Sotatercept, a first-in-class novel activin-signaling inhibitor, led to a 76% lower risk of a composite of death from any cause, lung transplantation or hospitalization for worsening pulmonary arterial hypertension (PAH) compared to placebo in high-risk adults with PAH, according to results from the ZENITH study presented during a Clinical and Investigative Horizons session at ACC.25 in Chicago and simultaneously published in NEJM. The trial was stopped early based on the efficacy results following a prespecified interim analysis.

A total of 172 patients with WHO functional classes III or IV PAH were randomized to either standard care (n=86) or add-on subcutaneous sotatercept (n=86) starting at 0.3 mg per kg body weight and escalating to 0.7 mg per kg. The patients had a mean age of 54 and most were women (77%) and White (87%), and all had a high one-year risk of death. The multicenter trial ran from December 2021 to July 2024.

While most demographic characteristics were balanced, the placebo arm had more women (82.6% vs. 70.9% in the treatment arm) and more participants with a BMI ≥30 (22.1% vs. 19.2%). Median follow-up in the treatment arm was longer at 10.6 months vs. 7.1 months in the placebo arm.

Results showed that 15 patients (17.4%) in the treatment group and 47 patients (54.7%) in the placebo group reached the primary endpoint, a composite of death from any cause, lung transplantation or hospitalization for worsening PAH (hazard ratio [HR], 0.24; p<0.001).

Seven patients (8.1%) in the treatment group and 13 (15.1%) in the placebo group died (HR, 0.42), with five of the deaths in the treatment arm (5.8%) and 12 in the placebo arm (14%) deemed to be due to adverse events. One patient (1.2%) in the treatment group and six (7.0%) in the placebo group had lung transplants, and eight patients (9.3%) in the treatment group and 43 (50.0%) in the placebo group were hospitalized for worsening PAH.

The most common adverse events withinthe treatment arm were epistaxis and telangiectasia. There were more adverse events considered to be treatment-related in the sotatercept arm (65.1% vs. 32.6%), but less serious adverse events (53.5% vs. 64.0%) and severe adverse events (37.2% vs. 50.0%).

"The incremental efficacy of the addition of sotatercept to background pulmonary arterial hypertension therapy probably relates to the mechanism of action of sotatercept," write study authors Marc Humbert, MD, PhD, et al. "By targeting the activin-signaling pathway, sotatercept improves the balance between growth-promoting factors and growth-inhibiting factors, addressing the core pathobiologic features of pulmonary arterial hypertension."