Mechanism of Action of Selexipag
Selexipag is an orally available, selective prostacyclin IP receptor agonist that is chemically distinct from prostacyclin, working through IP receptor agonism to produce vasodilation, anti-proliferation, and anti-platelet effects. 1
Molecular Pharmacology
Selexipag itself is a prodrug that is rapidly hydrolyzed by carboxylesterase 1 to yield its active metabolite (ACT-333679/MRE-269), which is approximately 37-fold more potent than the parent compound. 1, 2
Both selexipag and its active metabolite are highly selective for the prostacyclin IP receptor, demonstrating selectivity over other prostanoid receptors including EP1-4, DP, FP, and TP receptors. 1, 3
The chemical structure of selexipag is distinct from endogenous prostacyclin and prostacyclin analogs (prostanoids), making it the first non-prostanoid prostacyclin pathway agonist. 4, 5
Physiologic Effects
The IP receptor agonism produces three primary therapeutic effects: 1, 3
Pulmonary vasodilation: Potent vasodilatory effects occur in both extralobar and small intralobar pulmonary arteries, reducing pulmonary vascular resistance 3
Anti-proliferative effects: Inhibition of pulmonary arterial smooth muscle cell proliferation, addressing the vascular remodeling component of PAH 3
Anti-platelet aggregation: Concentration-dependent inhibition of platelet aggregation, though at clinically relevant concentrations this effect is minimal 1
Hemodynamic Impact
In Phase 2 studies, selexipag achieved a statistically significant mean reduction in pulmonary vascular resistance of 30.3% (95% CI −44.7%, −12.2%) and increased cardiac index by 0.41 L/min/m² (95% CI 0.10,0.71) compared to placebo after 17 weeks of treatment. 1
In preclinical PAH models (Sugen 5416/hypoxia rat model), selexipag significantly improved pulmonary artery obstruction, decreased right ventricular systolic pressure, decreased right ventricular hypertrophy, and improved survival rates. 3
Clinical Significance of Mechanism
The selective IP receptor agonism addresses one of the three well-established pathways in PAH pathogenesis (prostacyclin pathway), alongside the endothelin and nitric oxide pathways. 4
The long half-life of the active metabolite permits twice-daily oral dosing, providing significant convenience advantages over continuous infusion prostacyclin analogs while maintaining therapeutic plasma concentrations. 1, 5, 2
The mechanism translates to clinical benefit: in the GRIPHON trial of 1,156 patients, selexipag reduced the composite morbidity/mortality endpoint by 40% (hazard ratio 0.60, P < 0.001), demonstrating that IP receptor agonism effectively delays PAH disease progression. 4, 3