UPTRAVI Selexipag 800 ug Tablet, Coated, 60-count — NDC 66215-608-06 (Billing 66215-0608-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Selexipag is a prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP 1–4 , DP, FP, and TP).

12.2Pharmacodynamics Cardiac Electrophysiology At the maximum tolerated dose of 1,600 mcg UPTRAVI tablets twice daily, UPTRAVI does not prolong the QT interval to any clinically relevant extent. Platelet Aggregation Both selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC 50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of UPTRAVI tablets in healthy subjects from 400 to 1,800 mcg twice daily.

Pulmonary Hemodynamics A Phase 2 clinical study NS-304/-02 assessed hemodynamic variables after 17 weeks of oral treatment in adult patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating UPTRAVI tablets to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI] −44.7%, −12.2%) and an increase in cardiac index (median treatment effect) of

0.41L/min/m 2 (95% CI 0.10, 0.71) compared to placebo (N=10). A Phase 2 clinical study NS304P-P2-1 assessed hemodynamic variables in 6 Japanese pediatric patients with PAH WHO Functional Class II–III. The mean age was 9.2 years (range 3–13 years).

Five patients had idiopathic PAH, and 1 patient had postoperative congenital heart disease. Three patients were treatment-naïve, while 3 patients received background combination therapy. UPTRAVI was titrated and dosed the same as in the SALTO study [see Clinical Studies (14.2) ] .

A mean reduction of

5.55Wood units∙m 2 (95% CI −12.76, 1.67) in pulmonary vascular resistance index at week 16 was achieved. Drug Interaction In a study in healthy adult subjects, UPTRAVI tablets (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio.

12.3Pharmacokinetics The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, after both single- and multiple-dose oral administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1,800 mcg twice daily. The pharmacokinetics of selexipag and the active metabolite, after multiple-dose intravenous administration, were dose-proportional in the tested dose range from 450 to 1,800 mcg twice a day.

In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state following oral administration was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively. Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy subjects were similar.

The pharmacokinetics of selexipag and the active metabolite in PAH patients were not influenced by the severity of the disease and did not change with time. The corresponding UPTRAVI tablets and UPTRAVI for injection doses (Table 2) provide similar exposure to the active metabolite in PAH patients at steady-state, whereas the exposure to selexipag is approximately twice as high after intravenous administration compared to oral administration. Both in healthy subjects and PAH patie… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Selexipag is a prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP 1–4 , DP, FP, and TP).

12.3Pharmacokinetics The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, after both single- and multiple-dose oral administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1,800 mcg twice daily. The pharmacokinetics of selexipag and the active metabolite, after multiple-dose intravenous administration, were dose-proportional in the tested dose range from 450 to 1,800 mcg twice a day.

In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state following oral administration was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively. Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy subjects were similar.

The pharmacokinetics of selexipag and the active metabolite in PAH patients were not influenced by the severity of the disease and did not change with time. The corresponding UPTRAVI tablets and UPTRAVI for injection doses (Table 2) provide similar exposure to the active metabolite in PAH patients at steady-state, whereas the exposure to selexipag is approximately twice as high after intravenous administration compared to oral administration. Both in healthy subjects and PAH patients, after oral administration, exposure at steady-state to the active metabolite is approximately 3- to 4-fold that of selexipag.

Absorption The absolute bioavailability of orally administered selexipag is approximately 49%. Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite are reached within about 1–3 hours and 3–4 hours, respectively. Similar exposures were observed in pediatric study patients after taking whole tablets with water, taking with soft food, and dispersing in apple or orange juice.

Effect of Food In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to peak concentration (T max ) and ~30% lower peak plasma concentration (C max ). The exposure to selexipag and the active metabolite (AUC) did not significantly change in the presence of food. Distribution The volume of distribution of selexipag at steady-state is

11.7L. Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total and to the same extent to albumin and alpha1-acid glycoprotein). Metabolism Selexipag is hydrolyzed to its active metabolite, (free carboxylic acid) in the liver and intestine by carboxylesterases.

Oxidative metabolism, catalyzed mainly by CYP2C8 and to a smaller extent by CYP3A4, leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating metabolites in human plasma exceeds 3% of the total drug-related material.

Elimination Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8–2.5 hours. The terminal half-life of the active metabolite is 6.2–13.5 hours. Selexipag does not accumulate following twice daily repeat administration.

There is minimal accumulation of the active metabolite upon twice daily repeat administration suggesting that the effective half-life is in the range of 3–4 hours. The total body clearance of selexipag is

17.9L/hour. Excretion In a study in healthy subjects with radiolabeled selexipag, approximately 93% of radioactive drug material was eliminated in feces and only 12% in urine. Neither selexipag nor its active metabolite were found in urine.

Specific Populations No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag and its active metabolite have been observed in healthy subjects or PAH patients. Pedi… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology At the maximum tolerated dose of 1,600 mcg UPTRAVI tablets twice daily, UPTRAVI does not prolong the QT interval to any clinically relevant extent. Platelet Aggregation Both selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC 50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of UPTRAVI tablets in healthy subjects from 400 to 1,800 mcg twice daily.

Pulmonary Hemodynamics A Phase 2 clinical study NS-304/-02 assessed hemodynamic variables after 17 weeks of oral treatment in adult patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating UPTRAVI tablets to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI] −44.7%, −12.2%) and an increase in cardiac index (median treatment effect) of

0.41L/min/m 2 (95% CI 0.10, 0.71) compared to placebo (N=10). A Phase 2 clinical study NS304P-P2-1 assessed hemodynamic variables in 6 Japanese pediatric patients with PAH WHO Functional Class II–III. The mean age was 9.2 years (range 3–13 years).

Five patients had idiopathic PAH, and 1 patient had postoperative congenital heart disease. Three patients were treatment-naïve, while 3 patients received background combination therapy. UPTRAVI was titrated and dosed the same as in the SALTO study [see Clinical Studies (14.2) ] .

A mean reduction of

5.55Wood units∙m 2 (95% CI −12.76, 1.67) in pulmonary vascular resistance index at week 16 was achieved. Drug Interaction In a study in healthy adult subjects, UPTRAVI tablets (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio.

14 CLINICAL STUDIES

14.1Efficacy of UPTRAVI Tablets in Adult Patients with Pulmonary Arterial Hypertension The effect of UPTRAVI tablets on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1,156 adult patients with symptomatic (WHO Functional Class I [0.8%], II [46%], III [53%], and IV [1%]) PAH. Patients were randomized to either placebo (N=582), or UPTRAVI tablets (N=574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1,600 mcg twice a day.

The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6-minute walk distance (6MWD) plus worsening of Functional Class or need for additional PAH-specific therapy. The mean age was 48 years, the majority of patients were white (65%) and female (80%).

Nearly all patients were in WHO Functional Class II and III at baseline. Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%). At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%).

Patients on UPTRAVI tablets achieved doses within the following groups: 200–400 mcg (23%), 600–1,000 mcg (31%) and 1,200–1,600 mcg (43%). Treatment with UPTRAVI tablets resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value <0.0001) of the occurrence of primary endpoint events compared to placebo (Table 4; Figure 3). The beneficial effect of UPTRAVI was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (Table 4).

The observed benefit of UPTRAVI was similar regardless of the dose achieved when patients were titrated to their highest tolerated dose [see Dosage and Administration (2.1) ] . Figure 3 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHON Table 4: Primary Endpoints and Related Components in GRIPHON UPTRAVI N=574 Placebo N=582 Hazard Ratio (99% CI) p-value n % n % Primary endpoint events up to the end of treatment All primary endpoint events As first event: 155 27.0 242 41.6 0.60 [0.46, 0.78] <0.0001 Hospitalization for PAH 78 13.6 109

18.7Other disease progression (Decrease in 6MWD plus worsening functional class or need for other therapy) 38 6.6 100

17.2Death 28 4.9 18

3.1Parenteral prostanoid or chronic oxygen therapy 10 1.7 13

2.2PAH worsening resulting in need for lung transplantation or balloon atrial septostomy 1 0.2 2

0.3It is not known if the excess number of deaths in the UPTRAVI group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON. Figures 4A, B, and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C) all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label UPTRAVI at this point). Figure 4A Hospitalization for PAH as the First Endpoint in GRIPHON Figure 4B Disease Progression as the First Endpoint in GRIPHON Figure 4C Death as the First Endpoint in GRIPHON The treatment effect of UPTRAVI on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with an ERA, PDE-5i, both, or without background therapy) (Figure 5).

Figure 5 Subgroup Analyses of the Primary Endpoint in GRIPHON Note: Race group "Ot… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: In the 2-year carcinogenicity studies, chronic oral administration of selexipag revealed no evidence of carcinogenic potential in rats at 100 mg/kg/day and mice at 500 mg/kg/day which resulted in the exposures to the active metabolite more than 25 times the human exposure at the maximum recommended human oral dose of 1,600 mcg twice daily on an AUC basis. Mutagenesis: Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted genotoxicity studies.

Fertility: In rats administered with selexipag orally, the no effect dose for effects on fertility was 60 mg/kg/day which resulted in the exposure to the active metabolite approximately 175 times the human exposure at the maximum recommended human oral dose of 1,600 mcg twice daily on an AUC basis.