Ingrid Hein

May 24, 2017

WASHINGTON — For patients with inoperable chronic thromboembolic pulmonary hypertension, macitentan (Opsumit, Actelion) can lead to significant improvements in pulmonary vascular resistance and exercise capacity, according to results from a phase 2 study.

Improvements in hemodynamic assessments and 6-minute walk test distance were "remarkable," said investigator Hossein Ardeschir Ghofrani, MD, from the University of Giessen and Marburg Lung Center in Germany.

Dr Hossein Ardeschir Ghofrani

Treatment options for inoperable pulmonary hypertension caused by chronic obstruction of the pulmonary arteries are currently limited.

Not all patients are candidates for pulmonary thromboendarterectomy because of the location of the thrombi or other comorbidities. And riociguat (Adempas), the only drug approved for inoperable pulmonary hypertension, is available and reimbursed in a limited number of places, mostly in Europe.

Macitentan, however, is broadly approved and reimbursed for WHO group 1 pulmonary arterial hypertension, "so it should be available to a good many patients," Dr Ghofrani reported here at the American Thoracic Society 2017 International Conference.

MERIT Study

In the randomized, prospective Macitentan in the Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension (MERIT) trial, half the 80 patients with WHO class III or IV inoperable pulmonary hypertension were randomized to macitentan 10 mg daily for 24 weeks, and the other half were randomized to placebo.

Of the participants who were receiving therapy for pulmonary hypertension at baseline, 96% were receiving phosphodiesterase type 5 (PDE5) inhibitors and 24% were receiving oral or inhaled prostanoids.

The primary end point of pulmonary vascular resistance at 16 weeks, expressed as a percentage of baseline, was a significant 16% better in the macitentan group than in the placebo group (P = .04). There was no difference between people who continued their baseline therapy and those who did not, or between the different types of pulmonary hypertension treatment.

Mean improvement in 6-minute walk distance from baseline to 24 weeks — the main secondary end point and an indication of overall exercise capacity — was significantly better in the macitentan group than in the placebo group (35 vs 1 m; P = .03).

Dr Ghofrani and his colleagues also looked at exploratory end points. Improvement in mean Cardiac Index was better with macitentan than with placebo (0.4 vs 0.0 L/min per m²; P < .001), as were reduction in mean right atrial pressure from baseline to week 16 (2.6 vs 0.1 mm Hg; P = .21) and N-terminal pro B-type natriuretic peptide at week 24, expressed as a percent of baseline (72.6% vs 90.9%; P = .04).

Macitentan was well tolerated, and the findings were generally consistent with the known safety profile of macitentan.

The rate of peripheral edema, a known adverse effect of macitentan, was higher with macitentan than with placebo (22.5% vs 10.0%). However, "most of the cases were of mild or moderate intensity," Dr Ghofrani told Medscape Medical News.

The rate of anemia was also higher with macitentan (17.5% vs 2.5%). During the study period, one patient in each group experienced a reduction in hemoglobin to below 100 g/L.

In the macitentan group, no patients discontinued treatment or died. In the placebo group, five patients discontinued treatment prematurely and two patients died.

"The safety profile we saw was encouraging; we did not see any impact on systemic blood pressure," which can arise, particularly in patients receiving multiple medications, Dr Ghofrani explained.

Encouraging Results

"What impressed me the most was that we could achieve significant changes in secondary and exploratory end points," Dr Ghofrani said. "These are meaningful parameters we'd like to improve for our patients with severe symptoms."

"The entire pattern showed a positive response," he reported, so "we're pointed in the right direction."

"This is a very promising phase 2 trial," said Clark Files, MD, from the Wake Forest School of Medicine in Winston-Salem, North Carolina.

"It certainly warrants a phase 3 study," he told Medscape Medical News. "And it could be interesting to see the 6-minute walk distance as a primary end point."

The study was funded by Actelion Pharmaceuticals. Dr Ghofrani reports financial relationships with Actelion Pharmaceuticals, Bayer, Ergonex, Pfizer, Bellerophon Therapeutics, GlaxoSmithKline, and Novartis. Dr Files has disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2017 International Conference: Abstract 7601. Presented May 22, 2017.

Follow Medscape Pulmonary Medicine on Twitter @MedscapeLung and Ingrid Hein @ingridhein

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