Key Points:
- Macitentan and Tadalfil are frequently used in combination for PAH, which opens up the possibility of a fixed-dose combination pill.
- In the DUE study, macitentan/tadalafil FDC therapy was compared against macitentan and tadalafil monotherapy. The primary outcome was PVR reduction at 16 weeks.
- M/T FDC resulted in a significant reduction in PVR at 16 weeks compared to either macitentan or tadalfil monotherapy. There was a non-significant trend towards reduction in 6MWD at 16 weeks.
Macitentan and Tadalafil are frequently used in combination therapy for pulmonary arterial hypertension (PAH); however, a fixed-dose combination (with the potential to be taken as a single pill) has never been trialed against monotherapy. In a breaking presentation at the 2023 ACC Conference today, Dr. Kelly Chin (UTSW) and his team presented their study: “Efficacy and safety of macitentan tadalafil fixed dose combination in pulmonary arterial hypertension: results from the randomized controlled phase III A DUE study.”
The DUE trial (NCT03904693) was prospective, multicenter, double-blind, randomized, active-controlled, adaptive Phase III study which evaluated the efficacy and safety of macitentan/tadalafil FDC versus macitentan and tadalafil monotherapies in patients with PAH. Patients were randomized into one of three groups: macitentan 10 mg monotherapy, macitentan 10 mg / tadalafil 40 mg FDC, or tadalafil 40 mg monotherapy. The inclusion criteria comprised any adults WHO FC II or III PAH who were either treatment naïve or on a stable dose of ERA or PDE5i for at least 3 months. The primary endpoint was change in PVR, expressed as ratio of baseline.
A total of 187 patients were randomized: 35 in the macitentan arm, 44 in the tadalafil arm, and 108 in the FDC arm. The average age was 51, and 75% were women. 50% had idiopathic PAH. The primary outcome was change in PVR from baseline at Week 16. M/T FDC therapy resulted in significantly lower PVR when compared to macitentan monotherapy (PVR reduction 29%, ratio of geometric means (95% CL): 0.71 (0.61, 0.82), P<0.0001) and tadalafil (PVR reduction 28%, ratio of geometric means (95% CL): 0.72 (0.64, 0.80), P<0.0001). The secondary endpoint of change in 6MWD at Week 16 was not significant between groups, but there was a trend towards improvement in the FDC arm. FDC therapy had a similar safety profile to both macitentan and tadalafil monotherapy with no additional serious adverse events.
When discussing the clinical implications of the study at ACC, Dr. Chin stated: “Macitentan/tadalafil FDC was well tolerated and consistent with the safety profile of macitentan and tadalafil…DUE supports M/T FDC, as a single-tablet combination therapy, for initial dual combination therapy and rapid escalation, in line with the ESC/ERS 2022 guidelines on the use of dual combination therapy in PAH.”
