ARIAD Pharma (ARIA) Announces Publication of Brigatinib Preclinical Data in NSCLC
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ARIAD Pharmaceuticals, Inc. (Nasdaq: ARIA) announced the publication of preclinical data on brigatinib, its investigational oral tyrosine kinase inhibitor in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC). The design and preclinical characterization of brigatinib are described in an article titled, “The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models,” in the journal Clinical Cancer Research (Zhang, S.; et al. Clin Cancer Res. 2016, DOI: 10.1158/1078-0432.CCR-16-0569 Published 25 October 2016).
Activating gene rearrangements in ALK account for approximately three to seven percent of NSCLCs. Disease progression in patients treated with the first-generation ALK inhibitor crizotinib can be associated with secondary resistance mutations in ALK, or the development of brain metastases. Resistance mutations in ALK, including G1202R, have also been associated with disease progression in patients treated with the second-generation ALK inhibitors ceritinib and alectinib. In the preclinical studies described in the paper, brigatinib was shown to be a highly potent and selective inhibitor of ALK, inhibiting ALK at lower concentrations than crizotinib, ceritinib, and alectinib. Furthermore, in these studies, brigatinib was the only inhibitor that showed activity against all 17 tested ALK mutants that have been associated with preclinical or clinical resistance to existing ALK inhibitors, including G1202R. In addition, compared to crizotinib, brigatinib was shown to significantly prolong survival of mice with ALK+ tumors in the brain.
“We believe that these preclinical findings support a molecular basis for the promising systemic and intracranial activity in ALK+, crizotinib-resistant NSCLC patients being treated with brigatinib in clinical trials and further validate our ongoing clinical research to understand the potential of brigatinib to address mutations associated with disease progression,” said Victor M. Rivera, Ph.D., vice president of preclinical & translational research at ARIAD. “In addition, we believe that these findings support testing brigatinib as initial therapy in ALK+ NSCLC patients, to see if the greater in vitro potency of brigatinib also manifests in human trials as deeper and more durable responses compared to crizotinib, and whether emergence of ALK resistance mutations can be delayed or even circumvented.”
ARIAD has commenced the Phase 3 ALTA 1L clinical trial to compare brigatinib and crizotinib in ALK+ NSCLC patients who have not received prior ALK inhibitors.
Brigatinib Medicinal Chemistry Publication
In addition, the medicinal chemistry strategy leading to the discovery of brigatinib was published in an article titled, “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase,” in the Journal of Medicinal Chemistry, (Huang, W.-S.; et al. J. Med. Chem. 2016, 59, DOI: 10.1021/acs.jmedchem.6b00306).
“This publication details, for the first time, specific design elements that ARIAD scientists utilized in synthesizing brigatinib. Brigatinib features an innovative phosphine oxide recognition motif that is designed to enhance potency and selectivity while also conferring favorable pharmacologic properties,” said William C. Shakespeare, Ph.D., vice president of drug discovery at ARIAD. “Brigatinib is the only phosphine oxide-containing molecule to have advanced to late stage clinical trials, showcasing how our innovative chemistry platform can deliver novel drug candidates designed to tackle challenging clinical problems.”
About Non-Small Cell Lung Cancer and ALK
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies indicate that chromosomal rearrangements in ALK are key drivers in a subset of NSCLC patients as well. Since ALK is generally not expressed in normal adult tissues, we believe that it represents a promising molecular target for cancer therapy. Approximately three to eight percent of patients with NSCLC have a rearrangement in the ALK gene.
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