BOULDER, Colo., June 5 /PRNewswire-FirstCall/ -- Pharmion Corporation today announced interim data for MGCD0103, the oral isotype-selective histone deacetylase (HDAC) inhibitor licensed from MethylGene, Inc. at the American Society of Clinical Oncology (ASCO) 2006 Annual Meeting held in Atlanta. The interim data were presented on two studies: one evaluating MGCD0103 in patients with hematological cancers (leukemia and Myelodysplastic Syndromes, or MDS), in which three of nine evaluable patients receiving the two highest doses achieved complete bone marrow responses, and the second study in patients with solid tumors, in which five patients experienced stable disease.
"We have seen clear marrow responses in patients with highly-refractory acute myelogenous leukemia. These are very exciting findings for this rationally-designed oral drug with excellent pharmacodynamic characteristics. Additionally, this agent has a manageable safety profile," stated Dr. G. Garcia-Manero, MD, Associate Internist and Associate Professor of Medicine, The University of Texas MD Anderson Cancer Center and a principal investigator of the MGCD0103 Leukemia/MDS trial.
Clinical Activity and Safety of the Histone Deacetylase Inhibitor MGCD0103, Results of a Phase I Study in Patients with Leukemia or Myelodysplastic Syndromes (MDS) (Abstract 6500)
This Phase I, open label, dose escalation study has the objective of determining the maximum tolerated dose and the pharmacokinetic (PK) and pharmacodynamic (PD) properties of MGCD0103 as an oral monotherapy administered three-times weekly to patients with hematologic malignancies. Data on 23 patients enrolled as of May 2006 were presented. The maximum tolerated dose of this schedule was exceeded at 80 mg/m2 with nausea, vomiting, diarrhea, and/or fatigue as dose-limiting toxicities. Two patients with refractory AML and one patient with advanced MDS achieved complete bone marrow responses (bone marrow blast incidences were less than or equal to 5%). Both pharmacokinetic evaluations and the measurement of HDAC activity in peripheral white cells demonstrated a dose-dependent effect. Importantly, activity in patients was consistent with dose dependent inhibition of the HDAC target.
Phase I Study of Isotype-selective Histone Deacetylase (HDAC) Inhibitor MGCD0103 Given as a Three-Times Weekly Oral Dose in Patients with Advanced Solid Tumors (Abstract 3007)
This Phase I, open-label, dose-escalation study has the objective of determining the safety, tolerability, pharmacokinetics and pharmacodynamics of MGCD0103 as an oral monotherapy administered three-times weekly to advanced solid tumor patients. Data on 28 patients enrolled as of May 2006 were presented. The maximum tolerated dose and the recommended Phase II dose have not yet been determined. The most common toxicity reported was Grade 1-3 fatigue. Three patients with kidney cancer, one patient with non-small cell lung cancer and one patient with colon cancer experienced stable disease. The half-life of MGCD0103 was 9 hours, consistent with previous studies.
Additional Clinical Trials
In addition to the clinical trials evaluating MGCD0103 noted above, patients are currently enrolling in a Phase I monotherapy trial in hematological malignancies on a twice-weekly oral schedule and a Phase I/II combination trial with Vidaza(R) (azacitidine for injectable suspension) in patients with advanced MDS or AML. In the Phase I portion of this trial, MGCD0103 is administered orally, three-times per week in combination with standard Vidaza treatment. In the second quarter of 2006, together with its partners MethylGene Inc. and Taiho Pharmaceutical, the Company expects to begin a Phase I/II combination trial with an undisclosed chemotherapeutic and later in 2006 anticipates embarking on additional Phase II monotherapy trials.
About Histone Deacetylation (HDAC)
Histones are protein complexes around which DNA is wrapped. Histones play an important role in gene regulation since histone arrangement has an impact on the accessibility of DNA for transcription. Histones and DNA together are called chromatin. Histone acetylation exposes DNA so that gene expression can occur. Conversely, histone deacetylation leads to dense packing of chromatin and gene silencing. These processes are regulated by enzyme families called histone acetylases (HATs) and histone deacetylases (HDACs). In many cancerous tissues, through the activity of DNA methylation and histone deacetylation, tumor suppressor genes are silenced and not expressed. Using HDAC inhibitors, such as MGCD0103, the effect of HDACs may be blocked and tumor suppressor genes re-expressed to inhibit cancer. In humans, there are eleven different forms, or isotypes, of HDACs. MethylGene's research and observations suggest that only a subset may be involved in cancer.
About MGCD0103, an Oral HDAC Inhibitor
MGCD0103 is a rationally designed, oral, isotype-specific HDAC inhibitor. MGCD0103 is a non-hydroxamate compound which targets HDAC isoforms 1, 2, 3 and 11 in vivo. As a single agent therapy, it has completed one Phase I clinical trial with daily dosing in solid tumors and a second Phase I trial is underway in solid tumors on a three times per week schedule. Two Phase I clinical trials are ongoing in hematological cancers, one administered three times per week and the second twice per week. A Phase I/II combination trial with DNA methylation inhibitor Vidaza was initiated in November 2005 and enrollment is under way at major cancer centers in the United States. Additional combination Phase I/II and monotherapy Phase II trials are expected to begin in 2006.
DNA methylation and histone deacetylation are two of the more studied epigenetic regulators of gene expression. Epigenetics refers to changes in the regulation of gene expression. Epigenetic changes can silence gene expression and, unlike DNA mutations, may be reversed by targeting the enzymes involved. The silencing of key cell cycle control genes and tumor suppressor genes through these two mechanisms of epigenetic regulation have been demonstrated in vitro and in vivo in hematological malignancies and in solid tumors. Vidaza has been shown to reverse the effects of DNA hypermethylation with subsequent gene re-expression and likewise MGCD0103 has been shown, in vivo, to reverse the effects of inappropriate deacetylation resulting in gene expression reactivation. The epigenetic approach to cancer therapy is that rather than using molecules that kill both normal and tumor cells, the silenced genes are reactivated through targeted epigenetic therapy, re-establishing the cancer cell's natural mechanisms to control abnormal growth.
Vidaza was the first drug approved for the treatment of all five subtypes of myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
Vidaza is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to Vidaza.
Important Safety Information
Vidaza is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors.
In clinical studies, the most commonly occurring adverse reactions were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%) and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), aggravated fatigue (12.7%) and malaise (10.9%).
Because treatment with Vidaza is associated with neutropenia and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle.
Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Vidaza may cause fetal harm. While receiving treatment with Vidaza, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with Vidaza should not nurse.
The highest prevalence of MDS is in patients over 60 years of age. According to the American Cancer Society and the Aplastic Anemia and MDS International Foundation, there are approximately 10,000-30,000 new cases of MDS in the United States each year. Survival ranges from six months to many years for the different subtypes of MDS.
Pharmion is a biotechnology company focused on acquiring, developing and commercializing innovative products for the treatment of hematology and oncology patients in the U.S., Europe and additional international markets. Pharmion has a number of products on the market including the world's first approved epigenetic therapy, Vidaza(R), a DNA demethylating agent. For additional information about Pharmion, please visit the company's website at www.pharmion.com.
For more information or for complete prescribing information about Vidaza, please call 1.866.PHARMION.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, including summary statements relating to interim or preliminary results of clinical trials involving Pharmion's pipeline products. Such statements are based on current expectations and involve a number of known and unknown risks and uncertainties that could cause the final results to differ significantly from the results summarized by such statements. The clinical trials described in this release are being conducted by independent investigators and Pharmion does not control and cannot predict the final results of those trials. Top line results may not be confirmed upon full analysis of the detailed results of a trial and additional information relating to the safety, efficacy or tolerability of Pharmion's products may be discovered upon further analysis of clinical trial data and upon review and analysis of additional clinical trial data. Additional risks and uncertainties relating to Pharmion and its business can be found in the "Risk Factors" section of Pharmion's Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2006, its Annual Report on Form 10-K for the year ended December 31, 2005 and in Pharmion's other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made, and Pharmion undertakes no obligation to update publicly or revise any forward-looking statement, whether as a result of new information, future developments or otherwise. Pharmion also disclaims any duty to comment upon or correct information that may be contained in reports published by the investment community.
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