Bhayat, F

Blake, A

Feagan, B

Khalid, JM

Palo, W

Shetzline, M

Travis, SP

Travis, Simon

Oxford University Research Archive

P442Incidence of Pneumonia and Other Respiratory Tract Infections with Vedolizumab Treatment for Inflammatory Bowel Disease: Clinical Trial ExperienceBrian Feagan1, Fatima Bhayat2, Javaria Mona Khalid2, William Palo3, Aimee Blake2, Michael Shetzline4, Simon Travis51Robarts Research Institute, University of Western Ontario, London, ON, Canada; 2Takeda Development Centre Europe Ltd, London, UK;  3Takeda Development Center Americas, Inc., Deerfield, IL, USA; 4Takeda Pharmaceuticals International Co., Cambridge, MA, USA;  5University of Oxford, Nuffield Department of Medicine, Oxford, UKPresented at the 2017 European Crohn’s and Colitis Organisation Congress • 15–18 February 2017 • Barcelona, SpainBackground• Anti-tumour necrosis factor-alpha (TNFα) agents have revolutionised the treatment of autoimmune diseases, including ulcerative colitis (UC) and Crohn’s disease (CD); however, concerns remain regarding the safety of these agents1• Because of their systemic immunosuppressive effects, patients treated with anti-TNFα agents are at increased risk of infections, including respiratory tract infections (RTIs) such as pneumonia2–4• Vedolizumab (ENTYVIO®), approved for the treatment of adults with moderately to severely active UC or CD, is a humanised monoclonal antibody that targets α4β7 integrin and selectively blocks gut-specific lymphocyte trafficking5,6• Although RTIs have been reported with vedolizumab,5,6 its gut selectivity may reduce the risk of events of this type, including pneumonia, compared with therapies causing systemic immunosuppression (e.g. anti-TNFα agents)• Here, we aim to quantify the incidence rates of pneumonia and other RTIs associated with vedolizumab treatment in the clinical trial setting Methods• A post hoc analysis of adverse events (AEs) from three studies (Figure 1): ¡ GEMINI 1 and 2: phase 3 randomised, placebo-controlled trials designed to examine the efficacy and safety of vedolizumab (versus placebo) for ≤52 weeks7,8 ¡ GEMINI open-label extension (OLE): an ongoing, open-label safety extension assessing the long-term safety of vedolizumab. An interim data cut to 21 May 2015 was used; 2243 patients had been enrolled (1349 with CD; 894 with UC)9–11• Study population included patients who had previously participated in vedolizumab clinical studies (GEMINI 1, 2, 3 and a phase 2 extension study) and de novo patients9–11Figure 1. Clinical Data Sources7–11N=2243 (CD, n=1349; UC, n=894)GEMINI 1UCPhase 3 RCTInduction/maintenanceGEMINI 2CDPhase 3 RCTInduction/maintenanceOngoing, OLEUC/CDPhase 3Data cut to 21 May 2015Vedolizumab 300 mg or placebo for ≤52 weeks(N=1731; n=1434 and n=297)*Pooled analysis*N=1731 comprises combined vedolizumab and non-ITT (‘true’) placebo groups, respectively CD, Crohn’s disease; ITT, intention-to-treat; OLE, open label extension; RCT, randomised controlled trial; UC, ulcerative colitis• Lower RTIs (LRTIs), including pneumonia, and upper RTIs (URTIs) were defined for AEs based on the Medical Dictionary for Regulatory Activities (MedDRA; version 14.0) High Level Terms (HLTs): ¡ LRTIs: Lower Respiratory Tract and Lung Infections HLT ¡ URTIs: Upper Respiratory Tract Infections HLT• For each study and the pooled analysis of GEMINI 1 and 2, exposure-adjusted incidence rates (per 100 patient-years [PY]) were calculated for the incidence of any AE and any serious AE within the HLT, as well as for each individual MedDRA Preferred Term (PT) within the HLT • A Cox proportional hazards model was used to identify predictors for the incidence of any LRTI or any URTI for the individual and pooled GEMINI 1 and 2 resultsResultsBaseline Demographics and Disease Characteristics• Baseline demographics and disease characteristics are presented in Table 1Table 1. Baseline Demographics and Disease Characteristics: GEMINI 1, 2 and OLE Demographic/characteristic*GEMINI 1 (N=769)GEMINI 2 (N=962)Pooled  GEMINI 1 and 2 (N=1731)GEMINI OLE  (N=2243)Age (years), mean (SD) 40.3 (13.0) 35.9 (12.1) 37.9 (12.7) 39.1 (13.2)Female sex 313 (40.7) 514 (53.4) 827 (47.8) 1115 (49.7)Baseline disease activity, mean score (SD)†6.1 (1.6) 11.2 (3.8) 5.8 (1.7) NAConcomitant narcotic use 148 (19.2) 315 (32.7) 463 (26.7) 777 (34.6)Concomitant corticosteroid use 409 (53.2) 488 (50.7) 897 (51.8) 1133 (50.5)Concomitant immunomodulator use 257 (33.4) 321 (33.4) 578 (33.4) 618 (27.6)On-study surgery 64 (8.3) 139 (14.4) 203 (11.7) NADisease duration ≥7 years 267 (34.7) 483 (50.2) 750 (43.3) 1127 (50.2)Prior use of anti-TNFα therapy 384 (49.9) 607 (63.1) 991 (57.3) 1313 (58.5)Current smoker 47 (6.1) 250 (26.0) 297 (17.2) 406 (18.1)Former smoker 254 (33.0) 219 (22.8) 473 (27.3) 591 (26.3)Prior lung disease was not a specific exclusion criterion*Data presented as n (%) unless stated otherwise†Baseline disease activity scores based on partial Mayo Score for GEMINI 1 (UC), HBI score for GEMINI 2  (CD) and common index for pooled GEMINI 1 and 2. Common index ranged from 0 to 9 to allow the combination of baseline partial Mayo and HBI scores in the pooled analysisCD, Crohn’s disease; HBI, Harvey–Bradshaw Index; NA, not available; OLE, open-label extension;  TNFα, tumour necrosis factor-alpha; UC, ulcerative colitisExposure-Adjusted Incidence Rates and Outcomes of LRTIs and URTIs• In the pooled GEMINI 1 and 2 analysis, rates of LRTIs including pneumonia, bronchopneumonia and primary atypical pneumonia were similar in the vedolizumab and placebo groups (Figure 2)• There was no increase in the OLE incidence rates of these events relative to those in the pooled GEMINI 1 and 2 analysis (Figures 2 and 3)  ¡ Bronchitis, which is listed as a common AE in the vedolizumab summary of product characteristics,5 was the most frequently reported LRTI in both the vedolizumab and placebo groups in the GEMINI 1 and 2 population and in the OLE• The incidence rate of URTIs was higher in patients receiving vedolizumab than in those on placebo (Table 2) ¡ Nasopharyngitis and URTI (listed as very common and common AEs, respectively, in the vedolizumab summary of product characteristics5), were the most frequently reported URTIs in both the vedolizumab and placebo groups in the GEMINI 1 and 2 population and in the OLE• Sinusitis and pharyngitis are also reported as common AEs in the summary of product characteristics5Figure 2. Exposure-Adjusted Incidence Rates of LRTIs in the Pooled GEMINI 1 and 2 Studies4286100Exposure-adjusted incidnce rate *7.78.55.56.01.0 1.2 1.0 0.6<0.10.6<0.1 0 <0.1 0Any LRTI Bronchitis Pneumonia LRTI Bronchopneumonia LunginfectionPrimaryatypicalpneumoniaVedolizumab (n=1434) PY=1058Placebo (n=297) PY=171MedDRA preferred term*Exposure-adjusted incidence rate per 100 PY ([number of patients experiencing an AE of interest/total patient exposure time in years] × 100)AE, adverse event; LRTI, lower respiratory tract infection; MedDRA, Medical Dictionary for Regulatory Activities; PY, patient-yearsFigure 3. Exposure-Adjusted Incidence Rates of LRTIs in the OLE 3215460Exposure-adjusted incidnce rate *5.04.15.73.32.44.00.9 0.9 0.9 0.9<0.1<0.1 0.1 <0.1 0 <0.1 <0.1 0 <0.1 <0.1 0 <0.10.8 0.8Any LRTI Bronchitis Pneumonia LobarpneumoniaLRTI Broncho-pneumoniaLunginfectionPrimaryatypicalpneumoniaTotal (N=2243) PY=5430UC (n=894) PY=2285CD (n=1349) PY=3145MedDRA preferred term*Exposure-adjusted incidence rate per 100 PY ([number of patients experiencing an AE of interest/total patient exposure time in years] × 100)AE, adverse event; CD, Crohn’s disease; LRTI, lower respiratory tract infection; MedDRA, Medical Dictionary for Regulatory Activities; OLE, open-label extension; PY, patient-years; UC, ulcerative colitis• The rates of serious LRTIs and serious URTIs were low in the pooled GEMINI 1 and 2 analysis and the GEMINI OLE (Table 2) ¡ Two LRTIs (vedolizumab group during GEMINI 2) and two URTIs (one in GEMINI OLE and one in GEMINI 2) resulted in discontinuation; 3 out of 4 were considered non-serious• There were no deaths from upper or lower RTIs in patients treated with vedolizumab, compared with one death in the placebo groupTable 2. RTIs in GEMINI 1, 2 and OLEGEMINI 1 and GEMINI 2 pooled GEMINI OLEVedolizumab (n=1434) Total PY=1058Placebo (n=297) Total PY=171Vedolizumab (n=2243) Total PY=5430All*, n (IR)†Serious, n (IR)†All*, n (IR)†Serious, n (IR)†All*, n (IR)†Serious, n (IR)†Any LRTI Any URTI79 (7.7) 339 (38.7)5 (0.5) 2 (0.2)14 (8.5) 50 (33.0)1 (0.6) 0248 (5.0) 857 (23.5)20 (0.4) 6 (0.1)AE leading to discontinuationLRTI URTI2 (0.2) 1 (<0.1)1 (<0.1) 00 00 00 1 (<0.1)0 0DeathsLRTI URTI0 00 01 (0.6) 01 (0.6)‡ 00 00 0LRTIsBronchitis§ Pneumonia LRTI Lobar pneumonia Bronchopneumonia Lung infection Primary atypical pneumonia57 (5.5) 11 (1.0) 10 (1.0) 0 1 (<0.1) 1 (<0.1)  1 (<0.1)1 (<0.1) 2 (0.2) 1 (<0.1) 0 0 1 (<0.1)  010 (6.0) 2 (1.2) 1 (0.6) 0 1 (0.6) 0  00 0 0 0 1 (0.6) 0  0170 (3.3) 49 (0.9) 45 (0.8) 5 (<0.1) 1 (<0.1) 1 (<0.1)  1 (<0.1)0 18 (0.3) 0 2 (<0.1) 0 0  0URTIsNasopharyngitis§ URTI§ Sinusitis§ Pharyngitis§ Rhinitis TonsillitisLaryngitisTracheitisAcute sinusitisAcute tonsillitisChronic sinusitisTracheobronchitisRhinolaryngitisSinobronchitisPeritonsillar abscessPharyngotonsillitis180 (18.6)106 (10.5)44 (4.3)24 (2.3)13 (1.2)5 (0.5)3 (0.3)3 (0.3)2 (0.2)2 (0.2)2 (0.2)1 (<0.1)0000001 (<0.1)001 (<0.1)001 (<0.1)000000021 (12.8)19 (11.6)3 (1.8)1 (0.6)4 (2.4)02 (1.2)1 (0.6)1 (0.6)1 (0.6)001 (0.6)0000000000000000000485 (10.9)298 (6.1)194 (3.8)65 (1.2)34 (0.6)25 (0.5)19 (0.4)2 (<0.1)8 (0.2)16 (0.3)7 (0.1)1 (<0.1)02 (<0.1)1 (<0.1)1 (<0.1)1 (<0.1)1 (<0.1)2 (<0.1)0001 (<0.1)00000001 (<0.1)0*Includes serious and non-serious AEs†Exposure-adjusted incidence rate per 100 PY ([number of patients experiencing an AE of interest/total patient exposure time in years] × 100)‡Patient on placebo died due to bronchopneumonia, which was a serious AE§AE included in the vedolizumab summary of product characteristics5 AE, adverse event; IR, incidence rate; LRTI, lower respiratory tract infection; OLE, open-label extension;  PY, patient-years; URTI, upper respiratory tract infectionPredictors of RTIs• In the pooled GEMINI 1 and 2 studies, significant risk factors for LRTIs were female sex, prior anti-TNFα use and a history of being a smoker (current and former smoker; Figure 4) ¡ The proportion of patients who were current smokers was higher in females (19.7%) than males (14.8%) in the pooled GEMINI 1 and 2 population ¡ A higher proportion of patients with CD were smokers than those with UC (current smokers: female 29.2% and male 22.3% in the GEMINI 2 study; female 4.2% and male 7.5% in the GEMINI 1 study) ¡ Predictors of an LRTI were:UC population• Female sex (HR: 2.11; 95% CI: 1.07–4.14; p=0.0303) • Prior anti-TNFα use (HR: 2.20; 95% CI: 1.10–4.41; p=0.0265)CD population• Current smoker (HR: 2.37; 95% CI: 1.26–4.45; p=0.0076)• In the pooled GEMINI 1 and 2 studies, significant risk factors for URTIs were:• Current smoker (HR: 1.35; 95% CI: 1.04–1.75; p=0.0225)• Concomitant narcotic use (HR: 1.30; 95% CI: 1.04–1.64; p=0.0215) • Prior anti-TNFα use (HR: 1.50; 95% CI: 1.20–1.88; p=0.0004)UC population• Younger age (HR: 0.99; 95% CI: 0.97–1.00; p=0.0177• Prior anti-TNFα use (HR: 1.75; 95% CI: 1.28–2.39; p=0.0005) CD population• Current smoker (HR: 1.60; 95% CI: 1.16–2.19; p=0.0039)  • Concomitant narcotic use (HR: 1.36; 95% CI: 1.01–1.84; p=0.0451)Figure 4. Predictors of LRTIs in Pooled GEMINI 1 and 2 Data Age (years), mean (SD) 37.9 (12.7) 39.3 (12.8) 1.00 0.98–1.02 0.9939 All patients(N=1731)Patientswith AE(n=93)HR 95% CI p HR (95% CI)Female sex 827 (47.8) 59 (63.4) 1.84 0.0058 750 (43.3) 52 (55.9) 1.35 0.1730 991 (57.3) 65 (69.9) 1.70 0.0281 5.8 (1.70) 5.9 (1.72) 1.07 0.2777 463 (26.7) 28 (30.1) 0.87 897 (51.8) 43 (46.2) 0.83 0.3818 578 (33.4) 29 (31.2) 0.96 0.8616 297 (17.2) 25 (26.9) 1.97 0.0110 0.5653 473 (27.3) 31 (33.3) 1.74 0.0291 203 (11.7) 14 (15.1) 1.65 0.1948 1434 (82.8) 79 (84.9) 0.85 0.5847 Disease duration≥7 years Prior anti-TNFαtherapyBaseline diseaseactivity*, meanscore (SD)  Concomitantnarcotic use Concomitantcorticosteroid use  Concomitantimmunomodulatoruse Current smoker†Former smoker† On-study surgery Vedolizumabtreatment0.48–1.520.78–3.491.06–2.871.17–3.310.62–1.500.55–1.250.55–1.390.95–1.221.06–2.730.88–2.091.19–2.830DecreasedriskIncreasedrisk1 2 3 4Data presented as n (%) unless stated otherwise*Baseline disease activity scores based on partial Mayo Score for GEMINI 1 (UC), HBI score for GEMINI 2 (CD) and common index for pooled GEMINI 1 and 2. Common index ranged from 0 to 9 to allow the combination of baseline partial Mayo and HBI scores in the pooled analysis†HR relative to non-smokersCD, Crohn’s disease; HBI, Harvey–Bradshaw Index; LRTI, lower respiratory tract infection;  TNFα, tumour necrosis factor-alpha; UC, ulcerative colitisConclusions• In this post hoc analysis, vedolizumab treatment of inflammatory bowel disease was not associated with an increased incidence of LRTIs, including pneumonia, compared with placebo ¡ Most LRTIs and URTIs were not serious and did not result in treatment discontinuation• Patients receiving vedolizumab who were female, had previously used anti-TNFα therapies or were current/former smokers were found to have an increased risk of developing LRTIs ¡ The GEMINI trials were not statistically powered to detect these differences ¡ Anti-TNFα use2–4,12,13 and smoking14 have both been previously shown to increase the risk of pneumonia• Continuing pharmacovigilance will augment these data and current observational studies will further characterise these findingsReferences1. Grijalva CG et al. JAMA 2011;306:23312. Curtis JR et al. Arthritis Care Res 2014;66:9903. Lane MA et al. Medicine 2011;90:1394. Kalb RE et al. JAMA Dermatol 2015;151:9615. Takeda Pharma A/S. ENTYVIO® (vedolizumab) summary of product characteristics. Accessed February 20176. Takeda Pharmaceuticals America, Inc. ENTYVIO® (vedolizumab) Prescribing Information. Accessed February 20177. Feagan BG et al. N Engl J Med 2013;369;6998. Sandborn WJ et al. N Engl J Med 2013;369;7119. Takeda Pharmaceuticals Inc. Data on file. 201510. Loftus EV Jr et al. J Crohns Colitis 2016 Sep 28. pii: jjw177. [Epub ahead of print]11. Vermeire S et al. J Crohns Colitis 2016 Sep 28. pii: jjw176. [Epub ahead of print]12. Ali T et al. Drug Healthc Patient Saf 2013:5;7913. Lichtenstein GR et al. Am J Gastroenterol 2012;107:140914. Bello S et al. Chest 2014;146:1029AcknowledgmentsClinical trials were sponsored and conducted by Takeda Pharmaceuticals Company Ltd. Medical writing support was provided by Chameleon Communications International Ltd, UK (a Healthcare Consultancy Group Company) and sponsored by Takeda Pharmaceuticals Company Ltd. Analytical support was provided by Kelly Williams, formerly of Takeda Development Center Americas, USA.

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Incidence of pneumonia and other respiratory tract infections with vedolizumab treatment: clinical trial experience

Incidence of pneumonia and other respiratory tract infections with vedolizumab treatment: clinical trial experience

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