Therapeutics: vadadustat for anaemia

Anaemia is a common secondary disease to chronic kidney disease, particularly for those patients who are on dialysis

Treatment generally relies on drugs such as erythropoietin and its derivatives, but this can lead to substantial oscillations in haemoglobin levels and high levels of erythropoietin in the blood, and alternatives are limited.

Akebia Therapeutics is investigating an alternative drug, vadadustat. This titratable drug acts as an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, which induces endogenous erythropoietin synthesis and enhances iron mobilisation.

A Phase IIa multicentre, randomised, double-blind, placebo-controlled, dose ranging study was done in 93 adults with anaemia that was secondary to stage 3 or 4 chronic kidney disease.1

Subjects were given 240, 370, 500 or 630 mg of oral vadadustat once a day or a placebo for 6 weeks. All were also given 50 mg daily iron supplements.

The drug increased the total iron binding capacity and decreased the concentrations of both hepcidin and ferritin; adverse event profiles were similar across both treatment and placebo groups.

In a double-blind, randomised, placebo-controlled Phase IIb trial, non-dialysis-dependent chronic kidney disease patients were given once daily doses of vadadustat.2

In all, 55% of the patients on the drug achieved or maintained a mean haemoglobin level of 11 g/dL, or a mean increase of 1.2 g/dL over the predose average, compared with 10% of the placebo group. Adverse events were comparable.

Its effect has also been compared directly with epoetin alpha treatment.3 In an open label Phase II trial, 94 subjects undergoing dialysis who had previously been given epoetin alfa were given 300 or 450 mg of vadadustat, once a day, or 450 mg three times a week.

The primary endpoint was mean haemoglobin change from the prebaseline average and, for all the dose cohorts, there was no statistically significant mean change in haemoglobin, so the effect previously given by epoetin alfa was maintained.

A total of 83% of the subjects had some form of adverse events, which was similar across the groups. The most common were nausea, diarrhoea and vomiting, but no serious adverse events were attributed to the drug.

Top-line results of a Phase III study comparing its activity with darbepoetin alpha have been released via press release. Across this and a second Phase III trial, nearly 4000 patients on dialysis with anaemia were recruited for a non-inferiority study.

Subjects were given an oral starting dose of 300 mg/day, adjusted in increments of 150 mg up to a maximum of 600 mg. The primary endpoint was the mean change in haemoglobin between baseline and the primary evaluation period at 24–36 weeks, and the drug was found to be non-inferior to darbepoetin.

References

  1. E.R. Martin, et al., Am. J. Nephrol. 45, 380 (2017).
  2. P.E. Pergola, et al., Kidney Int. 90, 1115 (2016).
  3. V.H. Haase, et al., Nephrol. Dial. Transplant. 34, 90 (2019).

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