Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials Open Access

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease (IBD) of the colon characterized by symptoms including rectal bleeding, urgency, and tenesmus [1, 2]. The goals of UC therapy are to achieve and maintain long-term corticosteroid (CS)-free clinical and endoscopic remission, and to maintain health-related quality of life [3‒5]. Therapy involves a stepwise approach, with disease severity and extent typically guiding treatment selection [1, 2]. From 1990 to 2017, the global prevalence of IBD increased by approximately 85%, from 3.7 million to 6.8 million individuals, with the highest IBD age-standardized prevalence observed in the USA followed by the UK [6]. In Japan, survey and health claims database data suggest there has been an almost ten-fold increase in the prevalence of UC from 1991 to 2014 and a more than seven-fold increase from 2010 to 2019 [7, 8].

Japanese clinical practice guidelines recommend the use of advanced therapies such as biologics and small molecules for the treatment of patients with CS-refractory UC and those with CS-dependent UC who have failed immunomodulators [9]. A notable decrease in UC surgeries was observed between 2007 and 2017, coinciding with an increase in the use of advanced therapies [10]. However, advanced therapies such as infliximab and adalimumab can have high discontinuation rates after 1 year of treatment, potentially due to adverse events or lack of efficacy attributed to their immunogenic profile [11‒15]. Accordingly, there is a clear unmet need in this patient population for an efficacious and well-tolerated treatment for moderately to severely active UC prior to progression to more advanced therapies, a niche that small molecule therapies have the potential to fill.

Etrasimod is an oral, once-daily (QD), 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 were demonstrated in the phase 3 global, multicenter ELEVATE UC clinical program [16]. A significantly greater proportion of patients who received etrasimod 2 mg QD achieved the primary efficacy endpoint of clinical remission and all key secondary efficacy endpoints at week 12 and week 52 compared with those who received placebo. Additionally, both induction and maintenance treatments with etrasimod were well tolerated [16].

The ELEVATE UC 40 JAPAN trial (NCT04706793) was an extension study that enrolled patients from Japan who completed the global ELEVATE UC 12 trial (NCT03996369). Here, we report the combined findings of the ELEVATE UC 12 and ELEVATE UC 40 JAPAN trials in a single integrated analysis that assessed the efficacy and safety of etrasimod versus placebo in patients from Japan.

The ELEVATE UC clinical program included the global, multicenter, placebo-controlled phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) clinical trials; complete trial details are described elsewhere [16]. ELEVATE UC 40 JAPAN (NCT04706793) was a multicenter, double-blind, 40-week trial of patients from Japan who completed the 12-week ELEVATE UC 12 trial, resulting in a combined 52-week treatment period. Eligible patients were aged 16–80 years old with moderately to severely active UC (confirmed by endoscopy with ≥10 cm rectal involvement and on the basis of a modified Mayo score [MMS] 4–9 with a centrally read endoscopic subscore [ES] ≥2 and rectal bleeding subscore [RBS] ≥1) and a documented history of inadequate response, loss of response, or intolerance to at least one approved UC therapy. Patients continued the same blinded treatment (oral etrasimod 2 mg QD or placebo QD) they were assigned at baseline in ELEVATE UC 12. Patients were stratified according to prior experience with biologic/Janus kinase inhibitor (JAKi) therapy, baseline CS use, and baseline disease activity (MMS 4–6 or 7–9). The ELEVATE UC 12 trial was conducted between September 15, 2020, and July 12, 2021, and the ELEVATE UC 40 trial between December 25, 2020, and August 3, 2022. The efficacy of etrasimod versus placebo in this patient cohort (hereafter the “Japan cohort”) were examined at week 12 (ELEVATE UC 12) and week 52 (ELEVATE UC 40 JAPAN).

The primary efficacy endpoints in this integrated analysis were the proportion of patients achieving clinical remission (stool frequency subscore [SFS] = 0 [or = 1 with a ≥1-point decrease from baseline], RBS = 0, and ES ≤1 [excluding friability]) at week 12 and week 52. Key secondary endpoints comprised the proportion of patients achieving endoscopic improvement (ES ≤1), symptomatic remission (SFS = 0 [or = 1 with a ≥1-point decrease from baseline] and RBS = 0), and endoscopic improvement-histological remission (EIHR; ES ≤1 with histological remission measured by a Geboes Index score <2.0) at week 12 and week 52. CS-free clinical remission (remission at week 52 with no CS use for at least the last 12 study weeks immediately before week 52) and sustained clinical remission (clinical remission at both week 12 and week 52) were also assessed. Efficacy endpoints are reported using data from patients with a baseline MMS of 5–9, consistent with the ELEVATE UC 52 and ELEVATE UC 12 global analyses [16].

Safety was assessed in the Japan cohort up to week 52, and treatment-emergent adverse events (TEAEs) are reported. Safety events that were ongoing at the end of ELEVATE UC 12 that continued into ELEVATE UC 40 JAPAN are reported as one event. Safety data were listed and summarized by treatment group in all patients who received at least one dose of study treatment.

Efficacy and safety analyses in the Japan cohort were performed according to what treatment group patients were assigned at baseline in ELEVATE UC 12 and included all patients who received ≥1 dose of study treatment in ELEVATE UC 12. Efficacy and safety data were pooled from the initial 12-week ELEVATE UC 12 induction treatment period and the 40-week ELEVATE UC 40 JAPAN maintenance treatment period. For efficacy endpoints, calculation of 95% confidence intervals was based on a Wald-type test and percentage differences for patients who received etrasimod versus placebo were derived from crude analyses with no formal statistical testing. Patients missing an assessment at the specified analysis visit were considered nonresponders. The number and proportion of patients with TEAEs and serious adverse events (SAEs) were evaluated. All statistical analyses were performed using SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA).

In the Japan cohort, 32 patients who received etrasimod and 16 patients who received placebo completed ELEVATE UC 12 and were enrolled into ELEVATE UC 40 JAPAN. Of these, 18 (56.3%) and 4 (25.0%) etrasimod and placebo patients, respectively, completed treatment to week 52. Reasons for treatment discontinuation included disease worsening (etrasimod n = 10; placebo n = 10), physician decision (etrasimod n = 1; placebo n = 2), adverse event (etrasimod n = 1), withdrawal by patient or parent/guardian (etrasimod n = 1), and other reasons (etrasimod n = 1). Twenty-eight patients who received etrasimod and 14 patients who received placebo had a baseline MMS of 5–9 and were included in the analysis.

Patient baseline demographics, clinical characteristics, and prior/concomitant medications are summarized for the Japan cohort in Table 1. Age and the duration of UC were similar between Japan cohort treatment groups, whereas some differences were evident for sex and the extent of UC. Baseline MMS was lower in the etrasimod group (median 6.0; range 4.0–8.0) than in the placebo group (median 7.0; range 4.0–8.0). A lower proportion of patients who received etrasimod had biologic-/JAKi-experienced (12.5%; 4/32) compared with those who received placebo (56.3%; 9/16). A higher proportion of patients who received etrasimod were biologic-/JAKi-naïve (87.5%; 28/32) compared with those who received placebo (43.8%; 7/16). Concomitant use of 5-aminosalicylic acid (5-ASA) was reported in 90.6% (29/32) and 75.0% (12/16) of patients who received etrasimod or placebo, respectively.

In the Japan cohort, clinical remission was achieved by 14.3% (4/28) of patients who received etrasimod versus 7.1% (1/14) who received placebo at week 12. At week 52, clinical remission was achieved by 25.0% (7/28) of patients who received etrasimod versus 7.1% (1/14) who received placebo (Fig. 1a). At week 12 and week 52, a numerically greater portion of patients who received etrasimod versus placebo, respectively, also achieved endoscopic improvement (week 12: 17.9% [5/28] vs. 7.1% [1/14]; week 52: 28.6% [8/28] vs. 7.1% [1/14]), symptomatic remission (week 12: 39.3% [11/28] vs. 14.3% [2/14]; week 52: 39.3% [11/28] vs. 7.1% [1/14]), and EIHR (week 12: 10.7% [3/28] vs. 0.0% [0/14]; week 52: 25.0% [7/28] vs. 7.1% [1/14]) (Fig. 1b–d).

CS-free clinical remission at week 52 was achieved by 25.0% (7/28) of patients who received etrasimod, compared with 7.1% (1/14) of patients who received placebo (Fig. 2a). Sustained clinical remission at week 52 was achieved by 7.1% (2/28) of patients who received etrasimod, but no patients who received placebo (Fig. 2b).

TEAEs occurred in 84.4% (27/32) of patients who received etrasimod and 62.5% (10/16) of patients who received placebo (Table 2). SAEs occurred in 3.1% (1/32) versus 6.3% (1/16) of patients who received etrasimod versus placebo, respectively. In each treatment group, 1 patient discontinued treatment due to worsening of UC. The top three most common TEAEs reported among patients who received etrasimod were pyrexia (21.9%), headache (12.5%), and malaise (12.5%). One case each (3.1%; 1/32) of sinus arrhythmia, sinus bradycardia, and macular edema was reported in the etrasimod treatment arm. No events of decreased heart rate, atrioventricular block, and pulmonary function test abnormalities were reported. No deaths occurred.

In patients from Japan with moderately to severely active UC, a numerically greater proportion of patients who received etrasimod versus placebo achieved the primary efficacy endpoint of clinical remission at week 12 and week 52. Numerical improvements for etrasimod versus placebo were also observed for endoscopic improvement, symptomatic remission, EIHR, CS-free remission, and sustained clinical remission at both timepoints. These findings are consistent with those from the primary analyses of the ELEVATE UC 52 and ELEVATE UC 12 global populations, where patients who received etrasimod versus placebo achieved the primary and all key secondary efficacy endpoints at week 12 and week 52 [16].

Baseline characteristics were generally similar between the Japan cohort and global ELEVATE UC 52 and ELEVATE UC 12 populations but with some noticeable differences [16]. In the Japan cohort, 13% of patients who received etrasimod were biologic-/JAKi-experienced, compared with 37% in both the ELEVATE UC 52 and ELEVATE UC 12 populations [16]. In another large Japanese cohort of patients with UC, a similar proportion of 17% of patients were biologic-experienced [17]. Moreover, compared with the global analysis populations, patients who received etrasimod in the Japan cohort also had a higher rate of 5-ASA use but a lower rate of concomitant CS use at baseline [16].

Japanese clinical guidelines recommend 5-ASA therapies as first-line treatments for mild to moderate UC, with advanced therapies recommended for the treatment of patients with CS-refractory UC and those with CS-dependent UC who have failed immunomodulators [9]. Numerically greater improvements in efficacy have been observed for several advanced therapies in patients from Japan with UC, including the tumor necrosis factor inhibitors golimumab, adalimumab, and infliximab, and the integrin inhibitor vedolizumab [18‒21]. In a network meta-analysis of biologic-naïve patients with UC in Japan, all four of these agents were found to be more efficacious than placebo [22]. Despite the demonstrated efficacy of biologics, there remain subpopulations of patients with moderately to severely active UC in Japan who may still require surgery [17]. Risk factors for colectomy can include age ≥60 years, history of CS-refractory or -dependent UC, induction by apheresis, severe exacerbations, and treatment with calcineurin inhibitors [17]. Due to this heterogeneity of risk factors, it is necessary to treat patients according to their pathophysiology to ensure they receive the optimal treatment using a treat-to-target approach [5]. The relatively small Japanese population in the present analysis limits efficacy comparisons of etrasimod with other UC therapies. However, in a global network meta-analysis of biologics and small molecule therapies, etrasimod demonstrated high efficacy compared with other available UC therapies assessed with a treat-through approach [23]. As such, etrasimod has been shown to be an efficacious treatment in patients with moderately to severely active UC that can be considered alongside other advanced therapy options within existing clinical practice guidelines.

Safety findings in previous Japanese studies show the high comorbidity burden of patients treated with biologics [18, 19]. Similarly, advanced therapies such as JAKi have several safety outcomes that should be considered [24]. These findings suggest that there is a gap in the UC treatment landscape for an efficacious and well-tolerated treatment for use prior to advancing to biologics or other advanced therapies [16]. In the Japan cohort from the present study, no new safety events were observed. Etrasimod had a similar 52-week tolerability profile in the Japan cohort compared with that previously reported for the global ELEVATE UC 52 population [16]. Although a slightly higher proportion of patients had one or more TEAE in the Japan cohort compared with the global population, the proportions of patients with a SAE or TEAE leading to study discontinuation were similar. There was no observed increase in the risk of infections in patients treated with etrasimod versus placebo in the Japan cohort compared with the global population. Of note, pyrexia, headache, and malaise were the three most common TEAEs in the etrasimod group in the Japan cohort. Of TEAEs associated with S1P receptor modulation that met the criteria for the sponsor’s medical review in the global ELEVATE UC 52 and ELEVATE UC 12 primary analyses [16], sinus arrhythmia, sinus bradycardia, and macular edema, one occurrence of each event was reported. Further investigations of real-world data will reveal additional safety information in the Japanese UC patient population.

Limitations for this analysis include the use of a relatively small Japanese population sample size compared with the global ELEVATE UC 52 and ELEVATE UC 12 trial populations, which also precluded a formal statistical analysis to compare treatment outcomes within the Japan cohort. Efficacy analyses performed in the Japan cohort were conducted using different designs, analysis plans, and sample sizes versus for the global ELEVATE UC 52 and ELEVATE UC 12 trials; as such, efficacy results are not directly comparable. Therefore, inclusion of data from the global analyses is for contextualization only. Data for the dose suitability of etrasimod in patients from Japan are not reported here and will be reported separately.

In this population of patients from Japan with moderately to severely active UC, a greater proportion of patients who received etrasimod achieved all efficacy endpoints during induction and maintenance therapy compared with patients who received placebo. Efficacy and safety findings from the Japan cohort were generally consistent with those reported in the global ELEVATE UC 52 and ELEVATE UC 12 populations. This study indicates that etrasimod is an efficacious and safe treatment for moderately to severely active UC in patients from Japan.

The authors would like to thank the patients, investigators, and study teams who were involved in the etrasimod UC clinical program. Medical writing support, under the direction of the authors, was provided by Niall Tyrer, MBiolSci, 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).

All studies were registered with ClinicalTrials.gov and were conducted in compliance with the Declaration of Helsinki and were approved by the Institutional Review Boards at each investigational center participating in the studies. This full list of participating sites can be found on ClinicalTrials.gov via the trial identifiers NCT03996369 and NCT04706793. All patients provided written informed consent; a parent or legal guardian provided consent for patients <18 years of age who participated in the study. Further details on study protocols are provided in Sandborn et al., 2023 [16].

K.T. received consulting fees from Thermo Fisher Diagnostics KK, research grants from AbbVie and Takeda, and lecture fees from Takeda, AbbVie, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., Kyorin, Janssen, Zeria, Celltrion, Pfizer, Viatris Inc., Gilead Sciences, JIMRO, Thermo Fisher Diagnostics KK, and EA pharma. T. Hisamatsu received financial support for research from AbbVie, Boston Scientific, EA Pharma, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda; speaker’s bureau fees from AbbVie, EA Pharma, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., and Takeda; and consultancy fees from AbbVie, Bristol Myers Squibb, EA Pharma, Gilead, Janssen, Mitsubishi Tanabe Pharma, Nichi-Iko, and Pfizer Inc. H.N. received financial support for research from AbbVie GK, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., Ayumi Pharmaceutical, Nihon Kayaku Co., Ltd., Otsuka Pharmaceutical, TAIHO Pharmaceutical Co., Ltd., EA Pharma, and HOYA Pentax Medical; lecture fees from Mitsubishi Tanabe Pharma, Janssen Pharmaceutical KK, Takeda, AbbVie, Pfizer, Viatris Inc., Gilead Sciences, JIMRO, and Mochida Pharmaceutical Co., Ltd.; and is endowed chair for JIMRO, Kyorin, Mochida Pharmaceutical Co., Ltd., and Miyarisan Pharmaceutical Co., Ltd. K.M. received financial support for research from AbbVie, EA Pharma, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, and Nippon Kayaku; and lecture fees from AbbVie, Celltrion, Covidien, EA Pharma, Eli Lilly, Gilead, Janssen, JIMRO, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer Inc., Takeda, and Zeria Pharmaceutical. M.K., H.Y., and S.A. are employees and stockholders of Pfizer Inc. M.O. is an employee of Pfizer Inc. R.M. is an employee of Pfizer AG and a shareholder of Pfizer Inc. T. Hibi received lecture fees from AbbVie, EA Pharma Co., Ltd., Janssen Pharmaceutical KK, JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sandoz KK, Takeda, and Zeria Pharmaceutical Co., Ltd.; consultancy fees from AbbVie, Celltrion Healthcare Japan KK, EA Pharma Co., Ltd., Eli Lilly Japan KK, Gilead Sciences KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical, Nippon Kayaku Co., Ltd., Takeda, and Zeria Pharmaceutical Co., Ltd.; and research grants from AbbVie, ActivAid, Alfresa Pharma Corporation, Bristol Myers Squibb KK, Eli Lilly Japan KK, Ferring Pharmaceuticals Co., Ltd., Gilead Sciences KK, JIMRO Co., Ltd., JMDC Inc., Janssen Pharmaceutical KK, Kyorin, Miyarisan Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., and Zeria Pharmaceutical Co., Ltd.

This work was funded by Pfizer.

M.K., H.Y., M.O., and S.A. contributed to the conception and methodology of the study. S.A. contributed to the administration of the study. H.Y. and M.O. contributed to supervision. M.O. contributed to data curation. K.T., T.H., H.N., K.M., M.K., H.Y., M.O., S.A., R.M., and T.H. contributed to the conception and design of the study, the acquisition of data, the analysis and interpretation of data, the writing or critical revision of the manuscript, and approved the final version for submission. R.M. served as the primary lead clinician and medical monitor on this study, responsible for reviewing all safety data, performing data cleaning, analysis and interpretation, and authoring the clinical study report.

Clinicaltrials.gov: NCT03945188; NCT03996369; NCT04706793.

Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.