Macitentan

Merck’s Winrevair excelled in a phase 3 trial of high-risk pulmonary arterial hypertension patients, reducing the risk of death, lung transplantation and hospitalization by 76% versus placebo. The interim result was conclusive enough that Merck halted the trial and another Winrevair phase 3 study of newly diagnosed patients. The interim results of a phase 3 trial of Merck’s pulmonary arterial hypertension (PAH) treatment Winrevair were so conclusive that the company not only halted the study for efficacy, but did the same two months later in another trial of the first-in-class activin signaling inhibitor.Merck has revealed data from the study, providing further evidence of the value of Winrevair, which has been approved in more than 40 countries, including in the U.S. a year ago. The Zenith trial included 172 patients at the highest risk of mortality—those in the World Health Organization Functional Class (FC) III or IV—and achieved its primary endpoint of time to clinical worsening to first morbidity or mortality event.Winrevair added to maximum background therapy reduced the risk of all-cause death, lung transplantation and hospitalization by 76% versus placebo plus maximum background therapy. Patients received a subcutaneous dose of Winrevair every three weeks, and the median follow-up with patients was 10.6 months.“I’ve been doing clinical research for almost 30 years and have never seen a study with a hard-outcome endpoint with this effect size,” Joerg Koglin, M.D., Merck’s head of general medicine, global clinical development, said in an interview with Fierce Pharma. “There has not been a PH study that used an endpoint based on death, hospitalization or lung transplant. It also is the first PH phase 3 study that was ever stopped early. I think that puts the effect size in perspective.”Merck presented the Zenith data at the American College of Cardiology Annual Scientific Session & Expo on March 31 in Chicago. Results also were reported in The New England Journal of Medicine.   For Winrevair patients in Zenith, 17% had one or more major morbidity or mortality event, compared to 55% of patients in placebo arm. Of the 86 patients on each side of the study, there were seven deaths in the Winrevair arm (8%) compared with 13 in the placebo arm (15%).One patient on Winrevair had a lung transplant (1%) while six on placebo (7%) needed the procedure. PAH hospitalizations occurred in eight patients on Winrevair (9%) compared to 43 patients (50%) on placebo.Koglin said that Merck pursued an ambitious endpoint—not undertaken in other trials—because Winrevair is the first medicine that targets the underlying cause of PAH, while other therapies for the disorder ameliorate its symptoms.One secondary endpoint where the study came up short was overall survival. While there were nearly twice as many deaths (13) on the placebo side of the trial compared to Winrevair (seven), the difference did not achieve statistical significance.“When you run an interim analysis, you are using a much higher statistical bar because the interim analysis is much smaller,” Koglin explained.Setting up Winrevair for its FDA approval was the Stellar phase 3 study, which used exercise capacity as its primary endpoint. Patients who were on Winrevair added to standard of care improved their distance in a six-minute walk test by an average of 41 meters.While the Stellar trial included longtime PAH patients at a lower risk of mortality (from the FC II and III classes), Merck’s phase 3 Hyperion study focused on those who were diagnosed with the disorder within the previous 12 months.Hyperion was halted two months ago after a review of the interim results of the Zenith study. Merck’s chief medical officer Eliav Barr, M.D., said in a release that it would be unethical to give patients placebo when the superiority of Winrevair was clearly established.All 300 patients in both the Zenith and Hyperion trials were offered to receive Winrevair through the Soteria open-label extension study. Koglin said the company will reveal Hyperion data later this year.PAH is a rare, rapidly progressing disease in which the blood vessels in the lungs become thickened and narrower due to a dangerous buildup of cells, leading to shortness of breath and difficulty in the heart’s ability to pump blood to the lungs, which increases blood pressure and can lead to heart failure. Winrevair works by rebalancing the cell signaling.Roughly 40,000 people in the U.S. have the disorder. PAH strikes more women than men and most are in middle age, killing nearly half within five years of diagnosis. The condition begins as a more common disorder, pulmonary hypertension (PH), then can progress into PAH. Winrevair was initially developed by Acceleron and Celgene. Merck gained its rights with its $11.5 billion buyout of Acceleron in 2021. The company makes royalty payments on sales of Winrevair to Bristol Myers Squibb, which bought out Celgene in 2019.Merck reported 2024 sales of Winrevair at $419 million, with nearly half of that, $200 million, coming in the fourth quarter alone.Analysts from Citi said that the full dataset from Zenith shows the "paradigm shifting impact of Winrevair in PAH. ” Citi has boosted its 2025 sales projection of Winrevair from $1.3 billion to $1.5 billion, while lifting its 2030 peak sales estimate from $5.7 billion to $6.1 billion. Johnson & Johnson controls the PAH market with endothelin receptor agonist Opsumit and prostacyclin receptor Uptravi, which were approved in 2013 and 2015, respectively, and garnered combined sales of $4 billion in 2024.Last year, the FDA approved a combination tablet Opsynvi, which combines Opsumit and United Therapeutics’ Adcirca, which are often prescribed together for PAH. These therapies dilate the blood vessels to alleviate PAH symptoms.