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Stroke

Unmet Medical Need

Stroke is the third leading cause of death and leading cause of disability in the United States. There are approximately 700,000 strokes in the United States every year, resulting in deaths of approximately 150,000 people. Ischemic strokes, in which an obstruction such as a blood clot blocks blood flow to the brain, account for 87% percent of cases, and the remainder are hemorrhagic strokes caused by a ruptured blood vessel. Without blood flow, the affected area of the brain is deprived of oxygen and nutrients, and numerous pathological pathways are triggered. Brain cells can begin to die within minutes and further propagate the damage with the release of cytokines that can damage neighboring cells.

The only approved drug for ischemic stroke is tissue plasminogen activator (tPA), a thrombolytic agent that can dissolve clots. Several factors confound the use of tPA, however, resulting in fewer than 5% of stroke patients being treated. For example, tPA must be given within 3 hours after symptom onset, but it can be fatal in hemmorrhagic stroke and therefore requires that a CT scan be performed prior to administration. Further, research suggests that less than a quarter of stroke patients arrive at the hospital within 3 hours of symptom onset, another factor reducing the eligible patient population for tPA. Additionally, tPA does not address other pathological processes that cause neuronal cell death.

There is a significant unmet need in stroke for a therapy that can salvage brain cells by delaying the onset of cell death in nutrient deprived tissues until blood flow can be resumed. While the cells in the core of the affected portion, the infarct, cannot be recovered, there is a large surrounding region that is more mildly affected and represents tissue that may be salvaged. Because time is of the essence to rescue these brain cells, a neuroprotective strategy applicable to both ischemic and hemorrhagic stroke is advantageous because the type of stroke need not be determined prior to treatment.

Traumatic brain injury (TBI) represents another large unmet medical need with approximately 1.4 million cases of TBI in the US each year. Of these cases, some 240,000 require hospitalization. Currently, mannitol may be injected to treat brain swelling, but very little else is done to treat TBI.

Erythropoietin as a Neuroprotectant

Studies have shown that erythropoietin (EPO), a hormone best known for its role in promoting erythropoiesis, also exhibits important anti-inflammatory and neuroprotective effects under conditions of cerebral ischemia and hypoxia. In animal models of stroke, administration of recombinant EPO into the brain reduces the size of the infarct, indicating that EPO promotes survival of brain cells that would otherwise have died.¹ These results were extended to humans for the first time in the late 1990’s as part of a clinical study known as the “Göttingen EPO-Stroke-Trial”. In this small pilot study, stroke patients treated with recombinant EPO showed significantly better functional outcome and a less pronounced neurological deficit that the placebo group.²

Neuroprotective HIF-PHI

FibroGen research has shown that HIF-PHI induce cytoprotective genes in the central nervous system and demonstrate significant neuroprotection in relevant models of ischemic stroke with and without reperfusion injury (i.e. transient and permanent middle cerebral artery occlusion models). The neuroprotective efficacy of HIF-PHI therapy is not diminished even when drug is administered several hours post-injury. Efficacious doses of HIF-PHI induce circulating EPO to levels that are within physiological range and that are much lower than levels of recombinant human EPO reported to provide neuroprotection, suggesting the involvement of additional cytoprotective pathways in HIF-PHI-mediated protection against cerebral ischemia.^3-4

References

1. Brines ML, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. PNAS. 2000;97:10526–31.
2. Ehrenreich H, et al., Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495-505.
3. Langsetmo I, et al. Inhibition of HIF-prolyl hydroxylases with FG-4539 is neuroprotective in a rat model of transient middle cerebral artery occlusion. Presented at: International Stroke Conference 2007; February 7–9, 2007; San Francisco, CA.
4. Haque, N., et al (2008) Novel HIF Prolyl Hydroxylase Inhibitors Are Neuroprotective in Both Permanent and Transient Rodent Models of Middle Cerebral Artery Occlusion (MCAO). Keystone Symposia Molecular, Cellular, Physiological and Pathogenic Responses of Hypoxia: Abstract 214.