ATLANTA – Macitentan, a novel dual endothelin receptor antagonist with enhanced tissue penetration, significantly improves morbidity and mortality in patients with pulmonary arterial hypertension, according to findings from an industry-sponsored, randomized controlled phase III SERAPHIN study.
Macitentan treatment reduced the risk of occurrence of combined morbidity and mortality events by 30% in 250 patients randomized to receive 3 mg once daily and by 45% in 242 patients randomized to receive 10 mg once daily, compared with 250 patients who received placebo, Dr. Lewis Rubin reported at the annual meeting of the American College of Chest Physicians.
Dr. Lewis Rubin
The differences were highly significant for both macitentan doses, and the effect of treatment on this novel primary end point was observed irrespective of background therapy, which consisted mainly of phosphodiesterase type-5 (PDE-5) inhibitors.
Among patients using background therapy, risk was reduced by 17% and 38% for the 3 mg and 10 mg groups, respectively; in treatment-naive patients, the risk was reduced by 47% and 55% in the dosage groups, respectively, said Dr. Rubin of the University of California, San Diego.
The findings hold promise for improved long-term outcomes in patients with pulmonary arterial hypertension (PAH), Dr. Rubin said. "This primary morbidity/mortality end point captures clinically relevant events that reflect true disease progression," he noted, explaining that the end point included time to death, atrial septostomy, lung transplantation, initiation of intravenous/subcutaneous prostanoids, or worsening of PAH.
To meet the criteria for PAH worsening, participants had to experience a confirmed 15% or greater decrease in 6-minute walk distance and worsening of symptoms as defined by either a worsening in functional class, worsening symptoms of right heart failure, need for a new PAH treatment, or need for an intravenous diuretic. The majority of events contributing to achievement of the primary end point were associated with worsening of PAH, rather than death, he noted.
In addition to improvements with respect to the primary end point, macitentan treatment also was associated with improvement on the secondary end point of the composite of mortality or hospitalization due to PAH, with risk reduction of 33% and 50% in the 3-mg and 10-mg groups, respectively, compared with placebo, Dr. Rubin said.
Macitentan was well tolerated, with both the treatment group and the placebo group experiencing similar incidences of elevated liver aminotransferases and peripheral edema, although headache, nasopharyngitis, and anemia all occurred more frequently in the treatment groups.
Participants in the double-blind, event-driven SERAPHIN study (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) were individuals aged 12 years or older with PAH. Randomization began in May of 2008, and study end was predefined as the occurrence of 285 morbidity/mortality events, which occurred as of March 2012.
The findings are notable because existing PAH therapies, including bosentan and ambrisentan, have been approved based only on short-term trials with exercise capacity as the primary end point, and have potential for adverse events that can limit tolerability, Dr. Rubin said.
"So an endothelin receptor antagonist that has a better tolerability profile would be potentially desirable," he said.
Indeed, macitentan, which is a product of a tailored discovery program, has not only been shown to have enhanced tissue penetration and "superior in vivo efficacy in a number of animal models," but also to have no effect on bile salts. It, therefore, has diminished adverse effects on the rate of hepatic dysfunction that is seen, with varying degrees, as a manifestation of endothelin receptor antagonism, he explained.
"In addition, it has demonstrated unique sustained receptor binding, which also may be beneficial in long-term therapy," he said.
The SERAPHIN study was sponsored by Actelion, the maker of macitentan. Dr. Rubin disclosed that he has received payment for consulting and/or serving on speaker bureaus or advisory committees for Actelion, Pfizer, United Therapeutics, Lung LLC, Gilead, GlaxoSmithKline, Bayer, and GeNo.