medwireNews: In patients with WHO functional class III or IV pulmonary arterial hypertension (PAH) at high 1-year risk for death despite receiving the maximum tolerated dose of double or triple therapy, add-on therapy with sotatercept significantly lowers the risk for death and clinical worsening compared with placebo, suggests the ZENITH study.
Over a median follow-up of 10.6 months for the sotatercept group and 7.1 months for the placebo group, the risk for a composite endpoint event of death from any cause, lung transplantation, or hospitalization for at least 24 hours was reduced by 76% in 86 participants receiving the activin signaling inhibitor sotatercept, compared with the 86 participants receiving placebo. The respective rates were 17.4% versus 54.7%.
On the basis of the results of this prespecified interim analysis, “the data monitoring committee recommended stopping the trial for efficacy, a highly unusual occurrence for a randomized, placebo-controlled trial involving patients with pulmonary arterial hypertension,” say investigators Marc Humbert (Hôpital Bicêtre, Paris, France) and colleagues in The New England Journal of Medicine.
Furthermore, the team highlights that “all three event types of the composite primary end point appeared to occur less frequently among patients who received sotatercept than among those who received placebo.” The rates of death from any cause, lung transplantation, and hospitalization for at least 24 hours were 8.1% versus 15.1%, 1.2% versus 7.0%, and 9.3% versus 50.0%, respectively.
Humbert et al say that the phase 3 findings, which were simultaneously presented at the American College of Cardiology annual meeting (ACC.25) in Chicago, Illinois, USA, “underscore the value of sotatercept as an add-on therapy and its mechanistic ability to induce reductions in the risk of major outcomes, even in a heavily treated population.”
They suggest that the “incremental efficacy” of add-on sotatercept may be related to its action of targeting the activin signaling pathway, which “improves the balance between growth-promoting factors and growth-inhibiting factors, addressing the core pathobiologic features of pulmonary arterial hypertension.”
The mean age of the participants was 54.4 years, 76.7% were women, and around a quarter had WHO functional class IV PAH. While fewer participants in the sotatercept than placebo group had a BMI of 30 mg/kg2 or higher (16.3 vs 22.1%), demographics were generally balanced at baseline. The patients received either subcutaneous sotatercept at a starting dose of 0.3 mg/kg, escalated to a target dose of 0.7 mg/kg, or placebo every 21 days in addition to background therapy.
Nearly all the participants experienced adverse events (AEs), with no significant difference in the rate between patients in the sotatercept and placebo arms (98.8 vs 96.5%). AEs that occurred at least 5 percentage points more frequently in the sotatercept group than the placebo group included epistaxis (44.2 vs 9.3%), telangiectasia (25.6 vs 3.5%), gingival bleeding (10.5 vs 2.3%), vomiting (12.8 vs 5.8%), and back pain (10.5 vs 4.7%). Serious AEs occurred in 53.5% of sotatercept-treated patients and 64.0% of those given placebo.
No patients in the sotatercept group discontinued treatment due to AEs or serious AEs, compared with 4.7% of patients in the placebo group, and AEs leading to death occurred in 5.8% and 14.0% of patients, respectively.
“These findings are noteworthy given the longer duration of exposure in the sotatercept group, which would have been expected to lead to a higher incidence of adverse events in that group,” the investigators point out.
They add that the ongoing SOTERIA study will help to characterize the longer-term safety of the drug.
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N Engl J Med 2025; doi:10.1056/NEJMoa2415160
ACC.25; Chicago, Illinois, USA: 29–31 March
