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).¹
• A post hoc analysis from the GRIPHON trial evaluated the impact of comorbidities on the efficacy and safety of UPTRAVI. The results from the main analysis showed that UPTRAVI reduced the risk of a morbidity/mortality event compared with placebo in subgroups A (consisting of patients with <3 comorbidities and who met the hemodynamic criteria) and B (consisting of patients with ≥3 comorbidities and/or did not meet the hemodynamic criteria), with no evidence of an inconsistent treatment effect in subgroups (P_interaction=0.432 for baseline adjusted analyses).²
• EXPOSURE (EUPAS19085) is an ongoing, international, multicenter, prospective, real-world, observational study enrolling patients with PAH at initiation of a new PAH specific therapy in Europe and Canada.³
  • In a November 2021 analysis from the EXPOSURE study, patients who initiated UPTRAVI and had follow-up information were categorized according to the number of cardiovascular comorbidities present prior to or at UPTRAVI initiation. Hospitalization and mortality rates, to a large extent, were similar across the comorbidity subgroups (0, 1, and 2), except the ≥3 comorbidities subgroup for which the rates were higher. A majority of patients stayed on UPTRAVI therapy regardless of their comorbidity burden.⁴
  • In a November 2022 analysis from the EXPOSURE study, PAH patients were categorized by their 1-year mortality risk using the 4-strata risk approach (low, intermediate-low, intermediate-high risk, and high-risk group). The most prominent cardiovascular risk factors in the overall patient population at baseline were smoking (36%), systemic hypertension (31%), and obesity (30%). Cardiovascular risk factors were found across all risk groups, with risk factors increasing from the low risk group to the high risk group.^5,6

CLINICAL DATA

Phase 3 Study: GRIPHON

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 World Health Organization (WHO) Group 1 PAH.¹

The 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. Disease progression was defined as a decrease from baseline of ≥15% in the 6-minute walk distance (6MWD; confirmed by a second test on a different day) accompanied by a worsening in WHO functional class (FC; for patients with WHO FC II or III at baseline) or the need for additional treatment of PAH (for patients with WHO FC III or IV at baseline).¹

GRIPHON included 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.¹

Dosing of UPTRAVI or placebo in GRIPHON was initiated at 200 μg twice daily (BID) and increased weekly in steps of 200 μg BID, as tolerated, up to a maximum dose of 1600 μg BID. This dose adjustment phase occurred during the first 12 weeks of treatment and was designed to include dose reduction by 200 μg BID when an intolerable dose was reached to determine the highest tolerated dose. After 12 weeks, patients entered the maintenance phase of the study. The individualized maintenance dose was the dose the patient received for the longest duration until 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 vs 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.¹

Safety and Tolerability

The most common AEs in GRIPHON that occurred with a 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

Post Hoc Analysis from the GRIPHON Study - Impact of Comorbidities

Rosenkranz et al (2022)² conducted a post hoc analysis of the GRIPHON study to analyze the impact of comorbidities on the efficacy and safety of UPTRAVI in patients with PAH. Patients from the GRIPHON study were analyzed using 3 methods related to comorbidity.

• The first analysis (main analysis) categorized patients into subgroups according to the previously published criteria, combining comorbidity count (<3 and ≥3) and restrictive hemodynamic cut-offs (met or not met).
  • Comorbidities included:
    • Body mass index (BMI) ≥30 kg/m²
    • History of essential hypertension
    • Diabetes mellitus (any type)
    • Historical evidence of significant coronary artery disease (CAD; this included history of myocardial infarction [MI] or percutaneous coronary intervention, angiographic evidence of CAD [>50% stenosis in ≥1 vessel], positive stress test, previous coronary artery bypass graft, or stable angina).
  • Hemodynamic cut-offs consisted of pulmonary arterial wedge pressure (PAWP)/ left ventricular end-diastolic pressure (LVEDP) of ≤12 mmHg if the pulmonary vascular resistance (PVR) was ≥3.75 to <6.25 Wood units, or PAWP/LVEPD of ≤15 mmHg if the PVR was ≥6.25 Wood units.
  • Patients were divided into 2 subgroups; subgroup A consisted of patients with <3 comorbidities and who met the hemodynamic criteria and subgroup B consisted of patients with ≥3 comorbidities and/or did not meet the hemodynamic criteria.
• The second analysis (supporting analysis) categorized patients into 6 non-overlapping subsets according to the comorbidity count (0, 1, 2, 3, 4 and 5).
• The third analysis (supporting analysis) categorized patients into overlapping subsets according to the presence or absence of each specific comorbidity (BMI ≥30 kg/m², history of essential hypertension, diabetes, history of CAD, and atrial fibrillation).

Baseline Characteristics

Of the 1156 patients from the GRIPHON study, 1106 were included in the main analysis.

• Subgroups A and B comprised 962 (87.0%) and 144 (13.0%) patients, respectively. Approximately one-half of the patients in the GRIPHON study had comorbidities (n=584; 50.5%). A list of baseline characteristics is presented in Table: Baseline Characteristics.

Results

In the main analysis, UPTRAVI reduced the risk of a morbidity/mortality event compared with placebo in subgroups A and B, with no evidence of an inconsistent treatment effect in subgroups (P_interaction=0.432 for baseline adjusted analyses). In the supporting analysis, based on comorbidity count, the treatment effect of UPTRAVI vs placebo on morbidity/mortality was consistent across groups (P_interaction=0.948). In another supporting analysis, based on specific comorbidities, the treatment effect of UPTRAVI vs placebo on morbidity/mortality was not impacted by the presence of the specified comorbidities. Data regarding the impact of comorbidities on UPTRAVI treatment effect is summarized in Table: UPTRAVI Treatment Effect in Patients with Comorbidities.

Safety

In the main analysis, the median (range) UPTRAVI exposure was 69.9 (0.3-199.7) and 72.6 (0.6-216.7) weeks in subgroups A and B, respectively. The median (range) placebo exposure was 66.3 (0.9188.0) and 53.8 (0.7-192.0) weeks in subgroups A and B, respectively. The number of AEs, serious AEs, and AEs leading to study drug discontinuation in both subgroups are described in Table: AEs, Serious AEs, and AEs Leading to Study Drug Discontinuation in Subgroups A and B. The most frequent AEs occurring in both subgroups are summarized in Table: Most Frequent AEs in Subgroups A and B.

Information From EXPOSURE (EuroPean Observational Study of UPTRAVI in Real-lifE)

EXPOSURE (EUPAS19085) is an ongoing, international, multicenter, prospective, real-world, observational study enrolling patients with PAH at initiation of a new PAH specific therapy in Europe and Canada.³

Results: November 2021 Analysis

As of November 2021, patients who initiated UPTRAVI and had follow-up information were categorized according to the number of cardiovascular comorbidities (including BMI ≥30 kg/m², diabetes mellitus, history of systemic hypertension, and historical evidence of reported significant CAD) present prior to or at UPTRAVI initiation. A list of baseline characteristics is presented in Table: Baseline Characteristics. Data regarding the treatment patterns at UPTRAVI initiation and 6 months after UPTRAVI initiation is summarized in Table: PAH-specific Therapy at UPTRAVI Initiation and 6 Months After UPTRAVI Initiation. Data regarding the outcomes during UPTRAVI exposure are summarized in Table: Outcomes During UPTRAVI Exposure.⁴

Results: November 2022 Analysis

As of November 2022, 698 PAH patients newly initiating UPTRAVI were included in this analysis, of which 535 (77%) had follow up data that allowed for risk assessment at baseline. Of the 535 patients, 76 (14%) were in the low risk group, 168 (31%) were in the intermediate-low risk group, 182 (34%) were in the intermediate-high risk group, and 109 (20%) were in the high risk group.⁵ In the overall population (N=698) cardiovascular risk factors at baseline included being a former smoker (36%), systemic hypertension (31%), obesity (BMI >30 kg/m²; 30%), hyperlipidemia (18%), diabetes mellitus (16%), carotid and/or coronary arteriosclerosis (13%), cardiac arrythmia (13%), valvular heart disease (8%), systemic pulmonary shunt (recorded as cardiac shunts; 8%), and sleep apnea syndrome (7%). Cardiovascular risk factors were found across all risk groups, with risk factors increasing from the low risk group to the high risk group.^5,6

Literature Search

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