ABSTRACT
Background and aims
This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure−efficacy of vedolizumab intravenous (IV) and subcutaneous (SC).
Methods
A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (Cav,ss, Ctrough,ss) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD).
Results
Data were from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted Cav,ss for IV-Q8W and SC-Q2W was similar in UC and CD. Cav,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. Ctrough,ss values from IV and SC aligned well with pooled observed Ctrough by treatment group in UC and CD. Cav,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations.
Conclusion
Exposure−efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.
1. Introduction
Vedolizumab is a gut-selective antilymphocyte trafficking biologic, indicated for adult patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD) [Citation1,Citation2]. The recommended treatment regimen consists of a 6-week induction phase of 300 mg intravenous (IV) infusions (weeks 0, 2, and 6), followed by a maintenance phase of 300 mg infusions every 8 weeks (Q8W) or 108 mg subcutaneous (SC) injections every 2 weeks (Q2W). In the GEMINI 1 and VISIBLE 1 randomized clinical trials, IV and SC vedolizumab treatment in patients with UC produced statistically significant and clinically meaningful differences in the proportion of patients achieving clinical remission and endoscopic remission at week 52 versus placebo [Citation3,Citation4]. Similarly, in the GEMINI 2 and VISIBLE 2 trials, patients with CD who were treated with IV and SC vedolizumab had a significantly higher rate of clinical remission over 52 weeks than patients who received placebo [Citation5,Citation6].
In the VISIBLE 1 trial, in which patients with UC received vedolizumab SC 108 mg Q2W or IV 300 mg Q8W during maintenance, efficacy and vedolizumab exposure achieved with vedolizumab SC were comparable with the IV formulation, supporting vedolizumab SC as an equally effective treatment option for UC maintenance therapy in place of vedolizumab IV [Citation4]. In the VISIBLE 2 trial in CD, levels of exposure during maintenance with the SC formulation were comparable with the SC arm of the VISIBLE 1 UC study [Citation6].
In this analysis, vedolizumab IV and SC exposure−efficacy relationships during maintenance treatment of patients with UC and CD were analyzed using data from the GEMINI 1 and 2 and VISIBLE 1 and 2 studies. Understanding exposure – efficacy relationships is critical to achieving optimal treatment outcomes in inflammatory bowel diseases [Citation7]. Vedolizumab concentrations at week 6 of induction were previously shown to be positively associated with clinical remission in patients with UC and CD [Citation8]. The pooled analysis of four vedolizumab pivotal phase 3 trials offers a unique opportunity to increase the understanding of the exposure−response of two distinct formulations (IV and SC) of vedolizumab in patients with UC and CD to aid clinical decisions around transition from one formulation to another.
2. Materials and methods
2.1. Study population and design
The current analyses included data from patients who demonstrated a clinical response after receiving vedolizumab during the induction phase of the GEMINI 1 (ClinicalTrials.gov identifier, NCT00783718; EudraCT ID, 2008–002782–32) and VISIBLE 1 (NCT02611830; 2015–000480–14) studies for UC or the GEMINI 2 (NCT00783692; 2008–002783–33) and VISIBLE 2 (NCT02611817; 2015–000481–58) studies for CD and who were included in the pharmacokinetic (PK) population. The PK population was defined as all patients who received at least one dose of study drug (placebo or vedolizumab) and who had sufficient blood sampling to allow for PK evaluation. Clinical response at week 6 for the UC GEMINI 1 and VISIBLE 1 studies was defined as a reduction in complete Mayo score of ≥ 3 points and ≥ 30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point. Clinical response for the CD GEMINI 2 and VISIBLE 2 studies was defined as a decrease in CD activity index (CDAI) score of ≥ 70 points from baseline. The maintenance phase was assessed up to week 52 in all studies. In GEMINI 1 and GEMINI 2, patients received vedolizumab IV 300 mg at weeks 0, 2, and 6, with an evaluation at week 6 (in double-blind and open-label cohorts) before entering the maintenance phase (randomization of week 6 responders) in which they received vedolizumab 300 mg Q8W, vedolizumab every 4 weeks (Q4W), or placebo until week 52. In VISIBLE 1 and VISIBLE 2, an open-label induction with vedolizumab IV 300 mg at week 0 and week 2 was followed by a maintenance dose (randomization of week 6 responders) of vedolizumab Q2W or placebo until week 52. In VISIBLE 1, a reference maintenance arm of vedolizumab 300 mg Q8W was added for comparison purposes.
All four studies were conducted in agreement with the principles set out in the Declaration of Helsinki and were approved by national and institutional ethics committees. All participants provided written informed consent before entry into the studies.
2.2. Vedolizumab PK
In each of the trials, samples for trough serum vedolizumab concentrations (Ctrough) were collected within 30 minutes before dosing (Supplementary Methods). Concentrations were measured using an enzyme-linked immunosorbent assay [Citation8]. Average serum concentrations at steady state (Cav,ss) and trough concentrations at steady state (Ctrough,ss) were predicted using a previously described population PK model, which was also used to simulate transition from IV to SC vedolizumab formulations (Supplementary Methods) [Citation9–11]. The transition to vedolizumab SC can be conducted any time after these two IV induction doses are given, with the first SC dose replacing the next scheduled IV dose.
2.3. Clinical outcomes
In all studies, the primary efficacy endpoint was clinical remission at week 52. In patients with UC, clinical remission was defined as a complete Mayo score of ≤ 2 points and no individual subscore of > 1 point; in patients with CD, clinical remission was equivalent to a CDAI score of ≤ 150 points. Secondary endpoints included the proportion of patients with UC who demonstrated endoscopic remission (Mayo endoscopic subscore of 0) and the proportion of patients with CD with enhanced clinical response (≥100-point decrease in CDAI score from baseline [week 0]).
2.4. Population PK model and simulations
A previously described population PK model (Supplementary Methods) was used to estimate Cav,ss, which was calculated as the ratio of the area under the concentration-time curve for a dosing interval at steady state divided by the dosing interval time. The model included weight, albumin, vedolizumab antidrug antibodies, type of inflammatory bowel disease (UC or CD), and site of injection (thigh, abdomen, or upper arm) as covariates and utilized Markov chain Monte Carlo estimation methods. Simulations of the transition from IV to SC dosing were based on a 70-kg patient with normal serum albumin (4 g/l). The results are descriptive of the serum values that would be observed in such a typical patient. The population PK model was developed from the GEMINI studies and was updated with data from VISIBLE 1 and VISIBLE 2 [Citation9,Citation10].
2.5. Statistical analyses
Patient demographics and other baseline characteristics were summarized using descriptive statistics. All exposure and efficacy data were merged and formatted using R version 3.3.3 or higher (R Foundation for Statistical Computing, Vienna, Austria). Missing exposure data for patients who withdrew early were imputed assuming that they remained in the study receiving their assigned dosing regimen. Patients who discontinued before week 52 were treated as response failures (negative imputation). Missing covariate values were imputed at the median (for continuous covariates) or mode (for categorical covariates).
Efficacy endpoints were classified as binary responses. Data were evaluated using (i) graphical exploratory analyses of response rates by quartiles (Q1 to Q4) of model-predicted Cav,ss and Ctrough,ss; (ii) logistic regression of probability of response by model-predicted Cav,ss and Ctrough,ss; (iii) exploratory analyses to identify possible exposure−efficacy confounders; and (iv) for UC, an exploratory analysis of efficacy for patients with UC who had a propensity for low vedolizumab exposure across treatment regimens.
Logistic regression analyses were conducted using data pooled by disease category from all patients treated with vedolizumab or placebo, and were used to describe vedolizumab exposure−efficacy with adjustment for clinical and demographic covariates (Supplementary Methods). Covariates included in this analysis were based on the previous population PK/pharmacodynamic model and included baseline albumin (g/l), baseline endoscopic scores (UC only; moderate or severe), baseline rectal bleeding score (UC only; a score of 0 or 1, or a score of 2 or 3 at baseline), baseline fecal calprotectin (CD only; mg/kg), baseline C-reactive protein (CD only; nmol/l), and prior experience with anti−tumor necrosis factor (TNF) therapy (naïve, failure, or exposed but not failure).
To further evaluate characteristics that may lead to poor treatment response, multivariate regression analyses were performed for serum albumin levels, prior anti-TNF exposure, baseline rectal bleeding, and baseline endoscopic score as possible indicators of low exposure in patients with UC; albumin, fecal calprotectin, C-reactive protein, and prior anti-TNF were used as indicators of low exposure in patients with CD. Propensity scores were calculated to identify the covariates of efficacy that were correlated with low (Q1) or normal/high (Q2 to Q4) vedolizumab exposure within treatment arms.
3. Results
3.1. Study population
Data from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) treated with vedolizumab IV Q8W, IV Q4W, SC Q2W, or placebo during the maintenance phase were available for analysis (). The placebo group was included as a benchmark to assess efficacy response. All patients had moderately to severely active UC or CD at baseline, with severe disease in 52.0%, 66.0%, 44.0%, and 41.1% of patients in GEMINI 1, VISIBLE 1, GEMINI 2, and VISIBLE 2, respectively.
Table 1. Baseline characteristics of patients from GEMINI 1, VISIBLE 1, GEMINI 2, and VISIBLE 2 who were included in the analyses.
3.2. Transition from IV to SC dosing
Vedolizumab SC was only investigated as maintenance therapy, following at least two doses of vedolizumab IV for induction [Citation2]. Simulations show a faster steady state starting vedolizumab SC as the third dose rather than the fourth (). During maintenance, a transition from vedolizumab IV Q4W or vedolizumab Q8W to vedolizumab 108 mg Q2W ensured similar trough levels, but with a shorter time to reach steady state in the case of vedolizumab Q4W (). Simulations of the transition from IV Q2W dosing to SC QW dosing are shown in Supplementary Figure S1
Figure 1. Predicted concentration-time profiles during transitions from vedolizumab intravenous (IV) to subcutaneous (SC) at induction time (a) or during maintenance (b) in patients with Crohn’s disease or ulcerative colitis. (a) Transition after two IV induction doses (week 6, red) or three IV induction doses (week 14, blue dashed). (b) Transition from vedolizumab IV every 4 weeks to vedolizumab SC 108 mg every 2 weeks (Q2W) at steady state (red) compared with transition from vedolizumab IV every 8 weeks to vedolizumab SC 108 mg Q2W (blue dashed).
3.3. Vedolizumab exposure
Exposure from IV Q8W and SC Q2W treatment with respect to model-predicted Cav,ss was similar in UC and CD (). Exposure from IV Q4W, based on Cav,ss, was higher than from IV Q8W and SC Q2W. Model-predicted Ctrough,ss values from IV and SC treatment generally aligned well with pooled observed Ctrough in UC and CD (Supplementary Figure S2), showing good alignment between UC and CD. Model-predicted Cav,ss for the SC formulation was equivalent to the IV formulation ().
Figure 2. Model-predicted exposure quartile distributions across dosing regimens for patients with ulcerative colitis (a) and Crohn’s disease (b). The box edges and middle line correspond to the 25th, 50th, and 75th percentiles, whereas the whiskers extend to the nearest data point no more than 1.5 times the interquartile (IQR) above the 75th percentile or no less than the 25th percentile minus 1.5 times the IQR. Cav,ss, model-predicted average concentration at steady state; IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; SC, subcutaneous.
3.4. Exploratory vedolizumab exposure−efficacy relationships
Model-predicted exposure quartiles within each treatment arm were related to the rate of week 52 clinical remission and endoscopic remission in patients with UC, and the rate of week 52 clinical remission and enhanced clinical response in patients with CD.
In patients with UC, increased exposure was associated with increased efficacy (). Based on Cav,ss, patients treated with vedolizumab IV Q8W achieved clinical remission at rates (95% confidence interval) with Q1 exposure levels of 7.14% (0 − 33.5%) in VISIBLE 1 and 25.0% (12.4 − 43.6%) in GEMINI 1. The rates of clinical remission with Q4 exposure levels were 71.4% (45.0 − 88.7%) in VISIBLE 1 and 63.0% (44.2 − 78.5%) in GEMINI 1. This compares with remission rates for vedolizumab SC Q2W in VISIBLE 1 of 29.6% (15.7 − 48.7%) for Q1 and 63.0% (44.2 − 78.5%) for Q4 exposure levels. For endoscopic remission, rates between quartiles were more variable; however, the general pattern of higher rates of endoscopic remission with greater vedolizumab exposure was still evident. For example, endoscopic remission rates in VISIBLE 1 were 21.4% (6.8 − 48.3%) and 35.7% (16.2 − 61.4%) for Q1 and Q4 exposures of vedolizumab IV Q8W, respectively, and 22.2% (10.3 − 41.1%) and 37.0% (21.5 − 55.8%) for Q1 and Q4 exposures of vedolizumab SC Q2W, respectively ().
Figure 3. Achievement of clinical remission (a) and endoscopic remission (b) as a function of model-predicted average concentration at steady state (Cav,ss) quartile distributions across dosing regimens in patients with ulcerative colitis. Data are shown as means and 95% confidence intervals. Clinical remission rates for placebo: 14.3% (7.16 − 26.0%) for VISIBLE 1 and 18.2% (12.0 − 26.5%) for GEMINI 1. IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; SC, subcutaneous.
In patients with CD, higher exposure to vedolizumab was associated with a higher rate of clinical remission and enhanced clinical response (). In the IV Q8W, IV Q4W, and SC Q2W treatment arms, the rates of clinical remission in patients with exposure in Q1 as indicated by Cav,ss (38.5% [24.9 − 54.1%], 32.6% [25.4 − 40.7%], and 37.7% [27.2 − 49.5%], respectively) were comparable with placebo (34.3% [26.8 − 42.7%] for SC placebo and 36.1% [30.8 − 41.8%] for IV placebo). Similar results were observed for the rate of enhanced clinical response. The rate of clinical remission with IV Q8W and IV Q4W dosing increased markedly with higher exposure; rates were as high as 56.4% (41.0 − 70.7%) and 49.6% (41.5 − 57.8%) in the two treatment groups, respectively, with Q4 exposure for Cav,ss. The clinical remission rate with SC Q2W treatment increased from 37.7% (27.2 − 49.5%) in Q1 to 63.2% (51.3 − 73.7%) with Q3 exposure but decreased to 49.3% (37.8 − 60.8%) with Q4 exposure ().
Figure 4. Achievement of clinical remission (a) and enhanced clinical response (b) as a function of model-predicted average concentration at steady state (Cav,ss) quartile distributions across dosing regimens in patients with Crohn’s disease. Data are shown as means and 95% confidence intervals. Clinical remission rates for placebo: 34.3% (26.8 − 42.7%) for subcutaneous (SC) and 36.1% (30.8 − 41.8%) for intravenous (IV). Ctrough,ss, model-predicted trough concentration at steady state; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks.
3.5. Vedolizumab exposure−efficacy model covariates
In patients with UC, the covariate-adjusted logistic regression model for Cav,ss showed a significant effect of serum albumin (point estimate = 2.19, 95% CI: 0.58, 3.79; lower baseline albumin was associated with reduced probability of clinical remission) and prior failure with anti-TNF therapy (point estimate = −1.64, 95% CI: −2.91, −0.37; prior failure with anti-TNF was associated with reduced probability of clinical remission) (). On the other hand, the model for Ctrough,ss included a significant effect only of prior anti-TNF therapy failure (point estimate = −1.66 95% CI: −2.93, −0.39; Supplementary Table S1). Baseline endoscopic score and baseline rectal bleeding score did not significantly impact the odds of clinical remission. The exposure−covariate interactions (treatment by prior anti-TNF therapy status and treatment by baseline endoscopy) modestly improved model performance but were not significant. Visual predictive checks performed for the interaction models for Cav,ss and Ctrough,ss are presented in Supplementary Figure S3.
Table 2. Logistic regression parameter estimates of slope of exposure – response relationship using Cav,ss* as exposure metric for clinical remission and endoscopic remission at week 52 in patients with ulcerative colitis.
In patients with CD, baseline albumin (point estimate = 1.33, 95% CI: 1.19, 1.47) and prior anti-TNF therapy (point estimate = 2.12, 95% CI: 1.86, 2.38) also had a significant impact on clinical remission and enhanced clinical response as a function of Cav,ss () and Ctrough,ss (Supplementary Table S2). The exposure−calprotectin association was also significant (point estimate = 1.33, 95% CI: 1.12, 1.54); higher exposure to vedolizumab and higher baseline fecal calprotectin increased the odds of clinical remission and enhanced clinical response by ~ 30% (). Visual predictive checks for the interaction models for Cav,ss are presented in Supplementary Figure S4.
Table 3. Logistic regression parameter estimates of slope of exposure−response relationship using Cav,ss* as exposure metric for clinical remission and enhanced clinical response at week 52 in patients with Crohn’s disease.
3.6. Impact of patient disease characteristics on vedolizumab exposure in UC
In the GEMINI 1 study, patients with low vedolizumab exposure levels (Q1) were more likely to have low serum albumin concentrations, and in the VISIBLE 1 study, prior anti-TNF treatment exposure was associated with low vedolizumab levels. There were no obvious trends in exposure with baseline rectal bleeding or endoscopic scores.
A multivariate analysis was performed to fit a propensity score model relating probability of low within−treatment arm exposure to baseline rectal bleeding scores, baseline endoscopy scores, and anti-TNF therapy history (Supplementary Figure S5). Patients with more severe baseline disease characteristics (prior anti-TNF therapy failures, rectal bleeding scores of 2 or 3, and higher baseline endoscopy scores) were most likely to have low exposure. Conversely, patients with less severe disease who were also anti-TNF naïve had decreased probability of low exposure.
4. Discussion
This study characterized vedolizumab exposure−efficacy during the maintenance phase of treatment in patients with UC using pooled data from the GEMINI 1 and VISIBLE 1 clinical trials, and in patients with CD using pooled data from the GEMINI 2 and VISIBLE 2 trials. This analysis expands on previous exposure−efficacy analyses of IV vedolizumab at week 6 [Citation8,Citation12] and also compares data from administration of an IV Q4W dosing regimen as well as an SC formulation of vedolizumab against standard IV Q8W dosing. Exposure, as reflected by serum Cav,ss and Ctrough,ss levels, was similar between patients with UC and CD, and exposure based on Cav,ss was equivalent for the IV and SC formulations during maintenance treatment, even though Ctrough,ss for the vedolizumab SC 108 mg Q2W formulation was greater than Ctrough,ss for the vedolizumab IV 300 mg Q8W formulation.
Across the studies, exposure with respect to Cav,ss was comparable between standard dosing with IV Q8W and SC Q2W, whereas exposure was higher when dosing was escalated to IV Q4W. Differences in exposure between the treatments were more apparent with Ctrough,ss. Values were lowest with IV Q8W, which is not unexpected given the longer dosing interval.
Quartile analyses showed an overall trend of increased clinical improvement with higher vedolizumab Cav,ss and Ctrough,ss, indicating a positive relationship between exposure and efficacy for all treatment regimens. For UC, > 75% of patients (responders to induction) had week 52 endoscopic remission in the fourth quartile for vedolizumab exposure. Plots of the probability of clinical remission (UC and CD), endoscopic remission (UC), or enhanced clinical response (CD) for combined model-predicted exposure levels of vedolizumab showed increasing probability of response with increasing vedolizumab concentration (Supplementary Figure S3 and S4). Although this analysis does not define a therapeutic threshold vedolizumab concentration, analysis of the exposure−response relationship using data from the real-world retrospective ERELATE study demonstrated that predicted vedolizumab concentrations of 30.8 and 33.8 µg/ml at week 6 and 16.6 and 14.4 µg/ml at week 14 were associated with clinical remission and deep remission, respectively, at week 52 [Citation11].
Consistent with previous analyses, the logistic regression model shows that prior anti-TNF therapy and low serum albumin concentrations in patients with UC and CD were predicted to reduce the probability of response to vedolizumab [Citation13,Citation14]. In CD, the exposure/fecal calprotectin relationship was predictive of remission and enhanced clinical response, perhaps suggesting that patients with high baseline fecal calprotectin levels are those with a greater degree of clinical improvement with treatment. Anti-TNF therapy in patients with CD has been shown to lead to downregulation of mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) [Citation15], the ligand for the α4β7 integrin that is the target of vedolizumab. Disruption or modification of MAdCAM-1/α4β7 integrin signaling with prior anti-TNF therapy may, therefore, lead to a reduction in vedolizumab efficacy compared with no prior anti-TNF therapy.
Patients with UC with low exposure during IV Q8W dosing might benefit from IV Q4W or SC dosing instead because the rate of response to Q1 exposure with IV Q8W was similar to placebo, whereas response in low exposure groups with IV Q4W and SC dosing was markedly higher.
These analyses suggest that the vedolizumab SC formulation provides an additional therapeutic option during long-term maintenance therapy for UC and CD, as vedolizumab SC Q2W dosing is at least as efficacious as IV Q8W dosing and has an exposure−response profile similar to that of IV Q4W (). Evidence from the ongoing VISIBLE open-label extension study suggests that dose escalation to once-weekly SC maintenance dosing may allow recapture of lost response in some patients; however, further study is required to establish this effect [Citation16].
The importance of achieving comparable PK exposures between IV and SC administration of vedolizumab is that it enables a seamless transition from IV induction to SC maintenance dosing while maintaining therapeutic drug concentrations. The SC formulation may facilitate self-administration, thereby increasing convenience for the patient. Importantly, evidence from the VISIBLE open-label extension suggests that the timing of the switch from IV to SC dosing appears to have no effect on therapeutic response, with maintenance of therapeutic benefit, independent of initial IV treatment duration [Citation17].
5. Conclusion
In conclusion, this post hoc analysis demonstrates that IV and SC administration of vedolizumab have comparable exposure−efficacy relationships, indicating that both of these routes of administration are effective therapeutic options during maintenance treatment. The efficacy profile of the vedolizumab SC regimen in patients with a propensity for low exposure was similar to that of vedolizumab IV in similar patients.
The analysis also highlights the complexity of the vedolizumab exposure−efficacy relationship. The impact of confounding factors should be further studied in order to better understand the relationship and the impact of dose escalation in treatment for inflammatory bowel disease.
Declaration of interest
G D’Haens is a consultant for AbbVie, AgomAb, AM Pharma, AMT, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Gilead, GlaxoSmithKline, Gossamer Bio, Immunic, Index, Johnson & Johnson, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist, and Roche, and reports serving on speaker’s bureau for AbbVie, Arena, Bristol Myers Squibb, Galapagos, Gilead, Pfizer, and Takeda. M Rosario was an employee of the study sponsor, Takeda, at the time of this study. D Polhamus and NL Dirks are employees of Metrum Research Group. C Chen, K Kisfalvi, and C Agboton are employees of the study sponsor, Takeda. S Vermeire reports grant support from AbbVie, Merck Sharp & Dohme, Pfizer, and Takeda; speaker fees from AbbVie, Dr Falk, Ferring, Hospira, Merck Sharp & Dohme, Pfizer, Takeda, and Tillots; and consulting fees from AbbVie, Celgene, Ferring, Galapagos, Genentech/Roche, Hospira, Janssen, Merck Sharp & Dohme, Mundipharma, Pfizer, Second Genome, Shire, and Takeda. BG Feagan has received consulting fees from AbbVie, ActoGeniX, Albireo, Allergan, Amgen, AstraZeneca, Atlantic, Avaxia, Axcan, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Elan/Biogen, Eli Lilly, EnGene, Ferring, GICare, Gilead, Given Imaging, GlaxoSmithKline, Ironwood, Johnson & Johnson/Janssen, Kyowa Hakko Kirin, Lexicon, Lycera, Merck, Mesoblast, Millennium, Nektar, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics & Diagnostics, Protagonist, Receptos, Roche/Genentech, Salix, Shire, Serono, Sigmoid, Synergy, Takeda, Teva, TiGenix, Tillotts, UCB, Warner-Chilcott, Wyeth, Zealand, and Zyngenia; speaker fees from AbbVie, Johnson & Johnson/Janssen, Takeda, and UCB; financial support for research from AbbVie, Amgen, AstraZeneca/MedImmune, Atlantic, Boehringer Ingelheim, Celgene, Celltech, Genentech/Hoffmann-La Roche, Gilead, GlaxoSmithKline, Janssen Research & Development, Pfizer, Receptos/Celgene, Sanofi, Santarus, Takeda Development Center Americas, Tillotts, and UCB; and is a member of the Board of Directors of Robarts Clinical Trials. WJ Sandborn reports research grants from AbbVie, Abivax, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech, Gilead, GlaxoSmithKline, Janssen, Pfizer, Prometheus Biosciences, Seres, Shire, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Allakos, Amgen, Arena, AstraZeneca, Atlantic, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, ClostraBio, Eli Lilly, Forbion, Galapagos, Genentech (Roche), GlaxoSmithKline, Gossamer Bio, Index, iota, Janssen, Morphic, Novartis, Oppilan (now Ventyx Biosciences), Pfizer, Pharm-Olam, Polpharma, Progenity, Prometheus Biosciences, Protagonist, PTM, Seres, Shoreline, Sublimity, Surrozen, Takeda, Theravance Biopharma, Vedanta, Ventyx, Vimalan, Vivreon Gastrosciences, Xencor, and Zealand; stock or stock options in Allakos, BeiGene, Gossamer Bio, Oppilan (now Ventyx Biosciences), Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist, Shoreline, Ventyx, Vimalan, and Vivreon Gastrosciences; and is an employee of Shoreline. Spouse of WJ Sandborn reports being a consultant and holding stock options in Iveric Bio and Prometheus Laboratories; stock or stock options in Oppilan (now Ventyx Biosciences), Progenity, Ventyx, and Vimalan; and is an employee of and holds stock or stock options in Prometheus Biosciences.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Ethics statement
All four studies analyzed in this paper were conducted in agreement with the principles set out in the Declaration of Helsinki and were approved by national and institutional ethics committees. All participants provided written informed consent before entry into the studies.
Author contributions
M Rosario, D Polhamus, NL Dirks, C Chen, K Kisfalvi, and C Agboton contributed to the acquisition, analysis, and interpretation of the pharmacokinetic data. G D’Haens, S Vermeire, BG Feagan, and WJ Sandborn were primary investigators in the clinical trials on which the pharmacokinetic modeling was based and contributed to the interpretation of the data. All authors collectively contributed to the development of the manuscript and approved the final version for submission.
Supplemental Material
Download MS Word (426.7 KB)Acknowledgments
This work was funded by Takeda. Medical writing assistance was provided by Paul Hassan, PhD, of Excel Scientific Solutions, Horsham, UK, and was funded by Takeda. This work was presented in part at the 2019 European Crohn’s and Colitis Organization Congress, March 6-9, Copenhagen, Denmark, and the 2020 European Crohn’s and Colitis Organization Congress, February 12-15, Vienna, Austria.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/17512433.2024.2318465.
Data availability statement
The datasets – including the redacted study protocol, redacted statistical analysis plan, and individual participants’ data supporting the results reported in this article – will be available 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after their de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.
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References
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