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ATLANTA -- Macitentan, an investigational next-generation endothelin receptor antagonist for pulmonary arterial hypertension (PAH), met its efficacy endpoint and was well tolerated in a large clinical trial, it was reported here.

With a primary endpoint of time to first significant clinical event, patients receiving a 10-mg daily oral dose of macitentan showed a 45% reduction in risk compared with placebo in the 742-patient SERAPHIN trial (relative risk 0.55, log-rank P<0.0001), reported Lewis J. Rubin, MD, of the University of California San Diego.

A 3-mg macitentan dose also was significantly effective but less so, with a relative risk of 0.70 (P=0.0108) versus placebo for the primary endpoint, Rubin told attendees during a late-breaking abstract session at the American College of Chest Physicians annual meeting.

He acknowledged that the drug's efficacy according to a more conventional outcome measure, change in 6-minute walk distance, was relatively modest. The median improvement from baseline was just 14 meters (interquartile range 2 to 27) in the low-dose group after 6 months; with the 10-mg dose, the median improvement was 15 meters (IQR 2 to 28).

Another investigational agent for PAH that acts on a different pathway, riociguat, improved mean 6-minute walk distance by more than 35 meters relative to placebo in a different trial reported at the same session.

Two endothelin receptor antagonists are currently available for PAH treatment, bosentan (Tracleer) and ambrisentan (Letairis). Although effective, these agents come with significant safety issues that limit their utility, Rubin said.

These medications come with boxed warnings and are available only through restricted distributions programs. Hepatotoxicity is the major concern for bosentan, with monthly monitoring of liver enzymes required while on treatment. Both drugs carry significant risks for birth defects when used during pregnancy.

Macitentan was developed to have better tissue penetration than these agents and longer receptor binding. Studies leading up to the SERAPHIN trial suggested that it does not affect bile salts, an indication of reduced liver toxicity, Rubin said.

In SERAPHIN, patients with symptomatic PAH were randomized in about equal numbers to placebo or macitentan at 3 or 10 mg/day. Patients already taking endothelin receptor antagonists were excluded.

Approximately two-thirds of patients came into the study on other drug therapies, mostly phosphodiesterase-5 inhibitors such as sildenafil (Viagra, Revatio) but with a few also on oral or inhaled prostanoids. Those patients were allowed to stay on these medications.

At baseline, patients' average age was 46 (SD 16) and their mean 6-minute walk distance was 360 meters. The sample was about equally divided between WHO functional classes I/II and III/IV.

For the primary endpoint, significant clinical events included any of the following: death from any cause, receipt of atrial septostomy or lung transplant, initiation of intravenous or injectable prostanoids, or worsening of PAH.

This last event was recorded for patients who showed a sustained reduction in 6-minute walk distance of at least 15%, plus worsening of symptoms (defined as a step up in WHO functional class or appearance or worsening of right-side heart failure), plus a clinically determined need for additional PAH medications.

All events were adjudicated by an independent, blinded committee, Rubin said. The trial protocol called for it to be stopped when a total of 285 events had occurred; in fact, 287 were recorded.

Most events in the trial were in the worsened-PAH category. Of the 287 total, 224 were of this type. There were 54 deaths and one lung transplant. Eight patients started IV or subcutaneous prostanoids. No atrial septostomies were performed.

As the top-line results suggested, events were more common in the placebo group (116) and least common with high-dose macitentan (76).

The lower drug dose was not particularly effective, relative to placebo, in the subgroup of patients on background PAH drug therapy according to the primary endpoint, Rubin reported. The data indicated a small risk reduction (RR 0.83, P=0.27) with the 3-mg dose.

On the other hand, add-on macitentan at 10 mg did boost efficacy significantly, with a relative risk of 0.62 (P=0.009) compared with placebo.

In the smaller subgroup of patients taking macitentan as monotherapy, both doses were about equally effective, with relative risks for events of 0.45 and 0.53 versus placebo for the high and low doses, respectively (both P<0.01).

Because patients were taken off the study when events occurred, mean durations of treatment varied across treatment groups: 85 weeks for placebo, 100 weeks for the low macitentan dose, and 104 weeks for the high dose.

Some patients showed signs of liver toxicity, but not many, and they were equally distributed among treatment groups. Aspartate aminotransferase (AST) levels higher than three times the upper limit of normal were seen in 4.5% of the placebo group and in 3.6% and 3.4% of the low- and high-dose macitentan groups, respectively.

A similar pattern was seen for the combination of elevated AST and bilirubin.

However, anemia may be a concern with macitentan. Hemoglobin levels of 8 g/dL or less were seen in 0.4% of placebo-treated patients, compared with 1.7% of those taking 3 mg/day of macitentan and 4.3% of the high-dose group.

Peripheral edema was recorded in 16% to 18% of all treatment groups, suggesting that macitentan had no effect one way or the other.

Rubin characterized the overall safety profile as good. "Macitentan was generally well tolerated during long-term treatment," he said.

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