FDA Label Update Adds HYPERION Data to WINREVAIR for Newly Diagnosed PAH
核心洞察
The FDA approved a U.S. label update for WINREVAIR (sotatercept-csrk (搜索)) incorporating efficacy and safety data from the Phase 3 HYPERION trial in newly diagnosed PAH.
In HYPERION, adding WINREVAIR to background therapy cut the risk of clinical worsening events by 76% versus placebo (HR 0.24; 95% CI 0.14 to 0.41; p<0.0001).
First clinical worsening events occurred in 10.6% of WINREVAIR patients versus 36.9% of placebo patients in the 320-participant trial.
Merck (搜索) announced that the U.S. Food and Drug Administration has approved an update to the U.S. product label for WINREVAIR (sotatercept-csrk (搜索)) for injection, 45 mg and 60 mg, based on the Phase 3 HYPERION trial. The label now includes efficacy and safety data from HYPERION, which evaluated adults newly diagnosed with pulmonary arterial hypertension (搜索) (PAH, WHO Group 1 pulmonary hypertension) at intermediate to high risk of disease progression, providing insight into the role of WINREVAIR when added to background therapy within the first year of a PAH diagnosis.
WINREVAIR, an activin signaling (搜索) inhibitor, is FDA-approved for the treatment of adults with PAH to improve exercise capacity and WHO functional class (FC), and to reduce the risk of clinical worsening events, including hospitalization for PAH, lung transplantation and death.
HYPERION Efficacy Results
In HYPERION (N=320; 160 WINREVAIR, 160 placebo), adding WINREVAIR to background therapy reduced the risk of clinical worsening events by 76% in adults with PAH WHO functional class II or III compared with placebo (hazard ratio 0.24; 95% confidence interval, 0.14 to 0.41; p<0.0001).
The primary composite endpoint was time to death or first confirmed morbidity event, comprising all-cause death, unplanned PAH-related hospitalization lasting 24 hours or more, atrial septostomy, lung transplantation, or a decrease in 6-minute walk distance (6MWD) from baseline combined with at least one of the following: worsening of WHO FC, signs or symptoms of increased right heart failure, or addition or change of a background PAH therapy. A first clinical worsening event occurred in 10.6% (17 of 160) of patients who received WINREVAIR and 36.9% (59 of 160) of patients who received placebo. The treatment effect was consistent across all prespecified subgroups.
The trial enrolled participants within their first year of diagnosis, with a mean time since PAH diagnosis of 7.2 months. Seventy-two percent of participants were on double background therapy and 28% on triple background therapy; 17% were receiving prostacyclin infusion therapy.
"The HYPERION study included people with PAH who closely reflect those we see in everyday clinical practice, including individuals who were recently diagnosed, older adults and people managing other health conditions," said Dr. Vallerie McLaughlin, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and Director of the Pulmonary Hypertension Program at the University of Michigan in Ann Arbor. "The results of HYPERION provide evidence for the use of WINREVAIR in adults diagnosed with PAH within the previous year who were receiving background therapy. The addition of these data to the U.S. product label provide meaningful information when making treatment decisions and reflect the evolving treatment landscape for PAH."
Trial Design and Population
HYPERION (NCT04811092) was a global, double-blind, placebo-controlled trial in which 320 adults with newly diagnosed PAH (WHO FC II or III, diagnosis within 12 months of study screening) at intermediate to high risk of disease progression were randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg) or placebo, administered subcutaneously once every 3 weeks. The trial was stopped early based on positive results from the interim analysis of the ZENITH trial and a review of the totality of data from the WINREVAIR clinical program.
The median age of participants was 60 years (range: 18 to 88). Twenty-one percent were FC II and 79% were FC III. The most common PAH etiologies were idiopathic PAH (59%) and PAH associated with connective tissue diseases (30%). The REVEAL Lite 2 risk score was below 6 in 21% of participants, 6 to 7 in 51%, and 8 or higher in 28%.
The first secondary endpoint was multicomponent improvement, measured as the proportion of participants achieving all of the following at Week 24 relative to baseline: improvement in 6MWD (increase of 30 m or more), improvement in NT-proBNP (decrease of 30% or more, or maintenance or achievement of NT-proBNP below 300 ng/L), and improvement in WHO FC or maintenance of WHO FC II.
Safety Profile
The adverse reactions observed in HYPERION were generally consistent with those seen in the STELLAR trial. No severe reductions in platelet count below 50,000/mm3 occurred in the WINREVAIR group. The most common adverse reactions (10% or more for WINREVAIR and at least 5% more than placebo) in HYPERION were epistaxis (31.9% versus 6.9%), telangiectasia (26.3% versus 11.3%) and increased hemoglobin (11.3% versus 1.3%). Median duration of exposure was longer in the WINREVAIR group (443 days) than in the placebo group (350 days). Treatment discontinuation due to an adverse event occurred in 3% of the WINREVAIR group, with epistaxis the most common reason, and 0% of the placebo group.
The label update added safety information. WINREVAIR is contraindicated in patients with serious hypersensitivity, such as anaphylaxis or angioedema, to sotatercept-csrk (搜索) or any of its excipients, and serious hypersensitivity reactions have been reported in treated patients. Healthcare providers should monitor hemoglobin and 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. WINREVAIR may increase hemoglobin and lead to erythrocytosis, which if severe may raise the risk of thromboembolic events or hyperviscosity syndrome. It may also decrease platelet count and lead to severe thrombocytopenia, which may increase bleeding risk; thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Treatment should not be initiated if platelet count is below 50,000/mm3.
Across clinical studies, serious bleeding such as gastrointestinal or intracranial hemorrhage was reported in 4% versus 1% (STELLAR), 7% versus 5% (ZENITH) and 4% versus 2% (HYPERION) of patients taking WINREVAIR versus placebo. Postmarketing cases of gastrointestinal bleeding associated with angiodysplasias have been reported, and endoscopic evaluation should be considered in patients with recurrent or unexplained gastrointestinal bleeding. WINREVAIR may cause fetal harm when administered to a pregnant woman, and based on animal findings may impair female and male fertility. Breastfeeding is not recommended during treatment and for 4 months after the final dose.
ERS Guidelines Include WINREVAIR
Earlier in the month, the European Respiratory Society published clinical guidelines for the treatment of PAH. The guidelines are the first formal clinical guidelines to include WINREVAIR, with the update prompted by the current body of evidence for the therapy so that clinical practice guidelines reflect the current treatment landscape. The ERS guidelines give a "strong" recommendation for WINREVAIR in adult patients with PAH on background therapy who have not achieved low-risk status at follow up, including those at intermediate-low, intermediate-high or high risk, and grade the certainty of evidence as "high" out of four possible scores (very low, low, moderate or high). WINREVAIR is the only add-on PAH therapy to receive a strong recommendation in these guidelines.
"HYPERION is the third Phase 3 study of WINREVAIR in PAH and provides robust clinical evidence in adults with PAH when added to background therapy, including within the first year following a diagnosis," said Dr. Joerg Koglin, senior vice president, head of general and specialty medicine, global clinical development, Merck (搜索) Research Laboratories. "The totality of clinical evidence supporting the use of WINREVAIR to date continues to reinforce our confidence in its potential as a standard of care."
Prior Phase 3 Program
HYPERION follows two earlier Phase 3 trials. ZENITH (NCT04896008) randomized 172 adults with PAH (WHO FC III or IV) at high risk of mortality 1:1 to WINREVAIR (target dose 0.7 mg/kg) plus background PAH therapy or placebo plus background therapy, administered subcutaneously once every 3 weeks. STELLAR (NCT04576988) randomized 323 patients with PAH (WHO Group 1, FC II or III) 1:1 to WINREVAIR (target dose 0.7 mg/kg) or placebo plus stable background therapy, also dosed subcutaneously every 3 weeks.
WINREVAIR is the first activin signaling (搜索) inhibitor therapy approved to treat PAH. It improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, it induced cellular changes 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 (搜索).