BOULDER, Colo., Jan. 31 /PRNewswire-FirstCall/ -- Pharmion Corporation today announced that the Investigational New Drug (IND) application for the Company’s oral formulation of azacitidine is now active following its acceptance by the U.S. Food and Drug Administration (FDA). The Company submitted the IND for oral azacitidine in December 2006.
Pharmion currently markets the parenteral formulation of azacitidine, known as Vidaza(R) (azacitidine for injection) for the treatment of patients with Myelodysplastic Syndromes (MDS). Earlier this week the FDA approved a new drug application supplement to add intravenous use as a new route of administration to instructions in the prescribing information for Vidaza.
“DNA demethylating agents, like the approved parenteral formulation of azacitidine, Vidaza, have been shown to be a safe and effective therapy for MDS,” said Andrew Allen, Pharmion’s chief medical officer. “There is a significant body of evidence that shows that the biological effects of these agents may be improved or extended through sustained DNA demethylation, which could most realistically be provided through oral delivery. We are excited about testing this hypothesis in human clinical studies and reinforcing our leadership in the development of epigenetic anti-cancer therapies.”
A Phase 1 study of oral azacitidine will be initiated shortly in patients with MDS, acute myelogenous leukemia (AML) and malignant solid tumors. The trial will assess the safety, tolerability, bioavailability and pharmacokinetics of escalating single doses of orally administered azacitidine.
“The opportunity to explore chronic administration of a DNA hypomethylating agent with oral azacitidine is extremely exciting and may lead to important changes in the way we think about combination therapies as well as maintenance therapy after anti-cancer treatment,” said Dr. Guillermo Garcia-Manero, Chief, Section of Myelodysplastic Syndromes, M.D. Anderson Cancer Center. “If successful, this could transform certain cancers into chronically managed diseases.”
Following this initial study, a multicenter, open label Phase 1 dose escalation trial of orally available azacitidine will be initiated to determine the maximum tolerated dose, dose limiting toxicities and safety of a seven day oral dosing regimen of azacitidine in subjects with MDS or AML. Pharmacokinetics and pharmacodynamic effects of the orally administered azacitidine, as well as the FDA approved parenteral regimen, will be compared.
Following the Phase 1 studies, if oral azacitidine demonstrates adequate bioavailability, Pharmion will initiate a broad Phase 2 program in solid and hematological tumors where hypermethylation is known to play a role in tumor development and progression.
About Vidaza
On May 19, 2004, Vidaza became the first drug approved by the FDA for the treatment of patients with Myelodysplastic Syndromes (MDS). The FDA approved Vidaza, the first in a new class of drugs called demethylation agents, for treatment of all five MDS subtypes, which include both low-risk and high-risk patients. These subtypes include: refractory anemia (RA) or 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).
On January 29, 2007, the Company’s new drug application supplement to add intravenous (IV) use as a new route of administration to instructions in the prescribing information for Vidaza was approved by the FDA. With this approval, Vidaza may now be administered intravenously in a clinic or hospital setting. With IV administration, the dosing for Vidaza remains the same as the previously approved subcutaneous (SC) administration at 75 mg/m2 daily, for seven days, every four weeks.
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.
About Epigenetics
Azacitidine is the first of a new class of anti-cancer compounds known as epigenetic therapies. Epigenetics refers to changes in the regulation of gene expression, and DNA methylation and histone deacetylation are two of the more studied epigenetic regulators 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 has been demonstrated in vitro and in vivo in hematological malignancies and in solid tumors. These key growth control genes can be re-expressed in cancer cells when DNA hypermethylation is reversed by Vidaza and/or inappropriate histone deacetylation is inhibited by MGCD0103. 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.
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 by SC route 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%). The most common adverse reactions by IV route also included petechiae (45.8%), rigors (35.4%), weakness (35.4%) and hypokalemia (31.3%).
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.
About Pharmion
Pharmion is a biopharmaceutical 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 drug, Vidaza(R), a DNA demethylating agent. For additional information about Pharmion, please visit the company’s website at www.pharmion.com.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, including statements related to Pharmion’s future development plans for oral azacitidine. These forward-looking statements express the current beliefs and expectations of management. Such statements involve a number of known and unknown risks and uncertainties that could cause Pharmion’s actual results and timing of events to differ significantly from those expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include the potential failure of product candidates to demonstrate safety and efficacy in clinical testing; the ability to complete and initiate trials at the referenced times; the ability to conduct clinical trials sufficient to achieve a positive completion; the uncertainty of the regulatory approval process; uncertainties regarding market acceptance of products newly launched, and other factors that are discussed under the heading “Risk Factors” and elsewhere in Pharmion’s 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 Corporation
CONTACT: Breanna Burkart or Anna Sussman, Directors, Investor Relationsand Corporate Communications, both of Pharmion Corporation, +1-720-564-9150
Web site: http://www.pharmion.com/
