Continued Progress in Therapy for Pulmonary Arterial Hypertension
- Typhoid and paratyphoid fever are acquired through consumption of water or food contaminated by the feces of an infected or colonized person.
PAH
Pulmonary arterial hypertension (PAH) is a disorder characterized by precapillary pulmonary hypertension not caused by respiratory disease, obstruction of the pulmonary arteries, or certain less-common conditions. Investigations that were focused on imbalanced vasoconstriction and vasodilation produced groundbreaking demonstrations that survival might be improved with high-dose calcium-channel blockers in the small subgroup of patients with acute vasoreactivity on hemodynamic testing or with continuously infused prostacyclin regardless of acute vasoreactivity. Subsequent trials of agents targeting the prostacyclin, endothelin, or nitric oxide signaling pathways led to our current armamentarium of 10 Food and Drug Administration–approved drugs used alone or in combination to improve exercise capacity and quality of life and delay disease progression.
New Drugs
The discovery of disrupted transforming growth factor β (TGF-β) signaling involving altered function of the bone morphogenetic protein receptor type 2 (BMPR2) in patients with pulmonary arterial hypertension revealed new potential therapeutic targets. Sotatercept, a fusion protein designed to “trap” activin and growth differentiation factor 8 (GDF8) and GDF11, might restore a normal balance. In a phase 2 trial, sotatercept reduced pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension.
STELLAR
Hoeper et al. now report in the Journal the results of STELLAR, a phase 3, multinational, double-blind trial in which 323 adults receiving stable background therapy for pulmonary arterial hypertension were randomly assigned to receive subcutaneous sotatercept or placebo every 3 weeks. 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 observed with respect to eight of nine secondary end points, including the percentage of patients meeting a multicomponent measure requiring an increase of at least 30 m in the 6-minute walk distance together with achievement or maintenance of a favorable World Health Organization functional class and N-terminal pro–B-type natriuretic peptide level. Pulmonary vascular resistance was reduced, and some measures of quality of life were improved. Severe and serious adverse events were observed less frequently with sotatercept than with placebo. Bleeding and other adverse events of particular concern 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.
Conclusion
The trial was conducted on patients with idiopathic and heritable pulmonary arterial hypertension, which potentially increases the likelihood of a favorable response to sotatercept. Future studies should seek to identify which patients may (or may not) benefit from sotatercept. Assessments of potentially altered pulmonary vascular remodeling and right ventricular function are needed. Sotatercept might also improve 6-minute walk distance by improving the efficiency of skeletal muscles. The STELLAR trial provides encouraging data for a new direction in therapeutic strategies for pulmonary arterial hypertension.