Merck Stops HYPERION Trial for Winrevair in PAH Following Positive ZENITH Trial Results
The Phase III HYPERION trial was stopped early after strong positive interim results from the ZENITH trial demonstrated the efficacy of Winrevair (sotatercept-csrk) in treating pulmonary arterial hypertension, making it unethical to continue.
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Merck has announced an early end to the Phase III HYPERION trial (NCT04811092) evaluating Winrevair (sotatercept-csrk) in the treatment of pulmonary arterial hypertension (PAH) based on positive interim results from the Phase III ZENITH trial (NCT04896008).1-3 After an examination of findings from ZENITH and the entire Winrevair clinical trial program, as well as consultation with the FDA, Merck and an external steering committee concluded it would be unethical to continue HYPERION and will permit participants to access the medication in the SOTERIA open-label extension trial (NCT04796337).4
"After closely reviewing the robust efficacy data across a broad spectrum of patients evaluated in the Winrevair clinical development program, the steering committee has unanimously concluded that the HYPERION study, evaluating Winrevair versus placebo on top of background therapy, has lost clinical equipoise and should be stopped early,” Vallerie McLaughlin, MD, FACC, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and director of the Pulmonary Hypertension Program at University of Michigan, said in a press release. “PAH is a progressive and debilitating disease with a high incidence of morbidity and mortality, and we look forward to continuing to evaluate these patients and any potential impact to the treatment landscape as a result of these data.”1
Winrevair is an activin-signaling inhibitor that attaches to activin A and other TGF-β superfamily ligands. This has been found to enhance the balance between antiproliferative and proproliferative signaling to alter vascular proliferation. In turn, this action lowers inflammation and inhibits the proliferation of endothelial and smooth muscle cells in diseased vasculature, leading to thinner vessel walls, a partial reversal of right ventricular remodeling, and improved hemodynamics.5
The FDA approved Winrevair in March 2024 for adults with PAH, marking the first activin signaling inhibitor therapy to gain approval for the treatment of PAH.6 The regulatory action was based on findings from the Phase III STELLAR trial (NCT04576988), in which Winrevair was found to increase six-minute walking distance from baseline by 41 meters at week 24, with an 84% reduction in the risk of death and potential worsening of the condition.7
Trial Design
The global, double-blind, placebo-controlled HYPERION trial analyzed Winrevair plus background PAH therapy in patients newly diagnosed with intermediate or high-risk PAH. Investigators enrolled approximately 300 patients who were randomly assigned in a 1:1 ratio to receive Winrevair plus background therapy for PAH or placebo plus background PAH. The trial’s primary composite outcome measure was time to clinical worsening as measured by first confirmed morbidity or mortality event.
The global, double-blind, placebo-controlled ZENITH trial analyzed Winrevair plus maximum tolerated background PAH therapy on time to first event of all-cause death, lung transplantation, or worsening of PAH requiring hospitalization of ≥24 hours. Secondary endpoints included overall survival and transplant-free survival. Investigators enrolled 172 participants who were randomly assigned in 1:1 ratio to receive either Winrevair or placebo.
Results announced in November 2024 showed a statistically significant and clinically meaningful decrease in the risk of morbidity or mortality events among patients administered Winrevair compared to placebo. At that time, an independent data monitoring committee recommended ZENITH be stopped early based on the positive results.8
“Based on the strong, positive interim efficacy data from the ZENITH trial, as well as the totality of available Winrevair data, we concluded that it would not be ethical to continue the HYPERION study,” Eliav Barr, MD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in the release. “We are grateful to the dedicated community of patients who participated in these studies and are pleased to offer the option of receiving Winrevair through the Phase III SOTERIA open-label extension study.”1
References
1. Merck Announces Decision to Stop Phase 3 HYPERION Trial Evaluating WINREVAIR™ (sotatercept-csrk) Early and Move to Final Analysis. News release. Merck. January 30, 2025. Accessed January 30, 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/
2. Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13) (HYPERION). ClinicalTrials.gov. Updated October 24, 2024. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT04811092
3. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH). ClinicalTrials.gov. Updated December 19, 2024. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT04896008
4. A Long-term Follow-up Study of Sotatercept for PAH Treatment (MK-7962-004/A011-12) (SOTERIA). ClinicalTrials.gov. Updated January 27, 2025. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT04796337
5. Winrevair. Prescribing information. Merck & Co, Inc; 2024. Accessed January 30, 2025. https://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_pi.pdf
6. FDA Approves Merck’s WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1). Merck. March 26, 2024. Accessed January 30, 2025. https://www.merck.com/news/fda-approves-mercks-winrevair-sotatercept-csrk-a-first-in-class-treatment-for-adults-with-pulmonary-arterial-hypertension-pah-who-group-1/
7. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11)(STELLAR). ClinicalTrials.gov. Updated September 19, 2024. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT04576988
8. Merck Announces Pivotal Phase 3 ZENITH Trial Evaluating WINREVAIR™ (sotatercept-csrk) Met Primary Endpoint at Interim Analysis. News release. Merck. November 25, 2024. Accessed January 30, 2025. https://www.merck.com/news/merck-announces-pivotal-phase-3-zenith-trial-evaluating-winrevair-sotatercept-csrk-met-primary-endpoint-at-interim-analysis/
