Program: Oral and Poster Abstracts
Type: Oral
Session: 102. Regulation of Iron Metabolism: Iron Metabolism – Clinical and Translational
This study aimed to determine whether MMB’s clinical anemia benefit is driven by direct activity of MMB on the hepcidin pathway. We assayed MMB inhibitory activity on the BMP-receptor kinase pathway (the central driver of hepcidin transcription in hepatocytes) and assessed the activity of MMB in a rodent model of anemia of chronic disease (ACD). We demonstrate that MMB inhibits BMP6-induced in vitro production of hepcidin in cultured hepatocytes (HepG2 cells) with an EC50 = 651 +/- 203 nM (n=3). This inhibitory activity is mediated by direct suppresion of the BMP-receptor kinase Alk2 as MMB inhibits Alk2 enzymatic activity with an IC50 = 8.4 +/- 1.5 nM (n=3). Ruxolitinib has no activity on either Alk2 or the BMP-receptor kinase pathway. To understand whether MMB could modulate hepcidin levels in vivo and ameliorate anemia in vivo we assessed the effect of MMB in a peptidoglycan-polysaccharide fragment (PG-APS)-induced rat ACD model. Treatment with clinically relevant exposure levels of MMB for 3 days resulted in a dose dependent reduction in both liver RNA and serum protein hepcidin levels and caused an increase in serum iron. Furthermore, long-term treatment with MMB for 21 days increased the numbers and percent of reticulocytes and mature red blood cells in the bone marrow and increased Hgb and hematocrit to normal levels in the blood.
Our data suggest that MMB’s clinical anemia benefit results from inhibition of ALK2-mediated expression of hepcidin in the liver, which results in increased release of iron from sequestered cellular stores and enhanced erythropoiesis. A phase 2 translational study in anemic subjects with MPNs is scheduled to confirm this mechanism. The Alk2-mediated activity on iron metabolism through hepcidin could prove beneficial in a number of additional indications, and facilitate the combination of MMB with myelosuppressive agents.
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Disclosures: Warr: Gilead Science: Employment . Maciejewski: Gilead Science: Employment . Fowles: Gilead Science: Employment . Whitney: Gilead Sciences: Employment . Theurl: Gilead Science: Research Funding .
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