SERAPHIN: Novel PAH drug reduced morbidity, mortality rates

Pulido T. N Engl J Med. 2013;369:809-818.

  • August 28, 2013

Patients with pulmonary arterial hypertension assigned macitentan experienced lower rates of morbidity and mortality than patients assigned placebo, according to results from the phase 3 SERAPHIN trial.

Macitentan is an investigational dual endothelin-receptor antagonist (Actelion Pharmaceuticals). If the drug receives FDA approval, it will be marketed under the name Opsumit.

Different metrics

SERAPHIN was a multicenter, double blind, randomized, placebo-controlled, event-driven study. The researchers’ goal was to investigate the effects of macitentan on morbidity and mortality in patients with PAH.

Treatments for PAH have traditionally been evaluated based on improved exercise capacity in the short term, but that metric may not correlate well to improved clinical outcomes, according to recent analyses.

Tomás Pulido, MD, and colleagues assigned participants once-daily placebo (n=250), 3 mg macitentan (n=250) or 10 mg macitentan (n=242). The study population included those who had never before received treatment for PAH and those who had received treatments other than endothelin-receptor antagonists.

The primary endpoint was time from initiation to first occurrence of any of the following: death from any cause, atrial septostomy, lung transplantation, treatment with IV or subcutaneous prostanoids, or worsening of PAH. Secondary endpoints included 6-month change in 6-minute walk distance, 6-month change in WHO functional class, death or hospitalization due to PAH, and death from any cause. Mean follow-up period was 85.3 weeks for those assigned placebo, 99.5 weeks for those assigned 3 mg macitentan and 103.9 weeks for those assigned 10 mg macitentan.

Treatment benefits

The primary endpoint occurred in 46.4% of patients assigned placebo, 38% of those assigned 3 mg macitentan and 31.4% of those assigned 10 mg macitentan. The HR for 3 mg macitentan compared with placebo was 0.7 (95% CI, 0.52-0.96). The HR for 10 mg macitentan compared with placebo was 0.55 (95% CI, 0.39-0.76). The most frequently observed primary endpoint event was worsening of PAH. Treatment benefits occurred in those who had never before received treatment for PAH and in those who had.

Death or hospitalization due to PAH occurred in 33.6% of those in the placebo group, 26% of those in the 3-mg macitentan group and 20.7% of those in the 10-mg macitentan group. The HR for a 3-mg daily dose of macitentan compared with placebo was 0.67 (95% CI, 0.46-0.97). The HR for a 10-mg daily dose of macitentan compared with placebo was 0.5 (95% CI, 0.34-0.75).

After 6 months, the 6-minute walk distance decreased by a mean of 9.4 m in those assigned placebo vs. a mean increase of 7.4 m in those assigned 3 mg macitentan (treatment effect, 16.8 m; 95% CI, –2.7 to 36.4) and a mean increase of 12.5 m in those assigned 10 mg macitentan (treatment effect, 22 m; 95% CI, 3.2-40.8).

WHO functional class improved after 6 months in 13% of those assigned placebo, 20% of those assigned 3 mg macitentan (P=.04) and 22% of those assigned 10 mg macitentan (P=.006).

The adverse events most commonly associated with being assigned to macitentan vs. placebo were headache, nasopharyngitis and anemia. Rates of discontinuation due to adverse events were 12.4% in the placebo group, 13.6% in the 3-mg macitentan group and 10.7% in the 10-mg macitentan group.

Disclosure: The study was funded by Actelion Pharmaceuticals. See the full study for a list of the researchers’ relevant financial disclosures.

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