Efficacy and safety of etrasimod in Japanese patients with ulcerative colitis: results from a phase 2 dose-ranging study

Ken Takeuchi; Hiroshi Nakase; Tadakazu Hisamatsu; Katsuyoshi Matsuoka; Shoko Arai; Hirotoshi Yuasa; Motoki Oe; Ryosuke Ono; Michael Keating; Guibao Gu; Krisztina Lazin; Aoibhinn McDonnell; Koki Fukuta; Toshifumi Hibi

doi:10.5217/ir.2024.00213

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ORIGINAL ARTICLE Efficacy and safety of etrasimod in Japanese patients with ulcerative colitis: results from a phase 2 dose-ranging study: Ken Takeuchi¹, Hiroshi Nakase², Tadakazu Hisamatsu³, Katsuyoshi Matsuoka⁴, Shoko Arai^5,, Hirotoshi Yuasa⁶, Motoki Oe⁶, Ryosuke Ono⁶, Michael Keating⁷, Guibao Gu⁸, Krisztina Lazin⁹, Aoibhinn McDonnell¹⁰, Koki Fukuta^5,, Toshifumi Hibi¹¹; DOI: https://doi.org/10.5217/ir.2024.00213
Published online: April 25, 2025

¹Department of Gastroenterology, IBD Center, Tsujinaka Hospital Kashiwanoha, Kashiwa, Japan

²Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan

³Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan

⁴Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan

⁵Pfizer Japan Inc., Tokyo, Japan

⁶Pfizer R&D Japan, Tokyo, Japan

⁷Pfizer Inc, New York, NY, USA

⁸Pfizer Inc, La Jolla, CA, USA

⁹Pfizer AG, Zürich, Switzerland

¹⁰Pfizer Ltd, Sandwich, UK

¹¹Center for Advanced Inflammatory Bowel Disease Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan

Correspondence to Shoko Arai, Pfizer Japan Inc., Shinjuku Culture Quint Bldg 3-22-7 Yoyogi Shibuya-ku, Tokyo 151-8589, Japan. E-mail: shoko.arai@pfizer.com

Correspondence to Koki Fukuta, Pfizer Japan Inc., Shinjuku Culture Quint Bldg 3-22-7 Yoyogi Shibuya-ku, Tokyo 151-8589, Japan. E-mail: koki.fukuta@pfizer.com

• Received: December 17, 2024 • Revised: February 19, 2025 • Accepted: March 4, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
NOTES
Supplementary Material
REFERENCES

Abstract

Background/Aims
Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). However, its efficacy, safety, and the appropriate dosage have not been extensively investigated in the Japanese population.
Methods
This phase 2, multicenter, randomized, double-blind, placebo-controlled dose-ranging, 12-week trial was carried out among Japanese patients with moderately to severely active UC. Patients were randomized 1:1:1 to receive etrasimod 1 mg once daily (QD), etrasimod 2 mg QD, or placebo. The primary efficacy endpoint was the proportion of patients achieving clinical remission at week 12. Secondary efficacy endpoints and treatmentemergent adverse events (TEAEs) were also investigated. Efficacy endpoints were presented as proportions of patients achieving each outcome.
Results
Overall, 17, 19, and 18 patients received etrasimod 1 mg QD, etrasimod 2 mg QD, and placebo, respectively. One patient receiving etrasimod 1 mg (6.7%), 5 patients receiving etrasimod 2 mg (26.3%), and no patients receiving placebo (0%) achieved clinical remission. More patients receiving etrasimod versus placebo achieved secondary endpoints, except endoscopic normalization, at week 12. TEAEs were experienced by 9 patients receiving etrasimod 1 mg (52.9%), 13 patients receiving etrasimod 2 mg (68.4%), and 10 patients receiving placebo (55.6%). None of the TEAEs were serious and none experienced by patients receiving etrasimod led to treatment discontinuation.
Conclusions
Overall, etrasimod 2 mg QD for up to 12 weeks appeared efficacious and safe in these Japanese patients with moderately to severely active UC. All TEAEs were mild to moderate in severity. (ClinicalTrials.gov: NCT05061446)
Keywords: S1P receptor modulator; Etrasimod; Ulcerative colitis

INTRODUCTION

Ulcerative colitis (UC) is a chronic, immune-mediated disease characterized by relapsing and remitting, diffuse mucosal inflammation [1]. Symptoms include diarrhea, urgency, abdominal pain, bloody stool, weight loss, and fatigue [1]. The pathogenesis of UC is not fully understood, but has been found to be associated with elevated levels of inflammatory responses [1]. The global age-standardized prevalence rate of inflammatory bowel disease was 59.25 per 100,000 people in 2019, with the highest age-standardized prevalence rates of 210.54 per 100,000 people observed in the high-income Asia Pacific region [2]. Indeed, Japan has been noted as one of several countries in Asia experiencing a rapid increase in incidence in recent years, with the ratio of UC to Crohn’s disease in Asia estimated to be around 2.0 [3], and an estimated prevalence of UC of 211 per 100,000 in 2014 [4].

Existing first-line therapies to induce remission in UC include conventional therapies, such as 5-aminosalicylates (5-ASA) and corticosteroid therapy; however, corticosteroid therapy is not recommended for maintenance of remission [5]. Advanced therapies for UC include anti-tumor necrosis factor-α antibodies (e.g., infliximab, adalimumab, and golimumab) [6-8], anti-integrin antibodies (e.g., vedolizumab) [5], anti-interleukin (IL)-12/23 antibodies (e.g., ustekinumab) [9], anti-IL-23 p19 antibodies (e.g., mirikizumab and risankizumab) [10], and Janus kinase inhibitors (JAKi; e.g., tofacitinib, filgotinib, and upadacitinib) [11]. Despite the increased availability of advanced therapies, many patients show lack of response to therapy, or their responsiveness is reduced over time [12], and some treatments require regular administration by injection or infusion, or are associated with serious infections and malignancies [13,14]. This highlights the need for safe and effective oral UC treatment options.

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 efficacy and safety of etrasimod in patients with moderately to severely active UC have been demonstrated in a global 12-week phase 2 induction study (OASIS, NCT02447302) [15], and a corresponding global, long-term, open-label extension (OLE) study (OASIS OLE, NCT02536404) [16]. The OASIS OLE trial indicated that etrasimod 2 mg once daily (QD) was well tolerated up to 52 weeks, with most treatment-emergent adverse events (TEAEs) being mild to moderate in severity [16].

Two phase 3 studies, a 52-week trial comprising a 12-week induction period followed by a 40-week maintenance period with a treat-through design (ELEVATE UC 52; NCT03945188), and a 12-week (induction period only) trial (ELEVATE UC 12; NCT03996369), were also conducted among patients with moderately to severely active UC. In these global, phase 3, randomized, multicenter, double-blind, placebo-controlled studies, etrasimod led to a statistically significant improvement in the primary endpoint, clinical remission, at week 12 and week 52, with all key secondary endoscopic, symptomatic, and histologic endpoints met, including corticosteroid-free clinical remission at week 52 [17].

The efficacy and safety of etrasimod in Japanese patients were not investigated in the ELEVATE UC 52 trial. A small number of Japanese patients were included in the ELEVATE UC 12 and OASIS trials, and, upon completion of ELEVATE UC 12, could continue in the ELEVATE UC 40 JAPAN phase 3 trial (NCT04706793) for up to 52 weeks. Among the 42 Japanese patients with a modified Mayo score (MMS) of 5 to 9 who completed the ELEVATE UC 12 trial, numerically higher proportions of patients receiving etrasimod 2 mg QD achieved all efficacy endpoints, compared with placebo, up to 52 weeks [18]. Given the distinct genetic, environmental, and lifestyle factors that can influence drug response, it is crucial to investigate the efficacy and safety of etrasimod across a range of doses in Japanese patients to ensure optimal therapeutic outcomes in this specific population.

We present results from a phase 2, multicenter clinical trial that investigated the efficacy and safety of etrasimod 1 mg QD and 2 mg QD in Japanese patients with moderately to severely active UC over a 12-week period.

METHODS

1. Study Design

This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2 clinical trial (NCT05061446) conducted over a 12-week period, among Japanese patients with moderately to severely active UC. Patients were randomized approximately 1:1:1 to receive etrasimod 1 mg QD, etrasimod 2 mg QD, or placebo. The schedule of assessments comprised a 28-day screening period, a 12-week induction treatment period, and a 4-week follow-up period. The initial sample size population goal was to recruit 96 patients; however, recruitment was terminated early due to difficulties in patient recruitment, following an agreement in April 2023 with the Pharmaceuticals and Medical Devices Agency. At the time of recruitment termination, 54 patients had been successfully recruited and had initiated treatment, having received at least 1 dose of study treatment. These patients formed the full analysis set and safety analysis set. The modified full analysis set included patients with a baseline measurement and at least one post-randomization measurement, and varied depending on the outcome measure.

2. Key Inclusion Criteria

The inclusion criteria required that patients be of Japanese ancestry (i.e., both parents and 4 grandparents are/were of Japanese descent) and between 18–80 years old. Patients needed to have been diagnosed with UC ≥ 3 months prior to screening, with diagnosis confirmed by endoscopic and histologic evidence; active UC had to have been confirmed by endoscopy with ≥ 10 cm rectal involvement. Patients were required to have moderately to severely active UC defined as MMS of 4 to 9, including an endoscopic subscore (ES) ≥ 2 and rectal bleeding subscore (RBS) ≥ 1. Eligible patients were required to have a prior inadequate response, loss of response, or intolerance, to at least one of: (1) conventional therapy (oral 5-ASA compounds, corticosteroids, thiopurines), or (2) biologic or JAKi therapies for UC. Patients who had an inadequate response to biologic or JAKi therapies approved in Japan were permitted to have also received prior conventional therapies.

3. Key Exclusion Criteria

Patients were not eligible for enrolment if they had severe colitis as evidenced by (1) physician judgement that the patient was likely to require hospitalization for medical care or surgical intervention of any kind for UC within 12 weeks following randomization; (2) current evidence of fulminant colitis, toxic megacolon or recent history (within last 6 months) of toxic megacolon, or bowel perforation; or (3) previous total or partial colectomy. Patients were also excluded if they had a diagnosis of Crohn’s disease or isolated proctitis (defined as proctitis with < 10 cm rectal involvement), microscopic colitis or infectious colitis, a history of hospitalization for exacerbation of UC requiring intravenous steroids within 12 weeks of screening, a positive assay or stool culture for pathogens (or positive test for Clostridioides difficile toxin at screening), or pregnancy, lactation or positive serum β-human chorionic gonadotropin measured during screening.

During the study, patients were permitted to receive a therapeutic dose of an oral 5 ASA, provided the dose had been stable for ≥ 2 weeks immediately prior to randomization, an oral corticosteroid (prednisone at a stable dose of ≤ 20 mg QD, or equivalent corticosteroid), provided the dose had been stable for 4 weeks immediately prior to the screening endoscopy assessment, or probiotics (e.g., Saccharomyces boulardii), provided the dose had been stable for the 2 weeks immediately prior to randomization.

4. Efficacy Endpoints

The primary efficacy endpoint was the proportion of patients achieving clinical remission, defined as patients with stool frequency subscore (SFS) = 0 (or = 1 with a ≥ 1-point decrease from baseline), RBS = 0, and ES ≤ 1 (excluding friability), at week 12. The secondary efficacy endpoints included the proportion of patients achieving endoscopic improvement (defined as ES ≤ 1 [excluding friability]), symptomatic remission (defined as SFS = 0 [or = 1 with a ≥ 1-point decrease from baseline] and RBS = 0), endoscopic improvement-histologic remission (EIHR; defined as ES ≤ 1 [excluding friability] with histologic remission [Geboes Index score < 2.0]), clinical response (defined as a ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1), and endoscopic normalization (defined as ES = 0), all at week 12.

5. Evaluation of Etrasimod Pharmacokinetics

Plasma concentrations of etrasimod were assessed at several time points. Samples were collected pre-dose and 4 hours post-dose on week 0/day 1. Pre-dose (trough) samples were also collected at weeks 2, 4, 8, and 12, as well as at 2-week and 4-week follow-up visits.

6. Other Efficacy Endpoints

Exploratory efficacy endpoints included the proportion of patients achieving symptomatic remission (defined as SFS = 0 [or = 1 with a ≥ 1-point decrease from baseline] and RBS = 0; at weeks 2, 4, and 8), complete symptomatic remission (defined as SFS = 0 and RBS = 0; at weeks 2, 4, 8, and 12), noninvasive clinical response (defined as a ≥ 30% decrease from baseline in composite RBS and SFS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1; at weeks 2, 4, 8, and 12), and symptomatic response (defined as a ≥ 30% decrease from baseline in composite RBS and SFS; at weeks 2, 4, 8, and 12). Moreover, the proportion of patients with clinical remission (defined as a total Mayo score [TMS] ≤ 2 points with no individual subscore > 1-point) and response (defined as a ≥ 3-point and ≥ 30% decrease from baseline in TMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1) using TMS, histologic improvement and remission (defined by the Geboes Index [improvement: score < 3.1; remission: score < 2.0], Robarts Histopathology Index [RHI] and Nancy Histological Index [NHI]), and improvements in extraintestinal manifestations, at week 12, were also assessed.

7. Safety Assessments

Safety was assessed by monitoring TEAEs, clinical laboratory findings, 12-lead electrocardiograms (ECGs), physical examinations, vital signs, pulmonary function tests, and ophthalmoscopy and optical coherence tomography (OCT). Associated laboratory parameters, such as hepatic enzymes, renal function, and hematology values were collected. Patients reported TEAEs at any time, with the reporting period extending up to 30 days after the last administration of study treatment. All TEAEs, including their severity and relationship to study treatment, were recorded on the electronic Case Report Form. Any serious TEAEs had to be reported to the designated safety contact within 24 hours of becoming aware of the event. Incidence of selected adverse events (AEs) of interest are reported. The AEs of special interest (AESI) reported have been associated with the safety profile of S1P receptor modulators, including etrasimod, that may have relevance to the management of UC. These include cardiovascular events, macular edema, and infections, as reported previously [17].

The safety endpoints in the study included the incidence and severity of TEAEs, the incidence and severity of laboratory abnormalities and change from baseline in laboratory values (including hematology, serum chemistry, coagulation, and urinalysis), and the incidence of clinically significant 12-lead ECG and vital sign abnormalities and changes from baseline.

8. Other Assessments

1) Biomarker Assessment

The biomarker endpoints of the trial included change from baseline in levels of fecal calprotectin (fCAL; measured with the fluoroenzyme immunoassays methodology, using the EliA Calprotectin 2 kit where a value ≤ 50.00 mg/kg was considered normal), high sensitivity C-reactive protein (hsCRP; a value of < 5.00 mg/L was considered normal), and mean change and percentage change from baseline in absolute lymphocyte count (ALC; a range of 1.02 to 3.36 × 10⁹/L was considered normal), assessed at weeks 2, 4, 8, and 12. C_{trough,ss,W2–W12} was defined as the steady-state trough plasma concentration of etrasimod week 2–12.

2) Health-Related Patient-Reported Outcomes

Health-related patient-reported outcome endpoints included scores and change from baseline at week 12 for UC Patient-Reported Outcomes Signs and Symptoms (if available) and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), version 2, physical and mental component summary and domain scores, the proportion of patients with UC-related hospitalizations, and the proportion of patients requiring UC-related surgeries, including colectomy.

9. Statistical Analysis

The primary and secondary efficacy analyses were based on the full analysis set, patients with a baseline MMS of 5 to 9, per regulatory requirement. Supplemental analyses were repeated in the per protocol set, patients with an actual baseline MMS of 5 to 9 for the primary efficacy endpoint, in the full analysis set of patients with a baseline MMS of 4 to 9 for primary and secondary efficacy endpoints, and in the modified full analysis set of patients with an actual baseline MMS of 5 to 9 for secondary efficacy endpoints. Results were expressed as the number and proportion of patients meeting corresponding endpoints, difference in remission percentages and associated 95% confidence intervals (95% CIs) between patients treated with etrasimod compared with placebo, odds ratio and associated 95% CIs. Patients missing an assessment at the specified analysis visits were considered nonresponders. The pharmacokinetic data were summarized by time and by treatment group.

The safety data were listed and summarized by treatment group. All TEAEs were coded using Medical Dictionary for Regulatory Activities, version 25.1, and tabulated by System Organ Class and Preferred Term. Associated laboratory parameters, such as hepatic enzymes, renal function, and hematology values were grouped and presented together. Individual patient values were listed, and values outside of the standard reference range were flagged. The change from baseline for each of the vital signs and 12-lead ECG parameters were summarized. Incidence of abnormal vital sign parameters and outlier ECG results were tabulated.

10. Ethical Considerations

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by an Institutional Review Board at each investigative site. All patients provided written informed consent.

RESULTS

1. Demographics and Baseline Disease Characteristics

Patient disposition is summarized in Fig. 1. In total, 54 patients were included in the full analysis set, of which, 18 received placebo (33.3%), 17 received etrasimod 1 mg QD (31.5%), and 19 received etrasimod 2 mg QD (35.2%).

Patient demographics and baseline characteristics were generally well balanced across treatment groups. Most patients fell within the age range of 18–64 years; the mean ± standard deviation (SD) age for all patients was 43.3 ± 12.5 years (Table 1). Males made up 72.2%, 64.7%, and 57.9% in the placebo, etrasimod 1 mg, and etrasimod 2 mg groups, respectively.

Proctosigmoiditis/left-sided colitis was reported in a total of 23 patients (42.6%), pancolitis was reported in 21 patients (38.9%), and proctitis was reported in a total of 10 patients (18.5%). The baseline MMS and TMS were generally balanced across treatment groups, with mean ± SD values of 5.7 ± 1.4, 6.2 ± 1.2, and 6.3 ± 1.2 for MMS, and 7.5 ± 1.5, 8.0 ± 1.5, and 8.1 ± 1.4 for TMS, in patients receiving placebo, etrasimod 1 mg, and etrasimod 2 mg, respectively. The mean ± SD duration of UC for all patients was 6.4 ± 6.8 years, which was balanced across treatment groups (Table 1).

The majority of patients (96.3%) had been previously treated with oral 5-ASA compounds. Corticosteroids were used by 46 patients over the last 12 months. Prior use of biologics or JAKi was low among patients; 5 (9.3%) were previously treated with tumor necrosis factor inhibitors, 4 (7.4%) with anti-integrin antibodies, 3 (5.6%) with JAKi, and 1 (1.9%) with anti-IL-12/23 antibodies. At study baseline, 11 patients (20.4%) were receiving corticosteroid treatment.

2. Efficacy Endpoints

Among patients in the full analysis set with a baseline MMS of 5 to 9, no patients achieved clinical remission at week 12 in the placebo group (n = 14). However, 1 patient in the etrasimod 1 mg group (n = 15, 6.7%) and 5 patients in the etrasimod 2 mg group (n = 19, 26.3%) achieved clinical remission at week 12 (Fig. 2A). The percentage difference from placebo was 6.7% (95% CI, –6.0 to 19.3) and 26.3% (95% CI, 6.5 to 46.1) for the etrasimod 1 mg and etrasimod 2 mg groups, respectively. These results indicated that a numerically higher proportion of patients achieved clinical remission at week 12 in patients treated with etrasimod compared to placebo. Similar results were obtained in the corresponding supplementary analyses of patients with MMS of 4 to 9, the per protocol set, and the modified full analysis set.

Endoscopic improvement at week 12 was achieved by no patients in the placebo group (n = 14), 1 patient in the etrasimod 1 mg group (n = 15, 6.7%), and 5 patients in the etrasimod 2 mg group (n = 19, 26.3%) (Fig. 2B). The percentage difference from placebo was 6.7% (95% CI, –6.0 to 19.3) and 26.3% (95% CI, 6.5 to 46.1) for the etrasimod 1 mg and etrasimod 2 mg group, respectively.

Symptomatic remission at week 12 was achieved by no patients in the placebo group (n = 14), 3 patients in the etrasimod 1 mg group (n = 15, 20.0%), and 6 patients in the etrasimod 2 mg group (n = 19, 31.6%) (Fig. 2B). The percentage difference from placebo was 20.0% (95% CI, –0.2 to 40.2) and 31.6% (95% CI, 10.7 to 52.5) for the etrasimod 1 mg and etrasimod 2 mg group, respectively.

EIHR at week 12 was achieved by no patients in the placebo group (n = 14), 1 patient in the etrasimod 1 mg group (n = 15, 6.7%), and 1 patient in the etrasimod 2 mg group (n = 19, 5.3%) (Fig. 2B). The percentage difference from placebo was 6.7% (95% CI, –6.0 to 19.3) and 5.3% (95% CI, –4.8 to 15.3) for the etrasimod 1 mg and etrasimod 2 mg group, respectively.

One patient in the placebo group (n = 14, 7.1%), 5 patients in the etrasimod 1 mg group (n = 15, 33.3%), and 10 patients in the etrasimod 2 mg group (n = 19, 52.6%) achieved clinical response at week 12 (Fig. 2B). The percentage difference from placebo was 26.2% (95% CI, –1.2 to 53.6) and 45.5% (95% CI, 19.3 to 71.7) for the etrasimod 1 mg and etrasimod 2 mg group, respectively.

No patients achieved endoscopic normalization at week 12 in the placebo, etrasimod 1 mg, or etrasimod 2 mg treatment groups (data not shown).

3. Other Efficacy Endpoints

Other efficacy endpoints were assessed using the modified full analysis set: patients with an actual baseline MMS of 5 to 9. The proportion of patients achieving symptomatic remission through week 8 was numerically higher in patients treated with etrasimod compared with placebo, except for at week 2, when the proportion of patients achieving symptomatic remission in the etrasimod 2 mg and placebo groups was 0 (Fig. 3A). At week 8, 3 patients in the etrasimod 1 mg group (n = 15, 20.0%) and 7 patients in the etrasimod 2 mg group (n = 19, 36.8%) achieved symptomatic remission, compared with no patients receiving placebo (n = 14) (Fig. 3A). The proportion of patients achieving complete symptomatic remission was greater among those receiving etrasimod compared with placebo, except for at week 4. At week 12, 1 patient in the etrasimod 1 mg group (n = 15, 6.7%) and 3 patients in the etrasimod 2 mg group (n = 19, 15.8%) achieved complete symptomatic remission, compared with no patients receiving placebo (n = 14) (Fig. 3B). At week 12, 2 patients in the placebo group (n = 14, 14.3%), 10 patients in the etrasimod 1 mg group (n = 15, 66.7%), and 13 patients in the etrasimod 2 mg group (n = 19, 68.4%) achieved noninvasive clinical response (Fig. 3C). At week 12, 2 patients in the placebo group (n = 14, 14.3%), 10 patients in the etrasimod 1 mg group (n = 15, 66.7%), and 13 patients in the etrasimod 2 mg group (n = 19, 68.4%) achieved symptomatic response (Fig. 3D). At week 12, clinical remission using TMS was achieved by 1 patient in the etrasimod 1 mg group (n = 15, 6.7%), 4 patients in the etrasimod 2 mg group (n = 19, 21.1%), and no patients in the placebo group (n = 14), whilst clinical response using TMS was achieved by 6 patients in the etrasimod 1 mg group (n = 15, 40.0%), 8 patients in the etrasimod 2 mg group (n = 19, 42.1%), and 1 patient in the placebo group (n = 14, 7.1%) (Fig. 3E). At week 12, a numerically greater proportion of patients in the etrasimod 2 mg group achieved histologic improvement, defined by Geboes Index, RHI, and NHI scores, compared with etrasimod 1 mg and placebo (Fig. 3F). At week 12, histologic remission, defined by Geboes Index, RHI, and NHI scores, was each achieved by 3 patients in the etrasimod 1 mg group (n = 15, 20.0%) and in 2, 5, and 5 patients in the etrasimod 2 mg group (n = 19; 10.5%, 26.3%, and 26.3%, respectively). No patients receiving placebo achieved histologic remission at week 12 (Fig. 3F). Of all patients with extraintestinal manifestations at baseline, no patients had improvement at week 12 across treatment groups (data not shown).

4. Safety

Overall, both etrasimod doses were well tolerated throughout the study. TEAEs were experienced by 9 patients in the etrasimod 1 mg group (n = 17, 52.9%) and by 13 patients in the etrasimod 2 mg group (n = 19, 68.4%), compared with 10 patients in the placebo group (n = 18, 55.6%) (Table 2). Of these, 2 (n = 17; 11.8%), 4 (n = 19; 21.1%), and 1 (n = 18; 5.6%) patients in the etrasimod 1 mg, etrasimod 2 mg, and placebo groups, respectively, experienced TEAEs that were considered related to the study treatment by the investigator. The most common System Organ Classes of all-causality TEAEs in > 10% of all patients treated with etrasimod (1 mg and 2 mg combined) were gastrointestinal disorders (13.9%), infections and infestations (13.9%), general disorders and administration site conditions (11.1%) and investigations (11.1%). All TEAEs were mild to moderate (grades 1 and 2), with no severe, life-threatening, or death-related AEs (grades 3, 4, or 5) reported in any of the treatment groups. There were no discontinuations due to TEAEs in either etrasimod group; TEAEs of UC (flare/worsening) led to the discontinuation of study treatment in 2 patients in the placebo group (n = 18; 11.1%) (Table 2). No patients interrupted study treatment due to TEAEs, including for ALC < 200 cells/µL.

No all-causality serious AEs were reported in any of the treatment groups. TEAEs meeting the criteria for AESI were reported in 1 patient receiving placebo (herpes zoster; n = 18; 5.6%), no patients receiving etrasimod 1 mg (n = 17), and 1 patient receiving etrasimod 2 mg (bradycardia; n = 19; 5.3%) (Table 2).

The event of bradycardia experienced by 1 (5.3%) patient receiving etrasimod 2 mg was grade 1, transient, asymptomatic, and began and resolved on Study Day 1. The patient had a heart rate of 76 beats per minute (bpm) at baseline and 55 bpm, 42 bpm, 44 bpm, and 69 bpm at 1-, 2-, 3-, and 4-hours post-dose on Study Day 1. Other than sinus bradycardia (< 50 bpm), no other abnormal ECG parameters or cardiac-related symptoms were reported; this event was considered probably related to study treatment by the investigator, although no action was taken regarding study treatment, and no medication was given in response to the event.

The event of herpes zoster experienced by 1 (5.6%) patient receiving placebo was grade 1 and non-serious. It began on Study Day 37 and was not resolved by the time of the last follow-up visit. It was not considered related to study treatment by the investigator, and no action was taken regarding study treatment in response to the event.

No events of macular edema, progressive multifocal leukoencephalopathy, posterior reversible encephalopathy syndrome, malignancies, or severe infections were reported during the study.

In terms of AEs of interest, among 19 patients receiving etrasimod 2 mg, 1 patient (5.3%) experienced alanine aminotransferase increased and 1 patient (5.3%) experienced abnormal liver function. Both were considered treatment-related, although no action was taken regarding study treatment in response to these events. No patients met Hy’s Law criteria for potential drug-induced liver injury.

1) Other Safety Evaluations

Patients treated with etrasimod 1 mg and 2 mg demonstrated a decrease in heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) on day 1. The lowest mean SBP, compared with a pre-dose SBP on day 1 of –9.5 and –10.9 mmHg, was observed at 2 hours post-dose for etrasimod 1 mg and 3 hours post-dose for etrasimod 2 mg, respectively. The lowest mean DBP, compared with a pre-dose DBP on day 1 of –7.6 and –11.9 mmHg, was observed at 3 hours post-dose for both etrasimod 1 mg and 2 mg, respectively. The mean ± SD time from the first dose of treatment to the minimum heart rate on day 1 was 2.42 ± 1.09 hours and 2.61 ± 0.74 hours for the etrasimod 1 mg and etrasimod 2 mg groups, respectively. The incidence of markedly abnormal vital signs (SBP ≤ 90 or > 150 mmHg, DBP ≤ 50 or > 90 mmHg, or heart rate < 40, < 50 or > 100 bpm) was low post-day 1. The incidence of predefined ECG abnormalities was low and comparable across treatment groups, with 1 patient in the etrasimod 2 mg group experiencing a non-serious TEAE of bradycardia on day 1. This patient had a baseline heart rate of 76 bpm and a minimum heart rate of 42 bpm at 2 hours post-dose. The patient met the per protocol designated discharge criteria at 4 hours post-dose, and therefore no extended cardiac monitoring was performed. They did not experience any cardiac-related symptoms and continued with the study treatment. No other TEAEs based on ECG findings were reported. During the study, first-degree atrioventricular (AV) block was reported in 1 patient in the etrasimod 1 mg group (n = 17, 5.9%) on day 1 pre-dose, and in 1 patient in the etrasimod 2 mg group (n = 19, 5.3%) on day 1 post-dose. No second-degree or higher AV block was reported.

All patients across the placebo, etrasimod 1 mg, and etrasimod 2 mg groups underwent OCT exams at baseline and week 12. No clinically meaningful differences were observed with OCT examinations across treatment groups when comparing the results at baseline and week 12. There were no events of macular edema reported in the study and none of the 4 ophthalmic-related TEAEs were considered AESIs. In the etrasimod 1 mg group, 1 patient experienced grade 1 non-serious AEs of cataract and epiretinal membrane. In the etrasimod 2 mg group, 1 patient experienced a grade 1 non-serious AE of vitreous floaters. The patient continued on study treatment, with no dose interruption. Another patient in the etrasimod 2 mg group experienced a grade 2 non-serious AE of dry eye. All 4 events were deemed not to be related to the study treatment by the investigator.

The proportion of patients with pulmonary function test abnormalities was low in all treatment groups. One patient in the etrasimod 1 mg group had an abnormal pulmonary function test, which was not considered clinically significant by the investigator.

2) Clinical Laboratory Evaluation

In the safety analysis set, hematology and coagulation parameters, including hemoglobin, platelets, basophils, eosinophils, erythrocytes, monocytes, neutrophils, and coagulation factors, generally remained within the normal limits throughout the study period (Supplementary Table 1). Following treatment with etrasimod, a reduction in mean lymphocyte counts from baseline was observed for etrasimod 1 mg and etrasimod 2 mg groups at each measured week (Supplementary Table 1). The lowest mean ± SD lymphocyte count of 0.71 ± 0.23 × 10⁹/L and 0.61 ± 0.28 × 10⁹/L in the etrasimod 1 mg and 2 mg groups respectively, was measured at week 12, indicating a consistent and dose-dependent effect of etrasimod on lymphocyte counts (Supplementary Table 1). No TEAEs of decreased lymphocyte count were reported during the study.

Treatment with etrasimod did not substantially alter urinalysis parameters (Supplementary Table 1). Urinalysis results, over the study duration, showed that the majority of patients across all treatment groups tested negative for protein in urine and fell within the normal range for specific gravity and pH levels.

5. Pharmacokinetics

Following oral administration of etrasimod, steady state was achieved by week 2 and maintained through week 12. Apparent dose-proportional C_{trough,ss,W2–W12} was observed between etrasimod 1 mg and etrasimod 2 mg dose levels, with geometric means of 30.30 ng/mL and 71.60 ng/mL, respectively.

6. Other Assessments

1) Biomarker Assessment

Mean ± SD changes from baseline in ALC in the full analysis set with an actual baseline MMS of 5 to 9 are shown in Fig. 4A. At week 2, the mean ± SD percent change from baseline in ALC was 12.1% (28.0%) in the placebo group, –30.6% (19.8%) in the etrasimod 1 mg group, and –47.4% (16.2%) in the etrasimod 2 mg group (Fig. 4B). At week 4, the mean ± SD percent change from baseline in ALC was 20.0% ± 35.1% in the placebo group, –39.2% ± 16.8% in the etrasimod 1 mg group, and –53.4% ± 17.4% in the etrasimod 2 mg group. At week 8, the mean ± SD percent change from baseline in ALC was 19.1% ± 24.3% in the placebo group, –30.0% ± 40.5% in the etrasimod 1 mg group, and –48.3% ± 22.1% in the etrasimod 2 mg group. At week 12, the mean ± SD percent change from baseline in ALC was 17.0% ± 27.3% in the placebo group, –36.6% ± 33.2% in the etrasimod 1 mg group, and –54.8% ± 16.7% in the etrasimod 2 mg group.

At baseline, median fCAL was 669.3 mg/kg in the placebo group, 961.2 mg/kg in the etrasimod 1 mg group, and 1,041.9 mg/kg in the etrasimod 2 mg group. At week 12, the median change from baseline in fCAL was 863.1 mg/kg in the placebo group, and 468.0 mg/kg and –584.5 mg/kg in the etrasimod 1 mg and etrasimod 2 mg groups, respectively (Supplementary Table 2).

At baseline, median hsCRP was 1.3 mg/L in the placebo group, 1.6 mg/L in the etrasimod 1 mg group, and 1.7 mg/L in the etrasimod 2 mg group. At week 12, the median change from baseline in hsCRP was 0.1 mg/L in the placebo group, –0.5 mg/L in the etrasimod 1 mg group, and –1.3 mg/L in the etrasimod 2 mg group (Supplementary Table 2).

2) Health-Related Patient-Reported Outcomes

In the modified full analysis set with an actual baseline MMS of 5 to 9, lower UC Patient-Reported Outcomes Signs and Symptoms scores were reported in patients receiving etrasimod compared with placebo. Numerically greater changes in bowel movement signs and symptoms score, and functional symptoms score were observed at week 12 in patients receiving etrasimod. Among patients treated with etrasimod 2 mg, but not in patients treated with etrasimod 1 mg, there were greater improvements in the physical component summary and mental component summary scores of the Medical Outcomes Study SF-36. Patients treated with etrasimod 2 mg demonstrated greater improvement in all 8 SF-36 individual subscores, compared with placebo, except for physical functioning score. The SF-36 health utility index score at week 12 was comparable between treatment groups. There were no UC-related hospitalizations or surgeries in any of the treatment groups (Supplementary Table 3).

DISCUSSION

Here, we describe the results of the first phase 2 dose-ranging trial conducted in Japan showing that etrasimod 1 mg and 2 mg QD, for up to 12 weeks, was overall safe and effective in treating Japanese patients with moderately to severely active UC. These findings contribute to the understanding of appropriate dosing of etrasimod in the subset of Japanese patients with UC, and add to the data available on the broader global population from the phase 2 OASIS trial and phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials.

The primary endpoint of the trial, clinical remission at week 12, was met by a greater proportion of patients in the etrasimod 2 mg group than in the etrasimod 1 mg or placebo group, which may indicate a trend of dose proportionality. Furthermore, a greater proportion of patients receiving etrasimod 2 mg achieved all secondary endpoints, with the exception of endoscopic normalization and EIHR, compared with etrasimod 1 mg and placebo; etrasimod thus demonstrated an improvement in the signs and symptoms of UC in these patients with moderately to severely active UC. These findings align with the existing body of literature demonstrating the efficacy of etrasimod in UC, which report significant improvements in clinical and endoscopic outcomes following treatment with etrasimod 2 mg QD [17]. Furthermore, our results are also consistent with a global dose-ranging study of etrasimod 2 mg and etrasimod 1 mg QD, in which etrasimod 2 mg QD was more efficacious in primary and secondary endpoint achievement in a broader population of patients with UC [15]. However, further research is needed to compare etrasimod to other treatments for UC.

Certain AEs, including first-dose bradycardia or AV block and decreased lymphocyte counts are known adverse effects of S1P receptor modulators, such as etrasimod [17,19]. The safety profile of etrasimod in Japanese patients was similar to the profile identified in the global etrasimod clinical population with the incidence and severity of TEAEs experienced with etrasimod consistent with the existing literature [15,17]; all TEAEs in the current trial were of mild to moderate severity. The safety profile of etrasimod appears to be similar among Japanese patients when compared with other UC treatments, such as vedolizumab and ozanimod [19,20]. Additional characterization of the safety profile of etrasimod, including in Japanese patients, is ongoing, with a long-term OLE trial of up to 5 years’ duration in patients with moderately to severely active UC. This will allow for further global and Japanese-specific data.

The pharmacodynamic data from the trial revealed a reduction in ALC over time in patients receiving etrasimod. This is consistent with the known pharmacodynamic properties of S1P receptor modulators, including etrasimod [17,21], which modulates the activity of specific S1P receptor subtypes, reducing circulating lymphocytes and potentially dampening the inflammatory response in UC [22]. In summary, the results from this trial offer important pharmacodynamic insights into etrasimod, affirming its efficacy in Japanese patients with moderately to severely active UC, and shedding light on its mechanism of action and potential side effects.

Limitations of this trial were primarily related to the size of the patient sample, which was smaller than that used in the phase 2 OASIS trial [16] and the recruitment process. The small sample size may have allowed for the introduction of bias and limited the statistical power of the trial. This could potentially have affected the reliability and applicability of the results, the demographic and clinical profile of the study population, and the observed efficacy and safety outcomes. Similarly, the safety analysis may have been influenced by the smaller sample size and early termination of recruitment, per agreement with the Pharmaceuticals and Medical Devices Agency, potentially affecting the incidence and characterization of TEAEs.

In conclusion, in this limited number of patients, etrasimod 2 mg QD appeared to be efficacious and safe in Japanese patients with moderately to severely active UC; a numerically greater proportion of patients receiving etrasimod 2 mg achieved primary efficacy and most secondary efficacy endpoints, compared with those receiving etrasimod 1 mg and placebo. Pharmacokinetic data showed dose-proportional steady-state plasma trough exposure of etrasimod among patients receiving etrasimod 1 mg or 2 mg QD.

NOTES

Funding Source

This study was sponsored by Pfizer Inc.

Conflict of Interest

Takeuchi K has received lecture/speaker fees from AbbVie, Celltrion, EA Pharma, Janssen Pharmaceutical, Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Nippon Shinyaku, Pfizer Inc., Takeda Pharmaceuticals, and Zeria Pharmaceutical Co. Ltd.; healthcare and consultancy/advisory fees from Thermo Fisher Diagnostics K.K; and grant/research support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, EA Pharma, IQVIA, Janssen Pharmaceutical, Lilly, Pfizer, Shin Nippon Biomedical Laboratories Ltd, and Takeda Pharmaceuticals. Nakase H has received research support from AbbVie GK, AYUMI Pharmaceutical, EA Pharma, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Otsuka Pharmaceutical, PENTAX Medical, and Taiho Pharmaceutical; lecture fees from AbbVie GK, Gilead Sciences, Janssen Pharmaceutical, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Pfizer, Takeda Pharmaceuticals, and Viatris Inc; and is an endowed chair for JIMRO, Kyorin Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., and Mochida Pharmaceutical Co. Ltd. Hisamatsu T has received grant support from AbbVie GK, Boston Scientific Corporation, EA Pharma, JIMRO, Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceuticals, and Zeria Pharmaceutical Co. Ltd.; consultant fees from AbbVie GK, Bristol-Myers Squibb, EA Pharma, Eli Lilly, Gilead Sciences, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma, Janssen Pharmaceutical, JIMRO, Kissei Pharmaceutical Co. Ltd, Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Pfizer Inc, and Takeda Pharmaceuticals. Matsuoka K has received research support from AbbVie, EA Pharma, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., and Nippon Kayaku Co. Ltd.; and lecture fees from AbbVie, Celltrion, Covidien, EA Pharma, Eli Lilly, Gilead Sciences, Janssen Pharmaceutical, JIMRO, Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Pfizer Inc., Takeda Pharmaceuticals, and Zeria Pharmaceutical Co. Ltd. Arai S and Fukuta K are employees of Pfizer Japan Inc. and shareholders of Pfizer Inc. Yuasa Y is an employee of Pfizer R&D Japan and shareholder of Pfizer Inc. Oe M and Ono R are employees of Pfizer R&D Japan. Keating M is an employee and shareholder of Pfizer Inc. Gu G is an employee of Pfizer and owns Pfizer stocks. Lazin K is an employee of Pfizer AG and a shareholder of Pfizer Inc. McDonnell A was an employee of Pfizer Ltd. and shareholder of Pfizer Inc. at the time of the analysis. Hibi T received consultant fees from AbbVie GK, Celltrion, EA Pharma, Eli Lilly, Gilead Sciences, Mitsubishi Tanabe Pharma, Takeda Pharmaceuticals, and Zeria Pharmaceutical Co. Ltd.; grant/research support from AbbVie GK, Celltrion, EA Pharma, Eli Lilly, Gilead Sciences, Mitsubishi Tanabe Pharma, Takeda Pharmaceuticals, and Zeria Pharmaceutical Co. Ltd.; lecture/speaker fees from AbbVie GK, Activaid, Alfresa Pharma Corporation, Bristol-Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical, JMDC Inc., Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceuticals; and scholarship contributions from Alfresa Pharma Corporation, JIMRO, Kyorin Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd. Except for that, no potential conflict of interest relevant to this article was reported.

Nakase H, Matsuoka K, and Hibi T are editorial board members of the journal but were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

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-dataand-results for more information.

Author Contributions

Conceptualization: Keating M. Data curation: Ono R. Formal analysis: Oe M, Ono R. Funding acquisition: Keating M, Arai S. Investigation: Yuasa H, Oe M, Ono R, Keating M, Gu G, Lazin K. Methodology: Keating M, Arai S, Yuasa H, Oe M, Ono R, Gu G, Lazin K. Project administration: Arai S, Fukuta K. Software: Ono R. Resources: Keating M, Arai S. Supervision: Arai S, Fukuta K. Validation: Oe M, Ono R. Visualization: all authors. Writing – original draft: all authors. Writing – review & editing: all authors. Approval of final manuscript: all authors.

Additional Contributions

The authors would like to thank IQVIA Japan for patient safety monitoring. Medical writing support, under the direction of the authors, was provided by Karen Thompson, PhD, and Amy Churchlow, MSc, 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;175:1298-1304). During the preparation of this work the authors used Pfizer’s generative artificial intelligence tool MAIA to assist with writing the manuscript first draft. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Supplementary Material

Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).

Supplementary Table 1.

Clinical Laboratory Parameters (Safety Analysis Set)

ir-2024-00213-Supplementary-Table-1.pdf

Supplementary Table 2.

fCAL and hsCRP at Baseline and Change from Baseline at Week 12 (Full Analysis Set and Actual Baseline MMS of 5 to 9)

ir-2024-00213-Supplementary-Table-2.pdf

Supplementary Table 3.

SF-36 Scores at Baseline at Week 12 (Modified Full Analysis Set and Actual Baseline MMS of 5 to 9)

ir-2024-00213-Supplementary-Table-3.pdf

Fig. 1.

Patient disposition. Patients who discontinued the study or did not continue to the OLE had follow-up visits at week 2 and 4. aThe full analysis set comprised all randomly assigned patients who received at least one dose of study treatment. QD, once daily; OLE, openlabel extension; TEAE, treatment-emergent adverse event.

Fig. 2.

The proportion of patients achieving (A) the primary endpoint of clinical remission and (B) secondary efficacy endpoints at week 12 (full analysis set and actual baseline MMS of 5 to 9). Percentages were based on the number of patients in the analysis set. Patients missing an assessment at the specified analysis visits were considered nonresponders. ^aClinical remission was defined as patients with SFS=0 (or =1 with a ≥1-point decrease from baseline), RBS=0, and ES ≤1 (excluding friability); ^bEndoscopic improvement was defined as patients with ES ≤1; ^cSymptomatic remission was defined as patients with SFS=0 (or =1 with a ≥1-point decrease from baseline) and RBS=0; ^dEIHR was defined as patients with ES ≤1 with histologic remission measured by a Geboes Index score <2.0; ^eClinical response was defined as patients with a ≥2-point and ≥30% decrease from baseline in MMS, a≥1-point decrease from baseline in RBS or an absolute RBS ≤1. MMS, modified Mayo score; SFS, stool frequency subscore; RBS, rectal bleeding subscore; ES, endoscopic subscore; EIHR, endoscopic improvement-histologic remission; QD, once daily.

Fig. 3.

The proportion of patients achieving other efficacy endpoints, including (A) symptomatic remission, (B) complete symptomatic remission, (C) noninvasive clinical response, (D) symptomatic response, (E) clinical remission and clinical response using TMS at week 12, and (F) histologic improvement/remission at week 12 (modified full analysis set and actual baseline MMS of 5 to 9). QD, once daily; TMS, total Mayo score; MMS, modified Mayo score; RHI, Robarts Histopathology Index; NHI, Nancy Histological Index.

Fig. 4.

Mean (A) change from baseline and (B) percentage change from baseline in ALC (full analysis set and actual baseline MMS 5 to 9). Baseline is the last measurement taken prior to the first dose of study treatment. Only patients with a baseline MMS score between 5 and 9 are included. A range of 1.02 to 3.36×10⁹/L was considered normal. ALC, absolute lymphocyte count; MMS, modified Mayo score; QD, once daily; SD, standard deviation.

Table 1.

Demographics and Baseline Characteristics (Full Analysis Set)

Characteristic	Placebo QD (n = 18)	Etrasimod 1 mg QD (n = 17)	Etrasimod 2 mg QD (n = 19)	Total (n = 54)
Age on consent (yr), mean ± SD	38.5 ± 9.3	41.6 ± 14.0	49.5 ± 11.6	43.3 ± 12.5
Male sex, No. (%)	13 (72.2)	11 (64.7)	11 (57.9)	35 (64.8)
BMI (kg/m²), mean ± SD	21.5 ± 3.6	23.8 ± 5.1	24.0 ± 4.1	23.1 ± 4.4
Tobacco use (yes), No. (%)	8 (44.4)	6 (35.3)	5 (26.3)	19 (35.2)
Prior biologic/JAKi therapy use (yes), No. (%)	5 (27.8)	2 (11.8)	3 (15.8)	10 (18.5)
Baseline corticosteroid use-reported (yes), No. (%)	3 (16.7)	3 (17.6)	5 (26.3)	11 (20.4)
Prior failure of TNFi (yes), No. (%)	1 (5.6)	2 (11.8)	1 (5.3)	4 (7.4)
Prior failure of TNFi or vedolizumab (yes), No. (%)	1 (5.6)	2 (11.8)	3 (15.8)	6 (11.1)
Prior failure of oral 5-ASA only (yes), No. (%)	4 (22.2)	1 (5.9)	1 (5.3)	6 (11.1)
Extent of disease, No. (%)^a
Proctosigmoiditis/left-sided colitis	12 (66.7)	4 (23.5)	7 (36.8)	23 (42.6)
Pancolitis	4 (22.2)	10 (58.8)	7 (36.8)	21 (38.9)
Isolated proctitis	2 (11.1)	3 (17.6)	5 (26.3)	10 (18.5)
Duration of UC (yr), mean ± SD	6.6 ± 6.1	6.4 ± 6.0	6.1 ± 8.2	6.4 ± 6.8
Baseline MMS, mean ± SD	5.7 ± 1.4	6.2 ± 1.2	6.3 ± 1.2	6.1 ± 1.3
MMS group-reported (4-6), No. (%)	12 (66.7)	9 (52.9)	12 (63.2)	33 (61.1)
MMS group-reported (7-9), No. (%)	6 (33.3)	8 (47.1)	7 (36.8)	21 (38.9)

^a As per data recorded in the Case Report Form.

QD, once daily; SD, standard deviation; BMI, body mass index; JAKi, Janus kinase inhibitor; TNFi, tumor necrosis factor inhibitor; 5-ASA, 5-aminosalicylates; UC, ulcerative colitis; MMS, modified Mayo score.

Table 2.

Summary of TEAEs and Most Frequent TEAEs (Safety Analysis Set)

Category	Placebo QD (n = 18)	Etrasimod 1 mg QD (n = 17)	Etrasimod 2 mg QD (n = 19)	Etrasimod total (n = 36)
Any TEAEs^a	10 (55.6)	9 (52.9)	13 (68.4)	22 (61.1)
Related TEAEs^b	1 (5.6)	2 (11.8)	4 (21.1)	6 (16.7)
Any serious TEAEs^c	0	0	0	0
Any TEAEs leading to treatment interruption	0	0	0	0
Any TEAEs leading to study discontinuation	2 (11.1)	0	0	0
Any TEAEs leading to death	0	0	0	0
Most frequently reported TEAEs
Gastrointestinal disorders	5 (27.8)	4 (23.5)	1 (5.3)	5 (13.9)
Stomatitis	0	2 (11.8)	0	2 (5.6)
Chronic gastritis	0	1 (5.9)	0	1 (2.8)
Gastroesophageal reflux disease	0	0	1 (5.3)	1 (2.8)
Nausea	1 (5.6)	1 (5.9)	0	1 (2.8)
Infections and infestations	3 (16.7)	0	5 (26.3)	5 (13.9)
Coronavirus infection	0	0	1 (5.3)	1 (2.8)
COVID-19	1 (5.6)	0	1 (5.3)	1 (2.8)
Cystitis	0	0	1 (5.3)	1 (2.8)
Gastroenteritis	0	0	1 (5.3)	1 (2.8)
Nasopharyngitis	1 (5.6)	0	1 (5.3)	1 (2.8)
General disorders and administration site conditions	1 (5.6)	1 (5.9)	3 (15.8)	4 (11.1)
Malaise	0	1 (5.9)	1 (5.3)	2 (5.6)
Chills	0	0	1 (5.3)	1 (2.8)
Face edema	0	0	1 (5.3)	1 (2.8)
Edema peripheral	0	0	1 (5.3)	1 (2.8)
Vaccination site joint pain	0	0	1 (5.3)	1 (2.8)
Investigations	3 (16.7)	0	4 (21.1)	4 (11.1)
Alanine aminotransferase increased	0	0	1 (5.3)	1 (2.8)
Blood creatine phosphokinase increased	0	0	1 (5.3)	1 (2.8)
Gamma-glutamyl transferase increased	0	0	1 (5.3)	1 (2.8)
Hemoglobin decreased	1 (5.6)	0	1 (5.3)	1 (2.8)

Values are presented as number (%). The most common SOCs of all-causality TEAEs in >10% of all patients treated with etrasimod (1 mg and 2 mg combined) and any preferred terms (MedDRA version 25.1) within these SOCs with ≥1 event in the etrasimod 1 mg or 2 mg groups are reported.

^a One TEAE of bradycardia reported in 1 patient (5.3%) receiving etrasimod 2 mg met the criteria for AESI. This occurred on Study Day 1, was transient, resolved the same day, and was considered probably related to the study treatment. The patient continued on the study treatment. One TEAE of herpes zoster reported in 1 patient (5.6%) receiving placebo met the criteria for AESI. This began on Study Day 37, was not resolved at the time of the last follow-up visit and was not considered to be related to the study treatment. No action was taken in response to the event.

^b TEAEs classified as “probably related” or “related” are counted as related. Relationship was assessed by the investigator; missing relationship is counted as related.

^c Missing seriousness is counted as serious.

TEAEs, treatment-emergent adverse events; QD, once daily; COVID-19, coronavirus disease 2019; SOC, System Organ Class; MedDRA, Medical Dictionary for Regulatory Activities; AESI, adverse event of special interest.

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Efficacy and safety of etrasimod in Japanese patients with ulcerative colitis: results from a phase 2 dose-ranging study

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Efficacy and safety of etrasimod in Japanese patients with ulcerative colitis: results from a phase 2 dose-ranging study

Fig. 1. Patient disposition. Patients who discontinued the study or did not continue to the OLE had follow-up visits at week 2 and 4. aThe full analysis set comprised all randomly assigned patients who received at least one dose of study treatment. QD, once daily; OLE, openlabel extension; TEAE, treatment-emergent adverse event.

Fig. 2. The proportion of patients achieving (A) the primary endpoint of clinical remission and (B) secondary efficacy endpoints at week 12 (full analysis set and actual baseline MMS of 5 to 9). Percentages were based on the number of patients in the analysis set. Patients missing an assessment at the specified analysis visits were considered nonresponders. aClinical remission was defined as patients with SFS=0 (or =1 with a ≥1-point decrease from baseline), RBS=0, and ES ≤1 (excluding friability); bEndoscopic improvement was defined as patients with ES ≤1; cSymptomatic remission was defined as patients with SFS=0 (or =1 with a ≥1-point decrease from baseline) and RBS=0; dEIHR was defined as patients with ES ≤1 with histologic remission measured by a Geboes Index score <2.0; eClinical response was defined as patients with a ≥2-point and ≥30% decrease from baseline in MMS, a≥1-point decrease from baseline in RBS or an absolute RBS ≤1. MMS, modified Mayo score; SFS, stool frequency subscore; RBS, rectal bleeding subscore; ES, endoscopic subscore; EIHR, endoscopic improvement-histologic remission; QD, once daily.

Fig. 3. The proportion of patients achieving other efficacy endpoints, including (A) symptomatic remission, (B) complete symptomatic remission, (C) noninvasive clinical response, (D) symptomatic response, (E) clinical remission and clinical response using TMS at week 12, and (F) histologic improvement/remission at week 12 (modified full analysis set and actual baseline MMS of 5 to 9). QD, once daily; TMS, total Mayo score; MMS, modified Mayo score; RHI, Robarts Histopathology Index; NHI, Nancy Histological Index.

Fig. 4. Mean (A) change from baseline and (B) percentage change from baseline in ALC (full analysis set and actual baseline MMS 5 to 9). Baseline is the last measurement taken prior to the first dose of study treatment. Only patients with a baseline MMS score between 5 and 9 are included. A range of 1.02 to 3.36×109/L was considered normal. ALC, absolute lymphocyte count; MMS, modified Mayo score; QD, once daily; SD, standard deviation.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Efficacy and safety of etrasimod in Japanese patients with ulcerative colitis: results from a phase 2 dose-ranging study

Characteristic	Placebo QD (n = 18)	Etrasimod 1 mg QD (n = 17)	Etrasimod 2 mg QD (n = 19)	Total (n = 54)
Age on consent (yr), mean ± SD	38.5 ± 9.3	41.6 ± 14.0	49.5 ± 11.6	43.3 ± 12.5
Male sex, No. (%)	13 (72.2)	11 (64.7)	11 (57.9)	35 (64.8)
BMI (kg/m²), mean ± SD	21.5 ± 3.6	23.8 ± 5.1	24.0 ± 4.1	23.1 ± 4.4
Tobacco use (yes), No. (%)	8 (44.4)	6 (35.3)	5 (26.3)	19 (35.2)
Prior biologic/JAKi therapy use (yes), No. (%)	5 (27.8)	2 (11.8)	3 (15.8)	10 (18.5)
Baseline corticosteroid use-reported (yes), No. (%)	3 (16.7)	3 (17.6)	5 (26.3)	11 (20.4)
Prior failure of TNFi (yes), No. (%)	1 (5.6)	2 (11.8)	1 (5.3)	4 (7.4)
Prior failure of TNFi or vedolizumab (yes), No. (%)	1 (5.6)	2 (11.8)	3 (15.8)	6 (11.1)
Prior failure of oral 5-ASA only (yes), No. (%)	4 (22.2)	1 (5.9)	1 (5.3)	6 (11.1)
Extent of disease, No. (%)^a
Proctosigmoiditis/left-sided colitis	12 (66.7)	4 (23.5)	7 (36.8)	23 (42.6)
Pancolitis	4 (22.2)	10 (58.8)	7 (36.8)	21 (38.9)
Isolated proctitis	2 (11.1)	3 (17.6)	5 (26.3)	10 (18.5)
Duration of UC (yr), mean ± SD	6.6 ± 6.1	6.4 ± 6.0	6.1 ± 8.2	6.4 ± 6.8
Baseline MMS, mean ± SD	5.7 ± 1.4	6.2 ± 1.2	6.3 ± 1.2	6.1 ± 1.3
MMS group-reported (4-6), No. (%)	12 (66.7)	9 (52.9)	12 (63.2)	33 (61.1)
MMS group-reported (7-9), No. (%)	6 (33.3)	8 (47.1)	7 (36.8)	21 (38.9)

Category	Placebo QD (n = 18)	Etrasimod 1 mg QD (n = 17)	Etrasimod 2 mg QD (n = 19)	Etrasimod total (n = 36)
Any TEAEs^a	10 (55.6)	9 (52.9)	13 (68.4)	22 (61.1)
Related TEAEs^b	1 (5.6)	2 (11.8)	4 (21.1)	6 (16.7)
Any serious TEAEs^c	0	0	0	0
Any TEAEs leading to treatment interruption	0	0	0	0
Any TEAEs leading to study discontinuation	2 (11.1)	0	0	0
Any TEAEs leading to death	0	0	0	0
Most frequently reported TEAEs
Gastrointestinal disorders	5 (27.8)	4 (23.5)	1 (5.3)	5 (13.9)
Stomatitis	0	2 (11.8)	0	2 (5.6)
Chronic gastritis	0	1 (5.9)	0	1 (2.8)
Gastroesophageal reflux disease	0	0	1 (5.3)	1 (2.8)
Nausea	1 (5.6)	1 (5.9)	0	1 (2.8)
Infections and infestations	3 (16.7)	0	5 (26.3)	5 (13.9)
Coronavirus infection	0	0	1 (5.3)	1 (2.8)
COVID-19	1 (5.6)	0	1 (5.3)	1 (2.8)
Cystitis	0	0	1 (5.3)	1 (2.8)
Gastroenteritis	0	0	1 (5.3)	1 (2.8)
Nasopharyngitis	1 (5.6)	0	1 (5.3)	1 (2.8)
General disorders and administration site conditions	1 (5.6)	1 (5.9)	3 (15.8)	4 (11.1)
Malaise	0	1 (5.9)	1 (5.3)	2 (5.6)
Chills	0	0	1 (5.3)	1 (2.8)
Face edema	0	0	1 (5.3)	1 (2.8)
Edema peripheral	0	0	1 (5.3)	1 (2.8)
Vaccination site joint pain	0	0	1 (5.3)	1 (2.8)
Investigations	3 (16.7)	0	4 (21.1)	4 (11.1)
Alanine aminotransferase increased	0	0	1 (5.3)	1 (2.8)
Blood creatine phosphokinase increased	0	0	1 (5.3)	1 (2.8)
Gamma-glutamyl transferase increased	0	0	1 (5.3)	1 (2.8)
Hemoglobin decreased	1 (5.6)	0	1 (5.3)	1 (2.8)

Table 1. Demographics and Baseline Characteristics (Full Analysis Set)

As per data recorded in the Case Report Form.

Table 2. Summary of TEAEs and Most Frequent TEAEs (Safety Analysis Set)

One TEAE of bradycardia reported in 1 patient (5.3%) receiving etrasimod 2 mg met the criteria for AESI. This occurred on Study Day 1, was transient, resolved the same day, and was considered probably related to the study treatment. The patient continued on the study treatment. One TEAE of herpes zoster reported in 1 patient (5.6%) receiving placebo met the criteria for AESI. This began on Study Day 37, was not resolved at the time of the last follow-up visit and was not considered to be related to the study treatment. No action was taken in response to the event.

TEAEs classified as “probably related” or “related” are counted as related. Relationship was assessed by the investigator; missing relationship is counted as related.

Missing seriousness is counted as serious.