Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA38
Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator, which binds selectively to sphingosine 1-phosphate receptor subtypes 1 and 5. Ozanimod causes lymphocyte retention in lymphoid tissues. The mechanism by which ozanimod exerts therapeutic effects in MS is unknown, but may involve the reduction of lymphocyte migration into the central nervous system (CNS). Ozanimod is 10-fold more selective for S1P1 relative to S1P5 and has little activity on other S1P receptors (S1P2, S1P3, and S1P4). Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites (see section 5.2). In vitro, ozanimod and its active metabolites demonstrated similar activity and selectivity for S1P1 and S1P5. In humans, approximately 94% of circulating total active drug exposure are represented by ozanimod (6%) and the two major metabolites CC112273 (73%), and CC1084037 (15%) (see section 5.2).
Ozanimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible sequestration of lymphocytes in lymphoid tissues. In active-controlled MS clinical studies, mean lymphocyte counts decreased to approximately 45% of baseline at 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 30 days, with 90% of patients recovering to normal within 3 months (see sections 4.4 and 4.8).
Ozanimod may cause a transient reduction in HR on initiation of dosing (see sections 4.4 and 4.8). 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 desensitizes 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 was evaluated in two randomised, double-blind, double-dummy, parallel-group, active controlled clinical trials of similar design and endpoints, in patients with relapsing remitting MS (RRMS). Study 1 – SUNBEAM, was a 1-year study with patients continuing assigned treatment beyond month 12 until the last enrolled patient completed the study. Study 2 – RADIANCE was a 2-year study.
The dose of ozanimod was 0.92 mg and 0.46 mg given orally once daily, with a starting dose of 0.23 mg on days 1-4, followed by an escalation to 0.46 mg on days 5-7, and followed by the assigned dose on day 8 and thereafter. The dose of IFN β-1a, the active comparator, was 30 mcg given intramuscularly once weekly.
Both studies included patients with active disease as defined by having at least one relapse within the prior year, or one relapse within the prior two years with evidence of at least a gadolinium-enhancing (GdE) lesion in the prior year and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.0.
Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse. MRIs were performed at baseline (Studies 1 and 2), 6 months (SUNBEAM), 1 year (Studies 1 and 2), and 2 years (RADIANCE).
The primary outcome of both SUNBEAM and RADIANCE was the annualised relapse rate (ARR) over the treatment period (minimum of 12 months) for SUNBEAM and 24 months for RADIANCE. The key secondary outcome measures included 1) the number of new or enlarging MRI T2 hyperintense lesions over 12 and 24 months; 2) the number of MRI T1 GdE lesions at 12 and 24 months; and 3) the time to confirmed disability progression, defined as at least a 1-point increase from baseline EDSS sustained for 12 weeks. Confirmed disability progression was prospectively evaluated in a pooled analysis of Studies 1 and 2.
In SUNBEAM, 1346 patients were randomised to receive ozanimod 0.92 mg (n=447), ozanimod 0.46 mg (n=451), or IFN β-1a IM (n=448); 94% of ozanimod treated 0.92 mg, 94% of ozanimod treated 0.46 mg, and 92% of IFN β-1a IM treated patients completed the study. In RADIANCE, 1313 patients were randomised to receive ozanimod 0.92 mg (n=433), ozanimod 0.46 mg (n=439), or IFN β-1a IM (n=441); 90% of ozanimod treated 0.92 mg, 85% of ozanimod treated 0.46 mg, and 85% of IFN β-1a IM treated patients completed the study. Patients enrolled across the 2 studies had a mean age of 35.5 years (range 18-55), 67% were female, mean time since MS symptom onset was 6.7 years. The median EDSS score at baseline was 2.5; approximately one-third of the patients had been treated with a disease-modifying therapy (DMT), predominately interferon or glatiramer acetate. At baseline, the mean number of relapses in the prior year was 1.3 and 45% of patients had one or more T1 Gd-enhancing lesions (mean 1.7).
The results for SUNBEAM and RADIANCE are shown in Table 3. The efficacy has been demonstrated for ozanimod 0.92 mg with a dose effect observed for study endpoints shown in Table 3. Demonstration of efficacy for 0.46 mg was less robust since this dose did not show a significant effect for the primary endpoint in RADIANCE when considering the preferred negative binomial model strategy.
Table 3. Key clinical and MRI endpoints in RMS patients from Study 1 – SUNBEAM and Study 2 – RADIANCE:
| Endpoints | SUNBEAM (≥1 year)* | RADIANCE (2 year) | ||
|---|---|---|---|---|
| Ozanimod 0,92 mg (n=447) % | IFN β-1a ΕΜ 30 mcg (n=448) % | Ozanimod 0,92 mg (n=433) % | IFN β-1a ΕΜ 30 mcg (n=441) % | |
| Ozanimod | ||||
| Annualized Relapse Rate (Primary Endpoint) Relative Reduction | 0,181 | 0,350 | 0,172 | 0,276 |
| 48% (p<0,0001) | 38% (p<0,0001) | |||
| Proportion Relapse-free** | 78% (p=0,0002)1 | 66% | 76% (p=0,0012)1 | 64% |
| Proportion with 3-month Confirmed Disability Progression (CDP)†2 Hazard ratio (95% CI) | 7,6% Ozanimod vs. 7,8% IFN β-1a ΕΜ 0,95 (0,679, 1,330) | |||
| Proportion with 6-month CDP†2# Hazard Ratio (95% CI) | 5,8% Ozanimod vs. 4,0% IFN β-1a ΕΜ 1,413 (0,922, 2,165) | |||
| MRI Endpoints | ||||
| Mean number of new or enlarging T2 hyperintense lesions per MRI3 Relative Reduction | 1,465 | 2,836 | 1,835 | 3,183 |
| 48% (p<0,0001) | 42% (p<0,0001) | |||
| Mean number of T1 Gd enhancing lesions4 Relative Reduction | 0,160 | 0,433 | 0,176 | 0,373 |
| 63% (p<0,0001) | 53% (p<0,0006) | |||
* Mean duration was 13.6 months
** Nominal p-value for endpoints not included in the hierarchical testing and not adjusted for multiplicity
† Disability progression defined as 1-point increase in EDSS confirmed 3 months or 6 months later
# In a post hoc analysis of 6-month CDP which included data from the open-label extension (Study 3), the HR (95% CI) was found to be 1.040 (0.730, 1.482))
1 Log rank test
2 Prospectively planned pooled analysis of Studies 1 and 2
3 Over 12 months for Study 1 and over 24 months for Study 2
4 At 12 months for Study 1 and at 24 months for Study 2
In SUNBEAM and RADIANCE, treatment with ozanimod 0.92 mg resulted in reductions in mean percent change from baseline in normalised brain volume compared to IFN beta-1a IM (-0.41% versus -0.61%, and -0.71% versus -0.94%, respectively, nominal p-value <0.0001 for both studies).
The studies enrolled DMT naive and previously treated patients with active disease, as defined by clinical or imaging features. Post-hoc analyses of patient populations with differing baseline levels of disease activity, including active and highly active disease, showed that the efficacy of ozanimod on clinical and imaging endpoints was consistent with the overall population.
Patients who completed the Phase 3 SUNBEAM and RADIANCE studies could enter an open label extension study (Study 3 – DAYBREAK). Of the 751 patients initially randomised to ozanimod 0.92 mg and treated for up to 3 years, the (adjusted) ARR was 0.124 after the 2nd year of treatment.
The European Medicines Agency has deferred the obligation to submit the results of studies with ozanimod in one or more subsets of the paediatric population in MS (see section 4.2).
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 S1P1 and S1P5 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 time the recommended dose). Following multiple dosing, approximately 94% of circulating total active drug exposure 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.
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 (t1/2) 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 (t1/2) 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 t1/2 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 a dedicated hepatic impairment trial, following a single oral dose of 0.23 mg ozanimod, exposures (AUClast) for ozanimod and CC112273 were approximately 11% lower and 31% lower, respectively, in patients with mild hepatic impairment (Child-Pugh A; n=8) when compared to patients with normal hepatic function (n=7). Exposures (AUClast) for ozanimod and CC112273 were approximately 27% higher and 33% lower, respectively, in patients with moderate hepatic impairment (Child-Pugh B; N=8) when compared to patients with normal hepatic function (n=8). These differences were not considered clinically meaningful. The pharmacokinetics of ozanimod were not evaluated in patients with severe hepatic impairment. No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Use in patients with severe hepatic impairment is contraindicated (Child-Pugh class C) (see section 4.3).
No pharmacokinetic data are available on administration of ozanimod to patients aged 55 years and over.
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 (see section 5.1). 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 (see section 5.2), and even to the total human active drug (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 twoyear 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 drug (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 drug, 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 drug at the maximum human dose of 0.92 mg ozanimod. Ozanimod and metabolites were present in rat milk.
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