ZENITH
Trial question
What is the effect of sotatercept in high-risk patients with pulmonary arterial hypertension who are receiving the maximum tolerated dose of background therapy?
Study design
Multi-center
Double blinded
RCT
Population
Characteristics of study participants
77.0% female
23.0% male
N = 172
172 patients (132 female, 40 male).
Inclusion criteria: patients with pulmonary arterial hypertension and a high 1-year risk of death who were receiving the maximum tolerated dose of background therapy.
Key exclusion criteria: pulmonary arterial hypertension associated with portal hypertension, HIV infection, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis; pulmonary arterial hypertension other than WHO group 1; LVEF < 45%; clinically significant mitral or aortic valve disease; other clinically significant coexisting conditions or laboratory abnormalities.
Interventions
N=86 sotatercept (starting dose 0.3 mg/kg of body weight, escalated to target dose of 0.7 mg/kg every 3 weeks).
N=86 placebo (matching placebo every 3 weeks).
Primary outcome
Death, lung transplantation, or hospitalization for worsening pulmonary arterial hypertension
17.4%
54.7%
54.7 %
41.0 %
27.4 %
13.7 %
0.0 %
Sotatercept
Placebo
Significant
decrease ▼
NNT = 2
Significant decrease in death, lung transplantation, or hospitalization for worsening pulmonary arterial hypertension (17.4% vs. 54.7%; HR 0.24, 95% CI 0.13 to 0.43).
Secondary outcomes
Significant increase in transplantation-free survival (90.7% vs. 77.9%; HR 2.94, 95% CI 1.28 to 6.67).
No significant difference in death from any cause (8.1% vs. 15.1%; HR 0.42, 95% CI 0.17 to 1.07).
Significantly greater improvement in WHO functional class (55.8% vs. 27.9%; AD 27.4%, 95% CI 12.9 to 41).
Safety outcomes
No significant difference in adverse events.
Significant differences in epistaxis (44.2% vs. 9.3%), telangiectasia (25.6% vs. 3.5%).
Conclusion
In patients with pulmonary arterial hypertension and a high 1-year risk of death who were receiving the maximum tolerated dose of background therapy, sotatercept was superior to placebo with respect to death, lung transplantation, or hospitalization for worsening pulmonary arterial hypertension.
Reference
Marc Humbert, Vallerie V McLaughlin, David B Badesch et al. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. 2025 Mar 31. Online ahead of print.
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