FibroGen Announces the Initiation of an Open-label Phase 2 Study to Evaluate the Safety and Efficacy of FG-3019 in Individuals with Idiopathic Pulmonary Fibrosis
San Francisco, CA - January 12, 2011
FibroGen, Inc. today announced initiation of an open-label phase 2 study to evaluate the safety, tolerability, and efficacy of FG-3019, a human monoclonal antibody against connective tissue growth factor (CTGF), in individuals with idiopathic pulmonary fibrosis (IPF), a chronic, progressive, fatal lung disease for which there are no FDA-approved therapies.
The development of IPF is not completely understood but is thought to result from repetitive injury to epithelial cells that line the lungs. This initiates an abnormal wound healing process characterized by activation of cells called myofibroblasts, which produce and deposit excessive amounts of extracellular matrix (ECM). ECM deposition and tissue remodeling are key elements in the process of fibrosis that can eventually severely damage the lungs.
While different traumas and multiple biological factors can initiate the fibrotic process, CTGF is the final common element essential for chronic fibrosis.1,2 Studies have shown that CTGF causes transformation of multiple cell types into ECM-producing myofibroblasts and impairs important anti-fibrotic and pro-regenerative repair factors.3
Blockade of CTGF, in contrast, has been shown to favor a state of regenerative tissue repair:
- administration of FG-3019 was reported to reverse fibrotic processes in a model of radiation-induced lung fibrosis at the 2010 annual meeting of the American Thoracic Society (also see below “About CTGF and Idiopathic Pulmonary Fibrosis”);4
- preventative and curative effects resulting from genetic blockade of CTGF using siRNA were reported in a model of liver fibrosis at the 2008 annual meeting of the American Association for the Study of Liver Diseases5 and in a subsequent journal article;6 and
- reversal of vascular remodeling using FG-3019 in a model of type 1 diabetes mellitus was reported at the 2006 annual meeting of the American Diabetes Association.7
“What sets our program apart is that FG-3019 targets the central mediator of fibrosis whereas other approaches target modification of indirect fibrogenic factors or a single point in the process,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “CTGF is at the center of multiple positive feedback loops that, irrespective of etiology, drive the fibrosis process. We believe anti-CTGF is the only currently known therapeutic approach having potential to alter disease progression.”
The phase 2 study is expected to enroll 48 patients with progressive IPF, who will receive intravenous infusions of FG-3019 every 3 weeks for 45 weeks. Safety, tolerability, and the effect of FG-3019 on extent of lung fibrosis (as measured by CT scan), lung function, and shortness of breath will be assessed.
“This is an important study that will examine the ability of anti-CTGF therapy to attenuate fibrosis and improve lung function in patients with IPF,” said Frank Valone, MD, Chief Medical Officer of FibroGen. “Based on evidence from nonclinical studies that FG-3019 can reverse the process of lung fibrosis, we are hopeful that FG-3019 will prove clinically beneficial in patients with IPF.”
About CTGF and Idiopathic Pulmonary Fibrosis
IPF is a debilitating and life-threatening lung disease characterized by a progressive scarring of the lungs that hinders oxygen uptake. The cause of IPF is not known. As scarring progresses, patients with IPF experience shortness of breath (dyspnea) and difficulty with performing routine functions, such as activities of daily living. The prevalence of IPF has been estimated to be over 100,000 cases in the U.S. There are no FDA-approved treatments for IPF, and approximately two-thirds of patients die within five years after diagnosis. Patients are typically treated with corticosteroids and immunosuppressive agents, however, no therapies have been clinically proven to improve survival or quality of life for patients with IPF.
CTGF is implicated as a pathogenic factor in IPF. In patients with IPF, CTGF levels are elevated in transbronchial biopsy specimens and in bronchoalveolar lavage fluid. Increased levels of CTGF have also been observed in experimental models of lung fibrosis. In addition, CTGF can cause susceptibility to experimentally-induced lung fibrosis in otherwise resistant mice.
Independent investigative teams have corroborated the reversal and regenerative effects of anti-CTGF therapy in two models of lung injury using FG-3019 or similarly designed rodent antibodies. In the first study mentioned above, FG-3019 reversed the process of fibrosis and improved lung function in a model of radiation-induced lung fibrosis.4 This model closely represents progressive, radiation-induced lung damage in humans in which initial inflammatory stages are followed by extensive tissue remodeling and scar formation. The second study involving a model of bronchopulmonary dysplasia will be presented at an upcoming scientific congress.
FG-3019 has been the subject of clinical studies involving 125 patients to date, including a phase 1 study of patients with IPF. Two phase 2 studies of FG-3019 are ongoing in patients with advanced liver fibrosis due to chronic infection with hepatitis B virus and in patients with pancreatic cancer. Duration of treatment with FG-3019 has been up to 13 months. FG-3019 has been well tolerated in clinical studies to date with no adverse drug reactions.
About FibroGen, Inc.
FibroGen, Inc. was founded to discover and develop anti-fibrotic therapeutics. Using its expertise in the field of tissue fibrosis, in particular with matricellular proteins such as CTGF, and matrix assembly enzymes such as prolyl hydroxylases, FibroGen now is engaged in clinical development of anti-CTGF therapy and prolyl hydroxylase inhibitors for serious unmet medical needs. Current and planned clinical trials of FG-3019 will study the potential of anti-CTGF therapy to reverse liver and lung fibrosis and to improve clinical outcomes in pancreatic cancer. From its large proprietary library of prolyl hydroxylase inhibitors, FibroGen is developing multiple prolyl hydroxylase inhibitors designed to selectively activate HIF biology for the treatment of anemia, and elicit a rapid, multi-factorial, cytoprotective response for treating or preventing conditions resulting from acute ischemic injury and/or inflammation, including cardioprotection and inflammatory bowel disease, among others. FibroGen also develops and produces recombinant human collagens and gelatins using proprietary production technology that permits making collagen essentially identical to the native protein. Development of medical devices, such as corneal implants fabricated with recombinant human collagen Type III, is ongoing.
For more information about FibroGen, Inc., please visit www.fibrogen.com.
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- Mori T, et al. (1999) Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol 181: 153-159.
- Wang Q, et al. (in press) Cooperative interaction of CTGF and TGFβ in animal models of fibrotic disease. Fibrogenesis and Tissue Repair.
- Nguyen T, et al. (2008) CTGF inhibits BMP-7 signaling in diabetic nephropathy. J Am Soc Nephrol. 19(11):2098-107.
- Huber PE, et al. (2010) Reversal of established fibrosis by treatment with the anti-CTGF monoclonal antibody FG-3019 in a murine model of radiation-induced pulmonary fibrosis. Am J Respir Crit Care Med 181: A1054.
- Lawrencia C, Brigstock DR (2008) Targeted delivery of connective tissue growth factor siRNA to activated hepatic stellate cells resolves experimental liver fibrosis in mice. Hepatology 48:908A.
- Brigstock DR (2009) Strategies for blocking the fibrogenic actions of connective tissue growth factor (CCN2): From pharmacological inhibition in vitro to targeted siRNA therapy in vivo. J Cell Commun Signal 3:5–18.
- Langsetmo I, et al. (2006) Anti-CTGF human antibody FG-3019 prevents and reverses diabetes-induced cardiovascular complications in streptozotocin (STZ) treated rats. Diabetes, Vol. 55, Suppl.1: A122.