Data on Vadadustat ( AKB-6548 ) were presented at the 2014 European Renal Association - European Dialysis and Transplant Association ( ERA-EDTA ) 51st Congress held in Amsterdam.
Vadadustat is a once-daily, oral hypoxia-inducible factor prolyl hydroxylase ( HIF-PHD ) inhibitor in development for the treatment of anemia related to chronic kidney disease ( CKD ) who are not dependent on dialysis.

In the previously presented double-blind, placebo-controlled phase 2a trial, Vadadustat effectively increased haemoglobin ( Hb ) levels in patients with CKD in a controlled manner while keeping the maximum Hb level below 13 g/dL throughout the dosing period.
Vadadustat was generally well-tolerated across the dosing groups with no drug-related serious adverse events.

The phase 2a double-blind, placebo-controlled study enrolled patients with CKD stage 3, 4 or 5, not on dialysis, with haemoglobin less than or equal to 10.5 g/dL. Patients were randomized to receive either placebo ( n=19 ) or Vadadustat ( n=72 ) 240 mg, 370 mg, 500 mg or 630 mg once daily for six weeks.
Haemoglobin was monitored at each study visit during dosing and was used to determine if the dose of study medication was to be reduced or discontinued. A one-time dose reduction was allowed during the study for any subject responding in excess of protocol-defined Hb values.

As previously presented, Vadadustat increased total iron-binding capacity and increased Hb levels with a clear dose-response relationship.
There was no observed negative impact on key biomarkers of kidney health, with no change from baseline in vascular endothelial growth factor ( VEGF ), C-reactive protein and Cystatin-C, and there were no drug-related serious adverse events.

Vadadustat, a once-daily oral therapyis, is designed to stabilize hypoxia-inducible factor ( HIF ), a transcription factor that regulates the expression of genes involved with red blood cell ( RBC ) production in response to changes in oxygen levels, by inhibiting the hypoxia-inducible factor prolyl hydroxylase ( HIF-PHD ) enzyme.
Vadadustat exploits the same mechanism of action used by the body to naturally adapt to lower oxygen availability associated with a moderate increase in altitude.
At higher altitudes, the body responds to lower oxygen availability with increased production of HIF, which coordinates the interdependent processes of iron mobilization and erythropoietin ( EPO ) production to increase red blood cell production and, ultimately, improve oxygen delivery.
Due to its specific HIF effect, Vadadustat has the potential to restore coordination of the interdependent processes of iron mobilization and EPO production that are disrupted in patients with anemia related to CKD.

Vadadustat, a HIF stabilizer, may raise hemoglobin levels and red blood cell count predictably and sustainably, with an optimal safety profile and a dosing regimen that allows for a gradual and controlled titration.
Furthermore, Vadadustat may improve iron mobilization, potentially eliminating intravenous Iron administration and reducing the overall need for Iron supplementation. ( Xagena_2014 )

Source: Akebia Therapeutics, 2014

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