Sotatercept

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.

Looking to extend the reach of its pulmonary arterial hypertension (PAH) drug Winrevair (sotatercept-csrk) across the full spectrum of the disease, Merck & Co. unveiled detailed Phase III data Tuesday showing a 76% reduction in clinical worsening among newly diagnosed patients compared with placebo."The totality of Winrevair data to date continues to reinforce our confidence in its practice-changing potential," said Joerg Koglin, head of general and specialty medicine at Merck Research Laboratories.The HYPERION study tested the activin signalling inhibitor against placebo in 320 patients within their first year of a PAH diagnosis, who faced intermediate-to-high risk of progression and were on stable double- or triple-drug background therapy. A majority were not on prostacyclin-infusion therapy.Upcoming FDA decisionAs a comparison, patients in the pivotal STELLAR trial that was used to support Winrevair's US approval last year had been living with PAH for an average of 8.8 years by the time they were screened. The drug, which generated sales of $336 million in the second quarter, is currently marketed for patients with PAH at moderate-to-high risk of complications.Merck is aiming to fold data from the Phase III ZENITH trial into Winrevair's label to back its use in the most severe patients with PAH, with the FDA slated to rule by Oct. 25 (see – Spotlight On: Key PDUFA dates to watch in 4Q25).HYPERION, whose results were shared Tuesday at the European Respiratory Society (ERS) congress and also simultaneously published in NEJM, is focused on patients earlier in the course of the disease. The study was stopped ahead of schedule in January after Winrevair's showing in the ZENITH trial made it unethical to keep patients from the drug.Early, sustained benefitBeyond the sharp drop in the risk of clinical worsening — a composite measure that includes all-cause death, unplanned PAH-related hospitalisations, atrial septostomy, lung transplant or disease progression — Merck reported that only 10.6% of Winrevair-treated patients in the study experienced at least one clinical worsening event versus 36.9% on placebo. The company said Kaplan-Meier curves separated quickly and stayed apart, with patients showing a treatment benefit just six weeks after randomisation.Secondary endpoints showed 29.4% of Winrevair-treated patients achieved multicomponent improvement — including six-minute walk distance, NT-proBNP levels and functional class — versus 14.6% on placebo. Additionally, 60.1% maintained or achieved a low REVEAL Lite 2 risk score relative to baseline at week 24, compared with 47.9% on placebo. The drug did not reach statistical significance on the simplified French risk score.On the safety front, HYPERION mirrored what had been seen in earlier studies. Serious adverse events occurred in 24.4% of Winrevair patients versus 28.1% in the placebo arm.Moving to front-line?At the Morgan Stanley Annual Global Healthcare Conference earlier this month, Chief Medical Officer Eliav Barr offered a preview of the HYPERION results. "I think this will fill a really important gap," he said, "right at the time that physicians are thinking, 'I'm feeling a lot more comfortable with Winrevair. Now I really want to try to get to my earlier patients.'"Still, not everyone is convinced that the drug, developed under a licensing deal with Bristol Myers Squibb, will become the go-to first-line therapy for PAH. "The company will gain momentum and confidence as more studies turn out positive, but it is hard to compete with generics that are so cheap," said Adriano Tonelli, a pulmonary medicine specialist at Cleveland Clinic, in a recent interview with FirstWord.Merck could have "taken a little more risk and looked at [Winrevair] as the first medication, before even the oral. They could have compared it against something like a combination of tadalafil plus ambrisentan," Tonelli said, noting that HYPERION, with its requirement that patients be on some kind of background therapy, "is getting close to that, but not fully jumping in" front-line use.