Healthcare Industry News: imatinib
News Release - December 12, 2006
INNOVIVE Pharmaceuticals Presents Data on Oncology Drug Programs in Chronic Myelogenous Leukemia and Acute Myelogenous Leukemia at American Society of Hematology 48th Annual MeetingNEW YORK, Dec. 12 (HSMN NewsFeed) -- INNOVIVE Pharmaceuticals, Inc. (OTC Bulletin Board: IVPH ) today announced the presentation of additional data from its clinical and preclinical evaluation of the company's drug candidates INNO-406, an orally bioavailable dual Bcr-Abl and Lyn-kinase inhibitor for Gleevec®-resistant or intolerant chronic myelogenous leukemia, and INNO-305, a peptide immunotherapy for the treatment of acute myelogenous leukemia. Data were presented at the American Society of Hematology (ASH) 48th Annual Meeting and Exposition. Abstracts were published in the Nov. 16, 2006 issue of Blood, vol. 108, issue 11.
Abstract #2179: "The ATP Competitor INNO-406 (NS-187) Inhibits Proliferation and Survival of Mouse Cells Expressing Several imatinib Mesylate Resistant Bcr/Abl Mutants and Cells from CML Patients."
* Reporting on preliminary results from an ongoing Phase I clinical study, researchers confirmed that INNO-406 is a candidate for the treatment of various forms of CML. Early evidence of clinical activity has been demonstrated in Gleevec-resistant and Tasigna® (nilotinib) intolerant patients using hematologic, cytogenetic, and molecular measures. Of the six patients who have completed at least one month of treatment, three have evidence of clinical response. Preclinical data showed that 17 out of 18 mutations of the disease associated with Gleevec-resistance are sensitive to INNO-406, and this preclinical data was demonstrably predictive of the clinical activity reviewed to date. Dose escalating studies continue in an effort to determine a recommended Phase II dose.
Abstract #834: "Cyclosporin A, a P-gp Inhibitor, Augments the Anti-Central Nervous System Ph+ Leukemia Effects of INNO-406."
* Researchers found that INNO-406 alone inhibited growth of leukemia cells in mice harboring either wild-type or mutated Bcr-Abl such as E255K and M351T in the central nervous system. Researchers additionally found that Cyclosporin A significantly enhanced anti leukemia effects of INNO-406. Central nervous system relapse accompanying prolonged administration of imatinib mesylate (Gleevec®) has recently become apparent as an impediment to the treatment of Philadelphia chromosome-positive (Ph+) leukemia, largely due in part to limitations of imatinib and other kinase inhibitors in crossing the blood-brain barrier. The concentration of INNO-406 in the brain was doubled following prior administration of Cyclosporin A, enhancing the anti-leukemia effects of the therapy.
Abstract #2178: "BH3 Mimetic Augments the Induction of Apoptosis by INNO-406, a Novel Bcr-Abl/Lyn Inhibitor, in Bcr-Abl+ Leukemic Cells."
* Researchers found that Bcr-Abl inhibitors that induce apoptosis by activating BH3-only proteins, when combined with an inhibitor of anti apoptotic BCL-2 proteins, significantly augment the induction of apoptosis in wild-type and mutated leukemia cells. Specifically, researchers indicated that a double barreled approach combining INNO 406 with ABT-737, an inhibitor of BCL-2/BCL-XL, is highly effective for killing Bcr-Abl+ leukemic cells, including leukemia cells with mutated Bcr-Abl. This study shows that a double-barrelled approach for Bcr-Abl driven oncogenic signaling and the anti-apoptotic Bcl-2 family proteins is likely to be a more effective combination therapy for eradicating Bcr-Abl+ leukemic cells, even in Bcr-Abl+ leukemias bearing imatinib resistant Bcr-Abl point mutations.
Abstract #2177: "Cell Death Mechanisms Induced by INNO-406, a Novel Tyrosine Kinase Inhibitor for imatinib-Resistant Ph+ Leukemia."
* Researchers demonstrated that INNO-406 induces cell death in Philadelphia chromosome-positive leukemia cells via an independent pathway from imatinib mesylate. INNO-406 induced apoptosis as well as non-apoptotic cell death in primary Ph+ leukemic cells in xenografted mice models, suggesting the significance of involvement of caspase independent, non-apoptotic cell death in patients. Caspase-dependent apoptosis has been regarded as the principal mechanism for cell death by imatinib in Bcr-Abl+ leukemic cells.
Abstract #2123: "CXCR4 Up-Regulation by imatinib Mesylate Induces CML Cell Migration to Bone Marrow Stroma and Promotes Survival of Chemoresistant Quiescent CML Cells."
* Researchers found that tyrosine kinase inhibitors such as imatinib and INNO-406 increase the expression of CXCR4, inducing CML cell migration to bone marrow and promoting survival of CML progenitor cells. These results suggest that interfering with the protective effects of bone marrow stroma cells through the inhibition of CXCR4 expression could be beneficial for the eradication of chemoresistant CML cells.
Abstract #2167: "Centrosome Aberrations, Disturbed Mitotic Spindle Formation and G1 Arrest in Normal and Leukemic Cells Treated with the SRC/ABL Inhibitor Dasatinib."
* Researchers showed that dasatinib caused centrosomal aberrations and loss of spindle formation. Normal centrosome organization and spindle formation is essential for cell division. The ABL/LYN inhibitor INNO 406 was associated with both centrosome aberrations and disturbed spindle generation, suggesting an adverse effect on cancer cell proliferation. In comparison, imatinib and nilotinib treatment resulted in centrosome aberrations but not in loss of spindle formation.
Abstract #3706: "CD4+ Peptide Epitopes from the WT1 Oncoprotein Stimulate CD4+ and CD8+ T Cells That Recognize and Kill Leukemia and Solid Tumor Cells."
* Researchers have identified 3 CD4+ peptide epitopes from the WT1 protein that can stimulate a WT1 specific T cell response from a broad group of HLA-DRB1 types. A mutated peptide is able to simultaneously induce a robust CD4+ and CD8+ T cell response that is cytotoxic to cells expressing the native WT1 antigen. These studies provide the rationale for using the three WT1 CD4+ peptides in conjunction with CD8+ peptide epitopes (INNO-305) to vaccinate patients with WT1 expressing cancers.
INNO-406 (formerly known as NS-187) is an orally bioavailable, rationally designed, dual Bcr-Abl and Lyn-kinase inhibitor currently in a Phase I clinical study. According to a study published in the journal Blood (Dec. 1, 2005), INNO-406 is 25 to 55 times more potent than imatinib in vitro, and at least 10 times as effective as imatinib mesylate in suppressing the growth of Bcr-Abl bearing tumors. INNO-406 has demonstrated activity in 17 of 18 imatinib-resistant mutations. In addition to its Bcr-Abl inhibitory properties, INNO-406 inhibits Lyn kinase. Upregulation of Lyn kinase activity is a well recognized cause of imatinib resistance. Lyn kinase activation has also been documented in a variety of solid tumors, including prostate cancer.
INNO-305, also known as WT1 heteroclitic peptide immunotherapy, is in a Phase I clinical trial for the treatment of patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) as well as patients with non-small cell lung cancer (NSCLC) and mesothelioma. INNO-305 is unique among WT1 peptide cancer immunotherapeutics because of its ability to stimulate both CD8 and CD4 T-cells. It is believed that stimulating both types of T-cells may result in a more robust and ubiquitous immune response.
About INNOVIVE Pharmaceuticals
INNOVIVE Pharmaceuticals, Inc. acquires, develops and commercializes novel therapeutics addressing significant unmet medical needs in the fields of oncology and hematology. In addition to the recently acquired Tamibarotene for acute promyelocytic leukemia, the company has three drug programs in clinical development, INNO-406, INNO-206, and INNO-305, for the treatment of chronic myelogenous leukemia, small cell lung cancer, and acute myelogenous leukemia respectively. For additional information visit www.innovivepharma.com.
This material contains forward-looking statements as defined by the Private Securities Litigation Reform Act of 1995. These include statements concerning plans, objectives, goals, strategies, future events or performance and all other statements which are other than statements of historical fact, including without limitation, statements containing words such as "believes," "anticipates," "expects," "estimates," "projects," "will," "may," "might" and words of a similar nature. Such statements involve risks and uncertainties that could cause actual results to differ materially from those projected. Among other things, there can be no assurances that any of INNOVIVE's development efforts relating to its product candidates will be successful. Other risks that may affect forward-looking information contained in this press release include the risk that the results of clinical trials may not support INNOVIVE's claims, the possibility of being unable to obtain regulatory approval of INNOVIVE's product candidates, INNOVIVE's reliance on third party researchers to develop its product candidates and its lack of experience in developing pharmaceutical products. These and other risks are discussed in INNOVIVE'S Registration Statement on Form 10 and its periodic reports filed with the SEC. The forward-looking statements contained herein represent the judgment of INNOVIVE as of the date this material was drafted. INNOVIVE disclaims, however, any intent or obligation to update any forward-looking statements.
Gleevec® and Tasigna® are registered trademarks of Novartis Pharmaceuticals Corporation.
Source: INNOVIVE Pharmaceuticals
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