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 pulmonary arterial hypertension (PAH) WHO functional class (FC) II-IV, based on a pooled analysis of the PULSAR, STELLAR, and ZENITH trials.1

These data were presented at the 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.1

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.1,2

The editorial team at HCPLive 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 HCPLive. “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.3

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.4

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.5

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.1

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

Similarly, sotatercept improved transplant-free survival (HR, 0.44; 95% CI, 0.24-0.83; P = .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; P = .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.1

“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.

References

1. 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.

2. 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. doi:10.1056/nejmoa2213558

3. 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

4. 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. doi:10.1056/NEJMoa2024277

5. 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