Jesduvroq (daprodustat) approved by US FDA for anemia of chronic kidney disease in adults on dialysis

• Jesduvroq is the only oral HIF-PHI approved in the US, offering adults on dialysis with anemia of chronic kidney disease a new oral treatment option

GSK plc (LSE/NYSE: GSK) today announced that the US Food and Drug Administration (FDA) has approved Jesduvroq (daprodustat), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for the once-a-day treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least four months. Jesduvroq is the first innovative medicine for anemia treatment in over 30 years and the only HIF-PHI approved in the US, providing a new oral, convenient option for patients in the US with anemia of CKD on dialysis.

Tony Wood, President and Chief Scientific Officer, GSK, said: “Over the last several decades, there has been little innovation in anemia of CKD. We are proud to have developed Jesduvroq as a new oral treatment where there is a patient desire for more options.” 

The FDA approval is based on results from the ASCEND-D trial, assessing the efficacy and safety of Jesduvroq for the treatment of anemia of CKD in patients on dialysis. Results were published in the New England Journal of Medicine with additional results published in the New England Journal of Medicine supplementary appendix.

The Safety Information for Jesduvroq includes 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. 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 or for treatment of anemia of chronic kidney disease in patients who are not on dialysis.

CKD is an increasing global health burden affecting 700 million patients worldwide, with an estimated one in seven patients also developing anemia.^1,2 When left untreated or undertreated, anemia of CKD is associated with poor clinical outcomes and leads to a substantial burden on patients and healthcare systems.³ There is an unmet need for oral treatment options with efficacy and safety comparable to current treatments.

LaVarne Burton, President and Chief Executive Officer, American Kidney Fund, said: “Anemia of CKD can be a debilitating condition that is challenging to manage. This news means that patients on dialysis who are living with anemia of CKD now have another treatment option to help manage their anemia.”

A marketing authorisation application for daprodustat is currently under review with the European Medicines Agency, with a regulatory decision anticipated in the first half of 2023. In June 2020, daprodustat tablets were approved by Japan’s Ministry of Health, Labour and Welfare for the treatment of patients with anemia of CKD. In Japan, the brand name for daprodustat is Duvroq, where it is the market leader and preferred HIF-PHI.

About Jesduvroq (daprodustat)

Jesduvroq, a HIF-PHI, belongs to a novel class of oral medicines for the treatment of anemia of CKD in adult patients on dialysis. Inhibition of oxygen-sensing prolyl hydroxylase enzymes stabilises hypoxia-inducible factors, which can lead to transcription of erythropoietin and other genes involved in the correction of anemia, similar to the physiological effects that occur in the human body at high altitude.^4,5 Jesduvroq provides an oral treatment option for adult patients with anemia of CKD on dialysis.⁶ Jesduvroq is a tablet available in 5 dosage strengths: 1mg, 2mg, 4mg, 6mg, 8mg.

About the ASCEND Phase III clinical trial programme

The ASCEND programme included five Phase III trials to assess the efficacy and safety profile of daprodustat for the treatment of anemia of CKD across the disease spectrum. The programme enrolled over 8,000 patients who were treated for up to 4.26 years. Results from all five trials were presented at the American Society of Nephrology’s Kidney Week 2021.

Results from the pivotal cardiovascular outcomes trial, ASCEND-D, which investigated patients on dialysis, were published in the New England Journal of Medicine:⁶

• ASCEND-D (Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Dialysis) enrolled 2,964 dialysis patients with anemia of CKD who were switched to receive daprodustat ESA control from a standard of care ESA therapy. A uniform iron management protocol was instituted across both arms of the study. The study met its primary efficacy and safety endpoints. Results showed daprodustat improved or maintained Hb within target levels (10-11.5 g/dL) for these patients, and the primary safety analysis of the ITT population showed that daprodustat achieved non-inferiority of MACE compared to ESA control.

About anemia of chronic kidney disease

CKD is characterised by progressive loss of kidney function.⁷ Anemia is an important and frequent complication of CKD and is associated with increased morbidity, mortality and reduced quality of life.⁸ It is often poorly diagnosed and undertreated in patients with early-stage CKD.⁹ Over 700 million patients suffer from CKD worldwide, and an estimated 1-in-7 of these patients have anemia.^1,2 CKD affects approximately 39 million people in the US, of whom approximately 6 million are also affected by anemia.^1,2 There are approximately 810,000 patients who are end-stage renal disease (ESRD) in the US.¹⁰ Of which, there are 558,000 patients receiving dialysis.¹⁰ Of these patients receiving dialysis, 481,000 received hemodialysis and 77,000 received home or peritoneal dialysis.¹⁰ When left untreated or undertreated, anemia of CKD is associated with poor clinical outcomes and leads to a substantial burden on patients and healthcare systems.³

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

The following Important Safety Information is based on the Highlights section of the Prescribing Information for JESDUVROQ.  Please consult the full Prescribing Information for all labeled safety information, including BOXED WARNING for JESDUVROQ.

    Contraindications

• Strong cytochrome P450 2C8 (CYP2C8) inhibitors such as gemfibrozil.
• Uncontrolled hypertension.

    Warnings and Precautions   

• Risk of Hospitalization for Heart Failure: Increased in patients with a history of heart failure.
• Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed.
• Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported.
• Not indicated for treatment of anemia of CKD in patients who are not dialysis-dependent.
• Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy.

    Adverse Reactions   

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

    Drug Interactions

• Moderate CYP2C8 Inhibitors: Reduce starting dose of JESDUVROQ.
• CYP2C8 Inducers: Monitor hemoglobin and adjust the dose of JESDUVROQ as appropriate.

    Use in Specific Populations

• Pregnancy: May cause fetal harm.
• Lactation: Breastfeeding not recommended until one week after the final dose.
• Hepatic Impairment: Reduce the starting dose in patients with moderate hepatic impairment (Child-Pugh Class B). JESDUVROQ is not recommended in severe hepatic impairment (Child-Pugh Class C).

    Drug Abuse and Dependence

• Abuse of JESDUVROQ may be seen in athletes for the effects on erythropoiesis. Misuse of JESDUVROQ by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications.

Please consult the full Prescribing Information including Boxed Warning and Medication Guide.

About GSK

GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com/company

References

[1] Bikbov B, Purcell CA, Levey AS, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709-733.

[2] Stauffer et al. Prevalence of anemia in chronic kidney disease in the United States. PLoS One. 2014;9(1):e84943.

[3] Hanna RM et al. Burden of anemia in chronic kidney disease: beyond erythropoietin. Adv Ther. 2021;38(1):52-75.

[4] Ariazi JL, Duffy KJ, Adams DF, et al. Discovery and preclinical characterization of GSK1278863 (daprodustat), a small molecule hypoxia inducible factor-prolyl hydroxylase inhibitor for anemia. J Pharmacol Exp Ther. 2017;363(3):336-347.

[5] Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12(3):157-168.

[6] Singh A, et al. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021;385:2325-2335.

[7] Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease - A systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765.

[8] Palaka E, et al. The Impact of CKD Anaemia on Patients: Incidence, Risk Factors, and Clinical Outcomes-A Systematic Literature Review. Int J Nephrol. 2020 Jul 1;2020:769;2376

[9] St Peter WL, Guo H, Kabadi S, et al. Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States. BMC Nephrol. 2018;19(1):67.

[10] United States Renal Data System. 2022 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2022. Available at: https://usrds-adr.niddk.nih.gov/2022/end-stage-renal-disease/1-incidence-prevalence-patient-characteristics-and-treatment-modalities