From STELLAR to ZENITH: Sotatercept demonstrates efficacy in advanced pulmonary arterial hypertension

Another chapter in the treatment of pulmonary arterial hypertension (PAH) with Sotatercept: On March 31, 2025, the renowned New England Journal of Medicine published the results of the international Phase-3 ZENITH study. At the center: Sotatercept, an innovative, first-in-class Activin signaling pathway inhibitor, which dramatically reduced the risk of death, lung transplantation, or hospitalization in patients with advanced PAH. Leading scientists from the German Center for Lung Research (DZL) were also significantly involved in this groundbreaking study.

ZENITH Study: Hope for Patients with Severe PAH

The ZENITH study builds directly on the previously published STELLAR study (2023, also NEJM), which investigated Sotatercept in PAH patients at an earlier stage of the disease (WHO Functional Class II/III). STELLAR demonstrated significant improvements in physical performance and clinical parameters, as well as an 84% reduction in the risk of disease progression.

While STELLAR validated the use of Sotatercept in the middle stages of the disease, ZENITH now shows the benefit in the advanced phase—providing hard clinical endpoints such as mortality, transplantation, and hospitalization for the first time. The ZENITH study investigated the use of Sotatercept in 172 patients with advanced PAH at high risk of death within one year. All participants had already received the maximal tolerated standard therapy for PAH and were treated with either Sotatercept or placebo. The primary endpoint of the study was a "hard" clinical composite endpoint: death from any cause, lung transplantation, or hospitalization (≥24 hours) due to PAH deterioration.

Impressive Results:

• Only 17.4% of patients in the Sotatercept group experienced such an event, compared to 54.7% in the placebo group.

• This represents a 76% risk reduction (Hazard Ratio: 0.24; p<0.001).

• Sotatercept also demonstrated significant benefits in secondary endpoints, including quality of life, physical capacity (6-minute walk test), biomarkers (NT-proBNP), and pulmonary vascular resistance.

Study Termination Due to Superiority of the Study Medication

Due to the overwhelming superiority of Sotatercept, the study was prematurely terminated on November 25, 2024, based on the recommendation of the independent Data Monitoring Committee. Such an early termination—due to ethical concerns over continuing the placebo group rather than safety issues—underscores the medical breakthrough achieved with Sotatercept.

A Novel Mechanism of Action – Beyond Vasodilation

Sotatercept differs fundamentally from existing PAH medications. While traditional therapies mainly focus on expanding blood vessels (vasodilation), Sotatercept works at the cellular level to address the pathological remodeling of blood vessels in the lungs. It balances the disturbed ratio of growth and inhibitory signals in the TGF-β signaling pathway—a key pathobiological mechanism in PAH. "With Sotatercept, we are not only treating symptoms—we are intervening in the disease mechanisms. This is a completely new therapeutic dimension in PAH," explains Prof. Hoeper.

Significance for Patients: New Perspectives in a Previously Untreatable Disease

Despite significant progress in PAH therapy, the prognosis for many patients, especially those with advanced disease, has remained poor. The STELLAR and ZENITH studies now show that Sotatercept is a highly effective new treatment option for a wide range of PAH patients—from moderately affected individuals to high-risk patients. "We are at a historic turning point in PAH therapy. Sotatercept offers us the opportunity to control the disease in an entirely new way—even in patients who were previously considered untreatable despite maximal therapy," says Prof. Dr. Marius Hoeper, last author of the ZENITH study and DZL researcher at the BREATH center.

Source: From STELLAR to ZENITH: Sotatercept demonstrates efficacy in advanced pulmonary arterial hypertension

Original Publication: Humbert M, McLaughlin VV, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, Preston IR, Souza R, Waxman AB, Moles VM, Savale L, Vizza CD, Rosenkranz S, Shi Y, Miller B, Mackenzie HS, Kim SS, Loureiro MJ, Patel MJ, Koglin J, Cornell AG, Hoeper MM; ZENITH Trial Investigators. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. 2025 Mar 31. doi: 10.1056/NEJMoa2415160. Epub ahead of print. PMID: 40167274.