Готові списки джерел за темами / Ozanimod

Добірка наукової літератури з теми "Ozanimod"

Автор: Grafiati

Опубліковано: 14 березня 2023

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Статті в журналах з теми "Ozanimod"

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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Дисертації з теми "Ozanimod"

CIANFEROTTI, CLAUDIO. "Synthetic approaches to novel linkers for the bioconjugation of pharmaceutical active compounds." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1071010.

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Анотація:

Gli Antibody-Drug Conjugates (ADC) sono tra i farmaci più promettenti per la terapia mirata antitumorale. Gli ADC sfruttano infatti la capacità degli anticorpi monoclonali di indirizzare il trasporto di molecole citotossiche in modo selettivo al sito del tumore, con un miglioramento dell’efficacia della sicurezza del farmaco citotossico. La porzione linker di collegamento tra l’anticorpo e il farmaco è una componente cruciale di ogni ADC: deve essere stabile in plasma ma instabile all’interno della cellula, permettendo il rilascio del farmaco citotossico solo nell’ambiente citoplasmatico ed evitando un rilascio prematuro nella circolazione sanguigna. In questo progetto di tesi sono stati esplorati numerosi aspetti degli ADC. Abbiamo sviluppato il primo ADC coniugato con un acido idrossamico, l’inibitore dell’enzima istone deacetilasi vorinostat, connesso attraverso un linker degradabile dal metabolismo cellulare. Inoltre, il farmaco è meno potente di quelli solitamente usati negli ADC con una ridotta tossicità sistemica. Per quanto riguarda i “self-immolative spacers”, abbiamo sviluppato un nuovo linker ramificato che permette la possibilità di una sintesi modulare dei vari componenti: tale linker è capace di rilasciare un modello di farmaco citotossico mediante la riduzione di un gruppo disolfuro. Inoltre, sono stati effettuati anche studi verso un approccio convergente alla sintesi dei linker. Oltre al lavoro con i bioconiugati, sono stati sintetizzate alcune impurezze della sintesi industriale dell’agonista dei recettori della melatonina Tasimelteon ed è stata sviluppata una nuova sintesi stereoselettiva dell’agonista dei recettori della sfingosina Ozanimod.
Antibody-Drug Conjugates (ADCs) are emerging as the next generation anticancer therapeutic agents. ADCs take advantage of the specificity of monoclonal antibody to target the delivery of drugs to the tumor site, with an expectation of improving the efficacy and safety of the cytotoxic payload. The linker plays a key role in the development of ADC derivatives and its blood stability as well as its possible degradation into the cell need to be carefully tuned. The synthesis of the linker offers many opportunities for organic chemistry. In this thesis we explored several different aspects of the ADC field. We developed the first ADC charged with a hydroxamic acid payload (the HDAC inhibitor vorinostat), connected through a metabolic sensitive linker. Moreover, the presence of a not highly cytotoxic drug leads to a lower systemic toxicity compared the one generally observed with traditional ADCs. With regard to self-immolative spacers, we designed a novel multifunctional branched linker that offers the opportunity of a modular synthesis of the various ADCs components. This linker is able to release a model of an amine payload from a disulfide trigger moiety. Furthermore, we present also studies towards a convergent approach to the synthesis of the linker. Besides the work on bioconjugates, we report the preparation of several synthetic impurities of the melatonin receptors agonist Tasimelteon and a new protecting group-free stereoselective synthesis of the sphingosine-1-phosphate receptor agonist Ozanimod.

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Тези доповідей конференцій з теми "Ozanimod"

Venkatesan, Reshmii, Somaiah Chinnapaka, John Schappert, and Gnanasekar Munirathinam. "Abstract 2974: Preclinical evaluation of Ozanimod for prostate cancer treatment." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2974.

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Kammerer, Susanne. "Fast recapture of response with ozanimod after withdrawal in UC." In UEGW Week 2022, edited by Marjolijn Duijvestein. Baarn, the Netherlands: Medicom Medical Publishers, 2022. http://dx.doi.org/10.55788/49a646b8.

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Kammerer, Susanne. "Ozanimod treatment prompted substantial response after failure of response to induction." In UEGW Week 2022, edited by Marjolijn Duijvestein. Baarn, the Netherlands: Medicom Medical Publishers, 2022. http://dx.doi.org/10.55788/83087d65.

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Marsolais, D., N. Châteauvert, P. Blais-Lecours, P. Rola, T. Nguyen, and F. Lellouche. "A pilot trial for ozanimod therapy in hospitalized COVID-19 patients." In ERS International Congress 2022 abstracts. European Respiratory Society, 2022. http://dx.doi.org/10.1183/13993003.congress-2022.520.

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Taylor, Carly, Timothy Waterhouse, Michael Heathman, D. Alex Oh, H. Kiyomi Komori, and John S. Grundy. "P206 Model-predicted lymphocyte response and recovery profiles for the sphingosine 1-phosphate receptor modulators ozanimod and etrasimod." In Abstracts of the BSG Annual Meeting, 20–23 June 2022. BMJ Publishing Group Ltd and British Society of Gastroenterology, 2022. http://dx.doi.org/10.1136/gutjnl-2022-bsg.260.

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Harris, Sarah, Giancarlo Comi, Bruce AC Cree, Lawrence Steinman, James K. Sheffield, Harry Southworth, Ludwig Kappos, and Jeffrey A. Cohen. "067 Neurofilament light chain concentration predicts risk of relapse in participants with relapsing multiple sclerosis in phase 3 ozanimod trials." In ANZAN Annual Scientific Meeting 2021 Abstracts. BMJ Publishing Group Ltd, 2021. http://dx.doi.org/10.1136/bmjno-2021-anzan.67.

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Siegmund, B., W. Sandborn, G. D’Haens, D. Wolf, S. Hanauer, I. Jovanovic, S. Ghosh, et al. "Ozanimod for moderate-to-severe Ulcerative Colitis (UC): efficacy, safety, and histology results from the induction and maintenance periods of the Phase 3 TRUE NORTH Study." In Viszeralmedizin 2021 Gemeinsame Jahrestagung Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Sektion Endoskopie der DGVS, Deutsche Gesellschaft für Allgemein und Viszeralchirurgie (DGAV). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1733513.

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