Novel drug Sotatercept shows promise for PAH treatment in STELLAR trial- NEJM.

In what may signal the arrival of a new era in management of pulmonary artery hypertension (PAH), the recently published STELLAR trial has shown that Sotatercept, a novel fusion protein designed to “trap” activin and GDFs, significantly improves exercise capacity in PAH patients. These results were recently published in NEJM.

Despite the availability of at least 10 FDA approved drugs for PAH, this disease entity remains deadly for many patients, and available treatments provide insufficient functional and quality-of-life gains for many more.

The discovery of disrupted transforming growth factor β (TGF-β) signaling involving altered function of the bone morphogenetic protein receptor type 2 (BMPR2) in 70 to 80% of patients with heritable pulmonary arterial hypertension and 10 to 20% of those with idiopathic pulmonary arterial hypertension has revealed new potential therapeutic targets.

Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. Authors Hoeper et al, conducted a multicenter, double-blind, phase 3 trial in which adults PAH who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks.

The primary end point was the change from baseline at week 24 in the 6-minute walk distance (6MWD). Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in NTproBNP, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the PAH-SYMPACT Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores.

The results of this trial are impressive. At 24 weeks, the median change from baseline in 6-minute walk distance was 34.4 m with sotatercept and 1.0 m with placebo. Improvement was also observed with respect to eight of nine secondary end points.

Severe and serious adverse events were observed less frequently with sotatercept than with placebo. Bleeding and other adverse events of particular concern (e.g., telangiectasia, increased hemoglobin level, and thrombocytopenia) occurred more frequently with sotatercept. Overall, these results suggest that sotatercept may represent a new and clinically consequential addition to current medications for pulmonary arterial hypertension.

“Although pulmonary vascular resistance was decreased, effects beyond those within the pulmonary vasculature itself, such as increased hemoglobin concentrations with sotatercept, may improve exercise performance. By sequestering GDF8, a key determinant of muscle mass, sotatercept might also improve 6-minute walk distance by improving the efficiency of skeletal muscles”, noted Taichman et al in an accompanying editorial.

To conclude, STELLAR trial provides encouraging data for a new direction in therapeutic strategies for PAH, and it forces us to ask whether a new treatment era for the disorder has arrived.

Source: NEJM:

1. N Engl J Med 2023; 388:1524-1526

2. N Engl J Med 2023; 388:1478-1490