SUMMARY

• In a phase 3 study (GRIPHON) with a safety population of 1152 patients with pulmonary arterial hypertension (PAH; randomized 1:1), anemia was reported in 48 (8.3%) UPTRAVI-treated patients and 31 (5.4%) placebo-treated patients.¹
• A hemoglobin <8 g/dL was reported in 7 (1.3%) UPTRAVI-treated patients and 4 (0.7%) placebo-treated patients.¹
• No patients in GRIPHON discontinued treatment due to an anemia adverse event.¹
• In the open-label extension of GRIPHON with a median exposure to UPTRAVI of 31.7 months, 108 (11.3%) UPTRAVI-treated patients experienced anemia.²
• In the double-blind, placebo-controlled, phase 3b study (TRITON) that evaluated the efficacy and safety of initial triple oral therapy with UPTRAVI, macitentan, and tadalafil compared with initial double oral therapy with macitentan and tadalafil in newly diagnosed, treatment-naïve patients with PAH, 13.4% (16/119) of patients in initial triple therapy group and 8.7% (11/127) of patients in the initial double therapy group experienced anemia, respectively.^3,4
• A real-world analysis assessed the safety profile of UPTRAVI using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Decreased hemoglobin levels were noted in 218 patients, with the median time to onset of 48 (interquartile range [IQR], 8-161) days; the reporting odds ratio (ROR) was 2.36 (95% confidence interval [CI], 2.07-2.70).⁵
• The management of anemia in patients treated with UPTRAVI is at the discretion of the treating physician.
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

CLINICAL DATA

GRIPHON Study

The GRIPHON phase 3 study (Prostacyclin [PGI₂] Receptor agonist In Pulmonary arterial HypertensiON; AC-065A302) was a multicenter, double-blind, parallel group, placebo-controlled event-driven trial evaluating the efficacy and safety of oral UPTRAVI in adult patients with WHO Group 1 PAH.¹ Patients with symptomatic PAH (N=1156) were randomized 1:1 to receive UPTRAVI (n=574) or placebo (n=582) twice daily. The median duration of study treatment was 70.7 weeks and 63.7 weeks for patients who received UPTRAVI or placebo, respectively.

Anemia was reported in 48 (8.3%) UPTRAVI-treated patients and 31 (5.4%) placebo-treated patients.¹ In addition, iron deficiency anemia was reported in 5 (<1%) UPTRAVI-treated patients and 15 (3%) placebo-treated patients. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with UPTRAVI and 5.0% of placebo-treated patients. A decrease in hemoglobin concentration to below 8 g/dL was reported in 7 (1.3%) UPTRAVI-treated patients and 4 (0.7%) placebo-treated patients.¹

The incidences of anemia AEs were 10.6% (53/498) and 8.3% (41/493) in the UPTRAVI and placebo groups, respectively. In an analysis of patients with vitamin K antagonist (VKA) therapy at baseline, a hemoglobin decrease to ≤8 g/dL was reported in 1.8% (5/292) and 0.4% (1/283) in the UPTRAVI and placebo groups, respectively, and anemia was reported in 8.9% (26/292) and 5.3% (15/283) in the corresponding groups.⁶ In patients without VKA therapy at baseline, a hemoglobin decrease to ≤8 g/dL was reported in 0.7% (2/283) and 1.0% (3/294) in the UPTRAVI and placebo groups, respectively, and anemia was reported in 7.8% (22/283) and 5.4% (16/294) in the corresponding groups.

No patients in the study discontinued treatment due to an anemia adverse event.¹

In the open-label extension study of GRIPHON, 953 patients treated with UPTRAVI were included in the safety/tolerability set with a median (min, max) exposure to UPTRAVI of 31.7 (0.0, 106.0) months. A total of 108 (11.3%) patients experienced anemia with an incidence rate of 3.9 incidences per year per 100 treated patients. No data was reported regarding hemoglobin decrease.²

TRITON Study

TRITON was a multicenter, double-blind, randomized, placebo-controlled, phase 3b study that evaluated the efficacy and safety of initial triple oral therapy with UPTRAVI, macitentan, and tadalafil compared with initial double oral therapy with macitentan and tadalafil in newly diagnosed, treatment-naïve patients with PAH. Two hundred forty-seven patients were randomized 1:1 to initial triple therapy (n=123) or initial double therapy (n=124). Patients received UPTRAVI or matching placebo, at a starting dose of 200 mcg BID from day 15, gradually up titrated until the individual highest tolerated dose was attained (maximum up to 1600 mcg BID), until the end of the main observation period (when the last patient randomized reached week 26). The median follow-up duration was 77.6 weeks and 75.8 weeks in the initial triple therapy and initial double therapy groups, respectively.³

Safety Results

In the safety analysis set observed between the start of the first dose of study medication until the last dose of study medication plus 30 days or at the end of the main observation period (whichever occurred earlier), 13.4% (16/119) of patients in initial triple therapy group and 8.7% (11/127) of patients in the initial double therapy group experienced anemia, respectively.⁴

Real-World Evidence

Zhao et al (2023)⁵ conducted a real-world analysis that assessed the safety profile of UPTRAVI using the FAERS database. One of the commonly reported adverse events (AEs) with UPTRAVI treatment was decreased hemoglobin levels (n=218), with the median time to onset of 48 (IQR, 8-161) days; the ROR was 2.36 (95% CI, 2.07-2.70).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 27 December 2024.