Therapeutic efficacy of Macitentan

The effect of macitentan on pulmonary arterial hypertension (PAH) progression was confirmed in a multicenter, long-term (mean exposure time of approximately 2 years), placebo-controlled study involving 742 symptomatic PAH patients. These patients were randomly assigned to the placebo group, macitentan 3 mg group, or macitentan 10 mg group, with once-daily administration. Patients received macitentan as monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostaglandins.

The primary study endpoint was the time from the start of double-blind treatment to the first occurrence of death or a significant morbidity event. Significant morbidity events were defined as atrial septostomy, lung transplantation, initiation of intravenous or subcutaneous prostaglandins, or "other PAH worsening" within 7 days of addition during double-blind treatment. Other worsening was defined as meeting all of the following criteria: 1) a sustained reduction of ≥15% in 6-minute walk distance from baseline; 2) worsening of PAH symptoms (deterioration in WHO functional class); and 3) the need for additional PAH therapy. All these other worsening events were confirmed by an independent adjudication committee unaware of treatment assignments. A key secondary endpoint was the time to PAH-related death or PAH hospitalization.

The mean age of patients was 46 years (14% were 65 years or older). Most patients were White (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO functional class II, III, and IV, respectively.

Idiopathic or heritable PAH was the most common etiology in the study population (57%), followed by PAH associated with connective tissue diseases (31%), PAH associated with congenital heart disease and repaired shunts (8%), and PAH due to other etiologies [drugs and toxins (3%) and HIV (1%)].

At baseline, most enrolled patients (64%) were receiving stable doses of PAH-specific therapy, including oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostaglandins (6%).

Study results are described for the placebo group and the macitentan 10 mg group. The median treatment duration was 101 weeks in the placebo group and 118 weeks in the macitentan 10 mg group, with a maximum duration of up to 188 weeks.

Compared with the placebo group, treatment with macitentan 10 mg reduced the risk of primary endpoint events by 45% at the end of double-blind treatment. The benefit of macitentan 10 mg was mainly attributed to a reduction in clinical worsening events (deterioration in 6-minute walk distance, worsening of PAH symptoms, and the need for additional PAH therapy).

Consistent efficacy of macitentan 10 mg on the primary endpoint was observed across subgroups defined by age, sex, race, etiology, monotherapy or combination with another PAH therapy, baseline 6-minute walk distance, and baseline WHO functional class.

PAH-related death or PAH hospitalization was evaluated as a secondary endpoint. Patients treated with macitentan 10 mg had a 50% reduction in the risk of PAH-related death or PAH hospitalization compared with the placebo group.

Treatment with macitentan 10 mg resulted in a placebo-corrected mean increase of 22 meters in 6-minute walk distance at month 6, with a significant improvement already observed at month 3. Patients with poorer baseline WHO functional class had greater increases in 6-minute walk distance (placebo-corrected mean increases of 37 meters and 12 meters for patients in WHO functional class III/IV and I/II, respectively). The increase in 6-minute walk distance achieved with macitentan was maintained throughout the study period.

At month 6, 22% of patients treated with macitentan 10 mg experienced an improvement of at least one WHO functional class, compared with 13% in the placebo group.

Long-term Treatment of PAH

In patients treated with macitentan 10 mg in the placebo-controlled study and followed up long-term in the open-label extension study, the Kaplan-Meier estimated survival rates at 1, 2, 5, and 7 years were 95%, 89%, 73%, and 63%, respectively. The median exposure to macitentan was 4.6 years. These uncontrolled observations do not allow comparison with groups not receiving macitentan and cannot be used to determine the long-term effect of macitentan on mortality.

FDA，2025.04