Targeting the hepcidin–ferroportin pathway in anaemia of chronic kidney disease

• Published in: British journal of clinical pharmacology Vol. 85; no. 5; pp. 935 - 948
• Main Authors: Sheetz, Matthew, Barrington, Philip, Callies, Sophie, Berg, Paul H., McColm, Juliet, Marbury, Thomas, Decker, Brian, Dyas, Gregory L., Truhlar, Stephanie M.E., Benschop, Robert, Leung, Donmienne, Berg, Jolene, Witcher, Derrick R.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.05.2019
• Subjects: Adult; Anemia - blood; Anemia - drug therapy; Anemia - etiology; Anemia - metabolism; Animals; Bone Morphogenetic Protein 6 - antagonists & inhibitors; Bone Morphogenetic Protein 6 - metabolism; Cation Transport Proteins - antagonists & inhibitors; Cation Transport Proteins - metabolism; chronic kidney disease; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Ferritins - blood; Ferritins - metabolism; Healthy Volunteers; Hematologic Agents - pharmacology; Hematologic Agents - therapeutic use; Hemoglobins - analysis; Hepcidins - metabolism; Humans; immunoglobulins; Iron - blood; Iron - metabolism; Macaca fascicularis; Male; Mice; Middle Aged; Original; Rats; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - metabolism; Signal Transduction - drug effects; transport; Treatment Outcome; Young Adult; immunoglobulins; chronic kidney disease; transport
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.13877

Aims Erythropoiesis‐stimulating agents used to treat anaemia in patients with chronic kidney disease (CKD) have been associated with cardiovascular adverse events. Hepcidin production, controlled by bone morphogenic protein 6 (BMP6), regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anaemia in CKD patients. To investigate alternative therapies to erythropoiesis‐stimulating agents for CKD patients, monoclonal antibodies, LY3113593 and LY2928057, targeting BMP6 and ferroportin 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 LY3113593 and LY2928057, 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 levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower haemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (mean [90% confidence interval]) 1.98 [1.46–2.68] and 1.36 [1.22–1.51] 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 transferrin saturation and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in haemoglobin and reduction in ferritin (compared to placebo). Conclusion LY3113593 and LY2928057 pharmacological effects (serum iron and ferritin) were translated from preclinical‐to‐clinical development. Such interventions may lead to new CKD anaemia treatments.