Background: This review focuses on the treatment of pulmonary arterial hypertension (PAH) with
selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues.
Methods: We searched the relevant literature and summarized the current clinical trials concerning selexipag and
Results: With only few cases per million, PAH is a rare disease, but when untreated it can be life-threatening.
PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin
(PGI2). PAH-specific therapeutic approaches concentrate on these characteristics with drugs targeting the endothelin-
receptor (e.g. bosentan), phosphodiesterase-5 (e.g. sildenafil) or the prostacyclin-receptor (e.g. treprostinil).
Recently, the new drug selexipag acting as a non-prostanoid IP2-receptor agonist has been approved for PAH
therapy. The active form of selexipag (ACT-333679) was designed by the help of a medicinal chemistry program
and it was further modified by replacing the terminal carboxyl group with an N-acylsulfonamide group to form
the more stable oral drug, selexipag. Selexipag has a high selectivity for the IP2-receptor and differs from conventional
prostacyclin analogues in its chemical structure. In the GRIPHON trial selexipag was demonstrated to
significantly improve the primary composite endpoint of death or complications related to PAH (hazard ratio 0.6,
99% confidence interval, 0.46 to 0.78; P < 0.001) as well as exercise capacity in the form of the 6-minute walk
distance (12.0 m treatment effect, 99% confidence interval, 1 to 24; P = 0.003). However, no significant reduction
in all-cause mortality was achieved. Selexipag has also shown promising results in combination therapy with
phosphodiesterase-5 inhibitors (PDE-5i) and/or endothelin receptor antagonists (ERA). The most common adverse
effects (AEs), associated with selexipag, are headache, diarrhea, jaw pain, and nausea. Nevertheless,
Selexipag was generally well tolerated during the GRIPHON trial.
Conclusions: Selexipag is a valuable addition to PAH therapeutics especially by reducing the PAH-related hospitalizations
and thus improving quality of life in PAH patients.