SUMMARY

• EXPOSURE (EXPloratory Observational Study of Uptravi in Real lifE; EUPAS19085) is an ongoing, international, multicenter, prospective, observational study in patients with pulmonary arterial hypertension (PAH) initiating a new PAH-specific therapy in Europe and Canada.¹ 
• An interim analysis (data cut off: November 2022) described the clinical characteristics, treatment patterns, and outcomes of incident (PAH diagnosis within 6 months of enrollment) and prevalent (PAH diagnosis for >6 months at enrollment) patients.¹
  • The Kaplan-Meier (KM) estimates for time to first all-cause hospitalization in the incident group were 70% (95% confidence interval [CI], 65-74) and 57% (95% CI, 51-63) at 12 months and 24 months, respectively; in the prevalent group, 73% (95% CI, 67-78) and 59% (95% CI, 52-66) at 12 months and 24 months, respectively.
  • The KM estimates for time to all-cause death in the incident group were 88% (95% CI, 84-92) and 80% (95% CI, 74-84) at 12 months and 24 months, respectively; in the prevalent group, 90% (95% CI, 86-93) and 79% (95% CI, 73-84) at 12 months and 24 months, respectively.
• The EXPOSURE RISK study described 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.² 
  • Over the UPTRAVI exposure period, the proportion of patients hospitalized increased with increasing risk status (16%, 23%, 34%, and 42% for low, intermediate-low, intermediate-high, and high risk groups, respectively). 
  • The proportion of patients who died increased with increasing risk status (1%, 4%, 12%, and 21% for low, intermediate-low, intermediate-high, and high risk groups, respectively). 
  • 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 adverse events (AE) during the exposure period. 
• Another analysis described the clinical characteristics, treatment patterns, tolerability, and outcomes from the ongoing EXPOSURE study in patients with PAH associated with connective tissue disorder (PAH-CTD) treated with UPTRAVI in clinical practice.³ 
  • The 1-year KM estimate for time to first all-cause hospitalization in patients with PAH-CTD was 63% (95% CI, 46-76).
  • The 1-year and 2-year KM survival estimates in patients with PAH-CTD were 85% (95% CI, 69-93) and 71% (95% CI, 49-84), respectively. 
  • Overall, 79 (44%) patients in the PAH-CTD group discontinued UPTRAVI. 
• Another analysis utilizing EXPOSURE data described the clinical characteristics, treatment patterns, and outcomes of PAH patients with cardiovascular (CV) comorbidities receiving UPTRAVI.⁴  
  • Over the UPTRAVI exposure period, the proportion of patients hospitalized were 24%, 27%, 23%, and 36% in 0, 1, 2, and ≥3 comorbidities groups, respectively.
  • The proportion of patients who died were 6%, 11%, 2%, and 14% in 0, 1, 2, and ≥3 comorbidities groups, respectively.
  • A total of 32%, 34%, 29%, and 41% of patients in 0, 1, 2, and ≥3 comorbidities groups, respectively, discontinued UPTRAVI.
• Additional conference abstracts were identified in the literature search and included in the REFERENCES section for your review.^5,6 

CLINICAL DATA

EXPOSURE (EXPloratory Observational Study of Uptravi in ReallifE)

EXPOSURE (EUPAS19085) is an ongoing, international, multicenter, prospective, observational study of patients with PAH initiating a new PAH-specific therapy in Europe and Canada. It is a post-authorization safety study (PASS) that also characterizes the safety profile of UPTRAVI.^1,7

The study includes adult patients (aged ≥18 years) with group 1 pulmonary hypertension (PH; PAH), initiating a new PAH-specific therapy (excluding calcium channel blockers) within 1 month of enrollment or at enrollment. Patients who have newly initiated a PAH-specific therapy must not have been previously treated with that same drug.¹

There are 2 patient cohorts: the UPTRAVI cohort that includes patients initiating UPTRAVI within 1 month of enrollment, at enrollment, or during the observation period, and the Other PAH-specific therapy cohort that includes patients initiating any other PAH-specific therapy (excluding calcium channel blockers) less than 1 month prior to enrollment or at enrollment and who were never treated with UPTRAVI. Patients in the Other PAH-specific therapy cohort may initiate UPTRAVI during the study; from the time of UPTRAVI initiation they are considered as part of the UPTRAVI cohort and not the Other PAH-specific therapy cohort.⁷ 

Data From an Interim Analysis

Muller et al (2024)¹ conducted an interim analysis (September 17, 2017-November 30, 2022) that described the clinical characteristics, treatment patterns, and outcomes of incident (PAH diagnosis within 6 months of enrollment) and prevalent (PAH diagnosis for >6 months at enrollment) patients.

Results

Selected Baseline Characteristics

Of the 2069 patients enrolled, 1944 (incident, n=1110; prevalent, n=834) had follow-up data, of whom 69% of patients were female, and the median age was 63 years. The median (quartile [Q]1-Q3) time since PAH diagnosis was 2.4 (0-28.8) years; 52%, 27%, and 10% of patients had idiopathic PAH (IPAH), PAH-CTD, and PAH associated with congenital heart disease (PAH-CHD), respectively. Thirty-two percent of patients were World Health Organization (WHO) functional class (FC) II and 60% of patients were WHO FC III.¹

PAH-specific Treatment Patterns

At baseline, 48%, 43%, and 8% of patients in the incident group and 14%, 31%, and 49% of patients in the prevalent group were on monotherapy, double, and triple combination therapies, respectively.¹

The median (Q1-Q3) observation period was 17 (7.5-29.9) months for the incident group and 19.6 (10.2-32.2) months for the prevalent group. Overall, 199/530 (38%) incident patients escalated from oral/inhaled monotherapy to oral/inhaled double combination therapy, with a median (Q1-Q3) time to escalation of 3.4 (1.9-6.6) months. Seventy-eight out of 455 (17%) incident patients escalated from oral/inhaled double combination therapy to oral/inhaled triple combination therapy, with a median (Q1-Q3) time to escalation of 7 (3.4-12.7) months. At 6 and 12 months from baseline, most of the prevalent patients remained on the same treatment regimen received at baseline.¹

Hospitalization

Overall, 36% and 37% of patients were hospitalized in the incident and prevalent groups, respectively; 22% and 24% of patients had PAH-related hospitalizations in the incident and prevalent groups, respectively. The KM estimates for time to first all-cause hospitalization in the incident group were 70% (95% CI, 65-74) and 57% (95% CI, 51-63) at 12 months and 24 months, respectively; in the prevalent group, 73% (95% CI, 67-78) and 59% (95% CI, 52-66) at 12 months and 24 months, respectively.¹

Survival

Overall, 207 patients in the incident group and 161 patients in the prevalent group died; as per the physician’s judgement, 81 out of 144 (56%) deaths and 84 out of 131 (64%) deaths were PAH-related in the incident and prevalent groups, respectively. The KM estimates for time to all-cause death in the incident group were 88% (95% CI, 84-92) and 80% (95% CI, 74-84) at 12 months and 24 months, respectively; in the prevalent group, 90% (95% CI, 86-93) and 79% (95% CI, 73-84) at 12 months and 24 months, respectively.¹

Study Limitation

The analysis only included patients initiating a new PAH-specific therapy, potentially leaving out those initiating a more intensive treatment regimen. Additionally, only patients initiating UPTRAVI in Europe and Canada were considered, limiting generalisability of results to wider geographical regions.¹

Data From the EXPOSURE RISK Study

Lange et al (2024)² described 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.

Patients were grouped into low, intermediate-low, intermediate-high, or high risk groups to calculate the risk score.²

Results

Selected Baseline Characteristics

As of November 30, 2022, the risk assessment at baseline was calculated for 535 out of 698 (77%) patients, of whom 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, 6-mimute walk distance (6MWD), and N-terminal pro B-type natriuretic peptide (NT-proBNP) worsened with increasing risk groups.²

Titration and Dosing of UPTRAVI and PAH-specific Treatment Patterns

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] months; intermediate-low risk, 1.8 [1-2.8] months; intermediate-high risk, 1.8 [1.1-3] months). The majority of patients in all risk groups (85%-93%) had completed the 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).²

Transition to a 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).² The PAH-specific therapies at baseline are presented in the Table: Breakdown of PAH-specific Therapies at Baseline.

Hospitalization and Survival

The median (Q1-Q3) duration of UPTRAVI exposure was longer for the low risk group (11.5 [4-25.3] months) compared to the higher risk groups (intermediate-low risk, 11.4 [4-26.4] months; intermediate-high risk, 10.1 [3.7-24.1] months; high risk, 9 [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 low, intermediate-low, intermediate-high, and high risk groups, respectively); 71% of hospitalization cases in the high risk group were PAH-related compared to 47%-54% of cases in the other risk groups. 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.²

The proportion of patients who died increased with the increasing risk status during the UPTRAVI exposure period (1%, 4%, 12%, and 21% for low, intermediate-low, intermediate-high, and high risk groups, respectively); 80% of death cases in the high risk group were PAH-related compared to 0%-71% of cases in the other risk groups. At 1 year, the KM estimates for 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).²

Safety

A total of 12%, 14%, 15%, and 23% of 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 1 of the most frequently reported AEs for patients in the high risk group.²

Study Limitation

The study population was enrolled at the time of UPTRAVI initiation and may reflect patients experiencing deterioration. Additionally, the study population was prevalent and therefore subject to survivor bias. The study excluded the most severe patients who are not eligible to receive UPTRAVI.²

Analysis From EXPOSURE in Patients With PAH-CTD

Gaine et al (2024)³ described the clinical characteristics, treatment patterns, tolerability, and outcomes from the ongoing EXPOSURE study in patients with PAH-CTD treated with UPTRAVI in clinical practice.

Results

Selected Baseline characteristics

As of November 30, 2022, of the 698 patients who initiated UPTRAVI and had follow‐up information, 178 had PAH‐CTD. Of the PAH-CTD patients, 71% had systemic sclerosis, 8% had mixed CTD, 7% had systemic lupus erythematosus, 6% had rheumatoid arthritis, 4% had Sjogren’s syndrome, and 3% had undifferentiated CTD. The median age of the PAH-CTD population was 68 years and 88% were females, with a median time since diagnosis of 1.7 years. At baseline, 1%, 33%, 63%, and 3% had WHO FC I, II, III, and IV, respectively.³

Titration and Dosing of UPTRAVI and PAH-specific Treatment Patterns

The median (Q1-Q3) duration of UPTRAVI titration was 1.5 (0.7-2.8) months. Of the 151 patients who completed the titration, the median (Q1-Q3) UPTRAVI individualized dose was 600 (400-1000) mcg BID. By distribution, 30% of patients were in the low dose group (200 or 400 mcg BID), 41% of patients were in the medium dose group (600, 800, or 1000 mcg BID), and 23% of patients were in the high dose group (1200, 1400, or 1600 mcg BID). Eleven patients did not receive a dose consistent with the dosing groups.³

UPTRAVI was initiated as part of a triple combination therapy in 142 (80%) patients, with 131 (92%) taking UPTRAVI in combination with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE-5i) and 11 (8%) taking UPTRAVI in combination with an ERA and soluble guanylate cyclase (sCG) stimulator. Among the 13% of patients on double combination therapy, 13 (57%) patients were on UPTRAVI plus ERA and 10 (43%) patients were on UPTRAVI plus PDE-5i. Majority of patients (56%) initiating triple oral combination therapy escalated from double oral combination therapy, with most of them being on double combination therapy for at least 1 year before treatment escalation with UPTRAVI. Of the 91 (61%) patients on triple combination therapy at 6 months post baseline, 89 remained on triple combination therapy from baseline, and 2 escalated from double combination therapy at baseline. At 6 months post baseline, 21/143 (15%) patients de-escalated from triple to double combination therapy. At 12 months post baseline, the majority of patients (n=122) maintained the treatment regimen with fewer follow-up observations (15% and 56% of patients on double and triple combination therapies, respectively).³

Hospitalization and Survival

The 1-year KM estimate for time to first all-cause hospitalization in patients with PAH-CTD was 63% (95% CI, 46-76). The 1-year and 2-year KM estimates for time to first all-cause hospitalization in patients with IPAH (patient group used in the analysis for context) were 76% (95% CI, 66-83) and 66% (95% CI, 54-76), respectively. The 1-year and 2-year KM survival estimates for PAH-CTD patients were 85% (95% CI, 69-93) and 71% (95% CI, 49-84), respectively. The 1-year, 2-year, and 3-year KM survival estimates for IPAH patients were 93% (95% CI, 85-97), 87% (95% CI, 75-93), and 82% (95% CI, 67-90), respectively.³ The incidence rates, mortality rates, and hospitalizations are reported in the Table: Hospitalization and Mortality During the UPTRAVI Exposure Period.

Safety

UPTRAVI discontinuation occurred in 79 (44%) patients with PAH-CTD, with a median time to discontinuation of 4.3 months. The reasons for discontinuation were tolerability/AEs (20%), death (16%), PAH disease progression (4%), administrative (2%), treatment non-compliance (<1%), and unknown (<1%). There were 70 (39%) patients who experienced an AE while on UPTRAVI. The most frequent AEs occurring in ≥5% of patients were diarrhea (11%), headache (7%), and dyspnea (5%).³

Study Limitation

There was a lack of diversity of CTD subtypes within the EXPOSURE study as the underlying disease was mainly systemic sclerosis (71%).³

Analysis From EXPOSURE in Patients With CV Comorbidities

Soderberg et al (2022)⁴ described the clinical characteristics, treatment patterns, and outcomes of PAH patients with CV comorbidities receiving UPTRAVI.

As of November 2021, patients who initiated UPTRAVI and had follow-up information were categorized according to the number of CV comorbidities (including body mass index ≥30 kg/m², diabetes mellitus, history of systemic hypertension, and historical evidence of reported significant coronary artery disease) present prior to or at UPTRAVI initiation.⁴ 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.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 April 2025.