Selexipag, an orally available IP receptor agonist, in the treatment of pulmonary arterial hypertension: current evidence and future prospects

Introduction: Despite remarkable advances achieved with the introduction of specific treatments, the long-term prognosis of pulmonary arterial hypertension (PAH) remains poor. Parenteral prostacyclins provide a survival benefit. Oral medications acting on the prostacyclin pathway have been an unmet need for patient management.Areas covered: Selexipag has high specificity for the IP receptor and its active metabolite (ACT- 333679, or MRE-269) has a prolonged half-life of 9.4–12.6 h permitting dosing twice daily. The addition of selexipag to combination or as monotherapy resulted in a 40% reduction of the combined primary end point of a complication related to PAH. Selexipag is being currently evaluated in a randomized controlled trial of an initial triple oral treatment (TRITON trial, Clinicaltrials.gov NCT02558231) in newly diagnosed, treatment-naïve patients with PAH.Expert opinion: With selexipag approved, triple oral combination therapy addressing three important pathways will be available for patients with PAH. Still, important gaps of knowledge are: Which has the better efficacy versus side-effect profile in chronic treatment: selexipag and oral treprostinil? Is selexipag able to substitute for parenteral prostacyclins? Is there a way to uptitrate selexipag beyond 2x 1600 µg per day? If not, how can ‘receptor desensitization’ be overcome in long-term treatment?