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Clinical Benefits

Preclinical and clinical studies to date have shown several potential clinical benefits of HIF-PHIs compared with Erythropoiesis Stimulating Agents (ESAs):

• Increase access to anemia therapy with a less expensive oral therapy that could be used earlier, in a primary care setting of chronic kidney disease (CKD). Currently, most anemic nondialysis CKD patients do not receive anemia therapy. Further, only 5% of incident dialysis patients have received ESA therapy for more than one year. This undertreatment is largely due to the fact that while dialysis patients are under the care of nephrologists, most nondialysis CKD patients are in the care of primary care physicians (PCPs) who do not have ready access to ESAs. Infrastructure concerns including inventory and personnel costs make ESAs impractical for PCPs and thus not accessible to their nondialysis patients. Referral to nephrologists is delayed: ~40% of patients are not referred to a nephrologist until there is pressing need for dialysis. We believe that any effort to bring anemia treatment to nondialysis CKD patients will require a more easily accessible and less expensive solution: oral therapy.
• Treat anemia with circulating EPO levels lower than the supraphysiologic EPO levels that result from treatment with ESAs. ESA therapy leads to circulating levels of EPO hundreds of times higher than normal. Supraphysiologic levels of circulating EPO observed with ESA therapy have been associated with poor patient outcomes, particularly in patients who do not respond well to ESAs and require large doses. In contrast, erythropoietic responses induced by HIF-PHIs can be achieved by induction of circulating levels of endogenous EPO within the normal physiologic range.
• Treat the cohort of high-risk ESA hyporesponsive patients. Analyses by FDA and others have shown an association between high ESA doses and patient survival. Patients who require the highest doses, so-called “hyporesponders,” represent 20% of dialysis and 10% of nondialysis patients. Inflammation or infection is seen as the cause of ~70% of the hyporesponse. HIF-PHI efficacy in the presence of inflammation may present a significant efficacy advantage for HIF-PHI vs. ESA in these patients.
• Provide efficacy in the presence of inflammation, where ESAs are not effective. Inflammation defined as elevated CRP level is common in dialysis (~50% of patients) and in nondialysis (~15-33%). HIF-PHI has been shown in preclinical models to be effective in presence of inflammation where the ESA darbepoetin alfa was not, indicating a potential efficacy benefit for a significant number of CKD patients and ultimately for patients with anemia associated with other inflammatory diseases such as rheumatoid arthritis.
• Treat anemia without causing ESA-induced hypertension. Eighty percent of hemodialysis patients and 47% of late stage 3-5 CKD nondialysis patients have underlying hypertension. Hypertension contributes to progression of kidney disease and cardiovascular events and for this reason, blood pressure treatment goals are lower for CKD patients. Paradoxically, ESAs are associated with significant rates of hypertension (25-40%). In contrast, HIF-PHIs have been shown to be blood pressure neutral in clinical studies and to reduce blood pressure at erythropoietic doses in animal models when ESA increased blood pressure. As blood pressure neutrality compared with ESAs could translate into a significant cardiovascular outcome benefit for patients, FibroGen will study blood pressure rigorously in upcoming clinical studies.
• Reduce or potentially eliminate the need for supplemental iron. Finally, it is likely that the HIF-PHI mechanism may be able to generate erythropoiesis with significantly less or in some patients no iron supplementation. Although newer formulations of intravenous iron have not been associated with the frequency of hypersensitivity events (anaphylaxis) observed with older iron dextran, intravenous iron still shares similar access concerns with ESAs regard to cost and method of administration to darbepoetin.