Adding sotatercept to standard care lowers the risk of clinical worsening in patients recently diagnosed with pulmonary arterial hypertension (PAH) compared with placebo, according to the phase 3 HYPERION trial, presented at the 2025 European Respiratory Society Congress and simultaneously published Sept. 30 in NEJM.

Vallerie V. McLaughlin, MD, FACC, et al., randomly assigned 320 adults (mean age, 56 years; 73% women) with World Health Organization (WHO) functional class II or III PAH who were diagnosed less than one year earlier, had an intermediate or high risk of death and receiving double or triple background therapy to add-on therapy with subcutaneous sotatercept (starting at 0.3 mg/kg body weight, then escalated to a target of 0.7 mg/kg) or placebo every 21 days (n=160 in each group).

The trial was terminated early due to loss of clinical equipoise with the release of positive results from prior sotatercept trials.

The primary endpoint of clinical worsening was a composite of all-cause death, unplanned hospitalization of ≥24 hours for worsening PAH, atrial septostomy, lung transplantation or reduction in exercise test performance due to PAH.

Results showed that at a median of 13.2 months, one or more primary endpoint events occurred in 11% of patients receiving sotatercept vs. 37% receiving placebo (hazard ratio, 0.24; p<0.001).

Notably, the effect of sotatercept vs. placebo was mainly driven by fewer cases of deterioration in exercise test performance due to PAH (5% vs. 29% with any decrease from baseline in six-minute walk distance, accompanied by worsening of WHO functional class, symptoms or signs of increased right ventricular failure, initiation of new background therapy for PAH or a change to parenteral background therapy) and by fewer unplanned hospitalizations for worsening of PAH compared with placebo (2% vs. 9%).

The safety profile of sotatercept was consistent with previous trials. Adverse events were generally similar in both groups. The most common events with sotatercept were epistaxis (32%) and telangiectasia (26%). No atrial septostomy or lung transplantation cases were reported.

All-cause death occurred at a similar rate in the sotatercept and placebo groups (5% vs. 4%).

McLaughlin and colleagues write, "The HYPERION trial expands on evidence regarding the benefit-risk balance of sotatercept in patients with [PAH] by showing its efficacy and safety early in the disease course." They note that whether sotatercept can be used as first-line therapy for [PAH] remains to be determined.