Ozanimod Research Articles

Comparative efficacy of diroximel fumarate, ozanimod and interferon beta-1a for relapsing multiple sclerosis using matching-adjusted indirect comparisons.

Aim: Diroximel fumarate (DRF), ozanimod (OZA) and interferon beta-1a (IFN) are disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus OZA and IFN. We compared DRF versus OZA and DRF versus IFN using matching-adjusted indirect comparisons for efficacy outcomes, including annualized relapse rate (ARR), 12- and 24-week confirmed disability progression (CDP) and absence of gadolinium-enhancing (Gd+) T1 lesions and new/newly enlarging T2 lesions. Patients & methods: We used individual patient data from EVOLVE-MS-1 (NCT02634307), a 2-year, open-label, single-arm, phase III study of DRF (n=1057) and aggregate data from RADIANCE (NCT02047734), a 2-year, double-blind, phase III study that compared OZA 1mg once daily (n=433) and intramuscular IFN 30μg once weekly (n=441). To account for cross-trial differences, the EVOLVE-MS-1 population was restricted to those who met the inclusion/exclusion criteria for RADIANCE, then weighted to match the average baseline characteristics of RADIANCE. Results: After weighting, DRF and OZA had similar ARRs (0.18 and 0.17, respectively), with a rate difference (DRF vs OZA) of 0.01 (95% confidence interval [CI]: -0.04 to 0.06). DRF had a lower ARR than IFN (0.18 and 0.28, respectively), with a rate difference (DRF vs IFN) of -0.10 (95% CI: -0.16 to -0.04) after weighting. Outcomes for 12- and 24-week CDP favored DRF versus OZA; 12-week CDP favored DRF versus IFN, but there was not strong evidence favoring DRF over IFN for 24-week CDP. Compared with OZA and IFN, DRF had higher proportions of patients without Gd+ T1 lesions and patients without new/newly enlarging T2 lesions. Conclusion: Disability progression and radiological outcomes were favorable for DRF versus OZA, although no differences were observed in ARR. Clinical and radiological outcomes generally favored DRF versus IFN. These findings may be informative for patients and clinicians considering different treatment options for MS.

Cardiac Safety of Ozanimod Use, a Novel Sphingosine-1-Phosphate Receptor Ligand, in COVID-19 Patients Requiring Oxygen: Secondary Analysis of the COZI Randomized Clinical Trial

BackgroundOzanimod is a novel immune modulator that could be useful in viral pulmonary infections by reducing lung inflammation. It is an S1P receptor ligand known to induce bradycardia and more serious adverse cardiac effects, such as atrioventricular block and QT interval prolongation. We present a substudy of the COVID-19 Ozanimod Intervention (COZI) trial in which ozanimod was administered in acute pulmonary infection patients, to assess cardiac safety. MethodsIn this pilot randomized open-label trial, COVID-19 patients requiring oxygen support were randomized into 2 groups: standard-of-care + ozanimod (OZA) vs standard-of-care alone (SOC). All patients were monitored with a 14-day electrocardiogram monitor (CardioSTAT, Icentia, Quebec, QC) during their hospitalization. We evaluated the cardiac effects of ozanimod on heart rate (HR), PR interval length, and QT interval duration. ResultsA total of 42 patients were analyzed: 23 in the SOC group and 19 in the OZA group. Mean hourly HR over the first 10 days of treatment decreased in the OZA group, compared with that in the SOC group (P < 0.0001). The maximum decrease in HR occurred on day 3. The maximum decrease in HR occurred on day 3, without a significant difference between groups: 49 beats per minute (interquartile range, 42-59) in the OZA group, and 54 beats per minute (48–60) in the SOC group, P = 0.45. No high-degree atrioventricular block was recorded. QT and PR interval median values were within the normal range in both groups, without a significant difference. ConclusionsThe maximal reduction in HR occurred 3 days after the onset of ozanimod treatment in patients hospitalized for COVID-19, but it did not remain significant over the 10-day treatment period. No relevant cardiac adverse event was observed.

P637 Ozanimod efficacy with or without concomitant corticosteroids in 5-ASA–exposed, advanced therapy–naive, immunomodulator-naive patients with ulcerative colitis: a post hoc analysis of True North

Abstract Background Long-term corticosteroid (CS) use is not recommended for patients (pts) with ulcerative colitis (UC). Receiving early advanced therapy (AT) may help limit CS overuse, but there is a need to identify pt populations who may benefit most from receiving early AT as monotherapy. Previous post hoc analyses of the phase 3 True North (TN) study (NCT02435992) demonstrated ozanimod (OZA) efficacy in 5-aminosalicylate (5-ASA)–exposed, AT-naive, immunomodulator (IMM)–naive pts. This analysis further assessed the efficacy of OZA induction therapy with and without concomitant CS in this pt population by baseline (BL) endoscopic disease severity. Methods In TN, pts in Cohort 1 (C1) were randomised to OZA or placebo (PBO); pts in Cohort 2 (C2) received open-label OZA through Week (W) 10. Pts were on stable doses of oral 5-ASA and/or CS for ≥2 wk before screening and continuing through W10. 5-ASA–exposed, AT-naive, IMM-naive pts were grouped as moderate (Mayo endoscopy subscore [MES]=2 at BL) or severe (MES=3 at BL). Data were analysed in all moderate and severe pts and by concomitant CS use. Clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission were assessed at W10. Results Of the 464 5-ASA–exposed, AT-naive, IMM-naive pts, 237 had moderate (PBO, n=47; OZA C1, n=108; OZA C2], n=82) and 227 had severe (PBO, n=54; OZA C1, n=97; OZA C2, n=76) BL endoscopic disease. BL pt characteristics were generally similar between moderate and severe pts with or without concomitant CS use. Overall, OZA was significantly more effective in moderate pts and numerically more effective in severe pts vs PBO in C1, with numerically greater treatment differences in moderate vs severe pts (Figure 1A). The moderate and severe groups each had 51 pts (~22%) on concomitant CS. In moderate pts, numerically greater OZA vs PBO C1 treatment differences were observed in those without concomitant CS use vs those with concomitant CS use for clinical remission and clinical response; treatment differences were significant for all endpoints in pts without concomitant CS use (Figure 1B). In contrast, severe pts with concomitant CS use demonstrated greater OZA vs PBO C1 treatment differences vs those without concomitant CS use for all endpoints (Figure 1C). Results in OZA C2 were generally similar to OZA C1. Conclusion OZA treatment was efficacious in 5-ASA–exposed, AT-naive, IMM-naive pts with UC, with numerically greater efficacy in moderate pts than severe pts. Additionally, the results suggest that concomitant CS may not provide additional benefit over OZA monotherapy in moderate pts. These findings support OZA positioning after 5-ASA, but before CS, in pts with moderate UC.

P1009 Efficacy and safety of 4 years of continuous ozanimod treatment: an interim analysis of the True North open-label extension study

Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod (OZA) over 52 wk in patients (pts) with moderately to severely active ulcerative colitis (UC); the ongoing TN open-label extension (OLE) is assessing long-term efficacy and safety. This interim analysis of the TN OLE assessed pts with up to ~4 y of continuous OZA treatment. Methods Clinical responders after 52 wk of continuous OZA treatment (0.92 mg/d) during TN who subsequently entered the TN OLE were included in this analysis. Data were analysed up to OLE Week (W) 142, representing up to ~4 y of continuous OZA treatment. Symptomatic response (≥1-point and ≥30% decrease from baseline [BL] in the combined 6-point rectal bleeding subscore [RBS] + stool frequency subscore [SFS] and ≥1-point decrease in RBS or absolute RBS ≤1) and symptomatic remission (RBS=0 and SFS ≤1 [and ≥1-point decrease from BL SFS]) were evaluated from OLE W5 through OLE W142. Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at OLE W46, W94, and W142. Endpoints were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Adverse events were monitored throughout TN and the OLE. Results In all, 131 pts entered the OLE after achieving clinical response on OZA at W52 in TN. At the data cutoff, 87.0% of pts completed OLE W46, 71.8% completed OLE W94, and 64.1% completed OLE W142. Most (67.9%) pts had left-sided UC disease, 23.7% had concomitant CS use at TN BL, and 32.1% had prior exposure to tumour necrosis factor inhibitors. Symptomatic response and symptomatic remission were observed in 100.0% and 84.4% of pts, respectively, at OLE W5 in the OC analysis (93.1% and 78.6%, respectively, in the NRI analysis). By OLE W142, symptomatic response and symptomatic remission rates were 98.7% and 88.3%, respectively, in the OC analysis and 58.0% and 51.9%, respectively, in the NRI analysis. Rates of clinical and endoscopic endpoints during the OLE are shown in Figure 1A (OC) and 1B (NRI). Of note, 65.3% of TN W52 clinical responders achieved clinical remission and CS-free remission at OLE W142 in the OC analysis (35.9% in the NRI analysis). With this additional year of follow-up in the OLE, there were no new cases of bradycardia, third-degree atrioventricular block, hypertension, herpes zoster, or macular oedema, and no clinically meaningful change in malignancy exposure-adjusted incidence rates (Table). No serious hepatic events occurred. Conclusion Clinical responders after 1 y on OZA sustained response for an additional 3 y and achieved clinical remission with continuous OZA exposure. OZA is a safe, tolerable, and durable therapy for pts with UC.

DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension

Abstract Background The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142). Methods The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs). Results A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC &amp;lt;500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC &amp;lt;200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported. Conclusion The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.

Ozanimod Therapy in Patients With COVID-19 Requiring Oxygen Support: A Randomized Open-Label Pilot Trial

BackgroundSphingosine-1-phosphate receptor ligands (SRLs) dampen immunopathological damages in models of viral pneumonia. Research QuestionIs it feasible to administer an SRL therapy, here ozanimod, to acutely ill SARS-CoV-2-infected patients? Study Design and MethodsThe prospective, randomized, open-label, COVID-19 Ozanimod Intervention (COZI) pilot trial was conducted in three Canadian hospitals. Patients admitted for COVID-19 requiring oxygen were eligible. Randomization was stratified for risk factors of poor outcome and oxygen needs at inclusion. Participants were allocated to standard of care (SOC), or to standard of care plus ozanimod (OZA). Ozanimod (oral, once daily, incremental dosage) was administered for a maximum of 14 days. Primary endpoint investigated for size effect and variance over time was the assessment of safety and efficacy, evaluated by the daily score on the WHO-adapted 6-points ordinal scale for clinical improvement analyzed under the intention-to-treat principle. ResultsTwenty-three patients were randomized to SOC arm and 20, in the OZA arm from September 2020 to February 2022. Evaluation of efficacy showed non-significant reductions of median duration of respiratory support (6 (3-10) vs 9 (4-12) days, P=0.34), median duration of hospitalization (9 (6-12) vs 10 (6-18) days, P=0.20) and median time to clinical improvement (4 (3-7) vs 7 (3-11) days, P=0.12) for OZA compared to SOC. Heart rate was significantly lower with ozanimod (65 (63-67) vs. 71 (69-72) bpm, P<0.0001). However, QT and PR intervals were not affected. No severe adverse drug reaction was reported. InterpretationSRLs utility in severe pneumonia had never been tested in patients. We show for the first time that this new pharmacological agent can safely be administered to patients hospitalized for viral pneumonia, with potential clinical benefits. Bradycardia was frequent but well tolerated. Clinical Trial RegistrationClinicalTrials.gov number NCT04405102

S1134 Association of Nonswitched Memory B-Cell (MBC) Levels With Ozanimod (OZA) Efficacy in Patients (Pts) With Moderately to Severely Active Crohn’s Disease (CD): Results From the Phase 2 STEPSTONE Study

S1134 Association of Nonswitched Memory B-Cell (MBC) Levels With Ozanimod (OZA) Efficacy in Patients (Pts) With Moderately to Severely Active Crohn’s Disease (CD): Results From the Phase 2 STEPSTONE Study

Differential effects of selective versus unselective sphingosine 1-phosphate receptor modulators on T- and B-cell response to SARS-CoV-2 vaccination

Background: Sphingosine 1-phosphat receptor modulators (S1PRMs) have been linked to attenuated immune response to SARS-CoV-2 vaccines. Objective: To characterize differences in the immune response to SARS-CoV-2 vaccines in patients on selective versus unselective S1PRMs. Methods: Monocentric, longitudinal study on people with multiple sclerosis (pwMS) on fingolimod (FTY), siponimod (SIP), ozanimod (OZA), or without disease-modifying therapy (DMT) following primary and booster SARS-CoV-2 vaccination. Anti-SARS-CoV-2 antibodies and T-cell response was measured with electro-chemiluminescent immunoassay and interferon-γ release assay. Results: Primary vaccination induced a significant antibody response in pwMS without DMT while S1PRM patients exhibited reduced antibody titers. The lowest antibodies were found in patients on FTY, whereas patients on OZA and SIP presented significantly higher levels. Booster vaccinations induced increased antibody levels in untreated patients and comparable titers in patients on OZA and SIP, but no increase in FTY-treated patients. While untreated pwMS developed a T-cell response, patients on S1PRMs presented a diminished/absent response. Patients undergoing SARS-CoV-2 vaccination before onset of S1PRMs presented a preserved, although attenuated humoral response, while T-cellular response was blunted. Conclusion: Our data confirm differential effects of selective versus unselective S1PRMs on T- and B-cell response to SARS-CoV-2 vaccination and suggest association with S1PRM selectivity rather than lymphocyte redistribution.

Effects of horizontal versus vertical switching of disease-modifying treatment after platform drugs on disease activity in patients with relapsing–remitting multiple sclerosis in Austria

ObjectivesTo compare in a nationwide observational cohort the effectiveness, frequency and reasons for treatment interruption of dimethylfumarate (DMF) and teriflunomide (TERI) (horizontal switchers) versus alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR) and ozanimod (OZA) (vertical switchers) in patients with relapsing–remitting multiple sclerosis (pwRRMS) and prior interferon beta (IFN-beta) or glatiramer-acetate (GLAT) treatment.Materials and methodsThe “horizontal switch cohort” included 669 and the “vertical switch cohort” 800 RRMS patients. We used propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for bias in this non-randomized registry study.ResultsEstimated mean annualized relapse rates (ARR) were 0.39 for horizontal and 0.17 for vertical switchers. The incidence rate ratio (IRR) in the GLM model showed an increased relapse probability of 86% for horizontal versus vertical switchers (IRR = 1.86; 95% CI 1.38–2.50; p < 0.001). Analyzing the time to the first relapse after treatment switch by Cox regression, a hazard ratio of 1.58 (95% CI 1.24–2.02; p < 0.001) indicated an increased risk of 58% for horizontal switchers. The hazard ratios for treatment interruption comparing horizontal versus vertical switchers were 1.78 (95% CI 1.46–2.18; p < 0.001).ConclusionsHorizontal switching after a platform therapy resulted in a higher relapse and interrupt probability and was associated with a trend towards less EDSS improvement comparing to vertical switching in Austrian RRMS patients.

P585 Duration of response to ozanimod after treatment withdrawal: results from the phase 3 True North study

Abstract Background The phase 3 True North randomised trial demonstrated the efficacy and safety of ozanimod (OZA) in patients with moderately to severely active ulcerative colitis (UC). Temporary discontinuation of UC treatment can occur in clinical practice. Understanding the duration of response after treatment discontinuation can assist in clinical decision making. This analysis examined time to loss of OZA response in patients who discontinued OZA and switched to placebo (PBO) in the True North maintenance period (MP). Methods In True North, patients were randomised to once-daily oral OZA 0.92 mg or PBO or to open-label OZA during a 10-week induction period (IP). Patients with clinical response to OZA at Week 10 were rerandomised to OZA (OZA/OZA) or PBO (OZA/PBO) in the MP through Week 52. Disease relapse was defined as an increase in partial Mayo score (PMS) of ≥2 points vs Week 10 with absolute PMS ≥4, endoscopic subscore ≥2, and exclusion of other causes of increased disease activity unrelated to UC. A subanalysis compared outcomes in OZA/OZA and OZA/PBO patients who entered the MP after achieving clinical remission (CRM) or clinical response (CRS only, excluding patients in CRM) at Week 10. Results In the True North MP, 230 patients continued OZA (CRM, n=82; CRS only, n=148) and 227 patients switched to PBO (CRM, n=79; CRS only, n=148). Baseline characteristics were generally similar between groups. Patients in CRS only at Week 10 had a numerically higher proportion with severe disease and prior immunosuppressive medication use vs CRM patients (Table). Differences in disease relapse between groups became apparent after MP Week 8, after which a significantly higher proportion of OZA/OZA patients were without relapse vs OZA/PBO patients (Figure). MP Week 42 Kaplan-Meier estimates of no relapse were 86.1% and 62.6% for OZA/OZA and OZA/PBO patients, respectively. Additionally, patients in CRM at Week 10 had higher rates of nonrelapse during the MP vs those in CRS only at MP entry. Kaplan-Meier estimates of nonrelapse at MP Week 42 were 67.9% and 59.7% in OZA/PBO patients with CRM and CRS, respectively, and 90.9% and 83.4% in OZA/OZA patients with CRM and CRS, respectively. Conclusion This analysis shows that OZA is effective at preventing disease relapse over 42 weeks of maintenance treatment in patients who achieve clinical response at Week 10. These data show that OZA maintains disease control even in the event of temporary discontinuation. However, extended discontinuation should be minimized in clinical practice.

P609 Impact of prior biologic exposure on durability of recaptured response to ozanimod during the True North open-label extension study

Abstract Background In the phase 3 True North (TN) study, ozanimod (OZA) 0.92 mg once daily showed efficacy and safety for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis, and is approved for adults in the EU, US, and other countries for this indication. This analysis (data cutoff: 10 January 2022) evaluated the impact of prior biologic exposure on the long-term durability of response in pts who experienced disease relapse while on placebo (PBO) during the TN maintenance period (MP) and then recaptured response to OZA during the TN open-label extension (OLE). Methods Responders to OZA 10-week induction therapy who were biologic-naive or exposed to prior biologics at baseline were rerandomised 1:1 to OZA (n=230) or PBO (n=227) during the TN MP. Pts who relapsed while on PBO subsequently entered the OLE and reinitiated open-label OZA in this interim OLE analysis. Symptomatic, clinical, endoscopic, and histologic endpoints were evaluated by observed case (OC) and nonresponder imputation (NRI) analyses. Results This analysis included 38 biologic-naive and 38 biologic-exposed pts who entered the OLE after disease relapse on PBO (median time to relapse, 13.1 and 11.2 weeks, respectively). Symptomatic clinical response based on NRI was achieved by 26/38 (68.4%) of biologic-naive and 20/38 (52.6%) of biologic-exposed pts 5 weeks after restarting OZA in the OLE. Symptomatic clinical response by OC analysis at OLE Week 5 was achieved in 72.2% (26/36) and 55.6% (20/36) of biologic-naive and -exposed pts, respectively. Although a greater proportion of biologic-naive vs -exposed pts completed OLE Week 94 (65.8% vs 39.5%), OC rates of symptomatic clinical response at OLE Week 94 were similar (biologic-naive: 95.0% [19/20] vs biologic-exposed: 100.0% [13/13]). Key clinical, endoscopic, and histologic endpoints are shown in Fig 1. Durability of response between OLE Weeks 46 and 94 was similar in biologic-naive (40%–56%) vs -exposed pts (50%–67%) but varied depending on endpoints (NRI analysis). Reductions in mean [SD] total Mayo score were similar and sustained through OLE Week 94 in biologic-naive and -exposed pts (OLE Week 0: 8.9 [1.8] and 9.3 [1.6], respectively; OLE Week 46: 2.3 [1.7] and 4.2 [2.6], respectively; OLE Week 94: 2.6 [2.0] and 2.6 [1.4], respectively) (Fig 2). Conclusion In pts who lost clinical response after OZA treatment withdrawal, symptomatic clinical response was recaptured within 5 weeks of OZA reinitiation in the majority of pts, and clinical benefit was maintained for up to 94 weeks (extent of current analysis) in biologic-naive and -exposed pts. This suggests that in clinical practice, pts who experience a disease relapse after temporarily holding OZA may benefit from resumption of OZA.

S811 Evaluation of Ozanimod Efficacy and Safety in Older Patients With Ulcerative Colitis: Post Hoc Analysis From the Phase 3 True North Study

Introduction: Ozanimod (OZA), an oral S1P receptor modulator, is approved for the treatment (tx) of moderate/severe ulcerative colitis (UC) in the US and EU. Inflammatory bowel disease prevalence is increasing in older pts. Methods: This post hoc analysis examined OZA efficacy and safety in pts < 60y and ≥60y in True North (TN). Pts were randomized to double-blind (DB) OZA 0.92 mg or placebo (PBO; Cohort 1 [C1]) or received open-label OZA (Cohort 2 [C2]) during the 10-week (W) TN induction period (IP). Pts with clinical response to OZA at W10 were rerandomized to DB OZA or PBO in the maintenance period (MP) through W52. Results: This analysis included 562 pts < 60y (OZA, n=376; PBO, n=186) and 83 pts ≥60y (OZA, n=53; PBO, n=30) from C1 and 315 pts (< 60y) and 52 pts (≥60y) from C2. During MP, 196 pts (< 60y) and 34 pts (≥60y) continued on OZA; 196 pts (< 60y) and 31 pts (≥60y) were rerandomized to PBO. Demographics and baseline (BL) characteristics were generally well balanced across tx and age groups; older pts had less extensive disease, lower BL fecal calprotectin levels, and more polypharmacy. Adjusted tx differences favored OZA v PBO and were generally similar between age groups across all efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing) at W10 and W52. PBO response rates were higher in older v younger pts. During IP, tx-emergent adverse event (TEAE) incidence with OZA in C1 and C2 was lower in older pts; rates of serious TEAEs and TEAEs leading to tx discontinuation were similar in older v younger pts (Table). With continued OZA tx during MP, TEAEs occurred more often in older pts, serious TEAEs were less frequent in older pts, and TEAEs leading to tx discontinuation were similar in older v younger pts. Adverse events of special interest during MP were generally low overall, with the most common being infection (≥60y: 2 pts v < 60y: 3 pts), hepatic effects (≥60y: 0 pts v < 60y: 2 pts), macular edema (≥60y: 1pt v < 60y: 0 pts), malignancy (≥60y: 0 pts v < 60y: 2 pts), and pulmonary effects (≥60y: 0 pts v < 60y: 1 pt). One death from acute respiratory distress syndrome due to viral pneumonia occurred during IP in an older pt (64y) on OZA but was deemed unrelated to tx. Conclusion: OZA is a safe, tolerable, oral tx option for older UC pts with an absence of serious AEs of concern. OZA efficacy in older pts was comparable to younger pts. This study was limited by the small sample size, warranting larger future real-world studies. Table 1. - TEAEs in older and younger pts on OZA in TN TEAE, n (%) < 60 y ≥60 y IP C1: OZA (n=376) IP C2: OZA (n=315) MP: OZA-OZA (n=196) IP C1: OZA (n=53) IP C2: OZA (n=52) MP: OZA-OZA (n=34) ≥1 TEAE 153 (41%) 130 (41%) 94 (48%) 19 (36%) 16 (31%) 19 (56%) ≥1 serious TEAE 14 (4%) 21 (7%) 11 (6%) 3 (6%) 2 (4%) 1 (3%) ≥1 TEAE leading to tx discontinuation 13 (3.5%) 11 (3.5%) 2 (1%) 1 (2%) 3 (6%) 1 (3%)

S780 Impact of Ozanimod on Fecal Calprotectin Levels and the Association With Efficacy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 True North Study

Introduction: Ozanimod (OZA) is approved in the USA and EU for the treatment of moderate/severe ulcerative colitis (UC). OZA demonstrated efficacy in the phase 3 True North (TN) trial in patients (pts) with moderate/severe UC (NCT02435992). Infiltration of neutrophils in intestinal mucosa contributes to inflammation in inflammatory bowel diseases. Calprotectin, which is released by neutrophils, is a neutrophilic activity marker that is useful in monitoring UC disease activity. Methods: We assessed the effect of OZA on fecal calprotectin (FCP) levels and association with OZA efficacy in TN. During the 10-week (W) induction period, pts were randomized to double-blind (DB) OZA 0.92 mg or placebo (PBO) once daily (Cohort 1) or received open-label (OL) OZA once daily (Cohort 2). Pts with clinical response (CRS) to OZA at W10 were rerandomized to DB OZA or PBO for maintenance through W52. Efficacy endpoints (clinical remission, CRS, endoscopic improvement, mucosal healing, and histologic remission) and FCP levels were assessed at W10 and W52. Results: Change in FCP from baseline (BL) to W10 was assessed in 517 pts who received DB OZA (n=347) or PBO (n=170) and 293 who received OL OZA. Pts on OZA demonstrated reductions from BL in FCP at W10; this was significant vs PBO (P< .001, both cohorts) (Table). FCP reductions were significantly greater in pts with vs without CRS at W10 in all treatment groups (P< .001, all groups). Change in FCP from BL to W52 was assessed in 149 pts remaining on OZA and 109 who switched to PBO. FCP levels remained low through W52; pts on continuous OZA had significantly greater FCP reductions at W52 vs pts who switched to PBO (P=.0002). FCP reductions were significantly greater in pts with vs without CRS at W52 in OZA-OZA and OZA-PBO groups (P< .01, for both). Significantly greater reductions from BL in FCP occurred with OZA vs PBO at W10 and W52 regardless of prior biologic or tumor necrosis factor inhibitor exposure (P< .05, all groups). BL FCP level was predictive for CRS and histologic remission at W10 (P< .05, both endpoints). Reduction from BL in FCP at W10 was predictive and prognostic for all endpoints except CRS at W52 (P< .05, all endpoints). Conclusion: OZA treatment led to FCP reductions, indicative of decreases in intestinal neutrophil levels. BL FCP was predictive for OZA response. FCP reductions were predictive for OZA response and prognostic for UC. These findings may support use of FCP as a predictive biomarker for OZA response and prognostic biomarker in UC. Table 1. - Change from baseline in FCP at Weeks 10 and 52 FCP adjusted mean percent change (95% CI) Induction (Week 10) Maintenance (Week 52) Cohort 1 Cohort 2 Placebo (n=170) Ozanimod (n=347) Ozanimod (n=293) Ozanimod-placebo (n=109) Ozanimod-ozanimod (n=149) All patients 18.8 (-11.6, 59.6) -59.3 (-67.1, -49.7) -71.6 (-77.2, -64.5) -70.7 (-79.6, -57.7) -87.7 (-91.0, -83.3) Responders a -48.7 (-68.7, -16.0) -83.9 (-87.8, -78.8) -86.2 (-89.5, -81.8) -81.5 (-87.8, -71.7) -91.0 (-93.7, -87.1) Nonresponders b 54.9 (12.4, 113.5) -12.1 (-32.4, 14.4) -33.3 (-50.9, -9.5) -10.5 (-53.6, 72.9) -75.4 (-85.9, -57.2) aResponders during induction are pts who achieved CRS at W10, and responders during maintenance are pts who achieved CRS at W52.bNonresponders during induction are pts who did not achieve CRS at W10 and nonresponders at W52 did not achieve CRS at W52.

S761 Association Between Absolute Lymphocyte Count and Ozanimod Efficacy/Safety in Patients With Moderate/Severe Ulcerative Colitis: Results From the Phase 3 True North Study

Introduction: Ozanimod (OZA) is approved in the USA and EU for treatment (tx) of moderate/severe UC. OZA binding internalizes S1P1 receptors, reducing egress of lymphocyte subsets into circulation. OZA was approved in this patient (pt) population based on results of the phase 3 True North (TN) study (NCT02435992). Methods: We evaluated association between absolute lymphocyte count (ALC) and OZA efficacy/safety during TN’s induction period (IP) and maintenance period (MP). Pts were randomized to double-blind (DB) OZA 0.92 mg or placebo (PBO) or open-label (OL) OZA during 10-week (W) IP. Pts with clinical response to OZA at W10 were rerandomized to DB OZA or PBO for MP through W52. Rectal bleeding (RB), stool frequency (SF), composite Mayo, Physician’s Global Assessment (PGA), and endoscopy scores were assessed at baseline and as clinical outcomes at W10 and W52. Efficacy endpoints (EPs; clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10 and W52. Tx-emergent adverse events (TEAEs) and ALC were evaluated at baseline and W5, W10, W18, W28, W40, and W52. Results: During IP, 645 pts received DB OZA (n=429) or PBO (n=216) and 367 received OL OZA; for MP, 230 and 227 OZA-treated pts were rerandomized to OZA and PBO, respectively. Baseline ALC was not significantly correlated with clinical outcome at W10 or W52 as measured by changes from baseline RB, SF, Mayo, PGA, and endoscopy scores in pts on OZA or PBO. Baseline ALC was not predictive or prognostic for W10 and W52 responses based on the efficacy EPs. Reductions from baseline in mean ALC occurred by W5 with OZA and were significantly greater with OZA (53-54%) vs PBO (2.3%; P< .001). ALC plateaued by W10 and was maintained through W52 in pts on continuous OZA. ALC returned to PBO levels by W52 in pts who switched to PBO during MP. Change in ALC at W10 was generally not significantly correlated with changes in clinical outcomes at W10 or W52. Change in ALC at W5 was not predictive of W10 response; change in ALC at W10 was not predictive of W52 response. Reductions from baseline in ALC at all weeks were similar in OZA-treated pts with/without ≥1 TEAE and with/without infection TEAEs. Conclusion: ALC reductions occurring with OZA were reversed upon tx discontinuation and were not associated with TEAEs. Baseline ALC and ALC reductions were not predictive or prognostic for response. These findings support ALC as a pharmacodynamic biomarker but not as a prognostic or predictive biomarker.

S812 Hepatic Safety of Ozanimod in Ulcerative Colitis and Relapsing Multiple Sclerosis Phase 3 Trials

Introduction: Ozanimod (OZA) is a sphingosine 1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing forms of multiple sclerosis (MS) in the United States and European Union. Other S1P receptor modulators have shown substantial elevations in hepatic enzymes. Methods: The impact of OZA on liver function tests was assessed in this safety analysis from phase 3 UC and MS trials. In the 52-week (10-week induction period and 42-week maintenance period), randomized True North (TN) trial, patients (pts) with moderately to severely active UC were treated with placebo (n=216) or OZA 0.92 mg (equivalent to OZA HCl 1 mg) (n=796). In the randomized MS trials (SUNBEAM and RADIANCE), MS pts were treated with interferon beta-1a 30 µg (n=885) or OZA (n=882) for 12 and 24 months, respectively. Hepatic enzymes were assessed at baseline and Weeks 5, 10, 18, 28, 40, and 52 in TN, and at baseline and every 3 months for the MS trials. In the UC and MS trials, enzyme elevations were confirmed with a repeated test within 14 days. Results: Percentages of pts on OZA 0.92 mg with elevations in alanine transaminase (ALT), aspartate aminotransferase (AST), and bilirubin are shown in the Table; < 6% and < 2% of pts had ALT and AST elevations ≥3 x upper limit of normal (ULN), respectively, and < 2% had bilirubin elevations >2 x ULN. Of those with ALT ≥3 x ULN, 86.4% (19/22) of UC pts and 85.4% (41/48) of MS pts recovered to ALT < 3 x ULN within 3 months. Most hepatic treatment-emergent adverse events (TEAEs) were mild to moderate in UC and MS pts. In TN, 3 (0.4%) pts on OZA reported a hepatobiliary disorder TEAE, 1 (0.1%) of whom had hyperbilirubinemia. In the MS trials, 15 (1.7%) pts on OZA 0.92 mg reported a hepatobiliary disorder TEAE, 3 (0.3%) of whom had hyperbilirubinemia. Hepatic-related events leading to discontinuation, which were generally asymptomatic laboratory abnormalities, were reported in 4 (0.5%) UC pts and in 11 (1.2%) MS pts on OZA 0.92 mg. No serious hepatic TEAEs, Hy’s law cases, or severe drug-induced hepatocellular injuries occurred with OZA 0.92 mg in any of the trials. Conclusion: In this analysis of phase 3 UC and MS trials with OZA, elevations of aminotransferases and bilirubin occurring with OZA were infrequent, generally asymptomatic, and transient. These elevations, which generally resolved without study drug discontinuation, did not meet the criteria for Hy’s law or protocol-defined serious AEs. Table 1. - Maximum postbaseline ALT, AST, and bilirubin levels with OZA 0.92 mg Parameter TN (UC)(n=783) Sunbeam/Radiance (MS) (n=878) ALT >1 × ULN 215 (27.5) 373 (42.5) ≥3 × ULN 22 (2.8) 48 (5.5) ≥5 × ULN 8 (1.0) 14 (1.6) AST >1 × ULN 136 (17.4) 185 (21.1) ≥3 × ULN 14 (1.8) 9 (1.0) ≥5 × ULN 5 (0.6) 5 (0.6) Bilirubin >1 × ULN 32 (4.1) 122 (13.9) >2 × ULN 3 (0.4) 14 (1.6) >3 × ULN 1 (0.1) 3 (0.3)

S723 Duration of Response to Ozanimod After Treatment Withdrawal: Results From the Phase 3 True North Study

Introduction: The phase 3 True North (TN) randomized trial demonstrated efficacy and safety of ozanimod (OZA) in patients (pts) with moderately to severely active ulcerative colitis (UC). Temporary discontinuation of UC treatment can occur in clinical practice. Understanding the duration of response after treatment discontinuation can assist in clinical decision making. This analysis examined time to loss of OZA response in pts who discontinued OZA and switched to placebo (PBO) in the TN maintenance period (MP). Methods: In TN, pts were randomized to once-daily oral OZA 0.92 mg or PBO or to open-label OZA during a 10-week induction period (IP). Pts with clinical response to OZA at Week 10 were rerandomized to OZA (OZA-OZA) or PBO (OZA-PBO) in the MP through Week 52. Disease relapse was defined as an increase in partial Mayo score (PMS) of ≥2 points vs Week 10 with absolute PMS ≥4, endoscopic subscore ≥2, and exclusion of other causes of increased disease activity unrelated to UC. A subanalysis compared outcomes in OZA-OZA and OZA-PBO pts who entered the MP after achieving clinical remission (CRM) or clinical response (CRS only, excluding pts in CRM) at Week 10. Results: In the TN MP, 230 pts continued OZA (CRM, n=82; CRS only, n=148) and 227 pts switched to PBO (CRM, n=79; CRS only, n=148). Baseline characteristics were generally similar between groups. Pts in CRS only at Week 10 had a numerically higher proportion with severe disease and prior immunosuppressive medication use vs CRM pts (Table). Differences in disease relapse between groups became apparent after MP Week 8, after which a significantly higher proportion of OZA-OZA pts were without relapse vs OZA-PBO pts (Figure). MP Week 42 Kaplan-Meier (KM) estimates of no relapse were 86.1% and 62.6% for OZA-OZA and OZA-PBO pts, respectively. Additionally, pts in CRM at Week 10 had higher rates of nonrelapse during the MP vs those in CRS only at MP entry. KM estimates of non-relapse at MP Week 42 were 67.9% and 59.7% in OZA-PBO pts with CRM and CRS, respectively, and 90.9% and 83.4% in OZA-OZA pts with CRM and CRS, respectively. Conclusion: This analysis shows that OZA is effective at preventing disease relapse over 42 weeks of maintenance treatment in pts who achieve clinical response at Week 10. These data show that OZA maintains disease control even in the event of temporary discontinuation. However, extended discontinuation should be minimized in clinical practice.Figure 1 Table 1. - Baseline characteristics in pts in CRM vs pts in CRS only at Week 10 Pts in CRM a at IP Week 10 Pts in CRS b only at IP Week 10 OZA-PBO (n=79) OZA-OZA (n=82) OZA-PBO (n=148) OZA-OZA (n=148) Age, years, mean ± SD 45.0 ± 13.5 42.7 ± 13.9 42.0 ± 13.8 42.3 ± 13.4 Males, n (%) 45 (57.0) 41 (50.0) 77 (52.0) 76 (51.4) Years since UC diagnosis, mean ± SD 7.3 ± 7.0 7.4 ± 7.2 7.2 ± 7.3 8.9 ± 7.4 Prior therapies, n (%) 5-ASA CS Immunomodulator Anti-TNF Non-anti-TNF biologic 75 (94.9)51 (64.6)24 (30.4)13 (16.5)3 (3.8) 81 (98.8)54 (65.9)26 (31.7)15 (18.3)9 (11.0) 146 (98.6)117 (79.1)61 (41.2)52 (35.1)30 (20.3) 146 (98.6)109 (73.6)63 (42.6)61 (41.2)33 (22.3) Complete Mayo score c >9, n (%) 12 (15.2) 19 (23.2) 51 (34.5) 76 (51.4) Mayo endoscopic score = 3 (severe), n (%) 22 (27.8) 25 (30.5) 94 (63.5) 107 (72.3) Fecal calprotectin, median IQR, mg/kg 1027.8 (295.0, 2689.3) 851.6 (251.4, 2694.6) 1085.2 (434.4, 2579.3) 1285.0 (486.5, 2673.4) All data are reported at IP baseline.aCRM was defined as complete Mayo score of ≤2 with no individual subscore of >1 point.bCRS was defined as decrease from baseline of ≥3 points and at least 30% in the complete Mayo score and a decrease of ≥1 in RBS or an absolute RBS of ≤1.cThe sum of the rectal bleeding subscore, stool frequency subscore, Physician’s Global Assessment subscore, and endoscopy subscore.ASA, aminosalicylic acid; CRM, clinical remission; CRS, clinical response; CS, corticosteroid; IP, induction period; SD, standard deviation; TNF, tumor necrosis factor.

POSB17 Ozanimod for the Treatment of Biologic-Experienced Patients with Moderate-to-Severe Ulcerative Colitis: Results from a Systematic Literature Review and Network Meta-Analyses

To compare the relative efficacy of the oral selective sphingosine-1-phosphate receptor modulator ozanimod (OZA) versus other approved moderate-to-severe ulcerative colitis (UC) therapies in biologic-experienced patients via network meta-analyses (NMA). A systematic literature review was conducted to identify randomised clinical trials (RCTs) published from Jan 1, 2000 to Oct 21, 2020 that evaluated biological therapies (infliximab [IFX], adalimumab [ADA], golimumab [GOL], vedolizumab [VDZ], and ustekinumab [UST]) or an oral small molecule (tofacitinib [TOF]) for adults with moderate-to-severe UC. Bayesian NMAs were performed for clinical remission, clinical response, and endoscopic improvement in both induction (6-14 weeks) and maintenance (52-60 weeks) phases. Patients with prior exposure to or failure of prior advanced therapies (biologic therapies and TOF) were considered. Comparator treatments were limited to ADA, VDZ, UST, and TOF due to lack of biologic-experienced data for IFX and GOL. Nine RCTs were included in the induction network and seven were included in the maintenance network. In the induction phase, all therapies except ADA offered significant improvement over placebo (PBO) in clinical remission and clinical response. For endoscopic improvement, point estimates trended in favour of all therapies over PBO with statistically significant improvement for UST and TOF. OZA offered similar efficacy to all other therapies across endpoints except for a significant improvement in clinical remission (OR: 4.19, 95% CrI: 1.56-11.49) and clinical response (OR: 3.13, 95% CrI: 1.42-7.31) over ADA. In the maintenance phase, all therapies offered significant improvement over PBO across clinical remission, clinical response, and endoscopic improvement apart from UST 90 mg every 12 weeks. OZA offered similar efficacy to all other therapies across these endpoints. In biologic experienced patients, this NMA suggests OZA has similar efficacy to approved moderate-to-severe UC therapies except versus adalimumab, where OZA demonstrated superior induction efficacy on clinical remission and clinical response.

Matching-adjusted indirect treatment comparison of ozanimod versus teriflunomide for relapsing multiple sclerosis

BackgroundA growing number of immunomodulating disease-modifying therapies are available for treatment of relapsing multiple sclerosis (RMS). In the absence of randomized head-to-head trials, matching-adjusted indirect comparisons (MAICs) can be used to adjust for cross-trial differences and evaluate the comparative efficacy and safety of these agents. We used MAIC methodology to indirectly compare key outcomes with ozanimod (OZM) and teriflunomide (TERI) in the treatment of RMS. MethodsA systematic literature review was conducted to identify clinical trials evaluating the efficacy and safety of OZM vs TERI. Given the absence of head-to-head trials of OZM vs TERI, we used a matching-adjusted indirect comparison to adjust for potential treatment effect modifiers and prognostic factors while assessing confirmed disability progression (CDP), relapse, and safety outcomes. Individual patient data for OZM (SUNBEAM and RADIANCE Part B trials) and aggregate level data for TERI (ASCLEPIOS I/II, TOWER, OPTIMUM, and TEMSO trials) were used to evaluate the following outcomes: annualized relapse rate (ARR), proportion of patients relapsed, CDP at 3 and 6 months, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. ResultsAfter matching, baseline patient characteristics were balanced between OZM and TERI. Compared with TERI, OZM demonstrated significant improvements in ARR (rate ratio: 0.73; 95% CI: 0.62–0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44–0.70), overall AEs (OR: 0.35; 95% CI: 0.29–0.43), SAEs (OR: 0.53; 95% CI: 0.37–0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09–0.21). OZM demonstrated statistically significant improvements in CDP at 3 months (hazard ratio [HR]: 0.78; 95% CI: 0.66–0.92) but nonsignificant differences at 6 months (HR: 0.78; 95% CI: 0.60–1.01) compared with TERI. ConclusionIn this indirect treatment comparison of patients with RMS, OZM appeared to have an improved benefit–risk profile over TERI.

Role and Mechanism of Ozanimod (RPC1063) in Oligodendrocyte Precursor Cell Differentiation

Role and Mechanism of Ozanimod (RPC1063) in Oligodendrocyte Precursor Cell Differentiation

Abstract 2974: Preclinical evaluation of Ozanimod for prostate cancer treatment

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men of United States, after lung cancer. There are various treatment options such as surgery, radiation therapy, chemotherapy, and androgen deprivation therapy are availabale for PCa. However, invariably patients develop resistance to these therapies, resulting in the manifestation of aggressive and recurrent PCa. Hence, there is an urgent need for an effective treatment strategy for managing PCa. Previous studies have identified that the sphingosine 1-phosphate receptor (S1PR) as a potential target to treat prostate cancer. Ozanimod (OZM) is a selective sphingosine 1- phosphate receptor 1 (S1PR1) and (S1PR5) modulator, which is in phase 3 clinical trial for patients with relapsing multiple sclerosis and ulcerative colitis. The objective of this study is to determine the anticancer effects of OZM, an S1PR modulator using LNCaP, PC-3, and DU-145 as cellular models of PCa. These PCa cell lines were subjected to cell viability, colony formation and wound healing assays as endpoints to assess the anticancer effects of OZM. The cell viability assay results revealed that OZM had a differential effect on PCa cell lines with LNCaP cells being the most sensitive and DU-145, PC-3 showing similar sensitivities to OZM treatment. Furthermore, OZM treatment inhibited the colony formation characteristics of PCa cell lines in-vitro when compared with control in all the three cell lines. In wound healing assay, the migratory characteristics of PCa cell lines were inhibited by OZM in a dose dependent manner. These findings suggested that OZM has both tumor growth suppression and metastasis inhibition potential. Furthermore, Annexin V and Propidium Iodide staining assay revealed that OZM induces apoptosis in PC-3 and DU-145 cells. Following these findings, human apoptotic array study using LNCaP cells showed that anti-apoptotic protein molecules such as c-IAP1, clusterin, and livin were downregulated by OZM treatment in addition to inhibition of HIF-1α expression. The mechanistic study conducted using LNCaP cells by Western blot analysis revealed that OZM treatment upregulated BiP expression while downregulated PERK, IRE-1α which are protein markers associated with endoplasmic reticulum (ER) stress pathway. Furthermore, our results showed that c-myc was down-regulated and MAD, MAX transcription factors were upregulated when treated with OZM. Based on these findings, we suggest that OZM treatment modulates ER stress pathway and anti-apoptotic proteins leading to prostate tumor suppression. In conclusion, OZM might be a potential chemotherapeutic agent for treating both indolent and aggressive PCa. Citation Format: Reshmii Venkatesan, Somaiah Chinnapaka, John Schappert, Gnanasekar Munirathinam. Preclinical evaluation of Ozanimod for prostate cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2974.