ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced results of preclinical studies on its investigational anaplastic lymphoma kinase (ALK) inhibitor - AP26113 - showing potent inhibition of the target protein and of mutant forms that are resistant to the first-generation ALK inhibitor, which currently is in clinical trials in patients with cancer. ARIAD scientists presented these data today at the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C.
“This preclinical work supports our ongoing evaluation of AP26113 as a potential treatment for cancers that express ALK. We look forward to moving AP26113 into clinical trials as soon as possible.”
Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as anaplastic large cell lymphoma. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
An in vitro assay was used to identify mutations in ALK that confer resistance to the investigational dual Met/ALK inhibitor developed by Pfizer, Inc., PF-02341066 (PF1066), or to AP26113. This resistance-profiling method has successfully predicted the specific mutations that confer clinical resistance to other tyrosine kinase inhibitors, such as the BCR-ABL inhibitors used in chronic myeloid leukemia (CML). Multiple mutations in ALK were identified that conferred resistance to PF1066, but not to AP26113. Three of these ALK mutants were also tested in mouse tumor models, and in each case, AP26113 potently blocked tumor growth while PF1066 was ineffective.
"Similar to data on our investigational pan-BCR-ABL inhibitor, AP24534, these preclinical results suggest that more potent compounds, such as AP26113, may be able to minimize the development of mutation-based drug resistance," stated Timothy Clackson, Ph.D., senior vice president and chief scientific officer of ARIAD. "The data clearly support further study to determine if AP26113 can provide a more complete response than PF1066 in cancer patients with abnormal ALK expression."
In a second study, direct comparative studies were performed on AP26113 and PF1066 in a series of ALK-dependent cell culture and in vivo models. In all models, AP26113 was at least ten-fold more potent than PF1066. In addition, AP26113 exhibited approximately 100-fold selectivity for ALK-positive cell lines compared with an approximate 10-fold selectivity for PF1066, and demonstrated excellent properties, including the potential for once daily oral dosing.
"We specifically designed AP26113 as a highly potent and selective inhibitor of ALK with superior drug-like properties and best-in-class potential," added Clackson. "This preclinical work supports our ongoing evaluation of AP26113 as a potential treatment for cancers that express ALK. We look forward to moving AP26113 into clinical trials as soon as possible."
Additional Data and Recognition from AACR
ARIAD scientists also presented at AACR results from preclinical studies of its investigational pan-BCR-ABL inhibitor, AP24534, being studied in a Phase 1 clinical trial of patients with hematological malignancies, notably CML. The AACR program committee each year recognizes meritorious abstracts being presented in poster sessions at the Annual Meeting to help identify the best science in these large sessions. This year, the scientific abstract on AP24534 is recognized by the AACR program committee as a highly rated presentation that scored in the top three percent of all abstracts presented in the meeting's poster sessions.
In addition, Merck scientists presented data on ARIAD's investigational mTOR inhibitor, ridaforolimus, which is being co-developed by Merck & Co. In all, there are seven scientific presentations on ARIAD product candidates at the AACR meeting this year.
ARIAD Pharmaceuticals, Inc.