A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on September 11, 2005 under Uncategorized | 
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Piazza RG, Magistroni V, Andreoni F, Franceschino A, Tornaghi L, Varella-Garcia M, Bungaro S, Colnaghi F, Corneo G, Pogliani EM, Gambacorti-Passerini C
Leukemia. 2005 Aug 25;
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Peng B, Lloyd P, Schran H
Clin Pharmacokinet. 2005; 44(9): 879-94
Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature.Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100mg, 400mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 +/- 0.8 mug/mL at peak and 1.2 +/- 0.8 mug/mL at trough, exceeding the 0.5 mug/mL (1 mumol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count.Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and alpha(1)-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5 : 1.Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs.Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18-70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib.
Clinical pharmacokinetics of imatinib.
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Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Müller-Brüsselbach S, Ottmann OG, Duyster J, Hochhaus A, Neubauer A
Leukemia. 2005 Sep 1;
BCR/ABL-kinase mutations frequently mediate clinical resistance to the selective tyrosine kinase inhibitor Imatinib mesylate (IM, Gleevec((R))). However, mechanisms that promote survival of BCR/ABL-positive cells before clinically overt IM resistance occurs have poorly been defined so far. Here, we demonstrate that IM-treatment activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTor)-pathway in BCR/ABL-positive LAMA-cells and primary leukemia cells in vitro, as well as in a chronic phase CML patient in vivo. In fact, PI3K/Akt-activation critically mediated survival during the early phase of IM resistance development before manifestation of BCR/ABL-dependent strong IM resistance such as through a kinase mutation. Accordingly, inhibition of IM-induced Akt activation using mTor inhibitors and Akt-specific siRNA effectively antagonized development of incipient IM-resistance in vitro. In contrast, IM-resistant chronic myeloid leukemia (CML) patients with BCR/ABL kinase mutations (n=15), and IM-refractory BCR/ABL-positive acute lymphatic leukemia patients (n=2) displayed inconsistent and kinase mutation-independent autonomous patterns of Akt-pathway activation, and mTor-inhibition overcame IM resistance only if Akt was strongly activated. Together, an IM-induced compensatory Akt/mTor activation may represent a novel mechanism for the persistence of BCR/ABL-positive cells in IM-treated patients. Treatment with mTor inhibitors may thus be particularly effective in IM-sensitive patients, whereas Akt-pathway activation variably contributes to clinically overt IM resistance.Leukemia advance online publication, 1 September 2005; doi:10.1038/sj.leu.2403898.
Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development.
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Sheinerman FB, Giraud E, Laoui A
J Mol Biol. 2005 Sep 1;
Inhibition of protein kinase activity is a focus of intense drug discovery efforts in several therapeutic areas. Major challenges facing the field include understanding of the factors determining the selectivity of kinase inhibitors and the development of compounds with the desired selectivity profile. Here, we report the analysis of sequence variability among high and low affinity targets of eight different small molecule kinase inhibitors (BIRB796, Tarceva, NU6102, Gleevec, SB203580, balanol, H89, PP1). It is observed that all high affinity targets of each inhibitor are found among a relatively small number of kinases, which have similar residues at the specific positions important for binding. The findings are highly statistically significant, and allow one to exclude the majority of kinases in a genome from a list of likely targets for an inhibitor. The findings have implications for the design of novel inhibitors with a desired selectivity profile (e.g. targeted at multiple kinases), the discovery of new targets for kinase inhibitor drugs, comparative analysis of different in vivo models, and the design of “a-la-carte” chemical libraries tailored for individual kinases.
High Affinity Targets of Protein Kinase Inhibitors Have Similar Residues at the Positions Energetically Important for Binding.
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Appel S, Balabanov S, Brümmendorf TH, Brossart P
Stem Cells. 2005 Sep ; 23(8): 1082-8
The selective tyrosine kinase inhibitor imatinib (Glivec; Novartis International, Basel, Switzerland, http://www.glivec.com/content/home.jsp) is increasingly used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. In principle, the drug is well tolerated and clinical side effects are mostly moderate. However, it was shown that imatinib can affect the function of normal, nonmalignant cells, resulting in myelosuppression in treated patients. Recently, it has been demonstrated that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, in several in vitro studies and animal models, it was demonstrated that imatinib can affect the function and differentiation of antigen-presenting cells and inhibit the effector functions of T lymphocytes. Moreover, the induction of specific cytotoxic T cells seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib compared with patients receiving interferon-alpha. This is of importance because some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T-cell responses. Further studies investigating the effects of imatinib on normal hematopoiesis are of interest as they might lead to a better understanding of the clinically observed side effects and also might help identify new therapeutic applications of the drug, possibly in Bcr-Abl-negative myeloproliferative disorders and potentially as an immunomodulatory agent.
Effects of imatinib on normal hematopoiesis and immune activation.
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Mughal TI, Goldman JM
Front Biosci. 2006 Jan 1; 11: 209-20
Chronic myeloid leukemia cells contain a BCR-ABL oncoprotein with an enhanced tyrosine kinase activity, which is considered to be the principal ’cause’ of the leukemia. Though the precise mechanisms underlying the leukemogenesis remains enigmatic, the use of imatinib to inhibit the dysregulated kinase activity has proved remarkably successful in clinical practice. Imatinib was the first small molecule developed to inhibit BCR-ABL tyrosine kinase activity and its success introduced the current era of molecularly targeted therapies for a number of other malignancies. In patients with chronic myeloid leukaemia who develop resistance to imatinib, the Bcr-Abl signaling pathway is often re-established. This has led to the emergence of a number of alternative treatment strategies designed to target the leukemic cell which are resistant to imatinib.
Molecularly targeted treatment of chronic myeloid leukemia: beyond the imatinib era.
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Crossman LC, O’hare T, Lange T, Willis SG, Stoffregen EP, Corbin AS, O’brien SG, Heinrich MC, Druker BJ, Middleton PG, Deininger MW
Leukemia. 2005 Sep 8;
We have identified a gene polymorphism (K247R) within or close to the P-loop of BCR-ABL, which leads to the substitution of arginine for lysine. We investigated the allelic frequency of K247R by screening 157 CML patients and 213 healthy blood donors with conventional sequencing, restriction enzyme digest and single strand conformational polymorphism analysis, and found the arginine allele to be rare. Three out of five CML patients with the arginine allele of K247R failed to achieve a major cytogenetic response to imatinib, suggesting that the arginine allele may have reduced sensitivity. However, despite K247R’s position in or near to the P-loop, biochemical and cellular assays of imatinib and dasatinib sensitivity showed no alteration compared to wild type. Clinicians should be aware that possession of the arginine allele of K247R does not reflect a mutation that necessitates a change in the therapeutic strategy, unless there are other signs of inadequate response to drug.Leukemia advance online publication, 8 September 2005; doi:10.1038/sj.leu.2403935.
A single nucleotide polymorphism in the coding region of ABL and its effects on sensitivity to imatinib.
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Corm S, Biggio V, Roche-Lestienne C, Laï JL, Yakoub-Agha I, Philippe N, Nicolini FE, Facon T, Preudhomme C
Leukemia. 2005 Sep 8;
Coexistence of AML1/RUNX1 and BCR-ABL point mutations in an imatinib-resistant form of CML.
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Lele AV, Mirski MA, Stevens RD
Crit Care Med. 2005 Aug ; 33(8): 1854-6
OBJECTIVE: To discuss the pathophysiology and clinical implications of spurious hypoxemia in the setting of hyperleukocytosis. DESIGN: Case report and review of the literature. SETTING: A 22-bed, adult neurosciences critical care unit at a tertiary care hospital. PATIENT: A 49-yr-old male with chronic myelogenous leukemia. INTERVENTIONS: Administration of hydroxyurea and imatinib mesylate. MEASUREMENTS AND MAIN RESULTS: The patient was admitted to the neurosciences critical care unit with an acute nontraumatic subdural hematoma that required emergent surgical evacuation. His clinical course was notable for neurologic deterioration, sepsis, hyperleukocytosis, severe hypoxemia, and prolonged mechanical ventilation. An inverse relationship was observed between arterial oxygen tension and the magnitude of hyperleukocytosis. Hypoxemia resolved after the institution of chemotherapy and normalization of white cell count. Pulse oximeter saturation was normal throughout. CONCLUSIONS: Patients with hyperleukocytosis are at risk for severe hypoxemia, which may be real or spurious. Failure to recognize spurious hypoxemia can lead to unnecessary diagnostic tests and therapeutic interventions, exposing patients to avoidable risk. A diagnostic algorithm is proposed.
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del Pozo J, Martínez W, Pazos JM, Yebra-Pimentel MT, García Silva J, Fonseca E
Int J Dermatol. 2005 Aug ; 44(8): 677-80
A 74-year-old woman with chronic auricular fibrillation, arterial hypertension, hypercholesterolemia, ischemic cardiopathy, and peripheral arteriopathy presented with purpuric lesions on the lower limbs (Fig. 1) and, to a lesser extent, on the anterior area of the chest. The mucous membranes were not affected. In 1989, she was diagnosed with anemia that evolved until 1998, when a bone marrow biopsy revealed a myelodysplastic syndrome unclassified in French-American-British Group (FAB). The patient has required periodic transfusions since February 1999. A skin biopsy of the purpuric lesions revealed a leukocytoclastic vasculitis; the lesions cleared with topical corticosteroid treatment. In May 1999, the patient presented with inflammatory and painful lesions localized on the vulva (Fig. 2), which had evolved over several days, without fever. No lesions were observed in other locations. A cutaneous biopsy showed an intense dermal edema and a diffuse and polymorphous dermal infiltrate involving the follicular structures. Exocytosis, spongiosis, and mucin deposits, demonstrated by Alcian blue stain, were observed in the follicular epithelium. Mature neutrophils were predominant in the dermal infiltrate, but a small number of eosinophils and immature cells were also present (Fig. 3). The myelogenous origin of the immature lining cells was further confirmed by positive staining of intracytoplasmic granules with naphthol-ASD chloroacetate sterase (Leder’s stain). Vasculitis was not observed. Routine laboratory tests revealed 3030 leukocytes/mm(3) (60% neutrophils), a hemoglobin level of 8.4 g/dL, and 92,000 platelets/mm(3). Treatment with 30 mg/day of prednisone was started, and the lesions cleared slowly within 4 weeks. A new bone marrow biopsy in September 1999 showed a similar appearance to that taken in 1998. The patient died in January 2000 as a result of pneumonia with cardiac and respiratory failure. A 66-year-old man presented with a febrile syndrome that had evolved over 5 days, and painful and pruritic cutaneous lesions on the face and posterior neck (Fig. 4). Three months before, the patient was diagnosed with chronic myelogenous leukemia in acceleration phase. Examination revealed an edematous and erythematous face with pustular lesions on the surface, also involving the neck and the upper part of the back. The histopathologic examination revealed an intense edema and abscesses in the dermis. The infiltrate of these lesions was composed of mature neutrophils with the presence of abundant immature cells with a myelogenous aspect (Fig. 5). Analytical studies revealed 26,130 leukocytes/mm(3) (42% blasts). No specific treatment for Sweet’s syndrome was administered and the lesions showed an improvement within 5 days. Eight days after admission, the patient died as a result of acute hemorrhage, before treatment for leukemia was initiated.
Concurrent Sweet’s syndrome and leukemia cutis in patients with myeloid disorders.
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Roskoski R
Biochem Biophys Res Commun. 2005 Aug 26;
Signaling by stem cell factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Deficiencies of either produce defects in red and white blood cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of interaction with several enzymes and adaptor proteins.
Signaling by Kit protein-tyrosine kinase-The stem cell factor receptor.
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Savani BN, Rezvani K, Mielke S, Montero A, Kurlander R, Carter CS, Leitman S, Read EJ, Childs R, Barrett AJ
Blood. 2005 Aug 30;
Eighty patients with chronic myeloid leukemia (CML) received a T cell depleted stem cell transplant from an HLA identical sibling, with add-back of donor T cells on days 30-45 and day 60-100 in patients not developing grade >/=II acute GVHD. The outcomes for 54 chronic (CP) versus 26 advanced phase (AP) patients were respectively 85+/-5 vs 36+/-10%, overall survival; 13+/-5 vs 43+/-11%, TRM; and 76+/-6 vs 34+/-9% current LFS. The day 30 lymphocyte count (LC30) was strongly associated with outcome. For patients in CP with a count above the median of 300/microl, survival was 100 vs 70+/-9%; p=0.003; current LFS 100% vs 56+/-9%; p=0.002 and TRM 0% vs 26+/-8; p=0.006. Higher than median LC30 correlated significantly with molecular remission (MR) at 3, 6 and 12 months and with higher CD34 doses. Lymphocyte subset analysis performed in 20 cases available for phenotyping showed that LC30 was highly correlated with absolute CD56+ CD3- natural killer cell numbers (NK30) which also predicted for survival and MR. CD34 cell dose, LC30 and, NK30 but not day 30 CD3+ cell count were highly correlated and were significant predictors of transplant outcome. These results suggest that transplant CD34 cell doses of >5×10(6)/kg may improve outcome by increasing early recovery of NK cells.
Factors associated with early molecular remission following T cell depleted allogeneic stem cell transplantation for chronic myelogenous leukemia.
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Hung GY, Chiou TJ, Chang CY, Teng HW, Chen PM, Hwanga B
Int J Hematol. 2005 Aug ; 82(2): 159-61
We report the results of unrelated cord blood transplantation (CBT) in a 12-year-old boy with Philadelphia chromosome- positive chronic myelogenous leukemia in the chronic phase and a high body weight (68.5 kg at transplantation). Only 1 of the 2 units used engrafted. This unit was not human leukocyte antigen (HLA) class II identical with the patient and had a much larger number of nucleated cells than the other unit (approximately 2.4:1). To our knowledge, this case report is the first to describe successful CBT from two unrelated donors to a cancer patient, who had the highest body weight among CBT recipients in Taiwan.
Double-unit unrelated cord blood transplantation for chronic myelogenous leukemia.
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Li X, Vradii D, Gutierrez S, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Javed A
J Cell Biochem. 2005 Sep 7;
Many types of acute myelogenous leukemia involve chromosomal translocations that target the C-terminus of Runx1/AML1 transcription factor, a master regulator of hematopoiesis. The C-terminus of Runx1/AML1 that includes the nuclear matrix targeting signal (NMTS) is essential for embryonic development, hematopoiesis, and target gene regulation. During the onset and normal progression of hematopoiesis, several lineage-specific factors such as C/EBPalpha and PU.1 interact with Runx1 to regulate transcription combinatorially. Here we addressed the functional interplay between subnuclear targeting of Runx1 and gene activation during hematopoiesis. Point mutations were generated in the NMTS of the human Runx1 protein and tested for their effect on transcriptional cooperativity with C/EBPalpha and PU.1 at myeloid-specific promoters. We characterized five mutants that do not alter nuclear import, DNA binding or C/EBPalpha-dependent synergistic activation of the target gene promoters. However a critical tyrosine in the NMTS is required for subnuclear targeting and activation of the granulocyte-macrophage colony stimulating factor (GM-CSF) promoter. Furthermore, this point mutation is defective for transcriptional synergism with PU.1 on the macrophage colony stimulating factor (MCSF) receptor c-FMS promoter. Our results indicate that the NMTS region of Runx1 is required for functional interactions with PU.1. Taken together, our findings establish that subnuclear targeting of Runx1 is a critical component of myeloid-specific transcriptional control. (c) 2005 Wiley-Liss, Inc.
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Hernández-Boluda JC, Lis MJ, Goterris R, Arbona C, Terol MJ, Tormo M, Solano C
Transpl Infect Dis. 2005 Jun ; 7(2): 93-6
The association between cytomegalovirus (CMV) infection and the development of Guillain-Barré syndrome (GBS) in the setting of allogeneic hematopoietic stem cell transplantation (alloSCT) has been reported only occasionally. We describe here a 23-year-old patient diagnosed with acute myelogenous leukemia who underwent a partially HLA-mismatched alloSCT and soon after developed GBS along with a CMV infection. Serum autoantibodies to several ganglioside antigens were concomitantly detected. Despite therapy with ganciclovir and plasma exchanges, the patient’s clinical condition rapidly deteriorated, and he died 3 weeks later with persisting CMV antigenemia. Although a coincidental association cannot be excluded, it could be speculated that a pathogenetic link exists between the 2 disorders. In this sense, molecular mimicry between viral antigens and neural host tissues could be postulated as the hypothetical mechanism underlying the triggering of the autoimmune disease in the present case.
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Vural F, Donmez A, Dog?anav?argil B, Cagýrgan S, Alper H, Tombulog?lu M
Transfus Apher Sci. 2005 Sep 6; 33(2): 177-181
We present a patient with acute myelogenous leukemia who developed severe acute intestinal graft versus host disease (GVHD) after donor lymphocyte infusion (DLI) following non-myeloablative allogeneic peripheral blood stem cell transplantation (allo-PBCT). One month after DLI, patient developed severe abdominal cramps, watery diarrhea without any signs or symptoms of the skin and liver GVHD. Treatment with steroid, cyclosporine A, tacrolimus and mycophenolat mofetil were not effective in controlling intestinal symptoms. Extracorporeal photochemotherapy (ECP), a recently used procedure in the treatment of GVHD was employed periodically and the symptoms subsided gradually. Acute GVHD after DLI may occur severely and atypically, but being limited to the intestine has rarely been reported.
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Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia.
Gao H, Lee BN, Talpaz M, Donato NJ, Cortes JE, Kantarjian HM, Reuben JM
Leukemia. 2005 Sep 8;
Although imatinib mesylate (IM) is highly effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia (CML), it is known to suppress T-cell proliferation in vitro. As cytokines are required for T-cell proliferation, we investigated the effects of IM on cytokine synthesis by T cells of CML patients by assessing cytokine synthesis by activated CD4(+) and CD8(+) T cells in vitro. The activation of T cells in the whole blood of IM-treated patients (CML-IM) with Staphylococcus enterotoxin B resulted in significantly lower percentages of CD4(+) T cells that synthesized interleukin 2 (P=0.017), interferon-gamma (P=0.010), and tumor necrosis factor-alpha (P=0.009) than did the activated T cells of control subjects. The addition of exogenous IM to the cultures of peripheral blood mononuclear cells of CML-IM patients reduced Th1 cytokine synthesis by the CD4(+) T cells. Furthermore, IM therapy at clinical doses suppressed the tyrosine phosphorylation of ZAP70. These findings suggest that inhibition of ZAP70 signaling pathway and suppression of Th1 cytokine synthesis by CD4(+) T cells required the presence of IM at the time of T-cell activation through the T-cell receptor.Leukemia advance online publication, 8 September 2005; doi:10.1038/sj.leu.2403933.
Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia.
Posted by rob on September 10, 2005 under Uncategorized | Be the First to Comment
Sept. 9 (Bloomberg) — Bristol-Myers Squibb Co. may soon reap the rewards of an overhaul of its research strategy four years ago: U.S. approval of three new drugs that investors say will aid the company’s ailing stock.
The brand-named medicines Pargluva for diabetes and Orencia for rheumatoid arthritis, plus the generic-named dasatinib for blood cancer, would generate more than $1 billion a year each for the New York-based company, analysts and investors say.
Bristol-Myers shares have fallen 63 percent since Jan. 1, 2001. The drugmaker was sued by investors, settled a U.S. government inquiry into sales practices and lost as much as $2 billion in revenue after patents expired on best-selling drugs. The shares may rebound as a U.S. Food and Drug Administration advisory panel urged today that the agency approve Pargluva, three days after Orencia was recommended.
“Investors really need to start valuing the company for what they’re going to do in the next couple of years and not the screw-ups they had one to two years ago,” said Jon Fisher, who helps manage about $22 billion at Fifth Third Asset Management in Minneapolis, including shares of rival Pfizer Inc.
The FDA almost always follows recommendations of its panels of outside advisers. The FDA may decide later this year on Pargluva and Orencia, letting Bristol-Myers start selling Orencia next year and Pargluva in 2006, Deutsche Bank analyst Barbara Ryan says. Bristol-Myers says it may file for dasatinib approval by January.
Outperforming Rivals
FDA approval of the three drugs may make Bristol-Myers, the fifth-largest U.S. drugmaker, one of the better-performing stocks among large pharmaceuticals, investor Patrick Kaser says.
“Three years from now, Bristol could easily be viewed as one of the best,” says Kaser, who helps manage $20 billion at Brandywine Asset Management in Wilmington, Delaware, including Bristol-Myers shares.
Shares of Bristol-Myers rose 23 cents to $25.11 at 4 p.m. in New York Stock Exchange composite trading. They had risen 6.4 percent to $25.17 in the 12 months through Sept. 7, outperforming rivals Pfizer, Merck & Co. and Indianapolis-based Eli Lilly & Co., as investors anticipated approval of the Bristol-Myers drugs.
Success for Pargluva was not assured. The drug may pose risks of heart failure, the FDA said in a staff report released yesterday. Its side effects include swelling, and its use can’t be ruled out as a cause of heart complications, the report said.
More Benefits Than Risks
The company responded today in statements to an FDA advisory panel by saying the drug offers more benefits than risks. Bristol-Myers will instruct doctors in Pargluva’s labeling that they need to closely monitor patients taking the drug, said Brian Daniels, the company’s senior vice president for clinical development.
The FDA panel, meeting in Silver Spring, Maryland, gave a strong endorsement to the company’s statements, voting 8-1 today to recommend that the FDA clear Pargluva as a solo treatment and 7-2 as a combination drug with Bristol-Myers’s Glucophage.
Bristol-Myers isn’t the only drugmaker trying to revitalize a flagging drug discovery program. Merck, based in Whitehouse Station, New Jersey, and New York-based Pfizer have so far failed to develop drugs needed to compensate for revenue they will lose to competition from inexpensive generic copies.
Profit
Bristol-Myers, pounded by generic competition involving eight of its popular drugs, including treatments for cancer, diabetes and HIV/AIDS, won’t resume profit growth until 2007 when new drugs are marketed, Chief Executive Officer Peter Dolan said in July. Profit excluding items in 2005 will be “at the upper end” of its per-share range of $1.35 to $1.45, the company said, down from $1.70 in 2004.
Bristol-Myers in June agreed to pay $300 million to settle a three-year inquiry by U.S. prosecutors in Newark, New Jersey, into charges the company sold excess inventory to wholesalers to meet sales goals. The company agreed to appoint a retired judge to monitor the agreement, and Dolan said at the time that “we are determined that the mistakes of the past not be repeated.”
In all, the company has paid $839 million in the past two years to resolve criminal and regulatory investigations as well as lawsuits by shareholders.
Investors alleged the company misled them about a blood pressure medicine that failed to win FDA approval and the sales potential of the Erbitux cancer treatment that Bristol-Myers sells with partner ImClone Systems Inc., based in New York.
Redeploying
The company received no U.S. approval for any drugs developed in its own laboratories from 1997 to 2001, even after spending about $12.5 billion on research and development in the 1990s. Bristol-Myers decided to redeploy its R&D resources in 2001.
Only two new drugs were cleared for U.S. sales after 2001 – -the AIDS treatment Reyataz, approved in 2003, and Baraclude, a hepatitis B medicine, approved earlier this year.
“We needed to become a company that took advantage of what we developed internally,” says Dolan, 49, who’s been CEO since 2001.
Dolan has set a goal of having two-thirds of the products the company has for sale developed by its own labs, rather than licensed from partnerships with other drugmakers or biotechnology companies. He didn’t specify a timeframe.
“As you project out over a five-year to 10-year period, it’s critical for us to be able to anticipate the fruits of our R&D,” he says. “Our pipeline looks promising. We have to continue to transform our pipeline into patient and shareholder value.”
Narrowed Focus
Following a review, the company decided to narrow its research focus to 10 diseases from more than 30 while only developing medicines that treat an “unmet medical need,” says Bristol-Myer’s Daniels, 46.
“We have shown progress in not only doing clinical trials but with output, that is, approvals,” he says. “If you look at the next series of potential approvals in our pipeline, most of them are internally discovered compounds.”
The three medicines pending approval meet the criteria. Pargluva, also known as muraglitazar, would be the first in a new class of diabetes medicines that specifically treats a biological defect at the root of the illness, as well as lowering cholesterol, a common cause of heart disease for diabetics. AstraZeneca Plc, based in London, and Eli Lilly are developing similar medicines, part of a new class of drugs known as dual PPAR agonists.
Enhance Options
“What this medicine can and should do is really enhance the treatment options for patients,” says David Kendall, 44, a doctor at the International Diabetes Center in Minneapolis, who tested the drug in a study funded by Bristol-Myers.
The medicine may have worldwide sales of as much as $1.5 billion a year, Brandywine’s Kaser says. Bristol-Myers will market the drug with Merck, which will augment the sales potential. Sales of oral diabetic treatments totaled $10 billion last year, according to IMS Health Inc., a drug-research company based in Fairfield, Connecticut.
Orencia is the first of a new kind of medicine to treat rheumatoid arthritis, a severe form of the joint illness, says Harry Genant, 63, a professor at the University of California in San Francisco who has studied the drug. It would be an alternative for patients who didn’t respond to existing treatments, he says.
Competitors
Orencia, also known by its generic name abatacept, would compete with Enbrel, sold by Thousand Oaks, California-based Amgen Inc. and Madison, New Jersey-based Wyeth. Other competitors are New Brunswick, New Jersey-based Johnson & Johnson’s Remicade and Abbott Park, Illinois-based Abbott Laboratories’ Humira. Together, the competitors had worldwide sales last year of about $4.6 billion.
Orencia may have peak worldwide sales of $1 billion annually, analyst Albert Rauch at A.G. Edwards & Sons Inc. estimates.
The existing drugs have transformed the treatment of rheumatoid arthritis, Genant says. “They’ve had an enormous impact,” he says. At the same time, he says, the products are not effective in all patients and Orencia may work in some of those cases. “Abatacept may offer an alternative,” Genant says.
The company is seeking approval for dasatinib, which has yet to receive a brand name, for the treatment of a type of blood cancer called chronic myelogenous leukemia. It is also studying use of the treatment for a rare stomach cancer, and that would compete with Novartis AG’s Gleevac and Pfizer’s experimental Sutent.
Similar Medicines
Similar cancer medicines by Pfizer and one sold by Leverkusen, Germany-based Bayer AG and Emeryville, California- based Onyx Pharmaceuticals Inc. called sorafenib may eventually generate sales of as much as $1 billion annually. A half dozen analysts surveyed by Bloomberg hadn’t developed a sales forecast for dasatinib.
Bristol-Myers is relying on the new drugs to counter declining sales of its Pravachol cholesterol fighter and competition from generics. Pravachol demand has fallen as generic competitors began selling the medicine outside the U.S.
The treatment loses patent protection in the U.S. next year, making the new drugs key to restoring investor confidence.
“You’re really setting the tone that Bristol can deliver $1 billion-plus products to market,” Brandywine Asset Management’s Kaser says. “That’s something that a lot of people have been skeptical of.”
To contact the reporter on this story:
Nicole Ostrow in New York at nostrow@bloomberg.net.
Last Updated: September 9, 2005 16:05 EDT
