FDA Expands Indication for Sotatercept-csrk in Pulmonary Arterial Hypertension

In ZENITH (N=172; 86 WINREVAIR, 86 placebo), adding WINREVAIR to background therapy demonstrated a statistically significant and clinically meaningful 76% reduction in the risk of major morbidity and mortality outcomes in adults with PAH WHO functional class III or IV compared to placebo (HR: 0.24; 95% CI: 0.13, 0.43; p<0.0001). The trial’s composite primary efficacy endpoint events — time to first occurrence of all-cause death, lung transplantation or PAH-worsening hospitalization of ≥24 hours — occurred in 15 WINREVAIR-treated participants (17%) versus 47 placebo-treated participants (55%). Due to overwhelming efficacy based on the primary endpoint result, the ZENITH trial was stopped early at the interim analysis and patients were offered the opportunity to receive WINREVAIR through an open-label long-term follow-up study.

“For patients with PAH, the risk of serious events such as hospitalization, transplantation or death remains unacceptably high despite being maximally treated with traditional therapies,” said Dr. Vallerie McLaughlin, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and Director, Pulmonary Hypertension Program, University of Michigan in Ann Arbor. “Results from the pivotal ZENITH trial add to the growing body of data and support the potential for WINREVAIR as standard of care.”

Healthcare providers should monitor hemoglobin and platelets before each dose of WINREVAIR for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine if dose adjustments are required. WINREVAIR may increase hemoglobin and may lead to erythrocytosis, which if severe may increase the risk of thromboembolic events or hyperviscosity syndrome. WINREVAIR also may decrease platelet count and lead to severe thrombocytopenia, which may increase the risk of bleeding; thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Treatment should not be initiated if platelet count is <50,000/mm. See additional Selected Safety Information below.

The most common adverse reactions (≥10% for WINREVAIR and at least 5% more than placebo) in ZENITH were infections (67.4% vs 44.2%), epistaxis (45.3% vs 9.3%), diarrhea (25.6% vs 17.4%), telangiectasia (25.6% vs 3.5%), increased hemoglobin (15.1% vs 1.2%), rash (10.5% vs 4.7%), erythema (10.5% vs 3.5%) and gingival bleeding (10.5% vs 2.3%).The median duration of exposure was longer in the WINREVAIR group (435 days) than in the placebo group (268 days). In the WINREVAIR group, 1 patient (1%) discontinued study intervention due to an adverse event, compared with 4 patients (5%) in the placebo group.

“Merck’s leadership in PAH research is anchored in a comprehensive clinical program that continues to advance science and deliver meaningful evidence for physicians and patients,” said Dr. Joerg Koglin, senior vice president, global clinical development, Merck Research Laboratories. “This approval represents another step forward in our mission to deliver on the promise of WINREVAIR, an activin signaling inhibitor with an indication recognizing its impact to adult patients with PAH on the risk of clinical worsening events, including death, lung transplantation and PAH hospitalization."

About ZENITH

The ZENITH study (NCT04896008) was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 172 adult participants with PAH (WHO FC III or IV) at high risk of mortality were randomized in a 1:1 ratio to either WINREVAIR (target dose 0.7 mg/kg) (n=86) plus background PAH therapy or placebo (n=86) plus background PAH therapy administered subcutaneously once every 3 weeks.

The most common PAH etiologies were idiopathic PAH (50%), PAH associated with connective tissue diseases (CTD) (28%), and heritable PAH (11%). The mean time since PAH diagnosis to screening was 8 years. The study excluded patients diagnosed with human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement. Participants were on background PAH treatment, 72% on triple therapy, 28% on double therapy and 59% on prostacyclin infusion therapy. There were more participants in WHO FC III (74%) compared to WHO FC IV (26%). The REVEAL Lite 2 risk score was <9 for 2% of participants, 9 to 10 for 67% of participants and ≥11% for 30% of participants. The primary efficacy endpoint was time to first confirmed major morbidity or mortality event. Events were defined as all-cause death, lung transplantation or PAH worsening-related hospitalization of ≥24 hours. Secondary endpoints included overall survival and several additional measures.

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 pulmonary hypertension) to improve exercise capacity and World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events, including hospitalization for PAH, lung transplantation and death. 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.