Macitentan reduced morbidity and mortality in patients who had pulmonary arterial hypertension in an industry-sponsored phase III clinical trial, chiefly by slowing progression of the disease, according to a report published online Aug. 29 in the New England Journal of Medicine.
Two doses of macitentan, a dual endothelin receptor antagonist developed by altering the structure of bosentan to enhance efficacy and safety, were tested against placebo in 742 patients treated at 151 medical centers in 39 countries. The study subjects were patients aged 12 and older who had idiopathic or heritable pulmonary arterial hypertension (PAH), or PAH related to connective tissue disease, repaired congenital systemic-to-pulmonary shunts, HIV infection, drug use, or toxin exposure, said Dr. Tomás Pulido of Ignacio Chavez National Heart Institute, Mexico City, and his associates in SERAPHIN (Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome).
The study subjects were randomly assigned to receive 3-mg macitentan (250 patients), 10-mg macitentan (242 patients), or placebo (250 patients) once daily for a median treatment period of 115 weeks. The primary end point, a composite of a PAH event or death from any cause, was reached by 38% of patients receiving 3-mg macitentan and 31% of those receiving 10-mg macitentan, compared with 46% of patients receiving placebo.
Rates of hospitalization or death due to PAH also were significantly lower in patients who received active treatment, at 26% for 3-mg macitentan and 21% for 10-mg macitentan, compared with 34% for placebo. Six-minute walk distance increased by 7.4 m with 3-mg macitentan and by 12.5 m with 10-mg macitentan, but decreased by 9.4 m with placebo, the investigators said (N. Engl. J. Med. 2013 Aug. 29 [doi:10.1056/NEJMoa1213917]).
Similarly, WHO heart failure functional class improved in 20% of patients receiving 3-mg macitentan and 22% of those receiving 10-mg macitentan, compared with only 13% of those receiving placebo. And patients in both active treatment groups showed significant reductions in pulmonary vascular resistance as well as significant increases in the cardiac index, compared with those in the placebo group.
SERAPHIN was funded by Actelion Pharmaceuticals. Dr. Pulido reported ties to Actelion, Pfizer, Eli Lilly, Bayer, United Therapeutics, and Gilead, and his associates reported ties to numerous industry sources.