1Bristol Myers Squibb, Princeton, United States, 2University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States

Introduction: OZA is approved in multiple countries for treatment of moderately to severely active UC in adults. In the phase 3 TN study, OZA was efficacious for up to 52 wk in pts with moderately to severely active UC. CRP is a widely used serum indicator of inflammation and prognosis in inflammatory bowel disease.

Aims & Methods: The effect of OZA on CRP levels and the association of CRP levels with OZA efficacy were assessed in all TN pts. During the 10-wk induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or placebo (PBO) or received open-label OZA 0.92 mg in Cohort 2. Pts with clinical response to OZA at Week (W) 10 were rerandomized to OZA or PBO for maintenance through W52. Serum CRP levels were assessed at baseline (BL) through W52. Disease activity scores (rectal bleeding subscore [RBS], stool frequency subscore, Physician’s Global Assessment subscore, endoscopy subscore, and partial and total Mayo scores) were assessed at BL and W10. Efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10. Associations of CRP levels with disease activity and efficacy endpoints were assessed using Spearman’s correlation and logistic regression, respectively.

Results: 645 pts were randomized to OZA (n=429) or PBO (n=216) and 367 pts received open-label OZA for 10 wk; 230 and 227 OZA-treated pts who responded were rerandomized to OZA and PBO, respectively, for maintenance through W52 (69 PBO-treated pts who responded continued on PBO). Pts on OZA showed reductions from BL in CRP levels at W10, which was significant vs PBO (P<0.001, both cohorts) (Table). Reductions in CRP levels were significantly greater in pts with vs without clinical response at W10 in all treatment groups (P<0.001, all groups) (Table). Significantly greater reductions in CRP levels occurred with OZA vs PBO at W10 regardless of prior biologic or anti–tumor necrosis factor exposure (P<0.05, all groups). Reductions in CRP levels were maintained through W52; pts who continued OZA had similar reductions at W52 as pts who switched to PBO (Table). Decreases in CRP levels in W52 responders were maintained through W52 of treatment, while W52 nonresponder CRP levels started to rise following induction toward BL values (Table). BL CRP levels were significantly positively correlated with most BL disease activity scores (Spearman’s rho 0.2–0.3, P<0.05, all scores) except RBS. BL CRP levels and change in CRP levels at W5 were prognostic for W10 response. Higher BL CRP levels were associated with lower endoscopic improvement, mucosal healing, and histologic remission at W10 and greater reductions in CRP levels at W5 were associated with better clinical response at W10, independent of treatment. Change in CRP levels at W10 was significantly positively correlated with change in most disease activity scores at W10 with OZA and PBO (Spearman’s rho 0.1–0.3, P<0.05, all scores in both groups) except endoscopy with PBO.

Adjusted mean percent change from BL in CRP levels (95% CI)	Induction (Week 10)			Maintenance (Week 52)
	PBO (C1) (n=216)	OZA (C1) (n=429)	OZA (C2) (n=367)	OZA/PBO (n=227)	OZA/OZA (n=230)​​​​​​​​​
All pts	–1.2 (–13.3, 12.7) n=192	–26.8 (–33.3, –19.8) n=407	–25.7 (–32.7, –18.1) n=336	–19.9 (–30.9, –7.1) n=125	–23.5 (–32.7, –13.0) n=181
Respondersa	–39.9 (–52.5, –24.0) n=55	–45.9 (–52.2, –38.9) n=204	–40.4 (–47.5, –32.3) n=189	–33.1 (–44.1, –20.0) n=91	–30.9 (–40.4, –20.0) n=135
Nonrespondersb	12.0 (–3.5, 29.9) n=137	–10.7 (–20.9, 0.9) n=203	–7.4 (–19.8, 7.0) n=147	3.1 (–20.3, 33.4) n=34	–2.9 (–23.0, 22.6) n=46
aResponders are pts who achieved clinical response at W10 for the induction period and at W52 for the maintenance period. bNonresponders are pts who did not achieve clinical response at W10 for the induction period and at W52 for the maintenance period. C1, Cohort 1; C2, Cohort 2.

Conclusion: In moderately to severely active UC pts, OZA led to reductions in CRP levels. Higher BL CRP levels were associated with worse disease outcomes and greater reductions in CRP levels were associated with better disease outcomes regardless of treatment, supporting CRP levels as a prognostic biomarker for UC.

1Bristol Myers Squibb, Princeton, United States, 2University of Leuven, Leuven, Belgium

Introduction: OZA is a sphingosine 1-phosphate receptor modulator approved for the treatment of moderately to severely active UC. In the phase 3 TN study, OZA was efficacious for up to 52 wk with a favorable safety profile. IL-17A, a proinflammatory cytokine, sustains the release of other inflammatory mediators and is associated with inflammatory bowel disease.

Aims & Methods: This analysis assessed the effect of OZA on IL-17A levels and the association of IL-17A levels with OZA efficacy during TN. During the 10-wk induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or placebo (PBO) and pts in Cohort 2 received open-label OZA 0.92 mg. Pts with clinical response to OZA at Week (W) 10 were rerandomized to OZA or PBO for maintenance through W52. IL-17A levels were assessed at baseline, W10, and W52. Disease activity scores (rectal bleeding and stool frequency subscores, Physician’s Global Assessment subscore, endoscopy subscore, and partial and total Mayo scores) were assessed at baseline and W10. Efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10 and W52. Associations of IL-17A levels with disease activity and efficacy endpoints were assessed using Spearman’s correlation and logistic regression, respectively.

Results: In all, 645 pts were randomized to OZA (n=429) or PBO (n=216) and 367 pts received open-label OZA; 230 and 227 OZA-treated pts were rerandomized to OZA and PBO, respectively, for maintenance. Pts on OZA demonstrated reductions from baseline in IL-17A at W10, which was significant vs PBO (P<0.001, both cohorts) (Table). IL-17A reductions were significantly greater in pts with vs without clinical response at W10 in all OZA and PBO treatment groups (P<0.01, all groups) (Table). Significantly greater IL-17A reductions occurred with OZA vs PBO at W10 regardless of prior biologic or anti–tumor necrosis factor exposure (P<0.001, all groups). IL-17A reductions were maintained through W52; pts who continued OZA had significantly greater IL-17A reductions at W52 vs pts who switched to PBO (P<0.001) (Table). IL-17A reductions were significantly greater in pts with vs without clinical response at W52 (P<0.001, OZA and PBO groups) (Table). Baseline IL-17A levels were significantly correlated with all baseline disease activity scores (Spearman’s rho 0.1–0.2, P<0.05, all scores), but were not associated with treatment responses at W10. Change in IL-17A from baseline to W10 was significantly correlated with change in all disease activity scores at W10 with OZA and PBO (Spearman’s rho 0.2–0.4, P<0.05, all scores in both groups). Furthermore, greater reductions from baseline to W10 in IL-17A was significantly associated with higher probability of achieving clinical remission, clinical response, endoscopic improvement, and mucosal healing at W52 (P<0.05, all endpoints) in pts on continuous OZA through W52.

Change from baseline in IL-17A at W10 and W52
IL-17A adjusted mean percent change from baseline (95% CI)	Induction (W10)			Maintenance (W52)
	C1: PBO (n=216)	C1: OZA (n=429)	C2: OZA (n=367)	OZA/PBO (n=227)	OZA/OZA (n=230)
All pts	–10.5 (–18.1, –2.2) n=159	–33.5 (–37.5, –29.3) n=340	–40.3 (–44.0, –36.4) n=294	–37.5 (–43.6, –30.7) n=112	–50.7 (–54.9, –46.1) n=152
Respondersa	–27.8 (–38.0, –15.9) n=47	–46.6 (–50.6, –42.2) n=177	–46.6 (–50.6, –42.2) n=175	–44.1 (–50.3, –37.2) n=80	–55.8 (–60.0, –51.3) n=113
Nonrespondersb	–5.3 (–14.2, 4.5) n=112	–19.1 (–25.4, –12.2) n=163	–30.9 (–37.2, –24.0) n=119	–10.5 (–25.1, 7.0) n=32	–27.5 (–38.5, –14.6) n=39
aResponders are pts who achieved clinical response at W10 for the induction period and at W52 for the maintenance period. bNonresponders are pts who did not achieve clinical response at W10 for the induction period and at W52 for the maintenance period. C1, Cohort 1; C2, Cohort 2.

Conclusion: OZA led to IL-17A reductions, indicative of decreases in inflammatory responses. Higher baseline IL-17A was associated with higher baseline disease activity, and greater reductions in IL-17A were associated with better short- and long-term disease outcomes. These data support IL-17A as a good disease marker for UC.

1University of Leuven, Leuven, Belgium, 2Division of Digestive Diseases, University of Cincinnati, Cincinnati, United States, 3Center for Crohn’s Disease & Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta, United States, 4Cleveland Clinic, Cleveland, United States, 5Bristol Myers Squibb, Princeton, United States, 6Icahn School of Medicine of Mount Sinai, New York, United States

Introduction: Ozanimod (OZA) is approved for the treatment of moderately to severely active (mod/sev) ulcerative colitis (UC). OZA demonstrated superior efficacy vs placebo in the 52-wk phase 3 True North (TN) study in adults with mod/sev UC and demonstrated durable efficacy over ~3 years of continuous treatment in the open-label extension (OLE). Previous analyses reported greater clinical and mucosal efficacy during TN in patients (pts) who were biologic-naive vs biologic-experienced.

Aims & Methods: The goal of the present analysis was to evaluate the effect of prior biologic exposure on the durability of OZA efficacy in pts with mod/sev UC. Pts who achieved clinical response with or without remission after 52 wk of continuous OZA treatment during TN and entered the OLE were evaluated (data cutoff: 10 January 2022). Symptomatic clinical response and remission were evaluated through OLE W94, and clinical response, clinical remission, endoscopic improvement, and corticosteroid (CS)–free remission were evaluated at OLE W46 and W94 using observed case (OC) and nonresponder imputation (NRI) analyses. Data were analyzed in pts with and without prior biologic exposure at baseline. Pts exposed to only a Janus kinase inhibitor were not included in this analysis.

Results: In all, 128 pts with prior biologic information entered the OLE after achieving clinical response on continued OZA at TN Week (W) 52 (biologic-naive, n=82; biologic-experienced, n=46). Baseline pt characteristics in TN were generally balanced between both groups, except for longer disease duration, higher CS use at screening, and higher prior immunomodulator use in biologic-experienced pts. Complete and partial Mayo scores were higher in biologic-experienced pts at OLE entry. The proportions of pts with symptomatic response at OLE W5 were 100% (OC) in both biologic-naive and -experienced pts. At OLE W5, 90.8% (OC) of biologic-naive pts and 72.1% (OC) of biologic-experienced pts achieved symptomatic remission. Rates of symptomatic clinical response and clinical remission (OC) were maintained through OLE W94. In pts with clinical response with or without remission at TN W52, the proportions of biologic-naive and -experienced pts achieving clinical response, clinical remission, endoscopic improvement, and CS-free remission at OLE W46 and W94 are shown in the Table. Overall, greater efficacy was observed in biologic-naive vs -experienced pts across all endpoints. Notably, pts in clinical remission at TN W52 showed similar efficacy rates in both biologic-naive and -experienced pts, whereas biologic-naive pts demonstrated greater efficacy than biologic-experienced pts in those without clinical remission at TN W52. Similar patterns were seen using NRI analysis.

Efficacy at OLE W46 and OLE W94 by biologic exposure at baseline and clinical response at W52/OLE entry (OC analysis)		Biologic-naïve (n=82) Clinical response at TN W52a	Biologic-experienced (n=46) Clinical response at TN W52a	Biologic-naive (n=58) Clinical remission at TN W52b	Biologic-experienced (n=22) Clinical remission at TN W52b	Biologic-naive (n=24) Clinical response (without remission) at TN W52c	Biologic-experienced (n=24) Clinical response (without remission) at TN W52c
Clinical response,a % (n/N)	OLE W46	95.2 (60/63)	96.8 (30/31)	95.7 (44/46)	100.0 (17/17)	94.1 (16/17)	92.9 (13/14)
	OLE W94	90.9 (50/55)	92.0 (23/25)	95.0 (38/40)	92.3 (12/13)	80.0 (12/15)	91.7 (11/12)
Clinical remission,b % (n/N)	OLE W46	77.8 (49/63)	61.3 (19/31)	82.6 (38/46)	82.4 (14/17)	64.7 (11/17)	35.7 (5/14)
	OLE W94	70.9 (39/55)	64.0 (16/25)	77.5 (31/40)	69.2 (9/13)	53.3 (8/15)	58.3 (7/12)
Endoscopic improvement,d % (n/N)	OLE W46	82.6 (57/69)	68.8 (22/32)	86.3 (44/51)	88.9 (16/18)	72.2 (13/18)	42.9 (6/14)
	OLE W94	73.7 (42/57)	71.4 (20/28)	78.0 (32/41)	78.6 (11/14)	62.5 (10/16)	64.3 (9/14)
CS-free remission,e % (n/N)	OLE W46	74.6 (47/63)	61.3 (19/31)	80.4 (37/46)	82.4 (14/17)	58.8 (10/17)	35.7 (5/14)
	OLE W94	69.1 (38/55)	64.0 (16/25)	75.0 (30/40)	69.2 (9/13)	53.3 (8/15)	58.3 (7/12)
aClinical response: decrease from baseline in the 3-component Mayo score (sum of RBS, SFS, and MES) of ≥2 points and ≥35% and reduction of ≥1 point in RBS or an absolute RBS of ≤1 point. bClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from baseline SFS), and MES ≤1. cMet criteria for clinical response but not clinical remission. dEndoscopic improvement: MES ≤1 point. eClinical remission while off CS for ≥12 wk. MES, Mayo endoscopy subscore; RBS, rectal bleeding subscore; SFS, stool frequency subscore.

Conclusion: Clinical and symptomatic outcomes were maintained in biologic-naive and -experienced pts with mod/sev active UC receiving ~3 years of continuous OZA treatment. Greater efficacy was generally observed in biologic-naive pts; however, biologic-naive and -experienced pts who achieved clinical response with remission at TN W52 had similar efficacy during the OLE.

1University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, United States, 2University of Chicago Medicine, Department of Pathology, Chicago, United States

Introduction: Ozanimod regulates lymphocyte egress from the spleen and lymph nodes into the systemic circulation. The histologic changes which occur in the lymph nodes of patients on these therapies is unknown.

Aims & Methods: We aimed to describe histologic changes in lymph nodes from patients with UC who were treated with ozanimod and underwent subsequent colectomy due to treatment-refractory disease. This retrospective study included patients with UC undergoing total colectomy for treatment-refractory disease who were treated with ozanimod within the 2 months prior to colectomy and a cohort of patients with UC undergoing colectomy who did not have ozanimod exposure. Histology of the lymph nodes from the mesentery of colectomy specimens were reviewed blindly by a hematophatologist (JXC) and an expert GI pathologist (CRW). Histopathological parameters were scored and 2-tailed student’s unpaired t-test was used to determine significance between groups. Demographic and clinical data were recorded.

Results: From our series of 45 patients treated with ozanimod, 6 (13%) required surgery for treatment-refractory disease. Colectomy specimen data were available for 5 patients (1 patient had surgery at an outside center). Lymph node specimens from 6 control patients with UC who had colectomy were also examined. Demographic and clinical data are summarized in Table 1. The duration of ozanimod therapy prior to surgery ranged from 6 to 24 weeks. Histologic examination of lymph nodes showed that patients treated with ozanimod had significantly greater extent of dilated sinuses (p=0.03) and greater degrees of sinus histiocytosis (p=0.03) compared with control patients. In addition, there was a tendency towards more Castleman-like angiotrophic hyperplasia, plasma cell infiltration and subcortical interfollicular expansion in ozanimod treated patients (not statistically significant).

Ozanimod Case 1	50A	14B	FemaleC	Extensive colitisD	Infliximab, adalimumab, ustekinumab, vedolizumabE	6F	Treatment refractory diseaseG
Ozanimod Case 2	20	2	Male	Left sided colitis	Infliximab, vedolizumab, tofacitinib	12	Treatment refractory disease
Ozanimod Case 3	34	5	Female	Left sided colitis	Infliximab, ustekinumab, tofacitinib, vedolizumab	24	Treatment refractory disease
Ozanimod Case 4	24	2	Male	Extensive colitis	Infliximab, vedolizumab, tofacitinib, ustekinumab	16	Treatment refractory disease
Ozanimod Case 5	37	16	Male	Extensive colitis	Infliximab, adalimumab, ustekinumab, vedolizumab	8	Treatment refractory disease
Control Case 1	47	1	Male	Left sided colitis	Infliximab, vedolizumab, upadacitinib	n/a	Treatment refractory disease
Control Case 2	68	36	Male	Left sided colitis	Infliximab, ustekinumab, vedolizumab	n/a	Treatment refractory disease
Control Case 3	30	26	Female	Extensive colitis	Infliximab, golimumab, vedolizumab, tofacitinib	n/a	Treatment refractory disease
Control Case 4	32	4	Female	Left sided colitis	Infliximab, adalimumab	n/a	Treatment refractory disease
Control Case 5	29	5	Male	Extensive colitis	Adalimumab, ustekinumab, vedolizumab, tofacitinib	n/a	Treatment refractory disease

Table 1: Demographic and clinical data of patients with UC receiving ozanimod and control patients who underwent total colectomy
A Age (years); B Disease Duration (years); C Sex; D Disease Extent; E Prior Advanced Therapies; F Duration of ozanimod therapy (weeks); G Reason for colectomy

Conclusion: This study identifies unique histologic changes in the lymph nodes of patients with UC treated with ozanimod. These changes could be in keeping with the known mechanism of action of ozanimod and suggests that other inflammatory pathways were driving their disease activity in these patients. The significance of the changes, particularly the Castleman-like features, needs to be further investigated.

1Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom, 2UNC Chapel Hill, Chapel Hill, United States, 3Charité – Universitätsmedizin Berlin, Berlin, Germany, 4Amsterdam University Medical Center, Amsterdam, Netherlands, 5Goethe University Hospital, Frankfurt, Germany, 6Bristol Myers Squibb, Princeton, United States, 7Center for Crohn’s Disease & Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta, United States, 8University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States

Introduction: Many ulcerative colitis (UC) patients (pts) are suboptimally controlled on conventional therapies but are hesitant to move to biologics, indicating an unmet need for oral advanced therapies early in the treatment paradigm. Ozanimod (OZA), an oral, selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active UC in adults.

Aims & Methods: This post hoc analysis of the phase 3 True North clinical trial explored the efficacy of OZA in advanced therapy–naive UC pts who had active, symptomatic disease while on conventional therapies. OZA efficacy was assessed at Week (W) 10 in pts who had either moderate (Mayo endoscopy subscore [MES]=2) or severe (MES=3) endoscopic disease activity at baseline. Pts in Cohort 1 (C1) were randomized to OZA 0.92 mg or placebo (PBO) or received open-label OZA in Cohort 2 (C2) through W10. Pts were required to be on oral 5-aminosalicylate and/or corticosteroid for ≥2 wk before screening and continue through induction. Clinical endpoints (clinical remission, clinical response, endoscopic improvement, and mucosal healing) were assessed at W10. Treatment differences for OZA (C1) vs PBO were based on the Cochran-Mantel-Haenszel test, stratified by corticosteroid use at screening. Symptomatic clinical response and symptomatic clinical remission were assessed from W2 to W10.

Results: Of 616 advanced therapy–naive pts at baseline, 296 had moderate (PBO, n=64; OZA [C1], n=138; OZA [C2], n=94) and 320 had severe (PBO, n=73; OZA [C1], n=149; OZA [C2], n=98) endoscopic disease. Baseline pt characteristics were similar between groups, with higher prior immunomodulator use in severe (22%–34%) vs moderate (13%–23%) pts. Significantly higher symptomatic responses with OZA vs PBO were observed by W4 in moderate pts (OZA [C1] vs PBO: 67.4% vs 42.2%; difference: 23.0% [95% CI 8.6–37.3]) and by W5 in severe pts (OZA [C1] vs PBO: 51.0% vs 32.9%; difference: 17.6% [95% CI 4.1–31.2]). Similarly, significantly higher symptomatic remission rates were observed with OZA vs PBO by W5 in moderate pts (OZA [C1] vs PBO: 39.9% vs 18.8%; difference: 19.5% [95% CI 6.9–32.2]) and by W8 in severe pts (OZA [C1] vs PBO: 32.2% vs 16.4%; difference: 15.4% [95% CI 4.0–26.8]). OZA was more effective than PBO in achieving all clinical endpoints at W10 in moderate and severe pts (Table). Treatment differences (OZA [C1] vs PBO) were greater in moderate vs severe pts for clinical remission (22.8% [95% CI 11.7–33.9]; P<0.001 vs 8.0% [95% CI 1.7–14.2]; P=0.04), clinical response (27.2% [13.1–41.3]; P<0.001 vs 21.0% [8.2–33.8]; P=0.003), endoscopic improvement (28.7% [15.7–41.7]; P<0.001 vs 13.4% [5.2–21.7]; P=0.008), and mucosal healing (18.0% [8.1–27.9]; P=0.003 vs 5.4% [0.5–10.2]; P=0.09).

OZA vs PBO efficacy at W10 in advanced therapy–naive pts by baseline endoscopic disease activity
	Moderate disease (MES=2)			Severe disease (MES=3)
	C1: PBO (n=64)	C1: OZA (n=138)	C2: OZA (n=94)	C1: PBO (n=73)	C1: OZA (n=149)	C2: OZA (n=98)
Clinical remission,a n (%)	7 (10.9)	49 (35.5)	38 (40.4)	2 (2.7)	17 (11.4)	18 (18.4)
Clinical response,b n (%)	20 (31.3)	83 (60.1)	64 (68.1)	18 (24.7)	69 (46.3)	54 (55.1)
Endoscopic improvement,c n (%)	13 (20.3)	68 (49.3)	48 (51.1)	4 (5.5)	29 (19.5)	23 (23.5)
Mucosal healing,d n (%)	5 (7.8)	36 (26.1)	23 (24.5)	1 (1.4)	10 (6.7)	6 (6.1)
Pts with missing data were considered nonresponders. aClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from baseline SFS), and MES ≤1 point. bClinical response: decrease from baseline in the 3-component Mayo score (sum of RBS, SFS, and MES) of ≥2 points and ≥35% and a reduction of ≥1 point in RBS or absolute RBS of ≤1 point. cEndoscopic improvement: MES ≤1 point. dMucosal healing: MES ≤1 point and Geboes index score <2.0.

Conclusion: Pts with inadequate disease control while on conventional therapies were better controlled with OZA treatment than those who continued conventional treatments. Pts with moderate disease achieved greater benefit and responded more rapidly than those with severe disease. OZA is an effective oral advanced therapy option for pts suboptimally controlled on conventional therapies, especially those with moderate disease.

1Charité – Universitätsmedizin Berlin, Berlin, Germany, 2Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom, 3Amsterdam University Medical Center, Amsterdam, Netherlands, 4Dartmouth-Hitchcock Medical Center, Lebanon, United States, 5Mayo Clinic College of Medicine, Rochester, United States, 6Bristol Myers Squibb, Princeton, United States, 7University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States, 8UNC Chapel Hill, Chapel Hill, United States

Introduction: Conventional therapies, such as 5-aminosalicylate (5-ASA), corticosteroid (CS), and immunomodulators, are unable to maintain adequate disease control in many ulcerative colitis (UC) patients (pts), indicating a need for early use of advanced therapies. Ozanimod (OZA), an oral advanced therapy, is approved for the treatment of moderately to severely active UC. Previous studies have demonstrated superior OZA efficacy compared with placebo (PBO) in pts who were advanced therapy–naive and only exposed to conventional therapies.

Aims & Methods: The aim of the present post hoc analysis from the phase 3 True North study was to explore the efficacy of OZA maintenance therapy in advanced therapy–naive UC pts who had either moderate (Mayo endoscopic subscore [MES]=2) or severe (MES=3) baseline endoscopic disease activity. Pts continued on oral 5-ASA and/or CS during induction and CS were tapered during maintenance. In the induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or PBO or received open-label OZA in Cohort 2. OZA clinical responders at Week (W) 10 in either cohort were rerandomized to OZA (OZA/OZA) or PBO (OZA/PBO) during maintenance through W52. Clinical and mucosal endpoints of clinical remission, clinical response, CS-free remission, endoscopic improvement, histologic remission, and mucosal healing were assessed at W52. Treatment differences for OZA/OZA vs OZA/PBO were based on the Cochran-Mantel-Haenszel test, stratified by remission status and CS use at W10.

Results: A higher proportion of advanced therapy–naive pts with baseline moderate disease (53% [157/297]) vs severe disease (47% [140/297]) were rerandomized to either OZA or PBO during maintenance. Baseline demographic and clinical characteristics were generally similar across groups. Overall, more pts who continued on OZA vs switched to PBO achieved clinical and mucosal efficacy at W52, with moderate pts having better outcomes than severe pts (Table). Almost all efficacy endpoints in pts who continued on OZA vs those who switched to PBO were statistically significantly higher in moderate pts but only numerically higher in severe pts. Consequently, treatment differences (OZA/OZA vs OZA/PBO) were slightly greater in moderate pts than severe pts for clinical remission (19.8% [95% CI, 5.2–34.4]; P=0.009 vs 16.0% [1.5–30.4]; P=0.04), clinical response (15.1% [–0.1 to 30.4]; P=0.06 vs 10.0% [–6.2 to 26.2]; P=0.23), CS-free remission (16.2% [1.7–30.6]; P=0.03 vs 14.6% [1.6–27.5]; P=0.03), histologic remission (18.4% [3.6–33.1]; P=0.02 vs 9.5% [–4.8 to 23.8]; P=0.21), and mucosal healing (16.7% [2.2–31.2]; P=0.02 vs 10.0% [–3.3 to 23.3]; P=0.15), but were similar in moderate vs severe pts for endoscopic improvement (17.8% [2.4–33.1]; P=0.03 vs 18.2% [3.0–33.4]; P=0.02).

OZA efficacy at W52 of TN maintenance period in advanced therapy–naive pts	Moderate disease (MES=2)		Severe disease (MES=3)
	OZA/PBO (n=85)	OZA/OZA (n=72)	OZA/PBO (n=67)	OZA/OZA (n=73)
Clinical remission,a n (%)	22 (25.9)	34 (47.2)	14 (20.9)	26 (35.6)
Clinical response,b n (%)	43 (50.6)	48 (66.7)	31 (46.3)	40 (54.8)
CS-free remission,c n (%)	21 (24.7)	31 (43.1)	11 (16.4)	21 (28.8)
Endoscopic improvement,d n (%)	30 (35.3)	39 (54.2)	19 (28.4)	33 (45.2)
Histologic remission,e n (%)	21 (24.7)	32 (44.4)	14 (20.9)	22 (30.1)
Mucosal healing,f n (%)	19 (22.4)	29 (40.3)	11 (16.4)	19 (26.0)
Pts with missing data were considered nonresponders. aClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from baseline SFS), and MES ≤1 point. bClinical response: decrease from baseline in the 3-component Mayo score (sum of RBS, SFS, and MES) of ≥2 points and ≥35% and a reduction of ≥1 point in RBS or absolute RBS of ≤1 point. cClinical remission at W52 while off CS for ≥12 wk. dEndoscopic improvement: MES ≤1 point. eHistologic remission: Geboes index score <2.0. fMucosal healing: MES ≤1 point and Geboes index score <2.0. RBS, rectal bleeding subscore; SFS, stool frequency subscore.

Conclusion: OZA, as an oral advanced therapy, was efficacious as a maintenance therapy in moderate and severe advanced therapy–naive UC pts whose disease was initially inadequately controlled on conventional therapies. Pts with moderate vs severe disease may benefit more from OZA, as they showed numerically greater clinical, endoscopic, and histologic benefit while on continuous OZA treatment.

1Bristol Myers Squibb, Princeton, United States

Introduction: Ozanimod (OZA) is approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis. A previous phase 1 study of single dose OZA 0.23 mg showed a 31%–33% reduction of CC112273, the predominant active metabolite (MET) of OZA, in mild or moderate hepatic impaired participants (ppts) vs healthy ppts. That study was designed prior to identification of the 2 major METs of OZA (CC112273; CC1084037). Due to their slow accumulation and elimination, a new multiple dose study was designed with a long sampling schedule.

Aims & Methods: This multicenter, open-label phase 1 study (NCT04639115) evaluated the effect of mild (Child-Pugh [C-P] score 5–6) or moderate (C-P score 7–9) hepatic impairment on the multiple-dose pharmacokinetics (PK) of OZA and its 2 major active METs. Eligible ppts with hepatic impairment without active hepatitis were enrolled into the mild or moderate hepatic impairment groups (8 ppts each) based on their C-P scores. Ppts with normal hepatic function were matched to hepatic-impaired ppts by sex, age, weight, and smoking status. All ppts received once-daily OZA for 8 d in accordance with dose titration: 0.23 mg on Days (D) 1–4, 0.46 mg on D5–7, and 0.92 mg thereafter. Serial PK samples were collected on D1, D5, and D8, and additionally on D10, D12, and D15, and up to D72. Analysis of variance (ANOVA) fitted to the natural log-transformed PK parameters with hepatic function group as the fixed effect and the matching pair as a random effect was used to compare PK parameters between groups. Safety was assessed.

Results: All dosed ppts (N=26) completed the study. Each hepatic impairment group had 8 ppts; 10 ppts were in the normal hepatic function group, of whom 6 matched both mild and moderate hepatic-impaired ppts. Of the 16 hepatic-impaired ppts, 13 had documented hepatic cirrhosis. No clinically meaningful differences in total and unbound PK parameters for OZA and its major METs were observed between healthy and hepatic-impaired ppts on D1, D5, or D8 (dose titration) (Table). The unbound area under the plasma concentration-time curve from D8, time 0 to the time of last quantifiable concentration (AUC0-last) (up to 64 d after the D8 dose) of both METs increased ~2-fold in both mild and moderate hepatic-impaired ppts (Table). Although steady state for both METs was not achieved by D8, AUC0-last is a reasonable predictor of exposure at steady state. No correlation was observed between PK parameters for OZA or its major METs and measures of hepatic function (C-P score, serum albumin, and prothrombin time). No laboratory results (ie, absolute lymphocyte count), vital signs, physical examination, or 12-lead ECG results were reported as treatment-emergent adverse events.

Ratio of geometric LS mean (90% CI) for unbound PK parameters in ppts with hepatic impairment vs matched healthy ppts	PK parameter of interest	OZA	CC112273	CC1084037
Group comparison: Mild hepatic impairment (test) vs normal matched (reference)	D1 Cmax	134.42 (108.51, 166.52)	118.03 (77.19, 180.47)	NA
	D5 Cmax	135.60 (106.51, 172.63)	135.50 (92.26, 198.99)	141.26 (95.86, 208.17)
	D8 Cmax	186.48 (103.75, 335.19)	147.45 (87.15, 249.47)	145.26 (90.38, 233.45)
	D8 AUC0-last	182.53 (81.97, 406.46)	221.43 (106.61, 459.88)	229.74 (93.24, 566.10)
Group comparison: Moderate hepatic impairment (test) vs normal matched (reference)	D1 Cmax	136.12 (110.49, 167.71)	113.96 (85.55, 151.81)	NA
	D5 Cmax	124.92 (93.42, 167.04)	111.73 (80.73, 154.61)	120.98 (96.42, 151.80)
	D8 Cmax	168.91 (95.72, 298.09)	133.71 (84.78, 210.88)	135.77 (94.20, 195.68)
	D8 AUC0-last	145.87 (68.28, 311.64)	199.64 (119.55, 333.37)	212.36 (118.15, 381.70)
Note: The log-transformed PK parameters were analyzed using an ANOVA model with hepatic function group as a fixed effect and matching pair as a random effect. Cmax, maximum observed plasma concentration; LS, least squares; NA, not applicable.

Conclusion: Due to the lack of OZA PK differences between hepatic-impaired and healthy ppts during dose titration and the 2-fold increase of AUC0-last of both METs in hepatic-impaired ppts, a dose adjustment of OZA 0.92 mg once every other day is recommended in patients with mild or moderate hepatic impairment after completing the standard 1-week dose titration.

1Humanitas University, Milan, Italy, 2Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, United States, 3Atlanta Gastroenterology Associates LLC, Atlanta, United States, 4Nizhny Novgorod Regional Clinical Hospital, Nizhniy Novgorod, Russia, 5Bristol Myers Squibb, Princeton, United States, 6Mount Sinai Medical Center, New York, United States, 7Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, United States, 8University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States

Introduction: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for the treatment of moderately to severely active ulcerative colitis (UC) and for the treatment of relapsing multiple sclerosis (RMS). Ozanimod is a first-in-class S1P receptor modulator approved for UC, and one of several S1P receptor modulators used for the treatment of RMS. Ozanimod has been extensively studied in RMS with large patient populations and long exposure times, which can provide more insight into the safety profile of ozanimod in UC.

Aims & Methods: This analysis evaluated the tolerability and safety of long-term ozanimod 0.92 mg/day treatment from clinical trial data in adults with moderately to severely active UC and from clinical trial data in adults with RMS. The UC population included patients pooled from phase 2 (NCT01647516), phase 3 (NCT02435992), and respective open-label extension (OLE; NCT02531126) trials through January 10, 2022. The RMS population included patients treated with ozanimod 0.92 mg in DAYBREAK (NCT02576717; October 16, 2015–February 1, 2022), an ongoing OLE trial of patients from phase 1‒3 ozanimod studies. Safety outcomes included treatment-emergent adverse events (TEAEs) and TEAEs of special interest based on association with S1P modulation. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated to adjust for time on study.

Results: Mean (SD) ozanimod exposure in 1158 patients with UC was 28.4 (23.3) months (2714.9 total PY exposure); ozanimod exposure in 2494 patients with RMS was 56.4 (15.9) months (11,732.2 PY; UC and MS combined: 14,447.1 PY). TEAEs occurred in 74.6% of UC and 88.2% of RMS patients. Serious TEAEs were reported in 17.3% of UC and 14.1% of RMS patients, and TEAEs leading to ozanimod discontinuation in 9.3% and 3.6%, respectively. The most common TEAEs were lymphopenia (12.3%; EAIR 5.6/100 PY), anemia (8.4%; EAIR 3.7/100 PY), lymphocyte count decreased (7.9%; EAIR 3.5/100 PY), and nasopharyngitis (7.9%; EAIR 3.5/100 PY) in patients with UC, and nasopharyngitis (20.6%; EAIR 5.1/100 PY), headache (16.9%; EAIR 4.0/100 PY), and upper respiratory infection (11.9%; EAIR 2.7/100 PY) in patients with RMS. In UC and MS, respectively, EAIR/100 PY were 20.2 and 22.9 for any infection, 1.6 and 0.8 for serious infection, 1.2 and 1.4 for opportunistic infection, and 0.6 and 0.3 for malignancy. Alanine aminotransferase levels ≥5 times the upper limit of normal occurred in 2.3% and 0.8% of UC and RMS patients, respectively.

Conclusion: Long-term ozanimod 0.92 mg/day was generally well tolerated and safe for most patients with moderately to severely active UC or RMS.

1Bristol Myers Squibb, Princeton, United States, 2Robarts Research Institute, Western University, London, Ontario, Canada, 3Northwestern University Feinberg School of Medicine, Chicago, United States, 4University of Leuven, Leuven, Belgium, 5APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland, 6Laboratory Corporation of America, Durham, United States, 7Center for Crohn’s Disease & Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta, United States, 8Inflammatory Bowel Disease Center, Amsterdam University Medical Center, Amsterdam, Netherlands

Introduction: OZA, an oral selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active ulcerative colitis and is under investigation for CD. Clinical, endoscopic, and histologic improvements were observed after 12 wk of treatment with OZA in pts with moderately to severely active CD in the phase 2 STEPSTONE study. Differential decreases in circulating lymphocytes were observed in STEPSTONE, with reductions in T and B cells; however, natural killer cells and monocytes were unaffected. Circulating MBCs have not been widely studied in CD.

Aims & Methods: This exploratory analysis of STEPSTONE assessed the association between levels of circulating lymphocyte subsets and OZA efficacy. Pts received OZA 0.92 mg for 12 wk. Lymphocyte subsets were evaluated using multicolor flow analysis on blood samples collected before treatment and at Week (W) 12; differences between Day 1 and W12 were analyzed by Wilcoxon signed-rank tests. Change in disease activity from baseline to W12 was determined for Simple Endoscopic Score for Crohn’s Disease, size of ulcers, extent of ulcerated surface, extent of affected surface, presence of narrowing, Crohn’s Disease Activity Index (CDAI), Robart’s Histopathology Index (RHI), Geboes Histology Activity Score (GHAS), and stool frequency. Efficacy outcomes (ie, clinical response, clinical remission, endoscopic response, endoscopic remission, global GHAS remission, RHI remission, and RHI mucosal healing) were evaluated at W12. Associations of lymphocyte subset levels with disease activity changes and efficacy outcomes were assessed using Spearman’s correlation and logistic regression, respectively.

Results: Of the 69 pts enrolled, 52 had disease activity, efficacy outcome, and flow cytometry data at baseline and W12 and were included in this analysis. Most lymphocyte subsets assessed were significantly associated with 1 or 2 efficacy outcomes, whereas nonswitched MBCs were significantly associated with most outcomes, including endoscopic response-25, endoscopic response-50, endoscopic remission, global GHAS remission, and RHI mucosal healing (Table). Baseline levels of nonswitched MBCs were significantly correlated with change from baseline to W12 in extent of affected surface (Spearman’s rho = –0.44, P<0.05), RHI (Spearman’s rho = –0.34, P<0.05), and GHAS (Spearman’s rho = –0.47, P<0.05). Changes in levels of nonswitched MBCs were significantly correlated with change from baseline to W12 in CDAI (Spearman’s rho = 0.38, P<0.05), RHI (Spearman’s rho = 0.37, P<0.05), GHAS (Spearman’s rho = 0.43, P<0.05), and stool frequency (Spearman’s rho = 0.43, P<0.05).

Association of baseline lymphocytes with W12 efficacy	Clinical responsea	Clinical remissionb	Endoscopic response-25c	Endoscopic response-50d	Endoscopic remissione	Global GHAS remissionf	RHI remissiong	RHI mucosal healingh
CD4 EM T cell; CD8 CM T cell	NS; NS	NS; NS	NS; NS	NS; NS	NS; NS	0.0350 (–0.69); 0.0233 (–0.87)	NS; NS	NS; NS
CD8 skin-homing CCR4 EM cell	NS	NS	NS	NS	NS	NS	0.0155 (0.15)	NS
CD8 TEMRA (fully differentiated)	NS	NS	NS	NS	0.0484 (0.61)	0.0138 (0.95)	NS	NS
Naive CD8+ T cell; CD8 EM T cell	NS; NS	NS; NS	NS; NS	0.0449 (0.55); NS	NS; NS	NS; 0.0344 (0.79)	NS; NS	NS; NS
B cell	NS	NS	NS	0.0404 (0.68)	NS	NS	NS	NS
Nonswitched MBC	NS	NS	0.0368 (0.52)	0.0046 (0.86)	0.0163 (0.84)	0.0036 (1.20)	NS	0.0136 (0.95)
IgD-CD27 MBC	NS	NS	NS	NS	NS	0.0159 (0.88)	NS	NS
MBC	NS	NS	NS	NS	NS	0.0403 (0.76)	NS	NS
All lymphocyte subsets were measured in cells/µl. The values in each cell represent the P-value with logistic regression coefficient beta in parentheses. aCDAI reduction from baseline of ≥100 points. bCDAI score of <150. cDecrease of ≥25% in SES-CD from baseline. dDecrease of ≥50% in SES-CD from baseline. eSES-CD ≤4 points and SES-CD decrease ≥2 points with no SES-CD subscore >1 point. fNo active inflammation in any measured segment based on the GHAS. gNo active inflammation in any measured segment based on the RHI. hEndoscopic remission plus RHI remission. CM, central memory; EM, effector memory; NS, not specified; SES-CD, Simple Endoscopic Score for Crohn’s Disease; TEMRA, terminally differentiated effector memory.

Conclusion: After 12 wk of OZA treatment, higher levels of nonswitched MBCs at baseline were associated with endoscopic and histologic improvement, and reductions in nonswitched MBCs were associated with decreases in clinical and histologic disease activity. These data implicate nonswitched MBCs, which are involved in T cell–dependent immune responses and some inflammatory diseases, as a marker associated with OZA response in CD.

1Inflammatory Bowel Disease Clinic, Calgary, Alberta, Canada, 2University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States, 3University of Miami Miller School of Medicine, Miami, United States, 4Swedish Medical Center, Seattle, United States, 5Bristol Myers Squibb, Princeton, United States, 6Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy, 7Division of Digestive Diseases, University of Cincinnati, Cincinnati, United States

Introduction: Ozanimod (OZA), a selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active ulcerative colitis (UC) based on results from the phase 3 True North (TN) study, which demonstrated the efficacy and safety of OZA over 52 weeks. A subsequent post hoc analysis demonstrated the durability of OZA efficacy and favorable safety profile of OZA over 3 years during the ongoing TN OLE in patients (pts) with UC who achieved clinical response at TN Week (W) 52.

Aims & Methods: The present interim analysis of the TN OLE expands the evaluation of TN W52 clinical responders to include those who achieved clinical remission at TN W52 (ie, clinical remitters) vs those who did not (ie, clinical nonremitters) before entering the TN OLE. Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)–free remission were evaluated in TN W52 clinical remitters vs nonremitters at OLE W46 and OLE W94 using observed case (OC) and nonresponder imputation (NRI) analyses.

Results: In all, 131 pts entered the OLE as TN W52 clinical responders on continuous OZA therapy; of these pts, 63% (83/131) were clinical remitters. All pts had received 146 weeks of continuous OZA treatment up to OLE W94 or discontinued treatment. TN baseline demographic and disease characteristics were generally similar between the 2 groups, but a lower incidence of prior tumor necrosis factor (TNF) inhibitor use was reported in clinical remitters (25.3% [21/83]) vs clinical nonremitters (43.8% [21/48]); prior non–anti-TNF biologic use was similar between groups. Compared with clinical nonremitters, more clinical remitters achieved the evaluated efficacy endpoints at OLE W46 and OLE W94 in the OC analysis (Table). A similar trend was observed in the NRI analysis. Durability of response for all efficacy endpoints was sustained from OLE W46 to OLE W94 in most clinical remitters and nonremitters, respectively: 68.5% (37/54) and 75.0% (12/16); clinical response: 75.0% (48/64) and 75.9% (22/29); endoscopic improvement: 66.1% (41/62) and 68.4% (13/19); and CS-free remission: 67.9% (36/53) and 80.0% (12/15).

OZA efficacy at OLE W46 and OLE W94 in TN W52 clinical responders with or without clinical remission (OC analysis)
	Clinical remitters at TN W52 (n=83)		Clinical nonremitters at TN W52 (n=48)
	OLE W46	OLE W94	OLE W46	OLE W94
Clinical remission,a % (n/N)	97.0 (64/66)	94.4 (51/54)	93.5 (29/31)	85.2 (23/27)
Clinical response,b % (n/N)	81.8 (54/66)	75.9 (41/54)	51.6 (16/31)	55.6 (15/27)
Endoscopic improvement,c % (n/N)	86.1 (62/72)	78.6 (44/56)	59.4 (19/32)	63.3 (19/30)
CS-free remission,d % (n/N)	80.3 (53/66)	74.1 (40/54)	48.4 (15/31)	55.6 (15/27)
Note: Denominators for the OC analyses were based on the numbers of pts who completed OLE W46 or OLE W94 and had data available for the endpoints in question. aClinical remission: RBS=0 point and SFS ≤1 point, a decrease of ≥1 point from the baseline SFS, and endoscopy subscore ≤1 point. bClinical response: reduction from baseline in the 9-point Mayo score (sum of the RBS, SFS, and endoscopy subscore) of ≥2 points and ≥35%, and a reduction from baseline in the RBS of ≥1 point or an absolute RBS of ≤1 point. cEndoscopic improvement: endoscopy subscore of ≤1. dCS-free remission: clinical remission while off CS for ≥12 weeks.RBS, rectal bleeding subscore; SFS, stool frequency subscore.

Conclusion: Most pts who achieved clinical remission after 1 year of OZA had sustained efficacy for an additional 2 years of continuous OZA treatment. These findings provide further evidence for the long-term durability of OZA treatment in pts with moderately to severely active UC.

1Nancy University Hospital, Nancy, France, 2UNC Chapel Hill, Chapel Hill, United States, 3Charité – Universitätsmedizin Berlin, Berlin, Germany, 4Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom, 5University of Wisconsin School of Medicine and Public Health, Madison, United States, 6Bristol Myers Squibb, Princeton, United States, 7University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States, 8Houston Methodist-Weill Cornell, Houston, United States

Introduction: Many patients (pts) with ulcerative colitis (UC) do not achieve long-term remission with conventional therapies but are hesitant to switch to advanced therapies. Ozanimod (OZA) is an oral advanced therapy approved for the treatment of moderately to severely active UC. Durability of up to 3 years of continuous OZA treatment has been reported in the True North (TN) open-label extension (OLE).

Aims & Methods: The objective of the current analysis of the TN OLE was to assess the long-term durability of OZA treatment in pts who were inadequately controlled on conventional therapies at TN baseline. Advanced therapy–naive pts who were OZA clinical responders at TN Week 52 were grouped by baseline endoscopic disease activity as moderate (Mayo endoscopy subscore [MES]=2) or severe (MES=3). OZA efficacy (clinical remission, clinical response, corticosteroid (CS)-free remission, and endoscopic improvement) was evaluated at OLE W46 and OLE W94. Symptomatic clinical response (decrease from baseline in the combined 6-point rectal bleeding subscore [RBS] + stool frequency subscore [SFS] of ≥1 point and ≥30% and a decrease of ≥1 point in RBS or absolute RBS ≤1 point) and symptomatic clinical remission (RBS=0 and SFS ≤1 point [and decrease of ≥1 point from baseline SFS]) were assessed from OLE W5 to W94. All endpoints were assessed using observed case (OC) and nonresponder imputation (NRI) analyses.

Results: Of the 82 advanced therapy–naive pts who entered the OLE in clinical response after 52 wk of OZA treatment during TN, 45 had moderate baseline endoscopic disease and 37 had severe baseline endoscopic disease. Baseline demographic and clinical characteristics were generally similar across groups. Based on OC analysis, symptomatic clinical response and remission were observed in 100.0% and 90.5% of moderate pts, respectively, at OLE W5 and in 100.0% and 91.2% of severe pts, respectively, at OLE W5. Rates of symptomatic clinical response and remission were maintained through OLE W94. Rates of clinical remission, clinical response, CS-free remission, and endoscopic improvement at OLE W46 were similar in moderate and severe pts and were maintained through OLE W94 in the OC analysis (Table). Overall, the data followed similar patterns in the NRI analyses across endpoints.

Efficacy during the OLE by baseline endoscopic disease activity in advanced therapy–naive pts who entered the OLE in clinical response after 52 wk of OZA treatment during TN (OC analysis)
	Moderate disease (MES=2) (n=45)		Severe disease (MES=3) (n=37)
	OLE W46	OLE W94	OLE W46	OLE W94
Clinical remission,a n (%)	28/36 (77.8)	19/29 (65.5)	21/27 (77.8)	20/26 (76.9)
Clinical response,b n (%)	34/36 (94.4)	24/29 (82.8)	26/27 (96.3)	26/26 (100)
CS-free remission,c n (%)	26/36 (72.2)	18/29 (62.1)	21/27 (77.8)	20/26 (76.9)
Endoscopic improvement,d n (%)	35/39 (89.7)	21/30 (70.0)	22/30 (73.3)	21/27 (77.8)
aClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from baseline SFS), and MES ≤1 point. bClinical response: decrease from baseline in the 3-component Mayo score (sum of RBS, SFS, and MES) of ≥2 points and ≥35% and a reduction of ≥1 point in RBS or absolute RBS of ≤1 point. cClinical remission at W52 while off CS for ≥12 wk. dEndoscopic improvement: MES ≤1 point.

Conclusion: Advanced therapy–naive pts who experienced disease progression on conventional therapies had sustained efficacy on OZA for up to 3 years. Baseline endoscopic disease activity did not affect the long-term durability of OZA responders. OZA may be an appropriate advanced therapeutic option for sustaining long-term symptomatic and clinical benefit in pts with UC after loss of response to conventional treatments.

1Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy, 2Inflammatory Bowel Disease Clinic, Calgary, AB, Canada, 3University of Leuven, Leuven, Belgium, 4University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, United States, 5Bristol Myers Squibb, Princeton, United States, 6University of Miami Miller School of Medicine, Miami, United States

Introduction: Ozanimod (OZA) is approved in multiple countries for the treatment of moderately to severely active ulcerative colitis based on the results of the phase 3 True North (TN) clinical study. Previous data from the ongoing open-label extension (OLE) have demonstrated durability of efficacy in symptomatic, clinical, and mucosal endpoints for up to 3 years of continuous OZA treatment in patients who were clinical responders at TN Week (W) 52.

Aims & Methods: The present interim analysis of the TN OLE (data cutoff: 10 January 2022) explored whether the achievement of endpoints at TN W52, examined by increasing objectivity of the endpoint, would impact the durability of symptomatic and clinical outcomes with continuous OZA treatment up to OLE W94. OZA clinical responders at TN W52 who continued in the OLE were included in this analysis (n=131). These patients were categorized into subgroups based on the achieved endpoints of increasing objectivity (ie, clinical response, clinical remission, endoscopic improvement, complete endoscopic healing [endoscopy score = 0], histologic remission, mucosal healing, and stringent mucosal healing) at TN W52. The purpose was to determine whether these endpoints at TN W52/OLE baseline influence the proportion of patients maintaining symptomatic (ie, total/partial Mayo scores and symptomatic clinical response) and clinical (ie, clinical response, clinical remission, or corticosteroid [CS]–free remission) outcomes in the OLE. OLE outcomes were assessed up to OLE W94 using observed case (OC) and nonresponder imputation (NRI) analyses.

Results: Of the 131 patients included in this analysis, 114 (87%) completed OLE W46 and 94 (72%) completed OLE W94. Partial and total Mayo scores and symptomatic clinical responses (OC analysis) were similar and sustained over 94 wk of continuous OZA treatment during the OLE, regardless of the endpoint achieved at TN W52. Likewise, the maintenance of clinical response (OC analysis) at OLE W46 and OLE W94 was not impacted by the achievement of endpoints of increasing objectivity at TN W52 (Table). Achievement of clinical remission at TN W52 had an incremental benefit over clinical response at TN W52 for the maintenance of clinical remission and CS-free remission at OLE W94, but other endpoints of higher objectivity had no additional benefit (OC analysis) (Table). A similar pattern was observed for NRI analyses. Clinical outcomes were sustained from OLE W46 to OLE W94 regardless of the endpoint achieved at TN W52: clinical response: 71.4%–78.4%; clinical remission: 65.2%–70.0%; and CS-free remission: 63.6%–70.6%.

Endpoints (increasing in objectivity) at TN W52 (OC analysis), % (n/N)	Clinical responsea		Clinical remissionb		CS-free remissionc
	OLE W46	OLE W94	OLE W46	OLE W94	OLE W46	OLE W94
Clinical responsea (N=131)	95.9 (93/97)	91.4 (74/81)	72.2 (70/97)	69.1 (56/81)	70.1 (68/97)	67.9 (55/81)
Clinical remissionb (N=83)	97.0 (64/66)	94.4 (51/54)	81.8 (54/66)	75.9 (41/54)	80.3 (53/66)	74.1 (40/54)
Endoscopic improvement (MES ≤1; N=93)	97.3 (73/75)	95.2 (60/63)	78.7 (59/75)	73.0 (46/63)	77.3 (58/75)	71.4 (45/63)
Complete endoscopic healing (MES=0; N=50)	97.6 (40/41)	90.9 (30/33)	82.9 (34/41)	69.7 (23/33)	80.5 (33/41)	66.7 (22/33)
Histologic remission (Geboes index score <2.0; N=68)	98.1 (51/52)	95.3 (41/43)	82.7 (43/52)	74.4 (32/43)	80.8 (42/52)	72.1 (31/43)
Mucosal healing (MES ≤1 and Geboes index score <2.0; N=61)	97.9 (46/47)	94.7 (36/38)	80.9 (38/47)	71.1 (27/38)	78.7 (37/47)	68.4 (26/38)
Stringent mucosal healing (MES=0 and Geboes index score <2.0; N=37)	96.6 (28/29)	91.3 (21/23)	79.3 (23/29)	65.2 (15/23)	75.9 (22/29)	60.9 (14/23)
Denominators for the OC analysis were based on the numbers of patients who completed OLE W46 or OLE W94 and had data available for the endpoints in question. aClinical response: reduction from baseline in the 9-point Mayo score of ≥2 points and ≥35%, and a reduction from baseline in RBS of ≥1 point or an absolute RBS of ≤1 point. bClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from the baseline SFS), and endoscopy subscore ≤1 point. cCS-free remission: clinical remission while off CS for ≥12 wk. MES, mucosal endoscopy subscore; RBS, rectal bleeding subscore; SFS, stool frequency subscore.

Conclusion: Symptomatic response and clinical outcomes with OZA were durable up to W94 in the OLE. Maintenance of these long-term outcomes was not notably impacted by the achievement of increasingly more objective measures of responsiveness at W52 of TN.

1Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany, 2Robarts Research Institute, Western University, London, Ontario, Canada, 3Icahn School of Medicine at Mount Sinai, New York, United States, 4Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, United States, 5Division of Gastroenterology, Hospital Beatriz Ângelo, and Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal, 6Bristol Myers Squibb, Princeton, United States, 7University of Miami, Miller School of Medicine, Miami, United States, 8Feinberg School of Medicine, Northwestern University, Chicago, United States

Introduction: Ozanimod (OZA) is approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults. In the phase 3 True North (TN; NCT02435992) study, patient (pt) responses to OZA were heterogenous at Week (W) 52. Group-based trajectory modeling (GBTM) can be used to identify patterns of therapeutic responses in patient subpopulations.

Aims & Methods: This TN post hoc analysis employed GBTM to identify patterns of OZA response trajectories during the TN maintenance period (MP) in W10 OZA clinical responders who were rerandomized to continue OZA (OZA/OZA arm; n=230) in MP. Change from baseline (BL; TN W0) in partial Mayo score (PMS) was used as a variable for identifying pt clusters with various OZA response patterns. GBTM, a specialized application of finite mixture models,1 was used to estimate OZA response trajectories. GBTM was determined by maximum likelihood estimation, and the optimal model was selected using the Bayesian information criterion. The last observation carried forward imputation method was used for handling missing data. After modeling, clinical and mucosal outcomes at W52 were compared in the GBTM-identified pt clusters.

Results: Of the 230 pts in the MP OZA/OZA arm, 1 pt did not have postbaseline PMS data available and was excluded from this analysis. Five distinct groups of pt-response patterns to OZA therapy were identified during MP. At W10, a PMS response was observed in all 5 trajectory groups. Over the 42 weeks during MP, trajectory groups diverged into fast sustained improvement (Group 1; n=38 [16.6%, 38/229]); slow sustained improvement (Group 2; n=85 [37.1%, 85/229]); gradual improvement (Group 3; n=60 [26.2%, 60/229]); fast rebound (Group 4; n=25 [10.9%, 25/229]); and slow rebound (Group 5; n=21 [9.2%, 21/229]). Although all pts entering the MP were OZA clinical responders, 20% of pts did not demonstrate sustained improvement from BL in PMS (Groups 4 and 5), but 80% did demonstrate sustained improved from BL in PMS (Groups 1–3). From W10 onward, 26.2%, 37.1%, and 16.6% of pts achieved and maintained PMS reductions of at least 3.98, 5.27, and 6.71 points, respectively. Pts in Groups 4 and 5 had a slightly younger age at diagnosis and a higher W10 Geboes histologic index score than the other trajectory groups; notably, pts in Group 4 had the most corticosteroid use at screening (Table). At W52, more pts in Groups 1–3 combined achieved clinical response (74%) and clinical remission (46%) than those in Groups 4 and 5 combined (7% and 2%, respectively). Furthermore, Groups 1–3 combined had more pts with endoscopic improvement (56%) and mucosal healing (37%) at W52 than Groups 4 and 5 combined (7% and 2%, respectively).

Pt characteristics at BL (TN W0) or W10	Group 1: Fast sustained improvement (n=38, 16.6% [38/229])	Group 2: Slow sustained improvement (n=85; 37.1% [85/229])	Group 3: Gradual improvement (n=60; 26.2% [60/229])	Group 4: Fast rebound (n=25, 10.9% [25/229])	Group 5: Slow rebound (n=21, 9.2% [21/229])
Sex, male, n (%)	15 (39.5)	43 (50.6)	33 (55.0)	13 (52.0)	12 (57.1)
Age at UC diagnosis, y, mean (SD)	34.6 (12.4)	35.7 (14.1)	35.3 (13.0)	29.8 (11.5)	31.5 (11.0)
Corticosteroid use at screening, n (%)	11 (28.9)	28 (32.9)	14 (23.3)	11 (44.0)	7 (33.3)
Prior use of tumor necrosis factor antagonist, n (%)	9 (23.7)	28 (32.9)	22 (36.7)	9 (36.0)	7 (33.3)
Complete Mayo score at W10, mean (SD)	2.8 (1.7)	3.5 (1.8)	3.8 (1.9)	4.8 (2.1)	3.7 (1.6)
PMS at W10, mean (SD)	1.3 (1.0)	1.9 (1.2)	2.1 (1.4)	3.0 (1.8)	2.1 (1.2)
Mucosal endoscopy subscore of 2 (moderate) at baseline, n (%)	14 (36.8)	39 (45.9)	28 (46.7)	9 (36.0)	8 (37.1)
Mucosal endoscopy subscore of 3 (severe) at baseline, n (%)	24 (63.2)	46 (54.1)	32 (53.3)	16 (64.0)	13 (61.9)
Geboes continuous index score at W10, mean (SD)	5.9 (4.3)	5.8 (4.9)	7.0 (5.2)	7.7 (5.1)	7.6 (4.8)

Conclusion: Five groups of pt-response trajectories to OZA therapy were identified, with approximately 80% of pts in Groups 1–3 classified as having sustained response to OZA treatment. This analysis indicates that GBTM identifies clinically meaningful pt subgroups by pt-response patterns to OZA treatment. This approach needs to be validated in prospective studies.

References:

1. Nagin D. Group-based trajectory modeling: an overview. Ann Nutr Metab. 2014;65:205-210.

1Medical University of Vienna, Vienna, Austria, 2St. Mark’s Hospital & Imperial College, London, United Kingdom, 3Digestive Disease Associates, Gainesville, United States, 4University of Maryland School of Medicine, Baltimore, United States, 5Bristol Myers Squibb, Princeton, United States, 6Weill Cornell Medicine, New York, United States, 7NYU Grossman School of Medicine, New York, United States

Introduction: Ozanimod (OZA), a sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the European Union, United States, and other countries for the treatment of moderately to severely active ulcerative colitis (UC). Mucosal healing (MH), a key treatment goal for patients (pts) with UC, is associated with improved long-term pt outcomes.

Aims & Methods: The goal of this analysis was to determine the rate of early MH after treatment with OZA at Week (W) 10 using stringent MH criteria (mucosal endoscopy subscore [MES] = 0 plus histologic remission [Geboes score <2.0]) and to assess the relationship between achievement of stringent MH at W10 and clinical outcomes at W52. Outcomes were compared to pts achieving MH using a standard definition (MES ≤1 plus histologic remission). This analysis included pts from True North (NCT02435992) who achieved clinical response on once-daily oral OZA 0.92 mg at W10 and continued OZA during the 42-wk maintenance period. In this post hoc analysis, we examined MH, clinical remission, and corticosteroid (CS)–free remission at W52 in pts with stringent MH vs without stringent MH at W10 and with stringent MH vs with standard MH.

Results: Of the 230 pts who achieved clinical response on OZA at W10 and continued OZA during the maintenance period, 44 (19.1%) achieved MH using a standard definition and 13 (5.7%) achieved stringent MH at W10. Demographic and clinical characteristics were generally balanced between OZA-treated pts with stringent MH (n=13) and without stringent MH (n=217) at W10. Notably, there were fewer male pts with stringent MH vs without stringent MH, all pts with stringent MH had moderate disease (based on endoscopy), and more pts with stringent MH vs without stringent MH had left-sided UC disease. CS use at screening and prior tumor necrosis factor inhibitor (TNFi) use were lower in those with stringent MH vs without stringent MH. Similar differences in disease severity, extent of disease, and CS and TNFi use were seen in pts with stringent MH vs standard MH. At W52, more pts treated with OZA with stringent MH at W10 vs without stringent MH at W10 had clinical remission (53.8% vs 35.9%), CS-free remission (53.8% vs 30.4%), MH (61.5% vs 27.6%), endoscopic improvement (61.5% vs 44.7), and histologic remission (61.5% vs 31.8%). Except for endoscopic improvement, a slightly higher percentage of pts with stringent MH vs standard MH at W10 achieved clinical outcomes at W52 (Table).

Clinical outcomes at W52
W52 outcome, n (%)	With stringent MH (MES=0 and Geboes score <2.0) at W10 (n=13)	With standard MH (MES ≤1 and Geboes score <2.0) at W10 (n=44)	Without stringent MH (MES>0 and/or Geboes score ≥2.0) at W10 (n=217)
Clinical remission,a	7 (53.8)	21 (47.7)	78 (35.9)
CS-free clinical remissionb	7 (53.8)	20 (45.5)	66 (30.4)
MHc	8 (61.5)	23 (52.3)	60 (27.6)
Endoscopic improvementd	8 (61.5)	28 (63.6)	97 (44.7)
Histologic remissione	8 (61.5)	25 (56.8)	69 (31.8)
aRBS=0, SFS ≤1 (plus a ≥1-point reduction from baseline), and MES ≤1. bRemission with no CS use for ≥12 wk. cMES ≤1 and Geboes score <2.0. dMES ≤1. eGeboes score <2.0. RBS, rectal bleeding subscore; SFS, stool frequency subscore.

Conclusion: While difficult to achieve, a small proportion of pts treated with OZA experienced stringent MH by W10. Compared with pts who achieved standard MH at W10, those with stringent MH at W10 demonstrated numerically better clinical outcomes at W52 on OZA treatment. Achieving stringent MH at W10 correlated with better clinical, endoscopic, and mucosal outcomes at W52.