Macitentan and tadalafil combo may be better than either drug alone

Phase 3 trial of PAH treatment reports easier blood flow with once-daily tablet

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An investigational once-daily therapy, a single tablet combining macitentan and tadalafil, significantly improved pulmonary blood flow compared with macitentan or tadalafil alone in pulmonary arterial hypertension (PAH) patients taking part in the Phase 3 A DUE study.

Because these medications target different PAH-related pathways, current guidelines recommend initially treating PAH with both macitentan, sold as Opsumit, and tadalafil, sold as Adcirca.

“Targeting different pathways in the treatment of PAH has demonstrated clear clinical benefits, yet current treatment regimens are cumbersome and create a significant pill burden for patients, many of whom take a large number of pills each day to treat their PAH and various co-morbidities [co-existing conditions],” Kelly Chin, MD, a trial investigator and professor at the University of Texas Southwestern Medical Center, said in a press release.

Study findings “demonstrate that a single tablet combination has the potential to support initial dual combination therapy and rapid escalation from monotherapy, which may improve functional outcomes and help close the gap from guideline recommendations to clinical practice,” Chin said.

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Opsumit (macitentan) plus Adcirca (tadalafil) favored as initial PAH treatment

PAH is a progressive disorder characterized by the narrowing of the pulmonary arteries, the blood vessels that supply the lungs, resulting in high blood pressure. Macitentan and tadalafil are approved PAH medications that work through different mechanisms to widen vessels, improve blood flow, and lower blood pressure.

Guidelines by the European Society of Cardiology/European Respiratory Society (ESC/ERS) recommend both medications as an initial treatment of PAH patients without co-existing heart or lung problems.

The ongoing A DUE Phase 3 (NCT03904693) study, sponsored by Actelion, part of Johnson & Johnson, is testing its fixed-dose combination of macitentan (10 mg) and tadalafil (40 mg) against each therapy alone in 187 adults with PAH.

Enrolled patients either were treatment naïve or on a stable dose of similar medications for at least three months, and all had World Health Organization (WHO) functional class 2 or 3 disease. They were randomly assigned to a daily dose of the combination therapy, or to macitentan or tadalafil, for four months.

Meeting the trial’s primary goal, patients treated with the macitentan/tadalafil combination showed a marked improvement in pulmonary blood flow compared with those taking macitentan or tadalafil alone.

Pulmonary vascular resistance, a measure of the resistance that must be overcome for blood flow, was 29% lower in the combination group relative to those given macitentan and 28% lower against tadalafil, both statistically significant differences.

Although the A DUE study did not enroll enough participants to statistically demonstrate benefits in exercise capacity, clinically relevant improvements favoring macitentan/tadalafil was reported in distances walked in six minutes (6MWD).

Individuals treated with the combination walked a mean of 16 meters (about 52 feet) farther than those on macitentan and a mean of 25.4 meters (83 feet) farther than those given tadalafil.

The safety profile of the macitentan/tadalafil combination was similar to the known safety profiles of macitentan and tadalafil, and no new adverse events were reported.

Open-label treatment of enrolled patient following A DUE trial’s completion

Patients who complete the A DUE trial have the option of continuing or starting with the combination therapy for two years in an open-label study.

“The guiding light of our PH research is the goal of transforming PAH into a manageable condition, so we’re constantly looking for ways to improve both clinical outcomes and the treatment experience,” said James List, MD, PhD, with Janssen Research & Development, also part of Johnson & Johnson

“A single tablet combination has the potential to be an important new option for helping physicians optimize disease management with the potential to enhance convenience and help improve adherence and outcomes,” List added.

These findings were presented at the American College of Cardiology’s 72nd Annual Scientific Session & Expo Together With World Heart Federation’s World Congress of Cardiology, held March 4-6.

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