The US Food and Drug Administration (FDA) has approved a label update for sotatercept-csrk (WINREVAIR) to include efficacy and safety data from the phase 3 HYPERION trial in adults with pulmonary arterial hypertension (PAH) diagnosed within the previous 12 months.1
Sotatercept, an activin signaling inhibitor, already carries approval for adults with PAH (WHO Group 1) to improve exercise capacity and WHO functional class and to reduce clinical worsening events, including hospitalization, lung transplantation, and death. The HYPERION update extends label evidence to patients earlier in their disease course, adding to prior data from the STELLAR and ZENITH trials. This is the third phase 3 study of sotatercept in PAH to inform the product label.1
"The results of HYPERION provide evidence for the use of WINREVAIR in adults diagnosed with PAH within the previous year who were receiving background therapy," Vallerie McLaughlin, MD, the Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine and director, Pulmonary Hypertension Program, University of Michigan, said in a statement. "The addition of these data to the U.S. product label provide meaningful information when making treatment decisions and reflect the evolving treatment landscape for PAH."1
What was Sotatercept’s efficacy in HYPERION?
HYPERION (NCT04811092) was a global, double-blind, placebo-controlled trial enrolling 320 adults with newly diagnosed PAH (WHO functional class II or III, diagnosed within 12 months of screening) at intermediate to high risk of disease progression. These patients were randomly assigned in a 1:1 ratio to either sotatercept at a target dose of 0.7 mg/kg or placebo, added to background therapy every 3 weeks.1
Mean time since diagnosis was 7.2 months; 72% of participants were on double background therapy and 28% on triple therapy, with 17% receiving prostacyclin infusion. The trial was stopped early based on positive interim results from ZENITH and a review of the totality of sotatercept data.1
Adding sotatercept to background therapy reduced the risk of clinical worsening events by 76% compared with placebo (HR, 0.24; 95% CI, 0.14-0.41; P < .0001).
The primary composite endpoint was time to death or first confirmed morbidity event, encompassing all-cause death, PAH-related hospitalization of 24 hours or longer, atrial septostomy, lung transplantation, or a 6-minute walk distance decline combined with functional class worsening, right heart failure signs, or a background therapy change. A first clinical worsening event occurred in 10.6% (17/160) of the sotatercept group versus 36.9% (59/160) with placebo.1
What is WINREVAIR’s safety profile and dosing?
Safety findings in HYPERION were generally consistent with STELLAR. The most common adverse events (AEs) occurring in at least 10% of sotatercept-treated patients and at least 5% more than placebo were epistaxis (31.9% vs 6.9%), telangiectasia (26.3% vs 11.3%), and increased hemoglobin (11.3% vs 1.3%).1
No severe reductions in platelet count below 50,000/mm3 occurred in the sotatercept group. Treatment discontinuation due to an AE occurred in 3% of the sotatercept group, most commonly for epistaxis, versus 0% with placebo.1
The updated label carries additional safety guidance. Sotatercept is contraindicated in patients with serious hypersensitivity to the drug or its excipients, and clinicians should discontinue treatment and initiate emergency care if anaphylaxis or angioedema occurs.1
Hemoglobin and platelets should be monitored before each of the first 5 doses, or longer if unstable, and periodically thereafter; treatment should not be initiated if platelet count is below 50,000/mm3 given the drug's association with erythrocytosis and thrombocytopenia.1
"HYPERION is the third phase 3 study of WINREVAIR in PAH and provides robust clinical evidence in adults with PAH when added to background therapy, including within the first year following a diagnosis," said Joerg Koglin, MD, senior vice president, head of general and specialty medicine, global clinical development, Merck Research Laboratories.
How do guidelines recognize sotatercept in PAH?
The European Respiratory Society published updated PAH clinical guidelines this month, marking the first formal guidelines to incorporate sotatercept.1 The guidelines issue a "strong" recommendation, graded with "high" certainty of evidence, for sotatercept in adults with PAH on background therapy who have not achieved low-risk status, spanning intermediate-low, intermediate-high, and high-risk patients. Sotatercept is the only add-on PAH therapy to receive a strong recommendation in the update.
Beyond the label update, sotatercept's effects on right ventricular function drew separate attention from Anjali Vaidya, MD, of Temple University, who outlined 3 interconnected mechanisms behind the drug's cardiac impact in PAH at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany: afterload reduction, structural remodeling, and functional improvement.2 Vaidya pointed to reversals in pulmonary vascular resistance that exceeded those seen with prior PAH therapies, along with improvements in RV size, RV-to-LV relationships, and biomarkers including NT-proBNP, citing supporting data from the STELLAR and ZENITH trials.
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