Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study

Tadakazu Hisamatsu; Toshimitsu Fujii; Hiroshi Nakase; Katsuyoshi Matsuoka; Masayuki Saruta; Taku Kobayashi; Seika Inoue; Kazuhiro Toriyama; Dong Wang; Yoko Uchikawa; Go Fujimoto; Toshifumi Hibi

doi:10.5217/ir.2026.00031

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Original Article Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study: Tadakazu Hisamatsu¹, Toshimitsu Fujii², Hiroshi Nakase³, Katsuyoshi Matsuoka⁴, Masayuki Saruta⁵, Taku Kobayashi^6,7, Seika Inoue⁸, Kazuhiro Toriyama⁸, Dong Wang⁸, Yoko Uchikawa⁹, Go Fujimoto⁹, Toshifumi Hibi¹⁰; DOI: https://doi.org/10.5217/ir.2026.00031
Published online: July 10, 2026

¹Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan

²Department of Gastroenterology and Hepatology, Institute of Science Tokyo, Tokyo, Japan

³Department of Gastroenterology and Hepatology, Sapporo Medical University, Sapporo, Japan

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

⁵Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan

⁶Department of Gastroenterology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

⁷Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

⁸Medical Affairs, Bristol Myers Squibb, Tokyo, Japan

⁹Development Department, Bristol Myers Squibb, Tokyo, Japan

¹⁰Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan

Correspondence to Tadakazu Hisamatsu, Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka 181-8611, Japan. E-mail: thisamatsu@ks.kyorin-u.ac.jp

Selected data from this article were published as abstracts/posters at the 2024 annual meeting of the Japanese Society for Inflammatory Bowel Disease and the 2025 annual meeting of the Japanese Society of Gastroenterology.

• Received: January 23, 2026 • Revised: April 21, 2026 • Accepted: May 4, 2026

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
Graphical abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
NOTES
Supplementary Material
REFERENCES

Abstract

Background/Aims
There is limited evidence for ozanimod, an oral sphingosine 1-phosphate receptor modulator, in patients with ulcerative colitis (UC) before treatment is escalated to an immunomodulator (IM) or advanced therapy (AT), including biologics and Janus kinase inhibitors.
Methods
We performed post hoc analyses to examine the efficacy and safety of ozanimod 0.92 mg versus placebo in a subgroup of Japanese IM-/AT-naive patients with moderately to severely active UC, without concomitant corticosteroids (CS), enrolled in the randomized J-True North study.
Results
The analyses comprised 29 and 30 patients treated with ozanimod 0.92 mg and placebo, respectively. The clinical response rate was significantly greater in the ozanimod group at Week 12 (75.9% vs. 40.0%; P=0.0103) and Week 52 (62.1% vs. 16.7%; P=0.0010). Clinical remission, endoscopic improvement, and histologic remission rates at Weeks 12 and 52 were significantly better in the ozanimod group. Changes in the rectal bleeding subscore, stool frequency subscore, symptomatic response, and symptomatic remission were apparent by Week 2 in both groups, and tended to be better in the ozanimod group from Week 5 onward. Treatment-emergent adverse events occurred in 79.3% and 63.3% of patients in the ozanimod and placebo groups, respectively; the most frequent were nasopharyngitis (ozanimod vs. placebo: 17.2% vs. 13.3%) and pyrexia (13.8% vs. 10.0%, respectively).
Conclusions
This subgroup analysis demonstrated that ozanimod 0.92 mg was significantly more effective than placebo in Japanese IM-/AT-naive UC patients without concomitant CS therapy, consistent with the results of global trials. The safety profile of ozanimod 0.92 mg was consistent with prior studies. ClinicalTrials.gov (NCT03915769) and the Japan Registry of Clinical Trials (jRCT2080224654)
Keywords: Inflammatory bowel diseases; Ozanimod; Sphingosine 1-phosphate receptor modulators; Ulcerative colitis

Graphical abstract

INTRODUCTION

Ulcerative colitis (UC) is an immune-mediated disease characterized by inflammation and the accumulation of lymphocytes in the colon and rectum, with symptoms that commonly include diarrhea and rectal bleeding [1,2].

Initial treatment usually comprises standard therapies, such as 5-aminosalicylic acid (5-ASA), corticosteroids (CS), and immunomodulators (IM) [2,3]. However, in patients with uncontrolled disease, the treatment may need to be escalated to advanced therapies (ATs), such as biologics (e.g., anti-tumor necrosis factor [TNF]-α, anti-integrins, and anti-interleukin-12/23 agents), or Janus kinase (JAK) inhibitors. UC has become manageable in most patients with the introduction of ATs, helping to reduce hospitalization and the number of colectomy surgeries [4]. Nevertheless, ATs may exhibit limited efficacy in some patients or may exhibit some safety concerns, meaning drugs with a different clinical profile might be needed.

Sphingosine 1-phosphate (S1P) is a plasma membrane-derived sphingolipid involved in lymphocyte trafficking [5,6], and S1P receptor modulators (S1PRMs), such as ozanimod, have attracted much attention in recent years. Ozanimod was initially approved for multiple sclerosis [7] and has since demonstrated long-term efficacy in patients with moderately to severely active UC [8-12]. In particular, the global TOUCHSTONE [12] and True North [10] studies supported the approval of ozanimod in patients with UC. In the True North study [10], for example, ozanimod 0.92 mg achieved significantly higher rates of clinical remission during the induction (18.4% vs. 6.0%; P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at Week 10]; P<0.001) phases compared with placebo, coupled with improvements in other clinically relevant outcomes.

The efficacy and safety of ozanimod in Japanese patients with UC were subsequently investigated in the phase 2/3 J-True North study, where UC patients were randomized to receive once-daily ozanimod at doses of 0.46 mg or 0.92 mg or placebo for 12 weeks in the induction phase and 40 weeks in the maintenance phase [13]. The study achieved the primary outcome in terms of a reduction from baseline in the complete Mayo score of ≥ 3 and ≥ 30%, and a reduction from baseline in the rectal bleeding subscore (RBS) of ≥ 1 or an absolute RBS of ≤1 at Week 12 that were maintained through Week 52 among responders at Week 12. Additionally, the safety profile of ozanimod in Japanese patients was consistent with earlier studies and no new safety signals were identified.

According to the Japanese label [14], ozanimod can be prescribed to the broad range of patients with moderate-to-severe UC not controlled with conventional medications. However, it is unknown which patient populations may benefit most from ozanimod due to the limited data available to date. Additionally, there is currently no evidence or guidelines indicating when to use S1PRMs among existing ATs (i.e., biologics and JAK inhibitors). The approved labels for S1PRMs and certain ATs (e.g., infliximab, risankizumab, and upadacitinib) do not restrict use to patients who are CS-intolerant or CS-dependent, whereas most other ATs do include such requirements. This distinction in labeling primarily reflects differences in the inclusion criteria of their respective phase 3 studies [10,13,15-20] rather than inherent differences in their pharmacological properties. The proven efficacy of ozanimod in patients with moderately to severely active UC, including AT-naive patients [10,13], encouraged us to further explore the efficacy of ozanimod in those patients who had never been escalated to AT or IM. We explored whether ozanimod is useful in this setting by performing post hoc subgroup analyses of IM-/AT-naive patients, without concomitant CS therapy, enrolled in the J-True North study.

METHODS

The design of the J-True North study has been described in more detail previously [13].

1. Ethics

The J-True North study adhered to Good Clinical Practice guidelines and the ethical principles outlined in the Declaration of Helsinki. The study was registered on ClinicalTrials.gov (NCT03915769) and the Japan Registry of Clinical Trials (jRCT2080224654). Sixty-seven sites participated [13]. The study protocol and informed consent documents were approved by the responsible ethics committee/institutional review board at each participating site. All patients provided written informed consent prior to entering the study and before initiation of any study-related procedure.

2. Patients

The complete eligibility criteria have been previously described [13]. Briefly, Japanese patients aged 18–75 years with a diagnosis of UC ≥ 3 months before enrollment, evidence of UC extending ≥15 cm from the anal verge according to baseline endoscopy, and moderately to severely active UC (complete Mayo score of 6–12 with a Mayo endoscopy subscore [MES] of ≥ 2, RBS of ≥ 1, and a stool frequency subscore [SFS] of ≥ 1) were eligible. All patients must have been treated with 5-ASA and/or CS. Both treatments could be continued at a stable dose. If 5-ASA or CS were withdrawn prior to the study, the baseline endoscopy had to be performed ≥2 weeks after stopping those treatments. Patients who had previously been treated with IMs or ATs were also eligible, although the study population was limited to approximately 30% of patients with a history of biologic treatment. At the start of the study, tofacitinib was the only JAK inhibitor approved for UC in Japan. Patients with a history of IM or AT use and patients with concomitant CS use were excluded from the current analyses to yield a subgroup of IM-/AT-naive patients without ongoing CS treatment.

The main exclusion criteria for the overall study were: severe extensive colitis (likely to require colectomy or ileostomy within 12 weeks or current/recent evidence of fulminant colitis, toxic megacolon, or bowel perforation); diagnosis of another intestinal condition (Crohn’s disease, indeterminate colitis, presence/history of a fistula consistent with Crohn’s disease, microscopic colitis, radiation colitis, or ischemic colitis); positive stool examination for pathogens or toxin-producing Clostridioides difficile; and other disorders/diseases, including clinically relevant cardiovascular conditions and history of uveitis or macular edema, that were likely to interfere with the study or interpretation of results. The full inclusion and exclusion criteria are included in the Supplementary Methods.

3. Study Design

J-True North was a phase 2/3 clinical trial in which patients with moderately to severely active UC were randomized (1:1:1) to placebo, ozanimod 0.46 mg, or ozanimod 0.92 mg for a 12-week induction period [13]. Randomization was stratified by CS use at screening and prior use of biologics. Patients who completed the induction period with a clinical response (complete Mayo score of ≥3 and ≥30%, and a reduction from baseline in the RBS of ≥1 or an absolute RBS of ≤1 at Week 12) were eligible for entry into a 40-week maintenance period, where they received the same treatment as in the induction period (Supplementary Fig. 1).

4. Endpoints and Assessments

This manuscript presents post hoc analysis data for the subgroups of IM-/AT-naive patients without concomitant CS treatment among those patients who were randomized to and received either placebo or ozanimod 0.92 mg (approved dose) in the induction period. We performed analyses similar to those used for the primary and secondary endpoints described in the original J-True North publication [13].

Clinical response was defined as a reduction from baseline in the complete Mayo score of ≥ 3 and ≥ 30%, and a reduction from baseline in the RBS of ≥1 or an absolute RBS of ≤1 at Week 12. The clinical response was also determined at Week 52. Other endpoints—assessed at Weeks 12 and 52—included the following: clinical remission (RBS of 0 and SFS of ≤ 1 [and a decrease of ≥ 1 point from the baseline SFS] and MES of ≤ 1); endoscopic remission (MES of 0) (not reported in the original publication); endoscopic improvement (MES of ≤ 1); mucosal healing (MES of ≤ 1 and Geboes score of <2.0); and histologic remission (Geboes score of <2.0).

Safety was evaluated throughout the study in terms of treatment-emergent adverse events (TEAEs) and TEAEs considered related to the study drug (treatment-related TEAEs). TEAEs were categorized according to the Medical Dictionary for Regulatory Affairs Japanese (MedDRA/J) version 26.0. TEAEs of special interest (TEAESI) included bradycardia, heart conduction abnormalities, serious infections, malignancies, macular edema, and hepatic effects.

5. Statistical Analysis

Clinical response, clinical remission, endoscopic remission, endoscopic improvement, mucosal healing, histologic remission, symptomatic response, and symptomatic remission rates were compared between the placebo and ozanimod 0.92 mg groups using the Cochran–Mantel–Haenszel test stratified by CS use at screening (yes or no) and prior biologic therapy use (yes or no). Weighted differences with 95% confidence intervals (CIs) were determined. Analysis of covariance was used to determine the adjusted least-squares (LS) mean changes in RBS and SFS, with 95% CIs, for comparisons between the placebo and ozanimod 0.92 mg groups. Nominal P-values, without adjustment for multiplicity, are reported for the analyses that were not prespecified in the J-True North study. The frequencies of TEAEs, treatment-related TEAEs, and TEAESI were examined descriptively, as in the original report, in terms of the number and percentage of patients. SAS version 9.4 or higher (SAS Institute, Cary, NC, USA) was used for all data analyses.

RESULTS

1. Patient Disposition and Baseline Characteristics

Overall, 30 of 65 patients randomized to placebo and 29 of 65 patients randomized to ozanimod 0.92 mg were IM- and AT-naive without ongoing CS treatment, and therefore eligible for these post hoc analyses. Patient characteristics, including age, body mass index, and Mayo scores/subscores, were similar between the placebo and ozanimod groups. A greater proportion of patients had a history of CS treatment in the placebo group (80.0%) than in the ozanimod group (62.1%) (Table 1).

2. Efficacy

The clinical response rate at Week 12 was significantly superior in the ozanimod group than in the placebo group (75.9% vs. 40.0%: Δ =34.1%, 95% CI 10.0% to 58.2%; P=0.0103) (Fig. 1A). The clinical response rate at Week 52 was also significantly greater in the ozanimod group (62.1% vs. 16.7%: Δ =42.6%, 95% CI 19.8% to 65.4%; P=0.0010).

In terms of other endpoints, the clinical remission rate was significantly greater in the ozanimod group at Week 12 (31.0% vs. 0%: Δ =25.9%, 95% CI 9.4% to 42.5%; P=0.0032) and Week 52 (34.5% vs. 6.7%: Δ=23.0%, 95% CI 3.6% to 42.4%; P=0.0241) (Fig. 1B). The proportion of patients with endoscopic remission (MES of 0) was significantly greater in the ozanimod group at Week 52 (20.7% vs. 0%: Δ =18.5%, 95% CI 3.9% to 33.2%; P=0.0144), with a small numerical difference at Week 12 (10.3% vs. 0%: Δ=3.7%, 95% CI −3.4% to 10.8%; P=0.2918) (Fig. 1C). The proportions of patients with endoscopic improvement at Weeks 12 (34.5% vs. 6.7%: Δ =23.0%, 95% CI 3.6% to 42.4%; P=0.0241) and 52 (44.8% vs. 10.0%: Δ =30.7%, 95% CI 9.3% to 52.2%; P=0.0076) were significantly greater in the ozanimod group (Fig. 1D). The proportions of patients with mucosal healing tended to be numerically greater in the ozanimod group at Weeks 12 (10.3% vs. 0%: Δ=11.1%, 95% CI −0.7% to 23.0%; P=0.0630) and 52 (17.2% vs. 6.7%: Δ =8.1%, 95% CI −8.0% to 24.2%; P=0.3212) (Fig. 1E). Histologic remission was achieved in a greater proportion of patients in the ozanimod group at Weeks 12 (17.2% vs. 0%: Δ=18.5%, 95% CI 3.9% to 33.2%; P=0.0144) and 52 (27.6% vs. 6.7%: Δ =19.3%, 95% CI 0.5% to 38.0%; P=0.0484) (Fig. 1F).

In order to observe the timing of efficacy onset after the initiation of ozanimod, we investigated the changes in RBS and SFS from baseline to Weeks 2, 5, 9, and 12 during the induction period, and the results are shown in Fig. 2. Decreases in RBS and SFS were apparent by Week 2 in the placebo and ozanimod groups. These decreases became more pronounced over time in the ozanimod group. The changes in RBS were significantly greater in the ozanimod group at Weeks 5, 9, and 12, with an adjusted LS mean change of −1.2 at Week 12 versus −0.8 in the placebo group (Δ =−0.4, 95% CI −0.7 to −0.0; P=0.0343) (Fig. 2A). For SFS, the LS mean change was significantly greater in the ozanimod group at Week 9 (P=0.0150), but not at the other times. At Week 12, the adjusted LS mean changes were −1.0 versus −0.7 (Δ =−0.4, 95% CI −0.7 to 0.0; P=0.0556) (Fig. 2B).

By Week 2, there were increased proportions of patients with symptomatic response in both groups, and of patients with symptomatic remission in the ozanimod group. The proportions of patients with symptomatic response at Weeks 5, 9, and 12 were numerically, but not significantly, greater in the ozanimod group, with proportions of 79.3% versus 60.0% at Week 12 (Δ =17.8%, 95% CI −5.7% to 41.3%; P=0.1530) (Fig. 2C). Additionally, the proportions of patients with symptomatic remission at Weeks 5, 9, and 12 were significantly greater in the ozanimod group, with proportions of 55.2% versus 20.0% at Week 12 (Δ=31.9%, 95% CI 8.2% to 55.5%; P=0.0126) (Fig. 2D).

These changes in RBS, SFS, symptomatic response, and symptomatic remission mimicked the changes in the overall groups (i.e., including IM-/AT-experienced patients, regardless of CS use), although the changes in all 4 endpoints at Weeks 5, 9, and 12 were significantly greater in the ozanimod group than in the placebo group (Supplementary Fig. 2).

3. Safety

Ozanimod showed favorable tolerability in the study population (Table 2). TEAEs occurred in 63.3% of patients in the placebo group and in 79.3% of patients in the ozanimod group. No serious TEAEs or serious treatment-related TEAEs were reported in the placebo or ozanimod groups. There was 1 treatment-related TEAE that led to treatment discontinuation (macular edema) in the ozanimod group. Among patients included in the safety analysis, the most frequent TEAEs were nasopharyngitis (placebo and ozanimod groups: 13.3% and 17.2%, respectively) and pyrexia (10.0% and 13.8%, respectively). TEAESI in the ozanimod group were herpes zoster and macular edema, which occurred in 1 patient each (3.4%) (Table 3). There were no cases of bradycardia, malignancies, or other TEAESI.

DISCUSSION

We performed these post hoc analyses to investigate the value of using ozanimod in a subpopulation of IM-/AT-naive patients with UC, without concomitant CS therapy. The analyses revealed that ozanimod 0.92 mg (approved dose in Japan) exhibited superior efficacy to placebo during the induction and maintenance periods. These results reflect those of the overall patient populations in the J-True North study (Supplementary Fig. 2) [13] and the True North study [10]. Overall, our findings indicate that ozanimod is an effective treatment option for IM-/AT-naive patients without concomitant CS therapy.

The trends observed in this subgroup are consistent with those of prior studies demonstrating better efficacy of ozanimod or other therapies in AT-naive patients than in AT-experienced patients [18,21-24]. Analyses of the True North study revealed a tendency for greater effectiveness of ozanimod in AT (biologic, anti-TNF)-naive patients [10,21], and a meta-analysis of S1PRMs [25] indicated significantly greater efficacy in anti-TNF-naive patients (risk difference, 0.16; 95% CI, 0.12–0.20) compared with anti-TNF-experienced patients (risk difference, 0.08; 95% CI, 0.02–0.14) (test for subgroup differences: P=0.0395). Although the specific reasons for the greater efficacy in AT-naive patients cannot be ascertained, it is generally accepted that the response to treatment might be blunted in AT-experienced patients due to disease progression or activation of multiple cytokine pathways, limiting the potential effects of a single therapy, or that longer treatment may be needed to achieve a clinically meaningful response [22,26].

We noted significantly greater effects of ozanimod versus placebo on clinically relevant outcomes, especially clinical response and clinical remission at the end of the induction period (i.e., Week 12), that were maintained through to the end of the maintenance period (Week 52). To further explore the timing of onset of ozanimod efficacy, we examined the changes in RBS, SFS, symptomatic response, and symptomatic remission during the induction period. This revealed improvements in symptom-related outcomes by Week 2 after starting ozanimod, with significant between-group differences appearing from Week 5 onward. Overall, these findings are similar to those reported in the True North study [21]. This evidence suggests that ozanimod has a rapid onset of action in patients with UC.

Higher percentages of patients achieved endoscopic remission, endoscopic improvement, mucosal healing, or histologic remission in the ozanimod group than in the placebo group. Notably, nearly half of the patients with endoscopic improvement (MES of ≤ 1) achieved endoscopic remission (MES of 0) in the ozanimod group, whereas no patients achieved endoscopic remission at Week 52 in the placebo group. Accordingly, treatment with ozanimod not only achieved meaningful improvements in UC-related symptoms, but also led to improved intestinal morphology, as determined by endoscopy and histology, which were apparent during the induction period and improved further during the maintenance period.

Focusing on the placebo-treated patients in this population, 40.0% (12/30) achieved a clinical response at Week 12, and the clinical response was maintained through Week 52 in 41.7% (5/12) of these patients. This suggests that a subset of patients previously experiencing exacerbations can be managed with 5-ASA alone. However, this trend was not limited to the IM-/AT-naive subpopulation; it was also observed in the overall study population, most of whom were treated with 5-ASA alone, with corresponding rates of 32.3% (21/65) at Week 12 and 52.4% (11/21) at Week 52 [13]. Despite these observations, no patient in the placebo group achieved clinical remission at Week 12, suggesting benefits of ozanimod treatment.

Our findings can be discussed in the context of a similar subanalysis of AT-naive patients in True North, which included a larger cohort of 616 AT-naive patients (137 patients randomized to placebo, 287 to ozanimod cohort 1, and 192 to ozanimod cohort 2), including 464 who were also naive to IMs [21]. Similar to our analysis, that study revealed significantly greater percentages of patients achieved clinical response and remission at Week 10 in the ozanimod group than in the placebo group that were sustained through Week 52. Moreover, these improvements were observed in patients without concomitant CS therapy in the True North study, similar to our cohort.

Among this population of IM-/AT-naive patients, without concomitant CS, all of the patients had previously received 5-ASA, and approximately 90% had a history of therapeutic failure or intolerance to 5-ASA. Furthermore, approximately 70% of the patients had previously received CS. Accordingly, this population may include a mixture of patients who had never been treated with CS, or had been treated with CS at least once to induce remission, followed by disease worsening after CS cessation and met the inclusion criteria of the J-True North study [13]. Because the current analyses comprised patients who were not using a CS at the screening visit, this analysis population is unlikely to include any patients who relapsed during CS tapering. Therefore, the present findings suggest that ozanimod is an effective treatment option for patients who achieved remission with CS but whose disease could not be managed with 5-ASA. In addition, a pooled analysis of the J-True North and True North studies revealed greater efficacy of ozanimod versus placebo in terms of symptomatic response and symptomatic remission in 5-ASA-experienced, CS-naive patients [27]. These data suggest that ozanimod is effective in CS-naive patients, and might be a potential treatment option especially for those with medical reasons to avoid CS treatment such as diabetes or osteoporosis.

Considering the True North study comprised a greater proportion of biologic-experienced patients and a small proportion (<10%) of Asian patients, the results of that study are difficult to generalize to Japanese patients. Accordingly, this subanalysis provides useful information regarding the effectiveness of ozanimod in Japanese IM-/AT-naive patients, without concomitant CS, a patient population that has rarely been included in prior studies. Therefore, our findings could be useful for supporting treatment decisions and to stimulate future research in this setting.

The recent American Gastroenterological Association evidence synthesis of ATs for the management of moderate-to-severe UC highlighted some therapeutic options for biologic-naive patients, including the clinically important benefits of ozanimod and biologics [28]. The report ranked ozanimod “highly” for the induction of clinical remission. Considering the available evidence, the American Gastroenterological Association living guidelines for moderate-to-severe UC recommend higher-efficacy agents, including ozanimod, for AT-naive patients [29]. In general, CS therapy is the first-line treatment for patients with UC who fail to achieve remission with 5-ASA. For CS-dependent patients, an IM is given to maintain remission induced by CS. Patients contraindicated to IMs or patients with an insufficient therapeutic effect should start a biologic or JAK inhibitor as further treatment. Based on the present data, ozanimod is a potential treatment option for patients who are CS-dependent and patients who cannot use 5-ASA. Since S1PRMs are being developed and classified as ATs for patients with moderately to severely active UC, early intervention before CS would not be freely recommended in clinical practice, despite being permitted by their label. The 2026 Diagnostic Criteria and Treatment Guidelines for Ulcerative Colitis and Crohn’s Disease [30] described limited usage of ozanimod for CS-naive patients with 5-ASA, with specific examples (i.e., 5-ASA intolerance or presence of NUDT15 risk genotypes) as acceptable exceptions. Considering that the patient populations likely to benefit most from S1PRMs have not been defined, this should be further explored in prospective studies of various UC populations, together with the accumulation of real-world clinical data, with hypotheses generated based on the results of this study.

We also examined the safety of ozanimod 0.92 mg. TEAEs leading to treatment discontinuation were rare. Overall, the safety profile was consistent with the profiles reported in prior studies, including the overall population of J-True North [13], the overall population of True North [10], and the subanalysis of AT-naive patients in True North [21]. The most common TEAEs in the ozanimod 0.92 mg group were nasopharyngitis and pyrexia, TEAESI were infrequent, and no new safety signals were identified. Considering the results of J-True North and True North, there appear to be no ethnic differences in the safety profile of ozanimod. The safety data presented here should not be considered in isolation, but rather in conjunction with existing data to avoid overinterpretation due to the small sample size.

In summary, the evidence from this study demonstrates the efficacy and safety of ozanimod following failure of 5-ASA (with/without CS) in patients with UC. Further studies in a larger population may be needed to verify this strategy.

The limitations of the J-True North study are discussed in more detail in the earlier report [13]. In particular, long-term data from the open-label extension are still being accumulated and will be useful to confirm the long-term efficacy of ozanimod in IM-/AT-naive patients. The limited number of patients without prior or concomitant CS exposure precluded meaningful analyses in this population. As a post hoc analysis involving a selected subpopulation of patients, the sample size may not provide sufficient statistical power and some bias may arise due to patient selection, including false-negative results for some endpoints due to type II error. We should also consider the possibility that any differences in baseline characteristics between the ozanimod and placebo group such as the frequency of prior CS use (62.1% vs. 80.0%) might impact on the findings. Furthermore, missing values were imputed using the non-responder imputation method, which may introduce some error, and multiple testing of a single study may raise the risk of type I statistical error. For these reasons, the results presented in this manuscript should be considered with some caution.

In conclusion, although the results should be interpreted with caution owing to the limitations of the study, this subgroup analysis suggested that ozanimod 0.92 mg was more effective than placebo in the induction and maintenance phases in Japanese IM-/AT-naive patients with moderate-to-severe UC, without concomitant CS therapy, similar to the prior findings of the True North study. Another novel finding relates to the onset of efficacy and endoscopic remission (MES of 0) among Japanese patients. The safety profile of ozanimod 0.92 mg in this subgroup was favorable and consistent with the overall population in J-True North and a similar analysis of True North. Although ozanimod is broadly used in patients with UC across various treatment backgrounds, our results suggest that ozanimod may be an optimal treatment option for patients with UC following 5-ASA failure with or without CS. Thus, our results could be useful for guiding treatment decisions and stimulating future research examining the optimal treatments for such patients.

NOTES

Funding Source

This study was funded by Bristol Myers Squibb.

Conflict of Interest

Hisamatsu T has received research grants from Mitsubishi Tanabe Pharma, EA Pharma, AbbVie, JIMRO, Zeria Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Pfizer, Boston Scientific, and Mochida Pharmaceutical; consulting fees from EA Pharma, AbbVie, Janssen Pharmaceutical, Pfizer, Mitsubishi Tanabe Pharma, JIMRO, Mochida Pharmaceutical, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Abivax, Chugai Pharmaceutical, and MSD; and lecture fees from EA Pharma, AbbVie, Janssen Pharmaceutical, Pfizer, Mitsubishi Tanabe Pharma, JIMRO, Mochida Pharmaceutical, Bristol Myers Squibb, Eli Lilly and Company, and Gilead Sciences. Fujii T has received research grants from AbbVie, Alfresa, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Celgene, EA Pharma, Eisai, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical, Kissei Pharmaceutical, Mebix, Sanofi, and Takeda Pharmaceutical; and payments for lectures, presentations, and speakers’ bureaus from AbbVie, Bristol Myers Squibb, EA Pharma, Janssen Pharmaceutical, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichiiko, Nippon Kayaku, Takeda Pharmaceutical, Taiho Pharmaceutical, and Zeria Pharmaceutical. Nakase H has received payments for speakers’ bureaus from AbbVie, Mitsubishi Tanabe Pharma, Janssen Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Gilead Sciences, JIMRO, and EA Pharma; is the Chairman of the Japanese Society for Inflammatory Bowel Disease; is the Director of the Japanese Society of Gastroenterology; and reports an endowed chair from Mochida Pharmaceutical, JIMRO, Kyorin Pharmaceutical, and Miyarisan Pharmaceutical. Matsuoka K has received research grants from Mochida Pharmaceutical, AbbVie, Nippon Kayaku, and Zeria Pharmaceutical; personal fees from Takeda Pharmaceutical, Eli Lilly and Company, and Johnson & Johnson; and honoraria for lectures from Bristol Myers Squibb, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Johnson & Johnson, AbbVie, EA Pharma, Pfizer, Mochida Pharmaceutical, Kyorin Pharmaceutical, Zeria Pharmaceutical, Kissei Pharmaceutical, Gilead Sciences, Celltrion Healthcare, and Eli Lilly and Company. Saruta M has received research grants from AbbVie, Zeria Pharmaceutical, CMIC CMO, and Mochida Pharmaceutical; and payments or honoraria from AbbVie, Gilead Sciences, Kissei Pharmaceutical, Mochida Pharmaceutical, Takeda Pharmaceutical, EA Pharma, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Nobelpharma, and Viatris Pharmaceutical. Kobayashi T has received research grants from AbbVie, Alfresa Pharma, EA Pharma, Gilead Sciences, Nippon Kayaku, Eli Lilly and Company, Mochida Pharmaceutical, Janssen Pharmaceutical, Pfizer, Sekisui Medical, Samsung Medison, Takeda Pharmaceutical, Bristol Myers Squibb, Mitsubishi Tanabe Pharma, Zeria Pharmaceutical, JIMRO, and Helmsley Charitable Trust; consulting fees from Takeda Pharmaceutical, Alfresa Pharma, Zeria Pharmaceutical, Kyorin Pharmaceutical, Nippon Kayaku, Mitsubishi Tanabe Pharma, AbbVie, Pfizer, Janssen Pharmaceutical, JIMRO, and Galapagos; and payments or honoraria from EA Pharma, Kissei Pharmaceutical, Takeda Pharmaceutical, Pfizer, Nippon Kayaku, Alfresa Pharma, AbbVie, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Janssen Pharmaceutical, and Bristol Myers Squibb. Inoue S and Uchikawa Y are employees of and have received stock options in Bristol Myers Squibb. Toriyama K and Fujimoto G are employees of Bristol Myers Squibb. Wang D was an employee of and had received stock options in Bristol Myers Squibb at the time the study was conducted. Hibi T has received research grants from Alfresa Pharma, JIMRO, Kyorin Pharmaceutical, Miyarisan Pharmaceutical, and Mochida Pharmaceutical; consulting fees from AbbVie, Bristol Myers Squibb, Celltrion Healthcare, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical, and Takeda Pharmaceutical; and payments or honoraria from AbbVie, EA Pharma, Janssen Pharmaceutical, JIMRO, Kyorin Pharmaceutical, Mochida Pharmaceutical, Pfizer, and Zeria Pharmaceutical.

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

Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. Deidentified individual patient data will not be shared.

Author Contributions

Conceptualization: Hisamatsu T, Inoue S, Toriyama K, Wang D, Uchikawa Y, Fujimoto G, Hibi T. Data curation: Fujimoto G. Formal analysis: Fujimoto G. Funding acquisition: Inoue S, Wang D. Investigation: Hisamatsu T, Fujii T, Nakase H, Matsuoka K, Saruta M, Kobayashi T, Hibi T. Methodology: Inoue S, Toriyama K, Wang D, Uchikawa Y, Fujimoto G. Project administration: Toriyama K. Supervision: Hisamatsu T, Hibi T. Validation: Toriyama K, Fujimoto G. Writing–original draft: Toriyama K. Writing–review and editing: all authors. Approval of final manuscript: all authors.

Additional Contributions

The authors thank Nicholas D. Smith (LESPEDEZA, a division of Omnicom Health Japan K.K.) for medical writing support, which was funded by Bristol Myers Squibb.

Supplementary Material

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

Supplementary Methods

Inclusion/Exclusion Criteria

ir-2026-00031-Supplementary-Methods.pdf

Supplementary Fig. 1.

Design of the phase 2/3 J-True North study.

ir-2026-00031-Supplementary-Fig-1.pdf

Supplementary Fig. 2.

Symptomatic outcomes in the induction period in overall patients (placebo and ozanimod 0.92 mg groups). Changes in RBS (A), SFS (B), proportions of patients with symptomatic response (C), and proportions of patients with symptomatic remission (D) over time.

ir-2026-00031-Supplementary-Fig-2.pdf

Fig. 1.

Clinical response (A), clinical remission (B), endoscopic remission (C), endoscopic improvement (D), mucosal healing (E), and histologic remission (F) at Weeks 12 and 52. (A) Clinical response was defined as a reduction from baseline in the complete Mayo score of ≥3 points and ≥30%, and a reduction from baseline in the RBS of ≥1 point or an absolute RBS of ≤1 point. (B) Clinical remission was defined as RBS of 0 and SFS of ≤1 (and a decrease of ≥1 point from the baseline SFS) and MES of ≤1. (C) Endoscopic remission was defined as MES of 0. (D) Endoscopic improvement was defined as MES of ≤1. (E) Mucosal healing was defined as MES of ≤1 and Geboes score of <2.0. (F) Histologic remission was defined as Geboes score of <2.0. Δ represents the weighted difference. Missing values were imputed using the non-responder imputation method. Between-group comparisons were performed using the Cochran–Mantel–Haenszel test stratified by corticosteroid use at screening (yes or no) and prior biologic therapy use (yes or no). Nominal P-values are shown, without adjustment for multiplicity. CI, confidence interval; RBS, rectal bleeding subscore; SFS, stool frequency subscore; MES, Mayo endoscopy subscore.

Fig. 2.

Changes in RBS (A), SFS (B), proportions of patients with symptomatic response (C), and proportions of patients with symptomatic remission (D) over time. (C) Symptomatic response was defined as ≥1 point and ≥30% decrease in RBS+SFS score with a ≥1 point decrease of RBS from baseline or RBS of ≤1. (D) Symptomatic remission was defined as RBS of 0 and SFS of ≤1 (and a decrease of ≥1 point from the baseline SFS). Error bars (A, B) indicate standard error. RBS, rectal bleeding subscore; CI, confidence interval; LSM, least-squares mean; SFS, stool frequency subscore.

Table 1.

Patient Demographic and Clinical Characteristics

Characteristic	Placebo (n = 30)	Ozanimod 0.92 mg (n = 29)
Female sex, No. (%)	15 (50.0)	8 (27.6)
Age (yr), mean ± SD	43.5 ± 11.3	41.3 ± 12.5
BMI (kg/m²), mean ± SD	22.5 ± 3.1	22.7 ± 3.8
Time since UC diagnosis (yr), mean ± SD	10.1 ± 8.0	3.8 ± 4.4
Extent of UC, No. (%)
Left-sided	15 (50.0)	14 (48.3)
Extensive	15 (50.0)	15 (51.7)
Complete Mayo score, mean ± SD	8.1 ± 1.0	8.1 ± 1.6
9-Point Mayo score, mean ± SD	6.1 ± 1.0	6.2 ± 1.4
Mayo endoscopic subscore, No. (%)
2	13 (43.3)	10 (34.5)
3	17 (56.7)	19 (65.5)
Mayo rectal bleeding subscore, No. (%)
1	20 (66.7)	14 (48.3)
2	9 (30.0)	14 (48.3)
3	1 (3.3)	1 (3.4)
Mayo SFS, No. (%)
1	5 (16.7)	12 (41.4)
2	14 (46.7)	5 (17.2)
3	11 (36.7)	12 (41.4)
Prior medications, No. (%)^a
5-ASA	30 (100)	29 (100)
CS	24 (80.0)	18 (62.1)

^a The post hoc analysis comprised patients who were naive to immunomodulators or advanced therapies (i.e., Janus kinase inhibitor [tofacitinib] or biologics) and not using a CS.

SD, standard deviation; BMI, body mass index; UC, ulcerative colitis; SFS, stool frequency subscore; 5-ASA, 5-aminosalicylic acid; CS, corticosteroids.

Table 2.

Summary of TEAEs during the Induction or Maintenance Periods

Categories of TEAEs	Placebo (n = 30)	Ozanimod 0.92 mg (n = 29)
TEAEs	19 (63.3)	23 (79.3)
Serious TEAEs	0	0
Serious related TEAEs	0	0
TEAEs leading to treatment discontinuation	0	1 (3.4)
Related TEAEs leading to treatment discontinuation	0	1 (3.4)
TEAEs reported in ≥ 2 patients in either group^a,b
Nasopharyngitis	4 (13.3)	5 (17.2)
Pyrexia	3 (10.0)	4 (13.8)
COVID-19	1 (3.3)	3 (10.3)
Headache	2 (6.7)	2 (6.9)
Back pain	1 (3.3)	2 (6.9)
Hepatic function abnormal	1 (3.3)	2 (6.9)
Arthralgia	1 (3.3)	2 (6.9)
SARS-CoV-2 test positive	1 (3.3)	2 (6.9)
Edema peripheral	2 (6.7)	1 (3.4)
Vertigo	0	2 (6.9)
Diarrhea	0	2 (6.9)
Immunization reaction	2 (6.7)	0

Values are presented as number (%).

^a TEAEs in ≥2 patients in either the placebo or ozanimod group are shown.

^b By MedDRA/J version 26.0 Preferred Term.

TEAEs, treatment-emergent adverse events; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; MedDRA/J, Medical Dictionary for Regulatory Affairs Japanese.

Table 3.

Summary of TEAESI during the Induction or Maintenance Periods

Categories of TEAESI	Placebo (n = 30)	Ozanimod 0.92 mg (n = 29)
TEAESI	0	2 (6.9)
Bradycardia	0	0
Heart conduction abnormalities	0	0
Macular edema	0	1 (3.4)
Malignancy	0	0
Serious or opportunistic infection	0	1 (3.4)
Herpes zoster^a	0	1 (3.4)
Pulmonary effects	0	0
Hepatic effects	0	0
Posterior reversible encephalopathy syndrome	0	0
Progressive multifocal leukoencephalopathy	0	0
Events associated with orthostatic hypotension	0	0

Values are presented as number (%).

^a MedDRA/J version 26.0 Preferred Term.

TEAESI, treatment-emergent adverse events of special interest; MedDRA/J, Medical Dictionary for Regulatory Affairs Japanese.

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Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study

DOI: https://doi.org/10.5217/ir.2026.00031

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Fig. 1. Clinical response (A), clinical remission (B), endoscopic remission (C), endoscopic improvement (D), mucosal healing (E), and histologic remission (F) at Weeks 12 and 52. (A) Clinical response was defined as a reduction from baseline in the complete Mayo score of ≥3 points and ≥30%, and a reduction from baseline in the RBS of ≥1 point or an absolute RBS of ≤1 point. (B) Clinical remission was defined as RBS of 0 and SFS of ≤1 (and a decrease of ≥1 point from the baseline SFS) and MES of ≤1. (C) Endoscopic remission was defined as MES of 0. (D) Endoscopic improvement was defined as MES of ≤1. (E) Mucosal healing was defined as MES of ≤1 and Geboes score of <2.0. (F) Histologic remission was defined as Geboes score of <2.0. Δ represents the weighted difference. Missing values were imputed using the non-responder imputation method. Between-group comparisons were performed using the Cochran–Mantel–Haenszel test stratified by corticosteroid use at screening (yes or no) and prior biologic therapy use (yes or no). Nominal P-values are shown, without adjustment for multiplicity. CI, confidence interval; RBS, rectal bleeding subscore; SFS, stool frequency subscore; MES, Mayo endoscopy subscore.

Fig. 2. Changes in RBS (A), SFS (B), proportions of patients with symptomatic response (C), and proportions of patients with symptomatic remission (D) over time. (C) Symptomatic response was defined as ≥1 point and ≥30% decrease in RBS+SFS score with a ≥1 point decrease of RBS from baseline or RBS of ≤1. (D) Symptomatic remission was defined as RBS of 0 and SFS of ≤1 (and a decrease of ≥1 point from the baseline SFS). Error bars (A, B) indicate standard error. RBS, rectal bleeding subscore; CI, confidence interval; LSM, least-squares mean; SFS, stool frequency subscore.

Graphical abstract

Fig. 1.

Fig. 2.

Graphical abstract

Characteristic	Placebo (n = 30)	Ozanimod 0.92 mg (n = 29)
Female sex, No. (%)	15 (50.0)	8 (27.6)
Age (yr), mean ± SD	43.5 ± 11.3	41.3 ± 12.5
BMI (kg/m²), mean ± SD	22.5 ± 3.1	22.7 ± 3.8
Time since UC diagnosis (yr), mean ± SD	10.1 ± 8.0	3.8 ± 4.4
Extent of UC, No. (%)
Left-sided	15 (50.0)	14 (48.3)
Extensive	15 (50.0)	15 (51.7)
Complete Mayo score, mean ± SD	8.1 ± 1.0	8.1 ± 1.6
9-Point Mayo score, mean ± SD	6.1 ± 1.0	6.2 ± 1.4
Mayo endoscopic subscore, No. (%)
2	13 (43.3)	10 (34.5)
3	17 (56.7)	19 (65.5)
Mayo rectal bleeding subscore, No. (%)
1	20 (66.7)	14 (48.3)
2	9 (30.0)	14 (48.3)
3	1 (3.3)	1 (3.4)
Mayo SFS, No. (%)
1	5 (16.7)	12 (41.4)
2	14 (46.7)	5 (17.2)
3	11 (36.7)	12 (41.4)
Prior medications, No. (%)^a
5-ASA	30 (100)	29 (100)
CS	24 (80.0)	18 (62.1)

Categories of TEAEs	Placebo (n = 30)	Ozanimod 0.92 mg (n = 29)
TEAEs	19 (63.3)	23 (79.3)
Serious TEAEs	0	0
Serious related TEAEs	0	0
TEAEs leading to treatment discontinuation	0	1 (3.4)
Related TEAEs leading to treatment discontinuation	0	1 (3.4)
TEAEs reported in ≥ 2 patients in either group^a,b
Nasopharyngitis	4 (13.3)	5 (17.2)
Pyrexia	3 (10.0)	4 (13.8)
COVID-19	1 (3.3)	3 (10.3)
Headache	2 (6.7)	2 (6.9)
Back pain	1 (3.3)	2 (6.9)
Hepatic function abnormal	1 (3.3)	2 (6.9)
Arthralgia	1 (3.3)	2 (6.9)
SARS-CoV-2 test positive	1 (3.3)	2 (6.9)
Edema peripheral	2 (6.7)	1 (3.4)
Vertigo	0	2 (6.9)
Diarrhea	0	2 (6.9)
Immunization reaction	2 (6.7)	0

Categories of TEAESI	Placebo (n = 30)	Ozanimod 0.92 mg (n = 29)
TEAESI	0	2 (6.9)
Bradycardia	0	0
Heart conduction abnormalities	0	0
Macular edema	0	1 (3.4)
Malignancy	0	0
Serious or opportunistic infection	0	1 (3.4)
Herpes zoster^a	0	1 (3.4)
Pulmonary effects	0	0
Hepatic effects	0	0
Posterior reversible encephalopathy syndrome	0	0
Progressive multifocal leukoencephalopathy	0	0
Events associated with orthostatic hypotension	0	0

Table 1. Patient Demographic and Clinical Characteristics

The post hoc analysis comprised patients who were naive to immunomodulators or advanced therapies (i.e., Janus kinase inhibitor [tofacitinib] or biologics) and not using a CS.

SD, standard deviation; BMI, body mass index; UC, ulcerative colitis; SFS, stool frequency subscore; 5-ASA, 5-aminosalicylic acid; CS, corticosteroids.

Table 2. Summary of TEAEs during the Induction or Maintenance Periods

Values are presented as number (%).

TEAEs in ≥2 patients in either the placebo or ozanimod group are shown.

By MedDRA/J version 26.0 Preferred Term.

Table 3. Summary of TEAESI during the Induction or Maintenance Periods

Values are presented as number (%).

MedDRA/J version 26.0 Preferred Term.

TEAESI, treatment-emergent adverse events of special interest; MedDRA/J, Medical Dictionary for Regulatory Affairs Japanese.