SUMMARY

• The Phase 3 GRIPHON trial evaluated the long-term efficacy and safety of UPTRAVI tablets in 1156 patients with pulmonary arterial hypertension (PAH).¹ 
  • Bleeding events were adjudicated by an independent committee.¹ 
  • The incidence of treatment-emergent adverse events related to hemorrhage was similar between the UPTRAVI (15.7%) and placebo (15.8%) groups.² 
  • The incidence of treatment-emergent adverse events related to major hemorrhage was similar between the UPTRAVI (2.4%) and placebo (2.1%) groups.¹ 
• Additional data from other randomized controlled trials, uncontrolled trials, and a real-world registry study are described below.^3-9

CLINICAL DATA

Information from GRIPHON

Overall Study Design

GRIPHON (Prostacyclin [PGI₂] Receptor Agonist In Pulmonary Arterial HypertensiON) 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).¹ 

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.¹⁰

Treatment-emergent AEs denoting hemorrhage

Reports denoting hemorrhage during the GRIPHON study were analyzed as AEs of special interest.^2,11 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.^1,2,10 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.² 

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%) and 12/577 (2.1%) in the UPTRAVI and placebo groups, respectively (P=0.70).¹

Information from Additional Randomized Placebo-Controlled Clinical Trials 

Additional Clinical Data from Other Uncontrolled Studies

Information from SPHERE

SPHERE (SelexiPag tHe usErs dRug rEgistry) is a US-based, multicenter, prospective, observational, real-world registry that was established with the objective of assessing the real-world outcomes of UPTRAVI treatment of adult patients in the US. UPTRAVI was initiated at 200 mcg BID until the highest tolerated dose (up to a maximum of 1600 mcg BID) was attained. Of the total 829 patients, 759 had PAH (WHO group 1).^9,22 

The incidence of bleeding-related adverse events reported in the overall patient population (N=829) enrolled in table: Incidence of Treatment-emergent Adverse Events of Bleeding Events in SPHERE.²³

The SPHERE study has several limitations primarily associated with its observational nature. Similar to other observational studies, it experiences a higher rate of missing data compared to clinical trials, which can affect the interpretation of findings. However, these incomplete records are reflective of real-world clinical practice. Additionally, SPHERE exclusively recruits patients receiving selexipag, which means there is no comparator group available for evaluating relative treatment effects.^9,22 

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 April 2025.