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Introducing EVRENZO

  • The HIF pathway

    The HIF (hypoxia inducible factor) pathway plays a central role in erythropoiesis.1,2

    The HIF pathway is the physiological mechanism by which the body responds to low oxygen conditions, such as those experienced at high altitude.

    2_1_HIF mechanism_GIF_CKD

    Figure made by Astellas based on Locatelli ref 1

    Activation of the HIF-pathway leads to transcription of genes involved in iron (Fe) turnover and the production of Erythropoietin (EPO) resulting in increased red blood cell count (RBC) / haemoglobin (Hb)

    The HIF pathway affects all the key components of erythropoiesis:1
    • Increases erythropoietin (EPO) production
    • Suppresses hepcidin production
    • Increases iron absorption, transport and mobilisation

    The HIF pathway is critically important to oxygen sensing3

    Under normoxic conditions, the HIF pathway is not activated: the HIF-α subunit is rapidly degraded via HIF prolyl-hydroxylase (HIF-PH) in the presence of oxygen:3

    Normoxic conditions

    gene_transcription

    Figure made by Astellas based on Haase ref 3

    Under hypoxic conditions, the HIF pathway is activated: the HIF-α subunit is not degraded and dimerises with the HIF-β subunit inducing the transcription and translation of target hypoxia response genes involved in erythropoiesis, including:3-5

    evrenzo-three

    In CKD, oxygen sensing via HIF is disrupted, and this contributes to the development of anaemia.6

    A unique strategy to mimic the physiological response to hypoxia is to inhibit HIF-PH, facilitating the accumulation of HIF-α and the resulting induction of hypoxia response genes.1

    CKD, chronic kidney disease; HIF, hypoxia-inducible factor; HIF-PH, hypoxia-inducible factor prolyl-hydroxylase; EPO, erythropoietin.

    References

    • 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;45:187-199.
    • Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11:394–410.
    • Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21:S110–S124.
    • Biggar P, Gheun-Ho K. Treatment of renal anemia: Erythropoiesis stimulating agents and beyond. Kidney Res Clin Pract. 2017;36:209–223.
    • Del Vecchio L, LocateIIi F. Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease. Expert Opin Investig Drugs. 2018;27(7):613-621
    • Guedes M, Robinson BM, Obrador G et al. Management of Anemia in Nondialysis Chronic Kidney Disease: Current Recommendations, Real-World Practice, and Patient Perspectives. Kidney360. 2020;1(8):855-62

  • EVRENZO: a first-in-class treatment1

    EVRENZO is a HIF-PH inhibitor, a class of drug with an innovative mechanism of action.2

    EVRENZO mimics the body’s natural response to hypoxia by activating the HIF pathway2,3

    Mimicking hypoxia

    mimicking_hypoxia

    Figure made by Astellas based on EVRENZO SmPC ref 3

    EVRENZO inhibits HIF-PH, thus preventing breakdown of HIF-α and activating the HIF pathway2,3

    This induces transcription and translation of genes involved in erythropoiesis2,3

    HIF-PH inhibitors induce activation of the genes responsible for erythropoiesis, mimicking a hypoxic state.3

    EVRENZO reduces hepcidin levels and improves iron bioavailability3

    Through the inhibition of HIF-PH, EVRENZO stimulates a coordinated erythropoietic response that not only increases erythropoietin (EPO) levels, but also increases iron mobilisation, as well as helping to overcome the effects of inflammation by suppressing hepcidin.3

    enterocyte

    Figure made by Astellas based on Haase ref 4

    See how EVRENZO works

    EVRENZO Mechanism of action

    EVRENZO is indicated for the treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD)3

    CKD, chronic kidney disease; EPO, erythropoietin; HIF, hypoxia-inducible factor; HIF-PH, hypoxia-inducible factor prolyl-hydroxylase.

    References

    • Sanghani NS, Haase VH. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019;26(4):253-266.
    • Del Vecchio L, LocateIIi F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018;27(1):125-133.
    • EVRENZO SmPC 09.2024 sect. 5.1
    • Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21:S110–S124.

  • EVRENZO promotes a coordinated erythropoietic response1-3

    By inhibiting HIF-PH, EVRENZO stimulates a coordinated erythropoietic response that:1,2

    Introducing_evrenzo1

    Hb, haemoglobin; HIF-PH, hypoxia-inducible factor prolyl-hydroxylase; IV, intravenous; RBC, red blood cell.

    References

    • EVRENZO SmPC 09.2024 sect. 5.1
    • Del Vecchio L, LocateIIi F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018;27(1):125-133.
    • 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;45:187-199.

  • The place of EVRENZO in management of anaemia of CKD

    EVRENZO has the potential to change the clinical management of anaemia of CKD.1

    Instead of treating the conditon as a deficiency of EPO or iron, EVRENZO addresses multiple factors that contribute to anaemia.1

    Targeting the HIF pathway with HIF-PHIs may offer a comprehensive and physiological approach to the management of anaemia of CKD.2

    EVRENZO helps patients with anaemia of CKD:

    • To achieve and maintain their target Hb levels3
    • With a reduced use of IV iron compared to ESA3
    • And is orally administered three times weekly3,4

    EVRENZO (roxadustat) is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD)3

    EVRENZO is contraindicated in the following conditions:
    -Hypersensitivity to active substance, peanut, soya or any of the excipients
    -Third trimester of pregnancy
    -Breastfeeding

    CKD, chronic kidney disease; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; HIF, hypoxia-inducible factor; HIF-PHI, hypoxia-inducible factor prolyl-hydroxylase inhibitor; IV, intravenous; TIW, three times weekly.

    References

    • Del Vecchio L, LocateIIi F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018;27(1):125-133.
    • Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21:S110–S124.
    • EVRENZO SmPC 09.2024 sect. 4.1
    • Akizawa T, Iwasaki M, Yamaguchi Y et al. Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan. J Am Soc Nephrol. 2020;31:1628-1639.

  • Why EVRENZO?

    A first-in-class1 treatment for anaemia of CKD

    Innovation

    • Anaemia of CKD is complex and multi-causal in nature2-4
    • By stimulating a coordinated erythropoietic response, EVRENZO can help patients achieve and maintain Hb levels within the desired target range5

    Confidence

    • EVRENZO achieved and maintained target Hb levels (10-12 g/dL) (6,2 - 7,5 mmol/l) irrespective of dialysis status5
      • In patients not on dialysis, EVRENZO was statistically superior to placebo (p<0.0001) and non-inferior to ESA (p=0.844)5
      • In patients just started on dialysis, EVRENZO was non-inferior in Hb correction from baseline (95% CI; 0.28 [0.110, 0.451]) and maintenance (95% CI; 0.30 [0.228, 0.373]) compared with ESA5

    • The safety profile of EVRENZO was comparable to that of ESAs,5,9,10 and AEs were consistent with those commonly seen in patients with anaemia of CKD6-9

    Administration

    • EVRENZO offers oral administration with a three times weekly tablet5

    Examine the evidence
    See the patient perspective
    Listen to expert opinion

    AE, adverse event; CI, confidence interval; CKD, chronic kidney disease; Hb, haemoglobin; ESA, erythropoiesis-stimulating agent.

    References

    • Sanghani NS, Haase VH. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019;26(4):253-266.
    • 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;45:187-199.
    • Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23:1631–1634.
    • Fishbane S, Spinowitz B. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. Am J Kidney Dis. 2018;71(3):423–435.
    • EVRENZO SmPC 09.2024 sect. 5.1
    • Barratt J, Andric B, Tataradze A et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES) Nephrol Dial Transplant. 2021;36(9):1616–1628.
    • Csiky B, Schömig M, Esposito C et al. Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES). Adv Ther. 2021;38(10):5361–5380.
    • Charytan C, Manllo-Karim R, Martin ER et al. A Randomized Trial of Roxadustat in Anemia of Kidney Failure: SIERRAS Study. Kidney Int Rep. 2021;6(7):1829–1839.
    • Akizawa T, Iwasaki M, Yamaguchi Y et al. Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan. J Am Soc Nephrol. 2020;31:1628-1639.
    • EVRENZO SmPC 09.2024 sect. 4.8