Key Points:
- Pulmonary arterial hypertension (PAH) is a progressive disease with poor outcomes despite advancements in therapy.
- Sotatercept, a novel activin signaling inhibitor, targets vascular remodeling in PAH and has previously demonstrated efficacy in improving hemodynamics and clinical outcomes.
- The Phase 3 ZENITH trial showed that sotatercept significantly reduced the risk of composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension by 76% compared to placebo in high-risk PAH patients (WHO FC III/IV) on maximum tolerated background therapy.
Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by pulmonary vascular remodeling, increased pulmonary pressures, and high mortality rates. Despite recent therapeutic advancements, outcomes remain poor, particularly for patients with advanced disease (WHO functional class [FC] III/IV). Sotatercept, a first-in-class activin signaling inhibitor, has shown promise in addressing the underlying vascular remodeling of PAH.
Building on the success of the STELLAR trial, which demonstrated improvements in exercise capacity and hemodynamics in PAH patients with WHO FC II/III, the ZENITH trial evaluated sotatercept in patients at higher risk of mortality. Results were presented by Dr. Marc Humbert from Université Paris-Saclay at ACC 2025 as a late-breaking clinical trial and simultaneously published in The New England Journal of Medicine.
This Phase 3, multicenter, double-blind, placebo-controlled trial enrolled 172 adult patients with WHO FC III or IV PAH and pulmonary vascular resistance (PVR) ≥400 dynes·s·cm-5 who were receiving maximum tolerated background PAH therapy. Patients were randomized 1:1 to receive sotatercept (0.3 mg/kg, titrated to 0.7 mg/kg) or placebo every three weeks in addition to their stable PAH regimen.
The primary endpoint was time to first major morbidity or mortality event, defined as all-cause death, lung transplantation, or PAH-related hospitalization of ≥24 hours. Secondary endpoints included overall survival, transplant-free survival, NT-proBNP reduction, improvement in WHO FC, mean pulmonary artery pressure, and changes in the REVEAL Lite 2.0 risk score.
At a median follow-up of 10.6 months (range, 0.3-26.1), sotatercept significantly reduced the risk of major morbidity and mortality events by 76% compared to placebo (HR=0.24; 95% CI, 0.13-0.43; p<0.0001). Major events occurred in 17.4% of sotatercept-treated patients versus 54.7% in the placebo group, leading to early trial termination due to overwhelming efficacy.
Safety analyses showed no treatment discontinuations due to adverse events. Deaths occurred in 7 patients (8.1%) in the sotatercept arm versus 13 patients (15.1%) in the placebo arm. Lung transplantation was required in 1 patient (1.2%) receiving sotatercept versus 6 patients (7.0%) in the placebo group, and PAH-related hospitalizations were lower in the sotatercept group (9.0% vs. 50.0%).
Dr. Humbert highlighted the significance of these findings: “The ZENITH trial is the first PAH study with a primary endpoint exclusively comprising major outcomes—all-cause death, lung transplantation, and hospitalization for PAH. These results reinforce the potential of WINREVAIR (sotatercept) as a practice-changing therapy for a broad spectrum of PAH patients.”