Serum Vedolizumab Concentrations Research Articles

Real-life experiences of switching from intravenous to subcutaneous vedolizumab maintenance therapy in patients with inflammatory bowel disease.

A few prospective cohort studies support the safety of switching from intravenous to subcutaneous administration of vedolizumab during maintenance therapy in patients with inflammatory bowel disease. Real-life data on switching after intravenous induction therapy are lacking. The aim was to obtain real-world data on subcutaneous vedolizumab treatment in patients with inflammatory bowel disease after switching from intravenous vedolizumab induction or maintenance therapy, and to evaluate treatment persistence, safety, and changes in disease activity and serum vedolizumab concentrations. We performed a retrospective registry-based study of inflammatory bowel disease patients who received subcutaneous vedolizumab therapy in two tertiary centres. Altogether, 103 patients (26 Crohn's disease and 77 ulcerative colitis) switching from intravenous maintenance therapy (group 1) and 44 patients (14 and 30, respectively) switching from intravenous induction therapy (group 2) were included. At 6 months from baseline, 90.3% of the patients in group 1 and 90.9% of the patients in group 2 continued on subcutaneous vedolizumab. After the switch in group 1, disease activity remained stable. In group 2, clinical disease activity decreased significantly in ulcerative colitis patients (P = 0.002). The median serum vedolizumab concentration was 34.00 µg/ml during subcutaneous maintenance therapy in group 1, which was significantly higher than the median concentration during intravenous therapy (17.00 µg/ml, P < 0.001), but remained unchanged in group 2 after the switch (31.50 µg/ml). Based on these data, subcutaneous vedolizumab treatment is well-tolerated and the treatment persistence remains high after switching from intravenous to subcutaneous vedolizumab therapy.

Therapeutic Drug Monitoring as a Tool for the Clinical Outcome Prediction in Vedolizumab-Treated Patients: An Italian Pilot Study.

Over the years, vedolizumab (VDZ) has emerged as a more effective target therapy for inflammatory bowel disease. The aim of this work was to analyze a cohort of inflammatory bowel disease patients, evaluating the association between VDZ serum concentrations at 6 months from starting therapy and their clinical and biochemical indexes within one year of treatment, correlating drug levels with response and clinical remission. Forty patients treated with VDZ were enrolled. Drug concentrations were quantified through ELISA methods. VDZ levels correlated with hemoglobin levels at twelve months of therapy (p = 0.03) and with clinical remission at twelve months of therapy (p = 0.03); patients who reached clinical remission showed higher VDZ concentrations. A VDZ cut-off value of 43.1 μg/mL was suggested, predicting clinical remission at twelve months of therapy. A statistically significant association between VDZ levels at T6 and calprotectin <250 μg/g at T12 was found (p = 0.04). Furthermore, the optimal threshold value of VDZ levels at T6 associated with calprotectin <250 μg/g at T12 was identified: through levels higher than 45.2 µg/mL, we were able to predict remission one year after therapy. In the final regression multivariate model, no factor was retained as a predictor of clinical remission at one year of treatment. In conclusion, this is the first pilot study reporting a possible VDZ serum cut-off value able to predict not only the clinical remission at twelve months of therapy but also the calprotectin level, which is very important, as it is a surrogate marker of mucosal healing.

The relationship among vedolizumab drug concentrations, biomarkers of inflammation, and clinical outcomes in a Canadian real-world study

Abstract Background and Aims Therapeutic drug monitoring is used to optimize anti-tumour necrosis factor biologic effectiveness in inflammatory bowel disease, but its role with other biological classes is unclear. This study explores relationships between post-induction vedolizumab trough concentrations and biochemical outcomes in a real-world study of individuals with inflammatory bowel disease. Methods This retrospective analysis of data from a national patient support program between 2018 and 2020, included 436 individuals with Crohn’s disease or ulcerative colitis receiving vedolizumab. Optimal vedolizumab concentration thresholds (at weeks 6 and 14) were determined based on their ability to predict biochemical normalization (week 30 faecal calprotectin [&amp;lt;250 µg/g], C-reactive protein [&amp;lt;5 mg/l]). Thresholds best associated with each outcome were evaluated in multivariate analyses. Results Among patients with Crohn’s disease, week 6 serum vedolizumab concentrations (&amp;gt;41.65 µg/ml) predicted normalization defined by C-reactive protein: Spearman correlation coefficient [ρ] = −0.26, P = 0.002 and multivariate analysis (MVA)—OR: 3.22, 95% CI: 1.32–7.87, P = 0.01, and at week 14 (&amp;gt;22.25 µg/ml): ρ = −0.38, P &amp;lt; 0.0001, and MVA—OR: 3.21, 95% CI: 1.26–8.17 but not faecal calprotectin. Similarly, among patients with ulcerative colitis, week 6 vedolizumab concentrations (&amp;gt;39.65 g/ml) predicted normalization defined by C-reactive protein: ρ = −0.26, P = 0.005 and MVA—OR: 4.03, 95% CI: 1.30–12.52, P = 0.016, and at week 14 (&amp;gt;17.35 µg/ml): ρ = −0.39, P = 0.0001 and MVA—OR: 6.95, 95% CI: 1.81–26.77, P = 0.005, but not faecal calprotectin. Conclusions Induction and post-induction serum vedolizumab were not consistently associated with biochemical normalization. As such, proactive therapeutic drug monitoring for vedolizumab should not be routinely incorporated in a treat to target strategy for inflammatory bowel disease. Clinical Trial Registration Number NCT04567628.

Subcutaneous vedolizumab interval extension in inflammatory bowel disease patients: a case series.

Subcutaneous vedolizumab has demonstrated efficacy as a maintenance therapy in inflammatory bowel disease (IBD). However, data on the extension of subcutaneous vedolizumab injection intervals are lacking. Here, we present the first real-world data on subcutaneous vedolizumab interval extension in IBD patients. Nine patients (eight Crohn's disease patients and one ulcerative colitis patient) were included in the study. At interval extension (at baseline), all patients were in clinical and biochemical remission and requested an extension of their 2-weekly injection intervals due to side effects potentially related to subcutaneous vedolizumab. Patients increased their intervals to 3, 4, or 5 weeks. During a median follow-up of 10.0 months (IQR 6.5-19.5), no flare-ups were observed. After 6 months, median biochemical parameters remained stable compared to baseline levels (fecal calprotectin 24.0 µg/g [IQR 10.0-43.0] versus 28.0 µg/g [IQR 15.0-54.0], p = 0.553; C-reactive protein 3.4 mg/L [IQR 1.4-4.2] versus 3.1 mg/L [IQR 0.7-4.9], p = 0.172), while vedolizumab serum concentrations significantly decreased (22.0 µg/mL [IQR 20.0-33.0] versus 40.0 µg/mL [IQR 28.3-45.0], p = 0.018). After interval extension, almost all suspected vedolizumab-induced side effects disappeared within 6 months. Lengthening subcutaneous vedolizumab intervals in IBD patients in clinical and biochemical remission appears to be both effective and safe, potentially leading to substantial reductions in healthcare expenses.

Relationship between vedolizumab serum concentrations in the induction phase and early and sustained response in the first year of treatment in patients with ulcerative colitis

ObjectiveEvidence on the usefulness of proactive monitoring of vedolizumab serum concentrations during the induction phase of treatment is limited. The objective of our study was to evaluate the effectiveness of measuring such concentrations during this phase in predicting response to treatment in patients with ulcerative colitis with a view to determining whether patients would benefit from early monitoring of vedolizumab serum concentrations. MethodThis was a prospective descriptive study carried out at three public general hospitals. It included adult patients with ulcerative colitis who were initiated on vedolizumab at the participating hospitals from June 2019 to June 2020. Vedolizumab serum concentrations were determined at weeks 6 and 14. Response to treatment was biologically, clinically, and endoscopically evaluated at weeks 6, 14, and 52. An analysis was made of the relationship between vedolizumab serum concentrations at week 6 and early response to treatment, and of the relationship between the vedolizumab serum concentrations at weeks 6 and 14 and persistent response at one year. ResultsA total of 45 patients were included of whom 22 (49%) were considered non-responsive after one year and required intensification of treatment. The median (interquartile range) vedolizumab serum concentrations obtained at 6 weeks was higher in patients who obtained an early response and in those who maintained the response at one year than in those who did not respond to vedolizumab [27.4 (19.0-40.8) µg/mL vs 15.6 (13.4-28.5) µg/mL; p = 0.018] and [29.9 (19.2-43.2) µg/mL vs 18.2 (15.4-26.9) µg/mL; p = 0.022] respectively. Vedolizumab serum concentrations ≥ 17.3 µg/mL at week 6 were predictive of a good early response, and vedolizumab serum concentrations ≥ 26.1 µg/mL at week 6 predicted a sustained response at one year. No relationship was found between vedolizumab serum concentrations at week 14 and a sustained response. ConclusionsWe observed a relationship between vedolizumab serum concentrations determined at week 6, and early and maintained response to vedolizumab therapy in patients with ulcerative colitis, which supports early drug monitoring during the induction phase to individualize treatment and increase effectiveness.

Measuring Serum Vedolizumab and Vedolizumab Antibodies: Comparison of Commercial Assays with the Vedolizumab Clinical Development Assay.

Vedolizumab (VDZ) is an anti-α 4 β 7 integrin monoclonal antibody approved for inflammatory bowel disease treatment. VDZ serum and antidrug antibody (ADA) concentrations may be used for treatment optimization. In this article, the results of 5 commercial assays (Grifols, Immundiagnostik, Progenika, Sanquin, and Theradiag) measuring VDZ concentration and ADA were compared with those of the reference assays used in VDZ clinical studies. Our findings will assist clinicians in interpreting commercial assay results in the context of VDZ clinical trial data. VDZ-treated patient samples were used to evaluate the agreement between commercial assays and the reference VDZ serum concentration assay, based on linear regression, Bland-Altman, and qualitative agreement analyses. VDZ ADAs were detected using qualitative assays. Specificity, selectivity, accuracy, and precision were assessed using serum samples from healthy donors or patients with IBD (VDZ serum concentration <0.5 mcg/mL) spiked with VDZ, with/without other biologics (identical sample sets per assay). All assays were specific and selective for VDZ. Overall, the commercial assay results for VDZ-spiked samples correlated well with those of the reference serum concentration assay (R 2 ≥ 0.98). Compared with the Immundiagnostik and Theradiag assays, the Grifols, Sanquin, and Progenika assays had the best reference assay agreement (based on regression analysis, Bland-Altman plots, and qualitative agreement [Cohen's kappa ≥0.92]). All immunogenicity assays detected VDZ ADAs; only the reference assay detected VDZ ADAs in the presence of 15 mcg/mL VDZ, advising caution with commercial ADA assays if VDZ is present. All 5 commercial assays are suitable for VDZ therapeutic monitoring and ADA testing. However, the absolute values from the reference assays and the different commercial assays were not comparable, indicating that the same assay must be used for repeated monitoring of VDZ serum concentrations.

P495 Vedolizumab trough concentrations and histological remission in Ulcerative Colitis: Results from the LOVE-UC study

Abstract Background To date, the association between vedolizumab (VDZ) serum concentrations and histological remission in ulcerative colitis (UC) has not been studied prospectively. VDZ serum concentrations could potentially offer additional guidance for predicting histological remission. We studied the relationship between VDZ serum concentrations and histological remission in a prospective study. Methods LOVE-UC was a multicentre international (Belgium, the Netherlands, and Hungary) open label prospective study in patients with moderately to severely active UC treated with VDZ. VDZ serum concentrations were measured at trough prior to every infusion. Endoscopy was performed at baseline, week 26 and 52. Biopsies from the most severely affected area and endoscopy videos were scored by blinded central readers. Histological remission was defined as a Robarts Histopathology Index &amp;lt;3 without neutrophils. Patients who did not undergo histological assessment were regarded as not having reached histological remission. Endoscopic remission was defined as a Mayo endoscopic sub-score 0. Results A total of 121 patients (61 male, 62 with prior exposure to tumour necrosis factor antagonists, mean total Mayo score at baseline of 9) received at least one infusion of VDZ. At week 26, 37.2% (45/121) patients were in histological remission, 38.8% (47/121) were in histological remission at week 52. The corresponding rates of combined histological and endoscopic remission were 19.8% (24/121) and 20.7% (25/121), respectively. Median VDZ serum concentrations were numerically higher at all time points in patients who achieved histological remission at week 26 than in those who did not (Table 1). Concentration thresholds (sensitivity, specificity, positive predictive value, negative predictive value, area under the receiver operating characteristic curve) of 32.5 mg/L (66%, 68%, 54%, 74%, 0.681) at week 6 and 12.5 mg/L (76%, 60%, 61%, 70%, 0.724) at week 22 were associated with histological remission at week 26. Higher proportions of patients achieved histological remission at week 26 in higher VDZ serum concentration quartiles (Figure 1). Conclusion VDZ serum concentrations were positively associated with histological remission in UC, although the predictive value of serum concentrations for subsequent histological remission was modest.

P785 A retrospective cohort study on vedolizumab trough levels in Crohn’s disease patients

Abstract Background Background: Vedolizumab (VDZ), an α47-integrin inhibitor, is approved for the treatment of moderate to severe Crohn’s disease (CD). Exposure-response relationship for VDZ is less evident in CD. Here, we are exploring associations between serum VDZ serum concentrations and clinical/biomarker-defined endpoints from a single center, real-world cohort. Methods Methods: Electronic health data records of CD patients during their first year of treatment with VDZ from January 2014 – July 2022 at our tertiary care center were obtained. Serum drug levels (TDL) and their correlation with outcomes were assessed at specified timepoints – weeks 12 (± 2), 26 (± 4) and 52 (± 6). Clinical remission was assessed by patient reported outcomes as suggested in STRIDE II guidelines (stool frequency ≤ 3 and abdominal pain ≤ 1). Fecal calprotectin (fCP) values ≤ 150 µg/g marked biomarker remission. Vedolizumab drug levels were measured with IDKmonitor Vedolizumab drug level ELISA kit (Immundiagnostik AG, Germany), In case of missing data patients were categorized as non-responders. For association modelling, multivariable fractional polynomials and generalised additive models were used (R statistical software, v4.1.2; R Core Team). Results Results: In total, 58 patients (females = 55.2%) with at least two available data points were included (Table 1). Sixteen individuals (16/58, 27.6%) were naive for biologics therapies. 98.3% (57/58) reached week 12 (± 2). Both at weeks 26 and 52 91.4% (53/58) subjects still were on drug. Clinical remission was achieved in 51.7% (30/58), 49.1% (26/53) and 45.2% (24/53) cases at weeks 12, 26 and 52, respectively, with biomarker remission rates of 24.1% (14/58), 35.8% (19/53) and 27.6% (16/53) patients reached biomarker remission. TDLs differed only between clinical remitters and non-remitters at week 26 (Mann-Whitney-U-test, p = 0.04). Also, there was no significant association between clinical and biomarker remission at defined timepoints and corresponding TDLs (for all p &amp;gt; 0.05). TDLs at week 2 and 6 were correlated with fCP values at the same time (rho: -0.327, p = 0.03 at week 2 and rho: -0.356, p = 0.02 at week 6). When TDLs at week 2 and week 6 were taken into consideration and associated separately with therapy outcomes in a univariate regression, only association between serum levels at week 6 and biomarker remission at weeks 26 and 52 was found (p = 0.02 and p = 0.03, respectively). Conclusion Conclusion: The only association between serum drug levels and remission was found between TDLs at week 6 and biomarker remission at weeks 26 and 52 suggesting a complex exposure-response relation for vedolizumab in CD patients.

Pharmacokinetics and Safety of Vedolizumab Following Administration of a Single Intravenous Dose in Healthy Chinese Subjects.

Vedolizumab is a humanized monoclonal antibody, indicated for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), that specifically binds to the α4β7 integrin. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of vedolizumab following a single intravenous (IV) infusion in healthy adult Chinese subjects. Sixteen participants received a single IV infusion of vedolizumab (300mg). Blood samples were collected to measure vedolizumab serum concentrations. The safety of all subjects was monitored. The pharmacokinetic analysis showed that vedolizumab reached the maximum observed serum concentration (Cmax) at approximately 1.32hours. The mean Cmax and area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC0-t) and to infinity (AUC0-∞) were 137.25µg/mL, 2360days·µg/mL, and 2395days·µg/mL, respectively. The elimination of vedolizumab was relatively slow, with a mean terminal disposition phase half-life elimination (t1/2) of 20.23days. Six subjects were positive for anti-vedolizumab antibodies (AVAs) on day 106 and day 127. Finally, 4 out of 16 subjects (25.0%) had treatment-emergent adverse events (TEAEs), all of which were upper respiratory tract infections. Vedolizumab was well tolerated in healthy Chinese subjects when administered as a single-dose IV 300mg infusion. In this study, the rate of AVA positivity was 37.5%, which occurred near the end of the study; no significant differences in pharmacokinetic profiles were observed between the AVA-positive and AVA-negative groups. http://www.chinadrugtrials.org.cn : CTR20171528.

Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel diseases.

SummaryBackgroundSubcutaneous (SC) vedolizumab is effective in inflammatory bowel diseases (IBD) when administered after induction with two infusions.AimTo assess the effectiveness, safety and pharmacokinetics of a switch from intravenous (IV) to SC maintenance vedolizumab in patients with IBDMethodsIn this prospective cohort study, patients with IBD who had ≥4 months IV vedolizumab were switched to SC vedolizumab. We studied the time to discontinuation of SC vedolizumab, adverse events (AEs), changes in clinical and biochemical outcomes and vedolizumab concentrations at baseline, and weeks 12 and 24.ResultsWe included 82 patients with Crohn's disease (CD) and 53 with ulcerative colitis (UC). Eleven (13.4%) patients with CD and five (9.4%) with UC discontinued SC vedolizumab after a median of 18 (IQR 8–22) and 6 weeks (IQR 5–10), respectively. Four patients with CD switched to a different drug due to loss of response, nine switched back to IV vedolizumab due to adverse events, and three due to needle fear. Common AEs were injection site reactions (n = 15) and headache (n = 6). Median clinical and biochemical disease activity remained stable after the switch. Median serum vedolizumab concentrations increased from 19 μg/ml at the time of the switch to 31 μg/ml 12 weeks after the switch (p < 0.005).ConclusionsSwitching from IV to SC vedolizumab maintenance treatment is effective in patients with CD or UC. However, 9% of patients were switched back to IV vedolizumab due to adverse events or fear of needles.

OP29 Peripheral blood DNA methylation biomarkers accurately predict clinical- and endoscopic response to vedolizumab in a real-life cohort of Crohn’s Disease patients

Abstract Background Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with CD-specific phenotypes, suggesting that the methylome may be useful for classification and prediction of VDZ treatment response. Here, we sought to identify such DNA methylation biomarkers that can predict clinical- and endoscopic response to VDZ in CD patients. Methods We prospectively recruited adult CD patients that initiated VDZ treatment following a baseline colonoscopy in two cohorts: a discovery and validation cohort. Peripheral blood DNA methylation profiles were measured prior to treatment (T1), and after a median of 22 weeks (T2) using the Illumina Infinium HumanMethylation EPIC BeadChip array. Response (R) was defined as the strict combination of endoscopic- (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI and HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Twenty-one patients had deep remission (DR), defined as a combined endoscopic- (SES-CD≤2) and steroid-free clinical remission (HBI ≤4, no systemic steroids). Biomarker identification and classification analyses were performed using stability selection gradient boosting. Results In total, 64 CD patients were enrolled (discovery 16R/14NR and validation 20R/14NR). Both cohorts were comparable for age, sex and smoking status. Forty-nine (77%) patients had previously failed an anti-TNF agent. All patients had measurable serum vedolizumab concentration at T2 (median 14.5 (6.9 – 21.3) µg/mL). Through classification analysis at T1, we were capable of discriminating R from NR with high predictive performance (25 CpGs, AUC 0.88, F1-score of 0.84, PPV of 0.91 and NPV of 0.85). When analysing the methylome of patients in deep remission, we identified 23 CpGs with high predictive performance upon independent validation (F1-score 0.80, PPV of 0.71 and NPV of 0.86). Investigating the CpGs of interest implicated genes involved in endothelial cell-cell adhesion and integrin dependent T-cell homing, corroborating VDZ’s mode of action. Conclusion We demonstrate two novel 25- and 23-feature panels of epigenetic biomarkers that accurately predict response or deep remission to vedolizumab respectively. Similar analyses on infliximab, adalimumab and ustekinumab are currently ongoing as part of the EPIC-CD study.

Tissue Exposure does not Explain Non-Response in Ulcerative Colitis Patients with Adequate Serum Vedolizumab Concentrations.

Some patients with ulcerative colitis [UC] do not respond to vedolizumab treatment despite adequate drug exposure in serum. This study aimed to investigate vedolizumab in tissue and questioned whether insufficient tissue exposure could explain non-response in UC patients with adequate serum vedolizumab concentrations. A paired serum sample and colonic mucosal biopsy was collected from 40 UC patients [20 endoscopic responders, 20 non-responders] at week 14 of vedolizumab treatment. Vedolizumab, soluble [s]-mucosal addressin cell adhesion molecule-1 [MAdCAM-1], s-vascular cell adhesion molecule-1 [VCAM-1] and s-intercellular adhesion molecule-1 [ICAM-1] were measured in serum and/or tissue. Endoscopic response was defined as Mayo endoscopic sub-score ≤1. A significant positive correlation was observed between vedolizumab serum and colonic tissue concentrations [ρ = 0.84, p < 0.0001], regardless of the macroscopic inflammatory state of the tissue. Vedolizumab tissue concentrations were lower in non-responders than in responders [0.07 vs 0.11 µg/mg, p = 0.04]. In the subgroup of patients with adequate vedolizumab serum concentrations [>14.6 µg/mL], tissue vedolizumab was not significantly different between responders and non-responders [0.15 vs 0.13 µg/mg; p = 0.92]. Serum sMAdCAM-1 concentrations, but not serum sICAM-1 or sVCAM-1 concentrations, were significantly higher in responders than in non-responders with adequate vedolizumab serum concentrations [1.04 vs 0.83 ng/mL, p = 0.03]. Vedolizumab concentrations in colonic mucosal tissue of UC patients reflect the concentration in serum regardless of the macroscopic inflammatory state of the tissue. Our data show that insufficient tissue exposure does not explain non-response in UC patients with adequate serum vedolizumab concentrations.

Association Between Vedolizumab Levels, Anti-vedolizumab Antibodies, and Endoscopic Healing Index in a Large Population of Patients with Inflammatory Bowel Diseases

BackgroundThe aim of this study was to assess the relationship between serum vedolizumab (VDZ) concentrations and antibodies to VDZ (ATV) in a large cohort of patients with inflammatory bowel diseases. Furthermore, we evaluated the association between serum VDZ concentrations and a novel serum-based biomarker panel designated as the endoscopic healing index (EHI), developed and validated for identifying mucosal inflammation in patients with Crohn’s disease (CD).MethodsRetrospective study where results from patient samples submitted to a commercial clinical laboratory were included. Serum VDZ and ATV levels were analyzed using a drug-tolerant assay. In CD patients for whom both VDZ and EHI were available, VDZ concentrations were correlated with EHI. serum VDZ threshold analysis was performed using ROC curves, and the serum VDZ concentrations that best differentiated EHI < 20 (previously associated with endoscopic remission) were chosen.ResultsA total of 9356 patients were included in the VDZ/ATV analysis. Detectable ATV was observed in 2.9% patients with significantly lower serum VDZ concentrations when compared to those with undetectable ATV [3.9 µg/mL (0–9.0) vs. 11.3 µg/mL (5.9–20.6), p < 0.0001]. Of the patients with serum VDZ result, 287 patients had a concomitant EHI test. An inverse correlation was observed between VDZ concentration and EHI (rho = − 0.20, p < 0.001). A serum VDZ concentration ≥ 15.7 µg/ml was best correlated wi th an EHI < 20 [AUROC: 0.67 (95% CI 0.57–0.77)].ConclusionsIncidence of ATVs was low, but significantly associated with lower VDZ levels. A serum VDZ concentration threshold of ≥ 15.7 µg/ml was associated with endoscopic remission as defined by an EHI < 20.

Vedolizumab Serum Trough Concentrations and Response to Dose Escalation in Inflammatory Bowel Disease.

Serum vedolizumab concentrations are associated with clinical response although, it is unknown if vedolizumab concentrations predict response to dose escalation. The aim of this study was to identify if vedolizumab trough concentrations predicted the response to vedolizumab dose escalation. We assessed a retrospective cohort of patients on maintenance vedolizumab dosing at five tertiary care centers with vedolizumab trough concentrations. Multivariate logistic regression was used to control for potential confounders of association of vedolizumab concentration and clinical status. Those who underwent a dose escalation were further examined to assess if vedolizumab trough concentration predicted the subsequent response. One hundred ninety-two patients were included. On multivariate analysis, vedolizumab trough concentration (p = 0.03) and the use of immunomodulator (p = 0.006) were associated with clinical remission. Receiver operator curve analysis identified a cut off of 7.4 μg/mL for clinical remission. Of the fifty-eight patients with dose escalated, 74% of those with a vedolizumab concentration <7.4 μg/mL responded versus 52% of those with a vedolizumab trough concentration ≥7.4 μg/mL (p = 0.08). After adjustment for relevant confounders, the odds ratio for response with vedolizumab concentration <7.4 μg/mL was 3.7 (95% CI, 1.1–13; p = 0.04). Vedolizumab trough concentration are associated with clinical status and can identify individuals likely to respond to dose escalation. However, a substantial portion of patients above the identified cut off still had a positive response. Vedolizumab trough concentration is a potentially helpful factor in determining the need for dose escalation in patients losing response.

P464 Vedolizumab concentrations in colonic mucosal tissue of ulcerative colitis patients inversely correlate with the severity of inflammation

Abstract Background Multiple studies have reported the association between vedolizumab serum concentrations and endoscopic outcomes in patients with ulcerative colitis (UC). However, little is known about drug consumption in tissue and the relationship with mucosal inflammation. This study aimed to investigate vedolizumab concentrations in the tissue of UC patients and the correlation with their inflammatory state and serum levels. Methods A paired serum sample and colonic mucosal biopsy were collected in 36 UC patients at week 14 of vedolizumab treatment. In non-responders, defined as a Mayo endoscopic subscore of ≥2, inflamed colonic biopsies were taken in the sigmoid around 20–30 cm from the anal verge. In responders, defined as a Mayo endoscopic subscore ≤ 1, a biopsy was taken in a macroscopically uninflamed area at the same location. Biopsies were lysed by the addition of 10 μl lysis buffer (50 mM Tris, 0.1% Triton X-100 and 100 mM NaCl) per mg tissue and vortexed every 5 min during 1 h. Total protein content was measured and normalised to 3 mg/ml before analysis of the vedolizumab concentration using an in-house developed ELISA. Results are expressed as µg vedolizumab/mg total protein content. Results A positive correlation was observed between vedolizumab concentrations in tissue and serum (Spearman r = 0.8447, p &amp;lt; 0.0001), both in inflamed (r = 0.8609, p &amp;lt;0.0001, n = 16) and uninflamed tissue (r = 0.7925, p &amp;lt;0.0001, n = 20). The median tissue vedolizumab concentration in patients with Mayo endoscopic subscore 0, 1, 2 and 3 were 0.120, 0.074, 0.062 and 0.064 μg/mg, respectively (p &amp;lt; 0.01, see figure), indicating that tissue drug levels inversely correlate with the severity of inflammation. Vedolizumab tissue concentrations were significantly lower in non-responders compared with responders (0.064 vs. 0.112 μg/mg, p &amp;lt;0.05). Moreover, patients achieving Mayo endoscopic subscore 0 had significantly higher vedolizumab levels in colonic tissue compared with patients not achieving this outcome (0.120 vs. 0.065 μg/mg, p &amp;lt;0.02). Interestingly, a trend was observed towards higher serum-to-tissue ratios of vedolizumab in non-responders compared with responders (p = 0.0523). This finding suggests that if two patients have the same serum vedolizumab concentration, the patient with mucosal inflammation is more likely to have lower tissue levels than the patient with no or limited inflammation. Conclusion Vedolizumab concentrations in colonic mucosal tissue of UC patients inversely correlate with the severity of inflammation. As the serum-to-tissue ratio of vedolizumab is numerically higher in non-responders compared with responders, the relative distribution of vedolizumab in serum and tissue might be more important than the drug concentration alone.

DOP16 An evaluation of the exposure–efficacy relationship for subcutaneous vedolizumab maintenance treatment of Crohn’s disease: Pharmacokinetic findings from VISIBLE 2

Abstract Background The exposure–efficacy relationship and immunogenicity rates of the new vedolizumab subcutaneous (SC) formulation have been established for maintenance treatment of ulcerative colitis (UC).1 Here, we report vedolizumab SC exposure–efficacy and immunogenicity in Crohn’s disease (CD). Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a pivotal, phase 3, randomised, double-blind, placebo-controlled trial evaluating the efficacy and safety of vedolizumab SC (108 mg every 2 weeks) as maintenance treatment in patients with moderately to severely active CD. Following intravenous (IV) vedolizumab (300 mg Week 0 and 2) induction, patients with a clinical response at Week 6 (≥70-point decrease in CD activity index [CDAI] from Week 0) were randomised to blinded maintenance treatment and included in the analyses. Vedolizumab serum concentrations were measured prior to dosing using an enzyme-linked immunosorbent assay. Immunogenicity was assessed with a drug-tolerant electrochemiluminescence assay. Predicted vedolizumab trough concentrations at Week 52 were grouped by quartiles (Q), and Week 52 efficacy outcome rates calculated for each Q. Missing efficacy outcome data were imputed as failures. Efficacy outcomes were clinical remission (CDAI ≤150) and enhanced clinical response (≥100-point decrease in CDAI from Week 0 at Week 52). Results Following vedolizumab IV induction (N = 644), patients with a clinical response were randomised and received vedolizumab SC (N = 275) or placebo (N = 134) as maintenance treatment. At Week 52, patients on vedolizumab SC maintenance had a positive exposure–efficacy relationship for clinical remission (Q1: 37.7%; Q4: 50.7%) and enhanced clinical response (Q1: 37.7%; Q4: 53.6%; Figures 1 and 2). Overall, 7/275 (2.5%) patients on vedolizumab SC (following vedolizumab IV induction) developed anti-vedolizumab antibodies (AVAs): 3/7 patients were persistently AVA positive and 4/7 had neutralising antibodies. Five of 7 AVA-positive patients on vedolizumab SC did not achieve clinical remission and enhanced clinical response at Week 52; 2 of those patients were persistently AVA-positive. Immunogenicity was not associated with injection-site reactions or hypersensitivity reactions. Conclusion These preliminary results suggest a trend for higher vedolizumab SC serum concentrations with greater efficacy in CD, but the association was less pronounced than was reported in UC. (1) The AVA rate was similar to what was observed in prior vedolizumab IV studies. (2) In this study, vedolizumab immunogenicity appeared to be associated with clinical outcome. References

P823 DNA methylation profiles accurately predict vedolizumab response and remain stable during induction and maintenance treatment in Crohn’s disease

Abstract Background While the use of biologicals has revolutionised the treatment of Crohn’s disease (CD) in recent decades, many patients fail to respond or lose response over time. Predictors for treatment selection and/or success are lacking. Vedolizumab (VDZ) induces corticosteroid-free clinical remission in 29% and endoscopic remission in 36% of patients after 6 months. Accumulating evidence suggests that the epigenome, mainly DNA-methylation, is associated with certain CD phenotypes. Here, we investigated whether the DNA methylome of peripheral blood (PB) obtained from CD patients treated with VDZ was associated with clinical and endoscopic response or non-response to treatment. Methods We prospectively recruited CD patients scheduled to start VDZ treatment at regular dosage and who underwent baseline endoscopy. PB was collected prior to treatment (T1) and at a median of 14 weeks (T2) into treatment. Additionally, a third PB sample was collected after a median of 79 weeks (T3) into treatment for 10 CD patients. DNA methylation was measured using the Illumina Infinium Methylation EPIC BeadChip. After a median 27 weeks of treatment, patients were characterised as responders (R) or non-responders (NR) based on endoscopic changes (R= ≥50% reduction in SES-CD score) combined with either steroid-free clinical remission (≥3 point drop in HBI, no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein and faecal calprotectin). Results We analysed data of 16 R and 14 NR patients, 53% of which were female with a median age of 37. No significant differences in age, sex or smoking were observed between R and NR. All patients had measurable serum VDZ concentration at the second endoscopy. To identify response-associated biomarkers, we performed elastic net regression through repeated cross-validation. We identified 38 differentially methylated probes (DMPs) associated with response (Figure a), 7 of which were located in gene promoters. Performance-wise the DMPs displayed a sensitivity of 0.86 and a specificity of 0.8 in predicting response (Figure b). Notably, the degree of methylation for the response-associated DMPs did not change after 14 weeks of treatment (n = 30), or even after 79 weeks (n = 10). Conclusion Here, we show that the DNA methylome in peripheral blood is associated with response to VDZ. As the difference in methylation remained stable during induction and maintenance treatment with VDZ, inflammation did not appear to affect the response-associated DMPs. Our observations provide evidence towards the establishment of epigenetic marks with predictive biomarker capabilities, paving the road towards personalised treatment selection in CD.

P049 Biologic effect of anti-TNF exposure on vedolizumab induction

BACKGROUND: There are conflicting data on the impact of anti-TNF exposure on response to vedolizumab (VDZ). Post-hoc analyses of the VDZ registration (GEMINI) trials demonstrated decreased efficacy of VDZ in anti-TNF exposed subjects with real life experience reporting comparable efficacy rates. Reasons for this possible discrepancy remain unclear but include alterations in the biology post anti-TNF versus a marker of disease severity. We aimed to determine the influence of anti-TNF exposure on VDZ clinical, pk and biologic outcomes. METHODS: As part of an ongoing intensive pharmacokinetics (PK) monitoring IBD registry we identified patients initiating VDZ. Anti-TNF exposure history was recorded and categorized into none/remote or recent with exposure within 100 days of starting VDZ. Anti-TNF serum concentrations and anti-drug antibodies (ADA) were measured at week 0. Biomarker data including serum MAdCAM-1, α4β7, and TNFα were collected at each infusion. Pre-dose serum VDZ concentrations and anti-VDZ antibodies (ATV) were measured (Prometheus Laboratories Inc. San Diego, CA) at weeks 2, 6, and 14. Primary endpoint was steroid free clinical remission (SFCR) defined as a Harvey Bradshaw Index of &lt;5 or a partial Mayo ≤1 at week 14 and off steroids. Descriptive statistics (frequency and medians (interquartile range [IQR]) summarized data and univariate statistics tested associations. RESULTS: A total of 44 patients (17 CD; 27 UC) were included. Median age was 35 [18.5–47] years and disease duration was 7 [1.5–20.5] years. Forty-one percent (18/44) of patients were anti-TNF naïve and 73% of the 26 ever exposed were recent. Anti-TNF therapy was discontinued for primary non-response (n = 3), secondary loss of response (n = 15), adverse event (n = 8). Forty-three percent (19/44) achieved Week 14 SFCR (47% CD, 41% UC; P = 0.68). Median VDZ concentrations trended higher at weeks 6 and 14 in those who achieved week 14 SFCR (week 2: 30 vs 30.8 μg/mL, P = 0.76; week 6: 32.1 vs 27.1 μg/mL, P = 0.06; week 14: 16.5 vs 10.8 μg/mL, P = 0.13). SFCR was achieved in 42% of patients with recent anti-TNF exposure and 44% with remote/no anti-TNF exposure (P = 0.9). Median anti-TNF concentration at week 0 was 15.5 μg/mL [IQR 2.5–22.4] and correlated with week 0 TNFα concentration (r: −0.53, P = 0.05), but not with week 0 MAdCAM-1 (r = 0.04, P = 0.89), week 0 α4β7 (r = 0.06, P = 0.84) or VDZ concentration at week 2 (r: −0.28, P = 0.35). Weeks 0 and 14 serum MAdCAM-1 and α4β7 concentrations were not associated with SFCR nor anti-TNF exposure. Those achieving SFCR had similar percent decreases in serum MAdCAM-1 and percent increases in serum α4β7 concentrations as those who did not achieve SFCR. Within UC, median delta α4β7 concentrations were higher at all points in those achieving SFCR and could be seen as early as week 2 (week 2: 10,823 [IQR 9,235–16,425] vs 7,673 pg/mL [IQR 4,757–10,490], P &lt; 0.05; week 14: 15,118 [IQR 7,995–15,118] vs 7,833 pg/mL [IQR 7,986–10,628] P = 0.02). CONCLUSION(S): Unlike GEMINI, recent anti-TNF exposure did not influence VDZ induction of remission. Our findings suggest that the impact of anti-TNF may not be explained by its biologic effects and further research needed to understand the impact of anti-TNF and VDZ efficacy.

Vedolizumab Concentrations Are Associated with Long-Term Endoscopic Remission in Patients with Inflammatory Bowel Diseases.

The aim of this study was to assess the relationship of serum vedolizumab concentrations (SVC) during induction and endoscopic remission in patients with inflammatory bowel diseases (IBD) after 52weeks of therapy with vedolizumab. We also sought to assess the incidence of antibody to vedolizumab (ATV) formation, the effect of ATV on drug pharmacokinetics and efficacy, and identify variables associated with SVC through the first 30weeks of treatment. This is a prospective cohort study of patients with active IBD initiating standard therapy with vedolizumab. Collected variables included demographics, clinical disease activity, biomarkers, pre-infusion SVC, and ATV measured at weeks 2, 6, 14, 22, and 30. Primary outcome was steroid-free endoscopic remission at week 52. Fifty-five patients were included. Patients that achieved steroid-free endoscopic remission by week 52 had higher SVC at weeks 2, 6, 14, 22, and 30, but only achieved statistical significance at weeks 2 and 6. Only 3 out of the 55 study subjects (5.5%) had detectable ATV through the follow-up. Overall, there were a positive correlation between SVC and serum albumin and a negative correlation with C-reactive protein, fecal calprotectin, and body mass. Vedolizumab concentrations ≥ 23.2mcg/ml at week 2 were associated with endoscopic remission at week 52 (OR 8.8 [95% CI 2.6-29.7], p < 0.001). Vedolizumab concentrations during induction were associated with endoscopic remission at week 52. Interventional studies looking into improved efficacy with higher drug exposure are warranted.

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation.

SummaryBackgroundProspectively designed studies assessing the exposure‐response profile of vedolizumab are lacking. Observational exposure‐response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance.AimsTo (a) investigate the vedolizumab exposure‐response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short‐ and long‐term clinical outcomes in adults with ulcerative colitis in GEMINI 1.MethodsPropensity‐score‐based case‐matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti‐tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated.ResultsAmong 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 µg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52.ConclusionsIn this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short‐ and long‐term remission. Potential induction and maintenance target concentrations were proposed for further study.