GSK's NDA for Daprodustat, an Oral HIF-PHI for CKD-Related Anemia, Accepted by U.S. FDA with PDUFA Date Set for February 1, 2023

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Recently, GSK announced that the US FDA has accepted the New Drug Application (NDA) for daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) used to treat renal anemia caused by chronic kidney disease (CKD). The FDA has set the target action date for the NDA review as February 1, 2023.

The NDA for daprodustat is based on the positive results of the ASCEND Phase III clinical trial program, which includes five pivotal Phase III clinical trials evaluating the efficacy and safety of daprodustat in treating anemia due to CKD across the disease spectrum. The program enrolled over 8,000 patients who received treatment for up to 4.26 years. Results from two pivotal cardiovascular outcome trials (ASCEND-ND, ASCEND-D) were published in the November 2021 issue of The New England Journal of Medicine.

In the ASCEND program, each trial met the primary efficacy endpoint: in both dialysis and non-dialysis patients, daprodustat improved and/or maintained hemoglobin (Hb) levels within the target range (10-11.5 g/dL) compared to standard-of-care erythropoiesis-stimulating agents (ESA). Additionally, daprodustat did not increase the risk of major adverse cardiovascular events (MACE) compared to ESA.

Currently, daprodustat has been approved in Japan under the trade name Duvroq for the treatment of renal anemia, including CKD patients on dialysis and not on dialysis. In March 2022, the European Medicines Agency (EMA) accepted the Marketing Authorization Application (MAA) for daprodustat, which is currently under review. In 2022, GSK is expected to submit additional regulatory filings.

Public data shows that CKD is characterized by the gradual loss of kidney function, and anemia is a common complication of CKD. It is estimated that there are over 700 million CKD patients globally, with one in every seven patients suffering from anemia. If left untreated or inadequately treated, CKD-related anemia can lead to adverse clinical outcomes. HIF-PHI is a new class of oral medication that triggers the body's adaptation to hypoxic conditions and stimulates the bone marrow to produce more red blood cells.

Currently, three HIF-PHIs have been approved for marketing. Besides daprodustat (Duvroq), the other two are vadadustat (Vafseo) from Akebia/Otsuka Pharmaceutical and roxadustat (Evrenzo) from AstraZeneca/FibroGen. Among them, roxadustat was the first to be approved in China in December 2018, becoming the world's first approved HIF-PHI.

However, in terms of U.S. regulation, both roxadustat and vadadustat have encountered setbacks. Last August, when the FDA rejected roxadustat, it required AstraZeneca/FibroGen to conduct additional clinical studies. After agency reviewers delved into the clinical data of roxadustat, they found that compared with erythropoietin therapy in dialysis patients and placebo in non-dialysis patients, roxadustat was associated with increased mortality, thrombosis, severe infections, and other issues. Regarding vadadustat, in March this year, the FDA issued a complete response letter indicating safety concerns with the drug, such as higher risks of thromboembolic events and liver injury.

Reference Source:

1、US Food and Drug Administration accepts New Drug Application for daprodustat

2、After rivals' FDA rebuffs, GSK targets class-first oral approval in chronic kidney disease anemia