Abstract
Background
Biomarkers offer potential alternatives to endoscopies in monitoring ulcerative colitis (UC) progression and therapeutic response. This post hoc analysis of the ELEVATE UC clinical program assessed potential predictive values of fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) as biomarkers and associated responses to etrasimod, an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC, in 2 phase 3 clinical trials.
Methods
In ELEVATE UC 52 and ELEVATE UC 12, patients were randomized 2:1 to 2 mg of etrasimod once daily or placebo for 52 or 12 weeks, respectively. Fecal calprotectin/hsCRP differences between responders and nonresponders for efficacy end points (clinical remission, clinical response, endoscopic improvement-histologic remission [EIHR]) were assessed by Wilcoxon P-values. Sensitivity and specificity were presented as receiver operating characteristics (ROC) curves with area under the curve (AUC).
Results
In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 patients received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL/hsCRP concentrations were generally balanced. Both trials had lower week-12 median fCAL levels in week-12 responders vs nonresponders receiving etrasimod for clinical remission, clinical response, and EIHR (all P < .001), with similar trends for hsCRP levels (all P < .01). For etrasimod, AUCs for fCAL/hsCRP and EIHR were 0.85/0.74 (week 12; ELEVATE UC 52), 0.83/0.69 (week 52; ELEVATE UC 52), and 0.80/0.65 (week 12; ELEVATE UC 12).
Conclusions
Fecal calprotectin/hsCRP levels decreased with etrasimod treatment; ROC analyses indicated a prognostic correlation between fCAL changes during induction and short-/long-term treatment response.
Keywords: ulcerative colitis, biomarker, etrasimod, sphingosine 1-phosphate, phase 3 clinical trial
Key Messages.
What is already known?
Etrasimod is a once-daily, oral sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC).
What is new here?
We show associations between fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) levels with efficacy end points among patients treated with etrasimod and that fCAL levels may be an early indicator of long-term efficacy end point achievement.
How can this study help patient care?
The use of fCAL as a biomarker for efficacy outcomes in patients with UC treated with etrasimod could reduce the need for invasive endoscopy procedures.
Introduction
Ulcerative colitis (UC) is a chronic inflammatory disease caused by continuous mucosal colonic inflammation and characterized by intermittent symptom recurrence that may include bowel urgency, increased frequency of bowel movements, abdominal pain, and rectal bleeding.1,2 Treatment for UC aims to achieve symptomatic control and improve the appearance of the mucosa on endoscopy.3 Endoscopy with biopsies is the only way to establish a diagnosis of UC and, given that endoscopic healing is associated with improved remission rates and reduced risk of colectomy, is key in assessing disease severity.1 However, repeated endoscopic assessments in routine clinical practice are invasive, expensive, and may be impractical, leaving a need to explore noninvasive alternatives for disease monitoring.4
The identification of reliable, noninvasive biomarkers for UC disease activity can provide a surrogate to invasive endoscopy procedures.5 Fecal calprotectin (fCAL) is a complex consisting of calcium-binding proteins used as a biomarker of intestinal inflammation and is expressed by activated neutrophils (and, to a lesser extent, by macrophages and monocytes); fecal levels correlate with the number of neutrophils in the gut. fCAL has thus demonstrated utility as a monitoring biomarker in patients with UC.6 Meanwhile, high sensitivity C-reactive protein (hsCRP) is an acute phase protein expressed by hepatocytes in response to inflammatory cytokines. Recent American Gastroenterological Association (AGA) guidelines recommend monitoring fCAL as a reliable biomarker to determine treatment response and endoscopy assessment, depending on the individual patient’s medical history.4 Additionally, recent updates to treatment target statements from the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) initiative recommend normalization of fCAL (to 100-250 µg/g) and hsCRP (to values under the upper limit of normal [2.87 mg/L]7) as intermediate treatment targets in UC.3 Both fCAL and hsCRP have been shown to reflect clinical and histologic findings as observed in the phase 2 trials of patients with UC treated with ozanimod8 and tofacitinib.5 fCAL concentrations may be a predictor of clinical relapse in patients with UC,9 and, although nonspecific, fCAL is specific to the gastrointestinal tract.10 Conversely, hsCRP is a widely used surrogate biomarker in UC but may only be useful for cases of acute severe UC2 and can be influenced by extraneous noninflammatory factors such as age, sex, and body mass index.11,12
Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. The S1P1 receptor modulation regulates the trafficking of specific lymphocyte subsets out of the lymph nodes, leaving fewer peripheral immune cells available to traffic to sites of inflammation.13–15 Sphingosine 1-phosphate4 has been implicated in dendritic cell trafficking, and S1P5 in both the localization of natural killer cells and the egress of patrolling monocytes from bone marrow; however, their functions are not well understood.13,16 In the ELEVATE UC clinical program, the efficacy and safety of etrasimod in patients with moderately to severely active UC were demonstrated in a phase 3 induction and maintenance trial with a treat-through design (ELEVATE UC 52; NCT03945188) and a phase 3 induction trial (ELEVATE UC 12; NCT03996369).13 The clinical program found that greater proportions of patients receiving 2 mg of etrasimod once daily (QD) achieved the primary efficacy end point of clinical remission vs placebo, in addition to meeting all key secondary end points, in ELEVATE UC 52 at both weeks 12 and 52, and at week 12 in ELEVATE UC 12.13
This post hoc analysis assessed the potential predictive value of fCAL and hsCRP and their associations with responses to etrasimod among patients in the ELEVATE UC clinical program.
Methods
Patients and Trial Design
The trial designs and full inclusion and exclusion criteria for ELEVATE UC 52 and ELEVATE UC 12 were as previously described.13 Briefly, in 2 multicenter, randomized, double-blind, placebo-controlled studies, patients aged 16 to 80 years with moderately to severely active UC were randomized 2:1 to receive either 2 mg of etrasimod QD or placebo for 52 weeks or 12 weeks for ELEVATE UC 52 and ELEVATE UC 12, respectively. ELEVATE UC 52 featured a treat-through design comprising a 12-week induction period, followed by a 40-week maintenance period. ELEVATE UC 12 comprised an independent 12-week induction period. Patients were permitted to continue therapeutic doses of nonbiologic therapy for UC (oral 5-aminosalicylates, oral corticosteroids, or medicinal probiotics), provided the dose was stable prior to randomization and during treatment periods. In ELEVATE UC 52, patients receiving oral corticosteroid therapy at baseline were required to maintain their stable dose during the 12-week induction period; investigators were directed to taper corticosteroids after the week 12 assessment.
fCAL, hsCRP and Clinical Efficacy Measurement and End Points
For both the ELEVATE UC 52 and ELEVATE UC 12 trials, baseline fCAL was measured during the screening period and at weeks 2, 4, 8, and 12. For ELEVATE UC 52, fCAL was also measured at weeks 24 and 52. The hsCRP was measured during the screening period, on day 1 (baseline), and at weeks 2, 4, 8, and 12, and at 2-week follow-up. For ELEVATE UC 52, hsCRP was additionally measured at weeks 16, 20, 24, 32, 40, 48, and 52, and at 2-week follow-up. Sample handling is described in the Supplementary Methods.
The primary efficacy end points of ELEVATE UC 52 and ELEVATE UC 12 were the proportion of patients who achieved clinical remission at weeks 12 (both studies) and 52 (ELEVATE UC 52 only).13 Efficacy end points assessed in this post hoc analysis were clinical remission, clinical response, and endoscopic improvement-histologic remission (EIHR). For completeness, endoscopic improvement and histologic remission were also analyzed separately. Clinical remission was defined as stool frequency (SF) of the following levels: subscore = 0, or = 1 with a ≥1-point decrease from baseline; rectal bleeding (RB) subscore = 0; and endoscopic subscore (ES) ≤1 (excluding friability). Clinical response was defined as a ≥2-point and ≥30% decrease from baseline in Modified Mayo score (MMS) and a ≥1-point decrease from baseline in RB subscore or an absolute RB subscore ≤1. Endoscopic improvement-histologic remission was defined as an ES of ≤1 with histologic remission measured by Geboes Index score (<2.0). Endoscopic improvement and histologic remission were separately defined as an ES of ≤1 and as Geboes Index score <2.0, respectively. Patients were classified as responders or nonresponders based on the criteria for each efficacy end point.
Statistical Analysis
Data from patients with a baseline MMS of 4 to 9 in the full analysis set (FAS) populations of ELEVATE UC 52 and ELEVATE UC 12 were analyzed. The FAS included all randomized patients who received ≥1 dose of trial treatment. Median fCAL and hsCRP levels at protocol-specified visits were analyzed by visit and by treatment group, comparing responders vs nonresponders for clinical efficacy end points separately for the 2 trials.
For responder vs nonresponder analyses, 2-sided P values were based on the Wilcoxon rank-sum test comparing the distributions (medians) of fCAL and hsCRP concentrations at a given visit between patients who responded to treatment, as assessed by the achievement of clinical end points compared with those who did not respond in a treatment arm at the same visit.
The sensitivity and specificity of predicting a response in a clinical end point at a visit were calculated based on fCAL and hsCRP concentration and presented as receiver operating characteristic (ROC) curves with area under the curve (AUC). Youden Index was estimated as sensitivity + specificity −1. A higher Youden Index value indicates a better balance of sensitivity and specificity.17 Sensitivity and specificity were also calculated at different prespecified cut-offs for fCAL and hsCRP concentrations based on the estimated ROC curves. For each clinical efficacy end point at a visit and for each treatment group separately, a logistic regression model was fitted to evaluate the association between efficacy end point and biomarker value at the same visit as the only covariate. The AUC for each ROC curve was calculated from this model.
Based on Youden Indexes for different efficacy end points, another logistic regression model was fitted to clinical efficacy end points at a visit on dichotomized fCAL ≤250 µg/g (yes/no) as the only covariate, providing odds ratios (ORs) and 95% confidence intervals (CIs), in addition to descriptive statistics.
For all analyses described previously, missing fCAL values at weeks 12 and 52 were imputed using the LOCF method; missing baseline fCAL values were not imputed. Missing binary clinical end point data were handled by setting to nonresponse. Data from ELEVATE UC 52 and ELEVATE UC 12 were analyzed separately.
Results
Patient Demographics and Baseline Characteristics
In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 patients received etrasimod, and 144 and 116 received placebo, respectively. Patient demographics and baseline characteristics were generally similar between treatment groups in both ELEVATE UC 52 and ELEVATE UC 12 (Table 1). The median (range) age of patients enrolled in both trials ranged from 35.5 years (17-78 years; placebo; ELEVATE UC 52) to 40 years (18-78 years; etrasimod; ELEVATE UC 52). Male sex accounted for between 52.6% (etrasimod; ELEVATE UC 52) and 62.9% (placebo; ELEVATE UC 12) of patients (Table 1). Median (range) baseline fCAL concentrations were 1135.7 µg/g (5.4-46,189.8 µg/g; placebo; ELEVATE UC 52), 1084.1 µg/g (3.8-33,464.1 µg/g; etrasimod; ELEVATE UC 52), 834.6 µg/g (4.2-29,656.0 µg/g; placebo; ELEVATE UC 12), and 953.5 µg/g (7.9-41,794.2 µg/g; etrasimod; ELEVATE UC 12). Median (range) baseline hsCRP were 3.2 mg/L (0.3-108.4 mg/L; placebo; ELEVATE UC 52), 4.3 mg/L (0.2-102.4 mg/L; etrasimod; ELEVATE UC 52), 2.7 mg/L (0.2-96.7 mg/L; placebo; ELEVATE UC 12), and 3.5 mg/L (0.2-84.6 mg/L; etrasimod; ELEVATE UC 12).
Table 1.
Patient demographics and baseline characteristics (FAS, MMS 4-9).
| ELEVATE UC 52 | ELEVATE UC 12 | |||
|---|---|---|---|---|
| Placebo (N = 144) |
2 mg of etrasimod QD (N = 289) | Placebo (N = 116) |
2 mg of etrasimod QD (N = 238) | |
| Age, years; median (range) | 35.5 (17-78) | 40 (18-78) | 38.0 (17-72) | 37.5 (16-73) |
| Male, n (%) | 88 (61.1) | 152 (52.6) | 73 (62.9) | 135 (56.7) |
| Race, White; n (%) | 129 (89.6) | 256 (88.6) | 88 (75.9) | 176 (73.9) |
| BMI, kg/m2; median (range) | 25.2 (16.2-49.7) | 24.5 (13.0-51.1) | 24.3 (15.4-39.1) | 23.5 (15.8-40.4) |
| Duration of UC, years; median (range) | 4.5 (0.2-30.8) | 4.7 (0.3-37.9) | 4.8 (0-35) | 4.7 (0-31) |
| Extent of disease; n (%) | ||||
| Left-sided colitis/proctosigmoiditis | 90 (62.5) | 172 (59.5) | 63 (54.3) | 146 (61.3) |
| Pancolitis | 47 (32.6) | 93 (32.2) | 41 (35.3) | 77 (32.4) |
| Proctitis | 6 (4.2) | 22 (7.6) | 12 (10.3) | 15 (6.3) |
| MMS, median (range) | 7.0 (4.0-9.0) | 7.0 (4.0-9.0) | 7.0 (4.0-9.0) | 7.0 (4.0-9.0) |
| Naïve to biologic/JAKi therapy, n (%) | ||||
| No | 45 (31.3) | 84 (29.1) | 43 (37.1) | 89 (37.4) |
| Yes | 99 (68.8) | 205 (70.9) | 73 (62.9) | 149 (62.6) |
| Prior immunomodulator use,an (%) | ||||
| No | 95 (66.0) | 181 (62.6) | 67 (57.8) | 149 (62.6) |
| Yes | 49 (34.0) | 108 (37.4) | 49 (42.2) | 89 (37.4) |
| Corticosteroids use (weeks) over prior 12 months median (range) | 8.0 (0-56) | 8.0 (0-57) | 8.0 (0-54) | 8.0 (0-52) |
| Baseline corticosteroid use, n (%) | ||||
| No | 102 (70.8) | 196 (67.8) | 82 (70.7) | 173 (72.7) |
| Yes | 42 (29.2) | 93 (32.2) | 34 (29.3) | 65 (27.3) |
| Baseline MMS group, n (%) | ||||
| 4-6 | 57 (39.6) | 113 (39.1) | 53 (45.7) | 109 (45.8) |
| 7-9 | 87 (60.4) | 176 (60.9) | 63 (54.3) | 129 (54.2) |
| Baseline ES, n (%) | ||||
| 2 | 56 (38.9) | 123 (43.6) | 56 (48.3) | 109 (45.8) |
| 3 | 88 (61.1) | 163 (56.4) | 60 (51.7) | 129 (54.2) |
| fCAL,b µg/g; median (range) | 1135.7 (5.4-46,189.8) | 1084.1 (3.8-33,464.1) | 834.6 (4.2-29,656.0) | 953.5 (7.9-41,794.2) |
| hsCRP, mg/L; median (range) | 3.2 (0.3-108.4) | 4.3 (0.2-102.4) | 2.7 (0.2-96.7) | 3.5 (0.2-84.6) |
aImmunomodulators include azathioprine and/or mercaptopurine only.
bBaseline groups for fCAL values: ELEVATE UC 52: placebo, n = 143; etrasimod, n = 286; ELEVATE UC 12: placebo, n = 114; etrasimod, n = 238.
Full demographics and baseline characteristics were presented previously.13
Baseline was the last measurement taken prior to the first dose of trial treatment.
Abbreviations: BMI, body mass index; ES, endoscopic subscore; FAS, full analysis set; fCAL, fecal calprotectin; hsCRP, high-sensitivity C-reactive protein; JAKi, Janus kinase inhibitor; MMS, Modified Mayo score; N, number of patients in cohort; n, number of patients with characteristic; QD, once daily; UC, ulcerative colitis.
Median Absolute fCAL and hsCRP Values Over Time
In ELEVATE UC 52, significant reductions in median fCAL concentrations were observed as early as week 4 among patients in the FAS receiving etrasimod compared with those receiving placebo (Supplementary Figure 1A); significant differences were maintained through week 12. Although there were numerical differences between patients receiving etrasimod compared with placebo at week 52, the differences between treatment arms were not significant. An overall reduction from baseline in median fCAL was also observed in patients receiving placebo (Supplementary Figure 1A).
In ELEVATE UC 12, median fCAL decreased over time for patients receiving either etrasimod or placebo. No significant differences were observed over the trial duration between treatment arms, although median fCAL levels were generally lower in patients receiving etrasimod compared with placebo (Supplementary Figure 1A).
Median hsCRP concentrations trended downward over time for patients receiving etrasimod in both ELEVATE UC 52 and ELEVATE UC 12. Median hsCRP concentrations also trended downward over time for patients receiving placebo in ELEVATE UC 52, but no change was observed among those receiving placebo in ELEVATE UC 12 (Supplementary Figure 1B).
fCAL and hsCRP Levels in Responders vs Nonresponders to Etrasimod and Placebo Treatments
When patients receiving etrasimod were stratified by treatment response, median levels at the time-of-response assessment of fCAL were significantly lower in responders compared with nonresponders in both ELEVATE UC 52 and ELEVATE UC 12, indicating a correlation between fCAL concentration and achievement of end points (Figure 1). This was observed across clinical remission, EIHR, and clinical response end points at weeks 12 and 52 (all P < .01; Figure 1), and separately for endoscopic improvement and histologic remission (all P < .01; Supplementary Table 1). This correlation was also seen in patients receiving placebo; median fCAL levels were significantly lower in patients treated with placebo and achieving all efficacy end points compared with those who did not (Figure 1; Supplementary Table 1).
Figure 1.
Median (range) fCAL (µg/g) by responders and nonresponders receiving etrasimod and placebo in (A) ELEVATE UC 52 at week 12 and week 52 and (B) ELEVATE UC 12 at week 12 (FAS, baseline MMS 4-9). **P < .01; ***P < .001. P values were based on the Wilcoxon rank-sum test comparing the distributions (medians) of fCAL between responders and nonresponders within each treatment arm for each end point. Abbreviations: EIHR, endoscopic improvement-histologic remission; FAS, full analysis set; fCAL, fecal calprotectin; MMS, Modified Mayo score; n, number of responders/nonresponders for the end point; N, number of patients in cohort; QD, once daily; UC, ulcerative colitis.
Likewise, median hsCRP values were significantly lower in responders compared with nonresponders among patients receiving etrasimod in both ELEVATE UC 52 and ELEVATE UC 12 across clinical remission, EIHR, and clinical response end points (all P < .01; Figure 2). Consistent with fCAL, this correlation was also observed among patients receiving placebo. However, there was no significant difference between hsCRP levels in EIHR responders and nonresponders among patients receiving placebo in ELEVATE UC 12 at week 12 (Figure 2A).
Figure 2.
Median (range) hsCRP (mg/L) by responders and nonresponders receiving etrasimod or placebo in (A) ELEVATE UC 52 at week 12 and week 52 and (B) ELEVATE UC 12 at week 12 (FAS, baseline MMS 4-9). **P < .01; ***P < .001. P values were based on the Wilcoxon rank-sum test comparing the distributions (medians) of hsCRP concentrations between the response and nonresponse groups within each treatment arm for each end point. Abbreviations: EIHR, endoscopic improvement-histologic remission; FAS, full analysis set; hsCRP, high-sensitivity C-reactive protein; MMS, Modified Mayo score; n, number of responders/nonresponders for the end point; N, number of patients in cohort; n.s., nonsignificant; QD, once daily; UC, ulcerative colitis.
Relationship Between Efficacy End Points and fCAL and hsCRP in Etrasimod and Placebo Treatments
The prognostic correlation between fCAL and hsCRP in patients treated with etrasimod and clinical remission and EIHR end points is presented in Figure 3 and clinical response end point in Supplementary Figure 2.
Figure 3.
ROC (AUC) of (A-C) fCAL and (D-F) hsCRP with clinical remission and EIHR in patients treated with etrasimod in ELEVATE UC 52 and ELEVATE UC 12. fCAL and hsCRP values presented are representative of the same timepoint as clinical remission and EIHR efficacy end points presented. Abbreviations: EIHR, endoscopic improvement-histologic remission; fCAL, fecal calprotectin; hsCRP, high-sensitivity C-reactive protein; ROC (AUC), area under the receiver operating characteristic curve; UC, ulcerative colitis.
In ELEVATE UC 52, the AUC for the correlation between clinical remission and fCAL was 0.8210 at week 12 and 0.8379 at week 52 (Figure 3A and 3B; Supplementary Table 2). The AUC for the correlation between EIHR and fCAL was 0.8452 at week 12 and 0.8265 at week 52 (Figure 3A and 3B; Supplementary Table 2). Similarly, the AUC for the correlation between clinical remission and fCAL in ELEVATE UC 12 was 0.8185 at week 12 (Figure 3C; Supplementary Table 2) and 0.8049 for the correlation between EIHR and fCAL (Figure 3C; Supplementary Table 2).
The AUC for the correlation between clinical remission and hsCRP in ELEVATE UC 52 was 0.7542 and 0.7469 at week 12 and week 52, respectively (Figure 3D and 3E; Supplementary Table 2); the correlation between EIHR and hsCRP was 0.7379 and 0.6945 at week 12 and week 52, respectively (Figure 3D and 3E; Supplementary Table 2). In ELEVATE UC 12, the AUC for the correlation between each of these end points and hsCRP at week 12 was 0.6838 and 0.6520, respectively (Figure 3F; Supplementary Table 2).
Similar relationships were observed with these biomarkers and the clinical response end point (Supplementary Figure 2 and Supplementary Table 2). Consistent with the clinical remission and EIHR end points, AUC values for fCAL and clinical response were generally greater than the corresponding AUC values observed with hsCRP (Supplementary Figure 2 and Supplementary Table 2).
The prognostic correlations between fCAL and hsCRP and the efficacy end points in patients receiving placebo were generally consistent with the corresponding relationships observed in patients receiving etrasimod, with the exception of fCAL and clinical remission at week 52 in ELEVATE UC 52 (Supplementary Table 2).
For clinical remission at week 12, fCAL concentrations of 350 µg/g and 300 µg/g provided the highest Youden Indexes of 0.512 and 0.552 among patients receiving etrasimod in ELEVATE UC 52 and ELEVATE UC 12, respectively. For clinical remission at week 52, an fCAL concentration of 250 µg/g provided the highest Youden Index of 0.502 among patients receiving etrasimod in ELEVATE UC 52 (Supplementary Table 3).
For EIHR at week 12, fCAL concentrations of 100 µg/g and 300 µg/g provided the highest Youden Indexes of 0.540 and 0.482 among patients receiving etrasimod in ELEVATE UC 52 and ELEVATE UC 12, respectively. For EIHR at week 52, an fCAL concentration of 200 µg/g provided the highest Youden Index of 0.542 among patients receiving etrasimod in ELEVATE UC 52 (Supplementary Table 3).
For clinical response at week 12, fCAL concentrations of 250 µg/g and 350 µg/g provided the highest Youden Indexes of 0.411 and 0.340 among patients receiving etrasimod in ELEVATE UC 52 and ELEVATE UC 12, respectively. For clinical response at week 52, an fCAL concentration of 300 µg/g provided the highest Youden Index of 0.488 among patients receiving etrasimod in ELEVATE UC 52 (Supplementary Table 3).
Among patients receiving etrasimod, fCAL concentrations of 250 µg/g provided generally higher Youden Indexes for the different efficacy end points (Supplementary Table 3). A threshold of 250 µg/g fCAL was therefore selected for patient stratification by fCAL concentration. The summations and Youden Indexes for varying concentrations of fCAL are shown in Supplementary Tables 3 and 4 and in Supplementary Table 5 for hsCRP.
Proportions of Patients Meeting Efficacy End Points Stratified by fCAL Concentrations
Using the threshold of 250 μg/g fCAL, patients receiving etrasimod were stratified by fCAL concentrations ≤250 μg/g and >250 µg/g at each visit. A greater proportion of patients achieving efficacy end points at weeks 12 and 52 had ≤250 μg/g fCAL than those who had >250 μg/g fCAL across both ELEVATE UC 52 (Figure 4A) and ELEVATE UC 12 (week 12 only; Figure 4B). The OR (95% CI) values for patients achieving EIHR with fCAL concentrations ≤250 μg/g compared with >250 μg/g were 13.48 (6.12, 29.66; week 12) and 15.97 (7.30, 34.97; week 52) for ELEVATE UC 52 (Figure 4A), and 8.43 (3.56, 20.00; week 12) for ELEVATE UC 12 (Figure 4B).
Figure 4.
Proportion of patients treated with etrasimod achieving efficacy end points, stratified by fCAL concentrations ≤250 μg/g vs >250 μg/g in (A) ELEVATE UC 52 and (B) ELEVATE UC 12 (OR [95% CI]; FAS, baseline MMS 4-9). ***P <.001. OR (95% CI) compares the odds of clinical end point response among patients receiving etrasimod with fCAL ≤250 μg/g concentrations vs fCAL >250 μg/g concentrations at weeks 12 and 52. OR (95% CI) values and P values were obtained from a logistic regression model. Missing fCAL values at weeks 12 and 52 were imputed using the LOCF method; a missing baseline fCAL value was not imputed. Abbreviations: CI, confidence interval; EIHR, endoscopic improvement-histologic remission; FAS, full analysis set; fCAL, fecal calprotectin; LOCF, last observation carried forward; MMS, Modified Mayo score; n, number of responders/nonresponders for the end point; N, number of patients in cohort; OR, odds ratio; QD, once daily; UC, ulcerative colitis.
Findings for the placebo group were generally similar, in that a greater proportion of patients who had ≤250 μg/g fCAL achieved efficacy end points in both studies compared with those who had fCAL concentrations >250 μg/g (Supplementary Figure 3).
Median fCAL Concentrations at Baseline, Week 4, and Week 12 Among Patients Achieving Efficacy End Points at Week 12 and Week 52
Median fCAL concentrations among patients who received etrasimod and were subsequent week-12 responders vs nonresponders in ELEVATE UC 52 and ELEVATE UC 12 are shown in Figure 5, at baseline (Figure 5A, B, respectively), and week 4 (Figure 5C, D, respectively). Week 4 and week 12 median fCAL concentrations for patients who were subsequent week-52 responders vs nonresponders are also presented (Figure 5E, F, respectively). In ELEVATE UC 12, there were significant differences in median baseline fCAL concentrations in patients who received etrasimod and were subsequent responders at week 12 for clinical remission and clinical response end points compared with nonresponders at week 12 (P < .05; Figure 5B).
Figure 5.
Responder analysis of median fCAL concentration at (A-B) baseline and (C-D) week 4 by responders vs nonresponders at week 12 in ELEVATE UC 52 and ELEVATE UC 12, (E) week 4 by responders and nonresponders at week 52 in ELEVATE UC 52, and (F) week 12 by responders vs nonresponders at week 52 in ELEVATE UC 52 who received etrasimod (median [range]; FAS, MMS 4-9). *P < .05; ***P < .001. P values were based on Wilcoxon rank-sum test comparing the distributions (medians) of fCAL concentrations between responder and nonresponder groups within treatment arms for each end point. Missing fCAL values at weeks 4 and 12 were imputed using the LOCF method; missing baseline fCAL value was not imputed. Abbreviations: EIHR, endoscopic improvement-histologic remission; FAS, full analysis set; fCAL, fecal calprotectin; MMS, Modified Mayo score; n, number of responders/nonresponders for the end point; N, number of patients in cohort; n.s., nonsignificant; QD, once daily; UC, ulcerative colitis.
However, this was not observed in patients who were subsequent responders at week 12 for EIHR compared with nonresponders (Figure 5B). Among patients who received placebo in ELEVATE UC 52, baseline median fCAL concentrations in patients who were subsequent week-12 responders were numerically, but not significantly, lower for all efficacy end points except clinical response, where the difference was significant (Supplementary Figure 4A). In ELEVATE UC 12, differences in baseline median fCAL concentrations were not significantly different between patients who were subsequent responders and nonresponders for all end points (Supplementary Figure 4B).
At week 4, patients receiving etrasimod who were subsequent responders for efficacy end points at week 12 had significantly lower median fCAL concentrations compared with nonresponders at week 12 in both ELEVATE UC 52 (all P < .001; Figure 5C) and ELEVATE UC 12 (all P < .001; Figure 5D). This was also observed at week 4 and week 12 for subsequent responders at week 52 in ELEVATE UC 52 (all P < .001; Figure 5E and 5F). Among patients receiving placebo, median fCAL concentrations were significantly lower for responders vs nonresponders for the end points of clinical remission and EIHR (both P < .05), but not for clinical response in ELEVATE UC 52 (Supplementary Figure 4C), and for clinical remission (P < .001), but not EIHR or clinical response, in ELEVATE UC 12 (Supplementary Figure 4D). At week 12 for subsequent responders receiving placebo at week 52 in ELEVATE UC 52, median fCAL concentrations were significantly lower among responders compared with nonresponders for all end points (clinical remission and EIHR, P < .05; clinical response, P < .01) (Supplementary Figure 4F).
Discussion
This post hoc analysis assessed the relationship between fCAL and hsCRP as biomarkers of UC, with clinical efficacy end points in patients with moderately to severely active UC enrolled in the ELEVATE UC clinical program. Overall, these results indicate that fCAL and hsCRP levels numerically decreased over time with etrasimod treatment. The ROC analyses indicated a predictive relationship between biomarkers and treatment response. Based on ROC relationships with efficacy end points, fCAL—but not hsCRP—was a reliable predictor of clinical efficacy. These findings thus contribute to the understanding of the use of biomarkers in UC, their potential utility in predicting treatment outcomes, and reducing the overall cost and impact of UC care and disease monitoring, particularly among patients treated with etrasimod. By contributing to the understanding of the relationship between biomarkers, such as fCAL and hsCRP, and efficacy end points, patients with UC may be able to benefit from increased use of noninvasive monitoring in place of invasive endoscopies, which in turn has the potential to improve their health-related quality of life.
Clinical remission was used as the primary end point, consistent with US Food and Drug Administration (FDA) guidance for industry for UC clinical trial design and drug development.18,19 Meanwhile, EIHR was used as one of the key secondary end points, given that its stringent definition encompasses both endoscopic and histologic outcomes. Differences in fCAL concentrations between responders vs nonresponders were apparent as early as week 4, and they became more pronounced by week 12. When patients were stratified by response to treatment based on the achievement of clinical end points, there was a prominent relationship between biomarkers and efficacy end points of clinical remission, clinical response, and EIHR for both fCAL and hsCRP. Given that the relationship between fCAL and hsCRP and efficacy end points in responders was observed in patients receiving placebo and those receiving etrasimod, it is likely this relationship is a reflection of disease improvement, independent of treatment.
A greater proportion of patients achieved certain end points among those enrolled in ELEVATE UC 52 compared with ELEVATE UC 12; this may have been due to the attrition of nonresponders in the longer-term ELEVATE UC 52 trial. Due to the treat-through study design, patients remaining in the trial beyond week 12 likely also experienced an improvement while receiving placebo, given that they remained in the trial rather than enrolling in the open-label extension due to lack of disease improvement or disease worsening compared with baseline. This may explain the reduction in absolute fCAL at later timepoints in the placebo group in the responder analysis.
The ROC analyses for fCAL suggested that the fCAL cut-off concentration of 250 µg/g generally resulted in the highest summation of specificity and sensitivity. Indeed, a greater proportion of patients who had fCAL concentrations ≤250 µg/g achieved the efficacy end points compared with those with fCAL concentrations >250 µg/g. Nonresponders for both week 12 and week 52 had significantly higher fCAL concentrations at early timepoints compared with nonresponders. These data indicate that low fCAL concentrations ≤250 µg/g correlate with a greater likelihood of a response in clinical end points and support the consideration of fCAL testing in lieu of an endoscopic assessment. Additionally, low fCAL at week 4 or week 12 may be associated with achieving endoscopic end points at week 12 or week 52. The use of a 250 µg/g threshold is consistent with STRIDE-II guidelines, which state normalization of fCAL to 100 to 250 µg/g as an intermediate treatment target for UC.3 This is above the long-established threshold of 50 µg/g fCAL as a diagnostic criterion for differentiating between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).20,21 Understanding how fCAL concentrations above the diagnostic threshold correlate to treatment outcomes, using a 250 µg/g threshold, provides important context for the use of fCAL in disease monitoring among patients treated with etrasimod.
Meanwhile, ROC analyses for hsCRP suggested that the relationship between hsCRP and efficacy end points did not carry the same predictive value as that seen with fCAL, given that AUC values were generally lower for the relationships between hsCRP and efficacy end points than with fCAL.
Collectively, these results indicate that fCAL is a reliable biomarker of clinical efficacy for etrasimod, and that early changes in this biomarker may help to predict the subsequent achievement or maintenance of efficacy. In contrast, based on ROC relationships with efficacy end points, hsCRP was not observed to be a useful predictor of clinical efficacy in our analysis. Our results are consistent with both STRIDE-II and ECCO guidelines, which emphasize the utility of fCAL as a surrogate biomarker; ECCO guidelines cite a strong correlation between endoscopic inflammation and fCAL levels in UC, suggesting fCAL levels as an early target in IBD using a 4-phase approach to monitoring.3,22 Meanwhile, STRIDE-II guidelines note that hsCRP level normalization after treatment initiation should be considered a minimal obligatory short- to medium-term target but is insufficient for the longer term.3 As a general marker of inflammation, hsCRP has been noted to have poor sensitivity, with a negative hsCRP test not necessarily excluding the presence of a disease flare.22 Furthermore, hsCRP is not IBD-specific, and its elevation cannot differentiate IBD from infectious, or other causes of, colitis.22 Our results therefore inform the biochemical process involved with UC, while providing context for the use of fCAL in disease monitoring among patients receiving etrasimod.
These trials provide interesting data for patients treated with placebo. While clinical symptoms may improve in a clinical trial, this trial provides information to inform power calculations for studies of UC, especially for treat-through designs, with respect to the low but nonnegligible proportion of patients treated with placebo with biochemical improvements in fCAL and hsCRP.
These findings are consistent with those from a phase 2 trial of patients with UC treated with ozanimod, in which both fCAL and hsCRP concentrations decreased quickly after treatment induction and remained low throughout the ≥4 year open-label extension study.8 In addition to fCAL and hsCRP levels reflecting clinical and histologic findings among patients receiving ozanimod,23 the prominent difference in fCAL concentrations among responders compared with nonresponders has been noted in patients with UC receiving tofacitinib.5 fCAL as a biomarker has been validated in the broader UC patient population; a 6-month prospective study of patients with UC reported that, although there was a weak correlation between fCAL and symptoms, there was a strong correlation between fCAL and endoscopic activity or histopathology.24 This may be particularly relevant among certain patients with either low or high fCAL concentrations. In patients with UC, monitoring was found to be a successful surrogate for endoscopy among those with fCAL concentrations of either ≤50 μg/g or ≥250 μg/g, with a <5% false negative or false positive rate, respectively.25 Given that fCAL can be used to differentiate between IBD and IBS,20,21 the use of fCAL pre-endoscopic screening could substantially reduce the number of invasive measurements required in IBD diagnosis.26 In turn, it has been estimated that introducing routine fCAL monitoring could approximately halve the cost of IBD care, while aiding changes in clinical management in a similar proportion to historical colonoscopy-only monitoring.27
Limitations of this study included the post hoc nature of this analysis; additionally, these data were collected under a phase 3 controlled clinical trial setting that may not be fully representative of a general UC population. Further analyses using clinical registry or disease-specific observational data collection will help to further assess the generalizability of the data.
Conclusions
fCAL and hsCRP values corresponded with the end points of clinical remission, clinical response, and EIHR in both responders and nonresponders. fCAL and hsCRP levels were shown to decrease in patients treated with 2 mg of etrasimod QD. The use of ROC curves to compare fCAL and hsCRP to treatment response indicated a predictive correlation between biomarkers and treatment response; this relationship was more pronounced at week 52 in all end points. Collectively, these results suggest that fCAL and, to a lesser extent, hsCRP are reliable biomarkers of clinical efficacy end points and that early changes in these biomarkers may help to predict the subsequent achievement or maintenance of efficacy.
Supplementary Data
Supplementary data is available at Inflammatory Bowel Diseases online.
Acknowledgments
The authors would like to thank the trial participants, trial sites, and trial teams. The authors would also like to thank Kiyomi Komori for her significant contribution to these studies and analyses. This study was sponsored by Pfizer. Medical writing support, under the direction of the authors, was provided by Karen Thompson, PhD, CMC Connect, a division of IPG Health Medical Communications and was funded by Pfizer, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med. 2022;175(9):1298–1304).
Contributor Information
Vipul Jairath, Department of Medicine and Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
David T Rubin, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Bram Verstockt, Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Translational Research in Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
Ayhan H Çekin, Department of Gastroenterology, University of Health Sciences, Antalya Training and Research Hospital, Antalya, Turkey.
Maria T Abreu, Division of Gastroenterology, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Charlie W Lees, The Edinburgh Inflammatory Bowel Disease Unit, Western General Hospital, Edinburgh, Scotland, UK.
Marc Fellmann, Pfizer AG, Zürich, Switzerland.
John C Woolcott, Pfizer Inc, Collegeville, PA, USA.
Catherine Crosby, Pfizer Inc, La Jolla, CA, USA.
Joseph Wu, Pfizer Inc, Cambridge, MA, USA.
Abhishek Bhattacharjee, Pfizer Healthcare India Pvt Ltd, Chennai, Tamil Nadu, India.
David Herman, Pfizer Inc, La Jolla, CA, USA.
Guibao Gu, Pfizer Inc, La Jolla, CA, USA.
Britta Siegmund, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Author contributions
V.J. and B.S. contributed to the conception or design of the study. D.T.R., M.T.A., C.W.L., M.F., J.C.W., and C.C. contributed to the conception or design of the study, and analysis of data. B.V. contributed to the conception or design of the study, patient recruitment, and analysis of data. A.H.Ç. contributed to patient recruitment and the acquisition of data. D.H. and G.G. contributed to the conception or design of the study, patient recruitment, and acquisition of data.
Funding
This study was sponsored by Pfizer.
Conflicts of Interest
V.J. has received consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer Inc, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, TD Securities, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics; and has received speaker’s fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer Inc, Shire, Takeda, and Fresenius Kabi.
D.T.R. has received consultancy/advisory board fees from AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chronicles, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen, Kaleido Biosciences, Lilly, Pfizer Inc, Prometheus Biosciences, Reistone Biopharma, Seres Therapeutics, Syneos Health, Takeda, Target RWE, and Trellus Health; has received grant support from Takeda, Helmsley Charitable Trust, and GI Research Foundation; has participated in the Board of Trustees for Crohn’s & Colitis Foundation, and Cornerstones Health; and has stock options with Alike Health, AltruBio, Datos Health, and Iterative Health.
B.V. has received research support from AbbVie, Biora Therapeutics, Landos Biopharma, Pfizer Inc, Sosei Heptares, and Takeda; has received speaker’s fees from AbbVie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, Lilly, MSD, Pfizer Inc, R-Biopharm, Sandoz, Takeda, Tillotts Pharma, Truvion Healthcare, and Viatris; and has received consultancy fees from AbbVie, Alimentiv, Applied Strategic, Atheneum, BenevolentAI, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Landos Biopharma, Lilly, Mylan, Inotrem, Ipsos, Janssen, Pfizer Inc, Progenity, Sandoz, Santa Ana Bio, Sosei Heptares, Takeda, Tillotts Pharma, and Viatris.
A.H.Ç. declares no conflicts of interest.
M.T.A. has received consulting fees from AbbVie, Bellatrix Pharmaceuticals, Bristol Myers Squibb, Celsius Therapeutics, Cosmo Pharmaceuticals, Eli Lilly, Gilead, Janssen, Microba, Pfizer Inc, Prometheus Biosciences, Takeda, UCB, and WebMD Global LLC; and has received grant/research support from AbbVie, Bristol Myers Squibb, Genentech, Gilead, Janssen, Prometheus Biosciences, and Takeda.
C.W.L. has served as a speaker for AbbVie, Dr Falk Pharma, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda, and Warner Chilcott; has served as a consultant for AbbVie, Dr Falk Pharma, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health, and Vifor Pharma; and has received research funding from AbbVie and Gilead.
M.F., J.C.W., C.C., J.W., A.B., D.H., and G.G. is an employee and shareholder of Pfizer Inc.
B.S. has received lecture fees from AbbVie, CED Service GmbH, Chiesi, Falk, Forga Software, Galapagos, IBD Passport, Janssen, Materia Prima, Pfizer Inc, and Lilly; and has received consultancy fees from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene, CT-Scout, Endpoint Health, Galapagos, Gilead Sciences, Janssen, Landos Biopharma, Lilly, Pfizer Inc, PredictImmune, and PSI CRO.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
References
- 1. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel J-F.. Ulcerative colitis. Lancet. 2017;389(10080):1756-1770. doi: https://doi.org/ 10.1016/S0140-6736(16)32126-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Magro F, Gionchetti P, Eliakim R, et al. ; European Crohn’s and Colitis Organisation [ECCO]. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders. J Crohns Colitis. 2017;11(6):649-670. doi: https://doi.org/ 10.1093/ecco-jcc/jjx008 [DOI] [PubMed] [Google Scholar]
- 3. Turner D, Ricciuto A, Lewis A, et al. ; International Organization for the Study of IBD. STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570-1583. doi: https://doi.org/ 10.1053/j.gastro.2020.12.031 [DOI] [PubMed] [Google Scholar]
- 4. Singh S, Ananthakrishnan AN, Nguyen NH, et al. ; AGA Clinical Guidelines Committee. Electronic address: clinicalpractice@gastro.org. AGA clinical practice guideline on the role of biomarkers for the management of ulcerative colitis. Gastroenterology. 2023;164(3):344-372. doi: https://doi.org/ 10.1053/j.gastro.2022.12.007 [DOI] [PubMed] [Google Scholar]
- 5. Sandborn WJ, Panes J, Zhang H, Yu D, Niezychowski W, Su C.. Correlation between concentrations of fecal calprotectin and outcomes of patients with ulcerative colitis in a phase 2 trial. Gastroenterology. 2016;150(1):96-102. doi: https://doi.org/ 10.1053/j.gastro.2015.09.001 [DOI] [PubMed] [Google Scholar]
- 6. Sonoyama H, Kawashima K, Ishihara S, et al. Capabilities of fecal calprotectin and blood biomarkers as surrogate endoscopic markers according to ulcerative colitis disease type. J Clin Biochem Nutr. 2019;64(3):265-270. doi: https://doi.org/ 10.3164/jcbn.18-92 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sandborn WJ, Feagan BG, Rutgeerts P, et al. ; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721. doi: https://doi.org/ 10.1056/NEJMoa1215739 [DOI] [PubMed] [Google Scholar]
- 8. Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE study. J Crohns Colitis. 2021;15(7):1120-1129. doi: https://doi.org/ 10.1093/ecco-jcc/jjab012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Costa F, Mumolo MG, Ceccarelli L, et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease. Gut. 2005;54(3):364-368. doi: https://doi.org/ 10.1136/gut.2004.043406 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Pathirana WGW, Chubb SP, Gillett MJ, Vasikaran SD.. Faecal calprotectin. Clin Biochem Rev. 2018;39(3):77-90. [PMC free article] [PubMed] [Google Scholar]
- 11. Siemons L, Ten Klooster PM, Vonkeman HE, et al. How age and sex affect the erythrocyte sedimentation rate and C-reactive protein in early rheumatoid arthritis. BMC Musculoskelet Disord. 2014;15:368. doi: https://doi.org/ 10.1186/1471-2474-15-368 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Qin T, Liu W, Yin M, et al. Body mass index moderates the relationship between C-reactive protein and depressive symptoms: evidence from the China Health and Retirement Longitudinal Study. Sci Rep. 2017;7:39940. doi: https://doi.org/ 10.1038/srep39940 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): 2 randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401(10383):1159-1171. doi: https://doi.org/ 10.1016/S0140-6736(23)00061-2 [DOI] [PubMed] [Google Scholar]
- 14. Peyrin-Biroulet L, Christopher R, Behan D, Lassen C.. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 2017;16(5):495-503. doi: https://doi.org/ 10.1016/j.autrev.2017.03.007 [DOI] [PubMed] [Google Scholar]
- 15. Argollo M, Furfaro F, Gilardi D, et al. Modulation of sphingosine-1-phosphate in ulcerative colitis. Expert Opin Biol Ther. 2020;20(4):413-420. doi: https://doi.org/ 10.1080/14712598.2020.1732919 [DOI] [PubMed] [Google Scholar]
- 16. Bryan AM, Del Poeta M.. Sphingosine-1-phosphate receptors and innate immunity. Cell Microbiol. 2018;20(5):e12836. doi: https://doi.org/ 10.1111/cmi.12836 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32-35. doi: https://doi.org/ 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3 [DOI] [PubMed] [Google Scholar]
- 18. US Food and Drug Administration. Ulcerative colitis: developing drugs for treatment guidance for industry. Accessed December 15, 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ulcerative-colitis-developing-drugs-treatment [Google Scholar]
- 19. FDA. Ulcerative Colitis: Clinical Trial Endpoints: Guidance for Industry. Vol. 2024, 2016. [Google Scholar]
- 20. Tibble JA, Sigthorsson G, Foster R, Forgacs I, Bjarnason I.. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology. 2002;123(2):450-460. doi: https://doi.org/ 10.1053/gast.2002.34755 [DOI] [PubMed] [Google Scholar]
- 21. Walsham NE, Sherwood RA.. Fecal calprotectin in inflammatory bowel disease. Clin Exp Gastroenterol. 2016;9:21-29. doi: https://doi.org/ 10.2147/CEG.S51902 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Maaser C, Sturm A, Vavricka SR, et al. ; European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR]. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis. 2019;13(2):144-164. doi: https://doi.org/ 10.1093/ecco-jcc/jjy113 [DOI] [PubMed] [Google Scholar]
- 23. Sandborn WJ, Feagan BG, D’Haens G, et al. ; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280-1291. doi: https://doi.org/ 10.1056/NEJMoa2033617 [DOI] [PubMed] [Google Scholar]
- 24. Walsh A, Kormilitzin A, Hinds C, et al. Defining faecal calprotectin thresholds as a surrogate for endoscopic and histological disease activity in ulcerative colitis–a prospective analysis. J Crohns Colitis. 2019;13(4):424-430. doi: https://doi.org/ 10.1093/ecco-jcc/jjy184 [DOI] [PubMed] [Google Scholar]
- 25. Dulai PS, Battat R, Barsky M, et al. Incorporating fecal calprotectin into clinical practice for patients with moderate-to-severely active ulcerative colitis treated with biologics or small-molecule inhibitors. Am J Gastroenterol. 2020;115(6):885-894. doi: https://doi.org/ 10.14309/ajg.0000000000000596 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Mindemark M, Larsson A.. Ruling out IBD: estimation of the possible economic effects of pre-endoscopic screening with F-calprotectin. Clin Biochem. 2012;45(7-8):552-555. doi: https://doi.org/ 10.1016/j.clinbiochem.2011.10.015 [DOI] [PubMed] [Google Scholar]
- 27. Motaganahalli S, Beswick L, Con D, van Langenberg DR.. Faecal calprotectin delivers on convenience, cost reduction and clinical decision-making in inflammatory bowel disease: a real-world cohort study. Intern Med J. 2019;49(1):94-100. doi: https://doi.org/ 10.1111/imj.14027 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.