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Daykin, Nicola. "Ozanimod for relapsing remitting multiple sclerosis and how Brexit changed the journey." Journal of Prescribing Practice 4, no. 2 (February 2, 2022): 64–71. http://dx.doi.org/10.12968/jprp.2022.4.2.64.
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This article will focus on ozanimod, a medication that has been put forward for relapsing-remitting multiple sclerosis (RRMS). It will look at ozanimod's characteristics, including the pharmacokinetics and pharmacodynamics of the medication, and follow ozanimod's journey from clinical trials through the different licencing agencies, allowing ozanimod to be used as a treatment in multiple sclerosis (MS). Finally, this article will look at its journey through the National Institute for Clinical Excellence (NICE) to seek approval to be used as a medication to treat RRMS on the NHS. The article will also briefly reflect on the marketing authorisation changes in the UK since leaving the European Union (EU) and the impact of these changes.
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Harris, Sarah, Jonathan Q. Tran, Harry Southworth, Collin M. Spencer, Bruce A. C. Cree, and Scott S. Zamvil. "Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS." Neurology - Neuroimmunology Neuroinflammation 7, no. 5 (July 31, 2020): e839. http://dx.doi.org/10.1212/nxi.0000000000000839.
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ObjectiveTo better understand ozanimod's mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod's effect on circulating leukocyte subsets in patients with relapsing multiple sclerosis.MethodsAn open-label pharmacodynamic study randomized patients to oral ozanimod hydrochloride (HCl) 0.5 (n = 13) or 1 mg/d (n = 11) for ∼12 weeks (including 7-day dose escalation). Circulating leukocyte subsets were quantified using flow cytometry (days 28, 56, and 85) and epigenetic cell counting (days 2, 5, 28, 56, and 85) and compared with baseline (day 1) using descriptive statistics.ResultsOzanimod caused dose-dependent reductions in absolute lymphocyte counts. Observed by both methodologies, circulating CD19+ B- and CD3+ T-cell counts were reduced by >50% with ozanimod HCl 0.5 mg and >75% with 1 mg at day 85. Based on flow cytometry, ozanimod HCl 1 mg showed greater decreases in CD4+ than CD8+ T cells, greater decreases in both CD4+ and CD8+ central memory vs effector memory T cells, and reductions in mean CD4+ and CD8+ naive T cells by ≥90% at day 85. In the flow cytometry analysis, changes in monocytes, natural killer, and natural killer T cells were minimal. Using epigenetic cell counting, greater reductions for Th17 than T regulatory cells were determined.ConclusionOzanimod induced dose-dependent reductions in circulating B- and T-cell counts and differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells. Data characterized with both a novel epigenetic cell-counting method and flow cytometry support ozanimod's MOA.Clinical trial registration:clinicaltrials.govNCT02797015.
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Cohen, Jeffrey A., Giancarlo Comi, Douglas L. Arnold, Amit Bar-Or, Krzysztof W. Selmaj, Lawrence Steinman, Eva K. Havrdová, et al. "Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study." Multiple Sclerosis Journal 25, no. 9 (July 25, 2018): 1255–62. http://dx.doi.org/10.1177/1352458518789884.
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Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). Results: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24—end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Conclusion: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged.
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Panaccione, R., S. Danese, D. C. Wolf, J. B. Canavan, A. Jain, H. Wu, A. Petersen, A. Afzali, and M. T. Abreu. "P464 Effects of ozanimod on histologic remission and mucosal healing over 3 years of continuous treatment in patients with ulcerative colitis." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i591—i593. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0594.
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Abstract Background Ozanimod is approved in the European Union, United States, and other countries for the treatment of moderately to severely active ulcerative colitis in adults (UC). The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients with moderately to severely active UC. The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod. This interim analysis of the TN OLE evaluated the efficacy of ozanimod on histologic remission (HR) and mucosal healing (MH) in patients who received approximately 3 years of continuous ozanimod treatment. Methods In TN, patients were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo (Cohort 1) or to open-label ozanimod (Cohort 2) for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo for a 42-week maintenance period (MP). Patients with clinical response to ozanimod at Week 52 in TN were eligible to continue receiving ozanimod in the ongoing OLE. This interim analysis of the OLE (data cutoff: 10 January 2022, the point at which patient disposition was available for patients until OLE Week 94) included all patients on continuous ozanimod in the TN MP who achieved clinical response at Week 52 and enrolled in the OLE (n=131). Endoscopic and histologic endpoints were evaluated at OLE Weeks 46 and 94 (98 and 146 weeks of continuous ozanimod treatment, respectively) and reported using observed case analysis. Mean Mayo endoscopy scores were evaluated from TN baseline to OLE Week 94. Results Of the 131 total patients included in this analysis, 87% completed OLE Week 46 (98 weeks of continuous ozanimod) and 72% completed OLE Week 94 (146 weeks of continuous ozanimod). Patients had a mean age of 44 years and 52% were female. Most patients (68%) had left-sided UC, 69% had prior use of corticosteroids, 99% had prior use of 5-aminosalicylic acid, and 32% had prior use of tumor necrosis factor inhibitors. Most TN Week 52 clinical responders achieved endoscopic improvement (EI), HR, and MH at OLE Weeks 46 and 94 (Figure 1). Ozanimod treatment was associated with a reduction in mean Mayo endoscopy score to 1.0 at TN Week 52; this was sustained through OLE Week 94 (Figure 2). Conclusion In this interim analysis of the TN OLE, a large proportion of clinical responders after 1 year of ozanimod who remained on ozanimod for up to 2 years thereafter, achieved EI, HR, and MH after 2 and 3 years of continuous treatment. Long-term ozanimod use may be associated with sustained endoscopic and histologic benefits in patients with UC.
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Sandborn, William, Brian Feagan, Douglas Wolf, Geert D’Haens, Séverine Vermeire, Stephen Hanauer, Subrata Ghosh, Harry Southworth, and Sarah Harris. "EFFECT OF OZANIMOD ON FECAL CALPROTECTIN AND FECAL LACTOFERRIN, BIOMARKERS OF INTESTINAL INFLAMMATION, IN THE PHASE 2 TOUCHSTONE STUDY OF PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S6. http://dx.doi.org/10.1093/ibd/izaa347.014.
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Abstract Introduction Efficacy and safety of ozanimod, an oral sphingosine-1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, was previously demonstrated in the double-blind phase 2 TOUCHSTONE study (NCT01647516) in patients with moderate-to-severe ulcerative colitis. Here we report the effect of ozanimod on levels of fecal calprotectin (FCP) and fecal lactoferrin (FLF), two markers of intestinal inflammation. Methods Patients in TOUCHSTONE were randomized 1:1:1 to once daily oral ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg), ozanimod HCl 1.0 mg (equivalent to ozanimod 0.92 mg), or placebo for 8 weeks; responders at week 8 (based upon Mayo score) entered a maintenance phase through week 32. Stool collection occurred at baseline and weeks 8 and 32 to measure levels of FCP and FLF. Results A total of 197 patients were randomized and received treatment (n=65, placebo; n=65, ozanimod 0.5 mg; n=67, ozanimod 1 mg). Median baseline levels of FCP were 1272, 1477, and 1238 μg/g, respectively; baseline FCP levels were not associated with baseline Mayo score. Median baseline levels of FLF were 29.0, 30.6, and 29.9 μg/g, respectively; baseline FLF was related to week 8 Mayo score even after adjusting for baseline Mayo score. At week 8, FCP levels declined across treatment groups (median percent change from baseline, -53.4, -68.7, and -70.0 in placebo, ozanimod 0.5 mg and 1 mg groups, respectively); declines in FCP were maintained at week 32 (median percent change from baseline, -42.3, -72.6, and -80.6, respectively). At week 8, declines in FCP were greater in patients achieving clinical response (based on Mayo score) than in non-responders on ozanimod 1 mg. Declines in FCP at week 8 were also greater in patients achieving clinical remission than in those who did not, with greater declines with ozanimod 1 mg relative to 0.5 mg. FLF levels declined at weeks 8 and 32 across treatment groups, with greater changes in the ozanimod 1 mg group vs placebo (median percent change from baseline, week 8: -35.7, -61.0, and -84.7, respectively; week 32: -60.2, -62.5, -85.3, respectively, for placebo, ozanimod 0.5 mg, and ozanimod 1 mg). Reductions in FLF at week 8 were greater for treatment responders vs non-responders and for those achieving vs not achieving clinical remission in the ozanimod 1 mg group. Conclusion In TOUCHSTONE, treatment with ozanimod was associated with declines in FCP levels in treatment responders (for the 1 mg dose group) or those who achieved clinical remission (both doses). Ozanimod 1 mg was also associated with declines in FLF for treatment responders and those achieving remission.
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Armuzzi, A., R. K. Cross, G. Lichtenstein, J. Calkwood, A. Pai, M. Pondel, H. A. Ahmad, et al. "DOP45 Long-term cardiac safety of ozanimod in phase 3 clinical program of Ulcerative Colitis and relapsing multiple sclerosis." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i094—i095. http://dx.doi.org/10.1093/ecco-jcc/jjab232.084.
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Abstract Background Sphingosine-1-phosphate (S1P) receptor modulators may be associated with bradycardia and atrioventricular conduction delays. A previous analysis demonstrated first-dose ozanimod had minimal effects on cardiac function, including in patients (pts) with a known history of cardiovascular disease. This analysis evaluated long-term cardiac safety following continuous ozanimod treatment from the phase 3 ulcerative colitis (UC) True North trial and multiple sclerosis (MS) 12-mo SUNBEAM and 24-mo RADIANCE trials. Methods Ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg)–treated pts from True North and pooled SUNBEAM/RADIANCE trials were included. In True North, pts in Cohort 1 received double-blind ozanimod or placebo and pts in Cohort 2 received open-label ozanimod in the induction period; in the maintenance period, pts with clinical response to ozanimod at 10 weeks were rerandomized to double-blind ozanimod or placebo. In True North, ECGs were monitored at screening, day 1, wk-10, and wk-52; heart rate (HR) was monitored at every visit. In the MS trials, ECGs were monitored at screening, baseline, day 15, and end of treatment (EOT); HR was monitored similarly at the beginning, then every 3 mo until EOT. Cardiac-related treatment-emergent AEs (TEAEs) were reported. Results In the UC trial, continuous ozanimod treatment was not associated with any clinically significant changes in HR or ECG. The incidence of cardiac-related TEAEs with ozanimod during induction in Cohorts 1 and 2 was low (Table). In maintenance, cardiac-related TEAEs were reported in 1.3% (3/230) of pts in the continuous ozanimod group (Table); incidence was numerically higher in ozanimod pts with (2 of 57 pts [3.5%]) versus without (1 of 173 pts [0.6%]) prior history of cardiovascular disease. Cardiac-related serious AEs (SAEs) were uncommon (angina pectoris, coronary artery stenosis, pericarditis in 1 patient each). In the pooled MS studies, no clinically significant HR or ECG changes were associated with chronic treatment up to mo 24. The incidence of cardiac-related TEAEs was low with ozanimod (Table); incidence was similar among pts with (6 of 171 pts [3.5%]) versus without (24 of 711 pts [3.4%]) prior history of cardiovascular disease. Two of 882 patients experienced cardiac-related SAEs resulting in hospitalization with ozanimod in the MS studies (asymptomatic sinus bradycardia [HR 44 bpm] and symptomatic supraventricular tachycardia). Conclusion Ozanimod had a manageable long-term cardiac safety profile with a low incidence of bradycardia and few serious long-term cardiac safety findings in the phase 3 UC and MS ozanimod trials.
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Siegmund, B., J. Axelrad, M. Pondel, M. T. Osterman, H. A. Ahmad, A. Memaj, M. Regueiro, A. Armuzzi, and A. Afzali. "DOP43 Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active Ulcerative Colitis: Results from the induction period of True North." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i092—i093. http://dx.doi.org/10.1093/ecco-jcc/jjab232.082.
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Abstract Background Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, is approved in the US for the treatment of moderately to severely active ulcerative colitis (UC). In the pivotal phase 3 True North randomised controlled trial in moderate-to-severe UC, significantly more patients (pts) achieved clinical response and remission with ozanimod vs placebo (PBO) at week (wk) 10 of the induction period. Here, we report the rapidity of ozanimod-induced symptomatic response and remission in pts from True North (NCT02435992). Methods In True North, pts were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or PBO (Cohort 1) or received open-label ozanimod (Cohort 2) during induction. This analysis evaluated symptomatic response (defined as ≥1 point and ≥30% decrease from baseline in adapted partial Mayo score and ≥1 point decrease from baseline in rectal bleeding score [RBS] or absolute RBS ≤1) and symptomatic remission (defined as RBS of 0 and stool frequency score [SFS] ≤1 point and ≥1 point decrease from baseline at each study visit from wk 2 through 10. Results During induction, 645 pts were randomised to ozanimod (n=429) or PBO (n=216) in Cohort 1, and 367 pts received open-label ozanimod in Cohort 2. Baseline demographics and clinical characteristics were well balanced across groups. Differences in symptomatic response were observed between ozanimod and PBO recipients in Cohort 1 as early as 2 wk after ozanimod initiation (1 wk post-titration) for the overall population (36.1% vs 26.4%; difference: 9.6% [95% CI, 2.1–17.0]; Figure 1) and tumour necrosis factor inhibitor (TNFi)-naïve pts (38.5%, n=301 vs 29.1%, n=151; difference: 9.4% [95% CI, 0.2–18.5]), and as early as 4 wk for TNFi-exposed pts (42.2%, n=128 vs 27.7%, n=65; difference: 15.8% [95% CI, 1.8–29.8]). Differences in symptomatic remission were observed between ozanimod and PBO recipients in Cohort 1 as early as 5 wk after ozanimod initiation (4 wk post-titration) for the overall population (26.3% vs 16.7%; difference: 8.6% [95% CI, 1.8–15.4] Figure 2), as early as 4 wk for TNFi-naïve pts (27.2% vs 17.9%; difference: 9.4% [95% CI, 1.5–17.4]), and as early as 8 wk for TNFi-exposed pts (22.7% vs 12.3%; difference: 11.7% [95% CI, 1.3–22.1]). Rates of symptomatic response and remission in pts receiving open-label ozanimod (Cohort 2) were similar to those in pts receiving randomised ozanimod (Cohort 1). Conclusion In the overall population, ozanimod was associated with higher rates of symptomatic response and remission vs PBO as early as 2 and 5 wk, respectively, after treatment initiation. Both clinical endpoints were more rapidly achieved in TNFi-naïve vs TNFi-exposed pts.
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Dubinsky, M. C., U. Mahadevan, L. Charles, S. Afsari, A. Henry, G. Comi, K. Selmaj, and C. J. van der Woude. "DOP53 Pregnancy outcomes in the ozanimod clinical development program in relapsing multiple sclerosis, Ulcerative Colitis, and Crohn’s Disease." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S088—S089. http://dx.doi.org/10.1093/ecco-jcc/jjab073.092.
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Abstract Background Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, has demonstrated efficacy in patients with relapsing multiple sclerosis (rMS) and ulcerative colitis (UC), and is being studied in Crohn’s disease (CD). S1P1-3 receptors are involved in vascular formation during embryogenesis. Within studies in the ozanimod clinical development program, female participants of childbearing potential were required to use effective contraception while receiving and up to 3 months after discontinuing ozanimod; treatment discontinuation was required if pregnancy was confirmed. Here we review pregnancy outcomes data with ozanimod use in rMS, UC, and CD. Methods All pregnancies, including participant and partner pregnancies, in the ozanimod clinical development program with an initial diagnosis prior to a cut-off date of September 30, 2020 were assessed for pregnancy outcomes. Results At cut-off, safety data on 4131 participants were available. A total of 83 pregnancies were reported in the safety database of participants treated with ozanimod or their partners (Table). All pregnancy exposures occurred during the first trimester. Of the 60 pregnancies in ozanimod clinical trials, 9 were reported in patients with UC, and 3 in patients with CD. Participants discontinued study medication promptly except for those who elected pregnancy termination and did not discontinue study medication. Among all pregnancies in the ozanimod clinical development program, the incidence of spontaneous abortion in clinical trial participants was 15%; the rate in the general population is between 12% and 22%. The rate of preterm birth was 10.7% of live births; as reference, the global population estimate is 10.6% and the European estimate is 8.7%. No teratogenicity was observed. Outcomes in patients with UC included 2 live births that resulted in 2 full-term healthy newborns, 2 ongoing pregnancies, 2 spontaneous early losses, and 3 elective terminations. Conclusion While pregnancy should be avoided in patients on and 3 months after stopping ozanimod and clinical experience with ozanimod during pregnancy is limited, there has been no increased event of foetal abnormalities or adverse pregnancy outcomes seen with ozanimod exposure in early pregnancy.
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Shen, J., D. Tatosian, L. Sid-Otmane, N. Teuscher, L. Chen, P. Zhang, G. S. Tirucherai, D. Chitakara, and C. Marta. "P332 Population pharmacokinetics of ozanimod and active metabolite CC112273 in patients with ulcerative colitis." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S355—S357. http://dx.doi.org/10.1093/ecco-jcc/jjab076.456.
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Abstract Background Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and under development for ulcerative colitis (UC) and Crohn’s disease (CD). Following multiple dosing of ozanimod in healthy subjects, ozanimod and two of the active metabolites CC112273 and CC1084037 represent approximately 6%, 73%, and 15% of circulating total active drug exposure, respectively. Two separate pharmacokinetic (PK) models were developed for the most prominent metabolite CC112273 and ozanimod. CC1084037 was not modeled due to the high correlation between CC112273 and CC1084037 plasma concentrations. Therefore, this analysis aims to characterise the PK of ozanimod and the major metabolite CC112273 in UC and RMS population. Methods Subjects from 11 studies (Phase 1 to Phase 3) in healthy volunteers, RMS, and UC patients were included in this population PK analysis. The analyses included a total of 18901 concentrations from 2890 subjects for CC112273 and 18834 PK concentrations from 2977 subjects for ozanimod. A 2-compartment model was used to describe the concentration-time profiles of both ozanimod and CC112273, separately. The influence of weight, age, sex, race, disease, or smoking status and hepatic function on the PK of ozanimod and CC112273 were explored. The impact of concomitant corticosteroids on CC112273 PK were evaluated post hoc. Results While the overall apparent clearance of ozanimod was 7% lower in RMS patients compared to UC, similar exposures were observed in both populations. The most influential covariate on ozanimod PK was body weight, with a modest 23% increase in apparent clearance for a 102-kg subject relative to a 70-kg subject (Figure 1). The apparent clearance of CC112273 was 16% greater in RMS patients compared to UC patients, resulting in a slightly higher exposure for UC patients. Increasing body weight had a modest reduction in clearance, while smoking had the largest influence on CC112273 PK of approximately 108% increased clearance (Figure 2). Post-hoc results showed no impact of concomitant prednisone or prednisolone on the PK of CC112273. Other factors, including age, race, sex, or hepatic impairment did not impact the PK of ozanimod or CC112273 PK. Conclusion The population PK model of CC112273 indicates that covariates with the largest effect on CC112273 PK parameters were body weight and smoking status. However, no covariate impacted clearance by more than 25%. The PK of ozanimod and CC112273 were not meaningfully impacted by age including in the elderly, body weight, race, sex, hepatic function, or concomitant prednisone or prednisolone. Overall, the PK of ozanimod and CC112273 were comparable in UC and RMS patients.
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Shen, Jun, Daniel Tatosian, Lamia Sid-Otmane, Nathan Teuscher, Lu Chen, Peijin Zhang, Giridhar Tirucherai, Denesh Chitkara, and Cecilia Marta. "POPULATION PHARMACOKINETICS OF OZANIMOD AND ACTIVE METABOLITE CC112273 IN PATIENTS WITH ULCERATIVE COLITIS." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S17—S18. http://dx.doi.org/10.1093/ibd/izac015.025.
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Abstract BACKGROUND Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and moderately to severely active ulcerative colitis (UC) and under development for Crohn’s disease (CD). Following multiple dosing of ozanimod in healthy subjects, ozanimod and two of the active metabolites CC112273 and CC1084037 represent approximately 6%, 73%, and 15% of circulating total active drug exposure, respectively. Two separate pharmacokinetic (PK) models were developed for the most prominent metabolite CC112273 and ozanimod. CC1084037 was not modeled due to the high correlation between CC112273 and CC1084037 plasma concentrations. Therefore, this analysis aims to characterize the PK of ozanimod and the major metabolite CC112273 in UC and RMS population. METHODS Subjects from 11 studies (Phase 1 to Phase 3) in healthy volunteers, RMS, and UC patients were included in this population PK analysis. The analyses included a total of 18901 concentrations from 2890 subjects for CC112273 and 18834 PK concentrations from 2977 subjects for ozanimod. A 2-compartment model was used to describe the concentration-time profiles of both ozanimod and CC112273, separately. The influence of weight, age, sex, race, disease, or smoking status and hepatic function on the PK of ozanimod and CC112273 were explored. The impact of concomitant corticosteroids on CC112273 PK were evaluated post hoc. RESULTS While the overall apparent clearance of ozanimod was 7% lower in RMS patients compared to UC, similar exposures were observed in both populations. The most influential covariate on ozanimod PK was body weight, with a modest 23% increase in apparent clearance for a 102-kg subject relative to a 70-kg subject (Figure 1). The apparent clearance of CC112273 was 16% greater in RMS patients compared to UC patients, resulting in a slightly higher exposure for UC patients. Increasing body weight had a modest reduction in clearance, while smoking had the largest influence on CC112273 PK of approximately 108% increased clearance (Figure 2). Post-hoc results showed no impact of concomitant prednisone or prednisolone on the PK of CC112273. Other factors, including age, race, sex, or hepatic impairment did not impact the PK of ozanimod or CC112273 PK. CONCLUSION The population PK model of CC112273 indicates that covariates with the largest effect on CC112273 PK parameters were body weight and smoking status. However, no covariate impacted clearance by more than 25%. The PK of ozanimod and CC112273 were not meaningfully impacted by age including in the elderly, body weight, race, sex, hepatic function, or concomitant prednisone or prednisolone. Overall, the PK of ozanimod and CC112273 were comparable in UC and RMS patients.
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Swallow, Elyse, Oscar Patterson-Lomba, Lei Yin, Rina Mehta, Corey Pelletier, David Kao, James K. Sheffield, Tim Stonehouse, and James Signorovitch. "Comparative safety and efficacy of ozanimod versus fingolimod for relapsing multiple sclerosis." Journal of Comparative Effectiveness Research 9, no. 4 (March 2020): 275–85. http://dx.doi.org/10.2217/cer-2019-0169.
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Aim: Ozanimod and fingolimod are sphingosine 1-phosphate receptor–modulating therapies for relapsing multiple sclerosis. Patients & methods: Comparative effectiveness was assessed by matching adjusted indirect comparisons of safety and efficacy trial outcomes at first-dose cardiac monitoring, 1 year and 2 years. Results: After adjustment, baseline characteristics were similar. Ozanimod was associated with a lower risk of extended first-dose monitoring, conduction abnormalities including atrioventricular block. One-year risks of any adverse event (AE), mean lymphocyte count reductions and abnormal liver enzymes were lower with ozanimod. Two-year risks of AEs leading to discontinuation, any AEs, herpetic infections, bradycardia and abnormal liver enzymes were lower with ozanimod. Analyses of efficacy outcomes were similar. Conclusion: Ozanimod appears to have a favorable benefit-risk profile versus fingolimod.
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Bonek, Robert. "Ozanimod w terapii rzutowo-remisyjnej postaci stwardnienia rozsianego – opisy przypadków." Medycyna Faktów 15, no. 2 (55) (June 20, 2022): 236–39. http://dx.doi.org/10.24292/01.mf.0222.18.
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Stwardnienie rozsiane jest przewlekłą, zapalną, autoimmunologiczną i neurozwyrodnieniową chorobą ośrodkowego układu nerwowego charakteryzującą się obecnością zmian demielinizacyjnych rozsianych w przestrzeni i czasie. Jedną z opcji terapeutycznych mających zastosowanie w leczeniu modyfikującym przebieg choroby są modulatory receptora sfingozyno-1-fosforanu. Ozanimod jest nowym selektywnym modulatorem sfingozyno-1-fosforanu o potwierdzonej wysokiej skuteczności i bezpieczeństwie leczenia. Przedstawione przypadki chorych leczonych ozanimodem potwierdzają wcześniejsze wyniki badań w zakresie skuteczności i bezpieczeństwa tego leku w populacji chorych zarówno z wczesnym, jak i zaawansowanym rzutowo-remisyjnym stwardnieniem rozsianym.
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Panaccione, R., S. Danese, D. C. Wolf, J. B. Canavan, A. Jain, H. Wu, A. Petersen, L. Charles, A. Afzali, and M. T. Abreu. "P405 Long-term safety of 3 years of ozanimod in moderately to severely active ulcerative colitis: an interim analysis of the True North open-label extension." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i534—i535. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0535.
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Abstract Background The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure. Methods In TN, pts were randomised to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enrol in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposure-adjusted incidence rates per 100 patient-years (PY) were calculated. Results The average age of TN OLE study participants was 41.7 years (±13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious; TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%; EAIR 0.1/100 PY; 2 in TN and 1 in OLE; no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%; EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm3), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%]; EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events. Conclusion Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure).
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Sands, B. E., A. Dignass, P. Irving, M. Chiorean, M. Long, D. Eren, H. A. Ahmad, et al. "P316 Ozanimod is an efficacious oral therapy after, 5-ASA failure in immunomodulator- and biologic-naive patients with ulcerative colitis: post hoc analysis from True North." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i339—i340. http://dx.doi.org/10.1093/ecco-jcc/jjab232.443.
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Abstract Background Oral, 5-aminosalicylates (5-ASA) and corticosteroids (CS) are often the first-line treatment for ulcerative colitis (UC), and patients (pts) who fail these agents typically advance to chronic immunosuppressives. Ozanimod, an oral sphingosine, 1-phosphate receptor modulator, is approved for treating adults with moderately to severely active UC in the US. This post-hoc analysis from the pivotal phase, 3 True North randomised controlled trial evaluated the efficacy of ozanimod at week (wk), 10 (end of induction) in immunomodulator- and biologic-naive pts with moderate to severe UC who failed, 5-ASA with or without concomitant CS. Methods True North consisted of a, 10-wk induction period. Pts in Cohort, 1, stratified by CS use at screening, were randomised to either ozanimod, 0.92 mg (equivalent to ozanimod HCl, 1 mg; n=429) or placebo (n=216) once daily in a double-blind manner; pts in Cohort, 2 (n=367) received open-label daily ozanimod, 0.92 mg. At enrollment, pts were required to be on stable doses of oral, 5-ASA and/or CS for >2 wk and continued on the same dose throughout induction. Pts who received tofacitinib within, 2 wk of screening were excluded. This analysis focused on clinical remission, clinical response, endoscopic improvement, and mucosal healing efficacy outcomes in immunomodulator- and biologic-naive, 5-ASA exposed pts. Results Of, 464 pts treated with, 5-ASA and were immunomodulator- and biologic-naive, with or without CS, 205 were on ozanimod and, 105 were on placebo in Cohort, 1;, 158 received open-label ozanimod in Cohort, 2. Baseline characteristics were similar between groups in Cohort, 1. Compared with placebo at wk, 10, a higher proportion of ozanimod-treated patients achieved clinical remission (23.4% vs, 8.9%), clinical response (53.7% vs, 30.7%), endoscopic improvement (35.6% vs, 14.9%), and mucosal healing (18.0% vs, 5.0%; Figure, 1) in this subgroup. These results are consistent with previously published results of the overall study population,1 which demonstrated significantly greater proportions of patients receiving ozanimod vs placebo achieving clinical remission (18.4% vs, 6.0%), clinical response (47.8% vs, 25.9%), endoscopic improvement (27.3% vs, 11.6%), and mucosal healing (12.6% vs, 3.7%). Additionally, all efficacy endpoints were achieved by a greater proportion of patients on ozanimod vs placebo regardless of CS use at baseline (Figure, 2). Results were similar for open-label ozanimod-treated patients in Cohort 2. Conclusion Ozanimod demonstrated efficacy at wk, 10 in immunomodulator- and biologic-naive patients with UC who had failed, 5-ASA, regardless of CS use at baseline. Reference 1. N Engl J Med, 2021;385:1280.
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Dignass, A., M. Regueiro, J. F. Colombel, A. Jain, J. B. Canavan, H. Wu, G. Lawlor, M. T. Osterman, S. Vermeire, and D. T. Rubin. "P687 Durability of recaptured response to ozanimod during the True North open-label extension." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i817—i818. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0817.
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Abstract Background Ozanimod is approved in the EU, US, and other countries for treatment of moderately to severely active ulcerative colitis (UC) in adults. In the phase 3 True North (TN) study, ozanimod 0.92 mg once daily demonstrated efficacy and safety for up to 52 weeks in patients (pts) with moderately to severely active UC. This open-label extension (OLE) analysis evaluated the long-term durability of ozanimod based on symptomatic and clinical endpoints in pts who experienced disease relapse while on placebo during the TN maintenance period (MP) and then recaptured response to ozanimod during the OLE. Methods Responders to ozanimod 10-week induction therapy were rerandomised 1:1 to ozanimod (n=230) or placebo (n=227); this OLE interim analysis (data cutoff: January 10, 2022, at which point the OLE Week 94 disposition was available for pts) included all pts who relapsed on placebo during the MP and reinitiated ozanimod in the OLE. Endpoints included symptomatic response and remission, clinical response and clinical remission (which include endoscopy subscores), and corticosteroid (CS)-free remission (clinical remission while off CS for ≥12 weeks) evaluated using observed case (OC) and nonresponder imputation (NRI) analyses, and mean total Mayo score over time. Results A total of 77/227 pts (34%) rerandomised to placebo during MP experienced a relapse after a median of 12.7 weeks and all entered the OLE. Symptomatic response was achieved by 46/73 (63%) pts 5 weeks after restarting ozanimod in the OLE (NRI analysis: 60% at OLE Week 5) and in 32/33 (97%) by OLE Week 94 in the OC analysis. Symptomatic remission was also achieved by OLE Week 5 by 24/73 (33%) pts. Sustained efficacy of ozanimod reinitiation was also demonstrated comparing OLE Weeks 46 and 94 across clinical endpoints by OC analysis (clinical response, 76% and 86%; clinical remission, 44% and 59%; CS-free remission, 37% and 52%) and NRI analysis (clinical response, 42% and 31%; clinical remission, 25% and 22%; CS-free remission, 21% and 20%) (Figure 1). In addition, 56.3%, 52.6%, and 50% of pts who experienced clinical response, clinical remission, and CS-free remission, respectively, at OLE Week 46 continued to sustain these endpoints at OLE Week 94. Reductions in mean total Mayo score at OLE Week 46 were also sustained through OLE Week 94 (Figure 2). Conclusion Response to ozanimod was regained after temporary therapy discontinuation for most pts, and this response was durable for up to 2 years as demonstrated by both symptomatic and clinical endpoints in this interim analysis from the TN OLE study. These results suggest that pts who experienced disease relapse after temporarily holding ozanimod in clinical practice may benefit from resumption of ozanimod.
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Danese, S., M. T. Abreu, D. C. Wolf, J. B. Canavan, A. Jain, H. Wu, A. Petersen, L. Charles, R. Panaccione, and A. Afzali. "DOP37 Efficacy and safety of 3 years of continuous ozanimod treatment: an interim analysis of the True North open-label extension study." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i101—i102. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0077.
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Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod over 52 weeks in patients with moderately to severely active ulcerative colitis (UC). Patients completing 52 weeks of TN were eligible for the ongoing TN open-label extension (OLE) assessing the long-term efficacy and safety of ozanimod. Presented is the interim analysis of the TN OLE in patients with approximately 3 years of continuous ozanimod treatment. Methods This analysis evaluated patients who achieved clinical response after receiving 52 weeks of continuous ozanimod 0.92 mg during TN and subsequently entered the TN OLE (data cutoff: 10 January 2022, the point at which the OLE Week 94 disposition was available for patients). Patient-reported (rectal bleeding and stool frequency) and clinician-reported (Physician’s Global Assessment) outcomes were collected. Centrally read endoscopy was performed at OLE Weeks 46 and 94 (98 and 146 weeks of continuous ozanimod treatment, respectively). Efficacy data (clinical remission, clinical response, endoscopic improvement, and corticosteroid-free remission) were evaluated in the intent-to-treat population at OLE Weeks 46 and 94 using observed case (OC) and nonresponder imputation (NRI) analyses. Partial Mayo scores (PMS) were assessed from TN baseline to OLE Week 94. Adverse events were monitored throughout TN and the subsequent OLE. Results In all, 131 patients entered the OLE after achieving clinical response following 52 weeks of continuous ozanimod during TN; at data cutoff, 87.0% completed OLE Week 46 (98 weeks of continuous ozanimod) and 71.8% completed OLE Week 94 (146 weeks of continuous ozanimod). Patients had a mean age of 44 years and 52% were female. Most (68%) had left-sided UC disease, 24% had concomitant corticosteroid use at TN baseline, and 32% had prior exposure to tumour necrosis factor inhibitors. Most patients achieved clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement at OLE Week 46 in the OC (Figure 1A) and NRI (Figure 1B) analyses. At OLE Week 94, 91.4% of patients achieved clinical response in the OC analysis (NRI, 56.5%). Ozanimod was associated with a reduction in mean PMS during TN (PMS=6.2 at Week 0 and 0.9 at Week 52), and this was sustained through OLE Week 94 (PMS=0.9) (Figure 2). No new safety findings emerged from this analysis. Conclusion This interim analysis of the TN OLE found that most of the patients who achieved clinical response after 1 year of ozanimod had sustained efficacy for an additional 2 years. No new safety signals were observed with long-term ozanimod use.
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Vermeire, S., J. F. Colombel, M. V. Chiorean, S. Ghosh, A. Jain, G. Lawlor, M. T. Osterman, H. Wu, J. B. Canavan, and D. T. Rubin. "P773 Extended induction in the True North open-label extension study: clinical outcomes of ~2 years of ozanimod treatment." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i903—i904. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0903.
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Abstract Background Ozanimod is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis in adults. In the phase 3, 52-week, double-blind True North (TN) study, Week 10 clinical nonresponders to ozanimod could enter the open-label extension (OLE) to continue treatment. Previous analysis showed that approximately 50% of Week 10 nonresponders achieved symptomatic clinical response with extended induction during the OLE in as early as 5 weeks. The current analysis evaluated long-term clinical and symptomatic endpoints up to 2 years in this delayed responder subgroup. Methods Efficacy data were analysed for TN Week 10 ozanimod nonresponders who subsequently received open-label ozanimod in the OLE, both by whole subgroup and original study arms (double-blind [Cohort 1] and open-label ozanimod [Cohort 2]) (data cutoff: January 10, 2022). Endpoints included symptomatic clinical response, symptomatic clinical remission, total Mayo score, clinical response, clinical remission, and corticosteroid (CS)-free remission up to OLE Week 94 (104 weeks of continuous ozanimod treatment). Data were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 226 nonresponders at TN Week 10 entered the OLE (Cohort 1, n=150; Cohort 2, n=76). Males comprised 67% of this subgroup, and mean (SD) age was 39.6 (13.6) years. Symptomatic clinical response (Figure 1), symptomatic clinical remission, and reduction in partial Mayo scores were observed as early as OLE Week 5 and were maintained through OLE Week 94. Minimal change in total Mayo score was observed from TN Week 0 (baseline) to TN Week 10 (OLE Week 0), but significant reductions from baseline occurred by OLE Week 46 (–4.2 [2.7]) and OLE Week 94 (–5.3 [2.6]). Overall, 62% of patients achieved clinical response, 26% achieved clinical remission, and 24% achieved CS-free remission at OLE Week 46; these increased to 74%, 35%, and 33%, respectively, by OLE Week 94 in the OC analysis (Figure 2). Data were similar between Cohorts 1 and 2. Conclusion Symptomatic response in ozanimod nonresponders was observed as early as 5 weeks after extended induction with ozanimod. Delayed response to ozanimod was maintained for up to 2 years as demonstrated by both symptomatic and objective endpoints. Even in those with delayed initial response, efficacy of ozanimod was durable.
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Lamb, Yvette N. "Ozanimod: First Approval." Drugs 80, no. 8 (May 8, 2020): 841–48. http://dx.doi.org/10.1007/s40265-020-01319-7.
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Floden, L., T. P. Pham, J. Kumar, B. Becker, J. W. Shaw, and T. Tencer. "P468 Evaluation of work productivity and activity impairment in moderate-to-severe ulcerative colitis participants treated with ozanimod in the phase 3 True North study." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i441—i442. http://dx.doi.org/10.1093/ecco-jcc/jjab232.595.
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Abstract Background Ulcerative Colitis (UC) is an autoimmune disease which negatively impacts patients’ quality of life including work performance. This study examined the effect of ozanimod on work productivity and activity impairment (WPAI) in participants with moderate-to-severe UC in the phase 3 True North study. Methods Participants who received 1 mg QD ozanimod during a 10-week Induction Period (IP) and were clinical responders from both placebo-controlled and open-label cohorts were randomised to ozanimod (n=230) or placebo (n=227) for a 42-week Maintenance Period (MP). Work productivity was measured with the WPAI-UC patient-reported outcome instrument that assesses absenteeism, presenteeism, work productivity loss, and activity impairment due to UC over the previous week. The WPAI-UC was administered at Weeks 10, 28, 40, and 52. Differences in WPAI-UC domain scores at the end of the IP were evaluated using t tests. Mixed-effects models for repeated measures (MMRMs) were fit to estimate least-squares mean WPAI-UC scores adjusted for treatment, time (categorical), clinical variables, and corticosteroid use at Week 10. MMRMs were also applied to evaluate differences in WPAI domain scores between groups defined by clinical response, clinical remission, and endoscopy score. Generalised estimating equation (GEE) models were applied to estimate the odds of improving or remaining stable (using a ≥7% change threshold) on WPAI-UC domains for those on ozanimod versus placebo. Missing values were multiply imputed using a placebo-based imputation model; estimates were combined using Rubin’s rules. Results At the end of the IP, the ozanimod group had significantly lower impairment of work productivity and activity (WPA) than the placebo group (Tab 1). During MP, the ozanimod group reported significantly lower levels of impairment for presenteeism (14.0% vs 20.2%; P=.003), work productivity loss (15.9% vs. 22.4%; P=.005), and activity impairment (15.4% vs 22.3%; P=.0001) compared to the placebo group (Tab 2). At Week 52, participants with improved endoscopy score, in clinical remission, or in clinical response had significantly lower impairment in all WPAI-UC domains (Tab 3). Participants in the ozanimod group showed increased odds of improving or remaining stable compared to those in the placebo group for all WPAI-UC domains (Fig 1). Conclusion Participants in the ozanimod arm had significantly better work productivity at the end of induction. Among participants who received ozanimod and achieved response in IP, ozanimod maintenance treatment was associated with improvements in WPA. These improvements were greater among participants who achieved clinical response or remission or improved endoscopic score.
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Reinisch, W., J. Axelrad, H. A. Ahmad, M. Pondel, S. Ather, A. Elegbe, C. Sninsky, and R. Longman. "P431 Early mucosal healing at week, 10 with ozanimod predicts clinical outcomes at week, 52: Post hoc analysis of the phase, 3 True North clinical trial." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i415. http://dx.doi.org/10.1093/ecco-jcc/jjab232.558.
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Abstract Background Ozanimod, a sphingosine, 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, is approved in multiple countries for the treatment of relapsing multiple sclerosis and in the United States for the treatment of moderately to severely active Ulcerative Colitis (UC). A treat-to-target strategy for Inflammatory Bowel Disease (IBD) has been outlined in the Selecting Therapeutic Targets in IBD (STRIDE-II) consensus recommendations. Mucosal healing was identified as an important treatment target and may be associated with improved patient (pt) outcomes. Here we assess the relationship between early mucosal healing at week (wk), 10 and clinical outcomes at wk, 52 in ozanimod-treated pts with moderately to severely active UC in the phase, 3 True North trial (NCT02435992). Methods A subset of pts in True North were randomised to and/or received oral ozanimod, 0.92 mg (equivalent to ozanimod HCl, 1 mg) during the, 10-wk induction period, achieved clinical response at wk, 10 and continued ozanimod during the maintenance period. For this post hoc analysis, we examined clinical remission, corticosteroid (CS)-free remission, and mucosal healing at wk, 52 in pts with versus without mucosal healing at wk, 10. Clinical remission was defined as rectal bleeding subscore = 0, stool frequency subscore ≤1 (and ≥1-point reduction from baseline), and mucosal endoscopy subscore (MES) ≤1 without friability. CS-free remission was defined as remission with no CS use for ≥12 wk. Mucosal healing was defined as MES ≤1 without friability and a Geboes score <2.0. Results Demographics and disease characteristics were generally well balanced between ozanimod-treated pts with (n=44) and without (n=186) mucosal healing at wk, 10, albeit a higher proportion of pts without mucosal healing had prior biologic exposure. Higher proportions of ozanimod-treated pts who achieved mucosal healing at wk, 10 had clinical remission, CS-free remission, and mucosal healing at wk, 52 versus pts who did not achieve mucosal healing at wk, 10 (Figure). Among the ozanimod-treated pts who did not achieve mucosal healing at wk, 10, 24.2% went on to achieve mucosal healing at wk 52. Conclusion Using a novel, stringent definition for mucosal healing, which requires endoscopic improvement and histologic remission (Geboes <2.0), ozanimod-treated pts who achieved mucosal healing at wk, 10 had improved clinical, endoscopic, and histologic outcomes at wk, 52. A proportion of pts who did not reach mucosal healing at wk, 10 benefited from longer ozanimod treatment, achieving mucosal healing at wk 52.
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Danese, S., M. T. Abreu, A. Afzali, J. B. Canavan, A. Jain, H. Wu, A. Petersen, R. Panaccione, and D. C. Wolf. "P719 Symptomatic improvement and long-term stability of ulcerative colitis symptoms over 3 years of ozanimod treatment." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i848—i850. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0849.
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Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod over 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). Pts completing 52 weeks of TN were eligible for the ongoing TN open-label extension (OLE) assessing the long-term efficacy and safety of ozanimod. Presented here is the interim analysis of the TN OLE focused on the symptomatic efficacy of ozanimod in pts with approximately 3 years of continuous ozanimod treatment. Methods Pts who achieved clinical response after receiving 52 weeks of continuous ozanimod during TN and subsequently entered the TN OLE were evaluated (data cutoff: 10 January 2022, at which point the OLE Week 94 disposition was available for pts). Patient-reported (rectal bleeding subscore [RBS] and stool frequency subscore [SFS]) and clinician-reported (Physician’s Global Assessment) symptomatic outcomes were determined. Symptomatic clinical response (partial Mayo score [PMS] ≥1 point and ≥30% reduction in PMS with ≥1-point decrease in RBS or absolute RBS of ≤1) and symptomatic clinical remission (RBS=0 and SFS ≤1 [and decrease of ≥1 point from baseline SFS]) were evaluated at OLE Week 5 through OLE Week 94 (146 weeks of continuous ozanimod treatment) using observed case (OC) and nonresponder imputation (NRI) analyses. PMS, RBS, and SFS were assessed from TN baseline to OLE Week 94. Results In all, 131 pts entered the OLE after achieving clinical response following 52 weeks of continuous ozanimod during TN. At data cutoff, 87.0% completed OLE Week 46 (98 weeks of continuous ozanimod) and 71.8% completed OLE Week 94 (146 weeks of continuous ozanimod). Pts had a mean age of 44 years and 52% were female. Most (68%) had left-sided UC disease, 24% had concomitant corticosteroid use at TN baseline, and 32% had prior exposure to tumor necrosis factor inhibitors. Symptomatic clinical response and symptomatic clinical remission were observed in 100.0% (Figure 1A) and 84.4% (Figure 2A) of pts, respectively, at OLE Week 5 in the OC analysis (93.1% [Figure 1B] and 78.6% [Figure 2B] in the NRI analysis). Rates of symptomatic clinical response and symptomatic clinical remission were maintained through OLE Week 94 in the OC analysis and decreased slightly over time in the NRI analysis. Reductions in mean PMS from baseline were observed during TN and sustained through OLE Week 94. Reductions from TN baseline in RBS (Figure 3) and SFS (Figure 4) were also observed through OLE Week 94. Conclusion This interim analysis of the TN OLE focusing on symptomatic endpoints found that most pts who achieved clinical response after 1 year of ozanimod sustained symptom control for another 2 years.
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Vermeire, S., J. F. Colombel, D. T. Rubin, S. Ghosh, A. Jain, G. Lawlor, M. T. Osterman, H. Wu, J. B. Canavan, and M. V. Chiorean. "P715 Achievement and maintenance of endoscopic, histologic, and combined outcomes after extended induction in Week 10 nonresponders of ozanimod: 2-year interim analysis of the True North open-label extension study." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i844—i845. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0845.
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Abstract Background Ozanimod, a novel oral therapeutic option for patients with moderately to severely active ulcerative colitis, demonstrated significant improvements in clinical, endoscopic, and histologic endpoints in the phase 3, 52-week, double-blind True North (TN) study. Approximately one-third of the patients did not achieve clinical response to ozanimod after 10 weeks of TN induction therapy. However, a delayed response was observed in a subset of these nonresponders upon extended induction with ozanimod. The present analysis evaluated ozanimod efficacy on endoscopic and histologic endpoints in these delayed responders in the TN open-label extension (OLE) study. Methods Data were analysed for the overall delayed responder population and separately for the blinded (Cohort 1) and open-label (Cohort 2) cohorts (data cutoff: 10 January 2022, the point at which patient disposition was available for all patients up to OLE Week 94). Endpoints included endoscopic improvement (defined as an endoscopy subscore of ≤1 point), histologic remission (defined as Geboes index score <2.0), and mucosal healing (defined as endoscopy subscore of ≤1 point and Geboes index score of <2.0) up to OLE Week 94. The endpoints were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 226 patients (Cohort 1, n=150; Cohort 2, n=76) were nonresponders at Week 10 and entered the OLE (67% male; mean [standard deviation] age, 39.6 [13.6] years). At OLE entry, 24% of patients had moderate disease (Mayo endoscopic score [MES]=2) and 73% had severe disease (MES=3). Approximately half of these patients achieved symptomatic clinical response as early as 5 weeks of ozanimod open-label treatment. In OC analysis at OLE Week 46, 30% of patients achieved endoscopic improvement, 42% achieved histologic remission, and 24% achieved mucosal healing that further increased to 48%, 48%, and 39%, respectively, by OLE Week 94 (Figure 1A). In NRI analysis, the following patient proportions were observed at OLE Weeks 46 and 94: 18% and 19% (endoscopic improvement), 22% and 14% (histologic remission), and 13% and 11% (mucosal healing) (Figure 1B). Data were generally similar in Cohorts 1 and 2. Conclusion Delayed responders to ozanimod achieved and maintained mucosal healing over 2 years of continuous ozanimod treatment. Ozanimod treatment resulted in the healing of intestinal mucosal lesions, even in patients with moderate to severe disease who may have an initial delayed response to ozanimod.
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Cohen, Nathaniel, Tenzin Choden, David Choi, Noa Cleveland, Russell Cohen, Sushila Dalal, Atsushi Sakuraba, Ira Hanan, and David Rubin. "REAL WORLD EFFECTIVENESS AND SAFETY OF OZANIMOD: INITIAL RESULTS FROM A LARGE TERTIARY CENTER." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S109. http://dx.doi.org/10.1093/ibd/izac015.175.
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Abstract BACKGROUND In May 2021 the United Stated Food and Drug Administration (FDA) approved the use of ozanimod for moderate to severe ulcerative colitis (UC) based on the results of the pivotal phase 3 TRUE NORTH trials. We present the first report of real world data describing the use of ozanimod in clinical practice. METHODS This prospective, observational cohort study includes consecutive patients with active UC who initiated ozanimod at our center following FDA approval. We collected demographic, clinical, and laboratory data. Clinical disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI). Clinical response was defined as a decrease in ≥3 points in SCCAI from baseline, and clinical remission was defined as an SCCAI score of ≤ 2. Adverse events were extracted from the electronic medical records (EMR) and regular clinical pharmacist follow up. RESULTS 18 patients have initiated ozanimod therapy at our center. We observed 15 patients with UC, 1 patient with indeterminate colitis (IC), 1 patient with Crohn’s colitis, and 1 patient with lymphocytic colitis. All patients were included in the safety analysis and only patients with UC or IC were included in the effectiveness analysis. The mean age was 44.7 ± 18.5 with a mean age at disease duration of 9.6 ± 10.4. Ten (62%) patients were male, most patients 11 (69) had left sided colitis; 12 (75%) had previous biologic exposure. Additional demographics are described in Table 1. At week 4, follow up was available for 11 patients. Among these, 7 (64%) patients demonstrated clinical response, 2 (18%) were in clinical remission, and 1 patient achieved corticosteroid (CS) free remission. At week 8, follow up data was available for 7 patients; 3 (43%) patients had a clinical response and 1 (14%) patient achieved CS free remission (Figure 1A). 7 patients had complete blood counts at weeks 0 and 4, and all of these patients had a reduction in absolute lymphocyte counts (mean ± SD 1.46±0.47 109 cells/liter) (Figure 1B). There were 5 adverse events during the follow up period, none of which required treatment cessation. 1 patient had self-limited gastroenteritis, 1 patient had transient fatigue and another transient nausea. 1 patient developed mild liver enzyme derangement. 1 patient had non-specific chest pain and therapy was paused for a day until investigations returned negative. CONCLUSION This is the first real world data from a relatively treatment refractory cohort of UC patients and shows promising effectiveness and safety of ozanimod. Longer follow-up in larger patient cohorts is required to assess ozanimod’s role in clinical practice.
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Wendt, Trevor S., Yu Jing Li, and Rayna J. Gonzales. "Ozanimod, an S1PR1 ligand, attenuates hypoxia plus glucose deprivation-induced autophagic flux and phenotypic switching in human brain VSM cells." American Journal of Physiology-Cell Physiology 320, no. 6 (June 1, 2021): C1055—C1073. http://dx.doi.org/10.1152/ajpcell.00044.2021.
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Vascular smooth muscle (VSM) cell phenotypic expression and autophagic state are dynamic responses to stress. Vascular pathologies, such as hypoxemia and ischemic injury, induce a synthetic VSM phenotype and autophagic flux resulting in a loss of vascular integrity and VSM cell death respectfully. Both clinical pilot and experimental stroke studies demonstrate that sphingosine-1-phosphate receptor (S1PR) modulation improves stroke outcome; however, specific mechanisms associated with a beneficial outcome at the level of the cerebrovasculature have not been clearly elucidated. We hypothesized that ozanimod, a selective S1PR type 1 ligand, will attenuate VSM synthetic phenotypic expression and autophagic flux in primary human brain VSM cells following acute hypoxia plus glucose deprivation (HGD; in vitro ischemic-like injury) exposure. Cells were treated with ozanimod and exposed to normoxia or HGD. Crystal violet staining, standard immunoblotting, and immunocytochemical labeling techniques assessed cellular morphology, vacuolization, phenotype, and autophagic state. We observed that HGD temporally decreased VSM cell viability and concomitantly increased vacuolization, both of which ozanimod reversed. HGD induced a simultaneous elevation and reduction in levels of pro- and antiautophagic proteins respectfully, and ozanimod attenuated this response. Protein levels of VSM phenotypic biomarkers, smoothelin and SM22, were decreased following HGD. Furthermore, we observed an HGD-induced epithelioid and synthetic morphological appearance accompanied by disorganized cytoskeletal filaments, which was rescued by ozanimod. Thus, we conclude that ozanimod, a selective S1PR1 ligand, protects against acute HGD-induced phenotypic switching and promotes cell survival, in part, by attenuating HGD-induced autophagic flux thus improving vascular patency in response to acute ischemia-like injury.
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Ungaro, R., C. A. Siegel, B. A. C. Cree, K. W. Selmaj, H. A. Ahmad, A. Pai, S. Ather, et al. "P486 Treatment-emergent COVID-19 infections in ozanimod ulcerative colitis and multiple sclerosis clinical trials." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i452. http://dx.doi.org/10.1093/ecco-jcc/jjab232.613.
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Abstract Background Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients (pts) in active phase 3 open-label extension (OLE) studies. Methods A database search identified COVID-19 infection reports in ozanimod-treated pts with UC in the True North OLE and MS in the DAYBREAK OLE. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all pts with ≥1 event was analyzed. Results Among 2792 ozanimod-treated pts with UC or MS, 258 developed COVID-19 (confirmed: 215); thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most pts with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated pts with UC, 68 (11.1%) developed COVID-19 (confirmed: 55; Fig 1). A majority of UC pts with confirmed cases (45/55 [81.8%]) had nonserious COVID-19; most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC pt with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19‒related deaths were reported in UC pts. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160; Fig 2). Most MS pts with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases; most (158/160 [98.8%]) recovered (5 with sequelae) (Fig 1). No MS pts with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC pts (Fig 1) and 30 additional MS pts (Fig 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19‒related deaths in the MS program. One pt died from a presumed pulmonary embolism; this pt had received high-dose corticosteroids for MS relapse immediately before COVID-19 symptom onset. Another pt died from suspected COVID-19‒related respiratory failure. One tetraplegic, cachectic pt died from a lung abscess following COVID-19 infection. Conclusion In the UC and MS OLE studies, most pts with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (case-fatality rate 1.6% in MS, 1.2% overall).
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Vermeire, S., A. Dignass, J. F. Colombel, A. Jain, J. B. Canavan, H. Wu, G. Lawlor, M. T. Osterman, D. T. Rubin, and M. Regueiro. "DOP39 Endoscopic, histologic, and combined outcomes with reinitiation of ozanimod after temporary discontinuation: 2-year interim analysis of the True North open-label extension study." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i103—i104. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0079.
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Abstract Background Mucosal healing, evaluated by a combination of endoscopic and histologic examinations, is a desired outcome in ulcerative colitis (UC), but few long-term or open-label extension (OLE) studies of UC treatments have assessed these outcomes. In the phase 3 True North (TN) study, ozanimod 0.92 mg once daily demonstrated efficacy and safety for up to 52 weeks in patients with moderately to severely active UC. The current analysis evaluated long-term endoscopic and histologic endpoints in patients who reinitiated ozanimod after experiencing disease relapse when rerandomised to placebo during the TN maintenance period (MP). Methods Responders to ozanimod 10-week induction therapy were rerandomised 1:1 to ozanimod (n=230) or placebo (n=227); this OLE interim analysis (data cutoff: 10 January 2022, the point at which the OLE Week 94 disposition is available for patients) included all patients who relapsed on placebo during the MP and reinitiated ozanimod in the OLE. Endpoints included percentages of patients with endoscopic improvement (endoscopic subscore of ≤1 point), histologic remission (Geboes index score <2), and mucosal healing (endoscopy subscore of ≤1 point and Geboes index score <2) at OLE Weeks 46 and 94. Data were evaluated as observed case (OC) and nonresponder imputation (NRI) analyses. Results Seventy-seven (34%) patients rerandomised to placebo experienced a disease relapse in the TN MP. Median time to relapse was 12.7 weeks. At data cutoff, all 77 patients had either completed OLE Week 94 (51.9%) or discontinued treatment. At OLE Week 46, endoscopic improvement, histologic remission, and mucosal healing were achieved by 50%, 56%, and 42% of patients, respectively (OC analysis). Proportions with these endpoints further increased to 60%, 68%, and 48%, respectively, by OLE Week 94. Per NRI analysis, endoscopic improvement, histologic remission, and mucosal healing at OLE Weeks 46 and 94 were observed in 30% and 27%, 31% and 25%, and 23% and 17% of patients, respectively (Figure). Furthermore, 52% of patients with endoscopic improvement at OLE Week 46, 58% of patients with histologic remission at OLE Week 46, and 44% of patients with mucosal healing at OLE Week 46 continued to sustain the respective endpoints at OLE Week 94 with another year of ozanimod treatment. Conclusion In patients who experienced disease relapse after rerandomisation to placebo, reinitiation of ozanimod was associated with recapture of response and long-term endoscopic and histologic benefits, including histologic remission and mucosal healing. These data suggest that patients who experience disease relapse when ozanimod is temporarily discontinued may benefit from resumption of ozanimod treatment.
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Kuczynski, Andrea M., and Jiwon Oh. "Ozanimod for the treatment of relapsing forms of multiple sclerosis." Neurodegenerative Disease Management 11, no. 3 (June 2021): 207–20. http://dx.doi.org/10.2217/nmt-2021-0005.
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Multiple sclerosis (MS) is an inflammatory disease that causes chronic neurological disability in young adults. Modulation of sphingosine 1-phosphate (S1P) receptors, a group of receptors that, among other things, regulate egression of lymphocytes from lymph nodes, has proven to be effective in treating relapsing MS. Fingolimod, the first oral S1P receptor modulator, has demonstrated potent efficacy and tolerability, but can cause undesirable side effects due to its interaction with a wide range of S1P receptor subtypes. This review will focus on ozanimod, a more selective S1P receptor modulator, which has recently received approval for relapsing MS. We summarize ozanimod’s mechanism of action, and efficacy and safety from clinical trials that demonstrate its utility as another treatment option for relapsing MS.
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Brockmeier, Bernd. ""Geringer Zusatznutzen" für Ozanimod." NeuroTransmitter 32, no. 5 (May 2021): 16–17. http://dx.doi.org/10.1007/s15016-021-9149-y.
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Kathmann, Wiebke. "Ozanimod als neue Behandlungsoption." Gastro-News 9, no. 2 (April 2022): 60. http://dx.doi.org/10.1007/s15036-022-2493-3.
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Hof, Teresa, and Peter Hasselblatt. "Ozanimod bei Colitis ulcerosa." Gastro-News 8, no. 6 (December 2021): 28–29. http://dx.doi.org/10.1007/s15036-021-2431-9.
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Ciftci-Kavaklioglu, Beyza, and E. Ann Yeh. "Ozanimod in Multiple Sclerosis." European Neurological Review 14, no. 2 (2019): 73. http://dx.doi.org/10.17925/enr.2019.14.2.73.
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Mohamed, Rana, Cody Kern, Aaron Fein, Terrence Barrett, and Courtney Perry. "SUCCESSFUL CLEARANCE OF CYTOMEGALOVIRUS COLITIS IN ACUTE SEVERE ULCERATIVE COLITIS DURING INDUCTION OF OZANIMOD." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S110—S111. http://dx.doi.org/10.1093/ibd/izac015.177.
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Abstract INTRODUCTION Cytomegalovirus (CMV) colitis, commonly observed in patients with acute severe ulcerative colitis (UC), increases the risk for colectomy and treatment resistance. Unfortunately, corticosteroids and immunomodulators increase CMV reactivation and infection. The use of certain biologics such as anti-TNF mAb increase the risk for CMV colitis, while experience with newer biologics is limited leaving clinicians with few validated options. Ozanimod, an oral sphingosine-1-phosphate receptor modulator, was recently approved for induction and maintenance therapy for UC. Experience with ozanimod in the setting of UC complicated by CMV infection has not been reported to this date. We report here on a severe UC patient with tissue proven CMV ulceration that cleared the viral infection during ozanimod induction. CASE REPORT A 21-year-old male with UC treated with tofacitinib presented with five days of diffuse abdominal pain and 10-12 episodes of bloody diarrhea per day with CRP 341mg/L (<8.0mg/L) and calprotectin >3000μg/g (<49μg/g). Computed topography of the abdomen and pelvis showed diffuse wall thickening and mucosal enhancement throughout the entire colon and rectum. He was started on methylprednisolone 20mg TID for acute severe UC. He previously failed infliximab, adalimumab, ustekinumab, and vedolizumab. Colonoscopy showed pancolitis (Mayo score 3) with deep ulceration in the cecum. Random colon biopsies were consistent with active colitis with an area of CMV infection in an area of cecal ulceration (Figure 1). Serum CMV Quantitative PCR was 410IU/ml (normal <50IU/ml). The patient refused colectomy and was started on IV ganciclovir 5mg/kg q12h while transitioning to prednisone 40mg/day. Three weeks after initial presentation and eleven days after starting ganciclovir, the patient began ozanimod. He remained on ganciclovir for three weeks then transitioned to oral valganciclovir 900mg BID. The patient’s symptoms improved, CRP normalized, and calprotectin levels dropped (1200μg/g). Repeat colonoscopy performed eighteen days after ozanimod initiation revealed moderately-improved pancolitis (Mayo 2) with multiple healing cecal ulcers. Analysis of cecal ulceration IHC and peripheral blood PCR indicated clearing of the infection from the colon (Figure 2). DISCUSSION Cytomegalovirus colitis remains a common complication in severe UC, while avoidance of colectomy with viral clearance remains a challenge. Ozanimod and ganciclovir were chosen by this patient after refusing surgical resection. The improvement in clinical biomarkers of colitis and viral clearance suggest that ozanimod given with ganciclovir may be an exciting rescue therapy in these patients. Future studies will be needed to ascertain the rates of ozanimod response and CMV clearance in a larger patient cohort.
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Lassiter, Grace, Carlie Melancon, Tyler Rooney, Anne-Marie Murat, Jessica S. Kaye, Adam M. Kaye, Rachel J. Kaye, et al. "Ozanimod to Treat Relapsing Forms of Multiple Sclerosis: A Comprehensive Review of Disease, Drug Efficacy and Side Effects." Neurology International 12, no. 3 (December 3, 2020): 89–108. http://dx.doi.org/10.3390/neurolint12030016.
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Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators.
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Caldera, F., R. Maddux, R. Ungaro, A. Kaur, E. Brown, S. Hu, J. K. Sheffield, D. Silva, S. Harris, and B. A. C. Cree. "P516 Humoral immune responses to SARS-CoV-2 vaccines in an ozanimod open-label extension study." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i643—i644. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0646.
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Abstract Background Ozanimod, an oral sphingosine 1-phosphate receptor modulator, is approved in the European Union and United States for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS). A previous analysis of data from UC and multiple sclerosis (MS) open-label extension (OLE) studies showed that most patients with confirmed coronavirus infection (COVID-19) had nonserious infections, recovered, and did not require ozanimod discontinuation. Some immunomodulators and biologics may attenuate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response; therefore, this analysis evaluated humoral immune responses and predictors of response to SARS-CoV-2 vaccination in patients with RMS treated with ozanimod. Methods RMS participants who completed a phase 1–3 ozanimod trial could enter an OLE trial (DAYBREAK; NCT02576717) of ozanimod 0.92 mg/d. This analysis (January 2020‒October 2021) included DAYBREAK participants receiving mRNA or non-mRNA SARS-CoV-2 vaccines (1–2 doses, vaccine-dependent) with no evidence of recent infection (ie, nucleocapsid antibody negative). Receptor binding domain (RBD) antibody titers were analysed (Elecsys Anti-SARS-CoV-2 assay; Roche Diagnostics, Basel, Switzerland) prevaccination, after 1 dose, and <4, 4–8, 8–12, and >12 weeks after full vaccination. Fisher’s exact tests and regression models determined association with seroconversion and log2 antibody levels. Results Demographics were similar between the mRNA and non-mRNA vaccine recipients (Table). Seroconversion (≥0.8 U/mL spike RBD antibody) occurred in 100% (80/80) of fully vaccinated mRNA recipients and 62% (18/29) of fully vaccinated non-mRNA vaccine recipients. Higher spike RBD antibody levels were seen with mRNA (grand mean: 512.6 U/mL, range: 1.3–4572.0) vs non-mRNA (grand mean: 39.3 U/mL, range: 0.4–368.5) vaccines at all time points studied. Vaccination with a non-mRNA vaccine predicted lower antibody levels (beta: –5.90 [95% CI: –6.99 to –4.82]; P<0.0001) and less seroconversion (Fisher’s exact: P<0.0001), whereas age, sex, body mass index, and absolute lymphocyte count (ALC) did not. Conclusion Participants receiving ozanimod developed humoral immune response to SARS-CoV-2 vaccines, with 100% seroconversion after mRNA vaccination; this was independent of demographic characteristics and ALC levels at time of vaccination. However, some participants developed lower antibody concentrations and may benefit from booster doses. These findings provide important information for physicians managing ozanimod-treated patients with UC or MS.
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Dignass, A., M. Regueiro, J. F. Colombel, A. Jain, J. B. Canavan, H. Wu, G. Lawlor, M. T. Osterman, S. Vermeire, and D. T. Rubin. "DOP43 Extended induction in the True North OLE study: ozanimod efficacy in biologic-naive and biologic-experienced patients." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i110—i111. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0083.
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Abstract Background Prior exposure to biologics can influence response to subsequent lines of advanced therapies. Previous analyses showed that patients who did not achieve clinical response following 10 weeks of ozanimod treatment in the phase 3 True North (TN) study benefited from extended induction with open-label ozanimod in the TN open-label extension (OLE) study. As the impact of prior biologic exposure on outcomes with extended induction is unknown, the aim of this analysis was to evaluate that question. Methods Clinical nonresponders to ozanimod at TN Week (W) 10 entered the OLE (data cutoff: January 10, 2022, at which point the disposition was available until OLE W94 for all patients). Data were analysed in patients with and without prior biologic exposure at baseline. Disease activity was assessed at TN W0 (baseline) and at W10 (OLE entry). Symptomatic clinical response and remission were evaluated through OLE W94, and multiple clinical, endoscopic, and histologic endpoints were evaluated at OLE W46 and W94 using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 220 patients with prior biologic information entered the OLE after not achieving clinical response at TN W10 (biologic-naive, n=122; biologic-experienced, n=98). Disease activity at baseline was generally consistent between biologic-naive and experienced patients. About half of the ozanimod W10 nonresponders in both groups achieved symptomatic clinical response by OLE W5, with a higher proportion of biologic-naive patients maintaining response until OLE W94 in both OC and NRI analyses (Figure 1). Higher proportions of biologic-naive patients also sustained symptomatic clinical remission until OLE W94 in both OC and NRI analyses. In OC analysis, a higher proportion of biologic-naive patients achieved all clinical, endoscopic, and histologic endpoints at OLE W46 compared with biologic-experienced patients; by OLE W94, however, the proportions of patients who achieved all clinical, endoscopic, and histologic endpoints were generally consistent, regardless of prior biologic exposure (Figure 2). As expected, a smaller proportion of patients achieved the efficacy endpoints in the NRI analysis, with proportions being higher in biologic-naive patients; response rates were sustained between OLE W46 and W94 in each group. Conclusion Both biologic-naive and -experienced clinical nonresponders to ozanimod at the end of induction demonstrated response to extended induction with ozanimod. Delayed response was durable for up to 2 years of continuous ozanimod treatment in both groups, with higher proportions achieved in biologic-naive patients.
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Tatosian, D., J. Shen, L. Chen, J. Lavigne, N. Teuscher, S. Harris, D. Chitkara, G. S. Tirucherai, and C. Marta. "P315 Population pharmacokinetics and pharmacodynamics of ozanimod in ulcerative colitis." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S341—S342. http://dx.doi.org/10.1093/ecco-jcc/jjab076.439.
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Abstract Background Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and under development for ulcerative colitis (UC) and Crohn’s disease. Ozanimod and its major active metabolites CC112273 and CC1084037 block lymphocyte egress from lymphoid tissues, reducing the absolute lymphocyte count (ALC) in blood. To characterise the influence of patient characteristics on ALC response, a population PK/PD analysis was conducted. Methods A nonlinear mixed-effects Emax model described the ALC time course and relationship to CC112273 concentrations in healthy subjects and patients with UC or RMS. The analysed data included 34,449 ALC values obtained from 4122 subjects enrolled in 11 Phase 1, 2, and 3 clinical studies. The effect of age, sex, smoking status, disease type, body weight, total bilirubin, and baseline ALC on the maximum ALC reduction (Emax) and half-maximal concentration (EC50) were investigated. Simulations of typical ALC reductions for healthy subjects and patients with UC or RMS receiving 0.5 or 1 mg ozanimod were conducted to explore the influence of smoking and assess the time for ALC recovery. Results Increasing CC112273 concentrations were associated with reductions in ALC to a maximum of 74% from baseline, with an estimated EC50 of 2.8 nM CC112273. Healthy subjects, females, and higher body weights were associated with larger ALC Emax (Figure 1), while healthy subjects, increased age, nonsmokers and higher baseline ALC were associated with an increased EC50 (Figure 2). UC patients receiving 0.5 mg and 1 mg ozanimod HCl are predicted to have mean ALC reductions of 46.1% and 57.2%, respectively, with similar reductions for RMS patients of 48.0% and 57.4%. Smoking was associated with a 27.2% reduction in the ALC EC50, which partially offsets the reduced plasma CC112273 concentrations in smokers. Simulations show that 1 mg ozanimod has comparable ALC reductions of 57.4% in nonsmokers and 52.7% in smokers. Upon discontinuing ozanimod 1 mg in UC patients, a mean recovery time to normal (1 x 109/L ALC count) of 32.8 days was predicted, with 90% of the population recovering in 3 months. Overall results were consistent with findings from clinical trials. Conclusion Population analysis demonstrated a similar PK/PD relationship for ALC reductions in patients with RMS and UC. Smoking was not associated with substantial difference in ALC, consistent with no loss of efficacy in smokers. Upon discontinuation of ozanimod treatment, the majority of UC and RMS patients will recover lymphocyte counts to normal within 3 months.
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Tatosian, Daniel, Jun Shen, Lu Chen, Jean Lavigne, Nathan Teuscher, Sarah Harris, Denesh Chitkara, Giridhar Tirucherai, and Cecilia Marta. "POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF OZANIMOD IN ULCERATIVE COLITIS." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S16. http://dx.doi.org/10.1093/ibd/izac015.024.
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Abstract BACKGROUND Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and moderately to severely active ulcerative colitis (UC) and under development for Crohn’s disease. Ozanimod and its major active metabolites CC112273 and CC1084037 block lymphocyte egress from lymphoid tissues, reducing the absolute lymphocyte count (ALC) in blood. To characterise the influence of patient characteristics on ALC response, a population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted. METHODS A nonlinear mixed-effects Emax model described the ALC time course and relationship to CC112273 concentrations in healthy subjects and patients with UC or RMS. The analysed data included 34,449 ALC values obtained from 4122 subjects enrolled in 11 Phase 1, 2, and 3 clinical studies. The effect of age, sex, smoking status, disease type, body weight, total bilirubin, and baseline ALC on the maximum ALC reduction (Emax) and half-maximal concentration (EC50) were investigated. Simulations of typical ALC reductions for healthy subjects and patients with UC or RMS receiving 0.5 or 1 mg ozanimod were conducted to explore the influence of smoking and assess the time for ALC recovery. RESULTS Increasing CC112273 concentrations were associated with reductions in ALC to a maximum of 74% from baseline, with an estimated EC50 of 2.8 nM CC112273. Healthy subjects, females, and higher body weights were associated with larger ALC Emax (Figure 1), while healthy subjects, increased age, nonsmokers and higher baseline ALC were associated with an increased EC50 (Figure 2). UC patients receiving 0.5 mg and 1 mg ozanimod HCl are predicted to have mean ALC reductions of 46.1% and 57.2%, respectively, with similar reductions for RMS patients of 48.0% and 57.4%. Smoking was associated with a 27.2% reduction in the ALC EC50, which partially offsets the reduced plasma CC112273 concentrations in smokers. Simulations show that 1 mg ozanimod has comparable ALC reductions of 57.4% in nonsmokers and 52.7% in smokers. Upon discontinuing ozanimod 1 mg in UC patients, a mean recovery time to normal (1 x 109/L ALC count) of 32.8 days was predicted, with 90% of the population recovering in 3 months. Overall results were consistent with findings from clinical trials. CONCLUSION Population analysis demonstrated a similar PK/PD relationship for ALC reductions in patients with RMS and UC. Smoking was not associated with substantial difference in ALC, consistent with no loss of efficacy in smokers. Upon discontinuation of ozanimod treatment, the majority of UC and RMS patients will recover lymphocyte counts to normal within 3 months.
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Groh, Jan. "Ozanimod senkt Schubrate bei RRMS." InFo Neurologie + Psychiatrie 22, no. 11 (November 2020): 50. http://dx.doi.org/10.1007/s15005-020-1519-7.
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Alaskar, Dimah, Zainab AlMusa, and Turki AlAmeel. "Letter: Ozanimod and latent tuberculosis." Alimentary Pharmacology & Therapeutics 57, no. 3 (January 15, 2023): 353–54. http://dx.doi.org/10.1111/apt.17311.
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Danese, S., J. F. Colombel, T. Ponich, I. Jovanovic, P. Bossuyt, R. Longman, O. Alekseeva, et al. "DOP44 Long-term use of ozanimod in patients with moderately to severely active Ulcerative Colitis." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i093—i094. http://dx.doi.org/10.1093/ecco-jcc/jjab232.083.
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Abstract Background Ozanimod was approved by the FDA to treat patients (pts) with moderately to severely active Ulcerative Colitis (UC) based on the results from the 52-week (wk) phase 3 True North (TN) study. We sought to evaluate long-term efficacy and safety of ozanimod. Methods We examined data from an interim analysis of pts in the TN parent study who entered the ongoing TN open-label extension (OLE). Pts entered the TN OLE from the phase 3 TN study if they were non-responders at the end of induction, lost response during maintenance, or completed maintenance treatment, or from the phase 2 Touchstone OLE if they remained at study closure and received once-daily oral ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg). Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Wks 46, 94, and 142 in the TN OLE for all pts who entered the OLE from the TN parent study, and in the subset of pts in clinical response at the OLE entry. The data were analysed in the intent-to-treat population using observed cases (OC), which used the number of pts remaining in the study at the corresponding time point, and non-responder imputation (NRI), which used the number of pts remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed. Treatment-emergent adverse events were evaluated from the pooled phase 2 and phase 3 UC studies. Results A total of 823 pts from TN entered the TN OLE; as of the cut-off date (Sept 30, 2020), 64% completed Wk 46, 34% completed Wk 94, and 14% completed Wk 142 of the OLE. The most common reason for discontinuation was lack of efficacy (21%). Baseline demographics were similar as in the TN study. A total of 261 pts were in clinical response at the time of OLE entry. OC analyses showed that the percentage of pts achieving clinical remission, clinical response, endoscopic improvement, and CS-free remission was maintained over time (Table). Efficacy in the responders was higher compared to the total population and was comparable within the endpoints at Wks 46 and 94. Using the more conservative NRI analysis, the proportion of pts achieving each endpoint was lower than in the OC; however, after 94 wks of OLE treatment, 34% of all pts and 55% of the responders still maintained clinical response. No new safety signals were seen with longer-term ozanimod use in the 1158 pts in the pooled population. Conclusion UC pts from the phase 3 TN study demonstrated maintenance of response with long-term ozanimod treatment. These data reflect approximately 2 years of additional ozanimod treatment, with no new safety signals identified.
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Siegmund, B., G. Y. Melmed, P. M. Irving, A. Pai, A. Patel, J. K. Sheffield, F. Caldera, B. A. C. Cree, and M. C. Dubinsky. "P402 Incidence and outcomes of herpes zoster in the ozanimod phase, 3 ulcerative colitis and relapsing multiple sclerosis clinical program." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i395—i396. http://dx.doi.org/10.1093/ecco-jcc/jjab232.529.
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Abstract Background Patients with ulcerative colitis (UC) and patients with multiple sclerosis (MS) have an elevated risk of developing herpes zoster (HZ), caused by reactivation of latent varicella zoster virus (VZV). Increased incidence of HZ has been reported with sphingosine, 1-phosphatase (S1P) receptor modulators. This analysis examined the number of patients who failed screening due to a lack of demonstrated VZV immunity and the incidence of HZ from completed phase, 3 ozanimod clinical trials. Methods Safety results were included from True North (52-week trial) in patients with UC, and SUNBEAM (12-month trial), and RADIANCE (24-month trial) in patients with MS. All patients were required to have had a positive VZV IgG antibody status or completed VZV vaccination ≥30 days prior to randomization based on known effects of S1P modulators. Patients with a negative VZV antibody titer could choose to receive the VZV vaccination to qualify for the trial. Number of pre-screen failures because of lack of demonstrated immunity, occurrence of HZ, and association between HZ cases and lymphopenia were analyzed. Results Of, 1831 patients with UC screened for VZV immunity, 104 (5.7%) failed screening due to lack of documentation of VZV antibody or VZV vaccination ≥30 days before randomization;, 22% (23/104) subsequently received varicella vaccination and were rescreened and enrolled. Of, 3332 MS patients tested for VZV immunity, 309 (9.3%) tested negative and, 32% (98/309) of these patients were vaccinated prior to randomization. In the UC and MS trials, the incidence of HZ cases was low in ozanimod-treated patients (8 cases [1.0%] and, 5 cases [0.6%], respectively; Table, 1). All cases were distributed across a single dermatome, did not result in a complication of HZ, and were treated with oral antivirals while patients remained on ozanimod. None of the patients discontinued ozanimod because of HZ and none of the HZ cases were associated with grade, 4 lymphopenia (defined as an absolute lymphocyte count <0.2 x, 109/L). Conclusion In the ozanimod phase, 3 UC and MS trials, 5%–10% of patients screened did not have demonstrated VZV immunity;, 22%–32% of these patients received varicella vaccination, were rescreened and enrolled. The overall HZ incidence in clinical trials was low (≤1% of patients), all cases were distributed across a single dermatome, and no serious or complicated cases occurred in ozanimod-treated patients with VZV immunity. Additional studies are warranted to evaluate the incidence of HZ in clinical practice.
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Cohen, N. A., D. Choi, N. Garcia, N. Choi, E. Picker, N. Krugliak-Cleveland, R. Cohen, et al. "P562 Real world effectiveness and safety of ozanimod: One-year follow-up from a large tertiary center." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i692—i693. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0692.
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Abstract Background Ozanimod is a first in class sphingosine-1-phosphate receptor modulator approved by the FDA for moderately-to-severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. We provide one-year follow up results of our patient cohort treated with ozanimod. Methods This prospective, observational cohort study includes consecutive patients who initiated ozanimod at our center. We collected demographic, clinical, and laboratory data. Clinical disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI). Clinical response was defined as a decrease in ≥3 points in SCCAI from baseline with only patients with clinically active disease included in the analysis, and clinical remission was defined as an SCCAI score of ≤ 2. Results 47 patients have initiated ozanimod therapy at our center: 45 patients with ulcerative colitis (UC), 1 patient with Crohn’s colitis and 1 patient with lymphocytic colitis. Only patients with UC were included in the effectiveness analysis. Demographics are in Table 1: in the UC cohort, the mean age was 40.6 ±16.6 years, mean disease duration was 9.6 ±9.2 years, 26 (58%) were male, 23 (51%) had extensive colitis, and 34 (76%) had previous advanced therapy exposure. 19 had baseline endoscopy with a mean Mayo endoscopic score of 2.6 ±0.5. Clinical response, remission, and corticosteroid free remission (CSFR) rates at weeks 2, 4, 10, 24, and 52 are in Figure 1. At week 10, follow-up was available for 41 patients: 18 patients (55%) achieved clinical response, 24 (59%) clinical remission, and 22 (54%) achieved CSFR. At week 52, follow-up was available for 30 patients: 5 (17%) achieved clinical response, 5 (17%) clinical remission, and 4 (13%) achieved CSFR. There were no significant differences between advanced therapy naïve and experienced patients, including when stratified by the number of previous advanced therapies or prior use of vedolizumab (Figures 2A+B and 3). Patients with a > 75% reduction in absolute lymphocytes had numerically greater induction clinical response and remission rates (80% vs 54%, p=0.4 and 75% vs 53%, p=0.4, respectively). 13 patients experienced adverse events (AEs): hypertension (n=2), transient nausea (n=2), fatigue (n=3), dry skin (n=2), transient liver enzyme elevation (n=2) and transient headache (n=3). Two AEs required discontinuation – hypertensive crisis in a patient with a prior dx of hypertension, and fatigue. There were no episodes of symptomatic bradycardia. Conclusion We present one-year real world follow-up of ozanimod in a largely treatment-refractory cohort of patients with UC, and describe modest one-year effectiveness and a safety profile that is not different from that described in the clinical trials.
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Sandborn, William J., Brian G. Feagan, Stephen Hanauer, Severine Vermeire, Subrata Ghosh, Wenzhong J. Liu, AnnKatrin Petersen, et al. "Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study." Journal of Crohn's and Colitis 15, no. 7 (January 13, 2021): 1120–29. http://dx.doi.org/10.1093/ecco-jcc/jjab012.
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Abstract Background and Aims This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE]. Methods Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study. Results Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15–18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up. Conclusions There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126]
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Antonelli, E., R. Del Sordo, O. Morelli, V. Villanacci, and G. Bassotti. "Update on ozanimod for ulcerative colitis." Drugs of Today 58, no. 7 (2022): 351. http://dx.doi.org/10.1358/dot.2022.58.7.3408818.
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Eiden, Petra. "Frühe Reduktion der Läsionslast unter Ozanimod." InFo Neurologie + Psychiatrie 23, no. 7-8 (August 2021): 53. http://dx.doi.org/10.1007/s15005-021-2037-y.
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Ray, Katrina. "Ozanimod is efficacious in ulcerative colitis." Nature Reviews Gastroenterology & Hepatology 18, no. 11 (October 1, 2021): 748. http://dx.doi.org/10.1038/s41575-021-00532-3.
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Anja, Borchers. "MS-Therapie: Aktuelle Daten zu Ozanimod." Nervenheilkunde 37, no. 03 (February 2018): 216. http://dx.doi.org/10.1055/s-0038-1638278.
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Ottenjann, Henrike. ""Hit smart and early" mit Ozanimod." InFo Neurologie + Psychiatrie 25, no. 2 (February 2023): 53. http://dx.doi.org/10.1007/s15005-023-3181-3.
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Samjoo, Imtiaz A., Evelyn Worthington, Christopher Drudge, Melody Zhao, Chris Cameron, Dieter A. Häring, Dee Stoneman, Luisa Klotz, and Nicholas Adlard. "Efficacy classification of modern therapies in multiple sclerosis." Journal of Comparative Effectiveness Research 10, no. 6 (April 2021): 495–507. http://dx.doi.org/10.2217/cer-2020-0267.
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Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.
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Potì, Francesco, Carmine Giorgio, Irene Zini, Jerzy-Roch Nofer, Valentina Vivo, Simone Palese, Vigilio Ballabeni, Elisabetta Barocelli, and Simona Bertoni. "Impact of S1P Mimetics on Mesenteric Ischemia/Reperfusion Injury." Pharmaceuticals 13, no. 10 (October 9, 2020): 298. http://dx.doi.org/10.3390/ph13100298.
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Mesenteric ischemia/reperfusion (I/R), following the transient deprivation of blood flow to the gut, triggers an acute flogistic process involving the disruption of endothelial and epithelial barriers integrity, the activation of immune cells, and the abundant release of inflammatory mediators. Among them, the lipid mediator sphingosine-1-phosphate (S1P) is involved in maintaining epithelial and endothelial barrier integrity and in governing the migration of immune cells through the interaction with S1P1–5 receptors. Therefore, the present work aims to investigate the involvement of S1P signaling in intestinal I/R-induced injury by studying the effects of FTY720, the non-selective S1P1,3–5 agonist, and comparing them with the responses to ozanimod, selective S1P1,5 agonist, in a murine model of gut I/R. Intestinal edema, gut and lung neutrophil infiltration, and oxidative stress were evaluated through biochemical and morphological assays. The collected results highlight the protective action of FTY720 against the inflammatory cascade elicited by mesenteric I/R injury, mainly through the control of vascular barrier integrity. While these beneficial effects were mimicked by ozanimod and can be therefore attributed largely to the effects exerted by FTY720 on S1P1, the recruitment of myeloid cells to the injured areas, limited by FTY720 but not by ozanimod, rather suggests the involvement of other receptor subtypes.