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  Title	Merck to stop phase 3 HYPERION trial evaluating Winrevair early and move to final analysis
  ID	6416417
  External ID	7511861231
  Author	Unknown
  Published Date	Jan. 30, 2025, 10:35 p.m.
  Summary	Merck, known as MSD outside of the United States and Canada, announced the phase 3 HYPERION study evaluating Winrevair (sotatercept-csrk) versus placebo (both in combination with background therapy) i
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  URL	https://www.pharmabiz.com/newsdetails.aspx?aid=175010&sid=2
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• Content Details

  Content ID	3962596
  Key	e72a8044-d3c5-449f-8238-4669e54b5dc2
  Content	Merck, known as MSD outside of the United States and Canada, announced the phase 3 HYPERION study evaluating Winrevair (sotatercept-csrk) versus placebo (both in combination with background therapy) in recently diagnosed adults with pulmonary arterial hypertension (PAH, WHO Group 1) functional class (FC) II or III at intermediate or high risk of disease progression will be stopped early. The decision to stop the HYPERION study prior to its scheduled completion was based on the positive results from the interim analysis of the ZENITH trial and a review of the totality of data from the Winrevair clinical programme to date. The programme’s external steering committee and Merck made this decision in light of these data, which will enable all study participants to have the opportunity to access Winrevair. Merck discussed this decision to stop the HYPERION study early with the US Food and Drug Administration (FDA) and has informed HYPERION study investigators. "After closely reviewing the robust efficacy data across a broad spectrum of patients evaluated in the Winrevair clinical development programme, 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,” said Dr. Vallerie McLaughlin, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and Director, Pulmonary Hypertension Program, University of Michigan in Ann Arbor. “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.” “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,” said Dr Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “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 3 SOTERIA open-label extension study.” Findings from the HYPERION study will be available later this year and presented at a future medical congress. Winrevair is currently approved in the US and 38 countries based on the results from the phase 3 STELLAR trial. The HYPERION study (NCT04811092) is a global, double-blind, placebo-controlled clinical trial to evaluate Winrevair when added to background PAH therapy in newly diagnosed intermediate or high-risk PAH patients. Participants enrolled in the study had a diagnosis within 12 months of study screening of symptomatic PAH (WHO Group 1, classified as FC II or III) and presentation of idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin-induced PAH, post shunt correction PAH, or PAH presenting at least one year following the correction of congenital heart defects. The study enrolled approximately 300 study participants, who were randomized in a 1:1 ratio to either Winrevair plus background PAH therapy or placebo plus background PAH therapy. The primary composite outcome measure is time to clinical worsening (TTCW) as measured by first confirmed morbidity or mortality event. Clinical worsening events are defined as all-cause death, non-planned PAH worsening-related hospitalization of = 24 hours, atrial septostomy, lung transplantation, and deterioration in six-minute walk test from baseline combined with at least one of the following changes including worsening of WHO FC from baseline, signs/symptoms of increased right heart failure, addition of a background PAH therapy or change in the background PAH therapy delivery route to parenteral. Secondary outcome measures include improvement of six-minute walk distance (6MWD), improvement and maintenance or achievement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and improvement in WHO FC or maintenance of WHO FC II as well as additional measures. Participants in the HYPERION trial will have the opportunity to receive Winrevair as part of the open-label, long-term extension study, SOTERIA (NCT04796337), consistent with that study’s eligibility criteria. The ZENITH study (NCT04896008) is a global, double-blind, placebo-controlled clinical trial to evaluate Winrevair when added to maximum tolerated background PAH therapy on time to first event of all-cause death, lung transplantation, or PAH worsening related hospitalization of =24 hours, in participants with WHO FC III or IV PAH at high risk of mortality. ZENITH study inclusion criteria required Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of =9. The study enrolled 172 participants, who were randomized in a 1:1 ratio to either Winrevair plus background PAH therapy or placebo plus background PAH therapy. The primary composite outcome measure is time to first confirmed morbidity or mortality event. Events are defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of =24 hours. Secondary outcome measures include overall survival, transplant-free survival and several additional measures. Participants who have completed the ZENITH trial have the opportunity to receive sotatercept as part of the open-label, long-term extension study, SOTERIA (NCT04796337), consistent with that study’s eligibility criteria. STELLAR (NCT04576988) is a pivotal phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study designed to evaluate the safety and efficacy of Winrevair compared to placebo, as an add-on to background therapy for the treatment of adults with PAH (WHO Group 1). The primary endpoint was exercise capacity, as measured by 6MWD 24 weeks following initiation of treatment. Nine secondary outcome measures were assessed: proportion of participants achieving multicomponent improvement (consisting of improvement in 6MWD, improvement in NT-proBNP level, and either improvement in WHO FC or maintenance of WHO FC II); change from baseline in pulmonary vascular resistance (PVR); change from baseline in NT-proBNP levels; proportion of participants who improved in WHO FC; time to death or the first occurrence of a TTCW event; proportion of participants who maintained or achieved a low risk score using the simplified French Risk score calculator; change from baseline in the Physical Impacts domain score of PAH-SYMPACT; change from baseline in the Cardiopulmonary Symptoms domain score of PAH-SYMPACT; and change from baseline in the Cognitive/Emotional Impacts domain score of PAH-SYMPACT. SOTERIA (NCT04796337) is an ongoing open-label extension study evaluating the long-term safety, tolerability and efficacy of Winrevair when added to background therapy for the treatment of PAH in patients who have completed previous Winrevair studies without early discontinuation. The primary objective of SOTERIA is to evaluate long-term safety and tolerability. The secondary objective is to assess the continued efficacy of Winrevair, as measured by 6MWD, NT-proBNP, WHO FC, pulmonary vascular resistance, overall survival, and simplified French risk score. Results from the SOTERIA study were presented at the European Respiratory Society (ERS) International Congress in 2023. Winrevair is FDA-approved for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1) to increase exercise capacity, improve WHO functional class (FC) and reduce the risk of clinical worsening events. Winrevair is the first activin signalling inhibitor therapy approved to treat PAH. Winrevair improves the balance between pro-proliferative and anti-proliferative signalling to modulate vascular proliferation. In preclinical models, Winrevair induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodelling, and improved haemodynamics. Winrevair is the subject of a licensing agreement with Bristol Myers Squibb. Pulmonary arterial hypertension (PAH) is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. Approximately 40,000 people in the US are living with PAH. The disease progresses rapidly for many patients. PAH results in significant strain on the heart, leading to limited physical activity, heart failure and reduced life expectancy. The five-year mortality rate for patients with PAH is approximately 43%.
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