Framework to Assess the Benefits and Risks of Treatments and Dosing Regimens for Anemia of CKD

Background: Vadadustat (VADA) is an oral HIF prolyl hydroxylase inhibitor approved for treating anemia in adults with CKD on dialysis. VADA stabilizes HIF, stimulates endogenous EPO production, increases iron mobilization and RBC production. It is approved for use in 38 countries. The recommended starting dose for VADA is 300mg QD, with dose adjustments between 150-600mg to maintain Hb levels within target range. Alternative dosing regimens may be beneficial based on patient characteristics or preferences. We developed a framework to balance benefits and risks of VADA treatment with different treatment regimens. Methods: The framework was developed by first identifying and ranking treatment attributes associated with any treatment for CKD-related anemia including efficacy, safety, and tolerability outcomes. An importance value (0-100) was assigned to each attribute. Specific outcome measures and relevant responses associated with each attribute were identified. Weights for each response within an attribute were elicited. The result was the benefit-risk framework in which a given treatment regimen could be assigned a net benefit or clinical utility score based on its performance in the benefit-risk framework, with the utility scores ranging from 0-100 after normalization. Results: We identified and ranked 7 attributes (1 efficacy, 4 safety, and 2 tolerability/convenience) that contribute to the overall utility of a treatment for CKD anemia. Overall, efficacy (transfusion avoidance) contributed 25% to the utility score, while safety attributes (incidence of MACE, thromboembolic events, hospitalization for HF, and vascular access thromboses) contributed 60% of the net benefit; tolerability and convenience contributed the remaining 15% of utility. When combined with mathematical models predicting the probability of a given response for each attribute, the expected benefit-risk tradeoff for that regimen could be calculated and compared against alternative treatments or dosing regimens. Conclusion: This benefit-risk framework will be used to identify and optimize treatment regimens for VADA in comparison to the standard of care (ESAs). Funding: Commercial Support - Akebia Therapeutics, Inc.