SUMMARY

• Post hoc analysis of SERAPHIN comparing treatment-naïve incident and prevalent patients showed OPSUMIT significantly improved long-term outcomes in both groups.¹
• The frequencies of placebo-corrected AEs for OPSUMIT treatment with a difference >8% between incident and prevalent patients were nasopharyngitis, upper respiratory tract infection, viral respiratory tract infection, bronchitis, headache, dizziness, syncope, hypotension, and peripheral edema.¹
• The OPUS and OrPHeUS combined data sets provide additional insight into real-world use of OPSUMIT in incident and prevalent PAH.²
• The PRACMA study was a retrospective, observational study that evaluated changes in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk scores in patients with PAH receiving OPSUMIT over a period of at least 6 months follow-up.³
• An additional citation has been included in the REFERENCES section for your review.⁴

CLINICAL DATA

SERAPHIN Study

The Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) trial was a multicenter, double blind, randomized, placebo-controlled, event driven phase 3 study to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic PAH.^5,6 Participants ≥12 years of age (N=742) were randomized 1:1:1 to receive OPSUMIT, macitentan 3 mg, or placebo once daily. Participants were allowed to receive background therapy for PAH with either phosphodiesterase type 5 inhibitors (PDE-5i), oral or inhaled prostanoids, calcium channel blockers, or L-arginine, provided the participant had been on a stable dose for ≥3 months prior to randomization. The primary endpoint was time from treatment initiation to first morbidity or mortality event in all randomized participants up to end of treatment (EOT). This composite endpoint was defined as death, atrial septostomy, lung transplantation, initiation of intravenous (IV) or subcutaneous prostanoids, or worsening of PAH. One of the secondary endpoints included mortality and/or hospitalization due to PAH up to EOT.⁵

Participants who had idiopathic or heritable PAH or PAH related to connective-tissue disease, repaired congenital systemic to pulmonary shunts, human immunodeficiency virus (HIV), or drug use or toxin exposure were eligible. Full results for SERAPHIN can be found in the publication cited below in the REFERENCES section.⁵

Post Hoc Analysis of Treatment-Naïve Incident vs Prevalent Patients

Patient Characteristics

Among patients naïve to PAH-specific therapy (n=267), a comparison of incident (n=110, diagnosed ≤6 months prior to study entry) and prevalent (n=157, diagnosed >6 months prior to study entry) patients was conducted. The mean patient age was 49.1 (standard deviation [SD], 17.1) and 46.1 (SD, 16.3) years in the incident and prevalent groups, respectively. The mean time between diagnosis and study entry was 2.1 (SD, 1.6) months in the incident group and 47.7 (SD, 49.6) months in the prevalent group. In the overall incident and prevalent groups, significant differences were found in baseline etiology and geographical region. Notwithstanding the time from diagnosis to enrollment, both groups were similar with regard to other baseline characteristics.¹

Efficacy Outcomes

OPSUMIT decreased the risk of a morbidity/mortality event vs placebo (risk reduction [RR]) by 60% (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.20-0.79; P=0.007) in incident patients and by 53% (HR, 0.47; 95% CI, 0.24-0.92; P=0.023) in prevalent patients (see Figure: Effect of OPSUMIT on Morbidity and Mortality in Treatment-Naïve Incident and Prevalent Cohorts). OPSUMIT decreased the risk of PAH-related death or hospitalization vs placebo (RR) by 77% (HR, 0.23; 95% CI, 0.09-0.57; P=0.0007) in incident patients and by 62% (HR, 0.38; 95% CI, 0.16-0.92; P=0.026) in prevalent patients (see Figure: Effect of OPSUMIT on PAH-Related Death or Hospitalization in Treatment-Naïve Incident and Prevalent Cohorts). No statistically significant reduction was observed in all-cause mortality in patients treated with OPSUMIT vs placebo (see Figure: Effect of OPSUMIT on AllCause Mortality up to End of Study in Treatment-Naïve Incident and Prevalent Cohorts).¹

Safety

The median (interquartile range [Q] 1-Q3 exposure to study drug) treatment duration was 41.2 (21.9-97.6) weeks and 122.4 (38.4-147.1) weeks for incident patients who received placebo and OPSUMIT, respectively. Prevalent patients were treated for a median (Q1-Q3) of 111 (27.1146.3) weeks with placebo and 122.4 (82.3-151.6) weeks with OPSUMIT. When the frequencies of placebo-corrected AEs for OPSUMIT treatment are compared between incident (OPSUMIT, n=34; placebo, n=36) and prevalent (OPSUMIT, n=53; placebo, n=59) patients, 9 categories show a difference >8%: nasopharyngitis (3.6% incident vs 12.5% prevalent), upper respiratory tract infection (6.4% incident vs 10% prevalent), viral respiratory tract infection (14.7% incident vs 3% prevalent), bronchitis (6% incident vs 8.3% prevalent), headache (9.2% incident vs 6.4% prevalent), dizziness (11.9% incident vs 0.8% prevalent), syncope (-8% incident vs 0.2% prevalent), hypotension (-8.3% incident vs 10% prevalent), and peripheral edema (9.5% incident vs 4.7% prevalent).¹

Information From the OPUS/OrPHeUS Data Sets in PAH

OPsumit USers (OPUS) Registry was a prospective, multicenter, observational drug registry in the US (NCT02126943), which included patients newly treated with OPSUMIT, regardless of diagnosis and prior/ongoing PAH therapy. OPsumit Historical USers (OrPHeUS) cohort study was a retrospective, multicenter, US medical chart review (NCT03197688). OrPHeUS included patients who newly initiated OPSUMIT between October 2013 and December 2016. However, patients enrolled in OPUS were not allowed to participate in OrPHeUS.² The observation period was April 2014-June 2020 for OPUS, and October 2013-March 2017 for OrPHeUS.⁷

As of February 2020, OPUS/OrPHeUS had 4540 PAH patients with follow-up data, of whom 2024 (45%) were incident and 2386 (53%) were prevalent. The median time from PAH diagnosis in these groups, respectively, was 1.1 months and 36.2 months. One hundred thirty (3%) patients did not have a date of diagnosis. In the incident and prevalent groups, respectively, the median age was 63 years and 60 years; 74% and 77% of patients were female; 58% and 56% of patients had idiopathic/heritable PAH; 27% and 32% of patients were World Health Organization (WHO) functional class (FC) II and 58% and 56% of patients were WHO FC III; 43% and 28% of patients belonged to high N-terminal pro-B-type natriuretic peptide (NT-proBNP) risk category; the median 6-minute walk distance (6MWD) was 270 m and 318 m. Changes in 6MWD, WHO FC and NT-proBNP risk category were noted from baseline to follow-up at 12±6 months (Table: Change in Clinical Characteristics From Baseline to Follow-up at 12±6 Months).²

Treatment Patterns

• Of the 2024 incident patients, 1103 (54%), 828 (41%), and 93 (5%) initiated OPSUMIT as mono-, double, and triple therapies, respectively.²
  • At 6 months after initiation, 560 (28%), 492 (24%), and 61 (3%) patients continued with OPSUMIT as mono-, double, and triple therapies, respectively.
  • At 12 months after initiation, 390 (19%), 318 (16%), and 48 (2%) patients continued with OPSUMIT as mono-, double, and triple therapies, respectively.
• Of the 2386 prevalent patients, 684 (29%), 1201 (50%), and 501 (21%; including 2 patients who were receiving 4 classes of PAH therapy) initiated OPSUMIT as mono-, double, and triple therapies, respectively.²
  • At 6 months after initiation, 432 (18%), 788 (33%), and 358 (15%; including 3 patients who were receiving 4 classes of PAH therapy) patients continued with OPSUMIT as mono-, double, and triple therapies, respectively.
  • At 12 months after initiation, 309 (13%), 606 (25%), and 281 (12%; including 3 patients who were receiving 4 classes of PAH therapy) patients continued with OPSUMIT as mono-, double, and triple therapies, respectively.

Safety

The hepatic safety profile of OPSUMIT was similar between incident and prevalent patients (Table: OPSUMIT Exposure and AEs).²

Hospitalizations and Survival

Although newly diagnosed patients had greater disease severity at OPSUMIT initiation, hospitalizations and survival were similar in incident and prevalent PAH patients treated with OPSUMIT. The Kaplan-Meier (KM) estimates of time to first hospitalization in incident and prevalent patients, respectively, were 64% and 67.2% at 12 months and 51.8% and 52.5% at 24 months. The KM estimates of survival in incident and prevalent patients, respectively, were 89.8% and 90.8% at 12 months and 81.8% each at 24 months.²

Escribano-Subias et al (2020)³ conducted a retrospective, observational study to evaluate changes in REVEAL risk scores in incident and prevalent adult patients with PAH treated with OPSUMIT for ≥6 months follow-up in Spain (N=81).

Results

Patient Characteristics

• Mean age of participants was 57.2 years and 50.6% of patients had idiopathic or heritable PAH.
• Of the PAH patients, 33 were incident and 48 were prevalent.
• Forty-two percent, 44.4%, and 13.6% of patients received OPSUMIT monotherapy, OPSUMIT plus a PDE5i, or OPSUMIT plus prostacyclin with or without a PDE-5i, respectively.
• Mean baseline REVEAL risk score was 8.7 points.

Efficacy

• The mean REVEAL risk score was 7.2 points after ≥6 months follow-up.
• The mean change in REVEAL risk score among 57 patients who were valid to compute a REVEAL risk score was -1.4 (95% CI, -2 to -0.9) points over at least 6 months.
  • The mean change in REVEAL risk score over a period of at least 6 months among incident patients (n=23) receiving OPSUMIT monotherapy (n=15) or OPSUMIT plus a PDE5i (n=8) was -1.3 (95% CI, -2.5 to -0.2) and -2.8 (95% CI, -5.8 to -0.3), respectively.
  • The mean change in REVEAL risk score over a period of at least 6 months among prevalent patients (n=34) receiving OPSUMIT monotherapy (n=10), OPSUMIT plus a PDE5i (n=17), or OPSUMIT plus prostacyclin with or without a PDE5i (n=7) was -1.1 (95% CI, -2.2 to 0.04), -1.1 (95% CI, -2.1 to -0.04), and -1.4 (95% CI, -2.7 to - 0.1), respectively.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 04 June 2025.