UPTRAVI - Combination Therapy in Pulmonary Arterial Hypertension

SUMMARY

• GRIPHON was a phase 3 trial that evaluated the long-term safety and efficacy of UPTRAVI in patients with symptomatic pulmonary arterial hypertension (PAH). 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
  • The GRIPHON open-label extension (OLE) study was a multicenter extension of the double-blind GRIPHON trial designed to evaluate the long-term safety, tolerability, and survival outcomes of UPTRAVI in patients with PAH, with follow-up of up to 10 years. Among the 574 patients randomized to receive UPTRAVI, the median exposure was 35.8 months (2105.5 patient-years). The Kaplan-Meier (KM) survival estimates at 1, 5, and 10 years were 93%, 74%, and 60%, respectively. Safety findings showed that 99.7% of patients experienced at least one treatment-emergent adverse event (TEAE) and 64.1% experienced at least one serious adverse events (SAEs), with headache, diarrhea, nausea, and worsening of PAH being the most commonly reported AEs.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 combination therapy. Both initial triple and initial double combination 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, real-world 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 combination 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, 30.8%, 5.9%, 49.7%, and 8.4% of patients were receiving PAH-specific monotherapy, dual combination therapy with prostaglandin I₂ (prostacyclin; PGI₂), dual combination therapy without PGI₂, and triple combination therapy, respectively. No notable differences in treatment patterns were observed between the racial/ethnic groups.⁷
• EXPOSURE (EUPAS19085) is an ongoing, multicenter, prospective, observational study in patients with PAH initiating a PAH-specific therapy in Europe and Canada.^8,9 Several authors (Muller et al (2024)⁹, Gaine et al (2024)¹⁰, Lange et al (2024)¹¹ Soderberg et al (2025)^12,13) reported analyses of EXPOSURE data, consistently describing real-world treatment patterns of UPTRAVI as part of combination therapy, particularly triple combination therapy across different patient subgroups and study populations.
• The INSPECTIO study was a prospective, multicenter, observational study in patients with PAH designed to assess the impact of macitentan- and/or UPTRAVI-based therapy on disease progression and quality of life. A total of 176 patients were included; 44.9% and 27.3% received double and triple combination therapy at baseline, respectively. The proportion of patients receiving triple oral combination therapy increased over time, from 27.3% (48/176) at baseline to 33.8% (52/154) at 12 months and 36.0% (27/75) at 24 months.¹⁴
• The post hoc analysis of the INSPECTIO study evaluated patients with CTD-PAH (n=64/176) to support risk-based treatment strategies and compare outcomes with non-CTD PAH. Double combination therapy was more commonly used in patients with CTD-PAH (56.3%) compared with non-CTD PAH (38.4%). In contrast, triple combination therapy was more frequently used in the non-CTD PAH subgroup (32.1%) than in CTD-PAH patients (18.8%).¹⁵
• Escribano Subias et al (2026)¹⁶ conducted an ad hoc study analyzing pooled data from the SPHERE and EXPOSURE observational studies to evaluate real-world use of UPTRAVI, including patient characteristics, treatment patterns, and clinical outcomes. A total of 894 patients with PAH were included, with 67.1% receiving UPTRAVI as part of triple combination therapy at initiation.
• Additionally, retrospective studies, case reports, conference abstracts, and a conference poster are listed in the REFERENCES section for review.^17-34

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 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 or subcutaneous (SC) prostanoids or chronic oxygen therapy for worsening of PAH, or disease progression events. For WHO 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 were randomized to 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% 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 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.^2,35

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 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%).³⁶

Analyses From the GRIPHON OLE Study

The GRIPHON OLE was a multicenter, OLE of the GRIPHON study that evaluated the long-term safety and tolerability of UPTRAVI in patients with PAH. Patients previously enrolled in the GRIPHON double-blind study were eligible to enter the OLE after experiencing a morbidity event during the double-blind phase or upon completion of the double-blind study while still receiving treatment. These analyses extend prior findings from GRIPHON and its OLE by reporting observed safety and survival data for up to 10 years in the overall population. Additionally, long-term survival outcomes were assessed for PAH-specific combination therapy.³

Background therapy included an ERA and/or a PDE-5i at stable doses. In the GRIPHON OLE, ERAs, PDE5is, and riociguat were among the concomitant PAH therapies permitted during the study, and temporary use of inhaled, intravenous, or subcutaneous prostacyclin and/or its analogs was also allowed when medically indicated.³

Results

Patient Characteristics

Overall, 953 patients received UPTRAVI during the GRIPHON double-blind or OLE phases, including 574 randomized to UPTRAVI and 379 originally randomized to placebo who entered the OLE. Of the 574 patients randomized to UPTRAVI, 330 continued treatment in the OLE, while 244 did not enter the OLE phase. By the end of the study (June 2010 to September 2021), 162 patients (28.2%) had completed treatment and 412 (71.8%) had discontinued. In the overall UPTRAVI-treated population, 294 patients (30.8%) completed treatment and 659 (69.2%) discontinued.³ Seven hundred seventy-four (81.3%) of UPTRAVI treated patients (N=953) and 462 (80.5%) of UPTRAVI long-term patients (N=574) received UPTRAVI as part of combination therapy.^3,37 See Table: Background PAH-Specific Therapy at Time of UPTRAVI Initiation in UPTRAVI Long-Term Patients.^3,37

Exposure

In the UPTRAVI treated patients (N=953), the median exposure was 31.7 months (range, 0-126), with a total UPTRAVI exposure of 3279.6 patient-years.³⁸ Among UPTRAVI long-term patients (N=574), the median exposure duration was 35.8 months (range, 0-126), corresponding to 2105.5 patient-years of exposure. A total of 176 patients (30.7%) received UPTRAVI for ≥5 years and 10 patients (1.7%) for ≥10 years.³

Survival Outcomes

The median follow-up from UPTRAVI initiation was 54 months. In UPTRAVI long-term patients (N=574), KM survival estimates (95% CI) at 1, 3, 5, 8, and 10 years were 93% (90-95), 82% (78-86), 74% (69-78), 63% (57-69), and 60% (53-66), respectively. Among patients receiving UPTRAVI as part of triple combination therapy (n=179), KM survival estimates (95% CI) were 95% (89-97) at 1 year, 79% (67-87) at 5 years, and 73% (56-84) at 8 years. Among patients receiving double combination therapy (n=283), KM survival estimates (95% CI) were 93% (88-95), 69% (62-75), and 55% (46-63) at 1, 5, and 8 years, respectively. KM survival estimates (95% CI) showed that, for patients initiating double combination therapy ≤6 months from diagnosis, survival was 92% (84-96) at 1 year, 79% (69-87) at 3 years, 68% (57-77) at 5 years, 59% (46-69) at 8 years, and 56% (43-67) at 10 years. For those initiating therapy >6 months from diagnosis, survival was 93% (88-96) at 1 year, 78% (70-84) at 3 years, 70% (60-78) at 5 years, 49% (36-61) at 8 years, and 41% (27-56) at 10 years. Analyses by 4-strata risk category showed higher survival in low- and intermediate-low-risk groups than in higher-risk groups. The treatment effect of UPTRAVI was consistent across all risk categories.³

Safety

In the UPTRAVI treated patients (N=953), 99.6% of patients experienced ≥1 TEAE, and 62.6% experienced ≥1 SAE. In total, 309 patients (32.4%) discontinued treatment because of ≥1 adverse event, and 66 patients (6.9%) discontinued due to ≥1 prostacyclin-associated adverse event. The most frequently reported adverse events in the UPTRAVI long-term patients (N=953) were headache (68.1%), diarrhea (44.7%), pulmonary arterial hypertension worsening (33.6%), and nausea (32.8%), with exposure-adjusted incidence rates of 62.7, 21.3, 11.5, and 13.3 per 100 patient-years, respectively. Other frequently reported events (≥15%) included pain in jaw (28.1%), pain in extremity (18.3%), dyspnea (18.4%), vomiting (18.3%), peripheral edema (16.8%), dizziness (16.4%), myalgia (16.4%), and nasopharyngitis (15.8%). See Tables: Safety and Exposure and Summary of Most Frequent Adverse Events.^3,38

In the UPTRAVI long-term patients (N=574), 99.7% of patients experienced ≥1 TEAE, and 64.1% experienced ≥1 SAE. The most frequently reported AEs were headache (67.9%), diarrhea (46.2%), nausea (36.4%), and PAH worsening (35.4%), with exposure-adjusted incidences per year per 100 treated patients of 54.7, 21.1, 14.4, and 11.5, respectively. Overall, 223 patients (38.9%) discontinued treatment due to AEs, most commonly PAH worsening (16.7%), headache (3.7%), and right ventricular (RV) failure (3.3%). Discontinuation due to prostacyclin-associated AEs occurred in 8.2% of patients. By the end of treatment plus 30 days, 126 patients (22.0%) had died, most frequently due to PAH worsening (6.4%), RV failure (4.0%), sudden death (2.1%), and cardiac arrest (1.4%). See Tables: Safety and Exposure and Summary of Most Frequent Adverse Events.^3,38

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 combination 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 combination therapy (UPTRAVI, macitentan, tadalafil; n=123) or initial double combination therapy (placebo, macitentan, tadalafil; n=124). Fourteen patients assigned to initial triple combination therapy withdrew from the study and 109 patients assigned to initial triple combination therapy completed the main observation period. Twenty patients assigned to initial double combination therapy withdrew from the study and 104 patients assigned to initial double combination 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 combination therapy groups, respectively.⁴

Primary Endpoint

Initial triple and initial double combination 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 combination 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 combination therapy (HR, 0.59; 95% CI, 0.32-1.09; P=0.087).⁴

Safety

The most common AEs (Table: Safety Data up to End of Main Observation Period) with initial triple combination therapy that were reported at a higher frequency versus double combination 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 combination therapy group compared with 9 patients (7.1%) in the initial double combination 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. 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. KM estimates for survival in the pooled UPTRAVI and pooled control groups were 95.7% and 95.6% at month 12 and 93.1% and 89.9% at month 24, respectively, when UPTRAVI was administered as part of triple oral combination therapy within 6 months of diagnosis.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 combination 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 PAH-specific 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 combination therapy vs monotherapy: HR, 0.82; 95% CI, 0.62-1.07; P=0.1349; triple combination therapy vs monotherapy: HR, 0.79; 95% CI, 0.51-1.24; P=0.3100) and overall survival (dual combination therapy vs monotherapy: HR, 0.88; 95% CI, 0.55-1.38; P=0.5691; triple combination 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 combination therapy vs monotherapy: HR, 0.91; 95% CI, 0.66-1.25; P=0.5545; triple combination 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.⁷

Results

Baseline Characteristics

Among the 759 patients diagnosed with PAH, 72.3% (n=549), 15.4% (n=117), 5.9% (n=45), and 6.3% (n=48) were non-Hispanic White, Black/African American, Hispanic, and classified as Other, respectively.⁷

Of the 759 patients with PAH at the time of UPTRAVI initiation, 30.8%, 5.9%, 49.7%, and 8.4% of patients were receiving PAH-specific monotherapy, dual combination therapy with PGI₂, dual combination therapy without PGI₂, and triple combination therapy, respectively. No notable differences in treatment patterns were observed between the racial/ethnic groups.⁷

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

Information From EXPOSURE (EXPloratory Observational Study of Uptravi in Real-lifE; Ongoing Clinical Trial)

EXPOSURE (EUPAS19085) is an ongoing, multicentre, prospective, observational post-authorization safety study (PASS) of patients with PAH initiating a new PAH-specific therapy in Europe or Canada, with enrolment starting in September 2017. Patients ≥18 years with group 1 PAH initiating a PAH-specific therapy (excluding calcium channel blockers) within 1 month prior to enrolment or at enrolment were eligible and must not have been previously treated with the same drug.^8,9

The study includes two cohorts: an UPTRAVI cohort and an Other PAH-specific therapy cohort. Patients were followed from therapy initiation until death, study discontinuation, or last available data prior to data cut-off. These interim analyses includes patients enrolled from 17 September 2017 to 30 November 2022 with follow-up information. The study aims to describe demographics, disease characteristics, treatment patterns and clinical course; further characterize the safety profile of UPTRAVI; and compare rates of MACE and all-cause outcomes.^8,9

Several analyses of the EXPOSURE data have been published that report treatment patterns of UPTRAVI use in combination therapy for PAH.

Muller et al (2024) reported an interim analysis of the EXPOSURE study describing treatment patterns in incident patients with PAH (diagnosed within 6 months of enrollment), with complementary data for prevalent patients with PAH (diagnosed >6 months before enrollment). Of 2069 enrolled patients, 1944 had follow-up data, including 1110 incident and 834 prevalent patients ⁹

Treatment Patterns

Among incident patients at baseline, <1% (3/1110) patients initiated UPTRAVI monotherapy, <1% (8/1110) initiated UPTRAVI as part of double combination therapy, and 4.7% (52/1110) initiated UPTRAVI as part of triple combination therapy. Less than 1% of the 1110 incident patients newly initiated a PAH-specific therapy as part of a treatment regimen comprised of 4 or more PAH-specific therapies; researchers did not report if any of these newly initiated therapies were UPTRAVI. Researchers were unable to determine if a new PAH-specific therapy was initiated in 1% of the 1110 incident patients.⁹

Among prevalent patients at baseline, 9% (11/834) initiated monotherapy, 5% (46/834) initiated UPTRAVI as part of double combination therapy, and 44% (365/834) initiated UPTRAVI as part of triple combination therapy. Two percent of the 834 prevalent patients newly initiated a PAH-specific therapy as part of a treatment regimen comprised of 4 or more PAH-specific therapies, but it was not reported how many of these 2% were UPTRAVI. Researchers could not determine if PAH-specific therapy was newly initiated in 3% of the 834 prevalent patients. ⁹

Gaine et al (2024) analyzed data from the EXPOSURE study to describe the treatment patterns, tolerability, and outcomes of patients with (n=178) treated with UPTRAVI in clinical practice, with patients with idiopathic PAH (n=362) included for context.¹⁰

UPTRAVI Treatment Patterns

In the CTD-PAH subgroup, 80% of patients initiated UPTRAVI as part of triple oral combination therapy, predominantly with an ERA and a PDE-5i. Most patients receiving triple combination therapy were escalated from double combination therapy, typically after at least 1 year of prior treatment. At 6 months after baseline, most patients remained on triple combination therapy (89/143; 62%), while 15% (21/143) de-escalated to double combination therapy. Thirteen percent (23/178) newly initiated UPTRAVI as part of double combination therapy. Three percent newly initiated UPTRAVI as part of a combination regimen comprising 4 or more PAH-specific therapies. Only 3% of CTD-PAH patients newly initiated UPTRAVI as monotherapy. Researchers could not determine if UPTRAVI was newly initiated in 1% of the 178 CTD-PAH patients.

Among IPAH patients, 277/362 (77%) initiated UPTRAVI as part of triple oral combination therapy and 46/362 (13%) initiated UPTRAVI as part of double oral combination therapy.  Four percent newly initiated UPTRAVI as part of a combination regimen comprising 4 or more PAH-specific therapies. Only 2% of IPAH patients newly initiated UPTRAVI as monotherapy. Researchers could not determine if UPTRAVI was newly initiated in 4% of the 362 IPAH patients.¹⁰

Safety and Long-Term Outcomes

During median (Q1-Q3) UPTRAVI exposure of 8.6 (2.5-17.2) months in CTD-PAH and 11.1 (3.8-25.5) months in idiopathic PAH, 34% (60/178) and 27% (98/362) of patients, respectively, were hospitalized at least once. Overall, 79 (44%) patients with CTD-PAH and 134 (37%) IPAH patients discontinued UPTRAVI. The most frequent reasons for discontinuation were tolerability/adverse events in 36 (20%) CTD-PAH and 55 (15%) IPAH patients and death in 29 (16%) CTD-PAH and 34 (9%) IPAH patients. One‐ and two‐year Kaplan-Meier (KM) estimates of survival were 85% and 71% in CTD-PAH patients, and 93% and 87% in IPAH patients, respectively.¹⁰

Lange et al (2024) 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.¹¹

Adult patients with group 1 PH (PAH) initiating a new PAH-specific therapy from September 17, 2017, to November 30, 2022, were included in the analysis and were grouped as low, intermediate-low, intermediate-high, or high risk to calculate the risk score.¹¹

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.¹¹

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.¹¹ The PAH-specific therapies at baseline are presented in 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).¹¹

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.¹¹

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).¹¹

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.¹¹

Soderberg et al (2025) utilized data from EXPOSURE study, an ongoing real-world, post-authorization safety study conducted as a commitment to the European Medicines Agency, to perform prespecified comparative survival analyses between patients newly initiating UPTRAVI and those newly initiating other PAH-specific therapies. Propensity score methods were applied to approximate the effects of randomization.¹²

Results

Baseline Characteristics

By November 2022, a total of 2014 patients from 149 sites were available for analysis, including 698 patients in the UPTRAVI group and 1411 in the other PAH-specific therapy group. Patients in the UPTRAVI group were more frequently treated with combination background therapy compared with those in the other PAH therapy group. Following propensity score weighting, baseline characteristics were well balanced between the groups, with 658 patients in the UPTRAVI group and 612 in the modelled other PAH therapy group. Triple combination therapy or more was predominant in both groups (81% and 79% in the UPTRAVI and modelled other PAH therapy groups, respectively), while double combination therapy was reported in 90 (14%) and 90 (15%) patients in the UPTRAVI and modelled other PAH therapy groups, respectively. Patients in the UPTRAVI group were more likely to receive combination background therapy compared with those in the modelled other PAH therapy group.¹²

Survival Analyses

Total treatment exposure was 827.9 person-years (approximately 1.3 mean years) in the UPTRAVI group, during which 70 deaths (10.5%) were reported. In the modelled other PAH therapy group, treatment exposure was 840.5 person-years (approximately 1.4 mean years), with 108 deaths (17.6%) observed. The mortality rate ratio was 0.55 (95% CI, 0.31-0.99).^12,13

Information From INSPECTIO

The INSPECTIO study was a prospective, multicenter, observational study conducted across 29 referral centers in Italy in patients with PAH. It aimed to evaluate the effects of combination therapy on disease progression and quality of life by examining noninvasive risk parameters, echocardiographic and hemodynamic measures, and patient-reported outcomes (PROs).¹⁴

Adult patients (≥18 years) with PAH confirmed by right heart catheterization and receiving macitentan and/or UPTRAVI, either as monotherapy or in combination, were enrolled.¹⁴

Results

Baseline Characteristics

The study included 176 patients with a mean age of 62.1 years; most were female (75.0%). Most patients (68.2%) had prevalent PAH, defined as diagnosis more than 6 months before enrollment, with a median disease duration of 20.8 months. At baseline, 49 patients (27.8%) received monotherapy, while 79 (44.9%) and 48 (27.3%) received double and triple oral combination therapy, respectively.¹⁴

Effectiveness Outcomes

At 12 months, the mean increase in the number of noninvasive low-risk criteria was 0.15 (P=0.0167, Wilcoxon signed-rank test), which was statistically significant. Mean risk scores decreased, with REVEAL 2.0 decreasing by 1.0 (P=0.0142, ANOVA) and REVEAL Lite 2 decreasing by 0.8 (P=0.0111, ANOVA). Among patients with paired baseline and 12 month data, the mean RV outflow Doppler acceleration time increased by 8.08 ms (standard deviation [SD], 32.80) and average left ventricular volume increased by 8.12 ml (SD, 52.43). Mean systolic pulmonary artery pressure decreased by 2.12 mmHg (SD, 22.42) by echocardiographic assessment and by 7.9 mmHg (SD, 24.10) by hemodynamic assessment. Mean pulmonary artery pressure decreased by 3.7 mmHg (SD, 15.90), pulmonary vascular resistance decreased by 1.1 Wood units (SD, 2.40), and mean mixed venous oxygen saturation increased by 1.1% (SD, 4.50).¹⁴

Therapeutic Strategy and PROs

The proportion of patients receiving triple oral combination therapy was 27.3% (48/176) at baseline, 33.8% (52/154) at 12 months, and 36.0% (27/75) at 24 months. Overall, 17.6% of patients (31/176) experienced ≥1 PAH-related hospitalization. A total of 10.8% (19/176) of patients died during the study, and all deaths were assessed as unrelated to macitentan and/or UPTRAVI treatment. The mean emPHasis-10 quality-of-life score decreased by 1.5 points at 12 months (SD, 10.50).¹⁴

Safety

Overall, 60.2% of patients (106/176) experienced ≥1 AE, with 288 events reported. TEAEs included 8 events in 7 patients (4.0%) associated with macitentan, 18 events in 12 patients (6.8%) associated with UPTRAVI, and 1 event in 1 patient (0.6%) associated with combination therapy.¹⁴

Analysis From the INSPECTIO Study

This post hoc analysis of the INSPECTIO study was conducted to support clinical decision-making and inform risk-based therapeutic strategies in patients with CTD-PAH. The analysis focused on the CTD-PAH subgroup, evaluating baseline clinical and hemodynamic characteristics, longitudinal changes in noninvasive low-risk criteria over 12 months, and response to PAH-specific therapies. Additionally, comparisons were performed between CTD-PAH and non-CTD PAH populations to examine differences between these subgroups.¹⁵

Results

Baseline Characteristics

Of 176 evaluable patients in the overall study population, 64 were classified as having CTD-PAH. This subgroup was predominantly female (93.8%) with a mean age of 66.4 years (SD, 10.88). All patients had a confirmed diagnosis of PAH by right heart catheterization, with a median time of 18.3 months from diagnosis to study enrollment.¹⁵

Primary Endpoint

In the CTD-PAH subgroup, the mean number of noninvasive low-risk criteria (WHO FC I/II, 6MWD >440 m, and brain natriuretic peptide [BNP] <50 ng/L or NT-proBNP <300 ng/L) increased from baseline to 12 months, with a mean change of +0.20 and a median change of +1 (P=0.0389, Wilcoxon signed-rank test). In contrast, no statistically significant change was observed in the non-CTD PAH subgroup (P=0.1666).¹⁵

Secondary Endpoints

The CTD-PAH subgroup consistently had a higher proportion of patients in intermediate-risk categories than the non-CTD PAH subgroup. The mean 6MWD in the CTD-PAH subgroup increased from 336.5 m at baseline to 369.2 m at 12 months (Δ=+12.1 m; n= 41), although this change was not statistically significant (P=0.4091). In the non-CTD PAH subgroup, mean 6MWD decreased from 407.7 m to 400.2 m over the same period
(Δ=-5.7 m; n=69; P=0.6118). In the CTD-PAH subgroup, BNP levels showed no statistically significant change from baseline to 12 months (n=18; P=0.6022), while NT-proBNP levels decreased (n=32) within the CTD-PAH group, without reaching statistical significance (P=0.5384). In contrast, when comparing CTD-PAH and non-CTD-PAH patients, NT-proBNP decreased significantly in the non-CTD PAH subgroup (94.0 vs -498.0; P=0.0129).¹⁵

Over the 12-month observation period, echocardiographic and hemodynamic parameters in the CTD-PAH subgroup remained generally stable, with hemodynamic findings aligning with echocardiographic assessments. Regarding treatment patterns, a higher proportion of patients in the CTD-PAH subgroup received double combination therapy (56.3%) compared with the non-CTD PAH subgroup (38.4%), whereas triple combination therapy was more frequently used in the non-CTD PAH subgroup (32.1% vs 18.8%).¹⁵

Information From the Ad Hoc Analysis From SPHERE and EXPOSURE

This ad hoc analysis was conducted using pooled data from two large prospective, multicenter, observational studies, SPHERE (US) and EXPOSURE (Europe and Canada), to enhance the generalizability of findings across regions and to increase the sample size for evaluating treatment patterns and outcomes. The analysis aimed to describe real-world use of UPTRAVI, including patient demographics and clinical characteristics at initiation, as well as titration, dosing, discontinuation patterns, and hospitalization and survival outcomes.¹⁶

Results

Patient Characteristics

The analysis included adult patients with PAH who newly initiated UPTRAVI and had ≥1 follow-up assessment (by March 2020 for SPHERE and by November 2021 for EXPOSURE). Newly initiated treatment was defined as starting UPTRAVI within 60 days before or at enrollment in SPHERE and within 30 days before, at enrollment, or during the observation period in EXPOSURE. A total of 894 patients were included, comprising 505 from EXPOSURE and 389 from SPHERE. At baseline (UPTRAVI initiation), the median age was 61 years (Q1-Q3, 48-70), and the median time since PAH diagnosis was 2.7 years (Q1-Q3, 0.8-7.4). The study population was predominantly female (73.7%), with most patients diagnosed with idiopathic PAH (53.7%) and classified as WHO FC III (60.7%).¹⁶

Risk stratification was available for a subset of patients, of whom 21.8% were categorized as low risk, 39.8% as intermediate-low risk, 29.4% as intermediate-high risk, and 9.0% as high risk. Across increasing risk categories, median age, proportion of CTD-PAH, and prevalence of cardiovascular risk factors increased, along with mRAP and pulmonary artery wedge pressure, while time since diagnosis decreased. The distribution of demographic and clinical characteristics within the risk subset was consistent with that of the overall population.¹⁶

Treatment Regimen, UPTRAVI Titration, and Dosing

At treatment initiation, 67.1% of patients received UPTRAVI as part of triple combination therapy, while 20.9% received UPTRAVI as part of double combination therapy. The proportion of patients receiving double combination therapy increased from low to higher risk categories (10.1% to 34.0%), whereas triple combination therapy was less frequent in the high-risk group (64.2%) than in other risk groups (66.4%-72.9%). Overall, 16.8% of patients initiated UPTRAVI within 6 months of PAH diagnosis.¹⁶

UPTRAVI was discontinued during the titration phase in 77 patients (8.6%), with fewer discontinuations observed in the low-risk group. Among the 742 patients who completed titration, 25.1% achieved low individualized doses, 36.3% achieved medium doses, and 37.5% achieved high doses. Median exposure was 10.8 months (Q1-Q3, 3.3-18.6). Overall, 388 patients (43.4%) discontinued treatment, most commonly due to tolerability issues (19.4%) and death (7.7%). Discontinuations due to tolerability increased with risk status, ranging from 11.6% in the low-risk group to 32.1% in the high-risk group. The most frequently reported AEs leading to discontinuation included headache (3.9%), diarrhea (2.9%), nausea (2.2%), and myalgia (1.6%).¹⁶

Outcomes

During the observation period, 28.3% of patients (n=253) experienced hospitalization, and 7.8% (n=70) died. At 1 year, the proportion of patients free from all-cause hospitalization was 86%, 73%, 57%, and 45% in the low-, intermediate-low-, intermediate-high-, and high-risk groups, respectively. Corresponding KM survival estimates at 1 year were 100%, 96%, 91%, and 59%, respectively across these risk categories among patients with available risk data.¹⁶

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 April 2026.