FibroGen Reports New Research on Development of HIF Prolyl Hydroxylase Inhibitors Related to Endothelial Progenitor Cells, Anti-Inflammation, Cytoprotection and Erythropoiesis
Endothelial Progenitor Cells
Research suggests that endothelial progenitor cells (EPC) play a significant role in repairing ischemic tissue damage by promoting the formation of new blood vessels at sites of damage. EPC reside in the bone marrow and several growth factors and cytokines, including erythropoietin, stimulate EPC expansion in the bone marrow and mobilization to sites of ischemic damage.
-- Proliferation and mobilization of endothelial progenitor cells by HIF-PHI (Abstract #413)
FibroGen reported results of non-clinical studies showing that oral administration of the HIF-PHI FG-6513 to mice resulted in increased levels of erythropoietin in the circulation and larger populations of both EPC and hematopoietic progenitor cells in the bone marrow. In addition, the ability of FG-6513 to enhance mobilization of EPC from the bone marrow was observed as an increase in number and percent of EPC in the peripheral blood of mice treated with FG-6513. An observed increase in the number of EPC in the bone marrow and peripheral blood is another finding supportive of the capacity of FG-6513 to treat ischemic damage.
Overactive Type 1 Helper T Cells (TH1) cells are implicated in inflammatory and autoimmune diseases, such as inflammatory bowel disease and rheumatoid arthritis. The differentiation of TH1 cells from naive precursor cells (CD4+ TH0 cells) is dependent on the presence of the cytokine interleukin-12 (IL-12); thus, IL-12 has been a target for drug development targeting inflammation.
-- HIF-PHI attenuate IL-12 -driven inflammatory T Cell responses (Abstract #140)
FibroGen reported new in vitro data demonstrating that HIF-PHI inhibit IL-12-induced TH1 differentiation by attenuating IL-12 signaling. The presence of HIF-PHI during differentiation of TH1 cells blocked the induction of a subset of IL-12-responsive genes and resulted in reduced secretion of inflammatory cytokines, IFN-gamma and TNF-alpha, from mature TH1 cells. The latter result did not require the continued presence of HIF-PHI, indicating that the inhibitory effects of HIF-PHI on TH1 differentiation occur early by blocking IL-12 signaling, and thus are long-lasting. The results also showed the capacity of HIF-PHI to differentially affect cytokine function as evidenced by reduced IL-12 signaling but no inhibition of another T Cell differentiation pathway involving IL-4-dependent Type 2 Helper T Cell (TH2) cell differentiation.
FibroGen reported new data supporting the use of HIF-PHI designed to stimulate a multi-factorial cytoprotective response for the treatment of ischemic tissue damage.
-- Novel HIF-PHI are neuroprotective in both permanent and transient models of ischemic stroke (Abstract #214)
FibroGen previously reported that a cytoprotective HIF-PHI, FG-4539, was able to protect against tissue damage and facilitate sensorimotor recovery in rodent models of ischemic stroke.(1,2) At the Keystone Conference, FibroGen reported new data from a series of studies in which a panel of novel HIF-PHI were evaluated for their neuroprotective efficacy relative to their capacity to elevate circulating levels of erythropoietin, a known cytoprotective factor. Data presented for one of the HIF-PHI from this panel, FG-6515, demonstrated significant neuroprotection in rodent models of ischemic stroke with and without reperfusion injury. FG-6515 was up to 30-fold more potent than FG-4539 in its ability to protect against ischemic damage and the neuroprotective efficacy of FG-6515 was not diminished even when drug was administered up to 4 hours post-injury. Efficacious doses of FG-6515 induced circulating endogenous erythropoietin to levels that were within the physiological range and were much lower than levels of recombinant human erythropoietin reported to provide neuroprotection, suggesting the involvement of additional cytoprotective pathways in FG-6515-mediated protection against cerebral ischemia.
FibroGen also reported the results of new studies related to HIF-PHI designed to selectively stimulate erythropoiesis (production of red blood cells) and which are under evaluation for the treatment of anemia.
-- HIF-PHI correct anemia without exacerbation of hypertension in a model of chronic kidney disease (CKD) (Abstract #302)
The erythropoietic HIF-PHI, FG-2216, was evaluated for its effects on anemia and hypertension associated with CKD using a rat remnant kidney model (5/6th nephrectomy). Recombinant human erythropoietin (rHuEPO) was included in the study for comparison. The doses of FG-2216 and rHuEPO employed induced comparable increases in hemoglobin in anemic rats that had undergone nephrectomy, but there was a differential effect of FG-2216 versus rHuEPO on blood pressure (BP) and the hypertension associated with nephrectomy in this model. Treatment groups were prospectively stratified for comparable levels of hypertension prior to treatment with either FG-2216 or rHuEPO, and systolic BP increased significantly in the rHuEPO group but decreased significantly in the FG-2216 group. Thus, treatment with either FG-2216 or rHuEPO alleviated the anemia associated with 5/6th nephrectomy; however, only FG-2216 was able to increase hemoglobin levels without increasing systolic BP. Similar results were reported for another erythropoietic HIF-PHI, FG-4592.(3) These results indicate that HIF-PHI may provide clinical benefit over current therapies by allowing for correction of anemia without exacerbation of underlying hypertension and uremia.
-- HIF-PHI increase erythropoiesis without promotion of tumor progression in the presence or absence of concomitant chemotherapy (Abstract #364)
Anemia is a common complication of cancer and cancer chemotherapy despite widespread use of erythropoietin stimulating agent (ESA) therapies. FibroGen reported data from studies of FG-2216 and FG-4592 in three human xenograft tumor models, which in published studies were previously shown to exhibit hypoxia-induced HIF stabilization and HIF-dependent vascular endothelial growth factor (VEGF) expression, or which had constitutively active HIF. In addition, tumor progression in these models has been shown to be inhibited by anti-VEGF and antiangiogenic therapies. No stimulation of tumor progression and vascularization was observed, despite increases in erythropoietin and key hematology parameters, indicating FG-2216 and FG-4592 treatment promotes erythropoiesis without affecting tumor progression and vascularization in these models. In addition, HIF-PH inhibition did not compromise the anti-tumor activity of co-administered chemotherapeutic agents. FibroGen has reported similar results in several other tumor progression models.(4) Together, these data support further investigation of HIF-PHI for treatment of anemia in the oncology setting. As superphysiologic erythropoietin levels associated with intravenous dosing of rHuEPO have been associated with thrombotic events, the potential for HIF-PHI to correct anemia with only modest erythropoietin increases to normal physiologic levels may hold promise for future anemia treatment.
-- Induction of erythropoiesis in rodents by novel and distinct families of orally active HIF-PHI (Abstract #301)
Related to FibroGen's ongoing efforts to optimize HIF-PHI for the treatment of anemia, new data were reported on specific HIF-PHI chemotypes further optimized for potency, selectivity and capacity to overcome ESA hypo-responsiveness. Data were reported demonstrating that HIF-PHI overcome TNF-mediated suppression of erythropoietin production in vitro, exhibit efficacy in multiple species, and alleviate anemia due to renal insufficiency in the 5/6 nephrectomy model and due to inflammation in a rat model of anemia of chronic disease. The high potency exhibited by these next-generation compounds suggests the possibility of dosing below 1 mg/kg and with flexible daily and intermittent dosing regimens.
FibroGen, Inc. is a biotechnology-based drug discovery company using its expertise in the fields of tissue fibrosis, connective tissue growth factor (CTGF), and hypoxia-inducible factor (HIF) biology to discover, develop, and commercialize novel therapeutics for fibrotic disorders, diabetic complications, anemia, conditions associated with tissue damage or injury, cancer, and other areas of unmet medical need. FibroGen also develops and produces recombinant human collagens and gelatins using unique production technology that provides the basis for FibroGen's proprietary cosmetic dermal filler and biomaterials supply business.
For more information about FibroGen, Inc., please visit www.fibrogen.com.
1. I Langsetmo, et al. (2006) Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is Neuroprotective in a Mouse Model of Permanent Focal Ischemia (Poster #427) International Stroke Conference 2006, Kissimmee, Florida.
2. I Langsetmo, et al. (2007) Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is Neuroprotective in a Rat Model of transient Middle Cerebral Artery Occlusion (Poster # LB P15) International Stroke Conference 2007, San Francisco, California.
3. G Guo, et al. (2007) HIF-PH Inhibitor, FG-4592, Treats Anemia and Prevents Elevation of SBP in Uremic Rats (Abstract F-PO228). J Am Soc Nephrol 18:154A.
4. TW Seeley, et al. (2005) FG-2216: Tumor Progression Studies and Correction of Anemia of Chronic Disease in Xenograft Models (Abstract F-PO672). J Am Soc Nephrol 16:481A.
Laura Hansen, 650-866-7828
Posted: January 2008