SUMMARY

• A DUE was a prospective, multicenter, double-blind, randomized, active-controlled, triple-dummy, parallel group, group-sequential, adaptive phase 3 study (NCT03904693) that evaluated the efficacy and safety of OPSYNVI as a single-tablet combination therapy (STCT) vs macitentan 10 mg and tadalafil 40 mg monotherapies in patients with pulmonary arterial hypertension (PAH).¹
• A subgroup analysis of patients from the A DUE study was conducted based on their background therapy status (treatment-naïve, prior endothelin receptor antagonist [ERA], or prior phosphodiesterase-5 inhibitor [PDE-5i]) to evaluate the efficacy and safety of OPSYNVI vs macitentan 10 mg and tadalafil 40 mg monotherapies.²
  • In treatment-naïve and prior ERA/PDE-5i patients, the effect of OPSYNVI vs macitentan and tadalafil monotherapies on pulmonary vascular resistance (PVR) and 6-minute walk distance (6MWD) was consistent with that observed in the overall population. Adverse events (AEs), serious adverse events (SAEs), and AEs leading to treatment discontinuation were reported more by treatment-naïve patients than those who had prior ERA or PDE-5i therapy.
• The post hoc analysis of the A DUE study, which evaluated the effect of OPSYNVI vs pooled monotherapy (macitentan or tadalafil) in treatment-naïve patients or those who were on prior monotherapy at randomization, revealed reduction in PVR, increase in 6MWD, and reduction in N-terminal pro B-type natriuretic peptide (NT-proBNP) with OPSYNVI treatment from baseline to week 16 in both groups.³

CLINICAL DATA

The A DUE Study

A DUE was a prospective, multicenter, double-blind, randomized, active-controlled, triple-dummy, parallel group, group-sequential, adaptive phase 3 study (NCT03904693) that evaluated the efficacy and safety of OPSYNVI as a STCT vs macitentan 10 mg and tadalafil 40 mg monotherapies in patients with PAH, including treatment-naïve patients and patients on prior ERA or PDE-5i monotherapy at baseline.¹

Study Design/Methods

The double-blind treatment had 2 phases: a 2-week tadalafil titration phase followed by a maintenance phase. In week 1 of the titration phase, patients were given macitentan 10 mg, tadalafil 20 mg, or both once daily (as separate tablets), along with relevant placebos (to maintain blinding). In week 2, tadalafil was uptitrated to 40 mg once daily; patients on baseline PDE5i therapy (tadalafil 40 mg, sildenafil 60-120 mg, or vardenafil 10 mg daily) were administered tadalafil 40 mg once daily from day 1. The maintenance phase spanned from day 15 to the end of week 16, when patients received macitentan 10 mg, tadalafil 40 mg, or OPSYNVI once daily, along with the relevant placebos. Downtitration of tadalafil to 20 mg was permitted for tolerability issues, while downtitration of macitentan was not. On completion of the 16-week double-blind treatment, patients were enrolled in a 24-month open-label treatment where all patients received a single tablet of OPSYNVI (see Figure: Study Design).¹

Adult patients (aged ≥18 years) were included in the study if they had idiopathic, heritable, drug- or toxin-induced PAH, or PAH associated with connective tissue disease, human immunodeficiency virus infection, portal hypertension, or corrected congenital heart disease (simple systemic-to-pulmonary shunts ≥1 year after surgical repair) and were either PAH-specific treatment naïve or on a stable dose (≥3 months) of prior ERA (bosentan 250 mg total daily dose, macitentan 10 mg total daily dose, and ambrisentan 10 mg total daily dose) or PDE-5i (sildenafil 60-120 mg total daily dose, tadalafil 40 mg total daily dose, and vardenafil 10 mg total daily dose) monotherapy before baseline right heart catheterization. Patients were excluded if they had received treatment with a soluble guanylate cyclase stimulator, L-arginine, prostanoid, or prostacyclin-receptor agonist 3 months before commencing the study treatment and had received combination therapy with an ERA and a PDE-5i 3 months before the study treatment or were intolerant to ERA/PDE-5i combination therapy.^1,4

Please view the supplementary appendix for a complete list of inclusion/exclusion criteria.⁴

A DUE - Subgroup Analysis

Grünig et al (2023)^2,5 conducted a subgroup analysis of patients from the A DUE study based on their background therapy status (treatment-naïve, prior ERA, or prior PDE-5i) to evaluate the efficacy (PVR and 6MWD) and safety of OPSYNVI vs macitentan 10 mg and tadalafil 40 mg monotherapies.

Of the 294 patients screened between October 15, 2019, and August 23, 2022, 187 were randomized. Of the 108 patients randomized to OPSYNVI, 50 were treatment-naïve; however, 1 patient did not receive any treatment and was not included in the full analysis set, leaving 49 treatment-naïve patients in the OPSYNVI group; 21 patients were on prior ERA therapy and 37 on prior PDE-5i therapy. Of the 35 patients randomized to the macitentan group, 24 were treatment-naïve and 11 had prior ERA therapy. Of the 44 patients randomized to the tadalafil group, 25 were treatment-naïve and 19 had prior PDE-5i therapy. See Table: PAH Therapy at Baseline and Table: Baseline Demographics and Characteristics Based on Background Therapy Status for specifics regarding ERA and PDE-5i therapies at baseline.^1,2

Efficacy

A 30% reduction in PVR was observed among treatment-naïve patients who received OPSYNVI vs macitentan 10 mg monotherapy at week 16 (geometric mean ratio [GMR], 0.70; 95% confidence limit [CL], 0.58-0.84; P=0.0002). A 34% reduction in PVR was observed among treatment-naïve patients who received OPSYNVI vs tadalafil 40 mg monotherapy at week 16 (GMR, 0.66; 95% CL, 0.56-0.78; P<0.0001). A 32% reduction in PVR was observed in patients with prior ERA therapy who received OPSYNVI vs macitentan 10 mg monotherapy at week 16 (GMR, 0.68; 95% CL, 0.53-0.86; P=0.0025). A 19% reduction in PVR was observed in patients with prior PDE-5i therapy who received OPSYNVI vs tadalafil 40 mg monotherapy at week 16 (GMR, 0.81; 95% CL, 0.70-0.94; P=0.0066). The P-values were exploratory and were not adjusted for adaptive design or multiplicity; see Table: Geometric Mean Change in PVR at Week 16 Based on Background Therapy Status.^1,2,4,5

A 20.38 m change in 6MWD was observed among treatment-naïve patients who received OPSYNVI vs macitentan 10 mg monotherapy at week 16 (95% CL, -20.30 to 61.08; P=0.3214). A 33.04 m change in 6MWD was observed among treatment-naïve patients who received OPSYNVI vs tadalafil 40 mg monotherapy at week 16 (95% CL, -5.31 to 71.39; P=0.0902). An 8.49 m change in 6MWD was observed in patients with prior ERA therapy who received OPSYNVI vs macitentan 10 mg monotherapy at week 16 (95% CL, -41.00 to 57.95; P=0.7279). A 25.89 m change in 6MWD was observed in patients with prior PDE-5i therapy who received OPSYNVI vs tadalafil 40 mg monotherapy at week 16 (95% CL, 0.88 to -50.90; P=0.0427). The P-values were exploratory and were not adjusted for adaptive design or multiplicity.^2,5

Safety

AEs, SAEs, and AEs leading to treatment discontinuation were reported more by treatment-naïve patients than those who had prior ERA or PDE-5i therapies.² More information regarding the safety and tolerability based on background therapy status can be found below in Table: Safety and Tolerability Based on background Therapy Status.

A DUE - Post hoc Analysis

Grünig et al (2024)³ conducted a post hoc analysis of patients who were treatment-naïve or on prior monotherapy at randomization to evaluate the effect of OPSYNVI vs pooled monotherapy (macitentan or tadalafil) at treatment initiation and escalation.

Of the 108 patients randomized to the OPSYNVI group, 49 were treatment-naïve, 21 had prior ERA therapy, and 37 had prior PDE-5i therapy. Of the 35 patients randomized to the macitentan group, 24 were treatment-naïve and 11 had prior ERA therapy. Of the 44 patients randomized to the tadalafil group, 25 were treatment-naïve and 19 had prior PDE-5i therapy.³

Efficacy

The following changes were observed from baseline to week 16 for OPSYNVI vs pooled monotherapy: PVR reduction of 32% (treatment-naïve) and 24% (prior treated); 6MWD increase of 26.2 m (treatment-naïve) and 21.1 m (prior treated); and NT-proBNP reduction of 41% (treatment-naïve) and 27% (prior treated).³ Data regarding change in efficacy variables are presented in Table: Change From Baseline to Week 16 in Efficacy Variables With OPSYNVI and Pooled Monotherapy.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 February 2025.