Sotatercept

What is Sotatercept?

Sotatercept (Winrevair, sotatercept-csrk) is a recombinant fusion protein composed of the extracellular ligand-binding domain of human activin receptor type IIA (ActRIIA) linked to the Fc region of human IgG1. Originally developed by Acceleron Pharma as ACE-011 — initially for bone biology and ineffective erythropoiesis — the molecule was repositioned around the discovery that activin-pathway hyperactivity is a central driver of the pathologic vascular remodeling in pulmonary arterial hypertension (PAH). Sotatercept is FDA-approved as Winrevair, marketed by Merck (which acquired Acceleron in November 2021 for approximately $11.5 billion, with sotatercept as the lead asset), for the treatment of adults with pulmonary arterial hypertension (WHO Group 1, functional class II–III) to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events. The first-in-class designation reflects sotatercept being the first activin signaling inhibitor approved for any indication and the first PAH therapy that targets the underlying vascular biology of pulmonary arteriolar remodeling rather than the three established vasodilator pathways (endothelin, nitric oxide, prostacyclin). FDA approval was granted on March 26, 2024, on the basis of the Phase 3 STELLAR trial. Subsequent label-supporting evidence from the ZENITH trial (in patients at high risk of death with WHO functional class III–IV disease) extended sotatercept's evidence base to a sicker population, with an 84% relative risk reduction in the composite primary endpoint (death, lung transplantation, or hospitalization for worsening PAH) compared with placebo.

What Sotatercept Is Investigated For

Sotatercept's clinical evidence is unusual for a recently-approved therapy in that it has produced first-of-its-kind effect sizes against an established standard of care. The pivotal STELLAR trial (Hoeper et al., NEJM 2023) randomized 323 adults with PAH who were already on stable background therapy (mono-, double-, or triple-combination of endothelin receptor antagonists, PDE5 inhibitors or sGC stimulators, and prostacyclin pathway agents) to subcutaneous sotatercept every three weeks vs placebo. The primary endpoint — change in 6-minute walk distance from baseline at week 24 — improved by a median of 34.4 meters in the sotatercept group versus 1.0 meter in placebo (Hodges–Lehmann estimate of difference 40.8 m, P<0.001), with significant improvements in eight of nine prespecified secondary endpoints including multicomponent improvement (clinical worsening avoidance, NT-proBNP reduction, WHO functional class improvement). The Phase 2 PULSAR trial that preceded STELLAR (Humbert et al., NEJM 2021) had established proof-of-concept in 106 patients with significant pulmonary vascular resistance reductions and exercise-capacity improvements at 24 weeks. The ZENITH trial (Humbert et al., NEJM 2025) studied patients with WHO functional class III–IV PAH at high risk of mortality on background triple therapy; the composite primary endpoint of death, lung transplantation, or PAH-related hospitalization was met with an 84% relative risk reduction (HR 0.16) — an effect size unusual in advanced PAH, where most therapies have shown improvements in exercise capacity and hemodynamics but have not delivered hard outcome benefits of this magnitude. The SOTERIA long-term open-label extension (Preston et al., European Respiratory Journal 2025) reports interim efficacy and safety with multi-year exposure, with sustained 6-minute walk distance and hemodynamic improvements and a safety profile broadly consistent with the parent trials. The mechanistic story behind these effect sizes is that sotatercept addresses a different limb of PAH biology than the existing vasodilator classes: it rebalances pro-proliferative activin/TGF-β signaling against anti-proliferative BMP9/BMP10 signaling in the pulmonary vasculature, addressing the smooth-muscle and endothelial-cell hyperproliferation that drives vascular remodeling, rather than acting on vascular tone alone. The honest caveats are: the most clinically meaningful adverse events are mucocutaneous bleeding and telangiectasias (epistaxis, gingival bleeding), with the safety profile reflecting partial overlap with the BMP9/10-related vascular signal of the activin-receptor-trap class; thrombocytopenia and increased hemoglobin/hematocrit are dose-related and require monitoring; and sotatercept is a hospital/specialty-administered biologic with substantial annual list-price cost and limited real-world experience outside the trial populations.

History & Discovery

Sotatercept began life as ACE-011 at Acceleron Pharma, the same Cambridge, Massachusetts biotech that developed ACE-031 (wild-type ActRIIB-Fc, halted in DMD in 2011) and ACE-536 (luspatercept, modified ActRIIB-Fc, approved in β-thalassemia and MDS). ACE-011 — extracellular ActRIIA fused to IgG1 Fc — was originally explored for bone biology and ineffective erythropoiesis. The drug's repositioning into pulmonary arterial hypertension grew out of the recognition that activin-pathway hyperactivity is a central feature of pulmonary vascular remodeling, and that BMPR2 loss-of-function — the most common genetic driver of heritable PAH — produces exactly the activin/BMP imbalance that an activin-trap therapeutic could rebalance. The Phase 2 PULSAR trial (NCT03496207), published by Humbert and colleagues in NEJM in 2021, randomized 106 PAH patients on stable background therapy to subcutaneous sotatercept 0.3 or 0.7 mg/kg every three weeks vs placebo. The primary endpoint of pulmonary vascular resistance reduction at 24 weeks was met with statistically significant and clinically meaningful effect sizes, establishing the clinical rationale for advancing to Phase 3. The Phase 3 STELLAR trial (NCT04576988), published by Hoeper and colleagues in NEJM in April 2023, randomized 323 adults with PAH (WHO functional class II or III) on stable background mono-, double-, or triple-combination therapy to sotatercept (titrated from 0.3 to 0.7 mg/kg every three weeks) vs placebo. The primary endpoint — change in 6-minute walk distance from baseline at week 24 — was met with a Hodges–Lehmann estimate of difference of 40.8 m (P<0.001), and benefit was observed on eight of nine prespecified secondary endpoints including the multicomponent improvement endpoint, time to clinical worsening, NT-proBNP reduction, pulmonary vascular resistance reduction, and WHO functional class improvement. STELLAR served as the registrational trial supporting FDA approval of Winrevair on March 26, 2024 — the first new mechanism approved for PAH in over 15 years and the first activin signaling inhibitor approved for any indication. The Phase 3 ZENITH trial (NCT04896008), published by Humbert and colleagues in NEJM in May 2025, extended sotatercept's evidence base into a substantially sicker population: WHO functional class III or IV PAH at high risk of one-year mortality, on background triple therapy. The composite primary endpoint of death, lung transplantation, or PAH-related hospitalization was met with an 84% relative risk reduction (HR 0.16) versus placebo — a hard-outcome effect size that vasodilator-class therapies have not delivered in advanced PAH. The SOTERIA long-term open-label extension (Preston et al., European Respiratory Journal 2025) extends the safety and efficacy database with multi-year exposure. Merck's $11.5 billion acquisition of Acceleron Pharma in November 2021 was driven primarily by sotatercept and the unfolding STELLAR data; Reblozyl (luspatercept) had already been approved at the time of acquisition under the Celgene/BMS partnership and was not part of the Merck deal. The HYPERION trial (sotatercept in earlier-stage PAH), CADENCE trial (sotatercept in pulmonary hypertension associated with left heart disease, WHO Group 2), and additional studies in pediatric PAH and other forms of pulmonary hypertension are ongoing as of 2026.

How It Works

In pulmonary arterial hypertension, the small blood vessels in the lungs become abnormally thick and stiff over time. The cells that form their walls — smooth muscle and endothelium — keep dividing when they should be quiet. Two opposing signals control this balance: activin and BMP9/BMP10 are TGF-β superfamily proteins that, in healthy lungs, sit in equilibrium. In PAH, the activin (pro-growth) side gets too loud and the BMP9/10 (anti-growth) side gets too quiet — especially in patients with inherited BMPR2 mutations. Sotatercept is an engineered protein that floats in the bloodstream, binds activin A and related ligands, and prevents them from reaching the cell-surface receptors that drive the abnormal cell division. That tilts the balance back toward the quiet, anti-proliferative state and lets the pulmonary vessels remodel toward a healthier wall structure. It is the first PAH drug that targets the wall thickening directly rather than just relaxing the vessel.

Sotatercept is a recombinant homodimeric fusion protein composed of the extracellular ligand-binding domain of human activin receptor type IIA (ActRIIA) fused to the hinge-CH2-CH3 region of human IgG1 Fc. The Fc moiety supports homodimer formation (necessary for high-avidity ligand binding) and FcRn-mediated extended plasma half-life (supporting the every-three-weeks subcutaneous dosing schedule). In circulation, sotatercept binds and sequesters activin A, activin B, and (with reduced affinity) GDF11 and BMP9/BMP10, preventing them from engaging membrane-bound ActRII receptors on target cells. The pulmonary vascular pathology of PAH involves smooth-muscle and endothelial-cell hyperproliferation in the medium and small pulmonary arteries, producing the medial hypertrophy, intimal thickening, and plexiform lesions that characterize the disease. Two opposing TGF-β superfamily limbs regulate this proliferative balance: the activin/GDF arm signals through ActRII receptors paired with type I receptors (ALK4/ALK5) and downstream Smad2/3, driving smooth-muscle and endothelial proliferation; the BMP arm — particularly BMP9 (encoded by GDF2) and BMP10, signaling through endoglin (ENG), ALK1 (ACVRL1), and BMPR2 — drives Smad1/5/8 anti-proliferative and quiescence-promoting signaling. In PAH, this balance is disrupted: BMPR2 loss-of-function mutations are the most common genetic driver of heritable PAH (>70% of heritable cases), and even idiopathic and associated forms show reduced BMP9/BMPR2 signaling and increased activin/Smad2/3 signaling. Sotatercept's pharmacology rebalances this signaling axis by sequestering activin ligands. The net effect is reduced Smad2/3-driven proliferation and a relative restoration of BMP-pathway dominance — even in BMPR2-mutant patients, where the BMP-pathway signal is genetically reduced, lowering the activin counter-signal can restore functional balance. Preclinical data — Joshi et al., Scientific Reports 2022, with a sotatercept analog in monocrotaline and Sugen-hypoxia rat PAH models — showed reversal of established pulmonary vascular remodeling, improved hemodynamics, and reduced perivascular inflammation, supporting the disease-modifying rather than purely vasoactive mechanism. The distinctive class-effect adverse events of sotatercept — mucocutaneous bleeding, telangiectasias, gingival bleeding — are attributable to residual BMP9/10 sequestration, which produces a vascular phenotype reminiscent of hereditary hemorrhagic telangiectasia (HHT). HHT is caused by genetic loss-of-function in ENG, ACVRL1, or GDF2 (the BMP9 gene), producing exactly the telangiectasia/epistaxis phenotype observed in sotatercept-treated patients. Sotatercept's modified ActRIIA-Fc has lower BMP9/10 affinity than the wild-type-receptor ACE-031 predecessor (which used ActRIIB) and a different ligand-selectivity profile from luspatercept (modified ActRIIB-Fc), so the magnitude of the bleeding signal is bounded — but the signal is mechanism-intrinsic to the receptor-trap class. Dose-related increases in hemoglobin and hematocrit reflect sotatercept's effect on erythroid biology — the same biology that originally motivated Acceleron's interest in ACE-011 for ineffective erythropoiesis before the PAH repositioning. Thrombocytopenia, also dose-related, is monitored under the prescribing label.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Sotatercept:

• 01Whether the 24-week and 1-year hemodynamic and exercise-capacity benefits documented in STELLAR and ZENITH translate to long-term mortality benefit beyond the high-risk-population effect captured in ZENITH — addressed in part by SOTERIA but a long-term question.
• 02Whether sotatercept changes the natural history of PAH at the level of pulmonary vascular remodeling — imaging-based and pathologic endpoints in extended follow-up will inform this.
• 03Optimal sequencing of sotatercept relative to lung transplantation candidacy — whether earlier sotatercept use defers transplant in patients who would otherwise progress, or whether it should be reserved for select populations.
• 04Efficacy in earlier-stage PAH (HYPERION trial), in pulmonary hypertension associated with left heart disease (CADENCE trial, WHO Group 2), and in pediatric PAH — the labeled indication is currently adult Group 1 PAH only.
• 05Predictive biomarkers for response — BMPR2 mutation status, baseline activin/BMP9 ratios, and other biomarkers of pulmonary vascular biology have been explored but no validated biomarker yet selects responders.
• 06Combination biology — whether combining sotatercept with emerging therapies (seralutinib, BMP9 ligand-replacement strategies, other activin/TGF-β modulators) produces additive or synergistic benefit, and what the safety profile of such combinations would look like.
• 07Long-term bleeding-event characterization — telangiectasia development, location, and severity over multi-year exposure has not been fully characterized; whether the bleeding signal stabilizes or progresses with continued dosing is an open question.

Forms & Administration

Subcutaneous injection of reconstituted sotatercept-csrk powder, administered once every three weeks. Per the Winrevair label, the starting dose is 0.3 mg/kg with the first dose, then escalation to a target maintenance dose of 0.7 mg/kg from the second dose forward, subject to dose adjustments based on hemoglobin and platelet count. Winrevair is supplied as 45 mg or 60 mg single-dose vials of lyophilized powder, reconstituted with bacteriostatic water for injection and administered by a healthcare professional or, after appropriate training, self-administered. Administration is added on top of stable background PAH therapy (endothelin receptor antagonists, PDE5 inhibitors or sGC stimulators, prostacyclin pathway agents — typically as double or triple combination). Sotatercept is dispensed only through specialty distribution channels under Merck's distribution program; it is not available through compounding pharmacies, and there is no small-molecule equivalent.

Common Questions

Who Sotatercept Is NOT For

Drug & Supplement Interactions

Formal drug-interaction data on sotatercept are limited, in part because the molecule is a biologic with no cytochrome-P450 metabolism and minimal direct pharmacokinetic interactions. Mechanism-based and clinically relevant interactions are as follows. Sotatercept is added on top of background PAH therapy — endothelin receptor antagonists (ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil) or sGC stimulators (riociguat), and prostacyclin pathway agents (epoprostenol, treprostinil, selexipag). The pivotal STELLAR and ZENITH trials enrolled patients on stable mono-, double-, or triple-combination background therapy and dosed sotatercept on top, without dose adjustments to either sotatercept or the background agents. There is no evidence of pharmacokinetic interaction with these classes, and the clinical-effect benefits documented in the trials were obtained on top of those background regimens. Antiplatelet and anticoagulant therapy warrants specific attention given sotatercept's mucocutaneous bleeding signal (epistaxis, gingival bleeding, telangiectasias). Many PAH patients are on chronic anticoagulation for clinical indications; the combination is not contraindicated but requires monitoring and dose-modification consideration if clinically meaningful bleeding develops. Live vaccines have not been formally studied in sotatercept-treated patients; standard biologic-class precautions apply, and inactivated and recombinant vaccines should be administered per usual schedules. Concurrent use with other agents that modulate TGF-β superfamily signaling — luspatercept, bimagrumab, apitegromab, follistatin preparations — has not been studied and would produce overlapping pathway blockade with unpredictable cumulative effects, particularly with respect to red-cell biology and bleeding risk. There is no clinical scenario in which combining these agents would be appropriate outside a formal trial. Iron-overload management agents (deferasirox, deferiprone) and erythropoiesis-stimulating agents are not standard concomitants in PAH patients but, if used for other indications, warrant attention given sotatercept's effect on hemoglobin and hematocrit.

Safety Profile

Legal Status

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Myths & Misconceptions