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Assessing the Carcinogenicity of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, in
Heather Kowalski1, Debie Hoivik1, Michael Rabinowitz1
1Akebia Therapeutics, Inc., Cambridge, Massachusetts, USA.
Abstract:
Vadadustat is an investigational oral hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitor to treat anemia due to chronic kidney disease (CKD). Some studies suggest that HIF activation promotes tumorigenesis by activating angiogenesis downstream of vascular endothelial growth factor, while other studies suggest that elevated HIF activity may produce an antitumor phenotype. To evaluate the potential carcinogenicity of vadadustat in mice and rats, we dosed CByB6F1/Tg.rasH2 hemizygous (transgenic) mice orally by gavage with 5 to 50 mg/kg/d of vadadustat for 6 months and dosed Sprague-Dawley rats orally by gavage with 2 to 20 mg/kg/d for approximately 85 weeks. Doses were selected based on the maximally tolerated dose established for each species in previous studies. The tumors that were identified in the studies were not considered to be treatment-related for statistical reasons or within the historical control range. There was no carcinogenic effect attributed to vadadustat in mice or rats.
Insights
Vadadustat, a hypoxia-inducible factor prolyl-4-hydroxylase inhibitor for anemia in chronic kidney disease, showed no carcinogenic effects in 6-month mouse and 85-week rat studies.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- Anemia associated with chronic kidney disease (CKD) is a common complication.
- Hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitors, like vadadustat, are being investigated for CKD anemia treatment.
- The role of HIF activation in tumorigenesis is complex, with conflicting evidence regarding its potential to promote or inhibit tumor growth.
Purpose of the Study:
- To evaluate the potential carcinogenicity of the investigational drug vadadustat.
- To assess the long-term safety profile of vadadustat concerning tumor development in preclinical models.
Main Methods:
- CByB6F1/Tg.rasH2 hemizygous mice were administered vadadustat orally at doses of 5 to 50 mg/kg/d for 6 months.
- Sprague-Dawley rats received oral vadadustat at doses of 2 to 20 mg/kg/d for approximately 85 weeks.
- Dose selection was based on previously determined maximally tolerated doses for each species.
Main Results:
- Tumors identified in both mice and rats were not statistically linked to vadadustat treatment.
- Tumor incidence in treated animals remained within the historical control range for both species.
- No carcinogenic effect was attributed to vadadustat administration in either the mouse or rat studies.
Conclusions:
- Vadadustat did not demonstrate carcinogenic potential in the conducted rodent studies.
- These findings support the continued investigation of vadadustat for the treatment of anemia in patients with chronic kidney disease.
