SERAPHIN: Macitentan, Novel Endothelin-Receptor Antagonist, Boosts PAH Outcomes

August 29, 2013

BOSTON, MA — The novel dual endothelin-receptor antagonist (ERA) macitentan (Opsumit/ACT-064992, Actelion Pharmaceuticals), now under consideration by European and US regulators, significantly lowered the risk of clinical events compared with placebo over a mean of about two years in patients with pulmonary artery hypertension (PAH), in a rare long-term, event-driven PAH trial[1].

The drug given at 10 mg/day led to a 45% reduction (p<0.001) in a clinical primary end point that included death, initiation of IV or subcutaneous prostanoids, or worsening of PAH. The benefit was driven primarily by reductions in PAH worsening in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN).

The trial also tested a 3-mg/day dosage, which also significantly improved clinical outcomes (p=0.01), but to a lesser degree. "There was more improvement with the 10-mg dose, but both [dosages] fared pretty much equally in terms of adverse effects," Dr Tomás Pulido (Ignacio Chávez National Heart Institute, Mexico City, Mexico) told heartwire . Similar percentages of patients withdrew due to side effects in the placebo and both macitentan groups. And rates of a familiar ERA side effect, peripheral edema, were also similar across the board.

Hazard Ratio (95% CI) For Outcomes Using Macitentan 3 mg (Mean 99.5 Weeks) and 10 mg (Mean 104 Weeks) vs Placebo, by Intention to Treat, in SERAPHIN

End point Macitentan, 3 mg Macitentan, 10 mg
Primary end point* 0.70 (0.52–0.96) 0.55 (0.32–0.76)
PAH-related death or hospitalization 0.67 (0.46–0.97) 0.50 (0.34–0.75)

*Time from baseline to first occurrence of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension

Although ERAs as a drug class may be associated with liver toxicity, there were no signs of it in SERAPHIN, he said. "Increases in liver enzymes were lower than with some other [ERAs in other trials], and basically they were the same as with placebo."

Pulido is lead author on the SERAPHIN paper, which is published in the August 29, 2013 issue of the New England Journal of Medicine. Actelion had disclosed the primary-end-point outcomes in a press release on April 30, 2012 and announced on December 14 that the US Food and Drug Administration (FDA) had accepted macitentan for review in PAH.

Largest, Longest, and More

PAH is a rare condition; the trial took almost 20 months to enroll 250 patients at 151 centers in 39 countries around the world. Currently available agents for PAH, such as phosphodiesterase type 5 (PDI-5) inhibitors, prostacyclins, and other ERAs, came to formularies based on short-term trials with mostly functional end points, including functional class and six-minute-walk distance--which, incidentally, also improved on macitentan (p=0.006 and p=0.008, respectively).

Similarly, an FDA advisory panel recently recommended riociguat (Adempas, Bayer Healthcare), an oral soluble guanylate-cyclase (sGC) stimulator, for approval to treat PAH as well as inoperable chronic thromboembolic pulmonary hypertension (CTEPH), based on functional and biomarker end points in two short-term trials, PATENT-1 and CHEST-1 . The drug was associated with significantly improved six-minute-walk distance, pulmonary vascular resistance, natriuretic-peptide levels, and World Health Organization (WHO) functional class over 12 to 16 weeks, as reported by heartwire .

SERAPHIN is not only one of the largest PAH-drug trials, it followed patients for up to three years and "is the first time one has had morbidity and mortality as the primary end point," according to Pulido.

Combination PAH Drug Therapy Allowed

A total of 250, 250, and 242 patients were randomized to placebo, 3-mg macitentan, and 10-mg macitentan, respectively; PAH of almost any etiology was always confirmed by right-heart catheterization, and patients could be in WHO functional class 2–4. Patients using non-ERA oral or inhaled drugs for PAH at baseline continued them during the trial; no one could enter the study using other ERAs or IV or subcutaneous prostanoids.

Whether patients were taking the allowed concomitant agents had no apparent effect on the rate of PAH worsening, the most common event making up the primary end point, or on adverse effects.

"This is one of the strengths of the study," according to Pulido. "We showed that the benefit in the primary end point was the same with [PAH-drug-therapy]-naive patients as with patients treated with combination therapy."

The study was funded by Actelion Pharmaceuticals. Pulido reports grants paid to his institution from the National Heart Institute , Actelion, Bayer, United Therapeutics, and Gileon; c onsulting fees or honoraria from Actelion; s upport for travel to meetings for the study or other purposes from Actelion; consulting for Pfizer, Eli Lilly, and Bayer; and payment for lectures including service on speaker's bureaus from Bayer, Actelion, and Eli Lilly, Disclosures for the coauthors are listed on www.njem.org.

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