Whitehouse Station, NJ and Cambridge, MA, December 11, 2006 -- Merck & Co., Inc. (NYSE: MRK) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced results of a Phase I clinical trial for MK-0457 (also known as VX-680), an investigational small molecule inhibitor of Aurora, FLT-3, JAK-2 and BCR-ABL kinases. The study, conducted at The University of Texas M. D. Anderson Cancer Center and Duke University Medical Center, showed that MK-0457 demonstrated clinical activity in select patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL) with the T315I BCR-ABL mutation and also in patients with refractory JAK-2 positive myeloproliferative diseases (MPD). The results were presented in an oral presentation at the 48th Annual Meeting of the American Society of Hematology (ASH) in Orlando, FL.
"Many patients with leukemia develop resistance to standard anti-cancer therapies such as imatinib because of a mutation of the disease. T315I is one of the most common mutations in BCR-ABL, limiting patients' options with existing treatments," said Stephen H. Friend, M.D., Ph.D., executive vice president, Oncology, Merck Research Laboratories. "MK-0457 is the first compound to show clinical activity in patients with these treatment-resistant forms of blood cancer. Based on these initial results, we are moving forward with a broader Phase II trial in these patients."
Phase I Trial
The Phase I dose escalation clinical trial evaluated 44 adult patients with advanced leukemias and myeloproliferative disorders who were treated with MK-0457 given as a five-day intravenous infusion every two-to-three weeks. Out of the 15 patients with refractory CML, nine patients had a T315I BCR-ABL mutation. Eight of these nine T315I patients had either a hematologic and/or cytogenetic response to MK-0457 following multiple cycles of treatment. The six of 15 patients without the T315I BCR-ABL mutation did not exhibit any clinical responses. These results were presented today by Dr. Francis Giles, lead investigator from The University of Texas M. D. Anderson Cancer Center.
In addition, two patients in the study with Ph+ ALL carrying the T315I mutation had either hematologic and/or cytogenetic responses, including one patient who had a clinical response with a full molecular remission. Six of nine patients with myeloproliferative disorders having the V617F activating mutation in JAK-2 also had clinical responses. These clinical responses were consistent with drug effects observed in leukemic cells.
In the study, no drug-related non-hematological toxicities have been observed with MK-0457, therefore a maximum-tolerated dose has not yet been established. Side effects were observed in the trial and included a lower white blood cell count, nausea, hair loss, and inflammation in the mouth. This study was primarily designed to evaluate the safety of MK-0457 given as a 5-day continuous infusion, to determine maximum tolerated dose and dose-limiting toxicities, and to assess pharmacokinetics and pharmacodynamics. Larger clinical studies are needed to confirm the anti-cancer effects of MK-0457 in patients with CML, Ph+ ALL and MPD.
Preclinical Combination Studies Also Presented at ASH
Preclinical data, presented as a poster session at the meeting, demonstrated MK-0457 has potent single agent cytotoxic activity and showed synergy in combination with BCR-ABL inhibitors imatinib and dasatinib, idarubicin and cytabarine (Ara-C) in leukemia cell lines. In vitro, MK-0457 showed similar potency against BaF3 cells expressing wild type, T315I mutant or Y253F mutant BCR-ABL. In a panel of CML cell lines, co-treatment of MK-0457 and imatinib showed strong synergy and enhanced the imatinib-induced cell death (apoptosis) of K562 cells. Additional studies suggest sequential treatment of MK-0457 followed by either idarubacin or Ara-C showed greater synergy than simultaneous treatment.
"This study shows the importance of studying MK-0457, in combination with imatinib, dasatinib or other chemotherapy agents in patients with various forms of leukemia," said Dr. Friend. "The results of preclinical data support clinical evaluation of MK-0457 in combination with idarubicin and Ara-C in patients with AML and in combination with BCR-ABL inhibitors in CML and Ph+ ALL patients."
Aurora Kinases and Cancer
Cancer cells typically contain mutations in a number of genes, which ultimately result in uncontrolled cell growth and tumor metastasis. As enzymes specific for and essential to cell growth and division, Aurora kinases hold the potential to be important control points for slowing the growth and spread of tumors. Aurora kinases (also known as BTAK and STK15) are a family of serine-threonine kinases that are believed to play multiple roles in the development and progression of cancer, by acting as regulators of cell proliferation, by transforming normal cells into cancer cells and by down-regulating p53, one of the body's natural tumor suppressors. Aurora kinases are known to be over-expressed in many tumor types.
Discovery of MK-0457 (VX-680)
MK-0457 was discovered by scientists at Vertex's Oxford, U.K. research site as part of a broad research effort targeting the kinase gene family. Vertex researchers published the three-dimensional atomic crystal structure of Aurora-A kinase in 2002, a key scientific advance that enabled the design and optimization of multiple classes of small molecule Aurora kinase inhibitors. MK-0457 was advanced to preclinical development in 2002, following evaluation of the compound's activity in tumor cell lines and in animal models of tumor growth. In studies published early in 2004, Vertex demonstrated that MK-0457 induced tumor regression in xenograft models of human pancreatic and colon cancer. In addition, Vertex has presented data that shows that MK-0457 prolonged survival and induced sustained remission in an oncogene driven model of human acute myelocytic leukemia (AML).
In June 2004, Vertex entered into a global collaboration with Merck to develop and commercialize MK-0457 (VX-680) and other follow-on Aurora kinase inhibitors. As part of the collaboration, Vertex and Merck conducted a joint research program to characterize MK-0457's (VX-680) activity across a broad range of cancer types and identified additional drug candidates targeting the Aurora kinases.
Merck is moving forward with a Phase II trial to evaluate the efficacy and safety of MK-0457 in patients with CML and Ph+ ALL. The trial is not yet open for patient recruitment. If interested in more information about the trial, please visit www.clinicaltrials.gov or call 1-888-577-8839. The ClinicalTrials.gov identifier for this trial is NCT00405054.
About Merck Oncology
Merck Oncology focuses on all aspects of cancer care -- prevention, treatment, and supportive care. Through strong internal research capabilities, selective alliances and acquisitions, and enabling technologies such as the Molecular Profiling platform of Rosetta, Merck Oncology is looking to lead in the discovery, development and delivery of targeted anticancer therapies customized for patient subpopulations. Merck Oncology conducts research at sites in Boston, Seattle, West Point, Japan and Italy.
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with major pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, inflammation, autoimmune diseases, cancer, pain and bacterial infection. Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.
Vertex forward-looking statement
This press release may contain forward-looking statements, including statements that (i) Merck will move forward with a broader Phase II trial in patients with treatment-resistant forms of blood cancer; (ii) larger clinical trials will be conducted to confirm the anti-cancer effects of MK-0457 in patients with CML, PH+ ALL and MPD; and (iii) clinical trials will be conducted with MK-0457 in combination with idarubicin and Ara-C in patients with AML and in combination with BCR-ABL inhibitors in CML and Ph+ ALL patients. While management makes its best efforts to be accurate in making forward-looking statements, such statements are subject to risks and uncertainties that could cause the actual results of studies to vary materially. Those risks and uncertainties include, among other things, the risk that observed outcomes in clinical investigations of small numbers of patients will not be reflected in clinical trials involving larger numbers of patients, that unexpected and adverse outcomes in other ongoing clinical and nonclinical studies, or discussions with regulators about study design, will delay initiation of additional trials, and other risks listed under Risk Factors in Vertex's Form 10-K filed with the Securities and Exchange Commission on March 16, 2006. Vertex disclaims any obligation to update the information contained in this press release as new data become available.
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