• Among adults with a Winrevair dispense, more had Group 2/3 PH vs. Group 1 PAH.
• The adjusted risks for hospitalization and an ED visit were significantly increased in those with Group 2/3 PH vs. Group 1 PAH.

The risk for mortality and gastrointestinal/serious hemorrhage among Winrevair recipients did not differ between those with Group 2/3 pulmonary hypertension and those with pulmonary arterial hypertension, according to study results.

These real-world findings were presented as a poster at the European Respiratory Society International Congress.

“For the practicing clinician, these findings provide valuable real-world evidence regarding how sotatercept is being incorporated into routine pulmonary hypertension (PH) management,” Parth M. Rali, MD, FCCP, director of the Temple University Health System pulmonary embolism response team program and professor of thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, told Healio. “Clinical trials often enroll highly selected patients, whereas everyday practice involves patients with overlapping phenotypes, multiple comorbidities and varying degrees of disease severity.

“This analysis offers reassurance that the safety profile remains consistent in broader patient populations and highlights how clinicians are adapting novel therapies to address unmet needs,” Rali, also a member of Healio Pulmonology’s Peer Perspective Board, said. “It also reinforces the concept that PH is increasingly being viewed through a biologic and pathophysiologic lens rather than strictly through traditional WHO classification systems.”

Using the TriNetX Collaborative Research Network, Rali and colleagues evaluated 590 adults with a sotatercept (Winrevair, Merck) dispense after FDA approval to determine if the risks for hospitalization, ED visit, mortality, GI/serious hemorrhage and thrombocytopenia differ based on WHO Group 1 PAH vs. Group 2/3 PH (overlapping left heart disease and/or lung disease codes).

The major trials studying Winrevair (PULSAR, STELLAR, ZENITH) have rarely included patients with Group 2/3 phenotypes, according to the poster.

The FDA approved Winrevair for treating adults with Group 1 PAH in March 2024.

“The majority of prescribing remains within that population,” Rali told Healio. “However, in real-world clinical practice, the distinction between PH phenotypes is often less clear-cut than in clinical trials. We frequently encounter patients with overlapping features, particularly those with connective tissue disease-associated PH, where elements of Group 1 PAH may coexist with parenchymal lung disease or other contributors to PH.

“Because sotatercept has a novel mechanism of action targeting activin signaling pathways rather than acting as a traditional pulmonary vasodilator, many clinicians view it differently from conventional PAH therapies,” he continued. “The absence of significant vasodilatory effects has generated interest in exploring its potential role beyond classic Group 1 PAH.”

The studied population included more patients with Group 2/3 PH vs. Group 1 PAH (n = 413 [70%] vs. n = 177 [30%]). Within the mixed phenotype group, 191 (32%) had Group 2 PH, 182 (31%) had Group 3 PH and 40 (7%) had both Group 2 and 3 PH.

“The most notable finding was the degree to which clinicians are already adopting sotatercept across a broader spectrum of PH phenotypes in routine practice,” Rali said. “This reflects an unmet clinical need, particularly among patients who have limited therapeutic options despite substantial symptom burden and healthcare utilization.

“These findings parallel the growing scientific interest in extending sotatercept beyond Group 1 PAH,” Rali added. “Recent phase 2 data in Group 2 PH have shown promising signals, suggesting that the biologic pathways targeted by sotatercept may have relevance across multiple forms of pulmonary vascular disease.”

Compared with those with Group 1 PAH, researchers found that those with off-label phenotypes were older (median age, 58 years vs. 47 years) and had a higher proportion of patients on the background therapies of furosemide (44.8% vs. 35%), spironolactone (38.7% vs. 23.7%) and heparin/LMWH (49.9% vs. 22%).

Further, a larger proportion of those with Group 2/3 PH vs. Group 1 PAH used the following antithrombotic therapies: aspirin (19.6% vs. 7.3%), apixaban (14.8% vs. 6.8%) and clopidogrel (5.3% vs. 0%).

Those with Group 2/3 PH vs. Group 1 PAH also had significantly (P < .001) higher prevalences of various comorbidities:

• hypertension (82% vs. 53%);
• heart failure (90% vs. 59%);
• coronary artery disease (52% vs. 24%);
• COPD (36% vs. 0%);
• interstitial lung disease/pulmonary fibrosis (32% vs. 0%);
• chronic kidney disease (36% vs. 11%);
• connective tissue disease (32% vs. 15%);
• diabetes mellitus (30% vs. 13%);
• atrial fibrillation (26% vs. 13%);
• sleep apnea (57% vs. 37%);
• obesity (46% vs. 26%); and
• venous thromboembolism/pulmonary embolism history (28% vs. 11%).

In contrast, the proportion of patients with new pericardial effusion was comparable between the groups (mixed phenotype, 3.6% vs. Group 1 PAH, 3.4%).

In a model adjusted for age, sex and antithrombotic use, researchers observed a significantly increased risk for an ED visit 365 days after starting sotatercept among those with Group 2/3 PH vs. Group 1 PAH (aHR = 1.82; 95% CI, 1.27-2.61). This was also the case for all-cause hospitalization, as the mixed phenotype group had a significantly greater risk for this outcome (aHR = 1.43; 95% CI, 1.07-1.91).

“The utilization signal may reflect greater baseline cardiopulmonary burden rather than differential drug toxicity,” Rali and colleagues wrote on the poster.

The adjusted risks for all-cause mortality, GI/serious hemorrhage and thrombocytopenia did not significantly differ between those with Group 2/3 PH and those with Group 1 PAH.

“The safety findings were reassuring,” Rali said. “The propensity-matched analysis suggests that the safety profile observed in clinical trials is generally being reproduced in real-world settings across different phenotype groups.

“While ongoing surveillance remains important, it is encouraging to see that real-world experience aligns with what was demonstrated in the pivotal PAH studies,” he said.

Looking ahead, Rali told Healio studies will assess different outcomes over longer time periods.

“Future studies will likely move beyond short-term improvements in exercise capacity and hemodynamics and focus increasingly on meaningful long-term clinical outcomes,” Rali said. “Event-driven endpoints such as time to clinical worsening, hospitalization rates, disease progression and survival will become increasingly important.

“Additionally, future research will need to evaluate the durability of treatment benefit over extended periods and further characterize the long-term safety profile, including monitoring for known adverse effects and any emerging safety signals that may become apparent with broader use,” he continued.

Rali also noted that non-Group 1 PAH populations are being investigated in upcoming studies.

“Following encouraging phase 2 results in Group 2 PH, a phase 3 trial has been announced,” he said. “This represents a significant development for the PH community because effective therapies for Group 2 PH remain limited. These studies may ultimately help determine whether sotatercept’s benefits extend across a wider range of pulmonary vascular disorders.”

Parth M. Rali, MD, FCCP, can be reached at parth.rali@tuhs.temple.edu.