Bosutinib - Chronic Myelogenous Leukaemia (CML) Treatment, United States of America

Bosutinib is an investigational drug indicated for treating Philadelphia chromosome positive Chronic Myelogenous Leukaemia (Ph+ CML). The drug was originally developed by Wyeth Pharmaceuticals, which was taken over by Pfizer in October 2009.

Wyeth, in collaboration with Pfizer, is currently conducting phase III clinical trials on Bosutinib. Based on the results of the study, the company expects to submit the Marketing Authorization Application to the European Medicine Agency in 2011.

The company also plans to apply for the regulatory approval of the drug in treating previously treated Ph+ CML patients from the US Food and Drug Administration.

Chronic Myelogenous Leukaemia

Chronic Myelogenous Leukaemia (CML) is a cancer of the white blood cells. The disease is caused due to the presence of an abnormal chromosome - Philadelphia chromosome - which causes the production of the Bcr-Abl protein.

The Bcr-Abl protein contains the tyrosine kinase enzyme, which drives excessive white blood cells and immature stem cells to be produced in the bone marrow. The white blood and stem cells cause to replace the red blood cells and platelets.

The CML disease occurs mostly in elderly and middle-aged people, although it affects people of all ages, and is found more frequently in men than in women. The annual incidence of the disease is one to two per 100,000 people.

According to the National Cancer Institute (NCI) approximately 5,050 patients were diagnosed with the disease in the US alone in 2009. The NCI also estimated that 22,475 people with CML disease are surviving in the US as of 2009.

Bosutinib

Bosutinib contains the oral dual Src and Abl kinase inhibitor with potential anti-neoplastic activity. The drug can resist CML disease and other solid tumours because of its dual mechanism action.

Clinical trials

Wyeth started phase I / II clinical trials on bosutinib in January 2006. The study is being conducted across 98 centres in the US, Australia Canada, Germany, Finland, Argentina, Columbia, Austria, Chile and Brazil. It has enrolled 571 patients with Ph+ CML and is expected to complete by June 2013.

The purpose of the study is to find the safety and efficacy of 500mg of bosutinib in treating Ph+ CML patients. The study will establish the maximum tolerated dose (MTD) in CML patients.

Wyeth initiated phase III clinical trials on the drug in February 2008 and the study is scheduled to be completed by July 2017. The study has enrolled 502 patients with Ph+ CML disease.

It was designed to evaluate the safety and efficacy of bosutinib compared with imatinib in treating Ph+ CML. Imitanib is indicated for treating CML and is being marketed by Novartis.

The primary endpoint of the study is to find the cytogenetic response rate at one year. The secondary outcome measure is to find the duration of the complete cytogenetics response (CCyR), major molecular response, complete haematologic response, comparative safety and population pharmacokinetics.

Phase III preliminary data

Pfizer disclosed the preliminary data on the phase III clinical study on 6 December 2010. The data from the study showed that fewer patients who were administered with only bosutinib progressed to the advanced phase compared to the patients treated with imatinib. The study also found that there were fewer deaths in the bosutinib arm than in the imatinib arm.

The patients administered with bosutinib achieved CCyR faster in 13 weeks compared with the imatinib administered patients who achieved it in 25 weeks. The difference between the CcyR of bosutinib and imatinib was negligible (2%), indicating a failure in meeting the primary end point.

The study also found that the patients who were administered with bosutinib experienced more serious adverse events compared to imatinib. The adverse events in bosutinib treated patients were nausea, diarrhoea, rash and vomiting. The adverse events led 19.4% of the bosutinib patients discontinue the treatment where as only 5.6% of the imatinib patients discontinued it due to the adverse events. Discontinuation of the bosutinib arm of patients was principally due to liver enzyme elevations while in imatinib arm it was due to neutropenia.