Leukaemia- dasatinib

Chronic myelogenous leukaemia (CML), as with the most common forms of leukaemia, is the result of acquired genetic mutation, in this case to the Philadelphia chromosome and the BCR-ABL fusion gene. The fusion protein has tyrosine kinase activity, and the deregulation of signal transduction pathways caused by the mutation leads to abnormal cell cycling, an increase in cell proliferation and a failure of the apoptosis process. This target has already been successfully addressed by Novartis with imatinib (Glivec), a specific small molecule inhibitor of BCR-ABL, which has an estimated complete haematological response rate of 98% in newly diagnosed patients. However, very few patients achieve molecular remission, which suggests that leukaemic stem cells persist. Some patients also develop resistance, and it is less effective in patients with advanced CML. To counter these resistance problems, Bristol-Myers Squibb has developed a dual BCR-ABL and Src kinase inhibitor, dasatinib, and numerous clinical trials have been carried out.' In one multicentre Phase II study, 107 heavily pretreated CML patients who were resistant or intolerant to imatinib were given 70mg dasatinib tWice a day for a median of two months. A total of 23 of the 35 patients given a preliminary assessment achieved a major haematological response, and three patients who had not responded to imatinib had a response here. Prolonged myelosuppression was seen in 20 of the patients. In another Phase II study, 74 imatinibresistant or intolerant CML patients were given 70mg dasatinib twice a day on a continuous daily dosing schedule. Preliminary data on the first 34 patients showed that 16 had major haematological responses, seven of which were complete. Clinical response to dasatinib has been correlated to BCR-ABL mutation in a group of 25 CML patients.- A total of 13 different imatinib resistant point mutations were identified in the BCR-ABL domain, and 20 of the patients responded to therapy, showing that it remains active in patients with a variety of imatinibresistant mutations. Trials continue.

Hepatitis C is a viral infection that affects the liver, and while it can lead to fibrosis, cirrhosis, liver cancer and, ultimately, liver failure, all too often chronic sufferers are asymptomatic and remain unaware that they have been infected until symptoms appear, which can take as long as 20 years. At least three-quarters of those who are infected fail to fight off the virus and develop the chronic disease. Current treatments are effective in only around half of patients with the most virulent genotype of the virus, type I, which is also the most difficult form to treat. The normal regimen now consists of a combination of pegylated interferon and the antiviral drug ribavirin, but it has significant side-effects and not all patients are suitable candidates for treatment. Another approach is being taken by Idenix, which is developing along with Novartis a drug that targets HCV-specific viral enzymes, valopicitabine. It is orally available, and a pro-drug of a novel ribonucleoside analogue. A randomised, placebo-controlled, dose escalating Phase 1/11 trial was carried out in patients with chronic HCV-1 infection who also had non-cirrhotic liver disease, the majority of which had not responded to interferon treatment. 1 Patients were given doses of between 50 and 800mg a day for 15 days. It was rapidly converted to the active form in the body. Significant dose dependent reductions in viral load were seen, and it was generally well tolerated. It is also being investigated in combination with peg interferon alfa-2b, in treatment nah/e patients.2 A total of 30 subjects were given doses of valopicitabine escalating to 800mg over the first week. This remained at 800mg for the remainder of the 24 week treatment period, and peglnterferon given at 1 ~g/kg once a week starting on day 8 for those patients assigned to combination therapy. Preliminary results in 19 patients showed that those given the combination had a three times greater reduction in viral load than those given the new agent alone.