ACC23: J&J's combo pill of Opsumit plus tadalafil improves blood flow in PAH patients

With many pulmonary arterial hypertension (PAH) patients already taking Johnson & Johnson’s Opsumit (macitentan) or United Therapeutics' Adcirca (tadalafil), J&J has been pursuing a potential combination of the two therapies for several years.

In October of 2021—based on three bioequivalence studies—Health Canada approved Opsynvi for patients already on the two-pill regimen. Before that, in 2019, the company shared promising data on the combo.

Now, after a successful phase 3 trial, Opsynvi may be on its way to winning more regulatory green lights.

On Monday, results from a pivotal study called A DUE showed that Opsynvi—which consists of 10 mg of Opsumit and 40 mg of Adcirca—significantly improved blood flow through pulmonary blood vessels versus either drug as a monotherapy. The results were presented at the American College of Cardiology’s 72nd Annual Scientific Session in New Orleans.

The study enrolled 187 PAH patients in 19 countries worldwide with class II or class III of the progressive disease. Patients in class II have no symptoms at rest, but are uncomfortable and short of breath during normal activities such as climbing a flight of stairs. The activities of those in class III are greatly limited by shortness of breath, fatigue or near fainting when attempting things such as household chores.

For the study, participants were either not on treatment or were on a stable dose of an endothelin receptor antagonist (ERA), such as Opsumit, or a phosphodiesterase type 5 inhibitor (PDE5i), such as Adcirca, for at least three months.

Patients on the combo drug, Opsynvi, experienced a 29% reduction in pulmonary vascular resistance (PVR) over those on Opsumit alone and a 28% reduction over those on Adcirca alone. PVR is a measure of how much pulmonary circulation resists cardiac output.

The results were “not too surprising, because we have evidence that this combination is likely to be effective from prior studies,” Kelly Chin, M.D., director of the Pulmonary Hypertension Program at UT Southwestern Medical Center in Dallas and the study's principal investigator, said in an email.

“I did think that the magnitude of the decline in PVR was a little surprising,” Chin said. “The improvement for the fixed-dose combination group was quite large for a study where half of the patients were already on therapy.”

Even though A DUE was not geared to demonstrate a benefit on exercise capacity, investigators noted a clinically relevant improvement in patients' 6-minute walk distance. Opsynvi produced a 16-meter improvement in walk distance on average over Opsumit and 25-meter improvement over Adcirca.

Combining the treatments makes sense because they target two of the key pathways at play in the progression of PAH, Chin said.

"We are very excited about these data and look forward to discussing these findings with the U.S. Food and Drug Administration," said James List, M.D., Ph.D., Janssen's Global Therapeutic Area Head, Cardiovascular, Metabolism, Retina & Pulmonary Hypertension.

PAH is a specific, rare form of pulmonary hypertension (PH) that affects the right side of the heart and causes the walls of the pulmonary arteries—blood vessels leading from the right side of the heart to the lungs—to become thick, narrowing the space for blood to flow, and causing increased blood pressure to develop within the lungs. If left untreated, PH can lead to right ventricle failure, a serious type of heart failure.

Over the years, clinicians have come to realize that combination therapy is the most effective treatment for PAH and it is now regarded as the standard of care. With the complexities of combining medications with differing mechanisms of action, approaches must be considered carefully and monitored closely, according to guidelines from the European Society of Cardiology/European Respiratory Society (ESC/ERS).

"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," List said in a release. "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."

Opsumit, which was approved for PAH in 2013, achieved sales of $1.8 billion in each of the last two years. J&J’s other PH blockbuster Uptravi generated sales of $1.3 billion last year. J&J picked up both drugs in its $30 billion acquisition of Actelion in 2017.