Ongentys opicapone 25 mg Capsule, 30-count — NDC 64896-402-01 (Billing 64896-0402-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Opicapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine), and their hydroxylated metabolites.

When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).

12.2Pharmacodynamics COMT Activity Once-daily administration of ONGENTYS 50 mg caused inhibition of COMT activity in erythrocytes; the maximal inhibition seen was 84% and was maintained >65% over a 24-hour dosing interval in patients with Parkinson’s disease. Following termination of treatment, COMT inhibition slowly returns to baseline levels, with >35% inhibition still observed 5 days after the last dose. Effects on Levodopa Peak (C max ) and overall levodopa exposure (AUC) increased by 43-44% and 62-94%, respectively, in PD patients following once-daily administration of ONGENTYS at bedtime with levodopa/carbidopa administered every three or every four hours, as compared to after administration of levodopa/carbidopa alone.

C ardiac Electrophysiology At a dose 16 times the recommended dosage, ONGENTYS does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics Opicapone demonstrates dose-proportional pharmacokinetics over a 25 mg (0.5 times the recommended dosage) to 50 mg dose range. The pharmacokinetics of opicapone are similar in both PD patients and healthy subjects. Absorption After single-dose administration of ONGENTYS 50 mg, the median (range) plasma T max value was 2.0 (1.0-4.0) hours.

Effect of Food Following a moderate fat/moderate calorie meal, the mean peak plasma concentration (C max ) for opicapone decreased 62%, the mean overall plasma exposure (AUC) decreased 31%, and the T max was delayed by 4 hours. In Study 1, ONGENTYS was administered without regard to food. In Study 2, ONGENTYS administration and food consumption were separated by 1 hour [see Dosage and Administration ( 2.1 ), Clinical Studies ( 14 )].

Distribution Opicapone is highly bound to plasma proteins (>99%), which is independent of concentration. Elimination The mean elimination half-life of opicapone is 1 to 2 hours. Metabolism Sulphation is the primary metabolic pathway of opicapone, based on clinical studies and in vitro assessments.

Other metabolic pathways include glucuronidation, methylation (by COMT), reduction, and glutathione conjugation. Excretion After administration of a single dose of radiolabeled opicapone 100 mg (2 times the recommended dosage) to healthy subjects, approximately 70% of the dose was recovered in feces (22% as unchanged), 20% in expired air, and 5% in urine (<1% as unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of opicapone were observed based on age (i.e., 18 to 40 years of age and ≥ 65 years of age), sex, or race/ethnicity (i.e., Japanese, Caucasian, Asian, and Black).

Renal Impairment Based on population pharmacokinetic analyses, no clinically significant differences in the pharmacokinetics of opicapone were observed in patients with mild or moderate renal impairment (CLcr 30-89 mL/min using the Cockcroft-Gault equation) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or ESRD (CLcr <30 mL/min) have not been studied [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment The single-dose pharmacokinetics of opicapone was evaluated in subjects with mild (Child-Pugh: A) and moderate (Child-Pugh: B) hepatic impairment.

In subjects with mild hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 35%, which is not expected to be clinically signifi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Opicapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine), and their hydroxylated metabolites.

When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).

12.3Pharmacokinetics Opicapone demonstrates dose-proportional pharmacokinetics over a 25 mg (0.5 times the recommended dosage) to 50 mg dose range. The pharmacokinetics of opicapone are similar in both PD patients and healthy subjects. Absorption After single-dose administration of ONGENTYS 50 mg, the median (range) plasma T max value was 2.0 (1.0-4.0) hours.

Effect of Food Following a moderate fat/moderate calorie meal, the mean peak plasma concentration (C max ) for opicapone decreased 62%, the mean overall plasma exposure (AUC) decreased 31%, and the T max was delayed by 4 hours. In Study 1, ONGENTYS was administered without regard to food. In Study 2, ONGENTYS administration and food consumption were separated by 1 hour [see Dosage and Administration ( 2.1 ), Clinical Studies ( 14 )].

Distribution Opicapone is highly bound to plasma proteins (>99%), which is independent of concentration. Elimination The mean elimination half-life of opicapone is 1 to 2 hours. Metabolism Sulphation is the primary metabolic pathway of opicapone, based on clinical studies and in vitro assessments.

Other metabolic pathways include glucuronidation, methylation (by COMT), reduction, and glutathione conjugation. Excretion After administration of a single dose of radiolabeled opicapone 100 mg (2 times the recommended dosage) to healthy subjects, approximately 70% of the dose was recovered in feces (22% as unchanged), 20% in expired air, and 5% in urine (<1% as unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of opicapone were observed based on age (i.e., 18 to 40 years of age and ≥ 65 years of age), sex, or race/ethnicity (i.e., Japanese, Caucasian, Asian, and Black).

Renal Impairment Based on population pharmacokinetic analyses, no clinically significant differences in the pharmacokinetics of opicapone were observed in patients with mild or moderate renal impairment (CLcr 30-89 mL/min using the Cockcroft-Gault equation) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or ESRD (CLcr <30 mL/min) have not been studied [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment The single-dose pharmacokinetics of opicapone was evaluated in subjects with mild (Child-Pugh: A) and moderate (Child-Pugh: B) hepatic impairment.

In subjects with mild hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 35%, which is not expected to be clinically significant. In subjects with moderate hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 84%. Dosage adjustment for ONGENTYS is required in subjects with moderate hepatic impairment [see Dosage and Administration ( 2.2 )] .

ONGENTYS has not been studied in patients with severe hepatic impairment (Child-Pugh: C) [see Use in Speci fic Populations ( 8.7 )]. Drug Interaction Studies Clinical Studies No clinically significant differences in the pharmacokinetics of opicapone were observed when administered concomitantly with quinidine (index substrate of P-gp [MDR1]), acetaminophen, or rasagiline. No clinically significant differences in the pharmacokinetics of the following drugs were observed when administered concomitantly with opicapone: S-warfarin (index substrate of CYP2C9), R-Warfarin (substrate of CYP1A2 and CYP3A4), or repaglinide (index substrate of CYP2C8 and OATP1B1).

No clinically significant differences in the pharmacokinetics of the following drugs for the treatment of Parkinson’s disease were observed when administered concomitantly with opicapone: rasagiline, selegiline, pramipexole, ropinirole, or amantadine. In Vitro Studies Opicapone does not affect protein binding of warfarin, diazepam, digoxin, or tolbutamide, in vitro. CYP Enzymes : Opicapone is not an inhibitor or inducer of major CYPs.

Transporter Systems : Opicapone is a substrate of P-gp (MDR1) (see Clinical Studies), BCRP, MRP2, OATP1B3, and OATP2B1. No clinically significant transpo… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics COMT Activity Once-daily administration of ONGENTYS 50 mg caused inhibition of COMT activity in erythrocytes; the maximal inhibition seen was 84% and was maintained >65% over a 24-hour dosing interval in patients with Parkinson’s disease. Following termination of treatment, COMT inhibition slowly returns to baseline levels, with >35% inhibition still observed 5 days after the last dose. Effects on Levodopa Peak (C max ) and overall levodopa exposure (AUC) increased by 43-44% and 62-94%, respectively, in PD patients following once-daily administration of ONGENTYS at bedtime with levodopa/carbidopa administered every three or every four hours, as compared to after administration of levodopa/carbidopa alone.

C ardiac Electrophysiology At a dose 16 times the recommended dosage, ONGENTYS does not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES The efficacy of ONGENTYS for the adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes was evaluated in two double-blind, randomized, parallel-group, placebo- and active-controlled (Study 1, NCT01568073), or placebo-controlled (Study 2, NCT01227655) studies of 14-15 week duration. All patients were treated with levodopa/ DOPA decarboxylase inhibitor (DDCI) (alone or in combination with other PD medications). The double-blind period for each study began with a period for levodopa/DDCI dose adjustment (up to 3 weeks), followed by a stable maintenance period of 12 weeks.

Study 1 In Study 1, patients (n=600) were randomized to treatment with one of 3 doses of ONGENTYS. The intention to treat (ITT) population included patients treated with ONGENTYS 50 mg once daily (n=115) or placebo (n=120). Baseline demographic characteristics were similar across all treatment groups: approximately 60% of patients were male, mean age was 64 years, and all patients were Caucasian.

Baseline PD characteristics in the treatment groups were: mean duration of PD of 7 years for ONGENTYS 50 mg compared to 7.7 years for placebo, and mean onset of motor fluctuations of 2.2 years prior to study enrollment. Eighty-two percent of patients in both groups used concomitant PD medications in addition to levodopa; the most commonly used were dopamine agonists (68%), amantadine (23%), MAO-B inhibitors (20%), and anticholinergics (5%). The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed 3 days prior to each of the scheduled visits.

ONGENTYS 50 mg significantly reduced mean absolute OFF-time compared to placebo (Table 2). Table 2 : Study 1 - Absolute OFF-time ( Hours ) Change from Baseline to Endpoint N Baseline Mean ( S E ) LS Mean Change from Baseline (SE) Placebo-subtracted Difference (95% CI) Adjusted p-value a Placebo 120 6.17 hours (0.162) -0.93 (0.223) -- -- ONGENTYS 50 mg 115 6.20 hours (0.166) -1.95 (0.233) -1.01 (-1.620, -0.407) p=0.002 CI=confidence interval; LS =least squares; N=total number of patients; SE=standard error. a Adjusted p values were calculated using a gatekeeping procedure controlling for multiplicity.

ON-time without troublesome dyskinesia was a secondary efficacy endpoint in Study 1 (Table 3). Table 3: Study 1 - Absolute ON-time Without Troublesome Dyskinesia (Hours) Change from Baseline to Endpoint N Baseline Mean (SE) LS Mean Change from Baseline (SE) Placebo-subtracted Difference (95% CI) Nominal p-value a Placebo 120 9.61 (0.191) 0.75 (0.237) -- -- ONGENTYS 50 mg 115 9.54 (0.183) 1.84 (0.247) 1.08 (0.440, 1.728) p=0.001 CI=confidence interval; LS =least squares; N=total number of patients; SE=standard error. a Unadjusted p-value.

Study 2 In Study 2, patients (n=427) were randomized to treatment with either one of two doses of ONGENTYS once daily (n=283) or placebo (n=144). The intention to treat (ITT) study population included patients treated with ONGENTYS 50 mg once daily (n=147) or placebo (n=135). Baseline demographic characteristics (ONGENTYS 50 mg vs. placebo) were: mean age (66 years vs.

62 years), male (61% vs. 53%), Caucasian (78% vs. 66%) and Asian (21% vs.

31%). Baseline PD characteristics were generally similar across treatment groups with a mean duration of PD of 8.2 years, and a mean onset of motor fluctuations of 3.2 years prior to study enrollment. Eighty-five percent of patients treated with ONGENTYS 50 mg compared to 81% of patients who received placebo used concomitant PD medications in addition to levodopa; the most commonly used were dopamine agonists (70%), amantadine (21%), MAO-B inhibitors (20%), and anticholinergics (12%).

The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed 3 days prior to each of the scheduled visits. ONGENTYS 50 mg significantly reduced mean absolute OFF-time compared to placebo (Table 4). Ta… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No increase in tumors was observed when opicapone was administered orally to mice (0, 100, 375, or 750 mg/kg/day) for up to 2 years (84-93 weeks at the high dose). The highest dose tested is approximately 70 times the recommended dose (RHD) in humans (50 mg/day) on a body surface area (mg/m 2 ) basis. No increase in tumors was observed when opicapone was administered orally to rats (0, 100, 500, or 1000 mg/kg/day) for 2 years.

Plasma exposure (AUC) at the highest dose tested is approximately 24 times that in humans at the RHD (50 mg/day). Mutagenesis Opicapone was negative in in vitro (bacterial reverse mutation test (Ames), chromosomal aberrations in human peripheral blood lymphocytes) and in in vivo (rat bone marrow micronucleus) assays. Impairment of Fertility In male and female rats, oral administration of opicapone (0, 100, 500, or 1000 mg/kg/day) prior to and during mating and continuing in females to gestation day 6, resulted in no adverse effects on fertility or general reproductive performance.

Plasma exposure (AUC) at the highest dose tested is approximately 40 times that in humans at the RHD.