Baseline RV Dysfunction May predict Sotatercept response in PAH

Patients with pulmonary arterial hypertension (PAH) and worse baseline right ventricular ejection fraction (RVEF) had greater RVEF and pulmonary vascular resistance (PVR) improvements after 24 weeks of sotatercept, according to a 20-patient analysis presented at the American College of Chest Physicians (CHEST) 2026 Annual Meeting, held October 18 to 21 in Phoenix, Arizona.¹

Sotatercept (Winrevair), a first-in-class activin signaling inhibitor, reduced PVR and improved exercise capacity vs placebo when added to background therapy in the phase 3 STELLAR trial.² Determinants of individual response remain incompletely defined, and the current analysis sought clinical and physiologic factors associated with benefit.¹ The findings are from a conference abstract and have not yet been published in a peer-reviewed journal.

"The therapeutic effects of sotatercept appear most pronounced in patients with advanced RV dysfunction, suggesting that baseline RV phenotype may help inform treatment selection," wrote Eduardo A. Garcia Licerio, MD, and colleagues.¹

Sotatercept effects on RVEF and PVR by baseline right ventricular function

Investigators analyzed 20 participants with PAH from an open-label phase 2b trial evaluating sotatercept effects on exercise performance and RV function.¹ RVEF and PVR were measured at baseline and 24 weeks with cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing.¹ Response was defined as change above the cohort median in RVEF and PVR.¹

At baseline, median RVEF was 33.8% in responders and 46.5% in nonresponders.¹ Median baseline PVR was 7.9 Wood units (WU; interquartile range [IQR], 4.4-9.6) in responders and 14.2 WU (IQR, 13.2-20.3) in nonresponders.¹

After 24 weeks, median RVEF increased by 10.7% in responders and declined by 3.2% in nonresponders.¹ Median PVR fell by 6.7 WU in responders vs 1.1 WU in nonresponders.¹ The abstract did not report P values for these primary comparisons.

Secondary markers of sotatercept response in PAH

Responders had larger median reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP; −388.5 vs −99 pg/mL; P = .049), minute ventilation to carbon dioxide output (VE/VCO2) slope (−8 vs 0; P = .035), and right-to-left ventricular volume ratio (−0.430 vs −0.068; P = .024).¹

Changes in right ventricular mass-to-volume ratio (0.078 vs 0.019; P = .949) and right-to-left ventricular mass ratio (−0.166 vs −0.064; P = .180) did not differ between groups.¹ No significant differences in response were observed after stratification by age, sex, comorbidities, or background PAH-targeted therapy.¹

The investigators concluded the magnitude of benefit was proportional to the severity of baseline RV dysfunction, suggesting response relates more closely to preexisting RV impairment than to afterload alone.¹ They called for larger studies to validate predictors of response.¹

The analysis included 20 patients, and responder status was defined by a median split within the cohort, so half of participants were classified as responders by design. Patients with lower baseline RVEF also had more room for improvement, and the abstract did not report adjustment for multiple comparisons across the secondary measures.

The FDA updated the sotatercept label in September 2026 to include phase 3 HYPERION data in adults diagnosed with PAH within the past year.³

References

1. Garcia Licerio EA, Rischard FP, Vanderpool R, et al. Identifying predictors of response to sotatercept in individuals with pulmonary arterial hypertension. CHEST. 2026;170(4S). doi:10.1016/j.chest.2026.07.5113

2. Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558

3. HCPLive. FDA updates sotatercept label with HYPERION data in early PAH. https://www.hcplive.com/view/fda-updates-sotatercept-label-with-hyperion-data-in-early-pah. Published September 22, 2026. Accessed November 3, 2026.