ZEPOSIA Capsule Ref.[10374] Active ingredients: Ozanimod

The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 3.

Table 3. Exposure Parameters of Ozanimod and its Major Metabolite*:

C_max,ss = maximum observed plasma concentration at steady state, AUC_tau,ss = area under the plasma concentration-time curve during a dosage interval at steady state.
* Mean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified.
^† In healthy subjects.

Absorption

The T_max of ozanimod is approximately 6-8 hours.

Effect of Food

No clinically significant differences in the C_max and AUC of ozanimod were observed following administration of ZEPOSIA with a high-fat, high-calorie meal.

Distribution

The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) is 5590 L (27%). Human plasma proteins binding of ozanimod, CC112273 and CC1084037 is approximately 98.2%, 99.8%, and 99.3%, respectively.

Elimination

The mean (CV%) plasma half-life (t_1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t_1/2) of CC112273 and its direct interconverting metabolite CC1084037 was approximately 11 days (104%) in relapsing MS patients. The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%).

Metabolism

Ozanimod is metabolized by multiple enzymes to form circulating major active metabolites (e.g., CC112273 and CC1084037) and minor active metabolites (e.g., RP101988, RP101075, and RP112509) with similar activity and selectivity for S1P₁ and S1P₅. Ozanimod is metabolized by ALDH/ADH to form carboxylate metabolite RP101988 and by CYP3A4 to form RP101075. RP101075 is then metabolized either by NAT-2 to form RP101442 or by MAO-B to form CC112273. CC112273 is then metabolized by CYP2C8 to form RP112509 or reduced to form CC1084037. CC1084037 is metabolized by AKR 1C1/1C2 and/or 3β- and 11β-HSD to form CC112273. The interconversion between CC112273 and CC1084037 favors CC112273. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans.

Excretion

Following a single oral dose of radiolabeled ozanimod 0.92 mg, approximately 26% of the radioactivity was recovered in urine and 37% in feces, primarily composed of inactive metabolites.

Specific Populations

No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex. The effect of age (65 years of age and older) or hepatic impairment on the pharmacokinetics of ozanimod is unknown [see Use in Specific Populations (8.5, 8.6)].

Racial or Ethnic Groups

In a dedicated Japanese PK bridging study, following repeated dosing of 0.96 mg ZEPOSIA, ozanimod exposures (C_max and AUC_tau) were unchanged and CC112273 exposures (C_max and AUC_tau) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences are not considered clinically meaningful.

Patients with Renal Impairment

In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ZEPOSIA, exposures (AUC_last) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8). Based on this trial, renal impairment has no clinically important effects on pharmacokinetics of ozanimod or CC112273.

Smokers

Population PK analyses showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in nonsmokers. The clinical impact of smoking on ozanimod treatment for patients with RMS is not known.

Drug Interaction Studies

Clinical Studies

Strong CYP3A and P-gp Inhibitors: No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (P-gp and strong CYP3A inhibitor).

Strong CYP2C8 Inhibitors: Co-administration of ozanimod with gemfibrozil (a strong CYP2C8 inhibitor) increased exposure (AUC) of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively. No clinically significant differences in the AUC of ozanimod were observed when co-administered with gemfibrozil [see Drug Interactions (7.4)].

BCRP Inhibitor: Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on ozanimod exposure, but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). Co-administration of ozanimod with BCRP inhibitors may also increase exposure of CC112273 and CC1084037 [see Drug Interactions (7.5)].

Strong CYP2C8 Inducers: Co-administration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ZEPOSIA 0.92 mg reduced the exposure (AUC) for ozanimod, CC112273, and CC1084037 by approximately 24%, 60%, and 55%, respectively. The effect on CC112273 and CC1084037 is primarily caused by induction of CYP2C8 [see Drug Interactions (7.6)].

Monoamine Oxidase Inhibitors: No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted [see Drug Interaction (7.7)].

Oral Contraceptives: No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A.

In vitro, CC112273 and CC1084037 inhibited MAO-B (IC50 values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A).

Transporter Systems: Ozanimod, CC112273, CC1084037 and other metabolites do not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2-K. CC112273 and CC1084037 do not inhibit BCRP at clinically relevant concentrations.

Carcinogenesis

Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested.

Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors. At the highest dose tested (2 mg/kg/day), plasma exposure (AUC) for ozanimod was approximately 100 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD.

Mutagenesis

Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Metabolite CC112273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays. Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay.

Impairment of Fertility

Oral administration of ozanimod (0, 0.2, 2, or 30 mg/kg/day) to male and female rats prior to and during mating and continuing through gestation day 7 resulted in no adverse effects on fertility. At the highest dose tested (30 mg/kg/day), plasma ozanimod exposure (AUC) was approximately 1600 times that in humans at the maximum recommended human dose (MRHD) (0.92 mg/day); plasma AUCs for metabolites, CC112273 and CC1084037, at 30 mg/kg/day were 13 and 3 times, respectively, those in humans at the MRHD.

The efficacy of ZEPOSIA was demonstrated in 2 randomized, double-blind, double-dummy, parallel-group, active comparator-controlled clinical trials of similar design, in patients with relapsing forms of MS [Study 1 (NCT02294058) and Study 2 (NCT02047734)]. Patients in Study 1 were treated until the last enrolled patient completed 1 year of treatment. Patients in Study 2 were treated for 24 months. Both studies included patients who had experienced at least 1 relapse within the prior year, or 1 relapse within the prior 2 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 at baseline. Patients with primary progressive MS were excluded.

Patients were randomized to receive either ZEPOSIA 0.92 mg given orally once daily, beginning with a dose titration [see Dosage and Administration (2.2)], or interferon (IFN) beta-1a, the active comparator, 30 mcg given intramuscularly once weekly. Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse. Brain MRI scans were performed at baseline, 6 months (Study 1), 1 year (Studies 1 and 2), and 2 years (Study 2).

The primary endpoint of both Study 1 and Study 2 was the annualized relapse rate (ARR) over the treatment period (Study 1) and 24 months (Study 2). Additional 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 Gadolinium-enhancing (Gd+) 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 confirmed after 3 months and after 6 months. Confirmed disability progression was evaluated in a pooled analysis of Studies 1 and 2.

In Study 1, a total of 895 patients were randomized to receive ZEPOSIA (n=447) or IFN beta-1a (n=448); of these patients, 94% who received ZEPOSIA and 92% who received IFN beta-1a completed the study. The mean age was 35.4 years, 99.8% were White, and 65% were female. The mean time since MS symptom-onset was 6.9 years, and the median EDSS score at baseline was 2.5; 31% had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the prior year was 1.3 and 48% of patients had one or more T1 Gd-enhancing lesions (mean 1.8) on their baseline MRI scan.

In Study 2, a total of 874 patients were randomized to receive ZEPOSIA (n=433) or IFN beta-1a (n=441); of these patients, 90% who received ZEPOSIA and 85% who received IFN beta-1a completed the study. The mean age was 35.6 years, 98% were White, and 68% were female. The mean time since MS symptom onset was 6.6 years, and the median EDSS score at baseline was 2.5; 29% of patients had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the prior year was 1.3 and 43% of patients had one or more T1 Gd-enhancing lesions (mean 1.7).

The ARR was statistically significantly lower in patients treated with ZEPOSIA 0.92 mg than in patients who received IFN beta-1a 30 mcg IM. The number of new or enlarging T2 lesions and the number of GdE lesions were statistically significantly lower in patients treated with ZEPOSIA 0.92 mg than in patients who received IFN beta-1a.

There was no statistically significant difference in the three-month and six-month confirmed disability progression between ZEPOSIA and IFN beta-1a-treated patients over 2 years.

The results for Study 1 and Study 2 are shown in Table 4.

Table 4. Clinical and MRI Endpoints from Study 1 and Study 2:

* Through the treatment period (mean duration 13.6 months).
^† Over treatment period for Study 1 and over 24 months for Study 2.
^‡ Disability progression defined as 1-point increase in Expanded Disability Status Scale (EDSS) confirmed 3 months or 6 months later.
^§ Prospective planned pooled analysis of Studies 1 and 2.
^¶ Not statistically significant.
^# Over 12 months for Study 1 and over 24 months for Study 2.
^Þ At 12 months for Study 1 and at 24 months for Study 2.

A similar effect of ZEPOSIA on the ARR compared to IFN beta-1a was observed in exploratory subgroups defined by sex, age, prior non-steroid therapy for MS, and baseline disease activity.