HYPERION: Sotatercept Helps in PAH Even When Started Earlier in the Disease

Sotatercept-csrk (Winrevair; Merck Sharp & Dohme) added on top of standard therapies improves outcomes in patients who are less than a year out from a diagnosis of pulmonary arterial hypertension (PAH), according to findings from the HYPERION trial.

The rate of clinical worsening was significantly lower in patients treated with the first-in-class activin-signaling inhibitor versus placebo (10.6% vs 36.9%; HR 0.24; 95% CI 0.14-0.41), driven by less deterioration in exercise performance and a reduction in unplanned hospitalizations for worsening PAH

Vallerie McLaughlin, MD (University of Michigan, Ann Arbor), reported the data Tuesday at the European Respiratory Society Congress in Amsterdam, the Netherlands. The results were “markedly positive,” McLaughlin told TCTMD, noting that there was an “early and sustained separation of the Kaplan-Meier curves.” At 12 months, the number needed to treat was just five.

There are very good data on many of the therapies used for PAH, and getting patients on those established treatments remains the first step, she said. Where sotatercept will come into play is if it’s determined patients need something more after being reevaluated several months after being on these other therapies.

“If a patient is not meeting our treatment goals, if they have not improved to the point where they fall into what we call the low-risk category, which portends a better prognosis, we think about whether or not they would benefit from an additional drug,” McLaughlin said. “I think the data from HYPERION helps inform that decision. It gives some more data to that decision of what are the options to add in a patient who’s not meeting their goals on initial therapy.”

The results, published simultaneously in the New England Journal of Medicine, expands on the positive findings from other phase III trials of sotatercept—ZENITH and STELLAR—that included patients with more long-standing disease treated with standard PAH therapies like endothelin-receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin-pathway agents. The US Food and Drug Administration approved sotatercept for the treatment of PAH based on the STELLAR results in March 2024.

Until HYPERION, however, it had remained unclear what impact the drug, which is delivered subcutaneously every 3 weeks, would have in patients who initiated therapy within the first year after diagnosis. In addition, HYPERION included a population that was older, had more comorbidities, and was on less-aggressive background therapy compared with ZENITH and STELLAR, which is “more reflective of a contemporary population,” McLaughlin said.

Hooman Poor, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who was not involved in the trial, said “sotatercept is a wonder drug” that has “revolutionized” the treatment and prognosis of PAH patients.

He noted that prior positive trials with the drug included patients living with PAH for many years. “It’s an exceptionally exciting drug from that standpoint in that in patients who are advanced and sick, even the most advanced and most sick, it can have dramatic, jaw-dropping effects,” said Poor.

When considering using sotatercept earlier in the course of the disease, the side effects that have been observed—like nosebleeds, telangiectasia, and, in more recent reports, pericardial effusions and intrapulmonary bubble transport—become even more important, Poor indicated. “If it were a drug without any risk, people would be super excited just to use it [earlier] as well, but it’s sort of this risk-benefit scenario.”

Still, he said, “I think this is going to highlight that this drug is important and should be considered earlier in the use of PAH patients, not just after we’ve gone through all the other available therapies.”

Trial Stopped Early

HYPERION included patients who were diagnosed with World Health Organization functional class II or III group 1 PAH in the year before enrollment, had an intermediate or high risk of death, and were on stable doses of double or triple background therapy for at least 90 days before screening. The trial was stopped early due to loss of equipoise based largely on a prespecified interim analysis of the ZENITH trial that showed a clinically meaningful reduction in morbidity and mortality with sotatercept.

HYPERION ultimately included 320 patients (mean age 56 years; 73% women) randomized to add-on therapy with subcutaneous sotatercept—started at 0.3 mg/kg body weight and escalated to a target dose of 0.7 mg/kg—or placebo given every 21 days. At baseline, the mean time from PAH diagnosis was 7.2 months.

The primary endpoint was clinical worsening, a composite of all-cause death, unplanned hospitalization for worsening of PAH lasting at least 24 hours, atrial septostomy, lung transplantation, or deterioration in exercise testing performance due to PAH. Through a median follow-up of 13.2 months, sotatercept-treated patients were significantly less likely to meet this endpoint, with consistent results across subgroups.

Though statistical comparisons weren’t performed for the individual components of the composite endpoint, patients treated with sotatercept were less likely than those receiving placebo to have a deterioration in exercise performance due to PAH (5.0% vs 28.8%) and to have an unplanned hospitalization due to worsening disease (1.9% vs 8.8%). The rate of all-cause death was similar in the two groups (4.4% and 3.8%, respectively, in the sotatercept and control arms), and there were no cases of atrial septostomy or lung transplantation.

The two main drivers of the difference in the primary endpoint “are considered to be important because nonfatal clinical worsening events in patients with pulmonary arterial hypertension are associated with an increased risk of subsequent death, a relationship underscoring the need to monitor and prevent disease progression in these patients,” the researchers say.

With any drug, with any decision, one needs to think about the potential for benefit and the potential for harm. Vallerie McLaughlin

McLaughlin said the safety profile of sotatercept in HYPERION was consistent with that in prior trials. Nosebleeds (31.9% vs 6.9%) and telangiectasia (26.2% vs 11.2%) were more frequent with active treatment than with placebo, as were adverse events deemed to be related to treatment (57.5% vs 30.0%) and overall bleeding events (41.2% vs 16.2%). The rate of adverse events leading to discontinuation, however, was just 3.1% with active treatment (versus 0 with placebo).

“With any drug, with any decision, one needs to think about the potential for benefit and the potential for harm, and that’s a patient-by-patient decision,” McLaughlin said. Factors to be considered include disease severity, functional limitations, echocardiographic findings, hemodynamics, bleeding history, anticoagulant use, and others, she said. “I’m not saying this is for everyone. I’m saying it’s a thoughtful decision that needs to be taken up by the patient and their physician weighing the potential for benefit and the potential for risk.”

Getting More Comfortable With Sotatercept

HYPERION “provides us, essentially, with rationale to initiate this therapy earlier in patients and have that discussion because now we have at least the benefit standpoint of it,” Poor said, adding that it’s noteworthy that unplanned hospitalizations for worsening PAH were reduced because they “usually mean things are pretty bad.”

There was very little risk associated with using the drug in this earlier time period, he said, adding, however, that an assessment of longer-term risks will be important. That information, he said, comes from other studies and will also come from SOTERIA, the long-term extension trial.

For now, the HYPERION results don’t change how Poor will use the drug, partly, he said, “because I am already a huge proponent of the therapy.”

What is slowing uptake for some, Poor said, is that the trials were designed to add sotatercept to regimens that already included two or three drugs, leading physicians in practice to follow that approach.

With about 70% of patients in HYPERION on only dual therapy when they entered the trial, “it’s asking the question of should we move this therapy up in the line of treatment before initiating a prostacyclin for many of these patients,” Poor said. “I already have made that switch. But this may give additional support to consider that as an earlier-line therapy rather than waiting for later. Because I think many people are still hesitant about it, especially with respect to the risks.”

Overall, he added, “people are getting more comfortable with its use. I think people are seeing the real-life effects of it and how it has transformed the lives of these patients.”