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WINREVAIRTM (sotatercept-csrk) targets a key driver of PAH—imbalanced proliferative signaling—through activin signaling inhibition1,2

The image is divided into 3 columns. Column 1 (far left) illustrates how imbalanced signaling in PAH is caused by increased levels of Activin A which bind to ActRIIA, resulting in an increase in pro-proliferative ActRIIA signaling and a decrease in anti-proliferative BMPRII signaling. The imbalance of ActRIIA-BMPRII signaling underlying PAH results in pulmonary vascular hyperproliferation. Column 2 (middle) illustrates how, based on preclinical studies, WINREVAIR improves the balance in signaling by binding to excess Activin A. Column 3 (far right) illustrates how, based on preclinical studies, modulating pulmonary vascular hyperproliferation with WINREVAIR may lead to thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
The image is divided into 3 columns. Column 1 (far left) illustrates how imbalanced signaling in PAH is caused by increased levels of Activin A which bind to ActRIIA, resulting in an increase in pro-proliferative ActRIIA signaling and a decrease in anti-proliferative BMPRII signaling. The imbalance of ActRIIA-BMPRII signaling underlying PAH results in pulmonary vascular hyperproliferation. Column 2 (middle) illustrates how, based on preclinical studies, WINREVAIR improves the balance in signaling by binding to excess Activin A. Column 3 (far right) illustrates how, based on preclinical studies, modulating pulmonary vascular hyperproliferation with WINREVAIR may lead to thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
The image is divided into 3 columns. Column 1 (far left) illustrates how imbalanced signaling in PAH is caused by increased levels of Activin A which bind to ActRIIA, resulting in an increase in pro-proliferative ActRIIA signaling and a decrease in anti-proliferative BMPRII signaling. The imbalance of ActRIIA-BMPRII signaling underlying PAH results in pulmonary vascular hyperproliferation. Column 2 (middle) illustrates how, based on preclinical studies, WINREVAIR improves the balance in signaling by binding to excess Activin A. Column 3 (far right) illustrates how, based on preclinical studies, modulating pulmonary vascular hyperproliferation with WINREVAIR may lead to thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

WINREVAIR is the first and only PAH treatment to target the activin signaling pathway3

This figure illustrates a cross-section of a pulmonary artery comparing a normal artery with one with PAH. The vessel wall layers are labeled as endothelial cells (inner layer), smooth muscle cells (middle layer), and adventitia (outer layer). The vessel wall of the PAH artery is thicker than the normal artery and the lumen is narrower.
This figure illustrates a cross-section of a pulmonary artery comparing a normal artery with one with PAH. The vessel wall layers are labeled as endothelial cells (inner layer), smooth muscle cells (middle layer), and adventitia (outer layer). The vessel wall of the PAH artery is thicker than the normal artery and the lumen is narrower.
This figure illustrates a cross-section of a pulmonary artery comparing a normal artery with one with PAH. The vessel wall layers are labeled as endothelial cells (inner layer), smooth muscle cells (middle layer), and adventitia (outer layer). The vessel wall of the PAH artery is thicker than the normal artery and the lumen is narrower.
This figure describes PAH therapeutic targets and is organized into two domains: “Pulmonary vascular proliferation” on the left and “Pulmonary vascular tone” on the right. The left domain is associated with WINREVAIR and highlights its role as an activin signaling inhibitor acting on the activin signaling pathway. The stated primary effect is anti-proliferation. Within the “Pulmonary vascular tone” domain, three classes of therapies are shown: (1) endothelin receptor antagonists acting on the endothelin pathway; (2) phosphodiesterase type 5 inhibitors (PDE5is) and soluble guanylate cyclase (sGC) stimulators acting on the NO-sGC–cGMP pathway; and (3) prostacyclin derivatives acting on the prostacyclin pathway. The primary effect of these classes is vasodilation.
This figure describes PAH therapeutic targets and is organized into two domains: “Pulmonary vascular proliferation” on the left and “Pulmonary vascular tone” on the right. The left domain is associated with WINREVAIR and highlights its role as an activin signaling inhibitor acting on the activin signaling pathway. The stated primary effect is anti-proliferation. Within the “Pulmonary vascular tone” domain, three classes of therapies are shown: (1) endothelin receptor antagonists acting on the endothelin pathway; (2) phosphodiesterase type 5 inhibitors (PDE5is) and soluble guanylate cyclase (sGC) stimulators acting on the NO-sGC–cGMP pathway; and (3) prostacyclin derivatives acting on the prostacyclin pathway. The primary effect of these classes is vasodilation.

ActRIIA = activin receptor type IIA; BMP = bone morphogenetic protein; BMPRII = bone morphogenetic protein receptor type II; cGMP = cyclic guanosine monophosphate; NO = nitric oxide; PDE5i = phosphodiesterase 5 inhibitor; sGC = soluble guanylate cyclase.

WINREVAIR targets a novel pathway involved in regulating proliferative signaling, which is thought to be a key driver of pulmonary vascular remodeling2

References:
1. Hoeper MM, Badesch DB, Ghofrani HA, et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490.


2. Humbert M, McLaughlin V, Gibbs JSR, et al; PULSAR Trial Investigators. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021;384(13):1204-1215. 


3. DailyMed database. Advanced search: “activin signaling inhibitor” in Mechanism of Action section. National Library of Medicine. Accessed October 20, 2025. htt‍p‍s://dailymed.nlm.nih‍.‍g‍ov/dailymed/advanced-search.cfm

4. Sahay S, Chakinala MM, Kim NH, et al. Contemporary treatment of pulmonary arterial hypertension: a US perspective. Am J Respir Crit Care Med. 2024;210(5):581-592.

Report exposure during pregnancy or lactation to the Merck Sharp & Dohme LLC Adverse Event reporting line at 1-877-888-4231

Indication

WINREVAIR is an activin signaling inhibitor indicated for the treatment of adults with pulmonary arterial hypertension (PAH, Group 1 pulmonary hypertension) to improve exercise capacity and World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events including hospitalization for PAH, lung transplantation and death.

Selected Safety Information

Erythrocytosis: WINREVAIR may increase hemoglobin (Hgb). Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required.

 

Severe Thrombocytopenia: WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm3. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.

 

Serious Bleeding: In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% vs 1% (STELLAR) and 7% vs 5% (ZENITH) of patients taking WINREVAIR vs placebo, respectively. Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Do not administer WINREVAIR if the patient is experiencing serious bleeding.

 

Embryo-Fetal Toxicity: WINREVAIR may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose. Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.

 

Impaired Fertility: Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility.

 

Adverse Reactions: The most common adverse reactions (≥10% for WINREVAIR and at least 5% more than placebo) occurring in the STELLAR phase 3 clinical trial were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%), rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea (15.3% vs 10.0%), dizziness (14.7% vs 6.3%), and erythema (13.5% vs 3.1%). The most common adverse reactions in the ZENITH trial were infections (67.4% vs 44.2%), epistaxis (45.3% vs 9.3%), diarrhea (25.6% vs 17.4%), telangiectasia (25.6% vs 3.5%), increased hemoglobin (15.1% vs 1.2%), rash (10.5% vs 4.7%), erythema (10.5% vs 3.5%), and gingival bleeding (10.5% vs 2.3%).

 

Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.

 

Before prescribing WINREVAIR, please read the accompanying Prescribing Information. The Patient Information and Instructions for Use (1-vial kit, 2-vial kit) also are available.

Indication
Selected Safety Information

WINREVAIR is an activin signaling inhibitor indicated for the treatment of adults with pulmonary arterial hypertension (PAH, Group 1 pulmonary hypertension) to improve exercise capacity and World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events including hospitalization for PAH, lung transplantation and death.

Selected Safety Information

Erythrocytosis: WINREVAIR may increase hemoglobin (Hgb). Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required.

 

Severe Thrombocytopenia: WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm3. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.

 

Serious Bleeding: In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% vs 1% (STELLAR) and 7% vs 5% (ZENITH) of patients taking WINREVAIR vs placebo, respectively. Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Do not administer WINREVAIR if the patient is experiencing serious bleeding.

 

Embryo-Fetal Toxicity: WINREVAIR may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose. Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.

 

Impaired Fertility: Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility.

 

Adverse Reactions: The most common adverse reactions (≥10% for WINREVAIR and at least 5% more than placebo) occurring in the STELLAR phase 3 clinical trial were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%), rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea (15.3% vs 10.0%), dizziness (14.7% vs 6.3%), and erythema (13.5% vs 3.1%). The most common adverse reactions in the ZENITH trial were infections (67.4% vs 44.2%), epistaxis (45.3% vs 9.3%), diarrhea (25.6% vs 17.4%), telangiectasia (25.6% vs 3.5%), increased hemoglobin (15.1% vs 1.2%), rash (10.5% vs 4.7%), erythema (10.5% vs 3.5%), and gingival bleeding (10.5% vs 2.3%).

 

Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.

 

Before prescribing WINREVAIR, please read the accompanying Prescribing Information. The Patient Information and Instructions for Use (1-vial kit, 2-vial kit) also are available.