What is Sotatercept?
Sotatercept (brand name WINREVAIR, formerly MK-7962/ACE-011) is a recombinant fusion protein that combines the extracellular domain of the human activin receptor type IIA (ActRIIA) with the Fc portion of human IgG1. It functions as an activin signaling inhibitor, binding and sequestering ligands in the TGF-β superfamily — primarily activin A and activin B — that drive vascular remodeling in pulmonary arterial hypertension.
It is the first first-in-class therapy for PAH approved in over a decade and the only approved drug that targets the underlying signaling imbalance rather than the downstream vasoconstriction.
Mechanism of Action
In PAH, an imbalance between BMPR-II (bone morphogenetic protein receptor 2) signaling and ActRIIA signaling drives proliferative remodeling of the pulmonary arterioles, leading to elevated pulmonary vascular resistance. Sotatercept acts as a ligand trap:
- Binds activin A, activin B, GDF-8 (myostatin), and GDF-11 with high affinity
- Prevents these ligands from activating ActRIIA on smooth muscle and endothelial cells
- Restores the BMPR-II:ActRIIA balance toward antiproliferative signaling
- Reduces medial hypertrophy and intimal proliferation in the pulmonary vasculature
This is a disease-modifying mechanism — distinct from existing PAH drugs (endothelin receptor antagonists, PDE5 inhibitors, prostacyclin analogues) which all act on downstream vascular tone.
Clinical Evidence
STELLAR (Phase 3, 2023, NEJM) — 323 adults with PAH (WHO Group 1) on background therapy. Sotatercept added on top of standard care produced:
- 34-meter median improvement in 6-minute walk distance vs placebo at 24 weeks (primary endpoint)
- 84% reduction in risk of clinical worsening or death
- Improvements in WHO functional class, NT-proBNP, pulmonary vascular resistance
ZENITH (Phase 3, 2025, NEJM) — patients with advanced (high-risk) PAH. Trial stopped early for efficacy. Sotatercept reduced the composite of all-cause death, lung transplantation, or hospitalization for PAH worsening by 76%.
Approval History
- March 26, 2024 — FDA approval (BLA 761363) for adults with PAH (WHO Group 1) to increase exercise capacity, improve WHO functional class, and reduce risk of clinical worsening events
- August 2024 — EMA approval
Relationship to ACE-031
Sotatercept is the type IIA receptor counterpart of ACE-031 (sotatercept's "sister" molecule, which uses the type IIB receptor). Both came out of Acceleron Pharma's activin-trap platform. ACE-031 (ActRIIB-Fc) was halted in 2011 after vascular adverse events from BMP9/10 cross-inhibition. Sotatercept (ActRIIA-Fc) has a different ligand-binding profile and proceeded through development to approval.
Safety Profile
The most notable adverse events from clinical trials include epistaxis, telangiectasia, increased hemoglobin, and dizziness — reflecting the same activin-pathway pharmacology family as ACE-031, but with an apparently better therapeutic window at the doses used in PAH.
Long-term safety data are still accumulating; sotatercept carries warnings for serious bleeding, erythrocytosis, and thrombocytopenia.