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Item The approval process for biosimilar erythropoiesis-stimulating agents(American Society of Nephrology, 2014-09-05) Wish, Jay B.; Department of Medicine, IU School of MedicineA biosimilar drug or follow-on biologic drug is defined by the Public Health Service Act as a product that is "highly similar to the reference product notwithstanding minor differences in clinically active components and there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity and potency of the product." The advantage of biosimilar drugs is that they are significantly less expensive than the reference products, allowing for increased accessibility and cost savings. Recognizing these advantages, the US Congress passed the Biologics Price Competition and Innovation Act in 2009 as part of health care reform. The Biologics Price Competition and Innovation Act allows sponsors of biosimilar agents to seek approval by showing structural and functional similarity to the reference agent, with the extent of required clinical studies to be determined on the basis of the degree of biosimilarity with the reference product. The goal is to bring biosimilar agents to the market more efficiently while still protecting the safety of the public. The European Union has had such a process in place for a number of years. Two biosimilar epoetin agents have been approved in the European Union since 2007, and their companies are conducting trials to seek approval in the United States, because Amgen's patent protection for epoetin alfa expires in 2014. Trials completed for European Union approval of both agents showed similar efficacy and safety to the reference epoetin alfa. As with all biologics, immunogenicity concerns may persist because of the fragility of the manufacturing process and the worldwide experience with pure red cell aplasia as a result of epoetin therapy. The uptake of biosimilar epoetins after approval in the United States will depend on the balance of cost advantage against safety concerns. Competition in the marketplace will likely decrease the cost of the reference agent as well.Item Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease(Wiley, 2022) Koury, Mark J.; Agarwal, Rajiv; Chertow, Glenn M.; Eckardt, Kai-Uwe; Fishbane, Steven; Ganz, Tomas; Haase, Volker H.; Hanudel, Mark R.; Parfrey, Patrick S.; Pergola, Pablo E.; Roy-Chaudhury, Prabir; Tumlin, James A.; Anders, Robert; Farag, Youssef M.K.; Luo, Wenli; Minga, Todd; Solinsky, Christine; Vargo, Dennis L.; Winkelmayer, Wolfgang C.; Medicine, School of MedicinePatients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.Item A randomized trial of intravenous and oral iron in chronic kidney disease(Nature Publishing Group, 2015-10) Agarwal, Rajiv; Kusek, John W.; Pappas, Maria K.; Department of Medicine, IU School of MedicineAlthough iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m(2), intravenous -4.0 ml/min per 1.73 m(2), between-group difference -0.35 ml/min per 1.73 m(2); 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56-4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24-3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases.