Continued Progress in Therapy for Pulmonary Arterial Hypertension
Darren B. Taichman, Jane A. Leopold, Greg Elliott
N Engl J Med March 6, 2023
DOI: 10.1056/NEJMe2300324
Pulmonary arterial hypertension is a devastating disorder characterized by precapillary pulmonary hypertension not caused by respiratory disease, obstruction of the pulmonary arteries, or certain less-common conditions. Idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, and pulmonary arterial hypertension associated with a connective-tissue disease or exposure to drugs such as methamphetamine account for most cases in the developed world. For years, pulmonary arterial hypertension was considered to be an untreatable, progressive, and rapidly fatal condition.1
A new era of treatment for patients with pulmonary arterial hypertension began three decades ago. 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.2,3 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.4 Yet despite this era of remarkable progress, pulmonary arterial hypertension 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 revealed new potential therapeutic targets.5 In patients with pulmonary arterial hypertension, antiproliferative BMPR2-mediated signaling is reduced, whereas levels of pro-proliferative activin and growth differentiation factor 8 (GDF8) and GDF11 are elevated. Sotatercept, a fusion protein designed to “trap” activin and GDFs, might restore a normal balance. In a phase 2 trial, sotatercept reduced pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension.6
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.7 The results 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 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 (considered to be the minimal clinically important difference) 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 (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.
As exciting as these results are, questions and concerns remain. Trial participants were adults in a clinically stable condition, with more than 8 years on average since diagnosis. More than 90% of the participants had been receiving stable doses of two or three therapies specific for pulmonary arterial hypertension at enrollment, including prostacyclin infusion therapy in 40%. Thus, we do not know whether these results apply to children or to adults who are at higher risk, sicker, or in a less clinically stable condition or who have not received previous treatment. The trial was enriched for patients with idiopathic and heritable pulmonary arterial hypertension (59% and 18% of patients, respectively), groups that commonly harbor disease-causing mutations8; these findings potentially increase the likelihood of a favorable response to sotatercept. By contrast, only 15% of participants had connective-tissue disease–associated pulmonary arterial hypertension, less than half that typically encountered in clinical practice.8 Although the bleeding events and telangiectasias with sotatercept were considered to be mild and safety information from an open-label extension of the phase 2 trial is largely reassuring,9 ongoing vigilance is warranted, notably among patients with connective-tissue disease in whom telangiectasia-related epistaxis and gastrointestinal bleeding are particular concerns.
Future studies should seek to identify which patients may (or may not) benefit from sotatercept. Although approximately 40% of the participants met the multicomponent-improvement measure, 60% did not. Testing for BMPR2 mutations and circulating levels of activin or GDFs might predict which patients are likely to benefit. It may also provide data regarding the biologic effects of sotatercept. Although sotatercept is designed to restore balance to antiproliferative and pro-proliferative signaling in the pulmonary vasculature, the physiological mechanisms that mediate the clinical benefits observed in the STELLAR trial warrant study. Assessments of potentially altered pulmonary vascular remodeling and right ventricular function are needed. 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,10sotatercept 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, and it forces us to ask whether a new treatment era for the disorder has arrived. It’s too soon to know. But one thing is clear: the era of remarkable progress in the care of patients with this devastating disease has not come to an end.
