SUMMARY

• The phase 3 GRIPHON trial was conducted to evaluate the long-term safety and efficacy of UPTRAVI in patients with symptomatic pulmonary arterial hypertension (PAH). In this event-driven study, UPTRAVI significantly reduced the risk of a morbidity/mortality event by 40% compared with placebo. The most common adverse events (AEs) in GRIPHON that occurred with higher frequency on UPTRAVI compared with placebo were: headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing.¹
• At baseline, 110 patients (10%) were classified as PAH associated with congenital heart disease (PAH-CHD) in GRIPHON. PAH-CHD is one of the most common forms of associated PAH and includes patients with repaired congenital cardiac shunts. Additionally, data from randomized controlled trials are limited.²
• A subgroup analysis showed that the treatment effect of UPTRAVI in PAH-CHD (corrected defects) patients was consistent with its efficacy in the overall GRIPHON study population.²
• Consistent with the overall PAH study population, UPTRAVI was generally well-tolerated in patients with PAH-CHD over the long duration of treatment. The frequency of AEs was similar across the placebo and UPTRAVI treatment groups.²
• A search of the scientific literature retrieved single-center studies^3-5 that described the use of UPTRAVI in patients with PAH-CHD; relevant information from these publications is summarized in this letter.
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^6,7

CLINICAL DATA

Phase 3 Study: GRIPHON

The phase 3 study GRIPHON (Prostacyclin [PGI₂] Receptor agonist In Pulmonary arterial HypertensiON; AC-065A302) was a multicenter, double-blind, parallel group, placebocontrolled event-driven trial evaluating the efficacy and safety of oral UPTRAVI in adult patients with World Health Organization (WHO) Group 1 PAH. The primary endpoint of GRIPHON was to demonstrate the effect of UPTRAVI on the time to first morbidity or mortality event. A primary endpoint event was any of the following: death (all-cause), hospitalization for worsening of PAH, worsening of PAH resulting in need for lung transplantation or atrial septostomy, initiation of intravenous (IV) or subcutaneous (SC) prostanoids or chronic oxygen therapy for worsening of PAH, or disease progression events. For WHO functional class (FC) II or III, “disease progression event” was defined as a decrease in 6-minute walk distance (6MWD; ≥15% from baseline, confirmed by 2 tests on different days within 2 weeks) and worsening in FC. For WHO FC III or IV, “disease progression events” was defined as a decrease in 6MWD and a need for additional PAH treatment. All events were adjudicated by a blinded, independent critical event committee. Select secondary endpoints included change in 6MWD (measured at trough) from baseline to week 26 and absence of worsening in WHO FC at week 26.¹

GRIPHON completed enrollment in May 2013 with 1156 patients from 181 centers in 39 countries. Patients received UPTRAVI (n=574) or placebo (n=582). The median treatment duration was 63.7 and 70.7 weeks for patients receiving placebo and UPTRAVI, respectively, and the study was completed in April 2014, with 397 blinded, adjudicated primary endpoint events (end of study [EOS]). Dosing of UPTRAVI or placebo in GRIPHON was initiated at 200 mcg twice daily (BID) and increased weekly in steps of 200 mcg BID, as tolerated, up to a maximum dose of 1600 mcg BID. This dose adjustment phase occurred during the first 12 weeks of treatment and was designed to include dose reduction by 200 mcg BID when an intolerable dose was reached to determine the highest tolerated dose. After 12 weeks, patients entered the maintenance phase of the study. Starting at week 26, doses could be increased at scheduled visits; dose reductions were allowed at any time. For each patient, the individualized maintenance dose was the dose the patient received for the longest duration until end of treatment, that is, last intake of double-blind treatment with UPTRAVI or placebo plus 7 days (end of treatment [EOT]; last intake of double-blind treatment with UPTRAVI or placebo plus 7 days).¹

Efficacy: Primary Endpoint

UPTRAVI decreased the risk of a morbidity/mortality event versus placebo (risk reduction) by 40% (hazard ratio [HR], 0.60; 99% confidence interval [CI], 0.46-0.78; P<0.001). The beneficial effect of UPTRAVI was primarily attributable to a reduction in hospitalization for worsening of PAH and a reduction in disease progression events, with death from any cause, initiation of parenteral prostanoid or chronic oxygen therapy and PAH worsening resulting in need for lung transplantation or atrial septostomy representing fewer events.¹

Safety and Tolerability

The most common AEs in GRIPHON that occurred with higher frequency (≥5%) on UPTRAVI compared with placebo were headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. The proportion of patients discontinuing treatment due to an AE was 14.3% on UPTRAVI and 7.1% on placebo.¹

Prespecified Subgroup Analysis of Patients With PAH-CHD From the GRIPHON Study

Baseline Characteristics

A total of 110 PAH-CHD patients with repaired congenital cardiac shunts were enrolled in GRIPHON (n=60 UPTRAVI, n=50 placebo). Among the PAH-CHD patients, atrial septal defect was the most common defect (n=55, 50%), followed by ventricular septal defect (n=38, 34%), persistent ductus arteriosus (n=14, 13%), and unspecified defect (n=3, 3%). The baseline characteristics of the PAH-CHD patients are shown in Table: Baseline Characteristics of Patients With PAH-CHD After Defect Correction. Baseline characteristics of corrected PAH-CHD patients were balanced between treatment arms with the exception of N-terminal pro B-type natriuretic peptide (NT-proBNP). Corrected PAH-CHD patients were younger (mean age, 40.3 years) than patients in the non-CHD population (mean age, 48.9 years). In addition, a greater proportion of patients with corrected PAH-CHD were in WHO FC I and II and were treatment naïve at baseline when compared to non-CHD patients.²

Efficacy

In the corrected PAH-CHD population, 13 (26%) patients in the placebo arm and 9 (15%) patients in the UPTRAVI arm experienced a primary endpoint event. Consistent with the overall GRIPHON study population, UPTRAVI reduced the risk of the primary endpoint of morbidity/mortality in patients with PAH-CHD (corrected defects) versus placebo (risk reduction) by 42% (HR, 0.58; 95% CI, 0.25-1.37; Figure: Effect of UPTRAVI on the Primary Outcome Endpoint of Morbidity or Mortality Among Patients With PAH-CHD After Defect Correction).⁸ Hospitalization for worsening of PAH and disease progression accounted for the majority of primary endpoint events in the patients with corrected PAH-CHD; see Table: Events Related to PAH and Death for Patients With PAH-CHD After Defect Correction.²

At week 26, in patients with corrected PAH-CHD, the 6MWD increased by a median of 2 m from baseline in the placebo group and 11 m in the UPTRAVI group (treatment effect: 15 m, 95% CI, -7 to 40). For NT-proBNP, there was a treatment effect of -8 ng/L (95% CI, 88 to 69).²

Safety and Tolerability

In the patients with corrected PAH-CHD, the frequency of AEs was comparable in the placebo arm (98.0%) and UPTRAVI arm (95.0%). In addition, this is similar to the overall GRIPHON population (96.9% in the placebo arm and 98.3% in the UPTRAVI arm). The most frequent AEs are summarized below in Table: Most Frequent AEs.²

Information From the Literature

Single-Center Experience: Pediatric Population

Lafuente-Romero et al. (2021)³ described the use of UPTRAVI in 4 pediatric patients with CHD-PAH. Baseline patient and treatment characteristics are presented in Table: Baseline Patient and Treatment Characteristics.

All patients received their respective doses of UPTRAVI every 12 hours. The efficacy and safety analysis before and after treatment with UPTRAVI is presented in Table: Efficacy and Safety Analysis Before and After UPTRAVI Treatment.

Gallotti et al. (2017)⁴ described the use of UPTRAVI in 10 patients (mean age 16.5±5.7 years) with idiopathic PAH (IPAH) (n=5), PAH-CHD (n=4), and congenital diaphragmatic hernia (CDH; n=1). All the patients were on combination therapy prior to starting UPTRAVI and 4 patients were receiving continuous IV treprostinil therapy. Patient demographics are summarized in Table: Patient Demographics.

The 4 patients on continuous IV treprostinil therapy transitioned to UPTRAVI at a starting dose of 200 mcg BID while simultaneously decreasing IV treprostinil daily by 2 ng/kg/min for 5 days followed by a 2-day rest period. During this time, the UPTRAVI dose was increased by 200 mcg/dose per week. This cycle was repeated until treprostinil was completely discontinued and the UPTRAVI dose reached a total maintenance dose of 1600 mcg BID. If UPTRAVI related AEs occurred, dose increases were held for 1 week, allowing 2 weeks between uptitrations. All 4 patients successfully transitioned to a maximum UPTRAVI dose of 1600 mcg BID and remained stable by echocardiographic assessment and 6-minute walk test (6MWT).

Of the 4 patients with CHD, 3 reported improved energy, stamina, exercise tolerance, and decreased oxygen requirement after starting UPTRAVI. One patient who transitioned from IV treprostinil, reported clinical improvements, but with no significant changes in symptoms, 6MWT, or echocardiographic findings. Overall, the most common reported AEs were headaches, loose stools, and jaw pain.

Single-Center Experience: Adult Population

Jung et al. (2021)⁵ conducted a retrospective study that examined the efficacy and safety of UPTRAVI as an add-on therapy in patients with PAH-CHD (N=13). All patients were being treated with different PAH drugs (excluding prostanoids) at baseline. Baseline and hemodynamic characteristics of patients are presented in Table: Baseline and Hemodynamic Characteristics.

Efficacy

A total of 12 patients were included in the efficacy analysis (1 patient was excluded due to UPTRAVI discontinuation). Efficacy analysis before and after treatment with UPTRAVI is presented in Table: Efficacy Analysis in Individual Patients Before and After UPTRAVI Treatment.

Changes in risk assessment (based on the French registry group) showed improvement in 8 (66.7%) patients, no change in 3 (25.0%) patients, and worsening at the time of risk reassessment in 1 (16.7%) patient.

There was no patient who reached maximal maintenance dose of UPTRAVI (mean, 1166 mcg/day). Maximal maintenance dose was low (<1000 mcg/day), medium (1000-2000 mcg/day) and high (>2000 mcg/day) in 41.6% (n=5), 50% (n=6), and 8.4% (n=1) of patients, respectively. Half of the patients reached a dose of 20-60 mcg/day after weight adjustment. The medium-to-high dose group vs low dose group showed a significant change in 6MWD (88.3±26.4 min vs 55.3±27.6 min; P=0.043) and tricuspid regurgitation pressure gradient score (-33.7±10.9 mmHg vs 12.5±12.0 mmHg; P=0.015). No difference was observed in change in NT-proBNP levels between the groups.

Safety

The most common side effect was musculoskeletal pain, followed by headache, nausea, and diarrhea. No unexpected side effects were reported. Intolerable myalgia was reported in 1 patient with ventricular septal defect and Eisenmenger syndrome, which resulted in drug discontinuation and exclusion from the study. No deaths were reported.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 12 November 2024.