Preclinical data on brigatinib, an oral tyrosine kinase inhibitor in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK ) metastatic non-small cell lung cancer (NSCLC) was published today in the journal Clinical Cancer Research.

In addition, the medicinal chemistry strategy leading to the discovery of brigatinib was published in the Journal of Medicinal Chemistry.

Brigatinib is an investigational, targeted cancer medicine discovered at ARIAD Pharmaceuticals, Inc.

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.

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.”

“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.”

Source: Clinical Cancer Research