Phase 3 Trial Results Announced for Sotatercept-csrk in Pulmonary Arterial Hypertension

Merck has announced positive topline results from the Phase 3 HYPERION trial for sotatercept-csrk (WINREVAIR) in treating pulmonary arterial hypertension (PAH) functional class (FC) II or III at intermediate or high risk of disease progression.

HYPERION’s primary outcome was time to clinical worsening as measured by a composite endpoint of all-cause death, the need for non-planned PAH-related hospitalization ≥24 hours, atrial septostomy, lung transplantation, or PAH deterioration. Secondary outcomes were assessed at week 24 and included improvement in 6-minute walking distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and improvement in FC.1

“PAH is a progressive and debilitating disease with a poor prognosis that can be difficult to diagnose and treat,” said Vallerie McLaughlin, MD, Kim A. Eagle MD endowed professor of cardiovascular medicine and director, pulmonary hypertension program, University of Michigan in Ann Arbor. “The HYPERION study demonstrated that WINREVAIR on top of background therapy met its primary outcome measure of reduction in the time to clinical worsening events in adults who have been recently diagnosed with PAH.”1

Sotatercept-csrk is approved by the US Food and Drug Administration (FDA) for the treatment of adults with PAH FC I to increase exercise capacity, improve FC, and reduce the risk of clinical worsening events. Sotatercept-csrk is also the first activin signaling inhibitor therapy approved for PAH.1

A global, double-blind, placebo-controlled clinical trial, HYPERION evaluated sotatercept-csrk when added to background PAH treatment in newly diagnosed intermediate- or high-risk patients with PAH. A total of 320 participants enrolled in the study; these participants had a diagnosis of symptomatic PAH, classified as FCII (68/320; 21.3%) or III (252/320; 78.8%) within 12 months of study screening.1

Included PAH subtypes included idiopathic (190/320; 59.4%), heritable (19/320; 5.9%), PAH associated with connective tissue diseases (97/320; 30.3%), drug- or toxin-induced PAH (8/320; 2.5%), or PAH associated with congenital systemic-to-pulmonary shunts ≥1 year following repair (6/320; 1.9%). Patients with human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis were excluded.1

Patients were randomized to receive either sotatercept-csrk or placebo, both on top of background therapy. Participants were on either double (231/320; 72.2%) or triple (89/320; 27.8%) background PAH therapies for ≥90 days prior to screening.1

In January, Merck announced the decision to stop HYPERION early, moving instead to final analysis. This was based on positive results from sotatercept-csrk’s prior trial, ZENITH, and a review of the totality of data from the program to date. Investigators declared it unethical to continue the trial given the wealth of positive data already collected.2

Previous Phase 3 studies – STELLAR in 2023 and ZENITH in 2025 – indicated sotatercept-csrk’s efficacy in reducing major morbidity and mortality events in adults with PAH FC III or IV with background therapy. These trials demonstrated clinical worsening risk reductions of 84% and 76%, respectively.3,4

“To date, the strong clinical profile of WINREVAIR, a first-in-class activin signaling inhibitor, had been primarily established through previous studies in a prevalent patient population comprised of patients that were several years into their treatment journey,” said Joerg Koglin, MD, PhD, senior vice president, head of general and specialty medicine, global clinical developer, Merck Research Laboratories. “These positive results from HYPERION expand on the body of clinical evidence now including recently diagnosed adults, supporting the practice-changing potential of WINREVAIR in a broad spectrum of PAH patients, including those earlier in their treatment journey.”1

Results from the HYPERION trial will be presented at an upcoming medical conference later in 2025. Merck has not stated an expected date for regulatory submission.1

References

1. Merck Pharmaceuticals. Merck Announces Phase 3 HYPERION Study of WNREVAIR (sotatercept-csrk) Met Primary Endpoint in Recently Diagnosed Adults with Pulmonary Arterial Hypertension (PAH). BusinessWire. June 23, 2025. Accessed June 23, 2025. https://www.businesswire.com/news/home/20250623646523/en/Merck-Announces-Phase-3-HYPERION-Study-of-WINREVAIR-sotatercept-csrk-Met-Primary-Endpoint-in-Recently-Diagnosed-Adults-with-Pulmonary-Arterial-Hypertension-PAH

2. Merck Pharmaceuticals. Merck Announces Decision to Stop Phase 3 HYPERION Trial Evaluating WINTREVAIR (sotatercept-csrk) Early and Move to Final Analysis. January 30, 2025. Accessed June 23, 2025. https://www.merck.com/news/merck-announces-decision-to-stop-phase-3-hyperion-trial-evaluating-winrevair-sotatercept-csrk-early-and-move-to-final-analysis/

3. Merck Pharmaceuticals. Merck’s Investigational Activin Signaling Inhibitor Sotatercept Improved Six-Minute Walk Distance by 40.8 Meters at Week 24 Versus Placebo in Adults with Pulmonary Arterial Hypertension on Background Therapy. March 6, 2023. Accessed June 23, 2025. https://www.merck.com/news/mercks-investigational-activin-signaling-inhibitor-sotatercept-improved-six-minute-walk-distance-by-40-8-meters-at-week-24-versus-placebo-in-adults-with-pulmonary-arterial-hypertension-on-bac/

4. Merck Pharmaceuticals. WINREVAIR (sotatercept-csrk) Reduced the Risk of a Composite of All-Cause Death, Lung Transplantation and Hospitalization for Pulmonary Arterial Hypertension (PAH) by 76% Compared to Placebo in the Phase 3 Zenith Trial. March 31, 2025. Accessed June 23, 2025. https://www.merck.com/news/winrevair-sotatercept-csrk-reduced-the-risk-of-a-composite-of-all-cause-death-lung-transplantation-and-hospitalization-for-pulmonary-arterial-hypertension-pah-by-76-compared-to-placebo-i/