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Cytoprotection Clinical Studies

Phase 1 Study with FG-4539 Completed

FibroGen nominated FG-4539 as its first clinical candidate from the company’s cytoprotective HIF-PHI development program. FG-4539 has been demonstrated to provide functional cytoprotective effects in animal models of acute kidney injury,^1,2  myocardial infarction and stroke,^3,4  even when administered after injury had been incurred. Initial clinical development plans focused on evaluating FG-4539 in the context of myocardial infarction, where recombinant human EPO is being actively evaluated for its cytoprotective effect. FibroGen believes more complete cytoprotection can be obtained through HIF stabilization using HIF-PHI.

FG-4539 was the subject of a phase 1 study in which an escalating range of single doses were tested in normal volunteers to assess safety, pharmacokinetics and a select list of biomarkers expected to respond to induction by HIF stabilization. The study was a randomized, single-blind, placebo-controlled, single ascending dose study. Seven subjects (5 active and 2 placebo) were enrolled in each of 7 sequential dose groups. A total of 49 male subjects received FG-4539 or placebo during the study. No serious adverse events or dose-limiting toxicities were reported in this study, and none of the subjects were discontinued due to an adverse event. HIF-responsive gene induction by FG-4539 was potent with measurable increases in plasma EPO with the lowest dose. Subsequent doses elicited dose dependent increase in several other HIF-responsive genes that returned to baseline levels in 24 to 48 hours.

References

1. Guo et al. (2004) Improvement of Kidney Function in a rat model of renal ischemia-reperfusion injury by treatment with a novel HIF Prolyly Hydroxylase Inhibitor. JASN 2004;15:460A
2. Wang Q et al. (2006) Renoprotective and therapeutic efficacy of the HIF prolyl hydroxylase inhibitor FG-4539 in experimental ischemia-reperfusion induced acute kidney injury JASN 17:325A
3. Langsetmo I et al. (2006) Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is neuroprotective in a mouse model of permanent focal ischemia. International Stroke Conference 2006 Abstract 427
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