AVEO Presents Preclinical Efficacy Data on AV-412, a Novel Oral Tyrosine Kinase Inhibitor of EGFR/HER2 for EGFR Mutant and Drug-Resistant Lung Cancer
The molecularly targeted drugs - erlotinib (Tarceva(R)) and gefitinib (Iressa(R)) - inhibit EGFR kinase activity and are important therapies for patients with non-small cell lung cancer; however, recent clinical observations from independent groups suggest that lung cancer patients harboring the EGFR L858R mutation (approximately 44 percent of all EGFR mutants) exhibit poorer response rates, progression free survival and overall survival after treatment with EGFR kinase inhibitors when compared with patients harboring other EGFR mutations. This suggests the need for inhibitors that are more effective against patients with EGFR L858R mutations. In addition, resistance to EGFR kinase inhibitors uniformly develops over time often due to the acquisition of resistance mutations within the EGFR gene. Erlotinib and gefitinib have no effect on the EGFR L858R/T790M double mutant, which is estimated to account for approximately 50 percent of all drug resistance in EGFR mutant non-small cell lung cancer - representing a key unmet medical need.
"AV-412 showed potent inhibition of the EGFR L858R mutations and, in two well-established animal models, demonstrated dose-dependant tumor regression in both small and large lung tumors and complete regression of lung tumors at a dose where erlotinib is inactive," said Tuan Ha-Ngoc, President and CEO of AVEO Pharmaceuticals. "These data, while early, highlight the promise of AV-412 as an option for lung cancer patients who carry the EGFR L858R mutation, as well as patients who become resistant to first-generation tyrosine kinase inhibitors. We are looking forward to initiating Phase 2 trials as soon as we establish an appropriate dose in the current Phase 1 study, which was initiated last October."
To provide robust models for translational research supporting the development of novel agents for lung cancer, AVEO generated a series of inducible mouse lung cancer models using AVEO's Human Response Prediction(TM) Platform. Using this proprietary platform, AVEO generated several different models covering the most prevalent oncogenic mutations including EGFR(L858R), EGFR(L858R/T790M) and KRAS(G12V). Unlike studies in primary genetically engineered tumor models, this approach enables the quantitative and comparative analysis of different drugs, doses, schedules and combinations to optimize drug selection and clinical trial design in the clinic.
Utilizing these novel models, AVEO evaluated the activity of AV-412 in non-small cell lung cancer tumors. Data presented today at the AACR meeting show that AV-412 is highly active against tumors from the chimeric model carrying the EGFRL858R mutation, exhibiting an ED50 of 0.1 mg/kg as a daily dose. AV-412 is greater than 10 times more potent than erlotinib in this model, one mg/kg PO AV-412 resulted in complete tumor regression, whereas erlotinib is active at 10mg/kg, but inactive at 1mg/kg. More importantly, AV-412 was found to be active against tumors from chimeric lung adenocarcinomas carrying the erlotinib-resistant mutation EGFR L858R/T790M. These in vivo results suggest that AV-412 may exert potent clinical activity against non-small cell lung cancer tumors harboring EGFR L858R or EGFR L858R/T790M mutations.
AV-412 is a next generation oral tyrosine kinase inhibitor of EGFR/HER2 that could potentially treat patients with solid tumors. In preclinical studies, AV-412 has shown excellent activity in various tumor models, has a toxicity profile similar to other molecules in its class, and has shown preclinical activity against tumor cells that are resistant to first-generation tyrosine kinase inhibitors. The targets of AV-412 have been implicated in many significant human cancers including non-small cell lung cancer, metastatic breast cancer, pancreatic cancer, head and neck cancer and hormone refractory prostate cancer. AVEO's proprietary Human Response Prediction(TM) Platform offers an opportunity to exploit AV-412's unique characteristics and will provide further insight into potential clinical settings, tumor subtypes and responsive patient populations. AVEO acquired worldwide rights outside of Asia to AV-412 from Mitsubishi Pharma Corporation. For more information on the AV-412 clinical trial, visit www.clinicaltrials.gov and search using the keyword AV-412.
AVEO is a private biopharmaceutical company focused on the discovery and development of novel, targeted cancer therapeutics. The company utilizes its proprietary, genetically-defined cancer models for the identification and validation of novel cancer targets, and has begun to build an impressive portfolio of drug discovery and development programs around these high-value targets. AVEO also uses its Human Response Prediction(TM) Platform to identify genetic profiles that correspond with patient responsiveness. AVEO expects to commence Phase 2 clinical studies by Q3-2007 for AV-951, its oral, second-generation VEGF receptor inhibitor and most advanced clinical program. AV-412, AVEO's EGFR/HER2 inhibitor, is currently in Phase 1 clinical trials. AV-299, a novel anti-HGF mAb, is currently being manufactured by XOMA under a supply agreement in anticipation of entering the clinic in early 2008. AVEO is located in Cambridge, Massachusetts. For more information, please visit the company's website at www.aveopharma.com.
AVEO Pharmaceuticals, Inc.
JJ Owen, Ph.D., 617-299-5889;
Pure Communications, Inc.
Adriana Jenkins, 617-744-1713
Posted: April 2007