New drug sotatercept shows benefit in CpcPH-HFpEF patients

Patients who have heart failure with preserved ejection fraction (HFpEF) and high blood pressure in the lungs (pulmonary hypertension) experienced significant improvements in blood pressure and vascular health after taking the drug sotatercept, according to a study presented at the American College of Cardiology's Annual Scientific Session (ACC.26).

Group 2 pulmonary hypertension is due to left-sided heart abnormalities. The trial is the first to test sotatercept in a specific subset of patients with Group 2 pulmonary hypertension, including HPpEF and severe combined post and precapillary pulmonary hypertension (CpcPH).

CpcPH occurs when high pressure caused by heart problems backs up into the lungs and, over time, damages the lung's blood vessels—making it harder to breathe and limiting daily activities. HFpEF is a form of heart failure in which the heart's left ventricle does not relax fully and may be stiff. This reduces its ability to fill properly with blood between each heartbeat, leading to a variety of symptoms including fatigue, shortness of breath and swelling.

Sotatercept is a first-in-class drug that is designed to reduce abnormal proliferation of cells in blood vessel walls. It is approved for Group 1 pulmonary hypertension, which affects the pulmonary artery and can be caused by genes, toxins and some systemic diseases. While multiple therapies are available for treating Group 1 pulmonary hypertension, no previous drug has been proven effective for Group 2 pulmonary hypertension, including CpcPH-HFpEF.

"Patients and the scientific community have been waiting a long time for a treatment that shows benefit in CpcPH associated with HFpEF, as previous trials have failed and there are no approved therapies," said Mardi Gomberg, MD, MSc, a cardiologist and professor of medicine at the George Washington School of Medicine and Health Sciences in Washington and the study's lead author. "We have seen recent improvements in HFpEF therapies but none that are specific to the distinct clinical condition of CpcPH-HFpEF. These patients continue to have severe heart failure symptoms."

Researchers enrolled 164 patients with CpcPH-HFpEF in the Phase 2 trial. Patients were 75 years old on average, and 70% were female, which is reflective of the typical patient population for CpcPH-HFpEF. The participants were randomly assigned 1:1:1 to receive sotatercept at 0.3 mg/kg, at 0.7 mg/kg or a placebo. At 24 weeks, researchers assessed hemodynamic and clinical outcome measures of pulmonary hypertension.

Sotatercept treatment improved pulmonary arterial pressure with a statistically significant reduction in pulmonary vascular resistance, the primary endpoint. Pulmonary vascular resistance is a measure of how hard it is for blood to flow through the blood vessels in the lungs, which when narrowed, stiff or damaged, results in the heart working harder to move blood through them. Higher resistance means the heart is working under more stress, so a decrease in pulmonary vascular resistance means the strain on the heart is lower. Secondary endpoints also were better in those taking sotatercept, who showed improved six-minute walking distance and right heart function and a lower rate of clinical worsening events.

"It's really exciting because we see improvements in heart failure clinical markers as well as biomarkers of heart function in both the right side and the left side," Gomberg said. "The left atrial volume and left atrial pressure (measured as wedge pressure) improved, features that can put you at risk for a variety of bad outcomes with HFpEF. Seeing these improvements in addition to improvements in the pulmonary vasculature makes this a big deal."

Sotatercept showed a favorable safety profile, with rates of adverse events on par with those seen in previous clinical trials. Initial results suggest that the lower dose of sotatercept seems to optimize the benefit-risk in this patient population.

Also of note, the study included some patients who had previously undergone procedures to repair a heart valve at least a year prior to enrolling in the study. Although these patients represented only a small number of participants, the results revealed that this group experienced similar benefits from sotatercept with no indication of increased risk.

As a Phase 2 trial, the study was limited by a relatively small sample size; its 24-week placebo-controlled time period also limits the ability to draw conclusions regarding long-term safety and efficacy. Based on the positive results from the study, the researchers are planning to pursue a Phase 3 study to test sotatercept in CpcPH-HFpEF.

The study was funded by Merck, maker of sotatercept.

This study was simultaneously published online in Circulation at the time of presentation.

Gomberg will present the study, "Efficacy and Safety of Sotatercept in Combined Post- and Pre-capillary Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction: Results from the Phase 2 Cadence Trial," on Sunday, March 29, at 10:45 a.m. CT / 15:45 UTC in the Main Tent, Great Hall.