Chemical formula: C₂₃H₂₄N₄O₃ Molecular mass: 404.47 g/mol PubChem compound: 52938427
Ozanimod is a potent sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity to sphingosine 1-phosphate receptors 1 and 5. Ozanimod has minimal or no activity on S1P~2, S1P3, and S1P4. In vitro, ozanimod and its major active metabolites demonstrated similar activity and selectivity for S1P1 and S1P5. The mechanism by which ozanimod exerts therapeutic effects in MS and UC is unknown, but may involve the reduction of lymphocyte migration into the central nervous system (CNS) and intestine.
The ozanimod-induced reduction of lymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, with greater decreases in cells involved in the adaptive immune response. Ozanimod has minimal impact on cells involved in innate immune response, which contribute to immunosurveillance.
Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites including two major metabolites. In humans, approximately 94% of circulating total active substances exposure are represented by ozanimod (6%) and the two major metabolites CC112273 (73%), and CC1084037 (15%).
In active-controlled MS and placebo-controlled UC clinical studies, mean lymphocyte counts decreased to approximately 45% of baseline by 3 months (approximate mean blood lymphocyte count 0.8 × 109/L) and remained stable during treatment with ozanimod. After discontinuing ozanimod 0.92 mg, the median time to recovery of peripheral blood lymphocytes to the normal range was approximately 30 days, with approximately 80% to 90% of patients recovering to normal within 3 months.
In patients with UC, treatment with ozanimod resulted in a decrease in the inflammatory marker, faecal calprotectin (FCP) during the induction period, which was then maintained throughout the maintenance period.
Ozanimod may cause a transient reduction in HR on initiation of dosing. This negative chronotropic effect is mechanistically related to the activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation by ozanimod and its active metabolites leading to cellular hyperpolarisation and reduced excitability with a maximal effect on HR seen within 5 hours post dose. Due to its functional antagonism at S1P1 receptors, a dose escalation schedule with ozanimod 0.23 mg followed by 0.46 mg, and 0.92 mg successively desensitises GIRK channels until the maintenance dose is reached. After the dose escalation period, with continued administration of ozanimod, HR returns to baseline.
In a randomised, positive – and placebo-controlled thorough QT study using a 14-day dose-escalation regimen of 0.23 mg daily for 4 days, 0.46 mg daily for 3 days, 0.92 mg daily for 3 days, and 1.84 mg daily for 4 days in healthy subjects, no evidence of QTc prolongation was observed as demonstrated by the upper boundary of the 95% one-sided confidence interval (CI) that was below the 10 ms. Concentration-QTc analysis for ozanimod and the major active metabolites CC112273 and CC1084037, using data from another Phase 1 study showed the upper boundary of the 95% CI for model derived QTc (corrected for placebo and baseline) below 10 ms at maximum concentrations achieved with ozanimod doses ≥ 0.92 mg once daily.
Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites, including two major active metabolites, CC112273 and CC1084037, with similar activity and selectivity for S1P 1 and S1P 5 to the parent. The maximum plasma concentration (Cmax) and area under the curve (AUC) for ozanimod, CC112273, and CC1084037 increased proportionally over the dose range of ozanimod 0.46 mg to 0.92 mg (0.5 to 1 times the recommended dose). Following multiple dosing, approximately 94% of circulating total active substances are represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). At a dose of 0.92 mg orally once daily in RRMS, the geometric mean [coefficient of variation (CV%)] Cmax and AUC0-24h at steady state were 231.6 pg/mL (37.2%) and 4223 pg*h/mL (37.7%), respectively, for ozanimod and 6378 pg/mL (48.4%) and 132861 pg*h/mL (45.6%), respectively, for CC112273. Cmax and AUC0-24h for CC1084037 are approximately 20% of that for CC112273. Factors affecting CC112273 are applicable for CC1084037 as they are interconverting metabolites. Population pharmacokinetic analysis indicated that there were no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC.
The Tmax of ozanimod is approximately 6–8 hours. The Tmax of CC112273 is approximately 10 hours. Administration of ozanimod with a high-fat, high-calorie meal had no effect on ozanimod exposure (Cmax and AUC). Therefore, ozanimod may be taken without regard to meals.
The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) was 5590 L (27%), indicating extensive tissue distribution. Binding of ozanimod to human plasma proteins is approximately 98.2%. Binding of CC112273 and CC1084037 to human plasma proteins is approximately 99.8% and 99.3%, respectively.
Ozanimod is widely metabolised by multiple biotransformation pathways including aldehyde dehydrogenase and alcohol dehydrogenase (ALDH/ADH), cytochrome P450 (CYP) isoforms 3A4 and 1A1, and gut microflora and no single enzyme system predominates the overall metabolism. Following repeated dosing, the AUCs of the two major active metabolites CC112273 and CC1084037 exceed the AUC of ozanimod by 13-fold and 2.5-fold, respectively. In vitro studies indicated that monoamine oxidase B (MAO-B) is responsible for the formation of CC112273 (via an intermediate minor active metabolite RP101075) while CYP2C8 and oxido-reductases are involved in the metabolism of CC112273. CC1084037 is formed directly from CC112273 and undergoes reversible metabolism to CC112273. The interconversion between these 2 active metabolites is mediated by carbonyl reductases (CBR), aldo-keto reductase (AKR) 1C1/1C2, and/or 3β- and 11β- hydroxysteroid dehydrogenase (HSD).
The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%). The mean (CV%) plasma half-life (t½) of ozanimod was approximately 21 hours (15%). Steady state for ozanimod was achieved within 7 days, with the estimated accumulation ratio following repeated oral administration of 0.92 mg once daily of approximately 2.
The model-based mean (CV%) effective half-life (t½) of CC112273 was approximately 11 days (104%) in RMS patients, with mean (CV%) time to steady state of approximately 45 days (45%) and accumulation ratio of approximately 16 (101%) indicating the predominance of CC112273 over ozanimod. Plasma levels of CC112273 and its direct, interconverting metabolite CC1084037 declined in parallel in the terminal phase, yielding similar t½ for both metabolites. Steady state attainment and accumulation ratio for CC1084037 are expected to be similar to CC112273.
Following a single oral 0.92 mg dose of [14C]-ozanimod, approximately 26% and 37% of the radioactivity was recovered from urine and faeces, respectively, primarily composed of inactive metabolites. Ozanimod, CC112273, and CC1084037 concentrations in urine were negligible, indicating that renal clearance is not an important excretion pathway for ozanimod, CC112273, and CC1084037.
In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ozanimod, exposures (AUClast) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in patients with end stage renal disease (N=8) compared to patients with normal renal function (n=8). Based on this trial, renal impairment had no clinically important effects on pharmacokinetics of ozanimod or CC112273. No dose adjustment is needed in patients with renal impairment.
In single dose and multiple dose studies in subjects with chronic liver disease, there was no meaningful impact of mild or moderate chronic hepatic impairment (Child-Pugh class A or B) on the pharmacokinetics of ozanimod or the major metabolite CC112273 on Day 1, Day 5, or Day 8 of dosing. After dose escalation in the second trial, administration of 0.92 mg ozanimod resulted in increased CC112273 and CC1084037 mean unbound AUC0-last (measured up to 64 days post-dose) in subjects with mild or moderate chronic hepatic impairment of 99.64% to 129.74% relative to healthy control subjects. Patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B) are recommended to complete the 7-day dose escalation regimen, and then take 0.92 mg once every other day.
The pharmacokinetics of ozanimod were not evaluated in patients with severe hepatic impairment. Use in patients with severe hepatic impairment is contraindicated (Child-Pugh class C).
Population pharmacokinetic analysis showed that steady state exposure (AUC) of CC112273 in patients over 65 years of age were approximately 3-4% greater than patients 45–65 years of age and 27% greater than adult patients under 45 years of age. There is not a meaningful difference in the pharmacokinetics in elderly patients.
No data are available on administration of ozanimod to paediatric or adolescent patients (<18 years of age).
In repeated dose toxicology studies in mice (up to 4 weeks), rats (up to 26 weeks) and monkeys (up to 39 weeks), ozanimod markedly affected the lymphoid system (lymphopenia, lymphoid atrophy and reduced antibody response) and increased lung weights and the incidence of mononuclear alveolar infiltrates, which is consistent with its primary activity at S1P1 receptors. At the no observed adverse effect levels in chronic toxicity studies, systemic exposures to the disproportionate main active and persistent human metabolites CC112273 and CC1084037, and even to the total human active substances (ozanimod combined with the mentioned metabolites), were lower than those expected in patients at the maximum human dose of 0.92 mg ozanimod.
Ozanimod and its main active human metabolites did not reveal a genotoxic potential in vitro and in vivo.
Ozanimod was evaluated for carcinogenicity in the 6-month Tg.rasH2 mouse bioassay and the two-year rat bioassay. In the two-year rat bioassay, no treatment-related tumours were present at any ozanimod dose. However, metabolite exposure at the highest dose tested, was 62% of the human exposure for CC112273 and 18% of the human exposure for CC1084037 at the maximum clinical dose of 0.92 mg ozanimod.
In the 6-month Tg.rasH2 mouse study, hemangiosarcomas increased in a statistically-significant and dose-related manner. At the low dose (8 mg/kg/day), the hemangiosarcoma incidence was increased statistically significant in males and in both males and females at the mid and high dose levels (25 mg/kg/day and 80 mg/kg/day) compared to concurrent controls. In contrast to rats and humans, mouse S1P1 receptor agonism results in sustained production of placental growth factor 2 (PLGF2) and subsequently, persistent vascular endothelial cell mitoses, potentially leading to species specific hemangiosarcomas with S1P1 agonists. Therefore, S1P1 receptor agonism related hemangiosarcomas in mice may be species specific and not predictive of a risk in humans.
No other treatment-related tumours were present at any dose in the Tg.rasH2 mouse study. At the lowest dose tested, exposure in Tg.rasH2 mice to the disproportionate two main active human metabolites was for CC112273 2.95 fold and for CC1084037 1.4 fold above the human exposure at the maximum clinical dose of 0.92 mg ozanimod.
Ozanimod had no effect on male and female fertility up to approximately 150-fold the systemic exposure to total active substances (combined ozanimod and the metabolites CC112273 and CC1084037) at the maximum human dose of 0.92 mg ozanimod.
Embryofoetal development was adversely affected by maternal treatment with ozanimod, with low (rats) or no (rabbits) safety margins based on comparison of systemic exposures to total active substances, resulting in embryolethality and teratogenicity (generalised oedema/anasarca and malpositioned testes in rats, malpositioned caudal vertebrae and malformations of the great vessels in rabbits). The vascular findings in rats and rabbits are consistent with the expected S1P1 pharmacology.
Pre- and post-natal development was not affected by ozanimod administration up to the 5.6-fold the systemic exposure to total active substances at the maximum human dose of 0.92 mg ozanimod. Ozanimod and metabolites were present in rat milk.
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