Chronic myelogenous leukemia (CML) is a cancer of the blood in which too many granulocytes are produced in the bone marrow. In 95% of cases, the disease is caused by a chromosomal translocation resulting in the fusion of the Bcr and Abl genes. The resulting Bcr-Abl gene product is the major driver of the disease. The American Cancer Society estimates that about 4,600 patients were diagnosed with CML in 2005 and that 850 patients died of the disease in the same year. The prevalence of CML in the United States is estimated to be above 20,000.

 

The majority of patients diagnosed with Chronic Myeloid Leukemia (CML) are treated with imatinib mesylate (Gleevec ™). Imatinib works by inhibiting the abnormal Bcr-Abl protein that is produced in the leukemic blood cells. However, resistance to Gleevec has become a serious clinical concern for these patients as up to 13% per year will develop resistance to imatinib therapy. Resistance appears to occur through one of two major mechanisms: Bcr-Abl mutant proteins that overcome imatinib's effect or upregulation of pathways that are independent of Bcr-Abl, such as the Src-kinase family member Lyn.

 

INNO-406 (formerly known as NS-187) is an orally bioavailable, rationally designed, dual Bcr-Abl and Lyn-kinase inhibitor. According to a study published in the journal Blood (Dec. 1, 2005), INNO-406 is 25 to 55 times more potent than imatinib in vitro, and at least 10 times as effective as imatinib mesylate in suppressing the growth of Bcr-Abl bearing tumors. INNO-406 has demonstrated activity in 12 of 13 imatinib-resistant cell lines.

 

In addition to its Bcr-Abl inhibitory properties, INNO-406 is a potent and specific inhibitor of Lyn kinase. Upregulation of Lyn kinase activity is a well recognized cause of imatinib resistance. Lyn kinase activation has also been documented in a variety of solid tumors, including prostate cancer.

 

There are other Bcr-Abl inhibitors being developed for Gleevec-resistant CML including dasatanib by Bristol-Myers Squibb and nilotinib by Novartis. Because CML has become a chronic disease condition, Innovive believes that patients will require multiple drugs over the course of their disease. Because it targets both mechanisms of resistance seen with Gleevec, INNO-406 should be effective in treating Gleevec-resistant CML and may delay or even prevent the onset of resistance in treatment naïve CML patients. The ability of INNO-406 to specifically target the Bcr-Abl and Lyn kinases may result in a better side effect profile than agents that target multiple kinases such as a pan-Src inhibitor.

 

An international Phase 1 dose-ranging safety clinical trial has recently been completed. Once the data from this clinical trial are analyzed, the results will be announced and CytRx anticipates evaluating options for a possible Phase 2 protocol with the FDA in CML. INNO-406 has been granted Orphan Drug Status for the treatment of Philadelphia chromosome-positive (Ph+) CML by the FDA. 

 

CytRx holds rights to INNO-406 for all territories except Japan.

 

Bibliography
Shinya Kimura, Haruna Naito et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. BLOOD, 1 DECEMBER 2005; VOLUME 106: NUMBER 12