Vafseo: what flexibility did regulators accept, and why?

“Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD (Table 63). Key to interpreting the toxicology data is to understand that the nonclinical toxicology studies were conducted in healthy and non-anemic animals, in which vadadustat produces polycythemia.”

“However, a similar exposure-response to vadadustat would not necessarily occur in patients with anemia for whom increased erythropoiesis is the intent of treatment, and for which the degree of induced erythropoiesis is a primary efficacy and safety monitoring endpoint.”

“Vadadustat was negative for mutagenicity (Ames assay) but positive results were obtained in the in vitro CHO assay for chromosomal aberrations and the GreenScreen assay.”

“Overall, the in vivo chromosome aberration assay and COMET assays tested negative and, in conjunction with the negative Ames assay result, the weight of evidence suggests that vadadustat is not genotoxic, which is agreed.”