Harry,
Fibrogen's HIF-stabilizing small molecules may have a role to play here on the neuroprotective side as well, although of course this was not their original indication and they can likely improve their results if they focus on this actual indication. Still very early, though:
Abstract
Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is Neuroprotective in a Mouse Model of Permanent Focal Ischemia
February 17, 2006
International Stroke Conference 2006 , Kissimmee, Florida
Presentation #427
Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is Neuroprotective in a Mouse Model of Permanent Focal Ischemia. Ingrid Langsetmo, Christopher Jacob, Wen Bin Ho, Robert Stephenson, Oksana Sirenko, Parmjeet Sidhu, Lee Flippin, Todd Seeley, Steve Klaus, Al Lin, David Liu
FibroGen, Inc. 225 Gateway Blvd., South San Francisco, CA 94080.
Abstract: Stroke remains the third most common cause of death in the industrialized world behind heart disease and cancer. Current pharmacotherapy for stroke is severely limited and presents a major unmet medical need. FG-4539 is a novel HIF-prolyl hydroxylase inhibitor (PHI) that has been shown to stabilize HIF in vitro, protect against chemical ischemia in neuronal cell cultures and to increase expression of HIF responsive cytoprotective genes including erythropoietin in the brain after i.v. administration in mice. By analogy to hypoxic preconditioning, FG-4539 is neuroprotective when administered 6 or 24 hours prior to permanent middle cerebral artery occlusion in the mouse (pMCAO). To further examine the potential of FG-4539 as a neuroprotective agent for the treatment of stroke, the dose response and therapeutic window were evaluated in the pMCAO model. The right middle cerebral artery of male C57BL/6 mice was surgically exposed and coagulated by bipolar diathermy. Body temperature was maintained by use of a heating pad during and after surgery. Ischemic damage in the brain was assessed 24 hours after pMCAO by TTC staining. In a dose response study, animals that were administered FG-4539 at 6, 20 or 60mg/kg immediately after pMCAO demonstrated significant dose-dependent reductions in infarct volume (36-59%). In a time-course study designed to evaluate the therapeutic window, animals treated with 60 mg/kg of FG-4539 exhibited a significant reduction in infarct volume (55%) when FG-4539 was administered as late as 5 hours (longest time tested) after occlusion. These results show that FG-4539 and PHI can limit ischemic damage when given up to five hours after the ischemic insult and demonstrate proof of concept that cytoprotective PHI may be useful in the treatment of ischemic stroke.
Here's the accompanying PR:
Press Release
FibroGen Reports FG-4539, HIF-PH Inhibitor, Is Neuroprotective and Significantly Reduces Brain Tissue Damage in Preclinical Model of Ischemic Stroke
Kissimmee, Fla. – Feb. 17, 2006 - FibroGen, Inc., today announced that a single dose of FG-4539, its novel small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) in development for the treatment of ischemic disease, was neuroprotective and significantly reduced brain tissue damage in a preclinical model of permanent ischemic stroke. The potency of FG-4539 and the window of therapeutic opportunity observed following permanent middle cerebral artery occlusion (pMCAO) compare favorably to results from this model reported for the most promising neuroprotective therapies currently in development. The data were presented today at the International Stroke Conference 2006 (Abstract # 427; abstract).
Approximately 15 million people worldwide suffer a stroke each year resulting in death or cognitive deficits. The majority of these are ischemic strokes caused by a blood clot that prevents blood flow to the brain, thereby depriving the brain of oxygen and nutrients. As a result, numerous pathological pathways are triggered and lead to the propagation of neuronal cell death from the initial site of ischemic damage.
The U.S. Food and Drug Administration has approved tissue plasminogen activator, or tPA, (i.e., Alteplase) to treat ischemic stroke. tPA is a thrombolytic drug that helps to restore blood flow to the brain by dissolving the blood clot that causes ischemic stroke. In practice, however, the treatment window for administration of tPA is limited to three hours after onset of stroke symptoms, and less than 5% of patients receive tPA. In addition, tPA does not address other pathological processes that cause neuronal cell death.
“FG-4539 is a potential first-in-class therapy targeting HIF biology that is designed to coordinately activate a spectrum of cytoprotective factors to maximize therapeutic benefit in an ischemic emergency, such as stroke,” said David Y. Liu, Ph.D., Vice President of Research at FibroGen. “The results demonstrate the ability of a single dose of FG-4539 to elevate local expression of neuroprotective genes and confer significant protection to healthy brain tissue following stroke. We believe FG-4539 could be an important component of current stroke therapy and has the potential to improve patient outcomes, especially for the vast majority of patients who do not receive tPA.”
HIF-mediated factors known to confer cytoprotection against ischemic injury include those that promote cell survival and prevent programmed cell death (anti-apoptotic factors), such as erythropoietin (EPO); anti-oxidant enzymes, such as heme-oxygenase-1 (HO-1), which decrease free radical damage and limit reperfusion injury; and vasodilatory factors, such as nitric oxide and adrenomedullin (ADM), which enhance tissue perfusion (blood flow).
“Over the past decade, FibroGen has amassed extensive data documenting profound therapeutic effects of prolyl hydroxylase inhibitors to confer anti-ischemic and cytoprotective benefits on infarcted or hypoxic tissues,” said Thomas B. Neff, Chief Executive Officer at FibroGen. “In addition to the demonstrated protective effects of FG-4539 on neuronal tissue, preclinical models using FG-4539 and other selectively targeted FibroGen HIF-PH inhibitors demonstrate the therapeutic benefit of these compounds in protecting tissues and maintaining organ function in relevant animal models of ischemia in the kidney and heart. These data establish compelling rationale for clinical studies in stroke, cardiovascular, and renal settings.”
Therapeutic Window for Neuroprotective Action
In the study reported today, animals receiving FG-4539 exhibited a significant reduction in mean infarct volume (brain tissue damage) with maximal neuroprotective effects still observed even when the drug was administered after occlusion (53% – 62% average reduction compared to control group). Delayed administration of HIF-PH inhibitors as late as five hours after permanent occlusion did not result in any loss of neuroprotection, which suggests that the therapeutic window using FG-4539 may extend beyond this period. This compares favorably to published data using other neuroprotective agents, such as NXY-0591 and recombinant EPO2,3,4. Studies in which FG-4539 will be administered later than five hours post-occlusion are now underway to determine optimal dosing regimens.
EPO and Non-EPO Effects Confer Neuroprotection Using FibroGen HIF Technology
In the case of FG-4539, the pharmacodynamic properties include both production of systemic endogenous EPO and local production of endogenous EPO in the brain. Previous preclinical studies have demonstrated that recombinant EPO confers significant protection of neuronal tissue in cerebral ischemia models, albeit with a limited therapeutic window when administered post-occlusion in the pMCAO model. In previous research conducted by FibroGen, FG-4539 was as effective as high doses of recombinant EPO (e.g., 5,000 U/kg, which is approximately 50 times the erythropoietic dose) in reducing infarct size when both were administered systemically. FG-4539 was more effective in reducing the concomitant symptom of brain edema. The observed neuroprotective effects of FG-4539 were evident at doses that induced much lower circulating endogenous EPO as compared to the levels associated with recombinant EPO doses employed. FG-4539 induces EPO and EPO receptor expression locally in the brain rather than relying on induction of systemic EPO, which may contribute to optimal neuroprotective efficacy.
The neuroprotective capacity of FG-4539 in the absence of systemic EPO induction is evidenced at the lowest dose employed in the studies (6 mg/kg), where little to no increase in circulating endogenous EPO was induced, which was as effective as higher doses in reducing infarct size. FibroGen has also demonstrated the neuroprotective capacity of HIF-PH inhibitors that are optimized for induction of multiple HIF-dependent neuroprotective genes independent of induction of systemic or neuronal EPO. In that regard, FG-4539 was one of a specially selected group of compounds that was optimized to coordinately upregulate a select array of cytoprotective genes to maximize efficacy against ischemic injury, such as that induced by ischemic stroke.
“Additional studies are underway to examine the impact of non-EPO cytoprotective factors induced by HIF-PH inhibitors in a stroke setting and to correlate reductions in infarct size with improvements in cognitive function in longer-term transient occlusion models,” said Dr. Liu. “We are also studying HIF-PH inhibitors for their ability to prevent ischemia reperfusion injury and to induce rapid, localized production of cytoprotective factors at the site of brain tissue damage, which may provide better protection than recombinant EPO administered systemically.”
Separate Study Published in Journal of Biological Chemistry
In a separate study focused on the preconditioning effects of HIF-PH inhibitors published in the December 16, 2005 issue of the Journal of Biological Chemistry (JBC), a FibroGen compound given 6 and 24 hours prior to the onset of stroke was demonstrated to be effective in a pMCAO model5. This work was done in collaboration between FibroGen and researchers at Beth Israel Deaconess Medical Center and Harvard Medical School and Burke-Cornell Medical Research Institute at Weill Medical College of Cornell University.
A large body of research indicates that hypoxic preconditioning can prepare healthy tissues to better tolerate an otherwise fatal ischemic injury, such as stroke. There is substantial evidence that the protective effects of preconditioning are mediated through HIF, which activates the body’s numerous emergency responses to hypoxic stress.
“The recent JBC study suggests that HIF-PH inhibitors could be neuroprotective agents in clinical situations where the imminent risk of ischemic or oxidative neuronal injury is high, such as for elective surgeries,” said Dr. Rajiv R. Ratan, MD, Ph.D., Executive Director of the Burke-Cornell Medical Research Institute, Burke Professor of Neurology and Neuroscience at Weill Medical College of Cornell University, and senior author of the study reported in JBC.
Commenting on the data reported by FibroGen at the International Stroke Conference, Dr. Ratan said: “The new data suggest that administration of HIF-PH inhibitors following occlusion, or even following reperfusion, may result in significant neuroprotection. This is important because robust neuroprotective conditioning after the onset of stroke symptoms may significantly increase access to therapy for patients who suffer a stroke.”
FibroGen HIF-PH Inhibitor Therapeutic Platform
FibroGen is focused on the discovery and development of small molecule inhibitors of HIF-PH for therapeutic benefit in multiple clinical settings in which insufficient oxygen, or hypoxia, contributes to acute and chronic disease and dysfunction of healthy tissue. Using distinct HIF-PH inhibitors with unique pharmacodynamic profiles, FibroGen seeks to selectively harness and direct specific HIF-mediated biological pathways as required in different tissues to address organ-specific pathophysiologies. The Company’s first two HIF-PH inhibitors in clinical development are FG-2216 and FG-4592, which are designed to selectively stimulate HIF-2 mediated erythropoiesis for the treatment of anemia.
As part of a separate therapeutic program, FG-4539 is the Company’s lead HIF-PH inhibitor in development for the treatment of ischemic disease and settings in which cytoprotection could provide therapeutic benefit. Numerous compounds with desirable pharmacodynamic profiles have been created by FibroGen chemists for use in the ischemia/cytoprotection programs. In the kidney, for example, administration of FG-4539 and other FibroGen HIF-PH inhibitors protected kidney function from ischemia reperfusion injury6,7 and nephrotoxic radiocontrast agents. In preclinical myocardial infarction studies employing coronary artery ligation, treatment with a HIF-PH inhibitor preserved heart function and improved survival rate8,9. These results were confirmed in studies using additional HIF-PH inhibitors10.
In other HIF-PH inhibitor programs, FibroGen is developing compounds to selectively activate certain HIF-mediated pathways for other therapeutic purposes, including tissue remodeling, neurogenesis, and vasculogenesis, and HIF-mediated aspects of metabolism for treating certain metabolic disorders, such as obesity.
References
1. Sydserff SG, Borelli AR, Green AR, Cross AJ. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. Br J Pharmacol. 2002 Jan;135(1):103-12.
2. Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, Masuda S, Sasaki R. Erythropoietin Prevents Place Navigation Disability and Cortical Infarction in Rats with Permanent Occlusion of the Middle Cerebral Artery. Biochem Biophys Res Commun. 1998 Dec 9; 253(1):26-32.
3. Bernaudin et al. A Potential Role for Erythropoietin in Focal Permanent Ischemia in Mice. J Cereb Blood Flow Metab. 1999; 19:643-651
4. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31.
5. Siddiq A, Ayoub IA, Chavez JC, Aminova L, Shah S, LaManna JC, Patton SM, Connor JR, Cherny RA, Volitakis I, Bush AI, Langsetmo I, Seeley T, Gunzler V, Ratan RR. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem. 2005 Dec 16; 280(50):41732-43.
6. Bernhardt WM, Campean V, Kany S, Jurgensen J, Weidemann A, Warnecke C, William C, Guenzler V, Frei U, Amann K, Wiesener M, Eckardt K. Preconditional Activation of HIF Ameliorates Ischemic Acute Renal Failure. Keystone Symposia: Hypoxia and Development, Physiology and Disease 2006 Abstract Book: 57 (Abstract #113).
7. G. Guo, A. Lin, V. Guenzler, D. Liu, S. Klaus, M. Arend, L. Flippin, C. Witschi, Q. Wang. Improvement of Kidney Function in a Rat Model of Renal Ischemia-Reperfusion Injury by Treatment with a Novel HIF Prolyl Hydroxylase Inhibitor. J Am Soc Nephrol. 2004 15:461A.
8. Nwogu JI, Bean M, Geenen DL, De A, Brenner M, Buttrick PM. Inhibition of Myocardial Fibrosis Improves Survival and Prevents Progression of Heart Failure After Myocardial Infarction (MI). 73rd American Heart Association Scientific Sessions 2000 (Abstract # 108610).
9. Philipp S, Schiche A, Pilz B, Jürgensen J, Eckart K, Pagel I, Langenickel T, Günzler V, Willenbrock R. Prolyl 4-Hydroxylase Inhibition Induced HIF and Improved Cardiac Function after Myocardial Infarction. 75th American Heart Association Scientific Sessions 2002 (Abstract # 115482).
10. Nwogu JI, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation. 2001 Oct 30;104(18):2216-21.
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