Results of preclinical studies on its investigational anaplastic lymphoma kinase (ALK) inhibitor, AP26113, shows that AP26113 has a novel profile as a dual inhibitor of ALK and epidermal growth factor receptor (EGFR), an additional validated target in non-small cell lung cancer (NSCLC).
AP26113, developed by scientists at Ariad Pharmaceuticals, exhibits unique preclinical activity and confers a best-in-class potential in the treatment of non-small cell lung cancer (NSCLC).
Anaplastic lymphoma kinase or ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicated that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
Scientists at Ariad identified multiple potent compounds that inhibit ALK both in vitro and in vivo while maintaining significant selectivity over the highly similar insulin-like growth factor-1 receptor and insulin receptor tyrosine kinase.
AP26113 vs. crizotinib
As an ALK inhibitor, AP26113 overcomes mutation-based resistance in NSCLC models. Multiple mutations in ALK were identified that conferred resistance to the dual Met/ALK inhibitor crizotinib (PF-02341066, Pfizer), but not AP26113, including the L1196M “gatekeeper” mutation which has now been observed clinically in patients who initially responded to crizotinib and then relapsed.
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 ponatinib (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.”
AP26113 and EGFR
In addition to inhibition of ALK and its mutant forms, AP26113 was shown to inhibit the EGFR T790M mutant that is resistant to available EGFR inhibitors.
Activating mutations in EGFR are found in approximately 10% of NSCLC in Western populations and 30% of Asian NSCLC patients. The clinical utility of first-generation EGFR inhibitors, such as erlotinib, is limited by the development of resistance, linked in about 50% of patients to the emergence of the T790M “gatekeeper” mutation. This represents a potential target patient population of 125,000 resistant NSCLC patients globally, in addition to another 40,000 patients with ALK-positive NSCLC. Second-generation EGFR inhibitors targeting T790M are in development, but clinical efficacy has been limited due to toxicity related to the co-inhibition of native (unactivated) EGFR.
Preclinical studies show that AP26113 potently inhibited activated EGFR or its T790M mutant, both in cell culture and in mouse tumor models following once daily oral dosing. These studies have indicated that the effective oral doses were similar to those previously shown to be effective in resistant ALK models. When tested against the native form of EGFR, AP26113 lacked activity, indicating a favorable selectivity for activated EGFR.
“The EGFR inhibitory activity of AP26113 substantially changes its profile, significantly expanding the potential target patient population and commercial value of this tyrosine kinase inhibitor,” stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD Pharmaceuticals. “Resistant forms of EGFR-mutant lung cancer represent a large unmet medical need with no available therapies. We will be filing the IND for AP26113 this month and look forward to moving AP26113 into a Phase I/II clinical trial in the third quarter of this year.”
World Conference on Lung Cancer
Data on the EGFR activity of AP26113 will be presented at the upcoming International Association for the Study of Lung Cancer 14th World Conference on Lung Cancer (IASLC), to be held July 3 to 7, 2011, in Amsterdam, The Netherlands. The mini oral presentation and electronic poster entitled, “AP26113: a potent ALK inhibitor, is also active against EGFR T790M in mouse models of NSCLC,” will be presented on Tuesday, July 5, 2011.
Ariad Pharmaceuticals expects to file an IND for AP26113 in 2Q11 and to begin a Phase I/II clinical trial based on patients’ molecular diagnoses in 3Q11
For more information:
– Zhang S, Wang F, Keats J, Ning Y, Wardwell SD, et al. AP26113, a potent ALK inhibitor, overcomes mutations in EML4-ALK that confer resistance to PF-02341066.
Poster LB-298 (AACR 2010)
– Rivera VM, Anjum R, Wang F, Zhang S, Keats J, et al. Efficacy and pharmacodynamic analysis of AP26113, a potent and selective orally active inhibitor of Anaplastic Lymphoma Kinase (ALK). Poster #3623 (AACR 2010)