Posted by rob on December 29, 2005 under Uncategorized | 
The investigational drug AMN107 has produced treatment responses in some patients with chronic myeloid leukemia (CML) that does not respond to Gleevec? (imatinib mesylate), as well as in some patients with acute lymphoblastic leukemia (ALL) that is positive for the Philadelphia chromosome. These results were presented at the 47th annual meeting of the American Society of Hematology (ASH).
Chronic myeloid leukemia (CML), also called chronic granulocytic leukemia, is a cancer that originates in the immune cells. It affects approximately 4,600 people annually in the U.S. In the case of CML, large numbers of young immune cells do not mature, resulting in an excess accumulation of these cells. These leukemia cells then crowd the bone marrow and blood, suppressing formation and function of other blood cells normally present in these areas. In addition, the leukemia cells cannot perform their function properly, leaving patients susceptible to infection.
Chronic myeloid leukemia begins with a chronic phase, during which few clinical problems, if any, occur. However, when left untreated, the chronic phase progresses into acute phases; these phases, called the accelerated and blastic phases, are characterized by fast-growing and aggressive cancer. Patients reaching these acute phases have a poor prognosis for long-term survival.
Historically, the only curative option for patients with CML was an allogeneic stem cell transplant. However, treatment-related mortality and side effects can both be substantial in patients undergoing an allogeneic stem cell transplant; researchers have thus focused efforts on curative treatment options that are more easily tolerated.
Philadelphia chromosome-positive CML refers to the majority of cases of CML in which a genetic abnormality, referred to as the Philadelphia chromosome, results in the constantly activated growth of cancer cells. Roughly 30% of adult patients with ALL also have this genetic abnormality.
Gleevec is a biological agent that binds to and slows or stops the uncontrolled growth of cancer cells with this genetic mutation. Unfortunately, a small number of patients who are treated with Gleevec do not achieve anticancer responses; researchers are evaluating novel agents for this group of patients.
AMN107 is an investigational drug that targets the same protein as Gleevec, but through a different mechanism. AMN107 is reported to be significantly more potent than Gleevec. To evaluate AMN107 in the treatment of Gleevec-resistant leukemia, researchers from the MD Anderson Cancer Center in Texas conducted a phase I clinical trial among 119 patients with Gleevec-resistant CML in chronic, accelerated, or blastic phases or Philadelphia chromosome-positive ALL.
Treatment with AMN107 was generally well tolerated and produced notable anticancer activity. Among patients with CML, the rate of cytogenetic response (reduction of genetically abnormal cells) ranged from 22% to 100%, and the rate of hematologic response (normalization of blood cell counts) ranged from 44% to 100%. Among patients with ALL, rate of hematologic response ranged from 10% to 33%.
The researchers concluded that AMN107 has significant activity in patients with Gleevec-resistant CML and possibly in some patients with ALL.
Reference: Kantarjian HM, Ottman O, Cortes J, et al. AMN107, a novel aminopyrine inhibitor of Bcr-Abl, has significant activity in imatinib-resistant chronic myeloid leukemia (CML) or Philadelphia-chromosome positive acute lymphoid leukemia (Ph+ALL). Blood . 2005;106:15a. Abstract # 37.
Investigational Drug Shows Promise in Gleevec?-Resistent CML
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ATLANTA, GA — December 12, 2005 — In an update of a phase 1, dose-escalating study, researchers concluded that the data supports the therapeutic potential of dasatinib in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) patients who are imatinib-resistant or intolerant.
Results of the study were presented here on December 10th at the 47th Annual Meeting of the American Society of Hematology (ASH).
Imatinib mesylate (Gleevec) resistance in CML and Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL overproduction.
Dasatinib (BMS-354825) is a novel, oral, multitargeted kinase inhibitor, which targets BCR-ABL and Src protein kinase. Src is a signaling protein that specializes in messages that control cell growth. The drug is 325-fold more potent than imatinib in cells transduced with normal BCR-ABL genes, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutations.
In this update by researchers from the University of California, Los Angeles (UCLA) School of Medicine, Los Angeles, California, and the University of Texas MD Anderson Cancer Center, Houston, Texas, the investigators looked at the use of dasatinib in imatinib-resistant or intolerant patients with CML in late chronic phase, accelerated phase, myeloid blast crisis, or lymphoid blast crisis/Ph+ ALL. A blast crisis is the progression of diseases to an acute advanced phase.
Charles Sawyers, MD, director of the Prostate Cancer Program Area at the UCLA Jonsson Cancer Center, and professor of medicine at UCLA School of Medicine, Los Angeles, California, presented data available for 82 patients — 40 CP, 10 AP, 22 MBC, 10 lymphoid blast crisis/Ph+ ALL.
The 40 patients in late chronic phase, with 5 years median duration of CML, were treated with 15 to 180 mg of dasatinib either once-daily QD or BID for a median of 13 months. The rate of complete hematologic response in late chronic phase patients was 93%, while major cytogenetic responses were observed in 45% and complete cytogenetic response in 35%.
In advanced disease, 44 patients have been treated with dasatinib 70 to 240 mg BID for a median of 37 months. The rate of major hematologic response is 81% in accelerated phase, 61% in myeloid blast crisis, and 70% in lymphoid blast crisis/Ph+ ALL. The complete response rate is 45% in accelerated phase, 70% in lymphoid blast crisis/Ph+ ALL, and 35% in myeloid blast crisis.
The overall rates of major cytogenetic responses and complete cytogenetic responses in advanced disease were 43% and 25%, respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior cytogenetic response with imatinib.
Responses were durable in late chronic and accelerated phase, but relapses have occurred in the myeloid blast crisis and blast crisis/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations.
“We are encouraged by the results and are looking forward to seeing the results from ongoing phase 2 studies to confirm the effects of dasatinib in patients with all phases of the disease,” Dr. Sawyers said.
[Presentation title: Dasatinib (BMS-354825) in Patients With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome- Positive Acute Lymphoblastic Leukemia (Ph + ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study. Abstract 38]
News – Dasatinib Shown Effective for Treating Two Forms of Leukemia: Presented at ASH
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Offering promise in the battle against cancer, the results from five studies highlighting new advances in the treatment of chronic myeloid leukemia (CML) — a slow-progressing, malignant bone marrow cancer — will be presented at the 47th Annual Meeting of the American Society of Hematology.
“The survival rate for leukemia has improved in the past two decades, thanks to new agents designed to treat patients,” said Brian J. Druker, M.D., Oregon Health and Science University, Portland, Ore. “Continued research will only strengthen our understanding of the disease and support the therapeutic potential of current and developing treatments for chronic myeloid leukemia.”
CML is usually diagnosed by finding a specific chromosomal abnormality called the Philadelphia chromosome (Ph chromosome). The Ph chromosome is the result of translocation — a genetic chromosomal abnormality — between the long arms of chromosomes 9 and 22. The result is that part of the BCR (breakpoint cluster region) gene from chromosome 22 is fused with part of the ABL (abelson leukemia virus) gene on chromosome 9. The translocation takes place in a single bone marrow cell and, through the process of cell division and expansion, results in leukemia, the rapid growth of abnormal white blood cells in the bone marrow, blood, and body tissues.
The discovery of the Ph chromosome marked the first genetic abnormality consistently associated with a particular form of cancer. In addition to CML, Ph chromosome can also be found in some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Imatinib, which blocks the abnormal protein driving the overproduction of abnormal white blood cells, has become a standard therapy for patients not undergoing stem cell transplantation. It is now demonstrating continued control and reduction in levels of remaining disease in chronic phase CML (CML- CP) patients. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.
As a result, treatment options for patients with CML continue to expand. Various studies of potential new treatments for CML yield positive results in patients whose disease is resistant to imatinib. Both dasatinib and AMN107 have been shown to be effective in treating patients with CML whose disease has progressed on imatinib.
Continuing Reduction in Level of Residual Disease After Four Years in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase Responding to First-Line Imatinib (IM) in the IRIS Study [Abstract 163]
A recent report updated results of molecular monitoring of patients in the International Randomized Interferon vs. STI 571 (IRIS) study that prospectively compared imatinib therapy with interferon-alfa plus cytarabine. The IRIS study was initiated in June 2000, and demonstrated that after one year of imatinib treatment, an estimated 40 percent of CML-CP patients taking 400 mg per day achieved a major molecular response (MMR), defined as substantial reduction in BCR-ABL levels. This particular analysis assessed the level of BCR-ABL transcripts after approximately four years of imatinib treatment and showed continuing reduction in transcript levels.
The analysis was based on 101 patients who achieved complete cytogenetic response (CCyR) within one year, received first-line treatment for at least 24 months, and had blood collected for measuring transcript numbers at one year and four years after starting treatment. Results are expressed as a log reduction from a standardized baseline value for untreated patients. This means they are expressed as transcript copy numbers, with a one-log reduction equivalent to a fall from 100 to 10, and a two-log reduction a fall from 100 to one.
At one year, BCR-ABL transcript levels fell by at least three logs in 46 percent of the 101 patients. At the most recent measurement, at or after 44 months from start of study, 75 percent of patients demonstrated a reduction of at least three logs. Of these patients, more than half had already had a three-log reduction at year one, whereas 49 percent had not. Conversely, eight of the 47 patients with three-log reduction at one year had log reductions greater than three at four years. At the one- and four-year points, 20 percent and 36 percent of patients, respectively, achieved four-log reductions.
“The results are gratifying and show that patients in complete cytogenetic response who had an ‘adequate’ reduction in their BCR-ABL transcript levels at one year have a good chance at achieving a much greater reduction after four years of imatinib treatment,” said John M. Goldman, D.M., National Heart,
Lung, and Blood Institute (NHLBI), Bethesda, Md. “This is an important observation because it means that imatinib continues for at least four years to reduce the quantity of residual disease and so promises to offer patients with chronic phase CML very substantial prolongation of essentially normal life, compared with previous therapies.”
Control of Residual Disease in Imatinib (IM) Treated Chronic Myeloid Leukemia (CML) Patients with Peptide Vaccinations: Two Years Follow Up of CMLVAX100 Trial [Abstract 167]
In the past five years, the body of data concerning imatinib has defined its role as an effective first-line therapy for CML-CP patients. However, the persistence of disease in most patients, together with the evidence that discontinuation of imatinib inevitably results in a rapid loss of response, suggests that the cure for CML is unlikely using imatinib alone.
Researchers from the University of Siena in Siena, Italy, looked at the anti-tumor effect of a vaccine (CMLVAX100) targeting the BCR-ABL genes and how it reduced remaining disease in some patients with CML who have reached a maximum response to imatinib. After a median time of 24 months of imatinib treatment, a group of 21 patients showing different degrees of persistent residual disease started vaccinations with CMLVAX100. Vaccine treatment plans included six vaccinations at two-week intervals. In patients who responded to treatment, additional boosts of vaccine were provided every four to six months.
To date, 18 of the 21 patients have completed the immunization regimen, eight of whom received four additional boosts of vaccine. After six vaccinations, six patients with persisting, progressing disease reached a complete response, with three of them achieving an undetectable level of BCR-ABL transcript. In addition, three patients starting vaccinations with persistent molecular disease further reduced their BCR-ABL level, with one reaching molecular negativity. This suggests that CMLVAX100 works effectively with imatinib in CML-CP patients with persistent minimal residual disease.
Of the eight patients who underwent four additional boosts of vaccine, one reached a complete molecular response, five maintained the response obtained after immunization, and two patients (who previously achieved an undetectable level of BCR-ABL transcript) lost the complete molecular response (CMR), but maintained CCyR. This suggests that while beneficial, a six-month interval between boosts could be too long to maintain efficient immune control on residual leukemia cells.
“Although the number of patients who participated in the trial is small, this is a very important study,” said Monica Bocchia, M.D., University of Siena, Siena, Italy. “Researchers have been attempting to develop cancer vaccines for decades, and results in CML patients are a very encouraging step forward.”
Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome- Positive Acute Lymphoblastic Leukemia (Ph + ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study [Abstract 38]
Imatinib resistance in CML and Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (Ph + ALL) is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL overproduction. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor which targets BCR-ABL and SRC protein kinases. The SRC protein is a signaling protein that specializes in messages that control the growth of cells. The drug is 325-fold more potent than imatinib in cells transduced with normal BCR-ABL genes, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.
In an update of a phase I, dose-escalating study initiated in November 2003, researchers from the University of California, Los Angeles (UCLA) School of Medicine and The University of Texas M. D. Anderson Cancer Center looked at the use of dasatinib in imatinib-resistant or intolerant patients with CML in late chronic phase (CP), accelerated phase (AP), myeloid blast crisis (MBC), or lymphoid blast crisis (LBC)/Ph+ ALL. Data are available for 82 patients (40 CP, 10 AP, 22 MBC, 10 LBC/Ph+ ALL). A blast crisis is the progression of diseases to an acute advanced phase.
The 40 CP patients, with five years median duration of CML, were treated with 15 to 180 mg of dasatinib either once daily (QD) or twice daily (BID) for a median of 13 months. The rate of complete hematologic response (CHR) in CP patients was 93 percent, while major cytogenetic responses (MCyR) were observed in 45 percent and CCyR in 35 percent.
In advanced disease, 44 patients have been treated with dasatinib (70 to 240 mg BID) for a median of 37 months. The rate of major hematologic response (MHR) is 81 percent in AP, 61 percent in MBC, and 70 percent in LBC/Ph+ ALL. The complete response rate is 45 percent in AP, 70 percent in LBC/Ph+ ALL, and 35 percent in MBC.
The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior cytogenetic response with imatinib. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations.
“These data support the therapeutic potential of dasatinib in CML and Philadelphia chromosome positive acute lymphoblastic leukemia patients who are imatinib-resistant or intolerant,” said Charles Sawyers, M.D., Jonsson Cancer Center, UCLA School of Medicine, Los Angeles, Calif. “We are encouraged by the results and are looking forward to seeing the results from ongoing phase II studies to confirm the effects of dasatinib in patients with all phases of the disease.”
Efficacy of Dasatinib (BMS-354825) in Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Imatinib: First Results of the CA180013 ‘START-C’ Phase II Study [Abstract 41]
After three years of imatinib therapy, hematologic relapse occurs in seven percent of newly-diagnosed CML patients and 20 percent of CML chronic phase patients after failure to respond to current standard therapy. This is mostly associated with BCR-ABL mutations and/or clonal evolution — the development of chromosomal mutations that occurs in untreated CML and leads to progression of the disease. A previous phase I, dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant or intolerant patients with CML-CP.
This study (START-C [CA180013]), carried out by a multinational group of 75 investigators, is a follow-up on the use of dasatinib in CP imatinib resistant or intolerant patients.
A total of 394 patients were recruited to this phase II, open-label study. To date, data from 186 patients are available for analysis. Imatinib resistance (n=127) or intolerance (n=59) was defined as a failure to respond to imatinib at maximum tolerated doses or the occurrence of BCR-ABL mutations associated with virtual insensitivity to imatinib. Dasatinib was administered to patients at 70 mg BID, based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in patients lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks, while bone marrow was collected every three months.
Median time from diagnosis of CML was 63.8 months. Prior therapy included imatinib in 100 percent hydroxyurea or anagrelide in 86 percent, and interferon alpha in 70 percent of patients. Approximately 54 percent of patients received imatinib for more than three years.
Within the first six months, 90 percent of patients reached a complete hematologic response (87 percent resistant patients, 97 percent intolerant patients), and 45 percent achieved a major cytogenetic response (
Interim results of Phase II dasatinib studies in advanced disease were also presented. Of the myeloid blast crisis patients resistant to imatinib (n=68), 31 percent reached a major hematologic response, and 29 percent achieved a major cytogenetic response. Of the accelerated phase patients resistant to imatinib (n=99), 59 percent achieved a major hematologic response and 31 percent a major cytogenetic response.
“Despite the short follow-up, significant improvements of hematologic and cytogenetic responses were seen in pretreated CML patients in all phases of the disease, which further supports the activity of dasatinib in BCR-ABL positive leukemia,” said Andreas Hochhaus, M.D., University of Heidelberg, Mannheim, Germany. “This is very encouraging news for patients and should be viewed as a step forward in the treatment of CML.”
AMN107, a Novel Aminopyrimidine Inhibitor of BCR-ABL, Has Significant Activity in Imatinib-Resistant Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoid Leukemia (Ph + ALL) [Abstract 37]
AMN107 is an investigational oral compound which inhibits the activity of specific proteins, including BCR-ABL and 32 of 33 mutant forms of protein responsible for the development of CML. It is 10- to 50-fold more potent than imatinib against BCR-ABL-expressing cell lines, including most imatinib-resistant BCR-ABL mutants.
In research led by The University of Texas M.D. Anderson Cancer Center in Houston and the University of Frankfurt, Germany, 119 patients with imatinib-resistant CML in blast crisis (BC), AP, CP, or Ph+ ALL were treated with AMN107. Initial daily doses ranged from 50 mg QD to 1,200 mg QD, and 400 mg BID to 600 mg BID. Dose escalations occurred in 48 of the 69 patients in the once daily groups, and one patient in the 400 mg BID group escalated to 600 mg BID.
As of June 15, 2005, patients had been treated for a median of 120 days. AMN107 was well-tolerated, and the most common drug-related adverse events were constipation, nausea, and vomiting. Among CML patients who harbored a BCR-ABL mutation prior to treatment, 60 percent achieved a hematologic response and 41 percent achieved a cytogenetic response. In addition, 72 percent of CML patients who had no BCR-ABL mutation prior to taking AMN107 achieved a hematologic response, and 59 percent achieved a cytogenetic response. Ph+ ALL patients who harbored a mutation prior to treatment with AMN107 saw a 33 percent response rate.
“AMN107 was shown to have significant activity in patients with advanced imatinib-resistant CML and Philadelphia chromosome positive acute lymphoblastic leukemia,” said Hagop M. Kantarjian, M.D., The University of Texas M. D. Anderson Cancer Center, Houston, Texas. “Current therapies, though effective, still have many limitations, and new treatment options with proven safety and efficacy can only benefit this patient population.”
###
The American Society of Hematology (www.hematology.org) is the world’s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.
New Studies Identify Advances In Treatment Of Chronic Myeloid Leukemia
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The History Of Glivec
Category: Lymphoma/Leukemia News
Article Date: 27 Dec 2005
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The Glivec (imatinib) story begins with 2 Philadelphia researchers: Peter Nowell, MD, of the University of Pennsylvania School of Medicine, and David Hungerford, MD, of the Institute for Cancer Research. They were able to identify a genetic mutation in patients with CML (chronic myeloid leukaemia) in 1960.(1) The 2 researchers found that a section of DNA was missing from chromosome 22. This alteration soon became known as the Philadelphia (Ph) chromosome and could be detected in approximately 95% of patients with CML. The discovery meant that for the first time ever, scientists had discovered a genetic abnormality linked to a specific kind of cancer. The discovery of the link between the Ph chromosome and CML set off an explosion of research into the genetic causes of cancer.
The Great Shift
The next significant advance in the understanding of CML took place 13 years later through the work of Janet Rowley, MD, and researchers at the University of Chicago. They realised that the missing section of DNA from chromosome 22 (which characterised CML) had shifted to chromosome 9, a phenomenon known as “translocation.”(2) The recognition of this phenomenon paved the way for many later researchers, who have since been able to match dozens of translocations to various cancers. (In 1998, Nowell and Rowley received the Albert Lasker Medical Research Award, which is sometimes called the “American Nobel Prize”, for their work in CML.)
The remainder of the 1970s saw only incremental progress in genetic cancer research. However, in the 1980s, 2 researchers from the California Institute of Technology, David Baltimore, PhD, and Owen N. Witte, MD, identified the principal cause of CML. The Ph chromosome produces an enzyme that plays a central role in aberrant cell growth and division. The enzyme, a fusion protein (Bcr-Abl) that enhances tyrosine kinase activity, changes the cell’s normal genetic instructions. This aberrant enzyme sends out signals through multiple pathways within the cell, resulting in the overproduction of white blood cells in the body. The result is that, while a healthy cubic millimetre of blood contains 4,000 to 10,000 white blood cells, blood from a patient with CML contains 10 to 25 times this amount.(3) The massive increase in the number of white blood cells characterises CML.
Glivec: Realising a Dream
With the groundbreaking discovery that a single enzyme could cause the development of CML, medical researchers faced a rare opportunity. Unlike previous efforts, the genetic target was clear, and the development of a drug that could block Bcr-Abl could proceed rationally. Work soon began in early 1990 on the discovery of Bcr-Abl inhibitors by researchers at Novartis (then Ciba-Geigy).(4,5) The 2 lead researchers, Nicholas Lydon, PhD, and Alex Matter, MD, were particularly optimistic about one promising compound from a pool of several potential agents. However, it had only weak, non-specific activity against Bcr-Abl.
The task of improving this “promising compound” was assigned to 4 Novartis scientists, Drs. Juerg Zimmermann (Medicinal Chemistry), Elisabeth Buchdunger (Cell Biology), Helmut Mett (Screening and Enzymology), and Thomas Meyer (Enzymology). They soon began changing, adding, and deleting certain molecules to alter the original compound’s activity against Bcr-Abl.
After 2 years of painstaking experimentation, the team finally transformed the original compound-a weak, non-specific inhibitor-into a potent, specific inhibitor of Bcr-Abl. This agent effectively blocked the enzyme that leads to the proliferation of white blood cells in patients with CML. Their pioneering work led to a class of compounds with optimised activity against Bcr-Abl and other kinases.(6) The result of this monumental achievement was the filing of the basic patent application covering this class of inhibitors in 1993 and 1995.
Building on the Dream
Building on the enormous experimental achievement of Drs. Zimmermann, Buchdunger, Mett, and Meyer, Novartis began a collaboration in 1994 with Brian Druker, MD, a haematologist and oncologist with an interest in tyrosine kinases and CML. Their work profiled the activity of 2 compounds in cellular models of CML. They found that one compound, which would eventually be known as Glivec, showed selective in vitro activity against the Bcr-Abl protein, and it suppressed the proliferation of Bcr-Abl-expressing cells in vitro and in vivo in one critical study. Of equal significance, the compound did not demonstrate significant activity against normal cells,(7) which immediately distinguished it from traditional cancer treatments. Other researchers subsequently confirmed these findings.(8,9)
Over the next several years, Novartis conducted the additional research needed to start clinical trials, including elaboration of the chemical synthesis, studies of drug formulation, pharmacokinetics, and toxicology screenings.
These studies led to the original reports on this class of inhibitor that were first published by Novartis scientists in 1996.(10-13) While the results from initial oral bioavailability and toxicology studies showed promise, additional refinements were needed. Therefore, pre-clinical development of Glivec soon began, with Lydon directing a multidisciplinary team of scientists. Matter, Lydon, Druker, Baltimore, and Witte would eventually be awarded the 2001 Warren Alpert Foundation Prize for their work with Bcr-Abl. This honour seeks to recognise the full breadth of the development of a therapy-the basic scientific underpinnings, pre-clinical exploration, and clinical trial investigations.
References
1. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukaemia. Science. 1960;132:164-172.
2. Rowley D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-293.
3. Mughal T, Goldman J. Understanding leukaemia and related cancers. Oxford: Blackwell Science Ltd. 1999.
4. Lydon NB, Adams B, Poschet JF, et al. An E. coli expression system for the rapid purification and characterization of a v-abl tyrosine protein kinase. Oncogene Research. 1990;5:161-173.
5. Geissler JF, Roesel JL, Meyer T, et al. Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. Cancer Research. 1992;52:4492-4498.
6. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukaemia. J Clin Invest. 2000;105:3-7.
7. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 1996;2:561-566.
8. Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691-3698.
9. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380-394.
10. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Research. 1996;56:100-104.
11. Zimmermann J, Caravtti G, Mett H, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorgan Med Chem Lett. 1996;6:1221-1226.
12. Zimmermann J, Buchdunger E, Mett H, et al. Potent and selective inhibitors of the ABL-kinase: phenylamino-pyrimidine (PAP) derivatives. Bioorgan Med Chem Lett. 1997;7:182-192.
13. Zimmermann J, Buchdunger E, Mett H, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase c (PKC). Arch Pharm. 1996;329:371-376.
http://www.glivec.com
The History Of Glivec
Posted by rob on under Uncategorized |
PRINCETON, N.J., Dec. 28 /PRNewswire-FirstCall/ — Today, Bristol-Myers
Squibb Company (NYSE: BMY) announced that the Company has completed the
rolling submission of its New Drug Application (NDA) to the U.S. Food and Drug
Administration (FDA) for dasatinib to treat chronic myelogenous leukemia (CML)
in chronic, accelerated or blast phases, as well as Philadelphia chromosome-
positive (Ph+) acute lymphoblastic leukemia (ALL).
The NDA seeks approval of dasatinib – an investigational multi-targeted
kinase inhibitor – to treat adult CML and Ph+ ALL patients with resistance or
intolerance to prior therapy.
Dasatinib was discovered and is being developed by scientists within
Bristol-Myers Squibb laboratories.
About CML and ALL
CML is a slowly progressing cancer of the blood and bone marrow that
usually occurs during or after middle age and rarely occurs in children. ALL
is a rapidly progressing cancer of the blood and bone marrow that usually
occurs in children; although it can occur at any age. The Leukemia and
Lymphoma Society estimates that 4,600 new cases of CML and nearly 4,000 new
cases of ALL will be diagnosed in the United States this year.
About the Philadelphia Chromosome
Approximately 95 percent of people with CML and approximately 25 percent
of adults with ALL have a gene mutation called the Philadelphia chromosome, in
which part of the DNA from one chromosome (chromosome 9) moves to another
chromosome (chromosome 22). This translocation brings together two genes, one
from each chromosome: BCR (breakpoint cluster region) and ABL (Ableson
leukemia virus). The resulting hybrid gene, BCR-ABL, produces an abnormal
protein called Bcr/Abl tyrosine kinase that triggers uncontrolled cell growth.
About Bristol-Myers Squibb
Bristol-Myers Squibb is dedicated to the discovery, development, and
exhaustive exploration of innovative cancer fighting therapies that extend and
enhance the lives of patients living with cancer. More than 40 years ago,
Bristol-Myers Squibb built a unified vision for the future of cancer
treatment. With expertise, dedication and resolve, that vision led to the
development of a diverse global portfolio of anti-cancer therapies that are an
important cornerstone of care today. Hundreds of scientists at Bristol-Myers
Squibb’s Pharmaceutical Research Institute are studying ways to improve
current cancer treatments and identify better, more effective medicines for
the future.
Bristol-Myers Squibb is a global pharmaceutical and related health care
products company whose mission is to extend and enhance human life.
Visit Bristol-Myers Squibb on the World Wide Web at http://www.bms.com.
This press release contains “forward-looking statements” as that term is
defined in the Private Securities Litigation Reform Act of 1995. Such
forward-looking statements are based on current expectations and involve
inherent risks and uncertainties, including factors that could delay, divert
or change any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement can be
guaranteed. Among other risks, there can be no guarantee that dasatinib will
receive regulatory approval or, if approved, will be commercially successful.
Forward-looking statements in this press release should be evaluated together
with the many uncertainties that affect Bristol-Myers Squibb’s business,
particularly those identified in the cautionary factors discussion in Bristol-
Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2004
and in our Quarterly Reports on Form 10-Q. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement, whether as a
result of new information, future events or otherwise.
SOURCE Bristol-Myers Squibb Company
Web Site: http://www.bms.com
Bristol-Myers Squibb Submits New Drug Application for Dasatinib
