Adempas May Benefit PAH Patients Who Fail to Respond to PDE5 Inhibitors, Trial Indicates

Bayer’s Adempas (riociguat) can improve the lung and heart functioning of pulmonary hypertension patients who fail to respond to phosphodiesterase-5 inhibitors (PDE5i), a Phase 3 clinical trial suggests.

The RESPITE trial also showed that Adempas can improve biomarkers of pulmonary arterial hypertension, or PAH.

Researchers published the study in the European Respiratory Journal. The title was “RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors.”

Dr. Marius H. Hoeper led the study. He is with the Department of Respiratory Medicine at Germany’s  Hannover Medical School.

PAH increases the workload of the heart’s right ventricle. If left untreated, it can lead to heart failure and death.

At the moment, the disease is incurable. But various stand-alone and combination therapies can reduce its symptoms and improve patient outcomes.

The most commonly used PAH therapies are phosphodiesterase-5 inhibitors such as United Therapeutics’ Adcirca (taladafil) and Pfizer’s Revatio (sildenafil). The inhibitors fail to help some PAH achieve their treatment goals, however.

Adempas and PDE5is target different molecules in the same biological pathway. This would suggest that an Adempas and PDE5i combo could be effective. But such a combination increases the risk of adverse effects, studies indicate.

Researchers wondered whether switching from a PDE5i to Adempas could be an effective treatment strategy.

The 24-week RESPITE trial (NCT02007629) involved people in the World Health Organization (WHO) functional class III category of PAH. They can engage in very limited physical activity. They are likely to have difficulty breathing, to be chronically tired, have chest pain, and experience syncope, or temporary loss of consciousness due to insufficient blood flow to the brain.

Researchers took the patients off their PDE5i for three days before switching them to Adempas. They received Adempas for eight weeks, during which their dose was adjusted to an optimal level, followed by a maintenance phase of 16 weeks.

Fifty-one of the 61 patients, or 84 percent, completed the trial. While they were on Adempas, 50 patients, or 82 percent, also received a PAH treatment known as an endothelin receptor antagonist.

At week 24, most patients improved their score on a measure of exercise capacity known as the six-minute  walking distance test. Most also showed an improvement in a biomarker of heart failure, decreasing their levels of N-terminal prohormone brain natriuretic peptide. Twenty-eight patients, or 54 percent, improved their WHO functional class scores.

Importantly, 32 patients, or 52 percent, had Adempas-related adverse events, and 10, or 16 percent, serious adverse events. In addition, the condition of six patients, or 10 percent of the group, worsened. Two of the six died, although researchers said the deaths were not Adempas-related.

The results offered preliminary evidence that switching to Adempas “may be not only tolerable and safe, but also potentially beneficial in PAH patients with an insufficient response to their previous treatment,” the researchers wrote.

“Selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied,” the team emphasized. Another question that needs to be addressed is whether switching to Adempas sooner will yield more benefits. And still another is whether starting Adempas “at higher doses with shorter dose-adjustment periods is safe and feasible.”

Bayer has started a Phase 4 REPLACE trial (NCT02891850) to further investigate the benefits of a switch.