New preclinical data on ARIAD's ponatinib and AP26113 study presented at AACR meeting

Apr 3 2012

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the presentation of new preclinical data on its investigational pan-BCR-ABL inhibitor, ponatinib, and its investigational dual EGFR-ALK inhibitor, AP26113, at the American Association for Cancer Research Annual Meeting in Chicago. Both drug candidates, discovered using ARIAD's structure-based drug design platform, are potent inhibitors of multiple "gatekeeper" mutations that have been shown to confer clinical resistance to other targeted cancer medicines.    

The first study, "Ponatinib, a potent pan-BCR-ABL inhibitor, retains activity against gatekeeper mutants of FLT3, RET, KIT, PDGFR and FGFR1," was presented yesterday and shows that ponatinib overcomes resistant gatekeeper mutations well beyond BCR-ABL -- the drug's target in chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) -- in other clinically relevant tyrosine kinase targets.

The preclinical research conducted by ARIAD scientists assessed the activity of ponatinib using cell lines expressing activated forms of FLT3, RET, KIT, PDGFR and FGFR1, each a kinase target associated with a specific tumor type. Ponatinib potently inhibited the activity of these kinases and maintained potent activity against gatekeeper variants that have been shown to cause resistance to other tyrosine kinase inhibitors in acute myeloid leukemia, medullary thyroid cancer, gastrointestinal stromal tumor (GIST) and rare forms of leukemia driven by these tyrosine kinases.

"Ponatinib was designed to block the abnormal tyrosine kinase, BCR-ABL, which drives CML and Ph+ALL," said Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer of ARIAD. "The structural design feature that allows ponatinib to evade the BCR-ABL T315I gatekeeper mutation also enables the molecule to overcome analogous mutations in its other kinase targets. We are actively working with academic collaborators to set up clinical trials aimed at determining the potential role of ponatinib in these additional forms of drug-resistant cancer."

A second abstract, "AP26113 is a dual ALK/EGFR inhibitor: Characterization against EGFR T790M in cell and mouse models of NSCLC," will be presented today and describes the activity of AP26113, a dual inhibitor of EGFR and ALK, to overcome gatekeeper mutations of these targets. This preclinical research further confirms that AP26113 is a potent, reversible inhibitor of the T790M gatekeeper mutation of epidermal growth factor receptor (EGFR). Activated EGFR occurs in approximately 250,000 lung cancer patients worldwide, and the single T790M mutation accounts for over 50 percent of resistance to tyrosine kinase inhibitors in these patients who have limited treatment options available.

This poster also presents, for the first time, preclinical data demonstrating that AP26113 potently inhibits non-small cell lung cancer (NSCLC) cell lines that express an activating translocation of the ROS1 tyrosine kinase. Such ROS1 mutations have recently been identified as a feature of approximately two percent of all NSCLC, representing another area for further investigation of AP26113 in NSCLC patients in need of better therapeutic choices.