Selexipag for the Treatment of Pulmonary Arterial Hypertension

Abstract

BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P&lt;0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain. CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).<p>Laila Hübbert vid avdelningen för kardiovaskulär medicin samt Kardiologiska kliniken US, tillhör "GRIPHON Investigators".</p

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

“…The nonprostanoid IP receptor agonist, MRE-269 and its prodrug form, selexipag, which were developed to circumvent these limitations, have an extended elimination half-life (over 4 h in rats) (14) and a binding affinity for the human IP receptor that is 130-fold greater than that for other human prostanoid receptors (20). In the phase 3 GRIPHON (Prostacyclin [PGI 2 ] Receptor Agonist in Pulmonary Arterial Hypertension) study, selexipag treatment reduced the occurrence of the primary end point of death from any cause or a complication related to pulmonary arterial hypertension (hazard ratio 0.60; 99% CI 0.46-0.78; P , 0.001) (16). Adverse events typical of prostacyclin therapies (e.g., headache, diarrhea, and nausea) occurred more frequently with selexipag and were generally mild to moderate, with only a minority leading to discontinuation of therapy (16).…”

“…In the phase 3 GRIPHON (Prostacyclin [PGI 2 ] Receptor Agonist in Pulmonary Arterial Hypertension) study, selexipag treatment reduced the occurrence of the primary end point of death from any cause or a complication related to pulmonary arterial hypertension (hazard ratio 0.60; 99% CI 0.46-0.78; P , 0.001) (16). Adverse events typical of prostacyclin therapies (e.g., headache, diarrhea, and nausea) occurred more frequently with selexipag and were generally mild to moderate, with only a minority leading to discontinuation of therapy (16). Whether the advancement in small-molecule therapeutics will affect the development of new agents for nonrespiratory diseases remains to be seen.…”

Age, risk and outcomes in idiopathic pulmonary arterial hypertension

“…Such patients were not well represented in PAH studies. Some of the recent clinical trials in PAH had an upper age limit of 75 years, and the average age of the enrolled patients ranged from 48 to 54 years [20,21]. Hence, most of the available data on treatment responses in older patients have been derived from registries.…”

Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension

“…The main analysis showed that the magnitude of improvement in the 6‐MWD (10 to 36 m, 12 m difference between placebo and selexipag at week 26 across doses6) was in the lower range of 6‐MWD observed in other randomized, controlled trials. The PK/PD modeling yielded consistent results: a reference patient was predicted to have a 6‐MWD of 369 m with no exposure (placebo) and 392 m at the highest exposure.…”