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 vs macitentan 10 mg and tadalafil 40 mg monotherapies in patients with pulmonary arterial hypertension (PAH).¹ 
  • Patients were included in the A DUE study if they were either PAH-specific treatment-naïve or on a stable dose (≥3 months) of prior endothelin receptor antagonist (ERA; bosentan, macitentan, or ambrisentan) or phosphodiesterase-5 inhibitor (PDE-5i; sildenafil, tadalafil, or vardenafil) monotherapy before baseline right heart catheterization (RHC).^1,2
  • Of the 70 patients randomized to OPSYNVI _M (OPSYNVI group used for comparison vs macitentan 10 mg), 21 were on prior ERA therapy at baseline. Of the 86 patients randomized to OPSYNVI _T (OPSYNVI group used for comparison vs tadalafil 40 mg), 37 were on prior PDE-5i therapy at baseline.¹

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 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 (see Figure: Study Design).¹

Adult patients (aged ≥18 years) were included in the study if they were either PAH-specific treatment-naïve (PAH-specific treatment defined as prescribing prostanoids, prostacyclin receptor agonists, guanylate cyclase stimulators, ERAs, or PDE-5is to treat PAH³) 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 RHC.²

Patients were excluded if they were treated with the following: a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period before starting study treatment; combination therapy of ERA and PDE-5i in the 3-month period before starting study treatment; other therapies such as initiation of calcium channel blocker or change of dose within 3 months prior to RHC at screening.³

Of the 294 patients screened between October 15, 2019, and August 23, 2022, 187 were randomized. Overall, 108 patients were assigned to receive OPSYNVI, of whom 70 were randomized to OPSYNVI _M that was compared with the 10 mg macitentan monotherapy group (n=35) and 86 patients were randomized to OPSYNVI _T that was compared with the 40 mg tadalafil monotherapy group (n=44).¹ Information regarding patients on background therapy at baseline is summarized in Table: Background PAH Therapy at Baseline.

The primary endpoint was change in PVR from baseline to week 16. In the 70 patients who were randomized to OPSYNVI vs macitentan 10 mg monotherapy (OPSYNVI_M), the treatment effect was 0.71 (95% Confidence Limit [CL], 0.61-0.82; P<0.0001; 29% reduction in PVR) compared to macitentan monotherapy. In the 86 patients who were randomized to OPSYNVI vs tadalafil 40 mg monotherapy (OPSYNVI_T), the treatment effect was 0.72 (95% CL, 0.64-0.80; P<0.0001; 28% reduction in PVR) compared to tadalafil monotherapy.¹

In treatment-naive patients, the treatment effect of OPSYNVI (n=49) was 0.70 (95% CL, 0.58-0.84; P=0.0002; 30% reduction) and 0.66 (95% CL, 0.56-0.78; P<0.0001; 34% reduction) compared to macitentan (n=24) and tadalafil monotherapies (n=25), respectively. In patients receiving prior ERA therapy, the treatment effect of OPSYNVI (n=21) was 0.68 (95% CL, 0.53-0.86; P=0.0025; 32% reduction) compared to macitentan monotherapy (n=11) and in patients receiving prior PDE5i therapy, the treatment effect of OPSYNVI (n=37) was 0.81 (95% CL, 0.70-0.94; P=0.0066; 19% reduction) compared to tadalafil monotherapy (n=19).The most common adverse events (AEs) (occurring in ≥10% of the OPSYNVI treated patients) observed were edema and fluid retention (20.6%), anemia (18.7%), headache (16.8%), and peripheral edema (13.1%).¹

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 05 February 2026.