The final analysis of sotatercept as add-on therapy in recently diagnosed pulmonary arterial hypertension (PAH) as part of the Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13) (HYPERION) trial was stopped early following publication of other trials showing that the drug can improve patient outcomes when added to standard-of-care background therapy. An open-label extension, A Clinical Study of Sotatercept (MK-7962) in People With Pulmonary Arterial Hypertension (MK-7962-038) (SOTERIA), is continuing. Although the study was stopped before reaching the targeted enrollment, final analysis of the data published in September showed that the study met its primary end point.1
“Almost all of the medications in the pulmonary hypertension field were approved on the basis of one randomized, placebo-controlled, phase 3 trial,” said James R. Klinger, MD, FCCP, Professor of Pulmonary, Sleep, and Critical Care Medicine at the Brown University Warren Alpert Medical School and Rhode Island Hospital. “Sotatercept is the first drug in the field that has not one but now three different phase 3 studies showing efficacy. HYPERION builds up the database, suggesting that this is a very effective drug.”
Prior phase 3 studies—including the Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11) (STELLAR) and Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH) trials—found that sotatercept can improve exercise capacity and reduce clinical worsening for patients with long-standing PAH. HYPERION looked at patients with PAH diagnosed within one year from enrollment. Given prior results, positive outcomes for patients with newly diagnosed PAH are not surprising, Dr. Klinger said.2–3
HYPERION enrolled 320 adult patients: 160 each in the sotatercept plus background therapy and placebo plus background therapy groups. All had World Health Organization functional class II or III PAH, had intermediate or high risk of mortality, and were on standard-of-care background therapy.
The primary end point was clinical worsening of PAH, a composite of all-cause mortality, unplanned hospitalization for worsening PAH, atrial septostomy, lung transplantation, or deterioration in exercise testing due to PAH. Secondary end points included multicomponent improvements of 6-minute walk distance, N-terminal pro-brain natriuretic peptide decrease, improvement in functional class, and other measures.
The mean follow-up for HYPERION was 13.2 months. At least one primary end point occurred in 10.6% of the sotatercept group vs 36.9% of the placebo group (HR, 0.24 [95% CI, 0.14-0.41; P < .0001]). Deterioration in exercise performance due to PAH was seen in 5.0% of the sotatercept group vs 28.8% of the placebo group.
Among the sotatercept group, unplanned hospitalization for worsening PAH occurred in 1.9% of patients vs 8.8% of the placebo group. Death from any cause was similar, at 4.4% in the sotatercept group and 3.8% in the placebo group.
The most common adverse event in the sotatercept group was epistaxis (31.9%) and telangiectasia (26.2%).
Dr. Klinger noted that despite the clear efficacy and excitement surrounding sotatercept, there are many key questions that need to be answered. None of the trials to date have addressed the optimal duration of therapy, potential for disease progression if therapy is stopped, or effectiveness as monotherapy.
“This is a different kind of drug,” he said. “It is difficult to get into trouble with our conventional drugs. They are essentially vasodilators, dilating up blood vessels that haven’t been diseased yet, but the concern with this drug is that it is very nonfocal in its targeting. The primary side effect is erythrocytosis, underscoring the fact that you need some of these growth factors that the drug binds to regulate red blood cell production. The bigger problem is that some of the ligands that are scavenged are very important to modulating, preventing, and inhibiting abnormal vascular growth. More than 20% of patients developed visible telangiectasias, and we have no idea how many invisible ones develop in the gut, the lung, or the brain.”
CHEST, the American Thoracic Society, and the American Heart Association are all revisiting PAH guidelines and recommendations, Dr. Klinger added. He is Co-Chair of the CHEST Guideline and Expert Panel for PAH and was Co-Chair of the most recent recommendations published in 2019. The European Society of Cardiology (ESC) and European Respiratory Society (ERS) revised their PAH guidelines in 2022.
Per the ESC/ERS guidelines, patients are stratified into four risk groups after starting standard therapy. The lowest risk group remains on conventional therapy, Dr. Klinger explained, while patients in the other three groups have the option of adding additional pulmonary vasodilators or sotatercept.
“I think the current European guidelines have it right,” he said. “They leave it up to the practitioners to decide what they want to do based on each individual patient.”
References
1. 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(16):1599-1611. doi:10.1056/NEJMoa2508170
2. Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558
3. Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025;392(20):1987-2000. doi:10.1056/NEJMoa2415160
