Healthcare Industry News: Azacitidine
News Release - January 14, 2008
Pharmion Submits European Marketing Authorization Application (MAA) for Vidaza(R) in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)MAA submission based on data from largest Phase 3 study conducted in MDS
Vidaza therapy confers highly significant 9.4 month median overall survival advantage compared to conventional care regimens
Two year overall survival rate of 50.8% for Vidaza compared to 26.2% for conventional care regimens
BOULDER, Colo., Jan. 14 (HSMN NewsFeed) -- Pharmion Corporation (Nasdaq: PHRM ) today announced the submission of a MAA with the European Medicines Agency (EMEA) for VidazaŽ (Azacitidine for injection) in the treatment of patients with higher-risk MDS in the European Union (EU).
"We are pleased to submit this application to the EMEA, given the highly compelling data for Vidaza in the treatment of MDS," said Patrick J. Mahaffy, Pharmion's president and chief executive officer. "Vidaza is the only hypomethylating agent, and, in fact, the only drug to have shown an improvement in overall survival in this indication, and we believe it will become the standard of care throughout Europe for higher-risk MDS."
"Our study results presented late last year at the American Society of Hematology meeting confirm that Vidaza should be considered first-line therapy for patients with higher-risk MDS," said Pierre Fenaux, M.D., Professor of Hematology at the University of Paris, and Head, Department of Clinical Hematology, Hopital Avicenne, France, and principal investigator of the Phase 3 study. "Overall survival is the gold standard by which clinical benefit should be measured for patients, and these data demonstrate the tremendous benefit that Vidaza can provide these patients; this represents a significant advance in the treatment of MDS patients."
Vidaza has been designated as an Orphan Medicinal Product in the EU for the treatment of MDS, which, if approved, entitles the drug to ten years of market exclusivity for the approved indication. Vidaza has also been designated as an Orphan Medicinal Product in the EU for the treatment of acute myeloid leukemia (AML).
The application is based upon clinical data which includes the results from the Company's Phase 3 multi-center, international, randomized study of VidazaŽ (Azacitidine for injection) in the treatment of patients with higher-risk MDS. The primary objective of this Phase 3 trial was to demonstrate superiority in overall survival of Vidaza versus CCR. The study included 358 patients at sites in the U.S., Europe, and Australia. At baseline, approximately 90 percent of patients were considered to have higher- risk MDS, based on subsequent independent review of FAB subtypes or IPSS classification. Patients were assigned to treatment with Vidaza (N=179; 75 mg/m2/day SC for seven consecutive days every 28 days) or CCR. Patients assigned to CCR could receive either BSC alone (N=105), low-dose cytarabine (LDAC; N=49), or standard chemotherapy (Std Chemo; N=25). The median number of cycles for Vidaza was nine; the median number of cycles for the CCR arm was as follows: BSC seven cycles, LDAC 4.5 cycles and Std Chemo one cycle.
With a median follow-up of 21.1 months, Vidaza demonstrated a statistically significant overall survival advantage over CCR (24.4 months vs. 15 months; stratified log rank p=0.0001).The hazard ratio describing this treatment effect was 0.58 (95 percent confidence interval of 0.43 to 0.77). At two years, Vidaza demonstrated a two-fold advantage in overall survival over CCR (51 percent vs. 26 percent; log rank p<0.0001). Among patients with poor cytogenetic profiles (as defined by IPSS, 28 percent of enrolled patients), median survival was 17.2 months in the Vidaza arm, compared to six months in the CCR arm (log rank p=0.01). Forty-five percent of transfusion- dependent patients on Vidaza achieved transfusion independence compared to 11 percent of transfusion-dependent patients on CCR, and for patients on Vidaza, the median time to transformation to AML during the treatment period was 26 months, compared to 12 months for patients on CCR therapy.
Treatment with Vidaza was well tolerated, demonstrating a safety profile consistent with previous experience.
Vidaza is the first of a new class of anti-cancer compounds known as demethylating agents, a subset of a category of drugs referred to as epigenetic therapies. Epigenetics refers to changes in the regulation of gene expression. DNA methylation and histone deacetylation are two of the more widely studied epigenetic mechanisms.
In May 2004, the FDA approved Vidaza, the first in a new class of drugs called demethylation agents, for treatment of all five subtypes of Myelodysplastic Syndromes (MDS). 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).
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 Vidaza 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 Vidaza 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. Vidaza was approved in the U.S. for IV administration in January 2007.
Vidaza 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 mechanisms 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. 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.
Myelodysplastic syndromes, or MDS, are a group of diseases in which the bone marrow does not function normally, resulting in the production of malformed or immature blood cells. The majority of patients with higher-risk MDS eventually experience bone marrow failure. Up to 50 percent of MDS patients succumb to complications, such as infection or bleeding, before progressing to acute myeloid leukemia (AML). MDS patients have a median survival of four months to five years depending on risk stratification. Higher-risk patients have a median survival of five to 14 months. Alleviation of disease-related complications, including transfusion requirements and hematologic improvement are key treatment goals in lower-risk MDS. Altering the natural history of disease is one of the most important treatment goals in higher-risk MDS.
Important Safety Information
Vidaza is contraindicated in patients with a known hypersensitivity to Vidaza 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 Vidaza is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. In addition, Vidaza 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.
Pharmion is a leading global oncology company uniquely 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, VidazaŽ, a DNA demethylating agent. For additional information about Pharmion, please visit the company's website at http://www.pharmion.com.
1. Aul C, Giagounidis A, Germing U. Epidemiological features of myelodysplastic syndromes: results from regional cancer surveys and hospital-based statistics. Int J. Hematol. 2001;73(4):405-10.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on current expectations and involve a number of known and unknown risks and uncertainties that could cause Pharmion's future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. In particular, we can not assure you that our MAA for Vidaza will be acceptable to the EMEA or that Vidaza will ultimately receive a marketing authorization in the EU. Important factors that could cause or contribute to such differences include the regulatory status and timing of regulatory approvals for Vidaza; the impact of competition from other products sold by Pharmion's competitors in the EU; the regulatory environment and changes in the health policies and structure of various countries; acceptance and demand for new pharmaceutical products and new therapies, uncertainties regarding Pharmion's ability to enforce market exclusivities in member states of the EU; failure of third-party manufacturers to produce the product volumes required on a timely basis, fluctuations in currency exchange rates, and other factors that are discussed 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.
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