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Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis

Open AccessPublished:November 08, 2019DOI:https://doi.org/10.1053/j.gastro.2019.10.035

      Background & Aims

      Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC).

      Methods

      In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4–9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint.

      Results

      At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30–1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously; all 3 patients had evidence of atrioventricular block before etrasimod exposure.

      Conclusions

      In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      AE (adverse event), CI (confidence interval), LSM (least squares mean), MCS (Mayo Clinic score), S1P (sphingosine 1-phosphate), TEAE (treatment-emergent adverse event), TNF-α (tumor necrosis factor α), UC (ulcerative colitis)
      See editorial on page 467.

       Background and Context

      Etrasimod is an oral sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders that might be used to treat ulcerative colitis (UC).

       New Findings

      In a phase 2 randomized trial of patients with moderately to severely active UC, etrasimod (2 mg) was more effective than placebo in reducing clinical and endoscopic features of UC.

       Limitations

      Larger studies of more patients are needed to determine the efficacy and safety of etrasimod in patients with UC.

       Impact

      With further development, etrasimod might be used to treat patients with UC.
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      The current study aimed to determine the safety and efficacy of etrasimod in patients with moderately to severely active UC.

      Materials and Methods

       Study Design

      This phase 2, randomized, double-blind, parallel-group, placebo-controlled study of induction therapy with etrasimod was conducted from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries (Supplementary Materials). The study was conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and was approved by the institutional review board at each center. All patients provided written informed consent. All authors had full access to the data, control of the content of the manuscript, and final responsibility for the decision to submit for publication.

       Patients

      Eligible patients were aged 18–80 years with UC and a modified Mayo Clinic score (MCS) of 4–9, including a centrally read endoscopic subscore of ≥2 and a rectal bleeding subscore of ≥1. Patients with disease limited to the rectum were excluded. Disease activity was measured with a modified MCS (range, 0–9; composed of 3 subscores [endoscopic findings, rectal bleeding, and stool frequency], each with a range of 0–3). Higher scores indicate more severe disease. Stable doses of oral mesalamine and corticosteroids (prednisone ≤10 mg/d, budesonide ≤9 mg/d, or equivalent steroid) were permitted except for rectally administered agents, which had to be discontinued 2 weeks before the first dose of study drug; biologics were discontinued 60 days or more before randomization; and immunosuppressants were discontinued at randomization. Complete inclusion and exclusion criteria are provided in the Supplementary Materials.

       Randomization and Masking

      Patients were randomly assigned 1:1:1 to receive oral etrasimod 1 mg, etrasimod 2 mg, or placebo once daily for 12 weeks (Supplementary Figure 1). Randomization was performed centrally with a block size of 6 and was stratified by current use of corticosteroids and previous exposure to anti–TNF-α agents. Randomization codes were generated by a statistician not directly involved with the study. The sponsor, patients, and personnel involved with the conduct of the study, with the exception of the clinical supply staff, safety staff, and the statistician supporting the data safety monitoring board, were blinded to the identity of the study medication; placebo and study drug were supplied as capsules with the same appearance.

       Procedures

      Patients were assessed for efficacy at baseline and week 12 with the MCS,
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      including flexible proctosigmoidoscopy. Histologic severity was evaluated with the Geboes Index.
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      A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.
      Endoscopic scores were assessed from a single read by a central, blinded reader; histologic scores were assessed by a single blinded reader. Endoscopy and histology central readers were blinded to clinical information, treatment assignment, and visit sequence. Additional visits were performed for safety monitoring and collection of patient diary information. Blood samples were taken at each visit for clinical chemistry and hematologic analysis. Stool samples were taken during screening and at weeks 4, 8, and 12 for measurement of fecal calprotectin. Patients receiving corticosteroids at baseline continued treatment at stable doses; dose tapering was not permitted during the study period.

       Outcomes

      The primary efficacy endpoint was improvement from baseline in the modified MCS at week 12. The primary efficacy endpoint of improvement from baseline in the modified MCS was prespecified before database lock, a change from the primary endpoint of clinical remission in the original protocol made to reduce the estimated required sample size. The proportion of patients with clinical remission was retained as a prespecified exploratory outcome.
      Secondary efficacy endpoints were the proportion of patients at week 12 who achieved endoscopic improvement (defined as an endoscopic subscore of ≤1 point), improvement in the 2-component MCS (range, 0–6, including rectal bleeding and endoscopy findings), and improvement in the total MCS (range, 0–12, composed of the modified MCS plus Physician Global Assessment). Exploratory outcomes assessed at week 12 included clinical remission (Mayo Clinic endoscopic subscore ≤1 [with absence of friability], rectal bleeding score ≤1, and stool frequency score ≤1 with a frequency decrease of ≥1 point from baseline), clinical response (met the criteria for clinical remission or had a decrease in modified MCS of ≥2 points and a decrease of ≥30%, with either a rectal bleeding score of ≤1 or a decrease in rectal bleeding of ≥1), histologic improvement (Geboes score <3.1), histologic remission (Geboes score <2.0), and peripheral blood lymphocyte counts. After the study commenced, the secondary endpoints of improvement in the 2-component MCS and improvement in the total MCS were added. The proportion of patients at week 12 with clinical response (originally a secondary endpoint) and clinical remission (originally the primary endpoint) were made exploratory endpoints. AEs were coded using the Medical Dictionary for Regulatory Activities, version 20.1. Anemia was based on investigator diagnosis. The complete schedule of procedures and monitoring for AEs is described in the Supplementary Materials.

       Statistical Analysis

      Demographic and disease characteristics at baseline were summarized by using descriptive statistics with no formal statistical testing comparing groups. Primary and secondary efficacy endpoints at week 12 were analyzed in the intention-to-treat population (all randomized patients who received 1 or more doses of the study drug) by using the multiple imputation method for missing data (including missing subscores and individual components of composite endpoints). Sensitivity analyses were conducted for the primary endpoint and for clinical remission to test the robustness of results. Exploratory endpoints were analyzed in either the intention-to-treat population with multiple imputation or in the modified intention-to-treat population (all randomized patients who received 1 or more doses of study drug and had a measurement at baseline and at least 1 postrandomization measurement) for all other variables. The safety population consisted of all randomized patients who received 1 or more doses of the study drug. No missing data were imputed for repeated-measures analyses or safety analyses.
      The primary efficacy endpoint was analyzed by using an analysis of covariance model that incorporated treatment, current oral corticosteroid use, prior exposure to anti–TNF-α agents, and baseline value as covariates. All statistical testing was 1-sided at the .05 level of significance, as appropriate for a proof-of-concept, phase 2 study.
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      The primary comparison was between etrasimod 2 mg and placebo. Comparisons between all other groups were exploratory. Nominal P values were reported for all exploratory endpoints. A hierarchical testing strategy was prespecified and applied to all secondary endpoints. Any endpoint subsequent to a comparison that did not meet statistical significance was considered exploratory in the hierarchical order of improvement in modified MCS (the primary endpoint), proportion of patients achieving endoscopic improvement, improvement in 2-component MCS, and improvement in total MCS.
      The secondary endpoints of improvement in 2-component MCS and total MCS were analyzed by using the same model as the primary endpoint. The proportion of patients who achieved endoscopic improvement (a secondary endpoint) was analyzed with the Mantel–Haenszel method, adjusted for stratification factors of current corticosteroid therapy at baseline and previous exposure to anti–TNF-α agents.
      For the exploratory endpoints, the Mantel–Haenszel method was used for proportion-based efficacy endpoints. A mixed-effects model for repeated measures that included current corticosteroid use, previous exposure to anti–TNF-α agents, treatment, week, treatment-by-week interaction, and baseline value as covariates was used for longitudinal continuous efficacy endpoints. An unstructured covariance model was used for within-patient correlation for patient-reported outcomes. Dose-response analyses were performed by using an analysis of covariance model for continuous variables or a logistic regression model for categorical variables (treatment group and appropriate baseline covariates were included in the analysis model).
      Subgroup analyses for improvement of modified MCS used an analysis of covariance with terms for treatment, subgroup, treatment-by-subgroup interaction, and baseline value as covariate. Prespecified analyses were for subgroups of sex, age, race, current oral corticosteroid use, prior exposure to anti–TNF-α agents, response to anti–TNF-α agents, baseline fecal calprotectin, baseline C-reactive protein, and total MCS. Subgroup analyses by geographic region; exposure to anti-integrin agents, ≥1 biologic agent, ≥2 biologic agents, vedolizumab, and immunosuppressives; baseline lymphocyte count; duration of UC; and history of pancolitis, proctosigmoiditis, or pancolitis and proctosigmoiditis were post hoc.
      For comparison of the primary efficacy measure, a sample of approximately 39 eligible patients per group would provide approximately 80% power to detect a difference of 1.15 in improvement in the modified MCS at an overall level of significance of 0.05 (1-sided test) based on the estimated pooled standard deviation of 2.03. The use of a 90% confidence interval (CI) is appropriate and consistent with sample size consideration. The study was not powered to make formal statistical comparisons of the exploratory endpoints. For the exploratory endpoint of clinical remission, it was estimated that a sample of approximately 80 patients per group would be required to provide 80% power to detect a difference of 18% at an overall significance level of 5% (2-sided test).

      Results

       Patient Characteristics

      A total of 156 patients were randomly assigned to receive etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) (Supplementary Figure 2). Demographics and disease characteristics of the patient groups are shown in Table 1. Of the randomized patients, 141 (90.4%) completed the 12-week treatment phase of the study. Fifteen patients discontinued treatment; the most common reason for discontinuation was the occurrence of treatment-emergent AEs (TEAEs). Three patients in the etrasimod 1-mg group and 4 patients in the etrasimod 2-mg group discontinued because of TEAEs (Table 2). The median duration of exposure to the study drug was 12.1 weeks in each treatment group (minimum–maximum, 0.3–17.7 across all groups).
      Table 1Patient Demographics and Baseline Characteristics (Safety Population)
      CharacteristicsPlacebo (n = 54)Etrasimod 1 mg (n = 52)Etrasimod 2 mg (n = 50)
      Age, y, mean (SD)44.8 (14.85)43.2 (12.22)40.4 (12.39)
      Male sex, n (%)32 (59.3)30 (57.7)27 (54.0)
      White race, n (%)51 (94.4)48 (92.3)
      One patient reported race of both white and Asian–Japanese.
      49 (98.0)
      BMI, kg/m2
       Mean (SD)25.8 (4.6)24.9 (3.6)24.0 (5.5)
       Median (min–max)25.2 (18.2–41.1)24.2 (17.9–32.2)23.2 (17.7–46.6)
      Baseline total MCS
       Mean (SD)8.7 (1.72)
      n = 53.
      8.8 (1.43)8.9 (1.47)
       Median (min–max)9.0 (4–12)9.0 (6–12)9.0 (6–11)
      Baseline modified MCS
       Mean (SD)6.5 (1.51)
      n = 53.
      6.5 (1.23)6.6 (1.17)
       Median (min–max)7.0 (2–9)
      One patient was inadvertently enrolled with a baseline modified MCS of 2 (endoscopic score of 2, stool frequency subscore of 0, rectal bleeding subscore of 0). This patient was randomized and received at least 1 dose of study medication before the discrepancy was noted, and the patient was withdrawn from the study on day 15.
      7.0 (4–9)7.0 (4–8)
      Duration of UC, y
       Mean (SD)8.6 (7.16)7.0 (6.11)6.2 (4.69)
       Median (min–max)6.0 (1–32)5.3 (1–22)4.8 (1–18)
      History of disease extent, n (%)
      For history of proctosigmoiditis and pancolitis, the responses are not mutually exclusive. Some patients reported a history of both proctosigmoiditis and pancolitis: etrasimod 1 mg, n = 11; etrasimod 2 mg, n = 9; placebo, n = 8.
       Proctosigmoiditis34 (63.0)34 (65.4)30 (60.0)
       Pancolitis23 (42.6)20 (38.5)14 (28.0)
      Baseline fecal calprotectin, μg/g
       Mean (SD)2350.8 (3121.69)3051.7 (4977.91)
      n = 49.
      2491.8 (3679.85)
      n = 45.
       Median (min–max)1429.0 (67–16,226)1210.0 (30–24,190)1449.0 (71–21,559)
      Baseline CRP, nmol/L
       Mean (SD)79.30 (120.66)
      n = 53.
      142.98 (345.97)92.39 (139.10)
      n = 49.
       Median (min–max)34.57 (2.95–562.87)46.19 (2.00–2333.38)46.86 (2.76–732.40)
      Baseline IBDQ total score
       Mean (SD)125.5 (33.47)
      n = 53.
      122.0 (33.75)116.7 (32.78)
      n = 48.
       Median (min–max)127.0 (53–185)121.0 (56–187)116.5 (58–208)
      Prior and concomitant treatments
      Treatment duration is the total number of weeks receiving treatment for each individual using imputed partial dates. Duration of treatment summary includes prior and concomitant treatments.
       Current oral corticosteroids, n (%)16 (29.6)13 (25.0)18 (36.0)
      Duration, median (min–max), wk31.4 (1.1–1304.4)26.1 (1.6–260.9)25.7 (2.1–432.4)
       Previous anti–TNF-α agents, n (%)18 (33.3)15 (28.8)17 (34.0)
      Duration, median (min–max), wk41.4 (8.7–524.4)99.1 (28.3–321.9)54.4 (5.9–228.9)
       Previous immunosuppressants, n (%)33 (61.1)17 (32.7)26 (52.0)
      Duration, median (min–max), wk57.3 (1.1–652.0)104.4 (2.6–355.6)52.6 (4.0–417.4)
       Previous anti-integrin agent, n (%)12 (22.2)4 (7.7)7 (14.0)
      Duration, median (min–max), wk26.3 (2.1–240.0)54.1 (31.6–75.9)43.9 (16.1–80.7)
       Previous oral 5-aminosalicylates, n (%)53 (98.1)49 (94.2)46 (92.0)
      Duration, median (min–max), wk146.3 (19.3–1464.6)118.9 (25.3–1081.0)112.9 (17.3–792.3)
      BMI, body mass index; CRP, C-reactive protein; IBDQ, Inflammatory Bowel Disease Questionnaire; max, maximum; MCS, Mayo Clinic score; min, minimum; SD, standard deviation; TNF-α, tumor necrosis factor α; UC, ulcerative colitis.
      a One patient reported race of both white and Asian–Japanese.
      b n = 53.
      c One patient was inadvertently enrolled with a baseline modified MCS of 2 (endoscopic score of 2, stool frequency subscore of 0, rectal bleeding subscore of 0). This patient was randomized and received at least 1 dose of study medication before the discrepancy was noted, and the patient was withdrawn from the study on day 15.
      d For history of proctosigmoiditis and pancolitis, the responses are not mutually exclusive. Some patients reported a history of both proctosigmoiditis and pancolitis: etrasimod 1 mg, n = 11; etrasimod 2 mg, n = 9; placebo, n = 8.
      e n = 49.
      f n = 45.
      g n = 48.
      h Treatment duration is the total number of weeks receiving treatment for each individual using imputed partial dates. Duration of treatment summary includes prior and concomitant treatments.
      Table 2TEAEs (Safety Population)
      TEAEs were defined as AEs with an onset date on or after the first dose of study medication. Events were coded using the Medical Dictionary for Regulatory Activities, version 20.1.
      Placebo (n = 54)Etrasimod 1 mg (n = 52)Etrasimod 2 mg (n = 50)
      Patients with any TEAE, n (%)27 (50.0)31 (59.6)28 (56.0)
      Number of TEAEs, n646678
      Patients with TEAEs leading to death, n000
      Patients discontinued due to ≥1 TEAE, n (%) [number of events]03 (5.8) [5]4 (8.0) [4]
       Ulcerative colitis—worsening02 (3.8)2 (4.0)
       Anal abscess01 (1.9)0
       Electrocardiogram T-wave abnormal001 (2.0)
       Dehydration01 (1.9)0
       Hypokalemia01 (1.9)0
       Neurologic symptom001 (2.0)
      Patients with serious TEAEs, n (%) [number of events]6 (11.1) [7]3 (5.8) [3]0
       Gastrointestinal disorders, n (%)5 (9.3)2 (3.8)0
      Abdominal pain1 (1.9)00
      Ulcerative colitis—worsening3 (5.6)2 (3.8)0
      Duodenal ulcer perforation1 (1.9)00
       Hepatobiliary disorders, n (%)1 (1.9)
      Jaundice.
      00
       Infections and infestations, n (%)01 (1.9)
      Anal abscess.
      0
       Renal and urinary disorders, n (%)1 (1.9)
      Hydronephrosis.
      00
      Severity (all TEAEs), n (%) [no. of events]
       Grade 1—mild19 (35.2) [32]21 (40.4) [41]23 (46.0) [53]
       Grade 2—moderate14 (25.9) [26]18 (34.6) [23]14 (28.0) [23]
       Grade 3—severe5 (9.3) [5]2 (3.8) [2]2 (4.0) [2]
       Grade 4—life-threatening1 (1.9) [1]00
       Grade 5—death related to TEAE000
      Severity (treatment-related TEAEs), n (%) [no. of events]
       Grade 1—mild2 (3.7) [3]2 (3.8) [3]2 (4.0) [2]
       Grade 2—moderate3 (5.6) [3]2 (3.8) [2]4 (8.0) [5]
       Grade 3—severe000
       Grade 4—life-threatening000
       Grade 5—death related to TEAE000
      TEAE relation to study drug, n (%) [no. of events]
       Not related27 (50.0) [57]30 (57.7) [61]26 (52.0) [71]
       Related3 (5.6) [6]4 (7.7) [5]5 (10.0) [7]
      Treatment-related TEAEs of special interest, n (%)
      Treatment-related TEAEs included events categorized by the investigator as related. If relatedness was missing, the event was assumed to be related.
       Atrioventricular block, second degree (type 1)001 (2.0)
      One patient experienced 1 event each of atrioventricular block second degree (type 1) and heart rate lowering that were considered treatment related. One additional patient experienced 1 event each of atrioventricular block first degree and sinus bradycardia that were not considered treatment related. See Supplementary Materials for additional details.
       Heart rate lowering001 (2.0)
      One patient experienced 1 event each of atrioventricular block second degree (type 1) and heart rate lowering that were considered treatment related. One additional patient experienced 1 event each of atrioventricular block first degree and sinus bradycardia that were not considered treatment related. See Supplementary Materials for additional details.
      TEAEs reported by ≥2 patients in any treatment group, n (%)
       UC—worsening4 (7.4)5 (9.6)2 (4.0)
       Upper respiratory tract infection2 (3.7)4 (7.7)2 (4.0)
       Nasopharyngitis4 (7.4)2 (3.8)1 (2.0)
       Anemia
      Anemia was based on investigator diagnosis.
      2 (3.7)2 (3.8)3 (6.0)
       Urinary tract infection02 (3.8)2 (4.0)
       Abdominal pain2 (3.7)2 (3.8)0
       Headache1 (1.9)03 (6.0)
       Nausea2 (3.7)1 (1.9)1 (2.0)
       Fecal calprotectin increased2 (3.7)1 (1.9)1 (2.0)
       Arthralgia2 (3.7)1 (1.9)1 (2.0)
       Blood creatine phosphokinase increased01 (1.9)2 (4.0)
       γ-Glutamyl transferase increased01 (1.9)2 (4.0)
       Sinusitis01 (1.9)2 (4.0)
       Fever1 (1.9)02 (4.0)
       Anal fissure2 (3.7)00
       Hyperlipasemia002 (4.0)
       Neutrophil count increased
      Neutrophil count increase was based on investigator assessment of central laboratory values.
      02 (3.8)0
      AEs, adverse events; n, number of patients with observations; TEAE, treatment-emergent adverse event.
      a TEAEs were defined as AEs with an onset date on or after the first dose of study medication. Events were coded using the Medical Dictionary for Regulatory Activities, version 20.1.
      b Jaundice.
      c Anal abscess.
      d Hydronephrosis.
      e Treatment-related TEAEs included events categorized by the investigator as related. If relatedness was missing, the event was assumed to be related.
      f One patient experienced 1 event each of atrioventricular block second degree (type 1) and heart rate lowering that were considered treatment related. One additional patient experienced 1 event each of atrioventricular block first degree and sinus bradycardia that were not considered treatment related. See Supplementary Materials for additional details.
      g Anemia was based on investigator diagnosis.
      h Neutrophil count increase was based on investigator assessment of central laboratory values.

       Efficacy

       Primary Endpoint

      At week 12, the least squares mean (LSM) (standard error) improvement in the modified MCS was 1.94 (0.31), 2.49 (0.31), and 1.50 (0.30) points for the etrasimod 1 mg, etrasimod 2 mg, and placebo groups, respectively (Figure 1A and Supplementary Table 1). A significant difference in the magnitude of improvement in the modified MCS was shown at week 12 for the etrasimod 2-mg group compared with placebo (LSM difference, 0.99; 90% CI, 0.30–1.68; P = .009). The LSM difference between etrasimod 1 mg and placebo was 0.43 (90% CI, −0.24 to +1.11; nominal P = .15) (Figure 1A). At final data analysis, among 156 patients in the intention-to-treat population, 15 patients (8.9%) had missing data for the primary endpoint of modified MCS; missing data were imputed by using prespecified multiple imputation procedures and analysis methods. The results of sensitivity analyses support the findings for the primary efficacy endpoint of a statistically significant difference for change from baseline at week 12 in the modified MCS for the etrasimod 2-mg group (Supplementary Table 2).
      Figure thumbnail gr1
      Figure 1Primary and secondary efficacy endpoints at week 12 (intention-to-treat population). (A) LSM improvement from baseline in the modified MCS, which includes stool frequency, rectal bleeding, and endoscopy findings (primary endpoint). (B) The proportion of patients who achieved endoscopic improvement, defined as a score of ≤1 point on the Mayo Clinic endoscopic subscore (secondary outcome). (C) LSM improvement from baseline in the 2-component MCS, including rectal bleeding and endoscopy findings (secondary outcome). (D) LSM improvement from baseline in total MCS (secondary outcome). Values in parentheses indicate 90% confidence intervals. LSM, least squares mean; MCS, Mayo Clinic score.

       Secondary Endpoints

      At week 12, a significantly higher proportion of patients receiving etrasimod 2 mg achieved endoscopic improvement vs those receiving placebo (41.8% vs 17.8%; difference, 24.4%; 90% CI, 9.8%–39.0%; P = .003) (Figure 1B and Supplementary Table 1); 22.5% of patients receiving etrasimod 1 mg achieved endoscopic improvement (difference vs placebo, 4.1%; 90% CI, −9.1% to +17.2%; nominal P = .31). The etrasimod 2-mg group had significant improvement in the 2-component MCS vs placebo (LSM difference, 0.84; 90% CI, 0.36–1.32; P = .002); the etrasimod 1-mg group had a difference vs placebo of 0.39 (90% CI, −0.08 to +0.85; nominal P = .09) (Figure 1C and Supplementary Table 1). Total MCS improved significantly in the etrasimod 2-mg group vs placebo (LSM difference, 1.27; 90% CI, 0.37–2.17; P = .010); the difference in the etrasimod 1-mg group vs placebo was 0.60 (90% CI, −0.27 to 1.48; nominal P = .13) (Figure 1D and Supplementary Table 1).

       Exploratory Endpoints

      More patients receiving etrasimod 2 mg than those receiving placebo achieved clinical remission (33.0% vs 8.1%; nominal P < .001) (Figure 2A). Clinical response was achieved by 50.6% of patients treated with etrasimod 2 mg and 32.5% treated with placebo (nominal P = .03) (Figure 2B). Histologic improvement was reported in 31.7% of patients receiving etrasimod 2 mg vs 10.2% in those receiving placebo (nominal P = .006) (Figure 2C). Histologic remission occurred in 19.5% of patients treated with etrasimod 2 mg compared with 6.1% of patients receiving placebo (nominal P = .03) (Figure 2D).
      Figure thumbnail gr2
      Figure 2Selected exploratory efficacy outcomes at week 12. (A) The proportion of patients who achieved clinical remission, defined as having an endoscopic subscore ≤1 (with absence of friability), a rectal bleeding score ≤1, and a stool frequency score ≤1 with a frequency decrease of ≥1 point from baseline (intention-to-treat population). (B) The proportion of patients who achieved clinical response, defined as having met the criteria for clinical remission or having a decrease in the modified Mayo Clinic score of ≥2 points and a decrease of ≥30% with either a decrease in rectal bleeding of ≥1 or a rectal bleeding score of ≤1 (intention-to-treat population). (C) The proportion of patients with histologic improvement, defined as having a Geboes score <3.1 (modified intention-to-treat population). (D) The proportion of patients with histologic remission, defined as having a Geboes score <2.0 (modified intention-to-treat population). Values in parentheses indicate 90% confidence intervals.
      Absolute lymphocyte counts decreased in a dose-proportional manner starting at week 1 (Figure 3). At week 12, etrasimod 2 mg and etrasimod 1 mg resulted in decreases from baseline of 39.9% and 19.8%, respectively (nominal P < .001 for difference from placebo, for both doses). The results of all prespecified exploratory analyses are listed in Supplementary Table 3.
      Figure thumbnail gr3
      Figure 3Lymphocyte count over time (modified intention-to-treat population). Decrease in absolute circulating lymphocyte count from baseline to week 12. Percent change from baseline (Δ) is based on a mixed-effects model for repeated measures with current oral corticosteroid use, prior exposure to anti–TNF-α agents, treatment, week, treatment-by-week interaction as factors, and baseline value as covariates. P values are for the comparison with placebo in mean change from baseline. The error bars indicate standard error of the mean. The asterisks indicate nominal P < .001 vs placebo. CI, Confidence interval; TNF-α tumor necrosis factor α.

       Subgroup Analyses

      Overall, the results of subgroup analyses for improvement in modified MCS were similar to those for the primary analysis, including for patients with prior exposure to anti–TNF-α therapy. The exceptions were prior vedolizumab use and a history of pancolitis (Supplementary Figure 3).

       Safety

      The incidences of study drug–related TEAEs and TEAEs leading to discontinuation were higher in the etrasimod groups than the placebo group (Table 2). Overall, 55.1% of patients reported 1 or more TEAEs during the study, and TEAEs that were deemed to be related to the study drug were reported in 7.7% of patients. Ten serious TEAEs in 9 patients (5.8% of overall patients, 3 patients receiving etrasimod 1 mg and 6 patients receiving placebo) and 9 TEAEs leading to discontinuation of the study drug in 7 patients (4.5% of overall patients, 3 patients receiving etrasimod 1 mg and 4 patients receiving etrasimod 2 mg) were reported. Across all treatment groups, most TEAEs (75%) were mild to moderate (grades 1 or 2); no drug-related TEAEs were life threatening, and there were no patient deaths during the study. The most commonly reported TEAEs in all groups included UC worsening, upper respiratory tract infection, nasopharyngitis, and anemia. No patients treated with etrasimod reported a grade 3 or above TEAE of infection; disorders of the eye, blood (except anemia), hepatobiliary system, or lymphatic system; or lymphocyte count of <0.2 × 109/L. Three patients reported AEs of special interest (all were asymptomatic, and occurred on day 1): heart rate lowering and second-degree atrioventricular block type 1 in 1 patient receiving etrasimod 2 mg that resolved by hour 8 and did not recur with further dosing, and first-degree atrioventricular block in 2 patients receiving etrasimod 2 mg (1 reported as a TEAE of first-degree atrioventricular block and the other was pre-existing at baseline and assessed as not clinically significant by the site investigator). In all 3 patients, review of predose electrocardiogram and/or Holter monitoring results found evidence of atrioventricular block before etrasimod exposure. Details of cardiac events are provided in the Supplementary Materials, and all TEAEs are given in Supplementary Table 4.

      Discussion

      In this phase 2 study, etrasimod 2 mg was effective as induction therapy in patients with moderately to severely active UC. Once-daily etrasimod 2 mg led to a significantly greater improvement in modified MCS, which includes stool frequency, rectal bleeding, and endoscopy findings, compared with placebo. Treatment also resulted in significantly greater improvements in 2-component and total MCS and a significantly higher proportion of patients achieving endoscopic improvement compared with placebo. Although this proof-of-concept phase 2 study was not powered to make formal statistical comparisons for exploratory endpoints, more patients treated with etrasimod 2 mg achieved clinical remission and clinical response compared with placebo, and etrasimod 2 mg met most exploratory efficacy endpoints, including histologic improvement and histologic remission. Results with etrasimod 1 mg were greater than those with placebo for most outcome measures but had a nominal P > .05.
      The primary endpoint was changed to improvement in modified MCS from the proportion of patients who achieved clinical remission to reduce the sample size needed per treatment group (approximately 39 patients for modified MCS vs approximately 80 patients for clinical remission) to assess a treatment effect by etrasimod in this proof-of-concept phase 2 trial. The modified MCS is a continuous-variable outcome across 3 domains that was believed to be more sensitive to differences between etrasimod and placebo than the dichotomous outcome of clinical remission. The modified MCS includes the clinically relevant measures of endoscopic findings, rectal bleeding, and stool frequency while omitting the subjective Physician Global Assessment, which has been shown to have only fair agreement with endoscopic findings.
      • Regueiro M.
      • Rodemann J.
      • Kip K.E.
      • et al.
      Physician assessment of ulcerative colitis activity correlates poorly with endoscopic disease activity.
      Etrasimod 2 mg met the primary endpoint of a significant difference in the magnitude of improvement in modified MCS from baseline compared with placebo (Figure 1A) as well as the secondary endpoint of endoscopic improvement (Figure 1B), a clinically important component of the modified MCS. The clinically important endpoint of the proportion of patients with clinical remission was included as an exploratory outcome in the current study, with 33% of patients receiving etrasimod 2 mg experiencing clinical remission at week 12, compared with 8.1% of patients receiving placebo (nominal P < .001) (Figure 2).
      Treatment with etrasimod appeared to be generally safe and well tolerated in the study population. Fewer than 10% of patients discontinued in both treatment arms, mostly because of TEAEs. Although TEAEs leading to drug discontinuation were higher with active treatment than placebo, most TEAEs were mild to moderate in severity and were similar to those reported for other next-generation S1P receptor modulators.
      • Kappos L.
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      Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial.
      Cardiac events, including bradycardia, conduction abnormalities, or both, have been reported with S1P receptor modulators,
      • Cohen J.A.
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      • Kappos L.
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      ,
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      • Vaclavkova A.
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      • Tran J.Q.
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      Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator.
      usually occurring within hours of the first dose administration. S1P1, S1P2, and S1P3 receptor subtypes are expressed in cardiac tissue.
      • Camm J.
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      • et al.
      Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications.
      In humans, activation of S1P1 on the cell surface of cardiomyocytes results in the activation of the G protein–coupled inwardly rectifying potassium channel, which has a role in cardiac conduction and heart rate.
      • Camm J.
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      ,
      • Cannavo A.
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      Hyperpolarization of myocytes and a temporary reduction in excitability caused by S1P receptor activation of G protein–coupled inwardly rectifying potassium channels before S1P antagonism or S1P receptor internalization may explain the transient bradycardia observed with members of the S1P receptor modulator class of therapeutic agents.
      • Camm J.
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      • Cannavo A.
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      The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.
      For some S1P receptor modulators, the magnitude of first-dose cardiac effect necessitates titration of the study drug.
      ,
      • Sandborn W.J.
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      ,
      • Olsson T.
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      Because etrasimod had a relatively modest, transient, and asymptomatic first-dose effect in phase 1 studies,

      Peyrin-Biroulet L, Adams J, Turner S, et al. Safety and immune modulatory properties of etrasimod (APD334), a next-generation oral, selective sphingosine 1-phosphate receptor (S1PR) modulator, in healthy volunteers. Paper presented at: 13th Congress of the European Crohn’s and Colitis Organisation (ECCO); February 14–17, 2018; Vienna, Austria.

      no dose titration was used in the current study. Transient, asymptomatic, and low-grade (first-degree or second-degree type 1) atrioventricular block was seen in 3 patients receiving etrasimod 2 mg in the current study. In each instance, the change occurred on day 1 and resolved spontaneously. The one instance of second-degree atrioventricular block type 1 did not recur with further dosing. In all 3 patients, there was evidence of atrioventricular block before etrasimod exposure.
      Targeted small-molecule S1P receptor modulators, such as etrasimod, represent a new class for the treatment of immune-mediated inflammatory diseases with several advantages over conventional treatments, particularly over treatment with biologic therapies, including oral delivery and a once-daily dosing regimen. Because etrasimod is a small molecule, no immunogenicity is expected. Etrasimod is a selective S1P1, S1P4, and S1P5 receptor modulator,
      • Al-Shamma H.
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      • Carroll C.
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      The selective sphingosine 1-phosphate receptor modulator etrasimod regulates lymphocyte trafficking and alleviates experimental colitis.
      and its specificity for these receptor subtypes may contribute to its safety profile. S1P1, S1P4, and S1P5 are primarily associated with immune system regulation, and functional abrogation of S1P2 and S1P3 may have adverse cardiovascular and pulmonary effects.
      • Peyrin-Biroulet L.
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      Modulation of sphingosine-1-phosphate in inflammatory bowel disease.
      ,
      • Al-Shamma H.
      • Lehmann-Bruinsma K.
      • Carroll C.
      • et al.
      The selective sphingosine 1-phosphate receptor modulator etrasimod regulates lymphocyte trafficking and alleviates experimental colitis.
      In addition to its receptor subtype selectivity, etrasimod has a rapid onset and offset of action. In the current study in patients with moderately to severely active UC, a mean 39% reduction in lymphocytes was observed 1 week after treatment with etrasimod 2 mg. This confirmed the results of a previous study with healthy adults that showed the rapid onset and offset of action of etrasimod, with rapid depletion of circulating lymphocytes (approximately 53% depletion at day 3) and rapid recovery to within 5% of baseline within a week of treatment cessation.

      Schreiber S, Morgan M, Christopher R, et al. Etrasimod (APD334), a potent, selective, oral S1P receptor modulator with preclinical autoimmune disease-modifying activity exhibits favorable PK/PD properties in healthy volunteers. Paper presented at: Advances in Inflammatory Bowel Diseases (AIBD) 2016; December 8–10, 2016; Orlando, FL.

      ,

      Peyrin-Biroulet L, Adams J, Turner S, et al. Safety and immune modulatory properties of etrasimod (APD334), a next-generation oral, selective sphingosine 1-phosphate receptor (S1PR) modulator, in healthy volunteers. Paper presented at: 13th Congress of the European Crohn’s and Colitis Organisation (ECCO); February 14–17, 2018; Vienna, Austria.

      In contrast, ozanimod, an S1P receptor agonist with an elimination half-life of 17–21 hours
      • Tran J.Q.
      • Hartung J.P.
      • Peach R.J.
      • et al.
      Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator.
      and long-acting active metabolites with half-lives of approximately 10 days,

      Tran JQ, Zhang P, Surapaneni S, et al. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor agonist. Paper presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 11–13, 2019; Stockholm, Sweden.

      showed only approximately 15% reduction at day 3 and lymphocyte levels approximately 40% below baseline 2 weeks after the last dose in healthy adults.
      • Tran J.Q.
      • Hartung J.P.
      • Peach R.J.
      • et al.
      Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator.
      However, caution must be taken with cross-trial comparisons, and the true clinical significance of receptor specificity can be determined only by head-to-head comparisons and larger trials.
      The current study has some limitations. First, this induction study was only 12 weeks in duration, and the safety and efficacy during longer-term maintenance therapy remain to be elucidated. Second, a larger sample size is needed to fully determine the safety profile of etrasimod.
      In conclusion, etrasimod 2 mg was more effective than placebo for improving the modified MCS at week 12 in patients with moderately to severely active UC in this phase 2 trial. The safety and efficacy of etrasimod should be further characterized in phase 3 clinical studies.

       Data Sharing Statement

      The study protocol and data collected for the study, including individual patient data, will not be made available to others.

      Acknowledgments

      The authors would like to acknowledge the patients and staff of the participating study sites.
      Medical writing support was provided by Steven Goodrick, PhD, and Elizabeth Strickland, PhD, inScience Communications, Springer Healthcare (Philadelphia, PA), and funded by Arena Pharmaceuticals, Inc.
      Author contributions: All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript and take responsibility for the integrity of the work as a whole. The first author and the sponsor (Arena Pharmaceuticals, Inc) designed the study. Data were collected and analyzed by a contract research organization (Pharmaceutical Product Development). All authors had full access to the data. The authors and the sponsor jointly interpreted the data. The first author and medical writers from inScience Communications (funded by the sponsor) wrote the first draft of the manuscript. All authors participated in subsequent drafts and in the decision to submit the manuscript for publication and vouch for the completeness and veracity of the data and analyses reported and for the adherence of the trial to the protocol.

      Supplementary Material

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