SUMMARY

• The phase 3 SERAPHIN trial was conducted to assess the long-term safety and efficacy of OPSUMIT daily in patients with symptomatic pulmonary arterial hypertension (PAH). This event-driven study met its primary endpoint of time from treatment initiation to first morbidity or mortality event. OPSUMIT also significantly reduced the risk of hospitalization for PAH.¹
• Post hoc analysis of SERAPHIN comparing treatment-naïve incident and prevalent patients showed OPSUMIT significantly improved long-term outcomes in both groups.²
• The percentage of patients with serious adverse events (SAEs) was similar between OPSUMIT and placebo treatment. Adverse events (AEs) more frequent on OPSUMIT than on placebo by ≥3% were anemia, bronchitis, headache, and nasopharyngitis.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.²
• The OPUS and OrPHeUS combined data sets provide additional insight into real-world use of OPSUMIT in incident and prevalent PAH.³
• 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.⁴
• An additional citation has been included in the REFERENCES section for your review.⁵

CLINICAL DATA

Phase 3 Clinical Experience in PAH

Comparison of OPSUMIT and Placebo Treatment in the Study Population

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.^1,6 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 (PDE5i), 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.¹

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.¹

Efficacy

The hazard ratio (HR) for the primary efficacy endpoint with OPSUMIT (mean treatment period of 103.9 weeks) vs placebo (mean treatment period of 85.3 weeks) was 0.55 (97.5% confidence interval [CI], 0.39-0.76; P<0.001). The HR for the secondary endpoint of death and/or hospitalization due to PAH for OPSUMIT vs placebo was 0.50 (97.5% CI, 0.34-0.75; P<0.001).¹

Safety

One patient randomly assigned to placebo did not receive study drug and was excluded from the safety analysis.¹ Incidence rates of elevated liver aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3×upper limit of normal [ULN]) and peripheral edema were similar across all groups. AEs more frequent on OPSUMIT than on placebo by ≥3% were anemia, bronchitis, headache, and nasopharyngitis. The number of patients discontinuing treatment due to AEs was 31 (12.4%) in the placebo group and 26 (10.7%) in the OPSUMIT group. Two patients, 1 in each group, discontinued due to anemia.¹

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.²

Efficacy Outcomes

OPSUMIT decreased the risk of a morbidity/mortality event vs placebo (risk reduction [RR]) by 60% (HR, 0.40; 95% 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).²

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 111.0 (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 (-8.0% incident vs 0.2% prevalent), hypotension (-8.3% incident vs 10% prevalent), and peripheral edema (9.5% incident vs 4.7% prevalent).²

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.³ 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. One hundred thirty (3%) patients did not have a date of diagnosis (Table: Demographics and Baseline Characteristics for Incident and Prevalent Patients at OPSUMIT Initiation). Changes in 6MWD, WHO FC and N-terminal pro-B-type natriuretic peptide (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).³

Treatment Patterns

• Of the 2024 incident patients, 1103 (54%), 828 (41%), and 93 (5%) initiated OPSUMIT as mono-, double, and triple therapies, respectively.³
  • 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.³
  • 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).³

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 (Figure: KM Estimates of Time to First Hospitalization From OPSUMIT Initiation in Incident and Prevalent Patients and KM Estimates of Survival From OPSUMIT Initiation in Incident and Prevalent Patients).³

Extended Follow-up Data From OPUS/OrPHeUS

A publication is available that reported the extended follow-up data for the combined OPUS/OrPHeUS population from April 2014 to June 2020. The study consisted of 5654 new users of OPSUMIT (enrolled set), of whom 5650 patients had follow-up data (overall follow-up set) and among them 4626 patients were diagnosed with PAH (PAH follow-up set). The median (Q1-Q3) time from PAH diagnosis to OPSUMIT initiation for the overall and PAH follow-up sets, respectively, were 8.5 (1.5-40.5) and 7.7 (1.3-40.2) months. The overall follow-up set (n=5444) included a total of 2431 (44.7%) patients diagnosed with PAH for ≤6 months before OPSUMIT initiation and 3013 (55.3) patients diagnosed with PAH for >6 months before OPSUMIT initiation. Similarly, the PAH follow-up set (n=4496) included a total of 2081 (46.3%) and 2415 (53.7%) patients diagnosed with PAH for ≤6 months and >6 months before OPSUMIT initiation, respectively. The publication reported the efficacy and safety data pertaining to the overall and PAH follow-up sets; however, results specific to the treatment naïve incident and prevalent patients were not reported.⁷

Escribano-Subias et al (2020)⁴ 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 PDE5i, 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, -2.0 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 20 June 2024.