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, 80% of patients were on stable background therapy for PAH with either an endothelin receptor antagonist (ERA), a phosphodiesterase-5 inhibitor (PDE-5i), or both in GRIPHON. A subanalysis showed the effect of UPTRAVI was observed regardless of baseline PAH background therapy.¹
  • The most frequent AEs observed with UPTRAVI (headache, diarrhea, jaw pain, and nausea) were less frequent in the subgroups of patients receiving 1 or no PAH therapy at baseline compared with the subgroup of patients receiving 2 therapies.^1,2
  • In the GRIPHON open-label extension study, of the 953 patients treated with UPTRAVI, 774 (81.3%) were on background PAH therapy at baseline.³
• TRITON was a multicenter, double-blind, placebo-controlled, phase 3b study with newly diagnosed, treatment-naïve PAH patients randomized 1:1 to initial triple or initial double therapy. Both initial triple and initial double therapy improved the primary endpoint of pulmonary vascular resistance (PVR) by 54% and 52%, respectively, with no difference between the groups.⁴
• A post hoc pooled analysis of GRIPHON and TRITON patients was conducted to evaluate the effect of early UPTRAVI initiation (within 6 months of diagnosis) on PAH disease progression and survival. UPTRAVI reduced the risk of disease progression by 52% in the pooled UPTRAVI group compared to the pooled placebo control group. The majority of patients in the pooled analysis groups received UPTRAVI or placebo in combination with other PAH-specific medications (77% in the pooled UPTRAVI group and 74% in the pooled control group).⁵
• SPHERE was a United States (US)-based, multicenter, prospective, observational, realworld registry.⁶
  • Of the 759 patients with PAH, 95% of patients were already receiving treatment with other PAH-specific medications before UPTRAVI initiation. Approximately, half of the population received dual therapy consisting of an ERA and a PDE-5i, whereas one-third of the population received monotherapy with either an ERA or a PDE-5i.⁶
  • Among the 759 patients with PAH, 29.5%, 5.9%, 49.5%, 9.6%, and 0.4% of all patients were receiving PAH-specific monotherapy, dual therapy with prostacyclin I2 (PGI₂), dual therapy without PGI₂, triple therapy, and quadruple therapy. Similar therapy patterns were observed across non-Hispanic White, Black/African American, Hispanic, and other treatment groups.⁷
• EXPOSURE (EUPAS19085) is an ongoing, multicenter, prospective, observational study in patients with PAH initiating a PAH-specific therapy in Europe and Canada. This analysis describes the patient characteristics, treatment patterns, and outcomes at the time of treatment escalation with UPTRAVI and over the long term based on 1-year mortality risk score.⁸
  • At 6 months prior to baseline, majority of the patients were on double combination PAH-specific therapy (57%-63%) across all risk groups.
  • At baseline, UPTRAVI was initiated as a part of triple combination therapy (range, 74%-81%) in majority of patients across all risk groups.
• Additionally, retrospective studies, case reports, conference abstracts, and a conference poster are listed in the REFERENCES section for review.^9-22

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, 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.¹

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 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

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 to 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 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

Subanalysis of Combination Therapy and Monotherapy From the GRIPHON Study

At baseline, 80% of patients were receiving oral medication specific for PAH: either an ERA (14.7%), a PDE-5i (32.4%), or a combination of the two (32.5%).¹ Baseline characteristics across the prespecified treatment arms were similar.² The baseline and demographic characteristics for each subgroup are provided below in Table: Baseline and Demographic Characteristics.²

The individualized maintenance dose groups were represented in comparable frequency across the PAH therapy subgroups (Table: Distribution of Patients’ Individual Maintenance Dose by Low-, Medium-, and High-Dose Groups).²

Efficacy: Primary Endpoint

The effect of UPTRAVI was consistent for the primary endpoint across all 4 background therapy subgroups with the test for interactions indicating no heterogeneity (P=0.95).²

• UPTRAVI decreased the risk of morbidity/mortality events versus placebo with a risk reduction of 43% (HR=0.57; 99% CI, 0.32-1.03; P=0.0068) in patients who weren't on baseline PAH background therapy, 42% (HR=0.58; 99% CI, 0.37-0.91; P=0.0008) in patients who were on PDE-5i monotherapy background therapy, 37% (HR=0.63; 99% CI, 0.39-1.01; P=0.0058) in patients who were on ERA and PDE-5i combination background therapy, and 34% (HR=0.66; 99% CI, 0.32-1.35; P=0.0655) in patients who were on ERA monotherapy background therapy.^2,23

Efficacy: Secondary Endpoints

The effect of UPTRAVI on 6MWD is shown in the Figure: Change in 6MWD From Baseline to Week 26 (at Trough).

At week 26, in patients receiving no PAH therapy, PDE-5i monotherapy, ERA monotherapy, and ERA plus PDE-5i combination at baseline, absence of WHO FC worsening was reported in 67.7%, 75.3%, 73.3%, and 79.8% of placebo-treated patients and 83.0%, 78.7%, 72.3%, and 76.3%, of UPTRAVI-treated patients, respectively. For the analysis of absence of WHO FC worsening at week 26, missing values were imputed as ‘worsening’ for 18.3% of patients.²

Safety and Tolerability

The frequency of the most common serious adverse events (SAEs) was similar among placebo and UPTRAVI subgroups (Table: AEs and SAEs by Background PAH Therapy). Generally, an increase in the frequency of individual AEs was observed with increasing number of PAH drugs, regardless of the treatment group (placebo or UPTRAVI). The most frequent AEs observed with UPTRAVI (headache, diarrhea, jaw pain and nausea) were less frequent in the subgroups of patients receiving 1 or no PAH therapy at baseline compared with those receiving 2 therapies (Table: AEs Associated With Prostacyclin Therapy During the Maintenance Phase). No new types of AEs were observed with UPTRAVI in combination with an ERA and a PDE-5i.²

Exploratory Analysis in Patients Receiving Double Combination Therapy at Baseline

A post hoc exploratory analysis evaluated the efficacy and safety of UPTRAVI as a third agent in 376 patients receiving background double combination therapy and further analyzed these patients according to symptom burden at baseline as indicated by WHO FC. Consistent with the overall GRIPHON population, UPTRAVI decreased the risk of a morbidity/mortality event versus placebo by 37% (HR=0.63; 95% CI, 0.44-0.90) in patients receiving background double oral combination therapy. As in the overall population, the most frequently reported primary endpoint events were predominantly hospitalization due to PAH worsening and disease progression. When considering the symptom burden at baseline, UPTRAVI reduced the risk versus placebo by 64% (HR=0.36; 95% CI, 0.14-0.91) in patients with WHO FC II symptoms and 26% (HR=0.74; 95% CI, 0.50-1.10) in patients with WHO FC III symptoms at baseline. Overall, 34 (19.0%) UPTRAVI-treated patients and 15 (7.6%) placebo-treated patients discontinued treatment prematurely due to an AE. The most frequent AEs leading to discontinuation in the UPTRAVI group (for events with a >1% difference between UPTRAVI and placebo) were headache (4.5%), diarrhea (4.5%), nausea (2.8%), asthenia (1.7%), and exertional dyspnea (1.1%). The proportion of patients who reported AEs was similar between the treatment groups, and the proportion who reported SAEs was lower for the UPTRAVI-treated patients than for those treated with placebo (44.7 vs 52.8%).²⁴

Analysis From the GRIPHON Open-label Extension Study

The GRIPHON open-label extension study enrolled patients from the GRIPHON randomized controlled trial who experienced a morbidity event during the double-blind treatment or at end of study if they were still receiving the study treatment (n=953). The median (minimum, maximum) exposure to UPTRAVI in the study population (n=953) was 31.7 (0, 106) months, corresponding to a total of 3054.4 patient-years. Of the 953 patients treated with UPTRAVI, 774 (81.3%) were on background PAH therapy at baseline.³

Phase 3b: TRITON

TRITON was a multicenter, double-blind, placebo-controlled, phase 3b study with newly diagnosed, treatment-naïve PAH patients randomized 1:1 to initial triple (macitentan, tadalafil, and UPTRAVI) or initial double therapy (macitentan, tadalafil, and placebo). macitentan and tadalafil were initiated at randomization and UPTRAVI or placebo was added at day 15 (uptitrated until week 12). Safety and efficacy were blindly assessed until the last randomized patient completed the week 26 visit (end of the observation period).⁴

Results

A total of 247 patients were randomized to either initial triple therapy (UPTRAVI, macitentan, tadalafil; n=123) or initial double therapy (placebo, macitentan, tadalafil; n=124). Fourteen patients assigned to initial triple therapy withdrew from the study and 109 patients assigned to initial triple therapy completed the main observation period. Twenty patients assigned to initial double therapy withdrew from the study and 104 patients assigned to initial double therapy completed the main observation period. The baseline characteristics were balanced between the 2 groups. The median follow-up time was 77.6 and 75.8 weeks in the initial triple and initial double therapy groups, respectively.⁴

Primary Endpoint

Initial triple and initial double therapy improved PVR by 54% and 52%, respectively (Table: Primary and Secondary Endpoints at Week 26), with no difference between the groups.⁴

Secondary Endpoints

Initial triple and initial double therapy improved 6MWD, N-terminal pro B-type natriuretic peptide (NT-proBNP), hemodynamic endpoints such as mean pulmonary arterial pressure (mPAP), cardiac index, mean right atrial pressure (mRAP), and mixed venous oxygen saturation (SvO₂; Table: Primary and Secondary Endpoints at Week 26), and no worsening in FC was seen for 99.2% and 97.5% of patients, respectively, with no difference between groups. There was a 41% reduction in the risk of disease progression with initial triple versus initial double therapy (HR=0.59; 95% CI, 0.32 to 1.09; P=0.087).⁴

Safety

The most common AEs (Table: Safety Data up to End of Main Observation Period) with initial triple therapy that were reported at a higher frequency versus double therapy were headache, diarrhea, nausea, pain in extremity, jaw pain, and vomiting. The proportion of patients with AEs leading to discontinuation were similar between the initial triple and initial double combination groups. Two patients (1.7%) died in the initial triple therapy group compared to 9 patients (7.1%) in the initial double therapy group.⁴

GRIPHON and TRITON Post Hoc Pooled Analysis

The GRIPHON and TRITON post hoc pooled analysis was conducted to evaluate the effect of early UPTRAVI initiation on PAH disease progression and survival. The combined dataset included 649 newly diagnosed (≤6 months) patients with PAH. Patients randomized to UPTRAVI in each study formed the pooled UPTRAVI group (n=329) and patients randomized to placebo in each study formed the pooled control group (n=320). The majority of patients in the pooled analysis groups received UPTRAVI or placebo in combination with other PAH-specific medications (77% in the pooled UPTRAVI group and 74% in the pooled control group). Approximately 44% of patients in each group were on combination ERA + PDE-5i at baseline.⁵

In the pooled dataset, 67 (20%) patients in the pooled UPTRAVI group experienced a first disease progression event compared to 116 (36%) in the pooled control group. UPTRAVI reduced the risk of disease progression by 52% (HR 0.48; 95% CI, 0.35-0.66) compared to control. Kaplan-Meier (KM) estimates for survival in the pooled UPTRAVI and pooled control groups were 95.9% and 96.5% at month 6, 92.7% and 92.0% at month 12, and 87.8% and 83.3% at month 24, respectively. The HR for risk of all-cause death was 0.70 (95% CI, 0.46-1.10) for the pooled UPTRAVI group versus the pooled control group.⁵

The median exposure to study treatment was 16.7 months and 13.4 months in the pooled UPTRAVI and pooled control groups, respectively. The most frequent AEs observed in the pooled UPTRAVI group versus the pooled control group were headache (7.3% vs 5.5%), diarrhea (4.6% vs 2.8%), nausea (3.7% vs 2.2%), and peripheral edema (2.8% vs 3.3%). There were 85 (26%) patients in the pooled UPTRAVI group and 100 (31%) in the pooled control group who discontinued treatment due to an AE.⁵

Real-world Evidence

Information From SPHERE (SelexiPag: tHe usErs dRug rEgistry)

SPHERE was a US-based, multicenter, prospective, observational, real-world registry study (November 2016 to March 2020) undertaken to assess the real-world outcomes of UPTRAVI in routine clinical practice. The study also provided information regarding patient demographics and disease characteristics in the enrolled population.⁶

Of the total 829 patients with pulmonary hypertension (PH; WHO Group 1-5) enrolled in SPHERE, 759 had PAH (WHO Group 1), of whom 387 and 372 were newly and previously initiated on UPTRAVI, respectively. The median age at UPTRAVI initiation was 61 years and most of the PAH study population comprised of female patients (n=581 [76.5%]). The median time from PAH diagnosis to UPTRAVI initiation in the overall, newly initiated, and previously initiated populations were 2.7 years, 2.1 years, and 3.5 years, respectively. At baseline, most patients (n=387 [51%]) were categorized as WHO FC III, with a higher proportion of FC III noted among newly vs previously initiated patients. According to the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk calculator, used to assess the 1-year mortality risk, 324 (42.7%), 229 (30.2%), and 206 (27.1%) patients were in the low-risk, intermediate-risk, and high-risk categories, respectively.⁶

Most patients (95%) were already receiving treatment with other PAH-specific medications before UPTRAVI initiation, with approximately half receiving dual therapy consisting of an ERA and a PDE-5i and one-third receiving monotherapy with an ERA or a PDE-5i.⁶ Data regarding the use of concomitant PAHspecific medications before UPTRAVI initiation in the overall, newly initiated, and previously initiated patient populations is summarized in Table: PAH-Specific Concomitant Medications Before UPTRAVI Initiation in Patients With PAH.

Of the 759 patients with PAH, the 18-month ≥1 hospitalization rates were 39.4%, 39.7%, and 39.0% in the overall, newly initiated, and previously initiated populations, respectively. The estimated overall survival rates were 93.4%, 88.9%, and 97.8% at 12 months and 89.4%, 84.2%, and 94.5% at 18 months in the overall, newly initiated, and previously initiated populations, respectively. Time to first hospitalization (dual therapy vs monotherapy: HR, 0.82; 95% CI, 0.621.07; P=0.1349; triple therapy vs monotherapy: HR, 0.79; 95% CI, 0.51-1.24; P=0.3100) and overall survival (dual therapy vs monotherapy: HR, 0.88; 95% CI, 0.551.38; P=0.5691; triple therapy vs monotherapy: HR, 0.80; 95% CI, 0.37-1.76; P=0.5835) were similar between baseline PAH therapies.⁶

Of the 759 patients with PAH, the 18-month UPTRAVI discontinuation rates (due to an AE) were 22.0%, 32.0%, and 11.9% in the overall, newly initiated, and previously initiated populations, respectively. Rates of discontinuation of UPTRAVI due to an AE were similar irrespective of the number of baseline PAH therapies (dual therapy vs monotherapy: HR, 0.91; 95% CI, 0.661.25; P=0.5545; triple therapy vs monotherapy: HR, 0.65; 95% CI, 0.36-1.16; P=0.1472). See Table: AEs in the Total Enrolled Population for additional information related to safety in the overall patient population (N=829).⁶

Analysis of SPHERE Registry by Race and Ethnicity

Methods

An analysis of SPHERE data aimed to identify differences in patient demographics, disease characteristics, prescribed treatments, and patient outcomes across different racial/ethnic groups in the US. The analyses focused on non-Hispanic White, Black/African American, and Hispanic patient cohorts due to the small number of Asian patients enrolled in the study.⁷

Results

Baseline Characteristics

Among the 759 patients diagnosed with PAH, 72.3% (n=549), 15.4% (n=117), 5.9% (n=45), 3.4% (n=26), and 2.9% (n=22) were non-Hispanic White, Black/African American, Hispanic, Asian, and classified as other, respectively.⁷

Of the 759 patients with PAH at the time of UPTRAVI initiation, 29.5%, 5.9%, 49.5%, 9.6%, and 0.4% of all patients were receiving PAH-specific monotherapy, dual therapy with PGI₂, dual therapy without PGI₂, triple therapy, and quadruple therapy, respectively.⁷

For more information regarding patients receiving receiving PAH-specific combination therapy at UPTRAVI initiation by race/ethnicity, see Table: Number of PAH-specific Therapies at UPTRAVI Initiation by Race/Ethnicity.⁷

Information From EXPOSURE (EXPloratory Observational Study of Uptravi in ReallifE; Ongoing Clinical Trial)

EXPOSURE (EUPAS19085) is an ongoing, multicenter, prospective, observational study in patients with PAH initiating a PAH-specific therapy in Europe and Canada. The study aims to describe the patient characteristics, treatment patterns, and outcomes at the time of treatment escalation with UPTRAVI and over the long term based on 1-year mortality risk score.⁸

Adult patients with group 1 PH (PAH) initiating a new PAH-specific therapy from September 17, 2017, to November 30, 2022, were included in this analysis and were grouped as low, intermediate-low, intermediate-high, or high risk to calculate the risk score.⁸

Results

Baseline Characteristics

As of November 30, 2022, the risk assessment at baseline was calculated for 535 of 698 (77%) patients, of which 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. The overall population predominantly consisted of female patients (71%) with a median age of 60 years and prevalent (2 years) PAH disease Majority of the overall patients had idiopathic/heritable PAH (I/HPAH; 56%) and were categorized as WHO FC III (57%). Hemodynamic parameters and other parameters like WHO FC, 6MWD and NT-proBNP worsened with increasing risk groups.⁸

Titration and Dosing of UPTRAVI and PAH-Specific Treatment Patterns

Of the 698 patients in the overall population, 71% were on ERA, PDE-5i, and UPTRAVI for triple combination therapy at baseline.⁸ The PAH-specific therapies at baseline are presented in the Table: Breakdown of PAH-Specific Therapies at Baseline.

The median (Q1, Q3) duration of UPTRAVI titration was shorter for the high-risk group (1.6 [0.6, 2.4] months) compared to the other risk groups (low risk, 1.9 [0.9, 3.0] months, intermediate low 1.8 [1.0, 2.8] months, intermediate high 1.8 [1.1, 3.0] months). The majority of patients in all risk groups (85%-93%) had completed titration, 1%-10% were undergoing titration, and 5%-10% had discontinued UPTRAVI. For patients in the low-, intermediate-low-, and intermediate-high-risk groups, the median individualized dose was 800 mcg twice daily (BID), with a slightly lower dose for the high-risk group (median [Q1, Q3], 600 [400, 1000] mcg BID). Most of the patients were on double combination PAH-specific therapy (57%-63%) in all the risk groups at 6 months prior to baseline. At baseline, UPTRAVI was initiated as a part of triple combination therapy (range, 74%-81%) in majority of patients across all the risk groups. Transition to triple combination therapy with UPTRAVI from the time of diagnosis happened within a shorter period in patients at high risk (median [Q1, Q3], 1.6 [0.5, 4.1] years) compared to those at low risk (median [Q1, Q3], 3.2 [1.4, 9.3] years).⁸ The treatment patterns of all the risk groups and overall population are presented in the Figure: PAH-Specific Treatment Patterns at Baseline.

Hospitalization and Survival

In the low risk group, the median (Q1, Q3) UPTRAVI exposure duration was longer (11.5 [4.0, 25.3] months) compared to the higher risk groups (intermediate-low risk, 11.4 [4.0, 26.4] months; intermediate-high risk, 10.1 [3.7, 24.1] months; high risk, 9.0 [2.8, 17.2] months). The proportion of hospitalized patients increased with the increasing risk status during the UPTRAVI exposure period (16%, 23%, 34%, and 42% for the low-, intermediate-low-, intermediate-high-, and high-risk groups, respectively). In the high-risk group, 71% of hospitalization cases were PAH-related compared to the other risk groups (range, 47%-54%). At 1 year, 88%, 84%, 69%, and 58% of patients in the low-, intermediate-low-, intermediate-high-, and high-risk groups, respectively, were free from hospitalization.⁸

At 1 year, KM estimates of survival in the respective risk groups were 98% (low), 98% (intermediate-low), 93% (intermediate-high), and 80% (high); those at 2 years were 98% (low), 92% (intermediate-low), 81% (intermediate-high), and 67% (high).⁸

Safety

A total of 12%, 14%, 15%, and 23% patients in the low, intermediate-low, intermediate-high, and high risk groups, respectively, discontinued UPTRAVI due to tolerability or AEs during the exposure period. Diarrhea and headache were the most frequently reported AEs across all risk groups. Cardiac failure (n=6, 6%) was also one of the most frequently reported AEs for patients in the high-risk group.⁸

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 May 2024.