Adding sotatercept to standard therapy significantly reduces the risk of clinical worsening events for patients within their first year of diagnosis with pulmonary arterial hypertension (PAH), according to results from the HYPERION trial.¹˒² Sotatercept is a first-in-class activin-signalling inhibitor.
Sotatercept is an activin-signalling inhibitor designed to rebalance the pro- and anti-proliferative signalling pathways that are disrupted in PAH.
The phase 3, randomised, placebo-controlled HYPERION trial enrolled 320 adult patients with World Health Organization (WHO) functional class II or III PAH.² Participants had been diagnosed within the previous year, were at an intermediate or high risk of death, and were receiving stable double or triple background therapy. Patients were randomised to receive either subcutaneous sotatercept (escalated to a target dose of 0.7 mg/kg) or a placebo every 21 days as an add-on therapy. The primary endpoint was a composite of clinical worsening, defined as death from any cause, unplanned hospitalisation for worsening PAH, atrial septostomy, lung transplantation, or deterioration in exercise testing performance.
The trial was stopped early due to positive results from previous sotatercept trials. Over a median follow-up of 13.2 months, a primary endpoint event occurred in 10.6% of patients in the sotatercept group compared with 36.9% in the placebo group (hazard ratio, 0.24; 95% CI, 0.14 to 0.41; P<0.001).² The most frequent primary endpoint events were deterioration in exercise testing (5.0% vs 28.8%) and unplanned hospitalisation for worsening PAH (1.9% vs 8.8%). The most common adverse events associated with sotatercept were epistaxis (31.9%) and telangiectasia (26.2%).
The findings suggest a significant benefit for initiating sotatercept early in the treatment course for PAH. The study authors concluded, “Among adults with pulmonary arterial hypertension who had received the diagnosis less than 1 year earlier, the addition of sotatercept to background therapy resulted in a lower risk of clinical worsening than placebo.”²
The early termination of the trial limited the follow-up duration and enrolment, precluding a full assessment of longer-term efficacy and safety.
This study was funded by Merck Sharp & Dohme, a subsidiary of Merck in Rahway, New Jersey.
References
1. Asthana S, ed. Sotatercept May Benefit in Early Pulmonary Arterial Hypertension Care. Medscape. October 21, 2025. https://www.medscape.com/viewarticle/sotatercept-may-benefit-early-pulmonary-arterial-2025a1000sif
2. McLaughlin VV, Hoeper MM, Badesch DB, et al. Sotatercept for Pulmonary Arterial Hypertension within the First Year after Diagnosis. N Engl J Med 2025;393:1599-1611. https://doi.org/10.1056/NEJMoa2508170
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