No Benefit From Macitentan Seen in Systemic Sclerosis

Tara Haelle

May 11, 2016

Macitentan does not decrease new ischemic digital ulcers in patients with systemic sclerosis and slightly increases adverse effects, according to an industry-run study of two double-blind randomized controlled trials published in the May 10 issue of JAMA.

Considering macitentan's greater potency on endothelin (ET) receptors in vitro and on biomarkers compared with bosentan, "[i]t is unclear why this relative higher potency of macitentan did not result in an effect on digital ulcers," write Dinesh Khanna, MD, from the University of Michigan Scleroderma Program, Ann Arbor, and colleagues.

The phase 3, multicenter, parallel-group trials involved patients from 31 countries, first between January 2012 and November 2013, and then between February 2012 and February 2014 for the second trial. Both trials balanced study groups in terms of patient demographics, disease characteristics, and current medications. Although bosentan remains the only current treatment indicated for reduction of new digital ulcers in those with systemic sclerosis, the researchers did not conduct a head-to-head trial because bosentan is not approved in all countries where these two trials occurred.

"Although bosentan and macitentan both block the ETA and ETB receptors, a reduction in the formation of new digital ulcers has only been observed with bosentan," Dr Khanna and colleagues report. "The etiology of digital ulceration in systemic sclerosis is multifactorial, involving ischemic, inflammatory, and mechanical mechanisms, all of which influence clinical outcomes of digital ulcers, including repetitive microtrauma, thinning, dry skin, and underlying calcinosis."

In the first trial, Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients (DUAL-1), the researchers randomly assigned 289 patients (226 of whom completed the study) to receive a 3-mg oral dose of macitentan daily, a 10-mg oral dose of macitentan daily, or a placebo daily. The participants all had systematic sclerosis with a mean 3.4 active digital ulcers and were stratified according to whether they had three or fewer (69.6%) or more than three ulcers. Most of the participants were women (85.8%) and were an average age of 51.2 years. After assessment every 4 weeks during the first 16 weeks, the patients underwent follow-up assessments every 3 months until the end of the study.

At the end of the study, the 95 patients receiving 3 mg macitentan had an adjusted average 0.94 new digital ulcers, the 97 patients receiving 10 mg had an average 1.08 new ulcers, and the 97 patients receiving placebo had an average 0.85 new ulcers.

The DUAL-2 trial randomly assigned 265 patients (216 of whom completed the study) according to the same protocol with a similar population: 81.9% women, an average age of 49.6 years, and 3.5 mean active ulcers at baseline, 67.9% of whom had three or fewer ulcers. After reviewing unblinded data during a routine safety monitoring meeting in November 2013, an independent data monitoring committee halted the DUAL-2 trial early, although 74.7% of participants had already undergone at least 16 weeks of treatment.

At that time, the 88 patients receiving 3 mg of macitentan had a mean 1.44 new digital ulcers compared with 1.46 in the 88 patients receiving 10 mg and 1.21 in the 89 patients receiving a placebo. The committee concluded that although "risks of macitentan appeared modest, the possibility of any benefit was small and additional data were not expected to result in a positive primary outcome."

Neither trial showed a significant difference in new digital ulcers across the three groups. The placebo and 3-mg groups in DUAL-1 had an absolute difference of 0.09 new ulcers (95% confidence interval [CI], −0.37 to 0.54), whereas the difference between new ulcers in the placebo and 10-mg groups was 0.23 (95% CI, −0.27 to 0.72). Similarly, in DUAL-2, the absolute difference between the placebo and 3-mg groups was 0.23 (95% CI, −0.35 to 0.82), and for placebo vs 10 mg, 0.25 new ulcers (95% CI, −0.34 to 0.84).

In addition, no significant differences among the groups existed with regard to secondary endpoints. Total digital ulcers, disease severity, pain, and interference with daily activity all decreased across all treatment groups, whereas no effects were seen in any group regarding hand function, digital ulcer burden, overall hand pain related to ulcers, and complete ulcer healing.

During the average 40 weeks of treatment exposure in both trials, adverse events ranged from 71.3% to 85.1% across each of the six treatment groups. Headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis all occurred in at least 10% of patients receiving any dose of macitentan, at a rate at least 3% greater than that experienced the placebo groups. Infections were the most common serious adverse event, and serious events ranged from 11.4% in the DUAL-2 macitentan 3-mg group to 24.1% in the DUAL-2 macitentan 10-mg group.

"Limitations of the DUAL-1 and DUAL-2 studies include the lack of a clear classification system of digital ulcers that considers digital ulcer morphology and the different ulcer features, including presence of underlying calcinosis, size, bedding, perilesional skin, and borders, which potentially affect digital ulcer assessment and counts," the authors note. "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." Further, 23.5% of DUAL-1 participants and 24.9% of DUAL-2 participants were missing primary outcome data at the 16-week follow-up, although the authors determined the missing data were unlikely to have significantly affected statistical inference.

The research was funded by Actelion Pharmaceuticals Ltd, which was involved in the design and conduct of the study as well as collection, analysis, and interpretation of the data and preparation, review, and approval of the article. The authors report a range of financial ties, such as research support, consultancies, and speaker fees, with some of the following: Abbott, AbbVie, Actelion, Alexion, Amgen, Astra-Zeneca, Bayer, Biogen Idec, Bristol-Myers Squibb, Celgene, ChemoCentryx, CSL Behring, Cytori, EMD Serono, Genentech/Roche, Gilead, GlaxoSmithKline, InterMune, Inventiva, Janssen, Novartis, Pfizer, Sanofi-Aventis/Genzyme, Takeda, and UCB, as well as the Scleroderma Foundation, the Pulmonary Hypertension Association, the American College of Rheumatology, and the Vasculitis Foundation. Three coauthors are all employees and stockholders of Actelion Pharmaceuticals Ltd. One coauthor has received research grants and speakers fees from Actelion.

JAMA. 2016;315:1975-1988. Abstract

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