Sotatercept reduces mortality and morbidity in high-risk PAH
ACC.25 – In ZENITH, sotatercept reduced the risk of all-cause mortality, lung transplantation or hospitalization for worsening PAH by 76% compared with placebo in high-risk PAH patients.
This summary is based on the presentation of Marc Humbert, MD, PhD (Paris, France) at the ACC.25 Scientific Session - Efficacy And Safety Of Sotatercept In High-Risk Patients With Pulmonary Arterial Hypertension: Results From ZENITH Phase 3 Trial.
Introduction and methods
Pulmonary vascular remodeling plays a key role in the pathobiology of pulmonary arterial hypertension (PAH). An abnormal balance of pro-proliferative and anti-proliferative signaling leads to vessel wall hyperproliferation in PAH. Sotatercept is an activin signaling inhibitor, which restores the balance between anti- and pro-proliferative signaling. In the phase 3 STELLAR trial, sotatercept as an add-on therapy improved exercise capacity and clinical worsening in patients with WHO functional class II or III PAH. It remains unclear whether sotatercept can reduce mortality and major morbidity events such as PAH-related hospitalizations and lung transplantation in patients at high risk of death.
The phase 3 ZENITH trial was a multicenter, double-blind, randomized, placebo-controlled trial, in which 172 high-risk patients with PAH WHO functional class III and IV were randomized to sotatercept or placebo on top of background PAH therapy. The primary endpoint was time to first event of all-cause mortality, lung transplantation or PAH worsening-related hospitalization of ≥ 24 hours.
ZENITH was stopped early for efficacy in the interim analysis. Median follow-up was 10.6 months in the sotatercept arm and 7.1 months in the placebo arm.
Main results
Efficacy
- The incidence of the primary endpoint was significantly reduced in the sotatercept group compared with the placebo group (17.4 vs. 54.7%) (HR: 0.24; 95%CI: 0.13–0.43; P<0.0001).
- The effect of sotatercept on the primary endpoint was consistent across all prespecified subgroups, including PAH subtype, WHO functional class, prostacyclin infusion therapy, and PVR.
Safety
- Adverse events related to treatment were more common in the sotatercept group compared with the placebo group (65.1% vs. 32.6%).
- Compared with the placebo group, there were fewer adverse events leading to treatment discontinuation (0% vs. 4.7%), adverse events leading to death (5.8% vs. 14.0%) and serious adverse events (53.5% vs. 64%) in the sotatercept group, but more bleeding events (62.8% vs. 34.9%).
Conclusion
In the ZENITH trial among patients with PAH WHO functional class III and IV, treatment with sotatercept resulted in a 76% lower morbidity-mortality risk compared with placebo, despite maximal background therapy. The safety and tolerability profile of sotatercept was consistent with previous studies.
- Our reporting is based on the information provided at the ACC.25 Scientific Session -