kirin, Lexicon, Lilly, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Warner-Chilcott, Wyeth, Zealand, Zyngenia; has served on advisory boards for Abbott/AbbVie, Amgen, AstraZeneca, Avaxia Biologics, Bristol-Myers Squibb, Celgene, Centocor, Elan/Biogen, Ferring, JnJ/Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; and holds a directorship as CEO and Senior Scientific Director, Robarts Clinical Trials, Western University, London, Ontario.

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Figures

Figure 1

Patient distribution within the overall safety population. The overall safety population includes all patients who received ≥1 dose of study drug in the six studies. The phase 3 safety population includes patients from the phase 3 GEMINI studies only. Patients randomised to PBO in GEMINI 1, GEMINI 2 or GEMINI 3 and who enrolled into GEMINI LTS received open-label VDZ in that study. Thus, VDZ-exposed patients may also have been exposed to PBO. CD, Crohn's disease; LTS, long-term safety; PBO, placebo; PD, pharmacodynamics; PK, pharmacokinetics; UC, ulcerative colitis; VDZ, vedolizumab. aOne enrolled patient randomised to VDZ was not dosed. bIncludes 38 and 421 VDZ-naïve patients who enrolled directly into C13004 or GEMINI LTS, respectively. cIncludes data collected from 22 May 2009 to 27 June 2013.