Sotatercept

Two phase 3 trials of Merck's pulmonary arterial hypertension drug Winrevair have been halted because of overwhelming efficacy. The company has revealed results from one of those studies, the Hyperion trial. Two clinical trials of Merck’s pulmonary arterial hypertension (PAH) drug Winrevair were so conclusive that the studies were halted within the last year because the efficacy of the treatment was assured.Tuesday, Merck reported results from the phase 3 Hyperion study, which showed that Winrevair, when combined with background therapy, achieved its primary endpoint by reducing the risk of clinical worsening events by 76% compared with placebo in recently diagnosed adults.Of the patients on placebo, 37% experienced a clinically worsening event versus 11% on Winrevair. Worsening events were defined as all-cause death, unplanned PAH-related hospitalizations of greater than 24 hours, atrial septostomy, lung transplantation or PAH deterioration.All of the 320 patients in the trial were on background therapy, with half receiving Winrevair and the other half taking placebo. The participants were diagnosed within the last year, with more than 70% on double background therapy. The severity of disease for the patients was functional class (FC) II or III on a four-grade scale, as defined by the World Health Organization. The likelihood of disease progression for those in the study was classified as intermediate or high-risk.The study also showed a benefit for patients as early as six weeks after receiving Winrevair, and there was a consistent treatment effect across all prespecified subgroups—including participants with idiopathic PAH, those with connective tissue disease and those taking double background therapy and triple background therapy. Winrevair’s effects were also consistent between those classified as intermediate or intermediate-to-low risk of disease progression.“PAH is a rare condition that can progress quickly making diagnosis and early treatment critically important,” Vallerie McLaughlin, M.D., a professor at the University of Michigan, said in a release. “The patients with PAH enrolled in HYPERION were early in their treatment journey, had co-morbidities and were older, which reflects the type of patients we are diagnosing in a contemporary real-world setting.”Results from the study were presented Tuesday at the European Respiratory Society Congress and were published in The New England Journal of Medicine. The study also achieved two of its three secondary endpoints. While 29% of Winrevair patients met all three pre-specified standards for multicomponent improvement, 15% of those on placebo did the same.Two of the secondary endpoints were determined through different mortality risk assessment tools. While Winrevair succeeded using one measurement tool, REVEAL LITE 2, it came up short of reaching statistical significance in the simplified French risk score.The results add to the growing body of evidence of the effectiveness of Winrevair, which was approved in March 2024. Merck gained the first-in-class activin signaling inhibitor in its $11.5 billion acquisition of Acceleron Pharma in 2021.In the Stellar trial, which set up the FDA’s green light, patients on Winrevair plus standard of care improved their exercise capacity by an average distance of 41 meters in a six-minute walk test. The study also showed that Winrevair provided statistically significant improvements in eight of nine secondary measures, including extending the time to a clinical worsening event. In March of this year, Merck revealed data from the Zenith trial, which also was halted early and included 172 patients at the highest risk of mortality, those in the FC III or IV category. The study achieved its primary endpoint as Winrevair reduced the risk of clinical worsening events by 76% versus placebo, with both patient arms receiving maximum background therapy.Merck is off to a successful launch of Winrevair, which is primed to achieve blockbuster sales this year. In the second quarter, it generated revenue of $336 million, which was up from $280 million in the previous period. After results from Zenith were revealed, analysts from Citi jacked up their 2030 sales estimate for Winrevair to a range of $5.7 billion to $6.1 billion. 

Merck’s pulmonary arterial hypertension drug Winrevair cut the risk of “clinical worsening” — an endpoint made up of a variety of signs showing that a patient’s illness is progressing — by 76% in recently diagnosed patients. It’s an eye-opening statistic, but also comparable to previous trials . The difference is that Merck’s previous studies on Winrevair, also known as sotatercept, included patients with more advanced disease or those who had been diagnosed with PAH several years earlier. The latest study, a Phase 3 trial called HYPERION, instead assessed adding Winrevair on top of standard background treatments within the first year of diagnosis. The data were reported Tuesday at the annual European Respiratory Society meeting and published in the New England Journal of Medicine . With these data in hand, Merck hopes to convince prescribers to give its drug earlier. Winrevair, one of Merck’s biggest new drug launches, is expected to become a multibillion-dollar product. In the first half of this year, Winrevair generated $616 million in sales. The drug is currently approved to treat adults with PAH, which occurs when blood pressure in the arteries that carries blood from the heart to lungs is abnormally high. PAH can lead to shortness of breath, fatigue and chest pains, among other symptoms. Winrevair is meant to lower that blood pressure by blocking a protein known as activin in hopes of preventing those blood vessels from thickening. Merck is also awaiting Phase 2 results for the drug in certain patients with heart failure. That study will signal whether Merck could further expand the use case for Winrevair. The study likely completed this month, according to the federal clinical trials database , and is expected to read out this year. Merck declined to comment on the timing of the data. Though Merck’s past studies looked at Winrevair in patients later in the course of their disease, the FDA granted the drug a broad label in PAH. But the “clinical reality” was that Winrevair was primarily used in patients who had been diagnosed for a long time, akin to the patient populations of its earlier studies, according to Joerg Koglin, Merck’s head of general and specialty medicine. Those patients were likely on three background therapies for PAH before Winrevair, he told Endpoints News , whereas the majority of patients in the recently diagnosed study were on two. The primary endpoint of the study — “clinical worsening” — included events such as deterioration in performance on an exercise test, hospitalization or death. With a median follow-up of 13 months, 10.6% of patients in the sotatercept group experienced one of those events, while 36.9% in the placebo group did. That difference resulted in a hazard ratio of 0.24 and a P<0.001. Deterioration in performance on an exercise test accounted for a substantial proportion of those events; eight patients, or 5%, of the sotatercept group saw that happen, compared to 46 patients, or 28.8%, of the placebo group. “I believe the data will point physicians to the idea [that] if this is something that treats the underlying root cause of the disease, perhaps it makes sense to consider initiation of sotatercept earlier in an individual patient’s disease journey rather than later,” Koglin said. Koglin also pointed out that the difference between the Winrevair group and placebo arm became apparent within a few doses. Merck notably stopped this study early after a previous study (which was also stopped early) showed Winrevair cut the risk of death, lung transplantation and hospitalization. As a result, the program’s steering committee said it was no longer ethical to continue enrolling patients in a trial comparing Winrevair to placebo. Merck is also waiting for a label update by Oct. 25 to add the new information about reduced risk of death and other major events. The company also plans to submit the HYPERION results to the FDA. The HYPERION study enrolled 320 patients, divided into the two groups who got background therapies and then either sotatercept or placebo. Background therapies typically included a combination of endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogues. The side effects of Winrevair looked similar to past studies, with 31.9% of patients on Winrevair experiencing a nosebleed, the most common side effect in the trial. Editor’s note: This story was updated to add that Merck plans to submit the HYPERION results to the FDA.