Abstract: SA-PO811

A 29-Day Safety, Efficacy, and Pharmacodynamic Study of a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, Daprodustat, Administered TIW in Anemic Subjects on Hemodialysis (HD)

Session Information

Category: Dialysis

  • 605 Dialysis: Anemia and Iron Metabolism

Authors

  • Bailey, Christine K, GlaxoSmithKline, Collegeville, Pennsylvania, United States
  • Caltabiano, Stephen, GlaxoSmithKline, Collegeville, Pennsylvania, United States
  • Cobitz, Alexander Ralph, GlaxoSmithKline, Collegeville, Pennsylvania, United States
  • Huang, Chun, GlaxoSmithKline, Collegeville, Pennsylvania, United States
  • Mahar, Kelly M, GlaxoSmithKline, Collegeville, Pennsylvania, United States
  • Patel, Vickas, GlaxoSmithKline, Collegeville, Pennsylvania, United States
  • Zeig, Steven, Pines Clinical Research, Inc., Hollywood, Florida, United States
Background

This randomized, double-blind, placebo (PBO)-controlled study (funded by GSK) examined the relationship between daprodustat TIW dosing and hemoglobin (Hgb) level and safety over 29 days in 103 subjects on HD > 3 times weekly and who were previously receiving a stable dose of an erythropoiesis-stimulating agent (ESA).

Methods

Subjects with baseline Hgb of 9.0–11.5 g/dL discontinued ESAs and were randomized to receive daprodustat 10, 15, 25, or 30 mg TIW or PBO.

Results

Mean baseline Hgb was 10.6 g/dL for all randomized subjects. Switching from an ESA to daprodustat produced dose-dependent mean changes in Hgb (g/dL) from baseline and maximum EPO after 29 days (Table).

Day 29 pre-dose EPO levels were near or below baseline values, indicating no accumulation of EPO after daprodustat TIW treatment. At Day 29, mean hepcidin levels were reduced from baseline in a dose-dependent manner by an overall mean of 11.7% in subjects in the combined daprodustat group compared with a mean increase of 27.8% in the PBO group. Daprodustat was generally well tolerated, with an adverse event profile consistent with the HD population. No new safety concerns were identified.
Based on the TIW dose-response relationship in this study and the QD dose-response relationship in the prior study PHI113633, each characterized by a Bayesian Emax model, the dose conversion ratio between QD to TIW dosing of daprodustat was ~ 2.0 across the dose range.

Conclusion

These data inform the Hgb dose-response relationship of daprodustat in anemic HD subjects who were switched from a stable dose of ESA and treated with daprodustat TIW for 29 days. Daprodustat TIW treatment reduced hepcidin levels and increased plasma EPO levels in a dose-dependent manner. These data support future longer-term clinical studies in patients on HD to further explore daprodustat TIW to treat anemia of CKD.

 PBODaprodustat (mg)
 10152530
Mean change from baseline in Hgb (g/dL)−0.61−0.19−0.130.640.55
Median maximum observed plasma EPO levels (IU/L)13.130.956.7191.7455.1

Funding

  • Commercial Support