abstracts for alk drug
Presentation Abstract
Abstract Number: 3623
Presentation Title: Efficacy and pharmacodynamic analysis of AP26113, a potent and selective orally active inhibitor of Anaplastic Lymphoma Kinase (ALK)
Presentation Time: Tuesday, Apr 20, 2010, 9:00 AM -12:00 PM
Location: Exhibit Hall A-C, Poster Section 26
Poster Section: 26
Poster Board Number: 17
Author Block: Victor M. Rivera, Rana Anjum, Frank Wang, Sen Zhang, Jeffrey Keats, Yaoyu Ning, Scott D. Wardwell, Lauren Moran, Emily Ye, Dung Yu Chun, Qurish K. Mohemmad, Shuangying Liu, Wei-Sheng Huang, Yihan Wang, Mathew Thomas, Feng Li, Juan Miret, John D. Iuliucci, David Dalgarno, Narayana I. Narasimhan, Tim Clackson, William C. Shakespeare. ARIAD Pharmaceuticals, Inc., Cambridge, MA
Abstract Body: Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified in anaplastic large cell lymphoma (ALCL; NPM-ALK) and non-small cell lung cancer (NSCLC; EML4-ALK). The dual Met/ALK inhibitor PF-02341066 (PF1066) has demonstrated promising clinical activity against tumors carrying activating ALK gene rearrangements (Kwak ASCO 2009: #3509) validating ALK as a therapeutic target. Previously, AP26113 was identified as a novel, potent, orally bioavailable ALK inhibitor with demonstrated selectivity over related receptor tyrosine kinase family members IGF-1R and InsR and no inhibition of Met. Here the efficacy and exposure/activity relationship of AP26113 was further characterized in preclinical models and compared to that of PF1066. In a panel of 7 EML4-ALK or NPM-ALK positive NSCLC and ALCL cell lines, the concentration of AP26113 that inhibited growth by 50% (GI50) ranged from 4.2 - 30.8 nM. In each cell line the GI50 for PF1066 was ~10-fold greater (range 62 - 309 nM). In 4 cells lines tested, the IC50 for inhibition of ALK phosphorylation tracked with potency in cell proliferation assays and was 10-fold greater for PF1066 than AP26113. Across 3 ALK-negative NSCLC and ALCL cell lines the GI50s for AP26113 (503 - 2387 nM) and PF1066 (928 - 1773 nM) were similar. Overall, AP26113 exhibited ~100-fold selectivity for ALK-positive lines compared with a ~10-fold selectivity for PF1066. The in vivo activities of daily oral dosing of AP26113 (10, 25 and 50 mg/kg) and PF1066 (25, 50 and 100 mg/kg) were examined in Karpas-299 ALCL (2 week dosing) and H3122 NSCLC (3 week dosing) xenograft models. At the highest doses tested, strong regressions were achieved with AP26113, but not PF1066. Tumor growth inhibition by 25 mg/kg and 10 mg/kg doses of AP26113 in the ALCL and NSCLC models, respectively, was similar to that of 100 mg/kg PF1066. In a PK/PD study in the ALCL model, inhibition of ALK phosphorylation after administration of 100 mg/kg PF1066 was intermediate between that observed after administration of 10 or 25 mg/kg AP26113. Results from the analysis of plasma levels of each drug showed that AP26113 had equivalent efficacy to PF1066 at 4- to 10-fold lower levels of exposure (AUC and 24 h trough plasma levels). AP26113 demonstrated favorable properties including moderate in vitro plasma protein binding (=77% in mouse, rat, monkey, and human plasma), negligible inhibition of major CYP isoforms (IC50 > 10 µM for 3A4, 2C9, 2D6), and good oral bioavailability (multiple animal species). In animal models, AP26113 was well-tolerated at and above predicted clinically effective plasma levels. In conclusion, these data demonstrate that AP26113 is a highly potent and selective inhibitor of ALK and support the clinical evaluation of AP26113 in patients with ALK-driven tumors.
There is also a late-breaker whose abstract I could not yet find:
Title: AP26113, a potent ALK inhibitor, overcomes mutations in EML4-ALK that confer resistance to PF-02341066 (PF1066)
Date & Time: Tuesday, April 20, 2010, 2:00 PM - 5:00 PM
Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 2
Abstract: #LB-298
Presenter: Sen Zhang, Ph.D. (ARIAD Pharmaceuticals)
Location: Exhibit Hall A-C, Poster Section 39
If we judge by other kinase drugs, resistance nearly always develops eventually, and so even though the Aria drug is well behind the Pfizer drug there is plenty of room for a another drug in the same class. This is another class of drug where efficacy should hopefully be demonstrated in Phase I.
