Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension

Abstract

In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH).43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-mg increments from 200 mg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 mg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results.A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7--12.2; p50.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect.Our results encourage the further investigation of selexipag for the treatment of PAH.

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

“…eNOS has been shown to protect against STZ-induced diabetes, possibly through increased islet sensitivity or altered drug uptake through changes in vascular permeability and pancreatic blood flow, although the precise mechanisms have not been defined (36). In our studies, we found that treatment of STZ-eNOS 2/2 mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria without affecting other indices of podocyte injury or blood pressure, the latter effect being consistent with observations from clinical trials of selexipag in people with pulmonary arterial hypertension (46). Whether augmentation of nephrin phosphorylation in the setting of podocyte loss can preserve renal function in patients has yet to be determined.…”

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…Although selexipag and its metabolite have modes of action similar to that of endogenous prostacyclin (IP receptor agonism), they are chemically distinct from prostacyclin with a different pharmacology. In a pilot RCT in PAH patients (receiving stable ERA and/or PDE-5i therapy), selexipag reduced PVR after 17 weeks [241]. An event-driven phase 3 RCT that enrolled 1156 patients [248] has shown that selexipag alone or on top of mono-or double therapy with ERAs and/or PDE-5i was able to reduce by 40% (hazard ratio 0.60, P < 0.0001) a composite morbidity and mortality endpoint (including death from all causes, hospitalization for worsening of PAH, worsening of PAH resulting in the need for lung transplantation or atrial septostomy, initiation of parenteral prostanoids or chronic O 2 for worsening of PAH and disease progression).…”

Selexipag for the treatment of pulmonary arterial hypertension

“…[9] Selexipag: clinical efficacy Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where participants were randomized in a 3:1 ratio to selexipag or placebo. [10] The study demonstrated a 30.3% improvement in pulmonary vascular resistance (p = 0.0045) and a numerical increase in 6MWT of 24.2 m in participants already receiving a PDE-5i (27.2%), ERA (36.4%) or PDE-5i/ERA combination treatment (36.4%).…”