FDA accepts Daprodustat's marketing application, and the treatment of renal anemia is expected to add another weapon!

Chronic kidney disease (CKD) is a growing global public health burden, and patients with CKD are prone to renal anemia
.

It is reported that there are about 700 million CKD patients in the world, and 1/7 of them suffer from anemia
.

Left untreated or undertreated, CKD anemia is associated with poor clinical outcomes and imposes a heavy burden on patients and health care systems¹
.

 On April 19, 2022, GSK’s official website announced that the U.
S.
Food and Drug Administration (FDA) has accepted the marketing application for Daprodustat for the treatment of anemia in patients with CKD, with a PDUFA date of February 1, 2023¹
.

Why does Daprodustat improve renal anemia? Daprodustat is a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for the treatment of non-dialysis-dependent or dialysis-dependent renal anemia in adults.
Its mechanism of action is related to the promotion of erythropoiesis by hypoxia-inducible factor
.

 HIF-PHI can inhibit prolyl hydroxylase to stabilize the level of hypoxia-inducible factor, increase the production of endogenous erythropoietin, improve iron absorption and utilization, down-regulate the level of hepcidin, and then promote the synthesis of red blood cells, and finally achieve the purpose of treating anemia
.

 It is reported that in June 2020, Daprodustat was launched in Japan
.

In March 2022, the European Medicines Agency also accepted the marketing authorization application for Daprodustat, which is currently under review¹⁻³
.

The Phase 3 clinical trial of ASCEND confirmed the efficacy and safety of Daprodustat.
This marketing application is based on the results of the Phase 3 clinical trial of Daprodustat
.

Positive results were obtained from the ASCEND series, which included five Phase 3 trials involving more than 8,000 participants to evaluate the efficacy and safety of Daprodustat
.

Two of the pivotal cardiovascular outcome trials will reveal their results at American Kidney Week in 2021 (link: Another weapon in the fight against renal anemia, the latest two study results announced, Daprodustat is safe and effective | 2021 Kidney Week special report), and in 2021 Published in NEJM ²⁻³ at the end of the year
.

1ASCEND-ND study The ASCEND-ND study is a randomized, open-label Phase 3 clinical trial evaluating the efficacy of daprodustat and daepetin alfa in patients with nondialysis-dependent CKD anemia
.

 The included patients were non-dialysis-dependent CKD stage 3-5 patients who were not only not on dialysis at the time of enrollment, but also had no plans for dialysis in the next 90 days
.

In addition, enrolled patients had serum ferritin levels >100 ng/ml and transferrin saturation >20%, but developed anemia
.

 Divided into 4 study phases, namely screening, placebo, treatment and follow-up
.

The placebo period means that before the follow-up, patients received a placebo treatment for 4 weeks, and then were divided into the Daprodustat and Daepoetin alfa groups according to the ratio of 1:1
.

 The primary endpoint is 2 non-inferiority validation endpoints, which are (1) the primary efficacy endpoint: the mean adjusted difference in hemoglobin levels from baseline during the evaluation period (28-52 weeks), and the non-inferiority cut-off value is the mean adjusted difference in hemoglobin =-0.
75g/dl; (2) Primary cardiovascular endpoint: the hazard ratio of the first major adverse cardiovascular event (death due to cardiovascular events, non-fatal myocardial infarction or non-fatal stroke) in the two groups, non-inferior The cutoff value for efficacy was hazard ratio (HR) = 1.
25
.

 The main results of the study are as follows (Table 1): Table 1.
Results of the ASCEND-ND study In addition, the risk of other adverse events in the Daprodustat group was comparable to that in the Daepoetin alfa group²
.

2ASCEND-D study ASCEND-D is a randomized, open-label Phase 3 clinical trial in patients with dialysis-dependent CKD renal anemia with a hemoglobin level of 8.
0-11.
5g/dL
.

Enrolled patients were divided into Daprodustat group or ESAs group
.

Patient exclusion criteria, primary and secondary endpoints, and study staging were all consistent with the ASCEND-ND study
.

 The results of the study are as follows (Table 2): Table 2 Results of the ASCEND-D study, with the exception of the primary adverse cardiovascular endpoint, the two groups of patients had a similar risk of other adverse events³
.

Daprodustat is expected to become the first FDA-approved HIF-PHI drug in China's standard operating procedures for blood purification (National Health and Health Commission released the standard operating procedures for blood purification (2021 version)!) It is clearly recommended that dialysis patients with anemia can receive HIF-PHI treatment
.

The HIF-PHI drug roxadustat has been marketed in China, Japan, and the European Union, and is widely used in clinical practice in China
.

In addition to the approved roxadustat, ennarstat has also submitted a marketing application in China and has been accepted
.

 There are currently no HIF-PHI drugs approved by the FDA⁴⁻⁵
.

Therefore, Daprodustat is expected to be the first FDA-approved HIF-PHI drug
.

References: 1.
US Food and Drug Administration accepts New Drug Application for daprodustat.
19 April 2022.
Link: https:// -accepts-new-drug-application-for-daprodustat/2.
Singh AK, Carroll K, McMurray JJV, et al.
Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.
NEngl J Med.
2021 Dec 16; 385(25 ): 2313-2324.
3.
Singh AK, Carroll K, Perkovic V, et al.
Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.
N EnglJ Med.
2021 Dec 16; 385(25): 2325-2335.
4.
FibroGenReceives Complete Response Letter from the FDA for Roxadustat for Anemia of Chronic Kidney Disease.
Aug.
11, 2021.
Link: https://fibrogen.
gcs-web.
com/news-releases/news-release-details/fibrogen-receives-complete-response-letter -fda-roxadustat-anemia5.
AnnaBratulic.
FDA declines to approve Akebia's CKDanaemia drug vadadustat.
FirstWord PHARMA.
MARCH 31, 2022.
Link: https://firstwordpharma.
com/story/5536693