JESDUVROQ (daprodustat) Mechanism of Action

JESDUVROQ (daprodustat) Mechanism of Action

HIF PHI: A novel MOA for adult patients with Anemia of Chronic Kidney Disease (CKD) on dialysis for at least 4 months1-3

Oral JESDUVROQ activates the body’s natural adaptive response to hypoxia and stimulates the production of endogenous EPO.1,3

JESDUVROQ mechanism of action infographic
JESDUVROQ mechanism of action infographic

EPO, erythropoietin; Fe, iron; HIF-α, hypoxia-inducible factor-prolyl-alpha; HIF-β, hypoxia-inducible factor-prolyl-beta; HIF PHI, hypoxia-inducible factor-prolyl hydroxylase inhibitor; MOA, mechanism of action; OH, hydroxl ion; PHD, prolyl-4-hydroxylase domain.

Take a deeper look at the MOA of JESDUVROQ

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  • Chapter 1: Introduction to the HIF pathway

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    GSK
    The HIF Pathway

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    Narration:
    The hypoxia-inducible factor, or HIF, plays an important role in the regulation of erythropoiesis.1 HIF transcription factors are regulated by oxygen-dependent prolyl hydroxylase domain, or PHD, enzymes.2 In the presence of normal tissue oxygen conditions, PHD enzymes tag HIF-α subunits for proteasomal degradation.2

    On-screen text:
    PHD enzyme
    HIF-α subunit

    References:

    1. Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11(7):394-410.
    2. Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol. 2017;45(3):187-199.

    GSK
    For US Healthcare Professionals only.
    Trademarks are owned by or licensed to the GSK group of companies.
    ©2023 GSK or licensor.
    DPRVID230002 September 2023
    Produced in USA.

  • Chapter 2: CKD and reduced erythropoiesis

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    CKD and Reduced Erythropoiesis

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    Pathophysiologic changes that occur with CKD affect HIF pathway function and contribute to the development of anemia of CKD.1,2 In CKD, reduction in nephron mass can result in reduced oxygen consumption in the kidney.3 This results in the HIF pathway not being adequately activated.3,4 This, together with a decrease in the total number of renal erythropoietin-producing, or REP, cells contributes to the development of anemia of CKD through reduced erythropoietin production.1,4 In CKD, the HIF pathway can be pharmacologically activated to produce erythropoietin.3,4

    On-screen text:
    Erythropoietin
    Renal erythropoietin-producing (REP) cells

    References:

    1. Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11(7):394-410.
    2. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30(4):393-402.
    3. Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol. 2017;45(3):187-199.
    4. Souma T, Suzuki N, Yamamoto M. Renal erythropoietin-producing cells in health and disease. Front Physiol. 2015;6:167.

    GSK
    For US Healthcare Professionals only.
    Trademarks are owned by or licensed to the GSK group of companies.
    ©2023 GSK or licensor.
    DPRVID230003 September 2023
    Produced in USA.

  • Chapter 3: How JESDUVROQ (daprodustat) works

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    How JESDUVROQ (daprodustat) works
    Please see full Prescribing Information, including BOXED WARNING, at Jesruvroqhcp.com.

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    Narration:
    Oral JESDUVROQ (daprodustat) is the first oral Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitor indicated for anemia due to CKD in adults who have been receiving dialysis for at least four months.1 JESDUVROQ has not been shown to improve quality of life, fatigue, or patient well-being. JESDUVROQ is not indicated as a substitute for red blood cell transfusions in patients who require immediate correction of anemia or in patients who are not on dialysis.

    JESDUVROQ has a boxed warning for: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS

    • JESDUVROQ increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).
    • Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels.
    • No trial has identified a hemoglobin target level, dose of JESDUVROQ, or dosing strategy that does not increase these risks.
    • Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood cell transfusions.1

    Please see additional Important Safety Information continued in the video.
    Please see full Prescribing Information, including BOXED WARNING, at Jesduvroqhcp.com

    JESDUVROQ activates the body's natural adaptive response to hypoxia and stimulates endogenous erythropoietin production.2 JESDUVROQ is a reversible inhibitor of HIF-PHD enzymes, resulting in stabilization and nuclear accumulation of the HIF-α subunit, where it dimerizes with the HIF-β subunit, leading to increased transcription of erythropoietin and genes related to iron metabolism and utilization.1, 2,3 Through this novel mechanism of action, JESDUVROQ impacts an important mechanism in anemia of CKD, resulting in increased erythropoiesis.1, 2,3

    On-screen text:
    INDICATION
    JESDUVROQ is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least four months.

    Limitations of Use
    JESDUVROQ has not been shown to improve quality of life, fatigue, or patient well-being.
    JESDUVROQ is not indicated for use:

    • As a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
    • For treatment of anemia of chronic kidney disease in patients who are not on dialysis.

    IMPORTANT SAFETY INFORMATION

    WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS

    • JESDUVROQ increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).
    • Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels.
    • No trial has identified a hemoglobin target level, dose of JESDUVROQ, or dosing strategy that does not increase these risks.
    • Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood cell transfusions.

    Please see additional Important Safety Information continued in the video.
    Please see full Prescribing Information, including BOXED WARNING, at Jesduvroqhcp.com.

    JESDUVROQ
    HIF-α subunit
    PHD enzyme
    Active HIF transcription factor
    Erythropoietin

    References:

    1. JESDUVROQ Prescribing Information. Durham, NC: GlaxoSmithKline; 2023.
    2. Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for anemia in patients with CKD. Am J Kidney Dis. 2017;69(6):815-826.
    3. Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol. 2017;45(3):187-199.

    Scene 4
    Narration:
    Important Safety Information continued:

    CONTRAINDICATIONS
    JESDUVROQ is contraindicated in patients:

    • Receiving a strong CYP2C8 inhibitor such as gemfibrozil.
    • With uncontrolled hypertension. 

    WARNINGS AND PRECAUTIONS

    Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access

    JESDUVROQ increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting JESDUVROQ.

    A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels.

    No trial has identified a hemoglobin target level, dose of JESDUVROQ, or dosing strategy that does not increase these risks. Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis.
    Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur.

    Risk of Hospitalization for Heart Failure
    Hospitalization for heart failure was observed in 7.5% (3.3 per 100 Person Years [PY]) of patients on dialysis receiving JESDUVROQ and 6.8% (3.0 per 100 PY) of patients receiving recombinant human erythropoietin (rhEPO). Patients with a pre-existing history of heart failure were at increased risk of hospitalization for heart failure with JESDUVROQ (14.5%; 6.8 per 100 PY) compared to rhEPO (11.3%; 5.1 per 100 PY).

    Consider the patient’s history of heart failure when deciding whether to prescribe JESDUVROQ. Advise patients of the symptoms and signs of heart failure and to immediately report any worsening to their healthcare provider.

    Hypertension
    JESDUVROQ is contraindicated in patients with uncontrolled hypertension. Worsening of hypertension occurred in 24% (12 per 100 PY) of patients receiving JESDUVROQ and 24% (12 per 100 PY) of patients receiving rhEPO. Serious worsening of hypertension occurred in 3.1% of patients receiving JESDUVROQ and 3.1% of patients receiving rhEPO. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving JESDUVROQ. Monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed.

    Gastrointestinal Erosion
    Gastric or esophageal erosions occurred in 5.7% (2.5 per 100 PY) of patients receiving JESDUVROQ and 6.6% (2.9 per 100 PY) of rhEPO-treated patients. Serious erosions, including gastrointestinal (GI) bleeding and the need for red blood cell transfusions, were reported in 3.6% and 3.1% of those receiving JESDUVROQ and rhEPO, respectively. Consider this risk particularly in patients at increased risk for GI erosions, such as those with a history of GI erosion, peptic ulcer disease, use of concomitant medications that increase the risk of GI erosion, and current tobacco smokers and alcohol drinkers. Advise patients of the symptoms and signs of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur.

    Serious Adverse Events in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis
    The safety of JESDUVROQ has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting.

    In a large cardiovascular outcomes trial in adults with anemia of CKD who were not on dialysis, an increased risk of cardiovascular mortality, stroke, thromboembolism, serious acute kidney injury, hospitalization for heart failure, and serious gastrointestinal erosions was observed in patients treated with JESDUVROQ compared to rhEPO.

    Malignancy
    Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, JESDUVROQ has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 4.4% (1.9 per 100 PY) of patients treated with JESDUVROQ and 5.2% (2.3 per 100 PY) of patients treated with rhEPO. No evidence of increased carcinogenicity was observed in animal studies.

    ADVERSE REACTIONS
    Most common adverse reactions (incidence ≥10%) are hypertension, thrombotic vascular events, and abdominal pain.

    DRUG INTERACTIONS
    Moderate CYP2C8 Inhibitors: Concomitant administration of moderate CYP2C8 inhibitors (e.g., clopidogrel) increases daprodustat exposure. Reduce the starting dose of JESDUVROQ by half when initiating treatment in patients on a moderate CYP2C8 inhibitor except in patients whose starting dose is already 1 mg. Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with a moderate CYP2C8 inhibitor during treatment with JESDUVROQ.

    CYP2C8 Inducers: CYP2C8 inducers (e.g., rifampin) may decrease daprodustat exposure, which may result in loss of efficacy. Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with CYP2C8 inducers during treatment with JESDUVROQ.

    USE IN SPECIFIC POPULATIONS
    Pregnancy: JESDUVROQ may cause fetal harm. CKD is associated with maternal and fetal risks. Advise pregnant women of the potential risk to the fetus.

    Lactation: Given the serious adverse reactions seen in adults treated with JESDUVROQ, such as thrombotic vascular events, advise patients not to breastfeed during treatment with JESDUVROQ, and for one week after the final dose.

    Hepatic Impairment: Reduce the starting dose of JESDUVROQ by half in patients with moderate hepatic impairment (Child-Pugh Class B) except in patients whose starting dose is already 1 mg. JESDUVROQ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is not recommended in these patients.

    DRUG ABUSE AND DEPENDENCE
    Abuse: Abuse of JESDUVROQ may be seen in athletes for the effects on erythropoiesis. There are no data on the abuse of JESDUVROQ in humans. Misuse of drugs that increase erythropoiesis, such as JESDUVROQ, by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications.

    Please see full Prescribing Information, including BOXED WARNING, at Jesduvroqhcp.com

    on-screen text:
    Important Safety Information (cont’d)

    CONTRAINDICATIONS
    JESDUVROQ is contraindicated in patients:

    • Receiving a strong CYP2C8 inhibitor such as gemfibrozil.
    • With uncontrolled hypertension.

    WARNINGS AND PRECAUTIONS 
    Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access

    JESDUVROQ increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting JESDUVROQ.

    A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels. 

    No trial has identified a hemoglobin target level, dose of JESDUVROQ, or dosing strategy that does not increase these risks. Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis.
    Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur.

    Risk of Hospitalization for Heart Failure
    Hospitalization for heart failure was observed in 7.5% (3.3 per 100 Person Years [PY]) of patients on dialysis receiving JESDUVROQ. Patients with a pre-existing history of heart failure were at increased risk of hospitalization for heart failure with JESDUVROQ (14.5%; 6.8 per 100 PY) compared to rhEPO (11.3%; 5.1 per 100 PY). Consider the patient’s history of heart failure when deciding whether to prescribe JESDUVROQ.

    Hypertension
    Worsening of hypertension occurred in 24% (12 per 100 PY) of patients receiving JESDUVROQ. Serious worsening of hypertension occurred in 3.1% of patients receiving JESDUVROQ. Cases of hypertensive crisis have also been reported. Monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed.

    Gastrointestinal Erosion
    Gastric or esophageal erosions occurred in 5.7% (2.5 per 100 PY) of patients receiving JESDUVROQ. Serious erosions, including gastrointestinal (GI) bleeding and the need for red blood cell transfusions, were reported in 3.6% of patients receiving JESDUVROQ. Consider this risk particularly in patients at increased risk for GI erosions, such as those with a history of GI erosion, peptic ulcer disease, use of concomitant medications that increase the risk of GI erosion, and current tobacco smokers and alcohol drinkers.

    Serious Adverse Events in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis
    The safety of JESDUVROQ has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting.

    In a large cardiovascular outcomes trial in adults with anemia of CKD who were not on dialysis, an increased risk of cardiovascular mortality, stroke, thromboembolism, serious acute kidney injury, hospitalization for heart failure, and serious gastrointestinal erosions was observed in patients treated with JESDUVROQ compared to rhEPO.

    Malignancy
    Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, JESDUVROQ has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 4.4% (1.9 per 100 PY) of patients treated with JESDUVROQ.

    ADVERSE REACTIONS
    Most common adverse reactions (incidence ≥10%) are hypertension, thrombotic vascular events, and abdominal pain.

    DRUG INTERACTIONS
    Moderate CYP2C8 Inhibitors: Concomitant administration of moderate CYP2C8 inhibitors (e.g., clopidogrel) increases daprodustat exposure. Reduce the starting dose of JESDUVROQ by half when initiating treatment in patients on a moderate CYP2C8 inhibitor except in patients whose starting dose is already 1 mg. Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with a moderate CYP2C8 inhibitor during treatment with JESDUVROQ.

    CYP2C8 Inducers: CYP2C8 inducers (e.g., rifampin) may decrease daprodustat exposure, which may result in loss of efficacy. Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with CYP2C8 inducers during treatment with JESDUVROQ.

    USE IN SPECIFIC POPULATIONS
    Pregnancy: JESDUVROQ may cause fetal harm. CKD is associated with maternal and fetal risks. Advise pregnant women of the potential risk to the fetus.

    Lactation: Given the serious adverse reactions seen in adults treated with JESDUVROQ, such as thrombotic vascular events, advise patients not to breastfeed during treatment with JESDUVROQ, and for one week after the final dose.

    Hepatic Impairment: Reduce the starting dose of JESDUVROQ by half in patients with moderate hepatic impairment (Child-Pugh Class B) except in patients whose starting dose is already 1 mg. JESDUVROQ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is not recommended in these patients.

    DRUG ABUSE AND DEPENDENCE
    Abuse: Abuse of JESDUVROQ may be seen in athletes for the effects on erythropoiesis. There are no data on the abuse of JESDUVROQ in humans. Misuse of drugs that increase erythropoiesis, such as JESDUVROQ, by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications.

    Please see full Prescribing Information, including BOXED WARNING, at Jesduvroqhcp.com.

    GSK
    For US Healthcare Professionals only.
    Trademarks are owned by or licensed to the GSK group of companies.
    ©2023 GSK or licensor.
    DPRVID230004 September 2023
    Produced in USA.

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