Sotatercept for PAH Maintains Safety, Reduced Mortality in Long-Term Follow-Up

The activin signaling inhibitor sotatercept (Winrevair; Merck) not only maintained a consistent safety profile over a median 2.5 years of follow-up in individuals with pulmonary arterial hypertension (PAH), but also significantly reduced mortality compared with placebo, according to analyses presented at the American Thoracic Society (ATS) 2025 International Conference.

Sotatercept Reduces Mortality Risk by 85%

In the STELLAR Phase 3 trial (NCT04576988), 323 patients were randomized to sotatercept (n = 163) or placebo (n = 160).¹ Those who completed the study could enroll in the open-label SOTERIA extension study (NCT04796337), with 153 patients on sotatercept and 143 on placebo rolling over to SOTERIA.²

In one analysis at ATS 2025, researchers looked at mortality data from 15,680 person-weeks of risk exposure in the sotatercept arm, 14,633 person-weeks in the unadjusted placebo arm, and 7576 person-weeks in the rank-preserving structural failure time (RPSFT)–adjusted placebo arm.³ There were 3 deaths recorded in the sotatercept group and 11 among placebo recipients.

Exposure-adjusted event rates favored sotatercept, with 0.06 fewer deaths per 100 person-weeks compared with unadjusted placebo (0.02 vs 0.08) and 0.09 fewer compared with RPSFT-adjusted placebo (0.02 vs 0.11). Median survival was not reached, but the risk of mortality dropped by 85% for patients on sotatercept (HR, 0.17; 95% CI, 0.03-0.90; P = .037).

“In this analysis of two Phase 3 trials, sotatercept was shown to significantly reduce the risk of death compared to placebo,” the researchers said. “Future analyses of longer-term sotatercept exposure are warranted once all on-going trials are completed and unblinded.”

These findings echo those from the phase 3 ZENITH trial presented at the American College of Cardiology 2025 Annual Scientific Session.⁴ At about 10 months of follow-up, patients taking sotatercept saw a 76% relative risk reduction of the composite of major morbidity and mortality events compared with patients taking placebo (HR, 0.24; 95% CI, 0.13-0.43; P < .0001) despite maximal background therapy. The SOTERIA research team anticipates the trial to be complete in 2031.²

Sotatercept Safety Maintained at 2.5 Years

Safety data were derived from 431 patients across the STELLAR, SOTERIA, PULSAR (NCT03496207), and SPECTRA (NCT03738150) trials—all 4 funded by Acceleron Pharma, owned by Merck—totaling 1206 person-years at the most recent data cutoff of August 15, 2024.⁵ The analysis presented at ATS 2025 calculated time-at-risk exposure-adjusted incidence rates (TAR-EAIRs) for treatment-emergent adverse events (TEAEs), with a median of 2.5 years of exposure and the longest exposure time surpassing 6 years. Without treatment, the 5-year survival rate of PAH is about 57%, and this drops below 50% at 7 years.⁶

Participants received subcutaneous sotatercept at a target dose of up to 0.7 mg/kg every 3 weeks in addition to background PAH therapies.⁵ Investigators followed participants from the initiation of sotatercept—either in the parent trial or upon rollover into SOTERIA—until treatment discontinuation plus a 21-day safety window or until one of the data cutoffs.

Rates of serious TEAEs such as serious bleeding events, epistaxis or nosebleeds, increased hemoglobin, thrombocytopenia, and thrombotic events, remained stable across 3 data checkpoints in December 2022, November 2023, and August 2024. The study also previously reported common nonserious AEs like hemoglobin elevations, mild thrombocytopenia, telangiectasia, and bleeding, which are associated with the mechanism of activin-ligand pathway modulation. According to the researchers, this mirrors the manageable safety profile previously reported in STELLAR.

“In conjunction with preliminary data demonstrating durability of efficacy, these exposure-adjusted safety data from a pooled dataset support that the positive benefit-risk profile of sotatercept is maintained with longer-term treatment,” the investigators said.

References

1. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/​A011-11) (STELLAR). https://clinicaltrials.gov/study/NCT04576988. Updated September 19, 2024. Accessed May 29, 2025.
2. A Long-term Follow-up Study of Sotatercept for PAH Treatment (MK-7962-004/​A011-12) (SOTERIA). https://clinicaltrials.gov/study/NCT04796337. Updated May 1, 2025. Accessed May 29, 2025.
3. Thakur T, Chevure J, Watzker A, Lautsch D. Overall survival of patients on sotatercept: an analysis of STELLAR and SOTERIA trials. Presented at: ATS 2025 International Conference; May 19, 2025; San Francisco, CA. https://www.atsjournals.org/doi/10.1164/ajrccm.2025.211.Abstracts.A4975
4. Klein HE. Sotatercept reduces risk of death, transplant, or hospitalization in advanced PAH. AJMC®. March 31, 2025. Accessed May 29, 2025. https://www.ajmc.com/view/sotatercept-reduces-risk-of-death-transplant-or-hospitalization-in-advanced-pah
5. Preston IR, Gomberg-Maitland M, Hoeper MM, et al. Long-term safety and exposure-adjusted incidence rates of adverse events from pooled sotatercept studies (PULSAR, SPECTRA, STELLAR, and SOTERIA). Presented at: ATS 2025 International Conference; May 19, 2025; San Francisco, CA. https://www.atsjournals.org/doi/10.1164/ajrccm.2025.211.Abstracts.A4981
6. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448-456. doi:10.1378/chest.11-1460