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
- Dialysis: Anemia and Iron Metabolism
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
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.
| PBO | Daprodustat (mg) | ||||
| 10 | 15 | 25 | 30 | ||
| Mean change from baseline in Hgb (g/dL) | −0.61 | −0.19 | −0.13 | 0.64 | 0.55 |
| Median maximum observed plasma EPO levels (IU/L) | 13.1 | 30.9 | 56.7 | 191.7 | 455.1 |
Funding
- Commercial Support –