CHICAGO, June 2 /PRNewswire-FirstCall/ -- Exelixis, Inc. reported data from the Phase I clinical trial program for XL880, a novel small molecule compound that simultaneously inhibits MET and VEGFR2, targets implicated in tumor growth, tumor cell migration, and angiogenesis. Patricia M. LoRusso, D.O., Director of the Phase I Clinical Trials Program at the Barbara Ann Karmanos Cancer Institute, Professor of Hematology and Oncology at Wayne State University, and a lead investigator in the trial, presented the data in the Developmental Therapeutics: Molecular Therapeutics oral abstract session (Abstract #3526) at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO).
The data presented were taken from two Phase I studies of XL880 in patients with advanced solid tumors. One study evaluated an intermittent, weight-based dosing regimen and the other evaluated fixed daily dosing. Both studies included pharmacokinetic, pharmacodynamic, and tumor response analyses.
Five partial responses (>30% tumor regression by RECIST) were observed, including three in papillary renal cell cancer, one in medullary thyroid cancer, and one in hurthle cell thyroid cancer. Tumor shrinkage of less than 30% or prolonged stable disease of greater than 3 months was observed in an additional 20 patients. Additionally, in a best response evaluation as determined by RECIST criteria, investigators reported that 39 of 45 patients in the combined phase 1 studies had either tumor regression or stable disease.
"We consider the number of patients with responses or disease stabilization in these studies to be quite striking, particularly in light of these patients' advanced disease," said Dr. LoRusso. "We believe XL880 has significant potential as a novel cancer therapy, and the ongoing Phase II trials should provide important insight into the late stage development plans for the compound."
Histological analyses of tumor samples from four patients showed decreases in the phosphorylation of MET following administration of XL880. These decreases resulted in predicted downstream effects, including reduction of phosphorylated AKT levels and markedly increased tumor cell death. These effects were not observed in control samples of normal tissue obtained from the same patients. Pharmacokinetic analyses showed that peak and average concentrations over 28 days were higher with intermittent compared with daily dosing of XL880, reflecting the higher dose administered with the intermittent schedule, and the compound's long half life.
The data indicate that XL880 was generally well tolerated, and that the reported side effects were treatable and reversible. Dose limiting toxicities included hypertension, dehydration, hand-foot syndrome, tumor hemorrhage, and elevation of liver enzymes and lipase. Most of the common reported side effects are consistent with previously identified effects associated with inhibition of VEGF signaling, such as hypertension and proteinuria. Elevations in liver function tests also were observed and considered possibly related to XL880.
"We believe these results clearly demonstrate that XL880 simultaneously inhibits both MET and VEGFR2 in this clinical setting," said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. "Inhibition of both MET and VEGFR2 abrogates two major mechanisms tumors use to survive in hypoxic conditions. The clinical data with XL880 suggest that dual MET/VEGFR2 inhibition has the potential to translate into meaningful anti-tumor activity in patients with advanced cancer."
About XL880
XL880 has attractive pharmaceutical properties, with high solubility and oral bioavailability. In preclinical studies, XL880 inhibited its targets with nanomolar potency, and retained potent activity against mutationally activated forms of MET found in hereditary papillary renal cell carcinomas. The compound also demonstrated dose-dependent tumor growth inhibition in models of breast cancer, colorectal cancer, non-small cell lung cancer, and glioblastoma, and has been shown to cause substantial tumor regression in all models tested. Significantly, a single dose of XL880 completely inhibited tumor growth for 21 days in a glioblastoma model.
About Exelixis
Exelixis, Inc. is a development-stage biotechnology company dedicated to the discovery and development of novel small molecule therapeutics for the treatment of cancer and other serious diseases. The company is leveraging its fully integrated drug discovery platform to fuel the growth of its development pipeline, which is primarily focused on cancer. Currently, Exelixis' broad product pipeline includes investigational compounds in Phase II and Phase I clinical development for cancer and renal disease. Exelixis has established strategic corporate alliances with major pharmaceutical and biotechnology companies, including GlaxoSmithKline, Bristol-Myers Squibb Company, Genentech, Wyeth Pharmaceuticals and Sankyo. For more information, please visit the company's web site at http://www.exelixis.com/.
This press release contains forward-looking statements, including without limitation statements related to the potential efficacy of XL880. Words such as "suggest," "believes," "indicates," "should," and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Exelixis' current expectations. Forward-looking statements involve risks and uncertainties. Exelixis' actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, the potential failure of XL880 to demonstrate safety and efficacy in clinical testing. These and other risk factors are discussed under "Risk Factors" and elsewhere in Exelixis' quarterly report on Form 10-Q for the fiscal quarter ended March 30, 2007 and other filings with the Securities and Exchange Commission. Exelixis expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the company's expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
