Targeting the hepcidin‐ferroportin pathway in anemia of chronic kidney disease

Aims

Erythropoiesis stimulating agents (ESAs) used to treat anemia in patients with chronic kidney disease (CKD) has been associated with cardiovascular adverse events. Hepcidin production, controlled by BMP6, regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anemia in CKD patients. To investigate alternative therapies to ESAs for CKD patients, monoclonal antibodies, LY2928057 and LY3113593, targeting ferroportin and BMP6 respectively, were tested in CKD patients.

Methods

Preclinical in vitro/vivo data and clinical data in healthy subjects and CKD patients were used to illustrate the translation of pharmacological properties of LY2928057 and LY3113593, highlighting the novelty of targeting these nodes within the hepcidin‐ferroportin pathway.

Results

LY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation (TSat) levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower hemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (1.98 [1.46‐2.68] and 1.36 [1.22‐1.51]), mean [90%CI], fold‐relative to baseline following LY2928057 600 mg and LY311593 150 mg respectively in CKD patients). LY3113593 specifically blocked BMP6 binding to its receptor and produced increases in iron and TSat and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in hemoglobin and reduction in ferritin (compared to placebo).

Conclusion

LY2928057 and LY3113593 pharmacological effects (serum iron and ferritin) were translated from preclinical‐to‐clinical development. Such interventions may lead to new CKD anemia treatments.

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