Lung Story Short: A New Therapy for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) involves the obliteration of the small arterioles of the pulmonary vasculature. PAH is categorized as World Health Organization (WHO) group 1 pulmonary hypertension, based on the presence of elevated pulmonary arterial pressures, normal pulmonary capillary wedge/left heart pressures, and the absence of significant parenchymal lung, thromboembolic, and other causes of pulmonary hypertension. PAH causes progressive cardiopulmonary symptoms, which lead to eventual right heart failure and premature death.

Despite the diverse etiologies that can lead to PAH, ranging from human immunodeficiency virus (HIV) to connective tissue diseases, the resultant histopathology is strikingly similar. Microscopically, the disease is characterized by muscularization, collagenous “onion-skinning,” and plexiform lesions (representing fibrosis with thrombosis) of the pulmonary arterioles. The common endpoint suggests that several pathophysiologic pathways ultimately converge in the shared entity known as PAH.

Drug therapies for PAH have had varied success. For example, calcium channel blockers are safe and effective in only a small proportion of patients with PAH, testing for an acute response to vasodilators is required prior to use, and only recommended for patients with idiopathic, heritable, or drug-associated disease. Three other main classes of medications for PAH are currently available — endothelin receptor antagonist (ERAs), phosphodiesterase-5 (PDE5) inhibitors, and prostacyclins. Even with multiple drug classes, clinical outcomes for patients with PAH are poor; in a 2015 trial of combination therapy, 20%–30% of patients experienced the composite end-point of death, hospitalization for PAH, disease progression, or treatment failure within 2 years. New therapies would be welcome for this group of patients who experience profound morbidity and mortality.

The phase 2 PULSAR trial published in 2021 examined sotatercept, a novel fusion protein that binds molecules active in the bone morphogenic protein receptor type 2 (BMPR2) pathway, which is disrupted in many patients with PAH. The findings were promising, indicating that after 24 weeks of treatment, the pulmonary vascular resistance of patients randomized to sotatercept had decreased significantly. The corresponding phase 3 STELLAR trial has now been published in NEJM.

In this multicenter, double-blind trial, the primary endpoint of exercise capacity (a 24-week change in 6-minute walk distance) was 34.4 m in the sotatercept group and 1.0 m in the placebo group, with Kaplan-Meier curves separating at roughly week 10. The first eight of nine secondary endpoints, tested in a hierarchical fashion, also favored sotatercept. These results are particularly impressive considering that most patients were on triple therapy at enrollment, indicating relatively advanced disease.

As much as the results of the STELLAR trial have been anticipated, the outcomes will need to be verified in broader populations. Despite enrollment in 21 countries, most patients were white. Further, randomization may have been compromised by certain physical adverse events, (e.g., telangiectasias), and the primary endpoint of exercise capacity, while significant and technically meaningful, was only slightly above the threshold of clinical utility (30 m for the 6-minute walk distance). The lack of a between-group difference in quality-of-life measures may reflect this nuance. Most worrisome, the study did not include patients with schistosomiasis, the most common cause of PAH worldwide, or patients with HIV who are frequently underserved.

The investigators will continue to follow patients for at least 72 more weeks in the ongoing SOTERIA trial. We eagerly await these long-term data and studies in diverse populations to inform the care of patients with PAH worldwide.

Read the following NEJM Journal Watch summary for more details of this study.

Frederick A. Masoudi, MD, MSPH, MACC, FAHA, reviewing Hoeper MM et al. N Engl J Med 2023 Mar 6

Pulmonary arterial hypertension (PAH), while relatively rare, disproportionately affects younger individuals, particularly women, and has a dire prognosis. Although several classes of beneficial therapies are available — including phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and endothelin-receptor antagonists — morbidity and mortality remain high. This phase 3, manufacturer-sponsored trial (NCT04576988) assessed the efficacy of sotatercept, a compound that acts as a “ligand trap” for selected TGF-β superfamily members, which have been implicated in the pathogenesis of PAH.

Investigators randomized 323 individuals with PAH (median age, 48 years; 79% women; 89% white; 59% with idiopathic PAH; 61% on three agents to treat PAH) and WHO functional class II or III symptoms to receive subcutaneous sotatercept or placebo every 3 weeks in addition to usual care. At 24 weeks, the primary endpoint of 6-minute walk distance improved by a median of 34 meters in those treated with sotatercept compared with 1 meter in the placebo group, representing a statistically estimated comparative improvement of 41 meters (over the median baseline of approximately 400 meters). Several secondary endpoints also improved with sotatercept, including pulmonary vascular resistance, N-terminal pro–B-type natriuretic peptide level, and WHO functional class. Sotatercept was associated with higher rates of epistaxis, dizziness, telangiectasia, thrombocytopenia, and increased hemoglobin and systemic blood pressures.

Comment: This trial identifies a possible new class of therapies for PAH to complement available vasodilator therapies. Because participants were predominantly clinically stable patients with longstanding PAH and on stable therapeutic regimens, the demonstrated efficacy might differ in younger or sicker individuals. Also, the study did not have adequate power to assess an effect on mortality, and the proportion of patients with an identifiable cause of PAH was small. Thus, while the news is encouraging, there is much more we need to know. Notably, while sotatercept was granted a breakthrough designation from the FDA, it is not yet approved for use in the U.S.

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Clement Lee, MD, MSc, was a 2021–2022 NEJM Editorial Fellow and is a 2022-2023 Senior Editorial Fellow. He is currently an internal medicine hospitalist at Newton-Wellesley Hospital and a pediatric hospitalist at Boston Children's Hospital. He completed his internal medicine-pediatrics residency at Penn-CHOP.