Vallerie McLaughlin, MD, is a professor of medicine and director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan.

Vallerie McLaughlin, MD

Sotatercept Improves Composite Mortality Endpoint in Patients With PAH, With Vallerie McLaughlin, MD

Sotatercept has significantly improved a composite endpoint of mortality and major morbidity outcomes, transplant-free survival, and overall survival in patients with 

 WHO functional class (FC) II-IV, based on a pooled analysis of the PULSAR, STELLAR, and ZENITH trials.

American Heart Association’s Scientific Sessions 2025

, in New Orleans, Louisiana, by lead study author Vallerie McLaughlin, MD, Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine at the University of Michigan Medical School.

Sotatercept, a novel, first-in-class fusion protein, rebalances pulmonary vascular homeostasis towards growth-inhibiting and proapoptotic signaling by inhibiting ligands in the TGF-β superfamily. In PULSAR, STELLAR, and ZENITH, all of which were double-blind, placebo-controlled trials, sotatercept demonstrated its efficacy and a manageable safety profile in patients with PAH.

 spoke with McLaughlin to discuss the implications of these findings for PAH treatment on a larger scale.

“We pulled patients from 3 different trials to look at those 3 hard endpoints of death, lung transplantation, and PAH-related hospitalization, so that we have a larger number of patients and events to evaluate,” McLaughlin told 

. “And the results we found were very consistent.”

The phase 3 ZENITH trial investigated sotatercept when added to maximum tolerated background therapy, with primary endpoints of time to first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours. It ultimately enrolled 173 participants, who were randomly assigned in a 1:1 ratio to either sotatercept at a starting dose of 0.3 mg/kg and a target dose of 0.7 mg/kg or placebo, both of which were administered subcutaneously every 21 days for 24 weeks.

The phase 3 STELLAR study investigated a similar population, with a primary outcome of exercise capacity as measured by the 6-minute walk distance. This measurement was taken at 24 weeks following treatment initiation. A total of 324 patients with PAH were included and were then randomized to either sotatercept 0.7 mg/kg subcutaneously once every 3 weeks or placebo.

Finally, the phase 2 PULSAR trial followed 106 patients with PAH of WHO FC II-III, who were randomly assigned in a 3:3:4 ratio to either placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg subcutaneously every 21 days. Endpoints included changes in pulmonary vascular resistance, 6-minute walk distance, and echocardiographic parameters.

Following positive results from all 3 trials, McLaughlin and colleagues pooled data from patients receiving background therapy who were randomized to either sotatercept or placebo. The post-hoc analysis included the following endpoints: time to first morbidity event (including lung transplantation, PAH worsening-related hospitalization, and all-cause death), transplant-free survival, and overall survival.

A total of 323 patients who had received sotatercept and 278 patients who had received placebo were included in the analysis. Baseline characteristics were largely comparable, with investigators noting long-standing PAH as a significant commonality. When compared with placebo, the team found that sotatercept significantly reduced the risk of a first morbidity-mortality event (HR, 0.25; 95% CI, 0.16-0.4; 

 <.0001); a total of 25 patients experienced ≥1 event with sotatercept versus 68 patients with placebo.

Similarly, sotatercept improved transplant-free survival (HR, 0.44; 95% CI, 0.24-0.83; 

 = .005), wherein 16 patients with sotatercept and 27 patients with placebo experienced ≥1 event, and improved overall survival (HR, 0.49; 95% CI, 0.25-0.98; 

 = .0019), which saw 14 patients receiving sotatercept and 21 receiving placebo experience ≥1 event. Additionally, investigators highlighted all 3 Kaplan-Meier curves demonstrating clear separation between treatment arms by 3-6 months.

“The curves separating early and maintaining their separation really gives the sense that this drug is doing something to alter the course of the disease,” McLaughlin said. “Disease modification is a challenging term that means different things to different people, but I think what I feel comfortable saying is that it does alter the outcomes in patients with this very deadly disease.”

Editor's Note: McLaughlin reports disclosures with Janssen, Merck, Sonovie, Gossamer-Bio, Keros, Aerovate, and others.

McLaughlin V, Badesch D, Ghofrani AH, et al. Effect of Sotatercept on Mortality and Major Morbidity Outcomes in Patients with Pulmonary Arterial Hypertension: Pooled Analysis of the PULSAR, STELLAR, and ZENITH Trials. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of Sotatercept for treatment of pulmonary arterial hypertension. New England Journal of Medicine. 2023;388(16):1478-1490. 

Acceleron Pharma, Inc. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH). ClinicalTrials.gov identifier: NCT04896008. Updated August 22, 2025. Accessed November 10, 2025. 

https://www.clinicaltrials.gov/study/NCT04896008

Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021;384(13):1204-1215.

Acceleron Pharma, Inc. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11) (STELLAR). ClinicalTrials.gov identifier: NCT04576988. Updated September 19, 2024. Accessed November 10, 2025. 

https://clinicaltrials.gov/study/NCT04576988

Videos

McLaughlin discussed the previous ZENITH, PULSAR, and STELLAR trials, and how this pooled cohort analysis emphasizes sotatercept’s impressive efficacy.

Sotatercept could be a life-saving therapy for high-risk patients with pulmonary arterial hypertension (PAH), according to the ZENITH trial.

Approved in 2024 based on the STELLAR trial, which demonstrated its effects on exercise capacity, the ZENITH trial details statistically significant 76% reduction in relative risk for the primary outcome of all-cause mortality, lung transplantation, or hospitalization for worsening PAH.

“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 Marc Humbert, MD, PhD, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999.

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, the phase 3 ZENITH trial evaluated the efficacy of sotatercept as an add-on therapy for patients with PAH at high risk of death. Per trial protocol, all 172 participants were receiving the maximum tolerated dose of background therapy and were randomly assigned to receive sotatercept at starting dose of 0.3 mg/kg that was escalated to 0.7 mg/kg or placebo every 3 weeks.

The primary outcome of interest was a composite of all-cause mortality, lung transplantation, or hospitalization for worsening PAH, assessed using a time-to-first-event analysis. The trial was terminated early due to the efficacy findings from a prespecified interim analysis.

Data from ACC.25 suggested at least 1 primary endpoint event occurred among 17.4% of patients in the sotatercept group compared to 54.7% among the placebo group (Hazard Ratio [HR], 0.24; 95% CI, 0.13 to 0.43; 

<.001). When examining individual components of the outcome, investigators found death from any cause was reported in 8.1% of the sotatercept group and 15.1% of the placebo group (HR, 0.42; 95% CI, 0.17 to 1.07). Investigators noted this did not meet the criterion for significance at the interim analysis, which had a required 

 value less than .0021, and was not tested in subsequent secondary outcomes.

Investigators also pointed out use of sotatercept was associated with a reduction in risk for lung transplantation (1.2% and 7.0%; HR, 0.34; 95% CI, 0.15 to 0.78) and hospitalization for worsening PAH (9.3% vs. 50.0%).

For more on these results and how they inform the potential of sotatercept, check out our interview from ACC.25 with study investigator Vallerie McLaughlin, MD, professor of medicine and director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan.

ZENITH Shows Sotatercept Reduces Mortality, Risk of Transplant in PAH, with Vallerie Mclaughlin, MD

Relevant disclosures for McLaughlin include Bayer, Merck, Janssen Pharmaceuticals, Corvista, and others.

Humbert M, McLaughlin VL, Badesch DB. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. 

 (sotatercept-csrk) Reduced the Risk of a Composite of All-Cause Death, Lung Transplantation and Hospitalization for Pulmonary Arterial Hypertension (PAH) by 76% Compared to Placebo in the Phase 3 ZENITH Trial - Merck.com. Merck.com. Published March 31, 2025. Accessed April 1, 2025. 

https://www.merck.com/news/winrevair-sotatercept-csrk-reduced-the-risk-of-a-composite-of-all-cause-death-lung-transplantation-and-hospitalization-for-pulmonary-arterial-hypertension-pah-by-76-compared-to-placebo-i

Vallerie Mclaughlin, MD, discusses the ZENITH trial and its historic effects of sotatercept on mortality, transplant risk, and more in PAH.

Vallerie McLaughlin, MD

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