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ZENITH: A study of adults with PAH (WHO Group 1, FC III or IV) at high risk of mortality on background therapya

All patients were on stable

background therapy1

Triple 72%

Double 28%

Prostacyclin Infusions 59%

WHO FC at baseline

III 74%

IV 26%

In ZENITH, patients (N=172) were randomized 1:1 to receive WINREVAIR and background PAH therapy (n=86) or placebo and background PAH therapy (n=86). Patients were stratified by baseline REVEAL Lite 2 risk score and PAH subtype. WINREVAIR or placebo was administered once every 3 weeks by subcutaneous injection.
In ZENITH, patients (N=172) were randomized 1:1 to receive WINREVAIR and background PAH therapy (n=86) or placebo and background PAH therapy (n=86). Patients were stratified by baseline REVEAL Lite 2 risk score and PAH subtype. WINREVAIR or placebo was administered once every 3 weeks by subcutaneous injection.
In ZENITH, patients (N=172) were randomized 1:1 to receive WINREVAIR and background PAH therapy (n=86) or placebo and background PAH therapy (n=86). Patients were stratified by baseline REVEAL Lite 2 risk score and PAH subtype. WINREVAIR or placebo was administered once every 3 weeks by subcutaneous injection.

Patients were receiving stable maximum-tolerated doses of double or triple therapy for PAH beginning at least 30 days before screening.1


aZENITH was a global, double-blind, placebo-controlled, multicenter, parallel-group, phase 3 study of adults with PAH.1

The ZENITH study excluded patients diagnosed with human immunodeficiency virus (HIV)–associated PAH, PAH associated with portal hypertension, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement.

ZENITH primary endpoint

Time to first event of all-cause death, lung transplantation, or PAH worsening–related hospitalization of ≥24 hours 

ZENITH baseline characteristics

Actor Portrayal

Mean time from PAH diagnosis to screening

  • 8 years

Median age

  • 58 years (range: 18 to 75 years)

Most common etiologies

  • Idiopathic PAH: 50%
  • PAH-CTD: 28%

  • Heritable PAH: 11% 

Sex

  • Female: 77%

Race or ethnicity

  • White: 87%
  • Black/African American: 5%
  • Asian: 4%
  • American Indian or Alaska Native: 1%
  • Missing/other races: 3%

REVEAL Lite 2 risk score

  • <9: 2%
  • 9 to 10: 67% 
  • ≥11: 30%

REVEAL = Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management.

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Reference:


1.Humbert M, McLaughlin VV, Badesch DB, et al; ZENITH Trial Investigators. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025;392(20):1987- 2000.

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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.