Body Mass Index Does Not Impact Clinical Efficacy of Ustekinumab in Crohn’s Disease: A Post Hoc Analysis of the IM-UNITI Trial

Abstract

Background

This post hoc analysis aimed to evaluate the impact of BMI on the efficacy of ustekinumab in the IM-UNITI study.

Methods

The relationship between body mass index (BMI) and efficacy of ustekinumab was evaluated using data from a 44-week maintenance study of ustekinumab in Crohn’s disease (IM-UNITI, NCT01369355, YODA #2019–4105). The primary endpoints of interest were clinical remission (CR), defined as Crohn’s disease activity index <150 and corticosteroid-free CR at week 44. Patients were stratified into the following subgroups according to their BMI at study entry: underweight <18.5 kg/m², normal 18.5 to 25 kg/m², overweight 25 to <30 kg/m², and obese ≥30 kg/m². The χ ² test of linear trend was conducted for comparisons of frequencies between the 3 cohorts. Multivariate regression analyses evaluated possible association between BMI and efficacy outcomes of CR and corticosteroid-free CR, with adjustment for variables found significant on univariate analyses. Results are presented as odds ratios with 95% confidence intervals. Data were analyzed using Stata/IC 15.

Results

A total of 254 patients treated with ustekinumab were included in this analysis. At week 44 of IM-UNITI, rates of CR did not differ among those whose BMI was underweight (67.9%%; 19 of 28 patients), normal (51.3%; 60 of 117), overweight (45.1%; 32 of 71), or obese (55.3%; 21 of 38; P = 0.89). Multivariate logistic analysis did not find BMI to be a significant predictor of CR when adjusted for covariates. Ustekinumab drug level at week 44 was significantly lower in obese patients (median level 2.98 mcg/mL; interquartile range [IQR], 2.86) compared with patients who were overweight (4.84 mcg/mL; IQR, 3.51; P = 0.021) or had underweight or normal BMI (4.43 mcg/m;, IQR, 2.82; P = 0.014).

Conclusions

Although BMI impacts ustekinumab drug levels, there was no impact of BMI on clinical efficacy. Further studies of the pharmacodynamic effects of ustekinumab in patients with high BMI are needed.

INTRODUCTION

Crohn’s disease (CD) is a chronic inflammatory gastrointestinal (GI) disorder associated with significant morbidity.¹ The discovery of therapeutic monoclonal antibodies was a major breakthrough, and their use has improved the course of CD, with reduced long-term complications such as strictures, fistulas, and surgical resection.² The first class of therapies to be approved for inflammatory bowel diseases (IBDs) were the tumor necrosis factor (TNF) antagonists, including infliximab, adalimumab, certolizumab, and golimumab. Infliximab is unique among this class because it is the only agent that is dosed in adults according to body weight.^{3, 4}

Obesity is becoming more prevalent across the world.⁵ Over 35% of adults in the United States are obese.⁶ Obesity has been associated with increased risk of immune-mediated conditions, such as rheumatoid arthritis, and CD and has also been associated with worse prognosis of CD with higher rates of surgery and hospitalization.^7–11 It has been demonstrated that obesity is associated with higher rates of treatment failure in patients treated with fixed-dose TNF antagonists such as adalimumab,¹² and this may be due to higher rates of drug clearance.¹³ However, studies associating obesity with increased likelihood of failure of weight-adjusted infliximab therapy also suggest that obesity is independently associated with poor prognosis.¹⁴

Ustekinumab is a monoclonal antibody targeting the p40 subunit of interleukin-12 and interleukin-23. It has demonstrated efficacy for treatment of CD and is administered using a weight-based intravenous induction dose, followed by a fixed dose of 90 mg every 8 or 12 weeks.¹⁵ To date, no studies have addressed whether obesity influences response to ustekinumab in CD. Given the prognostic value of obesity in IBD and the observation that response to TNF antagonist therapy is influenced by body weight, the purpose of this study was to evaluate whether obesity impacts the efficacy of ustekinumab.

METHODS

Study Design

We used data from a phase 3 clinical trial program of ustekinumab for patients with active CD from the UNITI-1, UNITI-2, and IM-UNITI studies (ClinicalTrials.gov identifiers NCT01369329, NCT01369342, NCT01369355), which were published in 2016.¹⁵ The data set was obtained through the YODA Project (Yale Open Data Access #2019–4105) and by permission from Janssen Inc.¹⁶ Because data were previously collected and de-identified data were being used, no informed consent was required.

Participants

The UNITI studies’ design and eligibility criteria have previously been published.¹⁵ In short, adults with moderate to severe active CD based on a Crohn’s disease activity index (CDAI) score of 220 to 450 were enrolled in UNITI-1 and UNITI-2, the induction studies. The UNITI-1 study included patients with prior primary or secondary nonresponse to TNF antagonists, whereas the UNITI-2 included only patients with previous inadequate response to conventional therapy such as immunomodulators or glucocorticoids. In both induction studies, patients were randomly assigned to receive a single intravenous infusion of ustekinumab at 130 mg, a weight-based dose of ustekinumab at 6 mg/kg, or placebo. A response at week 6 based on improvement of CDAI >100 points was required for rerandomization into the maintenance portion of the study (IM-UNITI). Patients in IM-UNITI were randomized to receive subcutaneous injections of 90 mg of ustekinumab every 8 weeks (q8w), every 12 weeks (q12w), or placebo. The induction studies were 8 weeks in duration and the maintenance study was 44 weeks long. Endoscopy was not required for UNITI participation, but an endoscopic study was performed on a subset of included patients.

Variables

The eligible population for the current study was 257 subjects who received ustekinumab for maintenance in IM-UNITI. Three patients with incomplete or missing data for the week-44 CDAI were omitted from the analysis, leaving 254 subjects for analysis. Of these, 29 patients were randomized to the ustekinumab 90 mg q12w group, and 28 patients were randomized to the ustekinumab 90 mg q8w group and lost clinical response and received open-label ustekinumab 90 mg q8w.¹⁵ All of these patients were considered nonremitters within IM-UNITI and were treated similarly in our analyses. Patients who withdrew from the study before 44 weeks (n = 16) were also considered as nonremitters on an intention-to-treat basis for this analysis. Endoscopic scoring was performed during the clinical trial by 1 single-blinded reader who scored each ileocolonic segment (ileum, right colon, transverse colon, left colon, and rectum) using the simple endoscopic score for Crohn’s disease (SES-CD)¹⁷ and evaluated whether mucosal ulceration was present. From the 254 included patients, 28 participated in the endoscopic substudy and had endoscopy data available at week 44.

BMI Assessments

Our primary objective was to evaluate efficacy of ustekinumab for obtaining clinical remission at week 44 in CD patients according to their BMI at study entry in the following subgroups: underweight <18.5 kg/m², normal 18.5 to 25 kg/m², overweight 25 to <30 kg/m², and obese ≥30 kg/m². For all secondary analyses, BMI was categorized into 3 categories: underweight/normal <25 kg/m², overweight 25 to <30 kg/m², and obese ≥30 kg/m². We also planned secondary analyses of efficacy according to BMI stratified by tertiles and evaluated BMI as a continuous variable within a multivariate model. Body mass index was calculated using the following formula: (weight in kg/height in cm/height in cm) x 10,000.

Outcomes

Clinical remission (CR) was defined as CDAI <150. Corticosteroid-free CR was CDAI <150 among patients using corticosteroids at baseline. Endoscopic remission (ER) was defined as an SES-CD score <3. Mucosal healing (MH) was defined as the absence of ulceration. Ustekinumab drug levels were measured in mcg/mL using an electrochemiluminescent immunoassay (ECLIA) method on the Meso Scale Discovery (MSD) platform (Gaithersburg, MD).¹⁸

Statistical Analyses

Continuous variables are presented as means (and standard deviations) or as medians (and interquartile ranges [IQR]), and dichotomous variables are presented as proportions or percentages. All χ ² tests of linear trend were conducted for comparisons of frequencies among 3 cohorts. Mann-Whitney U tests were performed for comparisons of continuous variables that were not normally distributed. Patients who did not complete all 44 weeks of the study were considered nonremitters (intention-to-treat). In all cases, a P value of < 0.05 was considered significant.

Univariate analyses were conducted between baseline variables and the outcomes of interest. Variables for consideration were age, sex, race, region, smoking status, disease duration, disease location, presence of extraintestinal manifestations, baseline steroid use, baseline immunomodulator use, weight, intolerance or contraindication to immunomodulators, previous immunomodulator use or failure, previous steroid use or failure, previous TNF antagonist therapy, baseline C-reactive protein (CRP) <3 mg/L, baseline fecal calprotectin (FC) <250 mg/kg, induction dose received, and maintenance dose allocation. Variables found significant on univariate analyses (P < 0.05) were included within a multivariate logistic regression analysis to evaluate possible association between BMI (as a categorical or as a continuous variable) and efficacy outcomes of CR and corticosteroid-free CR. We also planned to evaluate the relationship between BMI and ER/MH using multivariate logistic regression. Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Data were analyzed using Stata/IC 15.

RESULTS

Demographics

Baseline characteristics from the 254 patients treated with ustekinumab during IM-UNITI who were included in this analysis are presented in Table 1. Of these, 28 (11.0%) were underweight, 117 (46.1%) had normal BMI, 71 (28.0%) were overweight, and 38 (15.0%) were obese. When patients were classified by tertiles, 83 were placed in the first tertile (BMI <21.15 kg/m²), 86 in the second tertile (BMI ≥21.15 and <26.22 kg/m²), and 85 in the third tertile (≥26.22 kg/m²).

Rates of Week-44 Clinical Remission Among Different BMI Cohorts

At week 44 of IM-UNITI, rates of CR were numerically higher in those with underweight BMI (67.9%%; 19 of 28 patients) compared with those whose BMI was normal (51.3%; 60 of 117), overweight (45.1%; 32 of 71), or obese (55.3%; 21 of 38), but this did not reach statistical significance (P = 0.89; Fig. 1). Separate analyses of the q8w ustekinumab and q12w ustekinumab arms also showed no significant differences in CR rates among the 4 subgroups (Table 2). There were also no significant differences seen in CR rates when comparing patients with prior biologic exposure and those who were biologic naïve.

BMI as a Predictor of Week-44 Clinical Remission

The results of univariate analyses associating baseline variables with the outcome of week-44 CR are presented in Supplementary Table 1. Baseline CRP <3 mg/L (P = 0.039) and baseline immunomodulator use (P = 0.005) were both found to be significant. When adjusted for these covariates, obese or overweight subjects were no more likely than those who were underweight or had normal BMI to achieve week-44 CR (OR, 1.09; 95% CI, 0.64–1.86; P = 0.753). Obese patients in particular did not have reduced odds of achieving week-44 CR compared with those with underweight or normal BMI (OR, 1.09; 95% CI, 0.51–2.32; P = 0.823). Whether analyzed in tertiles or as a continuous variable, BMI did not impact the odds of week-44 CR, when adjusted for covariates (Table 3).

BMI as a Predictor of Week-44 Corticosteroid-Free Clinical Remission

The results of univariate analyses evaluating baseline variables with the outcome of week-44 corticosteroid-free CR are also presented in Supplementary Table 1. Again, baseline CRP < 3 mg/L (P = 0.03) and baseline immunomodulator use (P = 0.002) were significant on univariate analysis. Overweight or obese patients were no more likely than those with underweight or normal BMI to achieve week-44 corticosteroid-free CR (OR, 1.21; 95% CI, 0.71–2.06; P = 0.485), when adjusted for covariates. Whether analyzed in tertiles or as a continuous variable, BMI did not have any association with week-44 corticosteroid-free CR (Table 4).

BMI as a Predictor of Week-44 Endoscopic Remission/Mucosal Healing

There was no significant relationship between BMI and wee- 44 ER/MH (Supplementary Tables 2 and 3). This held true whether BMI was analyzed as a categorical or continuous variable. This may be partly due to only a small number of patients in this cohort with week-44 endoscopic assessment (n = 28).

Impact of BMI on Ustekinumab Drug Level at Week 44

Table 5 shows the median ustekinumab levels for each BMI cohort. The median ustekinumab level was 2.98 mcg/mL (IQR, 2.86) in obese patients, which was significantly lower than the median levels of 4.84 mcg/mL (IQR, 3.51) in overweight patients (P = 0.021) and 4.43 mcg/mL (IQR, 2.82) in underweight patients or those with normal BMI (P = 0.014). The median drug level for the entire cohort of patients was 3.7 mcg/mL. When examining patients who had higher drug levels only (above the median value of 3.7 mcg/mL), clinical remission rates were not sign of ficantly different in obese (41.2%; 7 of 17 patients) or overweight patients (59.6%; 28/47) as compared with those with underweight or normal BMI (52.8%; 47 of 89; P = 0.422). In the subgroup of patients with fecal calprotectin <50 mg/kg, there was no difference observed between obese/overweight patients as compared with those with normal or underweight BMI when comparing those with drug levels ≥3.7 mcg/mL (P = 0.989) or those below this drug level (P = 0.633; Supplementary Table 4).

Impact of BMI on Fecal Calprotectin at Week 44

The median FC levels among patients in the 3 different BMI cohorts were similar. Obese patients had a median FC of 311 mcg/kg (IQR, 112–555), which was similar to the median of 298 mcg/kg (IQR, 42–569) observed in patients with underweight or normal BMI (P = 0.735). No significant difference was seen in the median FC between patients with underweight or normal BMI and those who were overweight (P = 0.127). The proportions of patients with FC <250 mcg/kg were also similar among the 3 groups (obese 42.3% [11 of 26 patients], overweight 60.7% [34 of 56], and underweight or normal BMI 48.1% [51 of 106]; P = 0.197). Similarly, no differences were seen in the proportion of patients with FC <50 mcg/kg (Table 6). Evolution of FC over time was evaluated in Figure 2, where the drop in fecal calprotectin over time was largest for overweight patients as compared with those who were obese, underweight, or normal.

DISCUSSION

To our knowledge, this is the first study to evaluate the association of BMI with efficacy of ustekinumab in patients with CD. Body mass index was not found to impact the clinical efficacy of ustekinumab. This lack of association remained after adjustment for other potential confounders in multivariate analyses and remained whether BMI was analyzed as a categorical or continuous variable. Our observation that BMI does not impact response to ustekinumab is important, given the increasing prevalence of obesity in developed countries.

Obesity has been described as a chronic, low-grade inflammatory state, with higher levels of systemic cytokines and adipokines.⁹ Obesity may modify the pharmacokinetics of biologic therapies. Body mass index has been found to increase drug clearance of TNF antagonists, with lower serum trough drug concentrations and shorter half lives in obese patients.^{19, 20} Although it is unclear why obesity affects drug clearance, a “sink” phenomenon has been hypothesized for TNF antagonists, where unbound targets “sop up” antibodies at low concentration.²¹ This could explain why obesity even affects response to weight-based dosing of infliximab.¹⁴

Given observations of altered TNF antagonist pharmacokinetics in obese patients, we also evaluated pharmacokinetics and found lower serum trough levels of ustekinumab in obese patients, despite similar rates of CR. It is possible that our definition of CR is not sufficiently responsive to capture underexposure to ustekinumab or that the dosing regimens used in UNITI achieved therapeutic levels for most subjects in all BMI strata. The similar rates of FC across the 3 BMI cohorts may suggest the latter. Indeed, a post hoc analysis evaluating ustekinumab pharmacokinetics in CD found trough concentrations above 0.8 mcg/mL to be associated with higher rates of CR.¹⁸

Although higher BMI negatively impacts response to TNF antagonists in other immune-mediated conditions such as rheumatoid arthritis, psoriasis, and spondyloarthropathy, a recent meta-analysis did not confirm this association for IBD.²² The authors hypothesized this may be due to higher dosing regimens in IBD. The visceral adipose tissue known as “creeping fat” may also play a larger role than subcutaneous fat in the pharmacokinetics of CD patients, as it has been demonstrated that levels of C-reactive protein, TNF-α, interleukin-6, and Escherichia coli are found at exponentially higher levels in the mesenteric fat of CD patients compared with the subcutaneous fat of the same patients.²³

Ustekinumab is also used as a treatment for psoriasis. Studies evaluating the relationship of BMI and efficacy of ustekinumab in psoriasis have generally shown a negative impact. A large prospective multicenter registry reported higher rates of ustekinumab discontinuation in psoriasis patients among patients with higher BMI.²⁴ A retrospective Japanese study reported a lower reduction in the psoriasis area and severity (PASI) index in patients with BMI ≥25 as compared with those with BMI <25 (85 vs 74%; P < 0.004).²⁵ These findings are inconsistent with our study, in which BMI was not found to impact efficacy. The lower dose and frequency of ustekinumab (45 mg q12w) used in psoriasis patients may be partly responsible for this, as the amount of drug exposure is 3-fold less than the 90 mg q8w commonly used in CD. This could also be explained by higher rates of obesity among psoriasis patients compared with healthy controls, particularly if extreme obesity (BMI >40 kg/m²) is more prevalent.²⁶ Another possible explanation is publication bias, as studies reporting no association are less likely to be published.

Limitations of this study include its retrospective post hoc nature, which may limit inference of causality in the interaction of BMI with CR. Within the trial, very few patients were obese, and none had extreme obesity, where the negative impact of obesity may be more pronounced. Confounding factors that impact CR were likely not evenly distributed between the 3 cohorts; and although attempts were made to control for this using a multivariate logistic regression model, there likely remains some residual confounding. Another limitation reflects the subjective nature of CR, measured using the CDAI. Inflammatory disease activity as measured by objective tests such as endoscopy and calprotectin does not necessarily correlate with symptoms, and patients may have active disease despite lack of symptoms.^27–29 This disconnect is particularly evident in those with a history of Crohn’s-related surgery, where active endoscopic disease often is present months to years before development of symptoms.³⁰ We attempted to account for this by assessing fecal calprotectin levels in the different cohorts, and the impact of BMI on ER, but the number of patients with endoscopic assessment was small. Lastly, BMI has been criticized as a measure of body composition and adiposity, and other measures may better reflect increased adiposity such as waist circumference or waist-hip ratio,^{31, 32} but these were not collected within the UNITI studies.

In conclusion, we did not observe a relationship between BMI and clinical efficacy of ustekinumab in CD. As the population changes and obesity becomes more prevalent in IBD patients, clinicians can feel comfortable in use of fixed-dose ustekinumab as a maintenance treatment in CD without concern for BMI. Further cohort studies are needed to understand whether BMI impacts efficacy in patients with extreme obesity.

Conflicts of Interest: NN holds a McMaster University Department of Medicine Internal Career Award. NN has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, and Ferring. JM has received honoraria from Janssen, AbbVie, Allergan, Bristol-Meyer-Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda, and Teva. WR has received support for the following is a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult he is a consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; he is an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC. This study, carried out under YODA Project #2019–4105, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C. The interpretation and reporting of research using this data is solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C.

Author Contribution: EW contributed to the acquisition and compilation of data, statistical analysis, and drafting of the manuscript. JM contributed to the study design and drafting of the manuscript. WR contributed to the study design and drafting of the manuscript. NN contributed to the study concept and design, acquisition and compilation of data, statistical analysis, data interpretation, and drafting of the manuscript. All authors approved the final version of the article.

REFERENCES