SUMMARY

• UNISUS is an ongoing phase 3 clinical trial looking to demonstrate the superiority of macitentan 75 mg in prolonging the time to first clinical event committee (CEC)adjudicated morbidity or mortality (MM) event in patients with symptomatic pulmonary arterial hypertension (PAH) compared with OPSUMIT. The study has an estimated study completion date of 2029.^1,2
• The phase 3 MACiTEPH study evaluating macitentan 75 mg in patients with chronic thromboembolic pulmonary hypertension (CTEPH) was stopped due to futility. The decision to stop the trial was made in accordance with a recommendation by the study’s independent data monitoring committee (IDMC) following a pre-planned interim analysis.³ Efficacy and safety data that are available are summarized below.⁴  

BACKGROUND

• Endothelial dysfunction is a key driver of PAH. Aberrant activation of the endothelin-1 pathway leads to enhanced endothelin A (ET)_A and endothelin B (ET)_B receptor-mediated vasoconstriction, as well as inflammation, proliferation, pulmonary vascular remodeling, and fibroblast activation.⁵ Preclinical evidence suggests the need to comprehensively inhibit both ET_A and ET_B receptors to effectively block pathway signaling.^6,7 Macitentan is an oral, dual endothelin receptor (ET_A/ET_B) antagonist that, at the dose approved for the treatment of PAH (OPSUMIT 10 mg once daily), leads to extensive inhibition of ET_A receptors and partial inhibition of ET_B receptors. Whether more complete ET_B receptor inhibition would improve PAH outcomes is not currently known.^7,8 

CLINICAL DATA

Phase 3 Trials

UNISUS

The Outcome Study Assessing a 75 mg Dose of Macitentan in Patients With PAH (UNISUS) is an ongoing, phase 3, prospective, multicenter, double-blind (DB), randomized, active-controlled, adaptive, eventdriven study to compare the efficacy, safety, and tolerability of macitentan 75 mg vs OPSUMIT. A total of 935 participants, aged 18 years or older, have been enrolled. The primary outcome measure is time to first CEC-adjudicated MM events. Time to first CECadjudicated MM event on treatment (up to 7 days after last dose of DB study intervention) is defined as time from baseline to the first of the following: all-cause death or interventionemergent adverse event (AE) with a fatal outcome, PAH-related hospitalization (including for worsening of PAH, atrial septostomy, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclins), or PAH-related disease progression. PAH-related disease progression is defined as more than 15% decrease in 6-minute walking distance (6MWD), worsening of symptoms of right-sided heart failure that require initiation of intravenous diuretics, or worsening of World health Organization (WHO) Functional Class (FC).¹

Key inclusion criteria:^1,9,10 

• Aged 18 years or older
• Idiopathic PAH, heritable PAH, or drug- or toxin-induced PAH, or PAH related to connective tissue disease, human immunodeficiency virus, portal hypertension or congenital heart disease
• Mean pulmonary arterial pressure >20 mmHg, and pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤15 mmHg, and pulmonary vascular resistance ≥3 wood units
• 6MWD ≥50 m and ≤440 m at screening
• WHO FC II, III, or IV
• PAH treatment-naïve or receiving stable (≥3 months) PAH-therapy prior to screening

The inclusion criteria noted above reflect pre-planned changes recommended by the independent data monitoring committee during their regular unblinded review of ongoing safety and tolerability data. These changes include expanding the patient population as well as reducing the frequency of safety monitoring visits during the up-titration phase.^9,10

The study has an estimated primary completion date of 2025 and an estimated study completion date of 2029. For additional information, including inclusion and exclusion criteria, please visit http://clinicaltrials.gov (Identifier NCT04273945).¹

MACiTEPH

A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent CTEPH (MACiTEPH) was a phase 3, prospective, randomized, DB, multicenter, placebo-controlled, parallel group, adaptive study assessing the effect of macitentan 75 mg vs placebo on exercise capacity. The study was stopped due to futility. The decision to stop the trial was made in accordance with a recommendation by the study’s IDMC following a pre-planned interim analysis. Please note that the results and analysis present are incomplete. Outcomes and AEs were not assessed for all patients.³

Of the 127 patients, 64 were treated with macitentan 75 mg and 63 were treated with placebo. The median duration of macitentan and placebo exposures were 24.5 weeks (min-max, 3.9-160.4) and 44 weeks (min-max, 4-147.9), respectively. In the macitentan group, 37 (57.8%) patients were female, and the mean age (standard deviation [SD]) was 64.7 (11.69) years.⁴

The least squares mean (standard error [SE]) 6MWD (primary endpoint) at week 28 was 9.7 (5.81) meters for the macitentan group (n=47) and 25.8 (5.78) meters for the placebo group (n=48). Seven out of 37 patients (18.9%) treated with macitentan and 6 out of 43 patients (14%) treated with placebo had improvements in WHO FC (secondary endpoint) at week 28.⁴

One patient died in the macitentan group; 17 and 14 patients reported serious AEs in the macitentan and placebo groups, respectively. Other AEs (not including serious AEs) were reported in 47 patients in the macitentan group and 38 patients in the placebo group. One patient who reached the target dose of macitentan 75 mg and completed the DB period entered the open-label (OL) period (104 weeks). Six patients on placebo who completed the DB period went on to take part in the OL period. The median duration of macitentan and placebo exposures in the OL period were 72 weeks (min-max, 8.1-84.6) each. During the OL period, no deaths or serious AEs were reported in the macitentan group, and 4 out of 6 patients reported serious AEs in the placebo group.⁴

For additional information on secondary endpoints and AEs, please visit http://clinicaltrials.gov (Identifier NCT04271475).⁴

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 January 2025.