"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," 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 U.S. and 38 countries based on the results from the Phase 3 STELLAR trial.
*World Health Organization
**Dr. McLaughlin is a member of the adult sotatercept steering committee, an investigator in the ZENITH and HYPERION trials and a paid consultant to Merck.
About HYPERION
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.
About ZENITH
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.
About STELLAR
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.
About SOTERIA
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.
About WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use, 45 mg, 60 mg
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 signaling inhibitor therapy approved to treat PAH. WINREVAIR improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, WINREVAIR induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
WINREVAIR is the subject of a licensing agreement with Bristol Myers Squibb.
Selected Safety Information for WINREVAIR in the U.S.
WINREVAIR may increase hemoglobin (Hgb). Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required.
WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm3. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.
In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR and 1% of patients taking placebo. Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Do not administer WINREVAIR if the patient is experiencing serious bleeding.
WINREVAIR may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose. Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.
Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility.
The most common adverse reactions occurring in the phase 3 clinical trial (≥10% for WINREVAIR and at least 5% more than placebo) were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%), rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea (15.3% vs 10.0%), dizziness (14.7% vs 6.2%), and erythema (13.5% vs 3.1%).
Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.
About PAH
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 U.S. 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%.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA (the "company") includes "forward-looking statements" within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
Please see Prescribing Information for WINREVAIR (sotatercept-csrk) at http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_pi.pdf, Patient Information for WINREVAIR at http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ppi.pdf, and Instructions for Use for WINREVAIR (1-vial kit, 2-vial kit) at https://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ifu_1-vial_2-vial_kits.pdf.
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