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Currently, only Roxastat has been approved for marketing in China among the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of renal anemia.
In September 2020, the American company Akebia issued an announcement that its product Vadaustat (HIF-PHI) has completed phase III clinical trials.
On April 29, 2021, Vadaustat's Phase III clinical trial data was published in the New England Journal of Medicine.
This article will combine the test data and the progress of the market to analyze Vadaustat for everyone.
Study design The phase III clinical trials of Vadaustat are divided into 2 items, all of which are international, randomized, open, active controlled, and non-inferiority trials.
Researchers mainly compared the effectiveness and safety of Vadaustat and erythropoietin (ESA) alfa epoetin in patients with non-dialysis chronic kidney disease.
The design of the two trials is almost the same, the only difference is the history of ESA treatment before enrollment.
For patients who have not used ESA before, the baseline hemoglobin concentration is less than 10g/dL, while for patients who have used ESA before, the baseline hemoglobin concentration is 8-11g/dL (US) or 9-12g/dL (other countries) between.
The endpoints of the trial are divided into efficacy endpoints and safety endpoints.
The primary and secondary efficacy evaluation periods are respectively from the 24th week to the 36th week and the 40th week to the 52nd week.
The evaluation index is the change in hemoglobin concentration from its baseline.
The primary safety endpoint of the trial was the proportion of patients who had a major adverse cardiovascular event (MACE) for the first time and the associated risk ratio (HR).
MACE included non-fatal myocardial infarction or non-fatal stroke and any death caused by cardiovascular disease.The secondary safety endpoint is the proportion of patients who expand MACE (on the basis of MACE plus hospitalization due to heart failure or thromboembolism) and related HR.
The results of the study were a total of 1,751 patients with non-dialysis chronic kidney disease who had not received ESA treatment and were included in trial 1.
Another 1,725 patients who had received ESA were included in trial 2.
A total of 3476 patients were enrolled in the two trials, and they were assigned to the Vadadustat group and the alfa epoetin group according to 1:1.
Trial 1 was followed up for an average of 1.
63 years, and Trial 2 was followed up for an average of 1.
80 years.
In terms of the primary efficacy endpoint, the increase interval of hemoglobin concentration in the Vadadustat group was 1.
43±0.
05g/dL, the epoetin alfa group was 1.
38±0.
05g/dL, and the least mean square between the groups was 0.
05±0.
05g/dL ( 95% CI, -0.
04 to 0.
15).
In terms of secondary efficacy endpoints, the increasing interval of hemoglobin concentration in the Vadadustat group was 1.
52±0.
05 g/dL, and the epoetin alfa group was 1.
48±0.
05 g/dL, and the least mean square between the groups was 0.
04±0.
05 g/dL (95 % CI, -0.
06 to 0.
14).
The least mean squares between the primary and secondary efficacy endpoints were lower than the pre-specified non-inferiority threshold (0.
75g/dL).
In terms of hematological efficacy, there is no significant difference between Vadadustat and epoetin alfa.
Among the primary safety endpoints, two trials were cross-analyzed and found that 22.
0% of patients in the Vadadustat group had MACE, and 19.
9% in the epoetin alfa group.
The HR of MACE in both groups was 1.
17 (95% CI, 1.
01 to 1.
36).
In terms of secondary safety endpoints, 25.
9% of patients in the Vadadustat group had extended MACE, compared with 24.
5% in the epoetin alfa group, and the HR of the two extended MACE groups was 1.
11 (95% CI, 0.
97 to 1.
27).
The results of the primary and secondary safety endpoints did not meet the pre-set non-inferiority threshold (HR 1.
25). In terms of cardiovascular risk, Vadaustat did not meet the non-inferiority criteria for cardiovascular safety.
The incidence of serious adverse events in the Vadadustat group was 49.
7% in patients who did not receive ESA treatment, and the incidence in patients who received ESA treatment was 55.
0%; while the incidence in the alfa epoetin group was 56.
5% and 58.
3%, respectively.
In general, there is no significant difference in the efficacy and safety of anemia between Vadaustat and ESA, but Vadaustat does not meet the pre-specified non-dialysis cardiovascular safety and non-inferiority standards for patients with chronic kidney disease.
It is worth noting that cardiovascular risk is not a problem with the HIF-PHI series of drugs.
Roxastat, a drug with the same mechanism that has been approved for marketing in China, has no cardiovascular risk.
Listing progress Akebia has submitted a new drug application to the US Food and Drug Administration.
The specific content is that Vaduastat is used to treat adult patients with chronic kidney disease anemia regardless of whether they are receiving dialysis.
At present, Vaduastat has passed the approval of the Pharmaceuticals and Medcial Devices Agency (PMDA) of Japan.
Summary Vadaustat's failure to achieve cardiovascular safety-related non-inferiority indicators is interesting news.
Clinicians can observe in actual work whether the same mechanism drug-rosastat has cardiovascular risk for patients with non-dialysis chronic kidney disease? References: 1.
Akebia.
Akebia Therapeutics Announces Positive Top-Line Results from Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients on Dialysis.
Press release.
May 5 2020.
2.
Mark E.
Neumann.
Phase 3 data published on anemia drug vadadustat.
Healio.
May 06, 2021.
3.
Chertow GM, Pergola PE, Farag YMK, et al.
Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.
N Engl J Med.
Apr 29, 2021.
4.
PMDA.
New Drugs Approved in June 2020.
Pharmaceuticals and Medcial Devices Agency.
May 07, 2021.
In September 2020, the American company Akebia issued an announcement that its product Vadaustat (HIF-PHI) has completed phase III clinical trials.
On April 29, 2021, Vadaustat's Phase III clinical trial data was published in the New England Journal of Medicine.
This article will combine the test data and the progress of the market to analyze Vadaustat for everyone.
Study design The phase III clinical trials of Vadaustat are divided into 2 items, all of which are international, randomized, open, active controlled, and non-inferiority trials.
Researchers mainly compared the effectiveness and safety of Vadaustat and erythropoietin (ESA) alfa epoetin in patients with non-dialysis chronic kidney disease.
The design of the two trials is almost the same, the only difference is the history of ESA treatment before enrollment.
For patients who have not used ESA before, the baseline hemoglobin concentration is less than 10g/dL, while for patients who have used ESA before, the baseline hemoglobin concentration is 8-11g/dL (US) or 9-12g/dL (other countries) between.
The endpoints of the trial are divided into efficacy endpoints and safety endpoints.
The primary and secondary efficacy evaluation periods are respectively from the 24th week to the 36th week and the 40th week to the 52nd week.
The evaluation index is the change in hemoglobin concentration from its baseline.
The primary safety endpoint of the trial was the proportion of patients who had a major adverse cardiovascular event (MACE) for the first time and the associated risk ratio (HR).
MACE included non-fatal myocardial infarction or non-fatal stroke and any death caused by cardiovascular disease.The secondary safety endpoint is the proportion of patients who expand MACE (on the basis of MACE plus hospitalization due to heart failure or thromboembolism) and related HR.
The results of the study were a total of 1,751 patients with non-dialysis chronic kidney disease who had not received ESA treatment and were included in trial 1.
Another 1,725 patients who had received ESA were included in trial 2.
A total of 3476 patients were enrolled in the two trials, and they were assigned to the Vadadustat group and the alfa epoetin group according to 1:1.
Trial 1 was followed up for an average of 1.
63 years, and Trial 2 was followed up for an average of 1.
80 years.
In terms of the primary efficacy endpoint, the increase interval of hemoglobin concentration in the Vadadustat group was 1.
43±0.
05g/dL, the epoetin alfa group was 1.
38±0.
05g/dL, and the least mean square between the groups was 0.
05±0.
05g/dL ( 95% CI, -0.
04 to 0.
15).
In terms of secondary efficacy endpoints, the increasing interval of hemoglobin concentration in the Vadadustat group was 1.
52±0.
05 g/dL, and the epoetin alfa group was 1.
48±0.
05 g/dL, and the least mean square between the groups was 0.
04±0.
05 g/dL (95 % CI, -0.
06 to 0.
14).
The least mean squares between the primary and secondary efficacy endpoints were lower than the pre-specified non-inferiority threshold (0.
75g/dL).
In terms of hematological efficacy, there is no significant difference between Vadadustat and epoetin alfa.
Among the primary safety endpoints, two trials were cross-analyzed and found that 22.
0% of patients in the Vadadustat group had MACE, and 19.
9% in the epoetin alfa group.
The HR of MACE in both groups was 1.
17 (95% CI, 1.
01 to 1.
36).
In terms of secondary safety endpoints, 25.
9% of patients in the Vadadustat group had extended MACE, compared with 24.
5% in the epoetin alfa group, and the HR of the two extended MACE groups was 1.
11 (95% CI, 0.
97 to 1.
27).
The results of the primary and secondary safety endpoints did not meet the pre-set non-inferiority threshold (HR 1.
25). In terms of cardiovascular risk, Vadaustat did not meet the non-inferiority criteria for cardiovascular safety.
The incidence of serious adverse events in the Vadadustat group was 49.
7% in patients who did not receive ESA treatment, and the incidence in patients who received ESA treatment was 55.
0%; while the incidence in the alfa epoetin group was 56.
5% and 58.
3%, respectively.
In general, there is no significant difference in the efficacy and safety of anemia between Vadaustat and ESA, but Vadaustat does not meet the pre-specified non-dialysis cardiovascular safety and non-inferiority standards for patients with chronic kidney disease.
It is worth noting that cardiovascular risk is not a problem with the HIF-PHI series of drugs.
Roxastat, a drug with the same mechanism that has been approved for marketing in China, has no cardiovascular risk.
Listing progress Akebia has submitted a new drug application to the US Food and Drug Administration.
The specific content is that Vaduastat is used to treat adult patients with chronic kidney disease anemia regardless of whether they are receiving dialysis.
At present, Vaduastat has passed the approval of the Pharmaceuticals and Medcial Devices Agency (PMDA) of Japan.
Summary Vadaustat's failure to achieve cardiovascular safety-related non-inferiority indicators is interesting news.
Clinicians can observe in actual work whether the same mechanism drug-rosastat has cardiovascular risk for patients with non-dialysis chronic kidney disease? References: 1.
Akebia.
Akebia Therapeutics Announces Positive Top-Line Results from Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients on Dialysis.
Press release.
May 5 2020.
2.
Mark E.
Neumann.
Phase 3 data published on anemia drug vadadustat.
Healio.
May 06, 2021.
3.
Chertow GM, Pergola PE, Farag YMK, et al.
Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.
N Engl J Med.
Apr 29, 2021.
4.
PMDA.
New Drugs Approved in June 2020.
Pharmaceuticals and Medcial Devices Agency.
May 07, 2021.
