ZEPOSIA Starter Kit ozanimod hydrochloride Kit — NDC 59572-890-28 (Billing 59572-0890-28)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Ozanimod has minimal or no activity on S1P 2 , S1P 3 , and S1P 4 .

The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis and ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the central nervous system and intestine.

12.2Pharmacodynamics Reduction in Blood Lymphocyte Counts In active-controlled MS and controlled UC clinical trials, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 × 10 9 /L), and low lymphocyte counts were maintained during treatment with ZEPOSIA [see Warnings and Precautions (5.1) ]. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months.

Reduction in Heart Rate ZEPOSIA may cause a transient decrease in heart rate on initiation of dosing [see Warnings and Precautions (5.3) ]. An up-titration schedule of ZEPOSIA 0.23 mg followed by doses of 0.46 mg, and 0.92 mg attenuates the magnitude of heart rate reductions [see Dosage and Administration (2.2) ]. Tyramine Challenge Test No clinically significant effect in tyramine induced pressor response was observed when steady state ZEPOSIA 0.92 mg (recommended dose) or 1.84 mg was co-administered with increasing doses of oral tyramine (a monoamine oxidase substrate).

Drug Interaction Studies Sympathomimetic Agents No clinically significant differences in heart rate or blood pressure was observed when ZEPOSIA 1.84 mg daily (two times the recommended dosage) for 28 days was co-administered with a single dose of 60 mg pseudoephedrine (a sympathomimetic agent) compared to pseudoephedrine alone. Beta Blocker or Calcium Channel Blocker The effect of co-administration of the maintenance dosage of ZEPOSIA, propranolol, or diltiazem, or administration with both a beta blocker and a calcium channel blocker taken together has not been studied [see Drug Interactions (7) ] .

Pulmonary Function Dose-dependent reductions in FEV 1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.7) ]. Cardiac Electrophysiology Following a 14-day titration regimen of once daily doses of ozanimod 0.23 mg for 4 days, 0.46 mg for 3 days, 0.92 mg for 3 days, and 1.84 mg (2 times the maximum approved recommended dose) for 4 days in healthy subjects, ZEPOSIA did not prolong the QTc interval to any clinically relevant extent [see Warnings and Precautions (5.3) ].

12.3Pharmacokinetics The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 7. Population pharmacokinetic analysis indicated no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC. Table 7: Exposure Parameters of Ozanimod and its Major Metabolite a a Mean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. b In healthy subjects.

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. Parameters Ozanimod CC112273 C max,ss 0.244 ng/mL (31.8%) 6.98 ng/mL (42.7%) AUC tau,ss 4.46 ng*h/mL (31.8%) 143.77 ng*h/mL (39.2%) Dose Proportionality The C max and AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg. Time to Steady State 102 hours (28.2%) b 45 days (45%) Accumulation Ratio 2.40 (21.1%) b 16 (101%) Absorption The T max of ozanimod is approximately 6 to 8 hours.

Effect of Food No clinically significant differences in the C max… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Ozanimod has minimal or no activity on S1P 2 , S1P 3 , and S1P 4 .

The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis and ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the central nervous system and intestine.

12.3Pharmacokinetics The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 7. Population pharmacokinetic analysis indicated no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC. Table 7: Exposure Parameters of Ozanimod and its Major Metabolite a a Mean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. b In healthy subjects.

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. Parameters Ozanimod CC112273 C max,ss 0.244 ng/mL (31.8%) 6.98 ng/mL (42.7%) AUC tau,ss 4.46 ng*h/mL (31.8%) 143.77 ng*h/mL (39.2%) Dose Proportionality The C max and AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg. Time to Steady State 102 hours (28.2%) b 45 days (45%) Accumulation Ratio 2.40 (21.1%) b 16 (101%) Absorption The T max of ozanimod is approximately 6 to 8 hours.

Effect of Food No clinically significant differences in the C max and AUC of ozanimod were observed following administration of ZEPOSIA with either a high-fat, high-calorie meal (1000 calories, 50% fat) or a low-fat, low-calorie meal (300 calories, 10% fat) compared to fasted conditions [see Dosage and Administration (2.2) ] . 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 (t1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t1/2) 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 S1P 1 and S1P 5 . 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 a minor active metabolite 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 Geriatric Patients Population pharmacokinetic analyses showed that steady state exposure (AUC) of CC112273 in UC patients over 65 years of age was approximately 3% to 4% greater than patients 45 to 65 years of age and 27% greater than adult patients under 45 years of age.

There is no meaningful difference in the pharmacokinetics in elderly patients with UC [see Use in Specific Populations (8.5) ] . Male and Female Patients No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight. 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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Reduction in Blood Lymphocyte Counts In active-controlled MS and controlled UC clinical trials, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 × 10 9 /L), and low lymphocyte counts were maintained during treatment with ZEPOSIA [see Warnings and Precautions (5.1) ]. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months.

Reduction in Heart Rate ZEPOSIA may cause a transient decrease in heart rate on initiation of dosing [see Warnings and Precautions (5.3) ]. An up-titration schedule of ZEPOSIA 0.23 mg followed by doses of 0.46 mg, and 0.92 mg attenuates the magnitude of heart rate reductions [see Dosage and Administration (2.2) ]. Tyramine Challenge Test No clinically significant effect in tyramine induced pressor response was observed when steady state ZEPOSIA 0.92 mg (recommended dose) or 1.84 mg was co-administered with increasing doses of oral tyramine (a monoamine oxidase substrate).

Drug Interaction Studies Sympathomimetic Agents No clinically significant differences in heart rate or blood pressure was observed when ZEPOSIA 1.84 mg daily (two times the recommended dosage) for 28 days was co-administered with a single dose of 60 mg pseudoephedrine (a sympathomimetic agent) compared to pseudoephedrine alone. Beta Blocker or Calcium Channel Blocker The effect of co-administration of the maintenance dosage of ZEPOSIA, propranolol, or diltiazem, or administration with both a beta blocker and a calcium channel blocker taken together has not been studied [see Drug Interactions (7) ] .

Pulmonary Function Dose-dependent reductions in FEV 1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.7) ]. Cardiac Electrophysiology Following a 14-day titration regimen of once daily doses of ozanimod 0.23 mg for 4 days, 0.46 mg for 3 days, 0.92 mg for 3 days, and 1.84 mg (2 times the maximum approved recommended dose) for 4 days in healthy subjects, ZEPOSIA did not prolong the QTc interval to any clinically relevant extent [see Warnings and Precautions (5.3) ].

14 CLINICAL STUDIES

14.1Multiple Sclerosis 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 [MS Study 1 (NCT02294058) and MS 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 dosage 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 8. Table 8: Clinical and MRI Endpoints from MS Study 1 and Study 2 a Through the treatment period (mean duration 13.6 months). b Over treatment period for Study 1 and over 24 months for Study 2. c Disability progression defined as 1-point increase in Expanded Disability Status Scale (EDSS) confirmed 3 months or 6 months later. d Prospective planned pooled analysis of Studies 1 and 2. e Not statist… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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.