SUMMARY

• SPHERE (SelexiPag: tHe usErs dRug rEgistry) is a United States (US)-based, multicenter, prospective, observational, real-world registry that was established with the objective of assessing the realworld outcomes of UPTRAVI treatment.¹
  • Of the 759 patients with pulmonary arterial hypertension (PAH) enrolled in SPHERE, most patients (95%) were already receiving treatment with other PAH-specific medications before UPTRAVI initiation, with approximately half receiving dual therapy consisting of an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 inhibitor (PDE-5i) and onethird receiving monotherapy with an ERA or a PDE-5i.¹
  • The median maintenance dose of UPTRAVI was 1100 mcg twice daily (BID; n=729) and the median duration of UPTRAVI titration was 8.1 weeks (N=759).^1,2
  • Over 18 months, 39.4%, 39.7%, and 39.0% of patients in the overall, newly, and previously initiated populations, respectively, experienced ≥1 hospitalization. The estimated overall survival rates in the overall, newly, and previously initiated populations, respectively, were 93.4%, 88.9%, and 97.8% at 12 months and 89.4%, 84.2%, and 94.5% at 18 months.¹
  • The 18-month UPTRAVI discontinuation rates (due to an adverse event [AE]) were 22.0%, 32.0%, and 11.9% in the overall, newly, and previously initiated populations, respectively.¹
• Of the 759 patients with PAH, 124 transitioned to UPTRAVI from another prostacyclin pathway agent (PPA; inhaled, 58 [47%]; oral, 14 [11%]; parenteral, 52 [42%]). At month 18, the overall survival rate for patients who transitioned to UPTRAVI was 89%. A total of 40% of transitioned patients experienced ≥1 all-cause hospitalization.³ 
• Of the 759 patients with PAH, 246 World Health Organization (WHO) group 1 patients self-reported having mental health comorbidities of depression (22.9%), anxiety or anxiety disorder (14.7%), or bipolar disorder (1.2%). Time to UPTRAVI initiation from diagnosis was longer in patients with mental health comorbidities (3.3 years) than those without (2.6 years). The overall survival rate at 36 months was 77% in patients with mental health comorbidities and 84% in those without.⁴ 
• Of the 759 patients with PAH, Hispanic patients (n=45) were younger at the time of diagnosis and UPTRAVI initiation, had greater time from diagnosis to UPTRAVI initiation, and had WHO functional class (FC) and REVEAL (Registry to EValuate Early And Long-term PAH disease management) 2.0/REVEAL Lite 2 risk scores that indicated less severe disease and lower risk compared to non-Hispanic White (n=549) or Black/African American patients (n=117).⁵

CLINICAL DATA

SPHERE (SelexiPag: tHe usErs dRug rEgistry)

SPHERE is a US-based, multicenter, prospective, observational, real-world registry that was established with the objective of assessing the realworld outcomes of UPTRAVI treatment in the US. It contains details of patients receiving UPTRAVI in routine clinical practice and provides information regarding patient demographics and disease characteristics in the enrolled population.¹

Methods

Adult (≥18 years old) patients on active UPTRAVI treatment and with documentation of their titration regimen were enrolled from November 2016 to March 2020 and followed-up for up to 18 months. Patients were either newly initiated (starting UPTRAVI ≤60 days before enrollment) or previously initiated on UPTRAVI (starting UPTRAVI >60 days before enrollment). Baseline assessments for the newly and previously initiated populations were defined as the first available measurements between the first UPTRAVI dose and enrollment and the closest measurement performed around the first UPTRAVI dose, respectively. Patients who previously received UPTRAVI in a clinical trial, previously discontinued UPTRAVI (for any reason) before enrolling in the study, or participated in a blinded clinical trial or trial of any unapproved drug were excluded from the study. Data collection was performed at routine clinical visits on a quarterly basis.^1,6

UPTRAVI was initiated at 200 mcg BID and then titrated at weekly intervals of 200 mcg BID until the highest tolerated dose (up to a maximum of 1600 mcg BID) was attained. The titration phase was defined as the period between UPTRAVI initiation, and the highest dose reached within 6 months of UPTRAVI initiation. The maintenance dose was defined as the first dose received post titration, which was maintained for ≥14 days without dose interruption and/or change and determined by tolerability.²

Each patient was assigned a 1-year mortality risk category at baseline using the REVEAL 2.0 risk calculator that defined risk categories as low (score ≤6), intermediate (score 7-8), and high (score ≥9).^1,6

Results

Baseline Characteristics

Of the total 829 patients with pulmonary hypertension (WHO groups 1-5) enrolled in SPHERE, 759 had PAH (WHO group 1), of whom 387 and 372 were newly and previously initiated on UPTRAVI, respectively. At baseline, most patients (n=387 [51.0%]) were categorized as WHO FC III, with a higher proportion of patients (n=216 [55.8%] vs n=171 [46.0%]) belonging to FC III in the newly vs previously initiated population. According to REVEAL 2.0, 324 (42.7%), 229 (30.2%), and 206 (27.1%) patients were in the low-, intermediate, and high-risk categories, respectively.¹ Information regarding the baseline characteristics in patients with PAH is summarized in Table: Baseline Characteristics in Patients With PAH.

Concomitant Medications

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.¹ Data on the use of concomitant PAHspecific medications before UPTRAVI initiation in the overall, newly, and previously initiated populations are summarized in Table: PAHSpecific Concomitant Medications Before UPTRAVI Initiation in Patients With PAH.

Dosing and Titration

Of the 759 patients with PAH, 729 received a median maintenance UPTRAVI dose of 1100 mcg BID (range, 100-3200). In the overall PAH population (N=759), the median duration of UPTRAVI titration was 8.1 weeks (range, 1.1-26.9), with 671 (88.4%) patients (newly initiated, n=338 [87.3%]; previously initiated, n=333 [89.5%]) titrating at speeds slower than 200 mcg BID per week and 88 (11.6%) patients (newly initiated, n=49 [12.7%]; previously initiated, n=39 [10.5%]) titrating at speeds equal to or faster than 200 mcg BID per week. Of the 759 patients with PAH, 114 (15.0%), 238 (31.4%), and 310 (40.8%) received a BID maintenance dose of UPTRAVI 200-400, 600-1000, and >1200 mcg, respectively, whereas 97 (12.8%) received a different or an unrecorded UPTRAVI dose.^1,2

Efficacy

Information regarding the changes in the WHO FC and REVEAL 2.0 risk category status from baseline to months 6, 12, and 18 in patients with PAH is summarized in Table: Changes in the WHO FC and REVEAL 2.0 Risk Category Status in Patients With PAH.¹

Among 759 patients with PAH, 39.4%, 39.7%, and 39.0% of patients in the overall, newly, and previously initiated populations, respectively, experienced ≥1 hospitalization over 18 months.¹

Patients in the high- or intermediate-risk category were more likely to be hospitalized than those in the low-risk category (high- vs low-risk: hazard ratio [HR], 2.85; 95% confidence interval [CI], 2.12-3.84; P<0.0001; intermediate- vs low-risk: HR, 1.69; 95% CI, 1.242.31; P=0.0009). Time to first hospitalization was similar between maintenance doses of UPTRAVI (600-1000 vs 200-400 mcg: HR, 1.29; 95% CI, 0.85-1.94; P=0.2313; >1200 vs 200-400 mcg: HR, 1.03; 95% CI, 0.68-1.54; P=0.9070) and between baseline PAH therapies (dual therapy vs monotherapy: HR, 0.82; 95% CI, 0.62-1.07; P=0.1349; triple therapy vs monotherapy: HR, 0.79; 95% CI, 0.511.24; P=0.3100).¹

The estimated overall survival rates in the overall, newly, and previously initiated populations, respectively, were 93.4%, 88.9%, and 97.8% at 12 months and 89.4%, 84.2%, and 94.5% at 18 months.¹

Patients in the high- or intermediate-risk category showed poorer overall survival than those in the low-risk category (high- vs low-risk: HR, 10.52; 95% CI, 5.54-19.99; P<0.0001; intermediate- vs low-risk: HR, 2.43; 95% CI, 1.16-5.10; P=0.0192). Overall survival was similar between maintenance doses of UPTRAVI (600-1000 vs 200-400 mcg: HR, 1.09; 95% CI, 0.56-2.12; P=0.7926; >1200 vs 200-400 mcg: HR, 1.04; 95% CI, 0.551.95; P=0.9095) and between baseline PAH therapies (dual therapy vs monotherapy: HR, 0.88; 95% CI, 0.55-1.38; P=0.5691; triple therapy vs monotherapy: HR, 0.80; 95% CI, 0.37-1.76; P=0.5835).¹

Safety

The mean (standard deviation [SD]) UPTRAVI treatment duration during the study period was 13.5 (6.3), 12.5 (6.7), and 14.6 (5.5) months, in the overall, newly, and previously initiated populations, respectively.¹ For information related to safety in the overall patient population (N=829), see Table: AEs in the Total Enrolled Population.

Among 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, and previously initiated populations, respectively.¹

Patients in the high-risk category were more likely to discontinue UPTRAVI due to an AE than those in the low-risk category; however, no differences were noted between those in the intermediate- and low-risk categories (high- vs low-risk: HR, 3.44; 95% CI, 2.44-4.85; P<0.0001; intermediate- vs low-risk: HR, 1.26; 95% CI, 0.85-1.87; P=0.2522). UPTRAVI discontinuation (due to an AE) was similar between baseline PAH therapies (dual therapy vs monotherapy: HR, 0.91; 95% CI, 0.66-1.25; P=0.5545; triple therapy vs monotherapy: HR, 0.65; 95% CI, 0.36-1.16; P=0.1472).¹

UPTRAVI discontinuation related to PAH progression was similar between maintenance doses of UPTRAVI (600-1000 vs 200-400 mcg: HR, 0.60; 95% CI, 0.32-1.14; P=0.1204; >1200 vs 200-400 mcg: HR, 0.91; 95% CI, 0.51-0.62; P=0.7450). Patients with PAH receiving a maintenance dose of 200-400 mcg were more likely to discontinue UPTRAVI due to an AE unrelated to PAH progression (600-1000 vs 200-400 mcg: HR, 0.46; 95% CI, 0.26-0.82; P=0.0081; >1200 vs 200-400 mcg: HR, 0.17; 95% CI, 0.08-0.34; P<0.0001).¹

Analysis of Patients in the SPHERE Registry Who Transitioned to UPTRAVI From Another PPA

Methods

An analysis of SPHERE data described the characteristics and outcomes of patients with PAH who transitioned to UPTRAVI from another PPA.³ 

Results

Baseline Characteristics

Of the 759 PAH patients enrolled, 124 transitioned to UPTRAVI from another PPA (inhaled, 58 [47%]; oral, 14 [11%]; parenteral, 52 [42%]). Majority of the transitioned patients were female (84%) and White (71%), with either idiopathic (57%) or connective tissue disease-associated PAH (25%). The median age at UPTRAVI initiation was 59 years. Among the 124 patients, 100 (80.6%) completed the 18-month observation period. Reasons for study discontinuation included death (18 [14.5%]), enrollment in another clinical trial (2 [1.6%]), loss to follow-up (3 [2.4%]), and physician decision (1 [0.8%]).³ 

Before study enrollment, the baseline right heart catheterization was performed at a median of 10.8 months. The median baseline mean pulmonary artery pressure and pulmonary vascular resistance of the patients who transitioned to UPTRAVI was 42 mmHg (interquartile range [IQR] 32, 55) and 5.1 Wood units (IQR 3.6, 9.0), respectively. The median 6-minute walk distance for transitioned patients was 324.0 meters (IQR 223.5, 420.0). The distribution of WHO FC I, II, III, and IV for transitioned patients was 8, 47, 51, and 10, respectively, and WHO FC was not reported in 8 patients. According to REVEAL 2.0, 54.8%, 25.8%, and 19.4% of transitioned patients were in the low-, intermediate-, and high-risk categories, respectively. Across all transitioned patients, the median maintenance dose was 1400 mcg, with a lower median dose of 1300 mcg for oral-transitioned patients and a higher median dose of 1600 mcg for IV-transitioned patients.³ 

Overall Survival and Safety

At month 18, the overall survival rate for patients who transitioned to UPTRAVI was 89%. Of the 18 deaths reported, 9 were related to PAH. Among patients who permanently discontinued UPTRAVI, 29 discontinued due to AEs; 19, related to PAH progression; 5, due to UPTRAVI-related AE; and 5, due to non-disease progression or UPTRAVI. A total of 14 (11.3%) patients who discontinued UPTRAVI transitioned to a prostanoid.³ 

All-Cause Hospitalization

A total of 40% of transitioned patients experienced ≥1 all-cause hospitalization. The time to first hospitalization was similar regardless of the PPA type transitioned from. Among the 58 patients with both baseline and 18-month WHO FC follow-up data, 64% had stable and 21% had improved WHO FC, with similar results regardless of the PPA type transitioned from.³ 

Analysis of Patients in the SPHERE Registry Based on Self-Reported Mental Health Comorbidities

An analysis of SPHERE data described the treatment and outcomes of patients with self-reported mental health comorbidities receiving UPTRAVI for PAH.⁴ 

Baseline Characteristics

A total of 246/759 (32%) WHO group 1 patients reported having mental health comorbidities of depression (22.9%), anxiety or anxiety disorder (14.7%), or bipolar disorder (1.2%). Among patients with and without mental health comorbidities, respectively, prior PAH-specific monotherapy was received by 82 (33%) and 142 (28%); dual therapy, by 123 (50%) and 298 (58%); and triple therapy, by 29 (12%) and 44 (9%). Patients with mental health comorbidities were less likely to receive dual ERA-PDE-5i therapy than those without (34% vs 45%). Other concomitant PAH-specific treatments in both groups were similar.⁴ 

In patients with mental health comorbidities, there was a longer time to UPTRAVI initiation from diagnosis (3.3 years) than those without (2.6 years). In both groups, the median duration of UPTRAVI titration was 8.1 weeks, with a median individualized dose of 1200 mcg BID. Persistence was similar in both groups. Discontinuation rates for AE unrelated to PAH progression were 9% in patients with mental health comorbidities and 11% in those without. The distribution of baseline WHO FC I, II, III, and IV in patients with mental health comorbidities was 6%, 25%, 57%, and 5%, respectively. Among the patients with mental health comorbidities, 44%, 34% and 22%, were in the low-, intermediate-, and high-risk categories, respectively, according to REVEAL 2.0.⁴

Overall Survival

The overall survival rate at 36 months was 77% in patients with mental health comorbidities and 84% in those without.⁴ 

All-Cause Hospitalization

Among patients with baseline and follow-up records at 18 months, 87% had stable (62%) or improved (25%) WHO FC, and 40% had stable (28%) or improved (12%) REVEAL 2.0 risk status versus baseline. The median time to the first hospitalization was 10.7 months (IQR 14.2) for patients with mental health comorbidities and 15.6 months (IQR 13.8) for those without.⁴ 

Analysis of Patients in the SPHERE Registry Based on 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.⁵

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.⁵

The median age at which patients were diagnosed with PAH and initiated on UPTRAVI was lowest among Hispanic patients (43.0 years and 51.0 years, respectively). The shortest median duration from PAH diagnosis to the initiation of UPTRAVI was observed in non-Hispanic White patients (2.6 years) while Hispanic patients experienced the longest time from diagnosis to initiation of UPTRAVI (4 years). For information related to patient demographics and clinical characteristics by Race/Ethnicity, see Table: Key Patient Demographics and Clinical Characteristics at UPTRAVI Initiation by Race/Ethnicity.⁵

FC and Risk Stratification

A larger proportion of Hispanic patients were classified as WHO FC II (42.2%) at baseline compared to non-Hispanic White (27.5%) and Black/ African American patients (26.5%) indicating less severe disease. A smaller proportion of Hispanic patients were classified as FC III (40%) compared to non-Hispanic White (53.4%) and Black/African American patients (50.4%). REVEAL 2.0/REVEAL Lite 2 risk calculators classified a greater proportion of Hispanic patients as low risk (53.3%/37.8%) compared to non-Hispanic White (39.9%/30.4%) and Black/African American patients (44.4%/30.8%).⁵

Risk of Hospitalization and Discontinuations

The risk of hospitalization was similar between patients newly or previously diagnosed at UPTRAVI initiation within any race/ethnicity group.⁵ At the end of the 18-month follow-up, 66.8% of all patients were still receiving UPTRAVI, and the rates of UPTRAVI discontinuation were similar across race/ethnicity groups (33%). For more information regarding UPTRAVI discontinuation, see Table: UPTRAVI Discontinuation by Race/Ethnicity.⁵

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 14 January 2025.