This open-label extension of the SERAPHIN trial evaluated the long-term safety and tolerability of a small daily dose of the endothelin receptor antagonist against pulmonary arterial hypertension (PAH) among patients from the original study.
Safety and survival data from the SERAPHIN open-label (OL) long-term multicenter single-arm noncomparative trial of 10-mg daily macitentan show the endothelin receptor antagonist is safe and tolerable over the longer term among patients who have pulmonary arterial hypertension (PAH).
These findings were published recently in Advances in Therapy, and they echo findings from SERAPHIN OL’s predecessor, the SERAPHIN trial, which investigated the ability of 10-mg daily macitentan to reduce morbidity and mortality in PAH. All patients (N = 550) had been participants in the first trial, and they all received the same dosage in the extension study. In addition, SERAPHIN OL evaluated the drug’s safety in overlapping sets: all patients (OL safety set) and patients first randomized to once-daily macitentan 10 mg (vs once-daily 3-mg macitentan or placebo) in the SERAPHIN study (n = 242; long-term safety/survival set).
“Long-term data from patients with PAH are sparse,” the authors wrote. “The SERAPHIN OL study provides data on long-term safety, tolerability and survival for patients with PAH treated with macitentan.”
Overall, 50.5% of the OL safety set completed treatment. The mean (SD) age of these patients was 47.7 (15.7) years, 80.0% were female, and most had World Health Organization functional class II (45.1%) or III (31.5%) disease and were receiving background PAH therapy (67.5%). Including the safety follow-up period of 28 days, this patient group also had a median macitentan exposure of 40.1 (range, 0.1-130.5) months, for 2074.7 patient-years. Approximately one-third of patients (31.3%) received 10-mg macitentan for at least 5 years.
The most common adverse effects (AEs) reported by patients were PAH worsening (28.5%) and upper respiratory tract infection (23.1%). Among the 11.3% with an AE that led to treatment discontinuation, the most common were PAH worsening (2.4%) and right ventricular failure (1.8%). Further, among the 31.8% who had died by the end of the follow-up period, PAH worsening was the most common reason (10.5%).
The incident rate of increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to 3 times the upper limit of normal (ULN) was 2.2 per 100 patient-years.
For the long-term survival set, the patients had a median macitentan exposure of 54.7 (range, 0.1-141.3) months, for 1151.0 patient-years. The most common was at least 5 years in 43%. In addition, 96.2% of patients were exposed to macitentan “without or prior to the addition of any new PAH therapies during the study,” the authors noted, and among those who started a concomitant PAH therapy (6.2%), a phosphodiesterase 5 inhibitor was the most common (3.3%).
Among this cohort, PAH worsening was again the most common AE (35.5%) and peripheral edema the second most common (26.0%). Sixteen percent had an AE that necessitated treatment discontinuation. Again, PAH worsening and right ventricular failure were the most common reasons, at 2.1% and 1.7%, respectively, for treatment discontinuation, and PAH the most common cause of death (9.1%) among the 32.2% of the long-term safety/survival who had died by the end of the treatment period.
In addition, the ALT/AST increase incident rate was close to equal vs the OL safety set, at 1.9 per 100 patient-years.
Kaplan-Meier estimates for survival show that more than half of the patients remained alive at the 9-year mark. These results show 95.0%, 84.0%, 73.3%, 62.6%, and 52.7% were alive at 1, 3, 5, 7, and 9 years, respectively.
“The 2 analysis sets provided complementary data on the safety of macitentan in PAH and showed that macitentan 10 mg was well tolerated by PAH patients,” the investigators concluded. “As safety and tolerability were consistent between the 2 sets, these results provide evidence on the safety of macitentan, including in a patient population with more advanced disease.”
Souza R, Delcroix M, Galié N, et al. Long-term safety, tolerability and survival in patients with pulmonary arterial hypertension treated with macitentan: results from the SERAPHIN open-label extension. Adv Ther. 2022;39(9):4374-4390. doi:10.1007/s12325-022-02199-x