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Mechanism of action for WINREVAIR (sotatercept-csrk)

WINREVAIR is the first and only activin signaling inhibitor1

Sotatercept-csrk, a recombinant activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, is an activin signaling inhibitor that binds to activin A and other TGF-β superfamily ligands

Sotatercept-csrk Improves the Balance Between the Pro-Proliferative (ActRIIA/Smad2/3-Mediated) and Anti-Proliferative (BMPRII/Smad1/5/8-Mediated) Signaling to Modulate Vascular Proliferation

BMPRII = bone morphogenetic protein receptor type II; TGF-β= transforming growth factor beta.

In rat models of PAH, a sotatercept-csrk analog reduced inflammation and inhibited proliferation of endothelial and smooth muscle cells in diseased vasculature.

These cellular changes were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

Mechanism of disease2,3

PAH is a condition characterized in part by vascular inflammation and excessive cell proliferation within the pulmonary arteries. These pathological changes contribute to thickened vessel walls and narrowed pulmonary arterial lumen. As a consequence, hemodynamics are compromised, and the right ventricle undergoes remodeling.

References:

  1. DailyMed database. Advanced search: “activin signaling inhibitor” in Mechanism of Action section. National Library of Medicine. Accessed November 1, 2024. https://dailymed.nlm.nih.gov/dailymed/advanced-search.cfm
  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. Maron BA. Pulmonary Hypertension. In: Libby P, Bonow RO, Mann DL, et al, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 12th ed. Elsevier;2022:1656-1677.

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Preparation and administration
FAQs

Indication

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

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 (eg, gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR and 1% of patients taking placebo. 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 occurring in the phase 3 clinical trial (≥10% for WINREVAIR and at least 5% more than placebo) 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 6.2%), and erythema (13.5% vs 3.1%).

 

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

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

WINREVAIR (sotatercept-csrk) is an activin signaling inhibitor indicated for the treatment

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

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 (eg, gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR and 1% of patients taking placebo. 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 occurring in the phase 3 clinical trial (≥10% for WINREVAIR and at least 5% more than placebo) 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 6.2%), and erythema (13.5% vs 3.1%).

 

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.

 

Erythrocytosis: WINREVAIR may increase hemoglobin (Hgb).

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.