This is also a remarkable success for the research hub in Hannover: Prof. Dr. Marius Hoeper, Acting Director of the Department of Respiratory Medicine and Infectious Diseases at Hannover Medical School (MHH), board member and senior researcher at BREATH, is the senior author of the publication and played a key role in the study's design, conduct, and analysis.

ZENITH Trial: New hope for patients with advanced PAH
The ZENITH trial builds directly on the previously published STELLAR trial (NEJM, 2023), which evaluated sotatercept in patients with less advanced PAH (WHO functional class II/III). STELLAR had already shown significant improvements in exercise capacity, clinical parameters, and an 84% risk reduction for disease progression.
While STELLAR validated sotatercept for use in moderate PAH, ZENITH demonstrates its benefit in more advanced stages of the disease, reporting for the first time hard clinical outcomes such as mortality, transplantation, and hospitalization. ZENITH enrolled 172 patients with advanced PAH and a high one-year mortality risk (REVEAL Lite 2 score ≥9). All participants were already receiving maximum tolerated background therapy. Patients were randomized to receive either sotatercept or placebo in addition to their standard treatment.

The results are compelling:

• Only 17.4% of patients in the sotatercept group experienced a primary endpoint event, compared to 54.7% in the placebo group.
• This corresponds to a 76% risk reduction (Hazard Ratio: 0.24; p<0.001).
• Sotatercept also showed clear advantages over placebo in secondary endpoints, including quality of life, 6-minute walk distance, NT-proBNP levels, and pulmonary vascular resistance.

Study stopped early due to efficacy
Owing to the strength of the interim results, the trial was stopped early on November 25, 2024, following the recommendation of the independent Data Monitoring Committee.
This type of early termination—not due to safety concerns, but due to the ethical implications of withholding an effective therapy from the control group—is rare in PAH research and underscores the potential of sotatercept as a transformative therapy.

A novel mechanism: more than vasodilation
Sotatercept differs fundamentally from existing PAH therapies. While conventional treatments primarily promote vasodilation, sotatercept targets the underlying vascular remodeling at the cellular level. It restores the balance between proliferative and anti-proliferative signals in the TGF-β signaling pathway, a central mechanism in the pathobiology of PAH. "With sotatercept, we are not just treating symptoms – we are intervening in the disease mechanisms themselves. This represents a completely new therapeutic dimension in PAH," explains Prof. Hoeper.

Clinical relevance: New perspectives for patients
Despite major advances in PAH management, prognosis for many patients—especially in advanced stages—remains poor. The STELLAR and ZENITH trials together provide robust evidence that sotatercept is a highly effective treatment option across a broad spectrum of disease severity, from moderately ill patients to those at highest risk.
“We are at a historic turning point in PAH therapy. Sotatercept gives us the opportunity to control this disease in an entirely new way — even in patients previously considered beyond treatment despite maximum therapy,” says Prof. Dr. Marius Hoeper, senior author of the ZENITH trial and principal investigator at BREATH.

Access the full publication here
 

Text: BREATH/AB

Photo: MHH/Figiel