Pulmonary Functional Imaging: Part 2—State-of-the-Art Clinical Applications and Opportunities for Improved Patient Care
Sotatercept Reduces Major Events In High-Risk PAH Patients
Sotatercept-csrk reduced the risk of major morbidity and mortality events in adults with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) functional class (FC) 3 or 4 at high risk of mortality, according to published results from the ZENITH trial.
Sotatercept is a recombinant activin receptor type IIA-Fc fusion protein designed to bind to activin A and other TGF- β superfamily ligands resulting in vascular proliferation regulation. It is currently approved under the brand name Winrevair™ for the treatment of adults with PAH (WHO Group 1) to increase exercise capacity, improve WHO FC, and reduce the risk of clinical worsening events.
The double-blind, placebo-controlled phase 3 ZENITH study (ClincialTrials.Gov Identifier: NCT04896008) enrolled 172 patients with WHO FC 3 or 4 PAH and a high 1-year risk of mortality (Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2.0 risk score ≥9) who were receiving maximum tolerated background therapy.
Study participants were randomly assigned to receive subcutaneous sotatercept (n=86) or placebo (n=86) every 21 days with background PAH therapy. The primary endpoint was the time to first confirmed morbidity or mortality event defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of at least 24 hours.
Findings showed sotatercept reduced the relative risk of major morbidity and mortality events by 76% (hazard ratio [HR], 0.24 [95% CI, 0.13-0.43]; P <.0001) compared with placebo. In the sotatercept arm, 17.4% of patients experienced at least 1 major morbidity or mortality event vs 54.7% of those in the placebo arm. The median duration of follow-up was 10.6 months (range, 0.3-26.1) and 7.1 months (range, 0.7-24.2) in the sotatercept and placebo groups, respectively.
Death from any cause (8.1% vs 15.1%), lung transplantation (1.2% vs 7.0%), and hospitalization for worsening PAH (9.3% vs 50.0%) occurred less frequently in the sotatercept group compared with the placebo group.
Notably, overall survival, a key secondary endpoint, did not reach the heightened statistical significance threshold at the interim analysis (HR, 0.42 [95% CI, 0.17-1.07]; P =.0313).
The most common adverse events reported with sotatercept were epistaxis and telangiectasia.
"The ZENITH study represents the first PAH clinical trial with a primary endpoint comprised entirely of major outcome measures – all-cause death, lung transplantation and hospitalization for PAH," said Dr Marc Humbert, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999. "Winrevair had a significant and clinically meaningful impact on the composite of these outcomes, and together with the growing body of evidence from the clinical development program, these data support the practice-changing potential of Winrevair for a broad range of patients with PAH."
Previously, Merck announced that the ZENITH trial would be stopped early based on strong efficacy data. All study patients were offered the opportunity to receive sotatercept through the open-label, long-term extension SOTERIA study (ClinicalTrials.Gov Identifier: NCT04796337).
This article originally appeared on MPR
Sotatercept FAERS Study Highlights Emerging Safety Signals In PAH Treatment
At the 2025 American College of Cardiology (ACC) meeting in Chicago, new real-world safety data were presented on sotatercept, a novel fusion protein for pulmonary arterial hypertension (PAH). A retrospective analysis of the FDA Adverse Event Reporting System (FAERS) revealed key adverse events (AEs) associated with sotatercept, including cerebrovascular accidents (CVAs), flushing, diarrhoea, neutropenia, and asthenia. The study emphasised a higher incidence of AEs in elderly patients (65–85 years), highlighting the need for vigilant monitoring in this population.
PAH is a rare and progressive disease characterised by increased pulmonary vascular resistance, ultimately leading to right heart failure. Despite therapeutic advancements, PAH remains associated with high morbidity and mortality, necessitating the development of new disease-modifying agents. Sotatercept, a first-in-class activin signalling inhibitor, has demonstrated significant improvements in exercise capacity and haemodynamic parameters in clinical trials. However, its long-term safety profile in broader patient populations is still being evaluated.
The FAERS analysis, which included 11 reported AEs as of June 2024, found that CVAs, flushing, diarrhoea, and neutropenia each accounted for 18.18% of reported cases. The age-based analysis revealed that 54.55% of AEs occurred in patients aged 65–85 years, with fewer incidents reported in younger cohorts. While no statistically significant differences were observed in AEs across organ system groups, the findings underscore potential safety concerns, particularly for elderly PAH patients.
Key opinion leaders (KOLs) have previously emphasised sotatercept's transformative impact on PAH management. A European KOL noted: "Sotatercept is probably the most important development in PAH over the past ten years. It will change the complete treatment landscape and positioning of other compounds in the treatment algorithm." This statement highlights the significant clinical and commercial implications of sotatercept's entry into the PAH treatment paradigm.
From a pharmaceutical strategy perspective, the FAERS findings introduce several critical considerations. First, the emergence of cerebrovascular events, although limited in frequency, may influence risk-benefit assessments during future regulatory reviews and labelling decisions. This could lead to targeted safety monitoring requirements or risk management plans (RMPs), particularly for older patients. Secondly, while sotatercept is positioned as an add-on therapy, the magnitude of its clinical benefits raises the possibility of earlier-line use. This could disrupt the current PAH treatment sequencing and challenge the market positioning of established endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE5is). Lastly, the real-world safety signals from FAERS may prompt payers to introduce stricter prior authorisation criteria or outcomes-based agreements, tying reimbursement to patient outcomes to mitigate potential safety risks.
Story Continues
Despite the identified AEs, sotatercept's novel mechanism of action and clinically meaningful efficacy gains position it as a valuable addition to the PAH treatment landscape. As longer-term real-world data and larger post-marketing studies become available, the comprehensive safety profile of sotatercept will become clearer, helping to define its optimal role in PAH management.
"Sotatercept FAERS study highlights emerging safety signals in PAH treatment" was originally created and published by Clinical Trials Arena, a GlobalData owned brand.
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PAH Therapies Improve Outcomes In PH-ILD
Pulmonary hypertension is a common consequence of interstitial lung disease (PH-ILD), with the highest rate seen among individuals who have idiopathic pulmonary fibrosis. Overall, most cases of PH in the setting of ILD are mild.
Hemodynamic parameters—pulmonary vascular resistance and mean pulmonary artery pressure (mPAP), in particular—improved in patients with interstitial lung disease (ILD)–precipitated pulmonary hypertension (PH-ILD) who were treated with common pulmonary arterial hypertension (PAH) treatments. Levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were also significantly reduced, according to findings published in Journal of Clinical Medicine Research.
This new research has implications for future use of precision medicine to better identify who among these patients is likely to benefit from PAH-targeted therapy, as well as which method of therapy administration is most effective. Presently, the FDA only allows PAH-targeted therapies in patients with PH who have chronic thromboembolic PH.
PH is a common consequence of ILD because of vascular and parenchymal remodeling, with the highest rate seen among individuals who have idiopathic pulmonary fibrosis. Most of these cases are considered mild, with their mPAP measuring 25 and 35 mm Hg via right heart catheterization.
Thirty-seven patients from the University of Chicago Medicine PH registry were included in this retrospective review, from among 1507 patients living with PH and enrolled in the registry between January 1, 1997, and October 30, 2021; ILD diagnosis was classified by subtype and radiographic pattern. Outcomes were compared before and after treatment by looking at demographics, ILD type, PAH-targeted therapy, hemodynamics, and NT-proBNP.
These results warrant further clinical investigation, and call for the use of precision medicine to phenotype patients with advanced PH, such as that seen with ILD.Image Credit: © Uladzislau-stock.Adobe.Com
Before PAH-Targeted TreatmentAt baseline, the mean (SD) patient age was 60.22 (10.54) years; most of these patients were female patients (78.4%), African American (54.1%) or Caucasian (40.5%), and had connective tissue disease–associated ILD (73%); and their most common comorbidity was connective tissue disease (73%). Usual interstitial pneumonia, in 46%, was the most common radiographic pattern.
Sixty-eight percent of patients had World Health Organization functional class (WHO FC) III disease and 19.4%, WHO FC II disease. The mean distance seen with the 6-minute walking distance (6MWD) test was 233 m among 10 patients, mPAP was 45 (11) mm Hg, PVR was 9 (4) Wood units, and median (IQR) NT-proBNP was 1498 (675-3208) ng/dL. Pulmonary function test (PFT) results were noteworthy, the study authors said, because of the numbers seen in relation to percent predicted for total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusion limitation of carbon monoxide (DLCO):
The most common type of PAH-targeted therapy was monotherapy with the phosphodiesterase-5 inhibitors (PDE5-Is; 51.4%), dual therapy with a PDE5-I and an endothelin receptor antagonist (ERA) was seen in 24.3%, and triplet therapy with a PDE5-I, ERA, and prostanoid was used by 2.7%.
After PAH-Targeted TreatmentAlthough significant improvements were not seen for WHO FC disease type or on exercise stress tests, PFT, and 6MWD tests, statistically significant improvements were seen in NT-proBNP, and hemodynamics.
After a mean 46-week follow-up, drops were seen in mean right atrial pressure (mRAP), mPAP, pulmonary capillary wedge pressure (PCWP), PVR, and in NT-proBNP:
Cardiac output and index both rose: 4.25 (1.31) to 5.17 (1.07) L/min and 2.11 (0.69) to 2.67 (0.65) L/min/m2, respectively.
The only adverse effect reported was a headache in 1 patient, but the authors attributed that to their study's retrospective nature.
ConclusionsKnowing that little data exist on the benefits of PAH-targeted therapy in a population who has PH-ILD, the present study authors highlight how their findings show improved hemodynamics—despite being "underpowered to detect associations between individual classes of PAH-targeted therapies and hemodynamics." Their results warrant further clinical investigation, and call for the use of precision medicine to phenotype patients with advanced PH, such as that seen with ILD.2
References
1. Selvan KC, Teerapuncharoen K, Bag R. Oral pulmonary arterial hypertension-targeted therapy in patients with pulmonary hypertension due to interstitial lung disease. J Clin Med Res. 2025;17(3):153-163. Doi:10.14740/jocmr6164
2. Singh N, Dorfmuller P, Shlobin OA, Ventetuolo CE. Group 3 pulmonary hypertension: from bench to bedside. Circ Res. 2022;130(9):1404-1422. Doi:10.1161/CIRCRESAHA.121.319970
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