Sotatercept

Activin receptor type IIA-Fc fusion protein approved by the FDA on March 26, 2024 as Winrevair (sotatercept-csrk) for pulmonary arterial hypertension, with later label updates from the ZENITH and HYPERION outcome trials.

Also referenced as: Sotatercept-csrk, ACE-011, MK-7962, Winrevair, Airwin

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What is Sotatercept?

Sotatercept is not a peptide. It is a recombinant fusion protein: a homodimer in which the extracellular domain of the human activin receptor type IIA (ActRIIA) is joined to the Fc domain of human immunoglobulin G1, about 78 kDa as a dimer according to the US label. The receptor domain is a soluble ligand trap for activin A and related transforming growth factor-beta superfamily ligands, while the Fc domain gives the molecule an antibody-like half-life. The US biologic is named sotatercept-csrk; the four-letter suffix is the FDA’s distinguishing tag for biologics and has no structural meaning.

Acceleron Pharma developed the molecule as ACE-011, first as a bone-anabolic agent, then for anemia, and finally, under Merck, as MK-7962 for pulmonary arterial hypertension (PAH). The FDA approved it as Winrevair on March 26, 2024 under BLA 761363 for adults with PAH (WHO Group 1 pulmonary hypertension), the first activin signaling inhibitor approved for that disease, and the label was expanded in 2025 and 2026 with outcome data from ZENITH and HYPERION. Its relatives include ACE-031, an ActRIIB-Fc fusion built for muscle, luspatercept, a modified ActRIIB-Fc approved for anemia, and the native regulator myostatin propeptide. Sotatercept has no presence in the research-peptide market.

How it works

• Traps activin and GDF ligands to rebalance SMAD signaling. PAH involves loss of bone morphogenetic protein (BMP) receptor II signaling and excess activin and growth differentiation factor signaling through shared SMAD effectors. GDF8, GDF11 and activin A are overexpressed in PAH lung lesions, and ActRIIA-Fc blocked their SMAD2/3 activation in vascular cells, reduced proliferation of pulmonary arterial smooth muscle and endothelial cells, and in rodent models improved hemodynamics, right ventricular hypertrophy and arteriolar remodeling, outperforming a vasodilator in a vasculoproliferative model (Yung et al., Science Translational Medicine, 2020;12(543):eaaz5660). The US label describes the same rebalancing of ActRIIA/SMAD2/3 against BMPRII/SMAD1/5/8 signaling. GDF-11 is among the ligands it neutralizes.
• Erythropoietic and bone effects are built into the target. In 31 healthy postmenopausal women, subcutaneous sotatercept at 0.1 to 1 mg/kg every 28 days produced dose-dependent increases in hemoglobin, hematocrit and red cell counts lasting up to 4 months, raised bone mineral density and bone-formation markers, and showed a mean terminal half-life of about 23 days (Sherman et al., Journal of Clinical Pharmacology, 2013;53(11):1121–1130). The label gives an effective half-life of about 24 days.
• Benefits beyond the pulmonary vasculature. A phase 4 study (NCT06409026) in 30 PAH patients with invasive exercise catheterization found that 24 weeks of sotatercept lowered pulmonary vascular resistance by 2.6 Wood units and mean pulmonary artery pressure by 12.5 mm Hg, improved right ventricle–pulmonary artery coupling, and raised hemoglobin by 1.7 g/dL through plasma-volume contraction rather than red cell mass, with greater skeletal muscle oxygen delivery (Reddy et al., Journal of the American College of Cardiology, 2026;88(4):415–432).

Research status

Early programs in bone, anemia and myeloma. The first human study was a single-dose trial of ACE-011 in postmenopausal women (Ruckle et al., Journal of Bone and Mineral Research, 2009;24(4):744–752). A phase 2a trial in 30 myeloma patients with osteolytic lesions found anabolic bone effects and higher hemoglobin, but 71% of sotatercept-treated patients needed dose interruptions, mostly for rising hemoglobin (Abdulkadyrov et al., British Journal of Haematology, 2014;165(6):814–823). In 74 transfusion-dependent patients with lower-risk myelodysplastic syndromes, 49% achieved erythroid hematologic improvement (Komrokji et al., Lancet Haematology, 2018;5(2):e63–e72). None of the hematologic indications reached a filing; luspatercept became the approved anemia product, and sotatercept was redirected to PAH.

PULSAR, phase 2 (NCT03496207). In 106 adults on background PAH therapy randomized to sotatercept 0.3 mg/kg, 0.7 mg/kg or placebo every 3 weeks for 24 weeks, the placebo-adjusted change in pulmonary vascular resistance was −145.8 dyn·s·cm⁻⁵ (P = 0.003) and −239.5 dyn·s·cm⁻⁵ (P<0.001), with 6-minute walk distance differences of 29.4 and 21.4 m; one patient in the 0.7 mg/kg group died of cardiac arrest (Humbert et al., New England Journal of Medicine, 2021;384(13):1204–1215). The single-arm SPECTRA study (NCT03738150) in 21 patients recorded a mean peak oxygen uptake gain of 102.74 mL/min at week 24 (Waxman et al., Circulation: Heart Failure, 2024;17(5):e011227).

STELLAR, phase 3 (NCT04576988). The pivotal trial randomized 323 adults with WHO functional class II or III PAH on stable background therapy to sotatercept titrated to 0.7 mg/kg or placebo every 3 weeks. The median change in 6-minute walk distance at week 24 was 34.4 m with sotatercept and 1.0 m with placebo, a Hodges-Lehmann difference of 40.8 m (95% CI 27.5 to 54.1; P<0.001); eight of nine hierarchically tested secondary endpoints were met, including pulmonary vascular resistance, NT-proBNP, functional class and time to death or clinical worsening (Hoeper et al., New England Journal of Medicine, 2023;388(16):1478–1490). The US label reports an 84% reduction in death or clinical worsening events through the data cutoff.

ZENITH, phase 3 (NCT04896008). In 172 patients with functional class III or IV PAH and a REVEAL Lite 2 score of 9 or more on maximum tolerated background therapy, the composite of death, lung transplantation or hospitalization of at least 24 hours for worsening PAH occurred in 15 patients (17.4%) on sotatercept versus 47 (54.7%) on placebo (hazard ratio 0.24; 95% CI 0.13 to 0.43; P<0.001); deaths were 8.1% versus 15.1% and lung transplants 1.2% versus 7.0%. The trial was stopped early at a prespecified interim analysis for efficacy (Humbert et al., New England Journal of Medicine, 2025;392(20):1987–2000). The FDA approved the ZENITH-based labeling revision and indication expansion on October 24, 2025.

HYPERION, phase 3 (NCT04811092). The trial enrolled 320 adults diagnosed with PAH less than 1 year earlier, at intermediate or high risk on double or triple therapy, and was terminated early for loss of clinical equipoise with 76 of 121 planned events. Clinical worsening occurred in 17 patients (10.6%) on sotatercept versus 59 (36.9%) on placebo (hazard ratio 0.24; 95% CI 0.14 to 0.41; P<0.001) over a median 13.2 months, driven by deterioration in exercise testing (5.0% versus 28.8%) and hospitalization (1.9% versus 8.8%); deaths were 4.4% versus 3.8%, and epistaxis and telangiectasia were the most common adverse events (McLaughlin et al., New England Journal of Medicine, 2025;393(16):1599–1611). The FDA added HYPERION to the label on September 21, 2026.

SOTERIA long-term extension (NCT04796337). At the November 8, 2023 cutoff, 426 participants from earlier trials had a mean 448.6 days of exposure (523 patient-years); 3.5% discontinued, 12 (2.8%) died, 5.2% had serious bleeding, and gains in walk distance, NT-proBNP and functional class were largely maintained at 1 year (Preston et al., European Respiratory Journal, 2025;66(1):2401435). The registry lists 815 estimated participants and primary completion on December 7, 2028.

Other populations. CADENCE (NCT04945460), a phase 2 trial in 164 patients with combined post- and precapillary pulmonary hypertension due to heart failure with preserved ejection fraction, met its primary endpoint with placebo-adjusted pulmonary vascular resistance changes of −1.02 Wood units (P = 0.004) at 0.3 mg/kg and −0.75 Wood units (P = 0.024) at 0.7 mg/kg but only modest walk-distance changes (Gomberg-Maitland et al., Circulation, 2026;153(19):1446–1459). A placebo-controlled phase 3 trial in that population (NCT07839585), planned for 352 participants with primary completion estimated for January 8, 2030, is registered but not yet recruiting. A single-arm Japanese phase 3 study in 46 patients (NCT05818137) cut pulmonary vascular resistance by 99.2 dyn·s·cm⁻⁵ and raised walk distance 41.8 m (Matsubara et al., JACC: Asia, 2026;6(3):297–309). A phase 2 pediatric study in children aged 1 to under 18 (NCT05587712) is recruiting, with primary completion estimated for September 21, 2028.

Regulatory status abroad. The European Commission authorized Winrevair on August 22, 2024 after a June 27, 2024 CHMP opinion; the EU indication now covers functional class II, III and IV in combination with other PAH therapies. Health Canada issued a Notice of Compliance on August 28, 2024 for class II or III and on December 3, 2025 extended it to class IV patients at high risk of mortality. Swissmedic authorized the product on September 13, 2024 through the Access Consortium review. In Japan, MSD K.K. applied on November 14, 2024 and Airwin for Subcutaneous Injection was approved in June 2025.

Common dosage forms

• Winrevair for injection, 45 mg and 60 mg single-dose vials. A sterile, preservative-free lyophilized powder supplied in one-vial and two-vial kits (45 mg, 60 mg, 90 mg and 120 mg) for subcutaneous injection; the label allows administration by a healthcare provider, the patient or a caregiver.
• Airwin for Subcutaneous Injection, 45 mg and 60 mg. The Japanese presentation of the same lyophilized vial product.
• No other presentation. No pen, intravenous or oral form exists.

Key considerations

• Regulatory status. The FDA Approved status reflects the March 26, 2024 approval of Winrevair (sotatercept-csrk) for injection under BLA 761363 for adults with pulmonary arterial hypertension (WHO Group 1). ZENITH and HYPERION data were added to the label on October 24, 2025 and September 21, 2026, the latter revision also adding a contraindication for serious hypersensitivity, and the product is also authorized in the EU, Canada, Switzerland and Japan.
• Bleeding and vascular signals track the mechanism. Serious bleeding was more frequent than placebo in every phase 3 trial, and angiodysplasia-related bleeding has been reported post-marketing. A FAERS analysis found consistent signals plus pulmonary arteriovenous fistula and pericardial effusion (Zhang et al., Cardiovascular Toxicology, 2026;26(1):12), although clinically significant pericardial effusions were uncommon and equally frequent with placebo in STELLAR and ZENITH (Hoeper et al., European Respiratory Journal, 2025;66(3):2500768).
• Hematologic monitoring is intrinsic to the drug. Because ActRIIA ligand trapping stimulates erythropoiesis, hemoglobin excursions and thrombocytopenia are expected class effects rather than idiosyncratic ones, and the label ties dosing to blood counts. Anti-drug antibodies were common in all three phase 3 trials without a detectable effect on efficacy.
• An add-on, not a replacement. Every PAH trial tested sotatercept on top of background therapy, and the EU label makes combination use part of the indication. The trials excluded HIV-, portal hypertension- and veno-occlusive disease-associated PAH, and the heart-failure population has only phase 2 hemodynamic data pending the phase 3 trial.
• Naming. ACE-011, MK-7962, sotatercept, sotatercept-csrk, Winrevair and Airwin all denote the same ActRIIA-Fc fusion protein. It is distinct from luspatercept (Reblozyl), an ActRIIB-based trap approved for anemia, from ACE-031, and from cibotercept, a separate ActRIIB ligand trap.