CML: imatinib class monologue
Chronic myeloid leukemia (CML) is a myeloproliferative disease that is characterized by the Philadelphia chromosome translocation caused (Ph) chromosome fusion gene encoding BCR ABL. The BCR ABL fusion gene is a deregulated kinase , can stimulate cell proliferation and apoptosis produced boycott.
Novartis' Gleevec (Gleevec, imatinib ) is the first approved tyrosine kinase inhibitor (TKI), the drug can change the inherent process of CML . 2008 , imatinib was $ 3.67 billion in sales , of which most of its sales from CML treatment. However, since receiving Gleevec treated patients had drug reactions , therefore, in chronic myeloid leukemia market has created a new market segment.
Imatinib : magic bullet
Chronic myeloid leukemia in clinical practice can be divided into chronic phase, accelerated phase and blast phase 3 phase. With imatinib CML ? clinical evaluation of the success of traditional Interferon-based chemotherapy has become redundant . Compared with interferon , daily oral administration of 400mg imatinib significant effect. Imatinib is already firmly established as a first-line treatment of patients with chronic phase CML status . While the high -dose imatinib (600 ~ 800mg / day ) are increasingly used for CML accelerated phase and blast phase , although these patients, imatinib little effect , but has been used as first-line medication.
Because drug resistance or compliance, therefore , not all patients can benefit from imatinib . Clinical trial follow-up data show that , in those receiving interferon treatment failure patients, only 44 % of patients can continue to use imatinib six years. In the world's major pharmaceutical markets , about 8.4% of new patients in the chronic phase of CML does not comply with imatinib resistant or experience. In addition, secondary resistance to imatinib may also occur , in which patients first use of imatinib is a good effect, and can be maintained for many years the disease progression , but then the disease will recur , faced with disease progression risk. Get full use of imatinib in patients with cellular response , more than 25% of patients will occur secondary resistance .
Dasa , Nile : fast follower
Imatinib resistance, stimulate pharmaceutical companies for the development of tyrosine kinase inhibitors , Bristol- Myers Squibb Company dasatinib (dasatinib, Sprycel) and nilotinib Novartis (nilotinib, Tasigna) is more prominent product, which two drugs were in 2006 , in 2007 the U.S. FDA approval. In vitro activity test showed that dasatinib on BCR ABL inhibitory activity is 325 times that of imatinib , dasatinib also inhibits Src family kinases. Nilotinib is an analog of imatinib , enhanced BCR ABL gene targeted.
These two drugs for the treatment of primary and secondary resistance to imatinib . Before listing these drugs , when imatinib therapy , or after emergence of suboptimal response and patient tolerance , patients using higher doses of imatinib 600mg daily dose has been approved in the U.S. , 800mg daily dose has been approved in Europe . These two drugs are marketed , about 33% of such patients now start using dasatinib or nilotinib , rather than the use of high -dose imatinib .
2008 , issued by the United States hematologist dasatinib nilotinib prescription number is three times the number of prescriptions . Since there is no relative comparison , therefore , the first listing of dasatinib only has certain advantages . Clinical trials have shown that dasatinib for those 400 or 600mg daily imatinib-resistant chronic patients, and better efficacy . And nilotinib have not shown such advantage.
But at least in the next few years, imatinib as first-line treatment of CML status insurmountable . Dasatinib Phase ? clinical trials and nilotinib as first-line CML drugs ( imatinib as the control drug ) clinical trial was launched in 2007 , 2010 will be published clinical trial data . Once the 2015 generic drug imatinib is listed, though two drugs as first-line treatment for CML is also approved, will bring them great challenge.
CML Market : Due to drug resistance is divided
Developing the next generation of drugs will solve CML patients currently approved tyrosine kinase inhibitors does not answer the question . It is unclear , tyrosine kinase inhibitors in other two of these patients have been or will be ineffective in the case resistance , using the first three tyrosine kinase inhibitor approved whether it can produce long-lasting response. If dasatinib and nilotinib in controlling drug resistance can replace high-dose imatinib , then dasatinib and nilotinib will sooner enter treatment programs.
CML in the development of new therapeutic drugs has a very important significance. Because the incidence of CML rise with increasing age : newly diagnosed patients, 65% are over 60 years old . Second-line therapy if a little earlier into the treatment program , the patient will inevitably earlier on drug resistance , thereby strengthening the demand for new drugs . On the other hand , allogeneic stem cell transplantation (ASTC) is better for younger patients , which is a possible cure. Failure for a variety of tyrosine kinase inhibitors in patients developing innovative medicines to maintain the efficacy of the ASTC and build a bridge between , this market is substantial, realistic.
Chronic myeloid leukemia is strongly focused on the research and development pipeline BCR ABL gene mutations and inhibits kinase activity , expression or activity of these kinases such as Src family kinase or by Aurora kinases like BCR ABL effects . BCR ABL most important is undoubtedly mutation T315I, which occupy all of the mutations in the tyrosine kinase inhibitor -resistant 15% , and for any one of the currently approved tyrosine kinase inhibitors will not produce response. Forefront of T315I active substance is ChemGenex 's Omacetaxine, is currently in two to register to point to the stage ?, ? clinical trials. Omacetaxine is a non- targeting of the protein synthesis inhibitor , ? clinical trials have demonstrated the drug 's safety and effectiveness . Mid-2009, will be submitted to the drug application , if successful , will be held in 2010 in the U.S. and Europe.
CML therapy market is still relatively young, not more than 10 years , although only three drugs, but has become very crowded. Since 2001 , the survival effect of imatinib in CML has major pharmaceutical market has grown twice as much medication . Although , CML incidence was slightly lower compared with other primary tumor , but also with the rise of aging . 2009 , the world's major pharmaceutical markets CML patients reached 91,500 , the annual growth of 9% to 11%.
2015 , CML therapeutic drug market will reach $ 9 billion of such a height , but will increase as imatinib generics market decline. Innovative medicines and T315I targeted drugs will increase the value of market segments , because CML patient population due to tyrosine kinase inhibitors are differentiated , in 2015 , this market segment will reach $ 900 million . With many patients due to drug resistance and longer use of imatinib , dasatinib and nilotinib . 2020 , T315I CML therapy targeted market will reach $ 500 million .
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