Abstract 2089: NT113, a potent and selective pan-ErbB inhibitor, is efficacious in vivo and has high brain penetrance.
Authors: Shen Wang , Pedersen Harry , Brown Dennis , Walling Jackie , James David , Ozawa Tomoko 
Published: August 2014

Background: The ErbB family of receptor tyrosine kinases EGFR (ErbB1), Her2 (ErbB2) and ErbB4 (Her4) function to transduce signals across the cell membrane in a wide variety of epithelial cells. ErbB dimerization results in the phosphorylation of intracellular tyrosine residues, activating diverse signaling pathways. These downstream pathways culminate in a variety of cellular responses, including cell growth, proliferation, differentiation and migration. In addition, interactions between ErbB receptors provide a mechanism for signal differentiation and amplification. Dysregulation of ErbB mediated signaling confers a growth advantage, and can result in cellular transformation and/or increased tumor metastatic potential. ErbB family members have been well validated cancer targets. Both antibodies and small molecule kinase inhibitors targeting individual ErbB receptors or both ErbB1/ErbB2 together have been approved for the treatment of human cancers. In addition, some ErbB targeting agents are in late stages of clinical testing.

A large fraction of glioblastoma multiforme (GBM, the most common and malignant primary brain tumor) harbors EGFRvIII activating mutation, and may represent an especially appropriate subgroup of this cancer for treatment with ErbB inhibitors.

Results: NT113 is a potent and selective pan-ErbB family kinase inhibitor. It also inhibits known mutant EGFRs resistant to first generation EGFR inhibitors, including the T790M gate keeper mutant. NT113 inhibited proliferation of ErbB kinase driven cell lines, and GBM cell lines harboring EGFRvIII mutations.

NT113 showed excellent oral PK in mouse and rat. rat, iv CL = 6.3 L/h/Kg, oral t1/2 = 15 h, F = 70%; mouse iv CL = 1.4 L/h/Kg, oral t1/2 = 16h, F = 100%. Importantly, NT113 showed significant brain exposure in rat oral PK studies, with brain/plasma ratio &gt; 4 at 2, 4 and 24 hr time points, while afatinib brain level was not detectable at all 3 time points. If these PK results are maintained in human patients, it may lead to significant clinical activity. Longer half life would allow the drug to better permeate into tumor, while the brain penetrance is favorable for insuring the clinical activity of NT113 for CNS cancer, as well as for brain metastasis of NSCLC and breast cancers.

In vivo, NT113 displayed excellent activities in NT87 gastric cancer xenograft models, and in NCI-H1975 (T790M gate keeper mutation) NSCLC xenograft models. In an intracrania GBM xenograft model with EGFRvIII mutation, NT113 completely suppressed the growth of tumor, and significantly prolonged the life span of the mice after two weeks of oral dosing.

Conclusion: NT113 appears to be a promising best-in-class agent for treating cancers whose growth is driven by both wild type and mutant ErbB. It is currently undergoing IND enabling studies.

Citation Format: Wang Shen, Harry Pedersen, Dennis Brown, Jackie Walling, David James, Tomoko Ozawa. NT113, a potent and selective pan-ErbB inhibitor, is efficacious in vivo and has high brain penetrance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2089. doi:10.1158/1538-7445.AM2013-2089