Abstract: FR-PO240
Molidustat, a Daily Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, and Vascular Endothelial Growth Factor in Patients with CKD
Session Information
- CKD: Clinical, Outcomes, Trials - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1902 CKD (Non-Dialysis): Clinical, Outcomes, and Trials
Authors
- Akizawa, Tadao, Showa University School of Medicine, Tokyo, Japan
- Macdougall, Iain C., King's College Hospital, London, United Kingdom
- Berns, Jeffrey S., University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States
- Takakura, Nobuyuki, Osaka University, Suita-shi, Japan
- Bernhardt, Thomas, Bayer AG, Berlin, Germany
- Taguchi, Megumi, Bayer Yakuhin, Ltd., Osaka, Japan
- Ogura, Eriko, Bayer Yakuhin, Ltd., Osaka, Japan
- Iekushi, Kazuma, Bayer Yakuhin, Ltd, Osaka, Japan
Background
Hypoxia-inducible factor (HIF) transcriptionally upregulates a large number of genes including erythropoietin (EPO) and vascular endothelial growth factor (VEGF). EPO gene upregulation is helpful in treating anemia, whereas VEGF upregulation could potentially exacerbate conditions such as diabetic retinopathy or malignancy. We studied whether molidustat is linked to changes in VEGF concentrations and related adverse events (AEs) in patients with chronic kidney disease (CKD).
Methods
Three Phase 2b studies (A: 16 weeks, placebo-controlled, fixed-dose; B: 16 weeks, darbepoetin-controlled, variable-dose; and C: up to 36 months, darbepoetin-controlled, extension) were conducted in anemic subjects with CKD who were not on dialysis. Plasma VEGF concentrations were compared between baseline and last visit. We also assessed adverse events (AEs) of diabetic retinopathy (DR), macular degeneration (MD) and malignancy as these may potentially be influenced by VEGF. Subjects with proliferative diabetic retinopathy and previous or concurrent cancer at baseline were excluded from the studies.
Results
The results of VEGF concentrations are shown in Table 1. DR and MD as AEs were reported in none of 101 subjects in (A), in 1 of 92 subjects (1.0%) in (B), and in 2 of 103 subjects (1.9%) in (C) in molidustat group. None were reported in comparator groups in the three studies. Malignancy as AEs were reported in 1 of 101 subjects (1.0%) in (A), in 1 of 92 subjects (1.0%) in (B), and in 3 of 103 subjects (2.9%) in (C) in molidustat group. In 2 of 41 subject (4.9%) AE was reported in darbepoetin group (C).
Conclusion
No notable differences in changes of VEGF from baseline to last visit between molidustat and comparator groups were observed. Comparable numbers of subjects with an AE of DR, MD and malignancy in molidustat and comparator groups were identified. Due to the small number of treated patients the findings will need to be confirmed in larger Phase3 studies.
Table1. VEGF concentrations at baseline and last visit
| VEGF (pg/mL) mean± SD | A | B | C | |||
| Molidustat (n=101) | Placebo (n=20) | Molidustat (n=92) | Darbepoetin (n=32) | Molidustat (n=103) | Darbepoetin (n=41) | |
| concentration at baseline | 133.2±147.3 | 137.8±163.5 | 138.3±164.7 | 109.4±71.9 | 135.3±127.8 | 114.6±83.3 |
| concentration at last visit | 157.7±167.3 | 104.6±102.2 | 141.1±120.0 | 111.2±85.6 | 118.4±114.4 | 116.3±108.9 |
Funding
- Commercial Support – Bayer AG