SUMMARY

• The phase 3 SERAPHIN trial was conducted to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic pulmonary arterial hypertension (PAH).¹
• The SERAPHIN trial included a hemodynamic substudy of 187 patients.²
  • A significant treatment effect with OPSUMIT was observed on cardiac index, pulmonary vascular resistance (PVR), and mean pulmonary arterial pressure (mPAP). Significant improvements in PVR and cardiac index were observed regardless of background PAH therapy or baseline World Health Organization (WHO) functional class (FC).²

CLINICAL DATA

Phase 3 Clinical Experience in PAH^1,3

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. Patients ≥12 years of age were randomized 1:1:1 to receive OPSUMIT, macitentan 3 mg, or placebo once daily.

Select inclusion criteria included hemodynamic confirmation of PAH via right heart catheterization (RHC).¹ Hemodynamic confirmation included all of the following: mPAP >25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) <15 mmHg and PVR ≥320 dyn⋅sec/cm⁵.

Patients were enrolled at 151 centers in 39 countries between May 2008 and December 2009. Overall, 742 patients were randomized to receive OPSUMIT (n=242), macitentan 3 mg (n=250), or placebo (n=250); mean treatment duration was 103.9, 99.5, and 85.3 weeks, respectively.

SERAPHIN Hemodynamic Substudy

A hemodynamic substudy was conducted at 44 centers in 16 countries. Centers were selected if they regularly followed patients by RHC. Patients were eligible if their baseline RHC was assessed within 3 months before randomization. The substudy included a second RHC performed at month 6. Prespecified outcomes included changes from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mPAP, PVR, and mixed venous oxygen saturation (SvO₂). Changes from baseline to month 6 in N-terminal pro b-type natriuretic peptide (NT-proBNP) was also analyzed in the substudy patients and in the overall SERAPHIN population.²

Overall, 187 patients participated in a hemodynamic substudy, with 68 randomized to placebo, 62 to macitentan 3 mg, and 57 to OPSUMIT. The majority were in WHO FC II and III, and half of the patients were on background PAH-specific therapy, mainly sildenafil. Table: Demographics and Baseline Characteristics below summarizes demographics and baseline characteristics of patients receiving OPSUMIT and placebo in the hemodynamic substudy. The baseline characteristics were consistent with the overall SERAPHIN population and were comparable across treatment groups. The mean (standard deviation [SD]) duration between RHC and study enrollment was 0.6 (1.1) months. At month 6, RHC was performed in 147 patients.²

Results

The efficacy results of patients receiving OPSUMIT vs placebo in the hemodynamic substudy are described. Cardiopulmonary hemodynamic parameters and NT-proBNP levels worsened from baseline to month 6 in placebo-treated patients and improved in patients treated with OPSUMIT (Table: Changes From Baseline to Month 6 and Values at Month 6 for Hemodynamic Parameters and NT-proBNP: OPSUMIT vs Placebo).

When compared with placebo, treatment effects in favor of OPSUMIT were observed for mPAP, CI, PVR, and NT-proBNP. OPSUMIT improved CI, mPAP, PVR, and NT-proBNP irrespective of WHO FC and background PAH-specific therapy (Table: Changes From Baseline to Month 6 for Hemodynamic Parameters and NT-proBNP by WHO FC: OPSUMIT vs Placebo, Table: Changes From Baseline to Month 6 for Hemodynamic Parameters and NT-proBNP by Background PAH-Specific Therapy: OPSUMIT vs Placebo).²

Further analyses of associations of CI, RAP, and NT-proBNP with disease progression from the SERAPHIN hemodynamic substudy are described in the publication by Galiè et al.²

Safety

The most frequently reported adverse events (AEs) in hemodynamic substudy patients receiving OPSUMIT vs placebo are reported in Table: Most Frequent AEs and Laboratory Abnormalities in Treatment Groups. Similar proportions of placebo and OPSUMIT-treated patients experienced ≥1 AE. OPSUMIT was associated with increased rates of headache, viral respiratory tract infections and bronchitis compared with placebo. No AEs related to RHC were reported.²

Literature search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 28 August 2024.