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ORLANDO, Fla. — The activin signaling inhibitor sotatercept has been studied in multiple research trials, but little is known about safety and effectiveness in real-world patients with pulmonary arterial hypertension (PAH). That is, until now. Mayo Clinic researchers reported the first clinical setting outcomes among 91 patients receiving this first-in-class treatment.

“We developed this registry to understand the real-world safety, efficacy, and tolerability of sotatercept in clinical practice. Overall, it was fairly safe, well tolerated, and effective, improving risk scores, 6-minute walk distance, and NT-proBNP [N-terminal pro-B-type natriuretic peptide],” said lead author Hilary M. DuBrock, MD, a pulmonologist, internist, and critical care specialist at Mayo Clinic in Rochester, Minnesota.

DuBrock presented the findings during a poster discussion session at the American Thoracic Society (ATS) 2026 International Conference.

Striking a Balance

The FDA approved sotatercept in March 2024 for adults with World Health Organization (WHO) Group 1 PAH to increase exercise capacity, improve WHO functional class, and reduce the risk for clinical worsening events.

Sotatercept relies on both pro-proliferative and antiproliferative signaling to control vascular proliferation. The recombinant activin receptor type IIA-Fc fusion protein binds to activin A and other transforming growth factor-beta superfamily ligands. 

Mixed PAH Phenotypes

DuBrock and colleagues assessed safety and effectiveness in a combined retrospective-prospective cohort study. They collected demographic, echocardiographic, laboratory, and hemodynamic data at baseline, 6 months, and at last follow-up visit.

The median participant age was 57 years, 79% were women, and the mean BMI was 28.

In terms of etiology, 48% of participants had idiopathic PAH, 20% had connective tissue disease-associated PAH, 14% had heritable PAH, and in 10% PAH was associated with drugs or toxins. One percent of participants were New York Heart Association (NYHA) functional class I, 31% were class II, 61% were class III, and 7% were class IV.

Key Findings

The mean 6-minute walk test at baseline was 375 m. At 6 months, the mean test distance improved by 38 m (P < .001).

The mean NT-proBNP level was 428 pg/mL at baseline. At 6 months, there was a mean 210 pg/mL decrease in this measurement, or a 56% improvement (P < .001).

Another significant change was a 1.0-point decrease in the REVEAL 2.0 score, or a 44% improvement (P < .001).

Changes in right ventricular (RV) systolic pressure, improvements in RV strain, and the ratio of these two factors did not significantly change at 6 months.

NYHA functional class improved in 39% of participants and remained unchanged in 61%. None of the participants experienced worsening classification.

“Overall, sotatercept in patients with pulmonary arterial hypertension in real-world clinical practice was associated with improvements in exercise capacity, in NT-proBNP, and right ventricular function,” DuBrock said.

A follow-up shunt study revealed no shunt in 48 patients, an intrapulmonary shunt in 24, and an intracardiac shunt in six participants.

Study limitations include a single-center design and missing data.

Safety Profile

Adverse events included any gastrointestinal (GI) bleeding in eight participants and telangiectasia in 17 patients. Twenty-five participants were hospitalized, four had a lung transplant, and there were five deaths.

Ten patients discontinued sotatercept due to treatment-emergent adverse effects, including three who experienced GI bleeds and one each who experienced cerebral bleeding, epistaxis, or thrombocytopenia. In addition, doses were held in 30 participants and doses were decreased in 21 patients.

“In terms of other adverse effects of special interest, we had 14% of patients develop either new or worsening pericardial effusion,” DuBrock said.

‘Very Informative’ Study

Asked to comment on the study, session co-moderator Rebecca R. Vanderpool, PhD, cardiovascular medicine researcher at The Ohio State University Wexner Medical Center in Columbus, Ohio, said, “I thought it was very informative of real-world experience. Sotatercept is a new drug, and it’s interesting to see how it works in the community settings and at medical centers.”

There are a lot of real-world questions about sotatercept, Vanderpool said, including: What is the effect on resistance and changes in pulmonary vascular resistance? What are the side effects? How does it work? Is it safe? Are there comorbidities that might be impacting therapy?

“It’s very interesting,” Vanderpool said. “How does that all show up in clinical practice?”

Study Is Ongoing

DuBrock and colleagues have treated more than 200 patients with PAH with sotatercept to date, and plan to continue collecting and analyzing outcomes.

The study was independently supported. DuBrock reported being a consultant for Merck. Vanderpool had no relevant financial relationships.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. He has a BA in chemistry and an MA in science, health, and environmental reporting/journalism.