Long-term Safety of Vedolizumab for Inflammatory Bowel Disease

Edward V. Loftus Jr; Brian G. Feagan; Remo Panaccione; Jean-Frédéric Colombel; William J. Sandborn; Bruce E. Sands; Silvio Danese; Geert D'Haens; David T. Rubin; Ira Shafran; Andrejus Parfionovas; Raquel Rogers; Richard A. Lirio; Séverine Vermeire

Disclosures

Aliment Pharmacol Ther. 2020;52(8):1353-1365.

Abstract and Introduction

Abstract

Background: Vedolizumab, a gut-selective α₄β₇ integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).

Aim: To report the final results from the vedolizumab GEMINI long-term safety (LTS) study.

Methods: The phase 3, open-label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab-naïve patients. Vedolizumab LTS was evaluated; efficacy and patient-reported outcomes were exploratory endpoints.

Results: Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03–112.2) for UC and 31.5 months (range: 0.03–100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion-related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug-related by local investigators (West Nile virus infection-related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long-term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks.

Conclusions: The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long-term use (NCT00790933/EudraCT 2008-002784-14).

Introduction

Ulcerative colitis (UC) and Crohn's disease (CD) are serious, chronic, idiopathic inflammatory bowel diseases (IBD) characterised by abdominal pain, faecal urgency and diarrhoea with blood and/or mucus.^[1,2] In addition to negative effects on health-related quality of life (HRQOL), these progressive diseases can lead to structural bowel damage, loss of function, disability and increase the potential for hospitalisation and surgery. Current treatment strategies typically include a combination of corticosteroids, immunosuppressors and biologic therapies to induce remission. Even with successful initial treatment, patients with UC or CD generally require long-term maintenance therapy.

Vedolizumab is a gut-selective monoclonal antibody directed against α₄β₇ integrin and approved for the treatment of moderately to severely active UC and CD.^[3,4] Previous Phase 3, double-blind, randomised, placebo-controlled studies demonstrated that maintenance treatment with vedolizumab for up to 1 year was effective and well-tolerated in patients with UC (GEMINI 1) or CD (GEMINI 2 and GEMINI 3).^[5–7] The GEMINI long-term safety (LTS) study continued assessment of patients treated in the GEMINI studies, in addition to enrolling vedolizumab-naïve patients, with the primary goal of evaluating the LTS of vedolizumab in patients with UC or CD.^[8–10] Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and HRQOL benefits.^[8,9] In this final analysis that includes over 2,000 patients, some with over 9 years of follow-up, we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
References
Appendix 1

Table 1. Baseline demographics and clinical characteristics ^a
Parameter	Ulcerative colitis (N = 894)	Crohn's disease (N = 1349)
Age,^b y, mean (SD)	41.2 (13.6)	37.8 (12.7)
≤35 years of age, n (%)	333 (37.2)	645 (47.8)
≥65 years of age, n (%)	42 (4.7)	34 (2.5)
Male sex, n (%)	522 (58.4)	606 (44.9)
Race, n (%)
White	762 (85.2)	1219 (90.4)
Black	14 (1.6)	28 (2.1)
Asian	105 (11.7)	82 (6.1)
Other/not reported	13 (1.5)	20 (1.5)
Disease duration, years, mean (SD)	8.1 (7.0)	10.1 (8.3)
Partial Mayo score, mean (SD)	6.0 (1.5)	NA
HBI score, mean (SD)	NA	10.9 (3.4)
CDAI score, mean (SD)	NA	314.0 (63.2)
History of extraintestinal disease manifestations, n (%)^c	299 (34.6)	1124 (83.8)
Concomitant medications corticosteroids at enrolment, n (%)	330 (36.9)	545 (40.4)
Prior therapy, n (%)
Corticosteroids	868 (97.1)	1295 (96.0)
Immunomodulators	666 (74.5)	1158 (85.8)
TNF antagonist therapies	415 (46.4)	898 (66.6)
Prior TNF antagonist failure,^d n (%)	380 (46)	848 (65)
Vedolizumab exposure, months, median (range)^e	42.4 (0.03–112.2)	31.5 (0.03–100.3)

Abbreviation: CDAI, Crohn's disease activity index; HBI, Harvey-Bradshaw Index; NA, not available; SD, standard deviation; TNF, tumour necrosis factor.
^aBaseline for rollover patients was defined as the last assessment before the first dose of vedolizumab in the previous studies. Baseline for de novo patients was defined as the last assessment before the first dose of vedolizumab in GEMINI LTS.
^bAge was defined as (1 + first dose date in GEMINI LTS—birth date)/365.25.
^cHistory of extraintestinal disease manifestations were not collected for patients in the Phase 2 long-term safety study.
^dCalculation includes only patients for whom TNF antagonist failure status was known.
^eIncludes exposure to vedolizumab in previous clinical studies, without incorporating data up to 16 weeks after last dose.

Table 2. Safety overview
Parameter	Ulcerative colitis (N = 894)		Crohn's disease (N = 1349)
Parameter	n (%)	Incidence/1000 person-years^a	n (%)	Incidence/1000 person-years^a
Any AE	829 (92.7)	1220.5	1295 (96.0)	1799.2
Disease exacerbation	321 (35.9)	105.2	476 (35.3)	121.4
Nasopharyngitis	252 (28.2)	93.9	342 (25.4)	94.1
Arthralgia	155 (17.3)	51.6	329 (24.4)	90.2
Abdominal pain	111 (12.4)	34.4	309 (22.9)	80.0
Headache	164 (18.3)	55.5	290 (21.5)	76.4
Upper respiratory tract infection	166 (18.6)	55.7	213 (15.8)	53.2
Nausea	105 (11.7)	32.3	231 (17.1)	57.7
Pyrexia	80 (8.9)	24.3	201 (14.9)	48.6
Severity of AE
Mild	163 (18.2)	NA	223 (16.5)	NA
Moderate	451 (50.4)	NA	656 (48.6)	NA
Severe	215 (24.0)	NA	415 (30.8)	NA
Treatment-related AEs	355 (39.7)	NA	623 (46.2)	NA
Treatment withdrawn due to AE	137 (15.3)	NA	229 (17.0)	NA
SAEs	277 (31.0)	90.9	548 (40.6)	146.5
Disease exacerbation	119 (13.3)	34.8	224 (16.6)	50.3
Abdominal pain	9 (1.0)	2.6	41 (3.0)	9.0
Anal abscess	0	0	33 (2.4)	7.3
Small intestinal obstruction	4 (<1)	1.1	25 (1.9)	5.5
Treatment-related SAEs	37 (4.1)	NA	79 (5.9)	NA
AESIs
Total infections	591 (66.1)	388.9	937 (69.5)	492.1
Serious infections	61 (6.8)	18.0	146 (10.8)	33.6
Malignancies	58 (6.5)	17.2	92 (6.8)	20.8
Infusion reactions	36 (4.0)	NA	67 (5.0)	NA
Hepatic events	29 (3.2)	8.4	63 (4.7)	14.1
PML	0	0	0	0
Deaths	4 (<1)^b	NA	6 (<1)^c	NA
Treatment-related death	1 (<1)^d	NA	1 (<1)^e	NA

Abbreviations: AE, adverse event; AESIs, adverse events of special interest; NA, not available; PML, progressive multifocal leukoencephalopathy; SAE, serious adverse event.
^aTime-adjusted incidence rate per 1000 patient-years = (number of patients experiencing an AE of interest/total person time in years) × 1000.
^bRespiratory failure, acute stroke, West Nile virus encephalitis, pulmonary embolism.
^cTraumatic intracranial haemorrhage, hepatocellular carcinoma, suicide, pneumonia, septicaemia, leiomyosarcoma.
^dOne patient who received long-term vedolizumab therapy subsequently died because of West Nile virus encephalitis. However, based on the mechanism of action of vedolizumab and available information, there is no known association between this event and vedolizumab therapy. There are also no other safety signals linking vedolizumab to the West Nile virus. Therefore, although this event was recorded by the principal investigator as treatment-related, there is no evidence to support this association.
^eDeath of 1 patient with Crohn's disease (hepatocellular carcinoma) was considered treatment-related by the treating physicians.

Table 3. Incidence of treatment-emergent extraintestinal manifestations in patients with UC or CD
	Ulcerative colitis (N = 894)		Crohn's disease (N = 1349)
	n (%)	Incidence/1000 person-years (95% CI)^a	n (%)	Incidence/1000 person-years (95% CI)^a
Any extraintestinal manifestation	172 (19.2)	70.6 (59.3, 81.9)	443 (32.8)	157.5 (140.6, 174.5)
Arthralgia	120 (13.4)	47.0 (38.2, 55.8)	269 (19.9)	84.1 (73.2, 94.9)
Arthritis	17 (1.9)	6.0 (3.1, 8.8)	47 (3.5)	12.4 (8.9, 16.0)
Anal fissure	15 (1.7)	5.3 (2.6, 7.9)	40 (3.0)	10.5 (7.2, 13.8)
Anal fistula	2 (<1)	0.7 (0, 1.7)	95 (7.0)	25.5 (20.2, 30.8)
Aphthous stomatitis	14 (1.6)	4.9 (2.3, 7.5)	54 (4.0)	14.3 (10.4, 18.2)
Erythema nodosum	6 (<1)	2.1 (0.4, 3.8)	30 (2.2)	7.8 (5.0, 10.7)
Iritis/uveitis^b	12 (1.3)	4.2 (1.8, 6.6)	13 (1.0)	3.4 (1.5, 5.2)
Pyoderma gangrenosum	3 (<1)	1.0 (0, 2.2)	3 (<1)	0.8 (0, 1.6)

Abbreviation: CI, confidence interval.
^aTime-adjusted incidence rate per 1000 person-years = (number of patients experiencing an adverse event of interest/total person time in years) × 1000.
^bIncludes iris and uveal tract infections, irritations and inflammations.

Table 4. Incidence of gastrointestinal infections of special interest in patients with UC or CD
Parameter	Ulcerative colitis (N = 894)		Crohn's disease (N = 1349)
Parameter	n (%)	Incidence/1000 person-years (95% CI)^a	n (%)	Incidence/1000 person-years (95% CI)^a
Gastrointestinal infections of special interest	122 (13.6)	46.9 (38.3, 55.6)	162 (12.0)	46.1 (38.8, 53.4)
Abdominal and gastrointestinal infections (pathogen unspecified)^b	92 (10.3)	34.9 (27.6, 42.3)	141 (10.5)	39.6 (32.9, 46.3)
Clostridium infections^c	26 (2.9)	9.1 (5.6, 12.6)	21 (1.6)	5.4 (3.1, 7.8)
Campylobacter infections^d	9 (1.0)	3.1 (1.1, 5.2)	8 (<1)	2.1 (0.6, 3.5)
Shigella infections^e	0	0	1 (<1)	0.3 (0, 0.8)
Yersinia infections^f	1 (<1)	0.3 (0, 1.0)	0	0
Bacterial infections (bacteria unspecified)^g	0	0	1 (<1)	0.3 (0, 0.8)

Abbreviation: CI, confidence interval; MedDRA, Medical Dictionary for Regulatory Activities.
^aTime-adjusted incidence rate per 1000 person-years = (number of patients experiencing an adverse event of interest/total person time in years) × 1000.
^bMedDRA preferred terms: gastroenteritis, diarrhoea infectious, gastrointestinal infection, enteritis infectious, enterocolitis infectious and gastric infection.
^cMedDRA preferred terms: Clostridium difficile colitis, Clostridial infection and Clostridium colitis.
^dMedDRA preferred terms: Campylobacter gastroenteritis, Campylobacter intestinal infection and Campylobacter infection.
^eMedDRA preferred term gastroenteritis shigella.
^fMedDRA preferred term gastroenteritis yersinia.
^gBacterial infections represent MedDRA preferred term gastroenteritis bacterial.

Authors and Disclosures

Edward V. Loftus Jr¹, Brian G. Feagan², Remo Panaccione³, Jean-Frédéric Colombel⁴, William J. Sandborn⁵, Bruce E. Sands⁴, Silvio Danese⁶, Geert D'Haens⁷, David T. Rubin⁸, Ira Shafran⁹, Andrejus Parfionovas¹⁰, Raquel Rogers¹⁰, Richard A. Lirio¹⁰ and Séverine Vermeire¹¹

¹Rochester, MN, USA
²London, ON, Canada
³Calgary, AB, Canada
⁴New York, NY, USA
⁵San Diego, CA, USA
⁶Milan, Italy
⁷Amsterdam, The Netherlands
⁸Chicago, IL, USA
⁹Winter Park, FL, USA
¹⁰Cambridge, MA, USA
¹¹Leuven, Belgium

Correspondence
Edward V. Loftus Jr, Mayo Clinic College of Medicine, Rochester, MN, USA. Email: loftus.edward@mayo.edu

Author contributions
All authors had access to the study data; contributed to manuscript drafting, critical review and revision. All authors approved the final manuscript for submission.

Declaration of personal interests
Edward V. Loftus: Financial support for research: AbbVie, Takeda, Janssen, UCB, Amgen, Pfizer, Genentech, Celgene, Receptos, Gilead, Bristol-Myers Squibb, and Robarts Clinical Trials; Consultancy: AbbVie, Takeda, Janssen, UCB, Amgen, Pfizer, Eli Lilly, Celltrion Healthcare, Allergan, Bristol-Myers Squibb, Gilead, Genentech, Celgene, and Boehringer Ingelheim. Brian G. Feagan: Consultancy: Abbott/AbbVie, ActoGeniX, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc, Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, enGene, Ferring Pharma, Roche/Genentech, gICare Pharma, Gilead, Given Imaging Inc, GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Hakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner Chilcott, Wyeth, Zealand, and Zyngenia; Grant/research support: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, and UCB Pharma; Membership (board of directors): Robarts Clinical Trials Inc. Remo Panaccione: Consultancy: AbbVie, Amgen, Allergan, AstraZeneca, Baxter, BMS, Celgene, Cubist, Eisai, Eli Lilly, Ferring, Genentech, Gilead, Janssen, Merck, Robarts, Salix, Samsung, Schering-Plough, Shire, Centocor, Elan, Glaxo-Smith Kline, UCB, Pfizer, and Takeda; Speaker's Bureau: AbbVie, Abbott, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire, Takeda; Research/Educational Support from: AbbVie, Abbott, Ferring, Janssen Pharmaceuticals, and Takeda. Jean-Frédéric Colombel: Consultancy/advisory board membership: AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen Pharmaceuticals, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres, Takeda, and Theradiag; Speaker: AbbVie, Ferring, Takeda, and Shire; Research support: AbbVie, Genentech, and Takeda; Stock options: Intestinal Biotech Development, and Genfit. William J. Sandborn: Research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, Celgene/Receptos, Pfizer, Prometheus Laboratories (now Prometheus Biosciences); consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Spouse: Opthotech - consultant, stock options; Progenity - consultant, stock; Oppilan Pharma - employee, stock options; Escalier Biosciences - employee, stock options; Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories) - employee, stock options; Ventyx Biosciences – employee, stock options; Vimalan Biosciences – employee, stock options. Bruce E. Sands: Consultancy: 4D Pharma, AbbVie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Capella Bioscience, Celgene, Celltrion Healthcare, Eli Lilly and Company, EnGene, F. Hoffmann-La Roche, Ferring, Gilead Sciences, Ironwood Pharmaceuticals, Janssen, Lyndra, MedImmune, Oppilan Pharma, Otsuka America Pharmaceutical, Palatin Technologies, Pfizer, Progenity, Prometheus Laboratories, Protagonist Therapeutics Rheos Medicines, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma, TiGenix, UCB, Valeant Pharmaceuticals North America, and Vivelix Pharmaceuticals; Research support: Takeda, Janssen, Theravance Biopharma, and Pfizer. Silvio Danese: Lecture fee(s): AbbVie, Ferring, Hospira, Johnson and Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, and Boehringer Ingelheim; Consultancy: AbbVie, Ferring, Hospira, Johnson and Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, and Boehringer Ingelheim. Geert D'Haens: Financial support for research: AbbVie, Buhlmann Laboratories, Ferring, DrFALK Pharma, Johnson and Johnson, GlaxoSmithKline, Medtronics, Millennium/Takeda, MSD, Photopill, Prometheus laboratories, Robarts Clinical Trials, and Setpoint; Lecture fee(s): AbbVie, Biogen, Ferring, DrFALK Pharma, Johnson and Johnson, Giuliani, Millennium/Takeda, MSD, Norgine, Otsuka, Shire, Tillotts, UCB, and Vifor; Consultancy: AbbVie, Ablynx, Actogenix, Amakem, Amgen, AM Pharma, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Cosmo, Elan, Ferring, Celgene/Receptos, Celltrion, Johnson and Johnson, Engene, Galapagos, Gilead, GlaxoSmithKline, Immunic Therapeutics, Lycera, Medimetrics, Medtronics, Millennium/Takeda, Mitsubishi Pharma, MSD, Mundipharma, Novo Nordisk, Otsuka, Hospira/Pfizer, PDL, Prometheus Laboratories, Protagonist, Salix, Samsung Bioepis, Sandoz, Setpoint, Shire, TEVA, Tigenix, Tillotts, Topivert, UCB, Versant, and Vifor; Directorship(s): Robarts Clinical Trials. David T. Rubin: Consultancy: AbbVie, Abgenomics, Allergan Inc, Amgen, Celgene Corporation, Forward Pharma, Genentech/Roche, Janssen Pharmaceuticals, Merck & Co Inc, Miraca Life Sciences, Mitsubishi Tanabe Pharma Development America Inc, Napo Pharmaceuticals, Pfizer, Salix Pharmaceuticals, Samsung Bioepis, Sandoz Pharmaceuticals, Shire, Takeda, and Target PharmaSolutions Inc; Grant support: AbbVie, Genentech/Roche, Janssen Pharmaceuticals, Prometheus Laboratories, Shire, Takeda, and UCB Pharma. Ira Shafran: Lecture fee(s): Takeda; Grant support: Takeda. Andrejus Parfionovas: Employee of Takeda. Raquel Rogers: Employee of Takeda. Richard A. Lirio: Employee of Takeda. Séverine Vermeire: Financial support for research: MSD, AbbVie, Takeda, Pfizer, and Johnson & Johnson; Lecture fee(s): MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, J&J, Tillotts Pharma and Genentech/Roche; Consultancy: MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, J&J, Genentech/Roche, Celgene, Mundipharma, Celltrion, SecondGenome, Prometheus, Gilead, Galapagos, Robarts Clinical Trials, Amgen, GlaxoSmithKline, Shire, Arena and ProDigest.