Sotatercept In High-Risk Patients With Pulmonary Arterial Hypertension - ZENITH

Mar 31, 2025
Font Size
A
A
A
Author/Summarized by Author:
Bradley A. Maron, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC
Trial Sponsor:
Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ)
Date Presented:
03/31/2025
Date Published:
03/31/2025
Date Updated:
03/31/2025
Original Posted Date:
03/28/2025
References

Contribution To Literature:

The ZENITH trial demonstrated that among high-risk adults with PAH on maximum tolerated dose of background therapy, treatment with sotatercept resulted in a lower risk of all-cause death, lung transplantation, and hospitalization (≥24 hours) for worsening PAH than placebo.

Description:

The goal of the phase 3 study was to evaluate the efficacy and safety of sotatercept in patients with pulmonary arterial hypertension (PAH) at high risk for death.

Study Design

Patients were randomly assigned in a 1:1 ratio to receive add-on subcutaneous sotatercept (starting dose, 0.3 mg/kg; escalated to target dose, 0.7 mg/kg) or placebo every 21 days, in addition to stable maximum tolerated doses of double or triple therapy for PAH; 85 patients were in both the sotatercept and placebo groups. The trial was stopped early at the prespecified interim analysis due to efficacy.

  • Total number of enrollees: 172
  • Duration of follow-up: median 10.6 months in the sotatercept group and 7.1 months in the placebo group
  • Mean patient age: 54.4 years
  • Percentage female: 76.7%

Inclusion criteria:

  • Adults 18-75 years of age
  • Symptomatic World Health Organization (WHO) group 1 PAH (idiopathic, heritable, drug- or toxin-induced, connective-tissue disease–associated, or with simple congenital systemic-to-pulmonary shunts ≥1 year after repair) or WHO functional class III or IV
  • REVEAL Lite 2 risk score of ≥9
  • Clinically stable and on stable doses of maximum tolerated double or triple background PAH therapies for ≥30 days prior to screening
  • Pulmonary vascular resistance ≥400 dyn·s·cm−5 (≥5 Wood units)
  • Pulmonary artery wedge pressure or left ventricular end-diastolic pressure of ≤15 mm Hg

Exclusion criteria:

  • PAH associated with portal hypertension
  • HIV
  • Pulmonary veno-occlusive disease
  • Pulmonary capillary hemangiomatosis
  • PAH other than group 1
  • LVEF <45%
  • Clinically significant mitral or aortic valve disease

Principal Findings:

Primary outcome: In patients with PAH with advanced stage disease and high risk of death within 1 year, the addition of sotatercept to maximum tolerated background PAH therapy caused a major decrease in the endpoint of composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening PAH, assessed in a time-to-first-event analysis compared to placebo. The clinical benefit of sotatercept was concise and dramatic, causing a 76% lower risk for the endpoint, and as a consequence, the study was discontinued early due to efficacy.

  • All-cause death: 8.1% in the sotatercept group and 15.1% in the placebo group
  • Lung transplantation: 1.2% in the sotatercept group and 7.0% in the placebo group
  • PAH-related hospitalizations: 9.3% in the sotatercept group and 50.0% in the placebo group

Secondary outcomes: The secondary analysis was based on predetermined hierarchical strata in which significance for the initial secondary endpoint of overall survival was needed in order for analysis of the next secondary endpoint, and so-forth. The results for overall survival did not achieve statistical significance when using the predetermined threshold that was established if the trial was discontinued early and, therefore, further secondary endpoint analyses were not pursued. It is worth noting that a conservative statistical threshold was used in this particular scenario (p<0.0021), and randomization to sotatercept caused substantial improvement in many of the secondary endpoints including clinical risk score and NT-proBNP level, among others.

Interpretation:

The results of the ZENITH trial provide compelling data to support the use of sotatercept in patients with severe PAH, a subgroup that often is viewed as otherwise end-stage. The magnitude of the clinical benefit observed in ZENITH is transformative by any standard, but has particular relevance in PAH, which is characterized by high disease burden and downward clinical trajectory in many patients. Now, clinicians are able to treat this high-risk subgroup using an approach that is proven and expected to mitigate the risk of major events that affect lifespan and life quality.

Like the prior clinical trials studying sotatercept, the safety profile includes an elevated rate of telangiectasias. The precise clinical relevance of this side effect, as well as nuisance bleeding (typically epistaxis) reported by some clinicians using sotatercept in practice will need further surveillance outside the framework of a randomized trial. Nonetheless, the results of ZENITH cast clear and focused light on the clinical benefit of sotatercept in even the sickest PAH patients, and in doing so, offer a much-needed measure of optimism to a disease that has long-been characterized as relentless by patients and caregivers alike.

References:

Humbert M, McLaughlin VV, Badesch DB, et al., for the ZENITH Trial Investigators. Sotatercept in Patients With Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med 2025;Mar 31:[Epub ahead of print].

Presented by Dr. Marc Humbert at the American College of Cardiology Annual Scientific Session (ACC.25), Chicago, IL, March 31, 2025.

Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Pulmonary Hypertension, Vascular Medicine

Keywords: ACC25, ACC Annual Scientific Session, Lung Transplantation, Pulmonary Arterial Hypertension, Vascular Diseases


< Back to Listings