All currently available EPO-stimulating agents (ESAs) flood the body with synthetic forms of EPO at levels 100- to 100,000-fold greater than normal physiologic levels of the naturally occurring molecule, said FibroGen CEO Thomas Neff. These supraphysiologic doses have been linked to increased risk of severe adverse events such as death, stroke, myocardial infarction and hospitalization for congestive heart failure, although the molecular cause is unknown. ESAs also increase the risk of seizures and high blood pressure, and some patients experience hypersensitivity reactions; such reactions led to the market withdrawal of Omontys (peginesatide) from Affymax of Palo Alto, California, and its partner Takeda of Osaka in February (Nat. Biotechnol. 31, 270, 2013).
By contrast, HIF-PH inhibitors work by triggering the body's natural response to hypoxia, similar to when a person is at high altitude. In a hypoxic environment, the transcription factor HIF triggers a wide range of coordinated responses in numerous tissues, namely erythropoiesis, vasculogenesis and cytoprotection, including cardioprotection, renoprotection and neuroprotection. HIF is a heterodimer, whose subunits are constantly made in nearly every cell in the body. HIF is not constantly functioning because, under normal oxygen conditions, HIF-PH puts on the brakes by degrading one of HIF's subunits. Under hypoxic conditions, as HIF-PH requires oxygen as a substrate, the brake is released, and HIF is free to function.
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