FibroGen announces FG-3019 interim results from phase 1/2 trial against pancreatic cancer

FibroGen, Inc. today announced interim results of a phase 1 / 2 trial of FG-3019, a therapeutic antibody against connective tissue growth factor (CTGF), in combination with gemcitabine and erlotinib in individuals with unresectable pancreatic cancer. FG-3019 has been well-tolerated, no dose-limiting toxicities have been observed, and dose escalation continues. The interim results were reported at 2011 Gastrointestinal Cancers Symposium, co-sponsored by The American Society of Clinical Oncology (ASCO), in San Francisco, CA (Abstract #269).

The phase 1 / 2 study is an open-label, single-arm, dose-escalation study to evaluate safety, tolerability, pharmacokinetics and ability of FG-3019 administered every 2 weeks to improve outcomes in chemotherapy-naïve patients with unresectable pancreatic cancer. Therapy with gemcitabine and erlotinib starts at day 15, concomitant with administration of the second dose of FG-3019. A safety monitoring committee determines whether escalation to the next dose level is permitted.

Enrollment in the first 4 dose cohorts (3, 10, 15, and 25 mg/kg FG-3019) is complete, and FG-3019 has been well-tolerated at all doses. Assessments of tumor response measured by CT are made according to Response Evaluation Criteria in Solid Tumors 1.0 (RECIST 1.0) guidelines at baseline and every 8 weeks. For dose cohorts of 15 mg/kg and higher, tumor metabolic activity is measured by PET at baseline and day 14 (prior to administration of chemotherapy). Data from patients in the first 3 dose cohorts.

Interim results demonstrated:

• for the first 3 dose cohorts combined, median overall survival is 9.1 months and median time to progression is 4.7 months with longest overall survival (median 9.4 months) and time to progression (median 7.7 months) observed in the highest dose cohort (15 mg/kg);
• best response according to RECIST indicated that one patient had a partial response, 9 patients had stable disease, 2 patients progressed, and 3 were not evaluable having discontinued the trial for reasons unrelated to treatment with FG-3019 before CT imaging at week 8;
• in the highest dose cohort (15 mg/kg) for those patients who were evaluated by PET;
• one patient in the 15 mg/kg cohort who continues on the study at 13.9+ months had a complete metabolic response in the primary tumor and a decrease in the biomarker CA 19-9 from 2400 U/mL to a level sustained below 60 U/mL; and
• survival was significantly higher for patients with low plasma levels of CTGF at baseline (median overall survival of 10.4 months).

"The development of safe and effective therapies for patients with pancreatic cancer is critical as chemotherapy has limited benefit in treating this aggressive cancer," said Albert Koong, M.D., Associate Professor of Radiation Oncology and Radiation Therapy at Stanford University Medical Center and Principal Investigator of the trial. "While these are early results from a small study, we are encouraged that FG-3019 appears to be well-tolerated at all dose levels tested thus far and may be having an effect on suppressing tumor activity as indicated by PET data."

"Our data suggest that increased exposure to FG-3019 is associated with improved outcomes," said Frank Valone, M.D., Chief Medical Officer of FibroGen. "The patients with the highest continuous drug exposure did not progress while on drug treatment, and one of these continues on treatment at fourteen months. We are planning to try higher doses of FG-3019 in additional groups of patients."

Prior Experimental Data Regarding CTGF and Pancreatic Cancer

FG-3019 Inhibits Tumor Growth and Metastasis in Pancreatic Cancer Models

Results from nonclinical models of pancreatic cancer have shown that blocking the expression or activity of CTGF reduces tumor growth and metastasis:

• In a study led by Amato Giaccia, Ph.D., Professor of Radiation Oncology and Radiation Biology at Stanford School of Medicine, researchers demonstrated that CTGF expression levels were elevated in pancreatic tumors, prompting further study of human pancreatic cancer cells that were engineered in the lab to express high levels of CTGF. When implanted into mice, these high-CTGF-expressing cells caused increased tumor growth in mice resulting from more cell proliferation and less apoptosis ("programmed" cell death, which is normally observed in diseased cells). The scientists also reported that tumor growth by the engineered cancer cells could be inhibited by FG-3019.
• In another study of FG-3019, researchers at Dartmouth Medical School led by Murray Korc, M.D., Professor of Pharmacology and Toxicology and Chair of Medicine, implanted human pancreatic cancer cells into the pancreas of mice and treated them with FG-3019 two weeks after implantation. At the end of the six-week study, mice treated with FG-3019 exhibited decreased tumor growth and metastasis compared to control mice.

Genetic Blockade of CTGF Blocks Tumor Growth

• In another study led by Dr. Giaccia, pancreatic tumor growth in mice was completely prevented by blocking the expression of CTGF in tumor cells. Additionally, animals implanted with tumor cells expressing lower levels of CTGF survived longer than those implanted with tumor cells expressing high levels of CTGF.

"We believe FG-3019 represents a unique approach to the treatment of pancreatic cancer as it appears that CTGF plays an important role in pathogenesis of pancreatic cancer," said Thomas B. Neff, Chief Executive Officer of FibroGen. "Therapies designed to blockade CTGF, such as FG-3019, may beneficially act on the tumor as well as reduce desmoplastic tissue development and stromal-tumor signaling."

Mr. Neff added: "With FG-3019 currently in three phase 2 studies - liver and lung fibrosis and pancreatic cancer - we believe we are in a good position to demonstrate first proof-of-concept for anti-CTGF therapy in modifying the natural course of progression for these life-threatening diseases. Each study addresses critical unmet medical needs."

CTGF in Desmoplastic Cancers

The role of CTGF as the central mediator of tissue remodeling and fibrosis (persistent and excessive scarring) is well-established in the scientific literature. Several recent studies also implicate CTGF in tumor progression, including tumor cell survival and metastasis, in which CTGF is a key link in the communication between tumor cells and their stroma (the area surrounding the tumor) during the desmoplastic reaction. Desmoplasia involves the formation and proliferation of fibroblasts (cells that produce fibers and structural elements found in the extracellular matrix) and of fibrous connective tissue around the growing cancer. Elevated CTGF levels have been detected in a number of late-stage desmoplastic cancers besides pancreatic cancer, including breast cancer, as well as glioblastoma and sarcomas. CTGF has also been shown to promote epithelial to mesenchymal transition (EMT), a process whereby normal epithelial cells become migratory, matrix-producing fibroblasts, shown to be important during invasion and metastasis.