SUMMARY

• During research and development, in vitro experiments¹ and a phase 1 study² investigated the potential for selexipag and its active metabolite, ACT-333679, to inhibit platelet aggregation. In the phase 3 GRIPHON (Prostacyclin [PGI₂] Receptor Agonist In Pulmonary Arterial HypertensiON) trial, bleeding events were adjudicated by an independent committee.³   
• Data from in vitro studies with plasma from humans and monkeys suggest that selexipag and its active metabolite, ACT-333679, inhibit platelet aggregation. In human plasma, platelet aggregation IC₅₀ values were 5.5±0.8 µM for selexipag and 0.21±0.04 µM for ACT-333679, compared to 0.019±0.002 µM for the prostacyclin analog beraprost.¹ 
• Results from the Phase 1 study² showed no consistent change in platelet aggregation across selexipag oral doses ranging from 400–1800 mcg twice daily (BID) at steady state. At the highest dose (1800 mcg BID), the maximum plasma concentrations (C_max) of selexipag (0.025 µM) and ACT-333679 (0.051 µM)² were well below platelet aggregation IC₅₀ values observed in the human plasma in vitro studies.¹ 
• Reports of adverse events (AEs) denoting hemorrhage during the GRIPHON study were analyzed. Overall, the proportion of patients with hemorrhage AEs was similar in the UPTRAVI group (90/575; 15.7%) compared to the placebo group (91/577; 15.8%).⁴
• Overall, while in vitro studies suggest selexipag has the potential to inhibit platelet aggregation in humans, clinical data indicate that, at therapeutic doses, there was no increased risk of major bleeding with UPTRAVI.
• Administration of doses not specified in the UPTRAVI product label is not recommended.

BACKGROUND

Selexipag (ACT-293987, formerly known as NS-304) is a selective agonist for the prostacyclin receptor (IP receptor). It was studied in the GRIPHON trial for the treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group I) and was found to delay disease progression and reduce the risk of hospitalization for PAH.³  It is chemically distinct from prostacyclin/PGI₂ and PGI₂ analogs.¹  Hydrolysis of selexipag yields the active metabolite ACT-333679, a highly selective, long-acting, agonist of the IP receptor.^1,5,6 The binding affinity of ACT-333679 (formerly known as MRE-269) for the human IP receptor is at least 130-fold higher compared with its affinity for other prostanoid receptors.¹ 

NONCLINICAL DATA

Information from in vitro experiments

Kuwano et al (2007) conducted in vitro experiments in which a potential inhibitory effect of selexipag on platelet aggregation, induced by 10 μM adenosine 5’-diphosphate (ADP), was investigated in platelet-rich plasma from humans, monkeys, dogs and rats. The results of these assessments, expressed as IC₅₀ values, are given in Table: Inhibitory potential of selexipag on platelet aggregation in plasma from humans, monkeys, dogs and rats, expressed as IC₅₀ (μM).^1,7 

The human IC₅₀ values for platelet aggregation (standard error of the mean) were 5.5±0.8 μM for selexipag and 0.21±0.04 μM for the active metabolite, ACT-333679. In comparison, the IC₅₀ value for the prostacyclin analog, beraprost was 0.019±0.002 μM¹  (Table: Inhibitory potential of selexipag on platelet aggregation in plasma from humans, monkeys, dogs and rats, expressed as IC50 [μM]).

In another in vitro study, platelet aggregation induced by 10 μM ADP was inhibited in a concentration-dependent manner, with an IC₅₀ value of 4.7 μM for selexipag and 0.12 μM  for ACT-333679.⁸ 

CLINICAL DATA

Information from Phase 1 study AC-065-101

The safety, tolerability and pharmacokinetic and pharmacodynamic properties of selexipag (400–1800 mcg; BID at steady state) in healthy male subjects (n=16), were investigated in a double-blind, placebo-controlled, randomized Phase 1 study. Pharmacodynamic assessments included measuring the effect of multiple ascending oral doses of selexipag on ADP-induced platelet aggregation ex vivo at steady state. The observed effects on platelet aggregation were variable without an obvious drug- or dose-dependent pattern.^2,8 

In this study, the maximum plasma concentrations (C_max, geometric mean) of selexipag and ACT˗333679 for the 1800 mcg BID dose at steady-state were 0.025 μM and 0.051 μM, respectively.² These C_max values are lower than the platelet aggregation IC₅₀ values that were determined for selexipag and ACT-333679 in in vitro studies.^1,2  Thus, multiple-dose administrations of selexipag in healthy subjects had no relevant effect on platelet aggregation test parameters across doses from 400 mcg up to 1800 mcg BID.⁴ 

Information from GRIPHON

Overall Study Design

The GRIPHON (Prostacyclin [PGI₂] Receptor Agonist In Pulmonary Arterial HypertensiON) study was a randomized, multicenter, double-blind, placebo-controlled, event-driven Phase 3 study designed to evaluate the long-term efficacy, safety and tolerability of UPTRAVI tablets in patients with symptomatic PAH. UPTRAVI or matching placebo was initiated at 200 mcg BID and up-titrated weekly in increments of 200 mcg BID until the individual highest tolerated dose was attained (ranging from 200–1600 mcg BID).³ 

A total of 1156 patients were enrolled in the study across 181 centers and 39 countries. Among 1156 patients randomized 1:1 to either UPTRAVI or placebo, four patients did not receive study drug, so the safety analysis set comprised 1152 patients.^3,9 

Treatment-emergent AEs denoting hemorrhage

Reports denoting hemorrhage during the GRIPHON study were analyzed as AEs of special interest.^4,10 A committee of 2 external expert medical reviewers, who were blinded to study treatment assignment, independently adjudicated each bleeding event as major or non-major according to International Society on Thrombosis and Hemostasis (ISTH) criteria.^3,4,9 The proportion of patients who had at least 1 AE denoting hemorrhage was 90/575 (15.7%) and 91/577 (15.8%) in the UPTRAVI and placebo groups, respectively.⁴ 

There was no increased risk of major bleeding with UPTRAVI, as shown by no significant difference in the frequency of adjudicated major bleeding events: 14/575 (2.4%) patients and 12/577 (2.1%) in the UPTRAVI and placebo groups, respectively (P=0.70).³

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 December 2024.