Winrevair excels at advanced PAH in Phase 3 trial, all offered treatment
ZENITH trial stopped early as interim analysis shows 'overwhelming efficacy'
Winrevair (sotatercept-csrk) significantly reduced the risk of all-cause death, a lung transplant, or hospitalization among adults with pulmonary arterial hypertension (PAH) at a high risk of dying enrolled in a Phase 3 clinical trial.
These top-line findings in the ongoing ZENITH trial (NCT04896008), testing the Merck treatment against a placebo while on background therapy, led an independent data monitoring committee to recommend the trial be stopped early. All enrolled patients now are invited to enter the open-label SOTERIA (NCT04796337) extension study and be treated with Winrevair.
“Based on the primary endpoint demonstrating overwhelming efficacy, all ZENITH study participants will be offered the opportunity to receive Winrevair,” Eliav Barr, MD, senior vice president and head of global clinical development at Merck Research Laboratories, as well as its chief medical officer, said in a company press release.
“This is the first study in PAH in which the interim analysis led to an early conclusion of the study due to overwhelming efficacy,” added Vallerie McLaughlin, MD, a trial investigator, and a professor of cardiovascular medicine and director of the pulmonary hypertension program at the University of Michigan in Ann Arbor.
PAH treatment tested in people in WHO functional class 3 or 4 at risk of dying
PAH is caused by the uncontrolled growth of endothelial cells that line the inside of the pulmonary arteries, the small vessels that transport blood through the lungs. This narrows the arteries and restricts blood flow, leading to high blood pressure, or hypertension, which makes the heart work harder to pump blood.
Due to a lack of blood flow through the lungs, PAH symptoms are often associated with low oxygen levels, including shortness of breath, fatigue, chest pain, and dizziness or fainting. In more advanced stages, PAH can lead to right heart failure due to the increased workload on the heart.
“PAH is a serious, progressive disease with a high incidence of morbidity and mortality,” Barr said.
Winrevair’s active ingredient is an activin signaling inhibitor, which works to block the activity of proteins implicated in the uncontrolled growth of endothelial cells. Given as an under-the-skin (subcutaneous) injection once every three weeks, it’s approved to treat adults with PAH in the U.S., Canada, and the European Union, Iceland, Liechtenstein, and Norway. Generally, these approvals pertain to PAH patients with WHO functional class 2 or 3, where the disease limits physical activity but people are comfortable at rest.
As an approved treatment, Winrevair aims to improve exercise capacity and World Health Organization (WHO) functional class, and reduce risk of disease-worsening events.
Significant decline in mortality, transplant, other risks with treatment
The ZENITH study enrolled 172 adults with advanced PAH in WHO functional class 3 or 4, all considered to be at a high risk of dying. In addition to standard PAH treatments, participants were randomly assigned to Winrevair (starting dose of 0.3 mg/kg, target dose of 0.7 mg/kg) or a placebo injection every three weeks.
Its main goal was the time to the confirmed morbidity or a mortality event, defined as either death by any cause, a lung transplant, or a hospitalization due to PAH complications lasting at least one day. Secondary measures include overall survival, transplant-free survival, and several clinical tests of disease severity.
In top-line data, Winrevair demonstrated a statistically significant and clinically meaningful reduction in the risk of morbidity or mortality events compared with the placebo. In an early assessment, adverse events were balanced between the two groups, Merck reported.
Based on the strength of these data and the monitoring committee’s recommendation, the trial was stopped and all ZENITH participants are being given the opportunity to continue or start with Winrevair as part of the SOTERIA extension study.
Top-line findings in Phase 3 trial to be detailed at future science meeting
“These findings are impressive, set a high evidentiary bar for studies of future candidates developed for the treatment of PAH and support the potential of Winrevair to be practice-changing in the management of PAH,” Barr said.
ZENITH results will be submitted to regulatory authorities, and they will be detailed at an upcoming medical meeting, Merck, known as MSD outside of the U.S. and Canada, reported.
“Winrevair has brought significant optimism to the field, and we thank the investigators and patients for being part of this important study,” McLaughlin said.
Meanwhile, the Phase 3 HYPERION (NCT04811092) trial is testing Winrevair in adults newly or recently diagnosed with PAH in WHO functional class 2 or 3, and are at an intermediate or high risk of disease progression. The Phase 2 MOONBEAM (NCT05587712) trial is evaluating the therapy’s safety and tolerability in children and adolescents, ages 1-17, with PAH. Both of these studies take place in multiple countries and are recruiting.
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