FG-4539 is an orally active small molecule inhibitor of HIF prolyl hydroxylase in clinical development for the treatment of conditions associated with tissue injury or damage in the brain (e.g., stroke), heart (e.g., myocardial infarction), and kidney (e.g., acute renal failure). In these medical conditions, organs are deprived of oxygen and nutrients essential for cell survival and function. By triggering the body's natural response to oxygen deficiency via the HIF system, FibroGen's HIF prolyl hydroxylase inhibitors activate factors that protect against tissue damage or injury by promoting cell survival and preventing programmed cell death (apoptosis). FG-4539 was chosen for its ability to coordinately activate a spectrum of cytoprotective factors to maximize therapeutic benefit in such situations when a vital organ is deprived of oxygen.

Over the past decade, FibroGen has amassed extensive data documenting profound therapeutic effects of prolyl hydroxylase inhibitors. HIF-activated factors that promote cell survival and prevent programmed cell death include anti-apoptotic factors such as EPO and VEGF; anti-oxidant enzymes, such as heme-oxygenase-1, which decrease free radical damage and limit reperfusion injury (damage from restoration of blood flow to a tissue or organ); and vasodilatory factors, such as nitric oxide and adrenomedullin, which enhance tissue perfusion (blood flow).

Preclinical Studies

The neuroprotective potential of HIF prolyl hydroxylase inhibitors has been demonstrated in models of permanent and transient ischemic stroke. In the permanent model, FG-4539 provided significant tissue protection in the brain when administered up to 5 hours after permanent occlusion of the middle cerebral artery. In a short-term study using the transient model of ischemic stroke, treatment with FG-4539 resulted in significant reductions in total tissue damage, core infarct size, and amount of edema (swelling) as assessed 48 hours post occlusion. Functional recovery was assessed in a long-term study using the transient model of ischemic stroke, and animals treated intermittently with FG-4539 exhibited accelerated recovery in grip strength and tactile adhesion tests when compared to controls. FG-4539 also has been shown to induce cytoprotective genes in the central nervous system.

Renal ischemia reperfusion injury models showed that FG-4539, administered either prior to or after injury, enhanced HIF-responsive gene expression and preserved renal function in both rats and mice.

Treatment with FG-4539 preserved kidney function in the model of radiocontrast-induced nephropathy (RCN) in the spontaneously hypertensive rat when administered prior to injury.