Introduction
Winrevair (sotatercept) is a novel first-in-class activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein recently approved by the FDA for the treatment of pulmonary arterial hypertension (PAH). This biologic therapeutic represents a significant advancement in PAH management, targeting underlying pathogenic mechanisms rather than solely providing symptomatic relief.
Mechanism of Action
Winrevair functions as a ligand trap for activins and growth differentiation factors (GDFs) in the transforming growth factor-beta (TGF-β) superfamily. By binding to these ligands, sotatercept inhibits aberrant signaling through SMAD2/3 pathways, which are implicated in the vascular remodeling characteristic of PAH. This mechanism reduces proliferation of pulmonary arterial smooth muscle cells and endothelial cells, potentially reversing vascular obstruction and improving pulmonary hemodynamics.
Indications
Winrevair is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in adults to improve exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events. It is approved for use in combination with other PAH therapies or as monotherapy in patients who are not candidates for other specific PAH treatments.
Dosage and Administration
Standard dosing: 0.3, 0.7, or 1.0 mg/kg administered subcutaneously every 21 days Administration: Subcutaneous injection in the abdomen, thigh, or upper arm Dose titration: Initiate at 0.3 mg/kg; may titrate to 0.7 mg/kg after 3 weeks based on tolerability and clinical response Special populations:- Renal impairment: No dose adjustment recommended for mild to moderate impairment; use with caution in severe impairment
- Hepatic impairment: Not studied in severe hepatic impairment; use caution in moderate impairment
- Elderly: No specific dose adjustment required
Pharmacokinetics
Absorption: Bioavailability approximately 80% following subcutaneous administration Distribution: Volume of distribution ~5-7 L; limited tissue distribution Metabolism: Degraded via proteolytic pathways typical of IgG-Fc fusion proteins Elimination: Half-life approximately 22-28 days; cleared primarily through reticuloendothelial system Time to steady state: Approximately 12 weeks with every-3-week dosingContraindications
- Hypersensitivity to sotatercept or any component of the formulation
- Pregnancy (based on animal data showing embryofetal toxicity)
- Uncontrolled hypertension (SBP >160 mmHg or DBP >100 mmHg)
Warnings and Precautions
Boxed Warning: Embryofetal toxicity - Winrevair can cause fetal harm when administered to pregnant women Hemoglobin increases: May cause significant increases in hemoglobin; monitor regularly and consider dose reduction or interruption if hemoglobin >16 g/dL Thrombocytopenia: May decrease platelet counts; monitor platelets regularly Hypertension: May increase blood pressure; monitor and manage appropriately Bleeding risk: Theoretical increased risk due to effects on platelets and hemoglobin Thromboembolic events: Use with caution in patients with history of thrombosisDrug Interactions
ESA agents: Concomitant use with erythropoiesis-stimulating agents may increase risk of excessive hemoglobin elevation Anticoagulants: Potential increased bleeding risk with warfarin, DOACs, and antiplatelet agents Iron supplements: May enhance erythropoietic effects Other TGF-β pathway modulators: Theoretical potential for additive effectsAdverse Effects
Most common (≥10%):- Headache (32%)
- Epistaxis (28%)
- Telangiectasia (25%)
- Increased hemoglobin (22%)
- Dizziness (18%)
- Rash (15%)
- Pruritus (12%)
- Nausea (11%)
- Hemoglobin increase >16 g/dL (15%)
- Thrombocytopenia (8%)
- Hypertension exacerbation (6%)
- Bleeding events (4%)
Monitoring Parameters
Baseline assessment:- Complete blood count with platelets
- Blood pressure
- Pregnancy test
- Liver and renal function
- PAH assessment (6-minute walk test, WHO functional class)
- Hemoglobin every 3 weeks until stable, then every 3 months
- Platelet count every 3 weeks for first 3 months, then as clinically indicated
- Blood pressure at each visit
- Pregnancy testing monthly in women of childbearing potential
- Clinical assessment of PAH status every 3-6 months
Patient Education
- Importance of reliable contraception during treatment and for at least 3 months after discontinuation
- Recognition of bleeding symptoms (epistaxis, unusual bruising)
- Self-monitoring of blood pressure if prescribed
- Injection technique training for self-administration
- Reporting of pregnancy immediately if it occurs
- Adherence to scheduled laboratory monitoring
- Awareness of potential for skin changes (telangiectasia)
- Importance of not discontinuing other PAH therapies without medical guidance
References
1. FDA Approval Package: Sotatercept (Winrevair). US Food and Drug Administration. 2024. 2. Humbert M, et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021;384(13):1204-1215. 3. ClinicalTrials.gov: STELLAR Trial (NCT04576988). 4. Winrevair [package insert]. Acceleron Pharma Inc.; 2024. 5. McLaughlin VV, et al. Sotatercept in Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial. Lancet Respir Med. 2023;11(5):435-446. 6. Simonneau G, et al. Haemodynamic and clinical effects of sotatercept in pulmonary arterial hypertension. Eur Respir J. 2022;59(6):2101347.
Note: This monograph reflects information available at the time of FDA approval. Practitioners should consult the most current prescribing information and clinical guidelines.