Macitentan failed to reduce digital ulcers in systemic sclerosis patients in a pair of randomized trials including approximately 500 adults. The findings were published online May 10 in JAMA.
Digital ulcers occur in 35%-68% of systemic sclerosis patients, and endothelin-1 (ET-1) has demonstrated overexpression in the plasma of these patients, wrote Dr. Dinesh Khanna of the University of Michigan, Ann Arbor, and colleagues (JAMA. 2016;315:1975-88. doi: 10.1001/jama.2016.5258).
Dr. Dinesh Khanna
To determine whether macitentan (Opsumit), a dual ET-receptor antagonist, reduced the number of new digital ulcers and their related disabilities, the researchers randomized adults aged 18 years and older with physician-diagnosed systemic sclerosis to oral macitentan doses of 3 mg or 10 mg or to placebo for 16 weeks. The first study, DUAL-1, enrolled 289 patients at a total of 70 centers in 17 countries; the second study, DUAL-2, included 265 patients from 73 centers in 20 countries. Macitentan is approved by the Food and Drug Administration for the treatment of pulmonary arterial hypertension.
A total of 226 patients completed DUAL-1 and 216 completed DUAL-2. Patients averaged 0.94 ulcers on 3 mg of oral macitentan, 1.08 ulcers on 10 mg of macitentan, and 0.85 ulcers on placebo in DUAL-1. The results were similar in DUAL-2, which was halted prematurely because the odds of benefits to the patients were deemed small.
No treatment effects were associated with either macitentan dose or placebo with regard to other endpoints, including complete healing of digital ulcers, hand function, and outcomes reported by physicians or patients. Serious adverse events occurred in 18% of the 3-mg macitentan group, 14% of the 10-mg group, and 13% of the placebo group in DUAL-1.
The results were limited by the lack of a standard classification system for digital ulcers, the researchers noted. However, “differences in physician attitudes and standard practices, and the lower than expected number of new digital ulcers after 16 weeks may have ultimately influenced the ability to demonstrate any treatment effect in the DUAL trials,” they said.
The study was funded by Actelion Pharmaceuticals, the manufacturer of macitentan. Dr. Khanna disclosed receiving grants from multiple organizations and companies and has received consulting fees from Actelion. Several coauthors are Actelion employees and stockholders.