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Pharmacology: Pharmacodynamics: Mechanism of action: The vasculo-protective effects of prostacyclin (PGI2) are mediated by the prostacyclin receptor (IP receptor). Decreased expression of IP receptors and decreased synthesis of prostacyclin contribute to the pathophysiology of pulmonary arterial hypertension (PAH).
Selexipag is an oral, selective, IP prostacyclin receptor agonist, and is structurally and pharmacologically distinct from prostacyclin and its analogues. Selexipag is hydrolysed by carboxylesterases to yield its active metabolite, which is approximately 37-fold more potent than selexipag. Selexipag and the active metabolite are high affinity IP receptor agonists with a high selectivity for the IP receptor versus other prostanoid receptors (EP1-EP4, DP, FP and TP). Selectivity against EP1, EP3, FP and TP is important because these are well-described contractile receptors in gastrointestinal tract and blood vessels. Selectivity against EP2, EP4 and DP1 is important because these receptors mediate immune depressive effects.
Stimulation of the IP receptor by selexipag and the active metabolite leads to vasodilatory as well as anti-proliferative and anti-fibrotic effects. Selexipag improves haemodynamic parameters and prevents cardiac and pulmonary remodeling in a rat model of PAH. In these PAH rats, pulmonary and peripheral vasodilation in response to selexipag correlate, indicating that peripheral vasodilation reflects pulmonary pharmacodynamic efficacy. Selexipag does not cause IP receptor desensitisation in vitro nor tachyphylaxis in a rat model.
PAH patients have variable degrees of IP receptor expression. Differences in maintenance dose of selexipag between individuals may be related to differences in IP receptor expression levels.
Cardiac electrophysiology: In a thorough QT study in healthy subjects, repeated doses of 800 and 1600 micrograms of selexipag twice daily did not show an effect on cardiac repolarisation (the QTc interval) or conduction (PR and QRS intervals) and had a mild accelerating effect on heart rate. The placebo-corrected increase from time-matched baseline heart rate 1.5 to 3 hours post-dose was 6-7 bpm at 800 μg twice daily and 9-10 bpm at 1600 μg twice daily.
Pulmonary Haemodynamics: A Phase 2 double-blind, placebo-controlled clinical study assessed haemodynamic parameters after 17 weeks of treatment in patients with PAH WHO functional classes II–III and concomitantly receiving ERAs and/or PDE-5 inhibitor. Patients titrating selexipag to an individually tolerated dose (200 micrograms twice daily increments up to 800 micrograms twice daily; N=33) achieved a statistically significant mean reduction in pulmonary vascular resistance of 30.3% (95% CL -44.7%, -12.2%; P = 0.0045) and an increase in cardiac index (mean treatment effect) 0.48 L/min/m2, 95% CL 0.13, 0.83 compared to placebo (N=10).
Clinical trials: Efficacy in Patients with Pulmonary Arterial Hypertension: The effect of selexipag on progression of PAH was demonstrated in a multi-centre, long-term (mean duration of exposure was approximately 1.5 years up to a maximum of 4.2 years), double-blind, placebo-controlled, parallel group, event-driven Phase 3 study (GRIPHON) in 1156 patients with symptomatic [WHO Functional Class (FC) I-IV] PAH. Patients were randomised to either placebo (N=582), or selexipag (N=574) twice a day in multiples of 200 micrograms. The dose was increased in weekly intervals by increments of 200 micrograms given twice a day to determine the individualised maintenance dose (200 - 1600 micrograms twice a day).
The primary study endpoint was the time to first occurrence of a morbidity or mortality event up to end of treatment defined as a composite of death (all-causes); or hospitalisation for PAH; or progression of PAH resulting in need for lung transplantation or balloon atrial septostomy; or initiation of parenteral prostanoid therapy or chronic oxygen therapy; or other disease progression events (patients in modified NYHA/WHO FC II or III at baseline) confirmed by decrease in 6MWD from baseline (≥ 15%) and worsening of NYHA/WHO FC or (patients in modified NYHA/WHO FC III or IV at baseline) confirmed by decrease in 6MWD from baseline (≥ 15%) and need for additional PAH specific therapy.
All events were confirmed by an independent adjudication committee, blinded to treatment allocation.
The mean age was 48.1 years (range 18-80 years of age) with the majority of subjects being Caucasian (65.0%) and female (79.8%). Approximately 1%, 46%, 53%, and 1% of patients were in WHO FC I, II, III, and IV, respectively, at baseline of whom three patients in WHO FC IV received selexipag.
Idiopathic or heritable PAH was the most common aetiology in the study population (58%) followed by PAH due to connective tissue disorders (29%), PAH associated with congenital heart disease with repaired shunts (10%), and PAH associated with other aetiologies (drugs and toxins [2%] and HIV [1%]). Patients with left ventricular dysfunction, moderate or severe obstructive or restrictive lung disease, moderate or severe hepatic impairment, or severe renal insufficiency were excluded from the study.
At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of specific therapy for PAH, either with an ERA (15%) or with a PDE-5 inhibitor (32%) or both an ERA and a PDE-5 inhibitor (33%).
Patients on selexipag achieved doses within the following groups: 200-400 micrograms (23%), 600-1000 micrograms (31%) and 1200-1600 micrograms (43%).
The overall median double-blind treatment duration was 63.7 weeks for placebo group and 70.7 weeks for the group on selexipag.
Treatment with selexipag 200-1600 micrograms twice a day resulted in a 40% reduction (99% confidence interval [CI]: 22 to 54%; two-sided-sided log rank p-value <0.0001) of the occurrence of morbidity or mortality events up to 7 days after last dose compared to placebo (Figure 1). The beneficial effect of selexipag was primarily attributable to a reduction in hospitalisation for PAH and a reduction in other disease progression events (Table 1). (See Figure 1 and Table 1).
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Click on icon to see table/diagram/imageThe observed benefit of selexipag was similar regardless of the dose achieved when patients are titrated to their highest tolerated dose (see Dosage & Administration). This was shown by the hazard ratio for the 3 pre-defined categories (0.60 for 200-400 micrograms twice daily, 0.53 for 600-1000 micrograms twice daily, and 0.64 for 1200-1600 micrograms twice daily), which was consistent with the overall treatment effect (0.60).
It is not known if the excess number of deaths in the selexipag group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON. Figures 2, 3 and 4 show time to first event analyses for primary endpoint components of hospitalisation for PAH (2), other disease progression (3), and death (4)-all censored 7 days after any primary endpoint event (because many patients on placebo transitioned to open-label UPTRAVI at this point). (See Figures 2, 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThe total number of deaths of all causes up to study closure was 100 (17.4%) for the UPTRAVI group and 105 (18.0%) for the placebo group (HR 0.97, 99% CI: 0.68-1.39).
The number of deaths due to PAH up to study closure was 70 (12.2%) for the UPTRAVI group and 83 (14.3%) for the placebo group.
Subgroup analyses were performed across subgroups of age, sex, race, aetiology, geographical region, WHO Functional Class, and by monotherapy or in combination with ERA, PDE-5 inhibitors or triple combination with both an ERA and a PDE-5 inhibitor. The treatment effect of UPTRAVI on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with ERA, PDE-5 inhibitors, or both, or without background therapy) (Figure 5). (See Figure 5.)
Click on icon to see table/diagram/imageSymptomatic endpoint: Exercise capacity was evaluated as a secondary endpoint. Treatment with UPTRAVI resulted in a placebo-corrected median increase in 6MWD measured at trough (i.e., approximately 12 hours post-dose) of 12 metres at Week 26 (99% CI: 1 - 24, two-sided p-value=0.005). In patients without concurrent PAH-specific therapy, the treatment effect measured at trough was 34 metres (99% CI: 10.0-, 63.0 one-sided p-value=0.0002).
Long-Term Treatment of PAH: In long-term follow up of patients who were treated with UPTRAVI in the pivotal study and the open-label extension (N=574), Kaplan-Meier estimates of survival of these patients across the GRIPHON study and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%, respectively. The median exposure to UPTRAVI was 3 years. These uncontrolled observations do not allow comparison with a control group not given UPTRAVI and cannot be used to determine the long-term effect of UPTRAVI on mortality.
Pharmacokinetics: The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, both after single- and multiple-dose administration, were dose-proportional up to a single dose of 800 micrograms and multiple doses of up to 1800 micrograms twice a day. After multiple-dose administration, steady-state conditions of selexipag and active metabolite were reached within 3 days. No accumulation in plasma, either of parent compound or active metabolite, occurred after multiple-dose administration.
In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval) at steady-state 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.
Exposure to selexipag and the active metabolite at steady-state was 30% and 20% higher, respectively, in PAH patients compared to healthy subjects. 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.
Absorption: Selexipag is rapidly absorbed and is hydrolysed by carboxylesterases to its active metabolite.
Maximum observed plasma concentrations of selexipag and its active metabolite after oral administration are reached within 1-3 h and 3-4 h, respectively.
The absolute bioavailability of selexipag is approximately 49%.
In the presence of food, the exposure to selexipag after a single dose of 400 micrograms was increased by 10% in Caucasian subjects and decreased by 15% in Japanese subjects, whereas exposure to the active metabolite was decreased by 27% (Caucasian subjects) and 12% (Japanese subjects). More subjects reported adverse events after administration in the fasted than in the fed state.
Distribution: 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).
The volume of distribution of selexipag at steady state is 11.7 L.
Biotransformation: Selexipag is hydrolysed to yield the active metabolite in the liver and in the intestine by carboxylesterases. Oxidative metabolism catalysed 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. Both in healthy subjects and PAH patients, after oral administration, exposure at steady-state to the active metabolite is approximately 3- to 4-fold higher than to the parent compound.
Elimination: Elimination of selexipag is predominantly via metabolism with a mean terminal half-life of 0.8-2.5 h. The active metabolite has a half-life of 6.2-13.5 h. The total body clearance of selexipag is 17.9 L/h. Excretion in healthy subjects was complete 5 days after administration and occurred primarily via faeces (accounting for 93% of the administered dose) compared to 12% in urine.
Special 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. In PAH patients, the exposure to selexipag and ACT-333679 decreased 9% and 4%, respectively, with increasing age from 23 to 72 years. PAH patients with body weights of 51 (96) kg showed 30% higher (20% lower) exposure to selexipag and 20% higher (10% lower) exposure to ACT-333679 compared to patients of 70 kg body weight. PAH male patients showed 13% lower exposure to ACT-333679 than female patients. These differences are smaller than the intersubject variability, which is larger than 30%.
Renal impairment: The AUC0-∞ values of selexipag and ACT-333679 were increased 1.73-fold and 1.61-fold, respectively, in subjects with severe renal function impairment (SRFI) compared to healthy subjects, and the t½ of ACT-333679 was prolonged 1.61-fold in patients with SRFI.
Hepatic impairment: In subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, after a single dose administration of 400 mcg of selexipag exposure to selexipag was 2- and 4-fold higher, respectively, when compared to healthy subjects. Exposure to the active metabolite remained almost unchanged in subjects with mild hepatic impairment and was doubled in subjects with moderate hepatic impairment. Only two subjects with severe (Child-Pugh C) hepatic impairment were dosed with selexipag. Exposure to selexipag and its active metabolite in these two subjects was similar to that in subjects with moderate (Child-Pugh B) hepatic impairment.
Based on pharmacokinetic modelling of data from a study in subjects with hepatic impairment, the exposure to the active metabolite at steady state in subjects with moderate hepatic impairment (Child-Pugh class B) after a once-daily regimen is expected to be similar to that in healthy subjects receiving a twice-daily regimen. The exposure to selexipag at steady state in subjects with moderate hepatic impairment during a once-daily regimen is predicted to be approximately 2-fold that seen in healthy subjects receiving a twice-daily regimen.
Toxicology: Preclinical Safety Data: Genotoxicity: Selexipag and its active metabolite are not genotoxic under in vivo conditions. The weight of evidence from a battery of genotoxicity studies indicates no cause for clinical concern.
Carcinogenicity: In 2-year carcinogenicity studies, selexipag produced possible increases in the incidences of thyroid adenomas in mice and Leydig cell adenomas in rats. The induction of such tumours is thought to reflect unique aspects of rodent biology that are not relevant to humans.
