A Study of Sotaterceptin Combination With Background Therapy for the Treatment of Pulmonary Arterial Hypertension - STELLAR

Nov 08, 2025
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Fred M. Kusumoto, MD, FACC
Date Updated:
11/08/2025
Original Posted Date:
03/06/2023
References

Highlighted text has been updated as of Nov. 8, 2025.

Contribution To Literature:

The STELLAR trial showed that sotatercept, an activin signaling inhibitor, is superior to placebo in improving six-minute walk distance (6MWD) among adults with symptomatic pulmonary arterial hypertension (PAH) on background therapy.

Study Design

Patients were randomized in a 1:1 fashion to either sotatercept (n = 163) or matching placebo (n = 160) for 24 weeks. Sotatercept was administered as a 0.3 mg/kg starting dose and increased to 0.7 mg/kg every 3 weeks. Patients were stratified by baseline World Health Organization (WHO) functional class (FC) and background PAH therapy.

  • Total screened: 434
  • Total number of enrollees: 323
  • Duration of follow-up: 24 weeks
  • Mean patient age: 47.9 years
  • Percentage female: 79%

Inclusion criteria:

  • Age ≥18 years
  • Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of WHO PAH Group 1 in any of the following subtypes:
    • Idiopathic PAH
    • Heritable PAH
    • Drug/toxin-induced PAH
    • PAH associated with connective tissue disease
    • PAH associated with simple, congenital systemic to pulmonary shunts ≥1 year following repair
  • Symptomatic PAH classified as WHO FC II or III
  • Baseline RHC performed during the screening period documenting a minimum pulmonary vascular resistance (PVR) of ≥5 wood units and a pulmonary capillary wedge pressure or left ventricular end-diastolic pressure of ≤15 mm Hg
  • On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for ≥90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice
  • 6MWD ≥150 and ≤500 m repeated twice at screening (measured ≥4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value)

Exclusion criteria:

  • Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5
  • Diagnosis of the following PAH Group 1 subtypes: HIV-associated PAH and PAH associated with portal hypertension; exclusions in PAH Group 1 also include schistosomiasis-associated PAH and pulmonary veno-occlusive disease
  • Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
  • Baseline platelet count <50,000/mm3 (<50.0 x 109/L) at screening
  • Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mm Hg or sitting diastolic blood pressure >100 mm Hg during screening visit after a period of rest
  • Baseline systolic blood pressure <90 mm Hg at screening
  • Pregnant or breastfeeding women
  • Any of the following clinical laboratory values at the screening visit:
    • Estimated glomerular filtration rate (eGFR) <30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease equation)
    • Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels >3 × ULN (bilirubin criterion waived if there is a documented history of Gilbert's syndrome)
  • History of full pneumonectomy
  • Pulmonary function test (PFT) values of forced vital capacity (FVC) <60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing more than mild interstitial lung disease at the screening visit or 1 year prior to it
  • Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
  • History of untreated more than mild obstructive sleep apnea
  • Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), defined as mild to severe hepatic impairment (Child-Pugh Class A-C)
  • History of restrictive, constrictive, or congestive cardiomyopathy
  • History of atrial septostomy within 180 days prior to the screening visit

Other salient features/characteristics:

  • White: 89%
  • Mean time since PAH diagnosis: 8.8 years
  • Background therapy: Prostacyclin infusion: 40%; triple therapy at baseline: 62.5%
  • Mean pulmonary artery pressure: 52.2 mm Hg

Principal Findings:

The primary endpoint, change at 12 weeks from baseline in 6MWD, for sotatercept vs. placebo, was: 40.1 vs. -1.4 m (p < 0.001)

Secondary outcomes for sotatercept vs. placebo:

  • Multicomponent improvement: 38.9% vs. 10.1% (p < 0.001)
  • Change in PVR: -234.6 dyn·sec·cm-5 (p < 0.001)
  • Change in N-terminal pro–B-type natriuretic peptide level: -441.6 pg/mL (p < 0.001)
  • All-cause mortality or ≥1 clinical worsening event: 5.5% vs. 26.3% (p < 0.001)
  • All-cause mortality: 1.2% vs. 3.8%
  • Bleeding events: 31.9% vs. 15.6%
  • Thrombocytopenia: 8.6% vs. 3.1%

Pooled post-hoc analysis of PULSAR, STELLAR, and ZENITH trials of sotatercept in PAH: A total of 323 patients were treated with sotatercept and 278 with placebo. Compared with placebo, sotatercept significantly reduced the risk of a first morbidity–mortality event (hazard ratio [HR], 0.25; 95% CI, 0.16–0.40; p<0.0001; 25 patients had ≥1 event with sotatercept vs. 69 patients with placebo), and improved transplant-free survival (HR, 0.44; 95% CI, 0.24–0.83; p=0.005; 16 vs. 27 patients with ≥1 event) and overall survival (HR, 0.49; 95% CI, 0.25–0.98, p=0.019; 14 vs. 21 patients with ≥1 event). By 3–6 months, all three Kaplan–Meier curves demonstrated clear separation between treatment arms.

Interpretation:

The results of this trial indicate that sotatercept, an activin signaling inhibitor, is superior to placebo in improving 6MWD among adults with symptomatic PAH on background therapy. There was also an improvement in all-cause mortality and clinical events. Bleeding events were more frequent with sotatercept. These data suggest a possible emerging role for sotatercept in this patient population.

In a pooled analysis of PULSAR, STELLAR, and ZENITH trials of sotatercept in patients with PAH, sotatercept significantly improved a composite endpoint of mortality and major morbidity outcomes, transplant-free survival, and overall survival.

References:

Presented by Vallerie V. McLaughlin, MD, FACC, at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 8, 2025.

Hoeper MM, Badesch DB, Ghofrani HA, et al., on behalf of the STELLAR Trial Investigators. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2023;388:1478-90.

Editorial: Taichman DB, Leopold JA, Elliott G. Continued Progress in Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2023;388:1524-6.

Presented by Dr. Marius M. Hoeper at the American College of Cardiology Annual Scientific Session (ACC.23/WCC), New Orleans, LA, March 6, 2023.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Hypertension

Keywords: ACC23, ACC Annual Scientific Session, Catheterization, Connective Tissue Diseases, Diuretics, Familial Primary Pulmonary Hypertension, Heart Failure, Hemorrhage, Hypertension, Pulmonary, Natriuretic Peptide, Brain, Pulmonary Arterial Hypertension, Secondary Prevention, Thrombocytopenia, AHA Annual Scientific Sessions, AHA25


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