ATLANTA, Georgia, December 9 /PRNewswire/ --
- Data Demonstrate 9.4 Month Median Overall Survival Benefit in Higher-risk MDS for Azacitidine Compared to Conventional Care Regimens (Log Rank p=0.0001)
- Two Year Overall Survival Rate of 50.8% for Azacitidine Compared to 26.2% for Conventional Care Regimens
- Highly Consistent Effect Across Patient Subgroups
- Data Presented at the 49th American Society of Hematology Meeting
Pharmion Corporation (Nasdaq: PHRM) today announced complete results from a Phase 3 multi-centre, international, randomized study of azacitidine for injection (Vidaza(R)) in the treatment of patients with higher-risk myelodysplastic syndromes (MDS) demonstrating that azacitidine provides a significant survival benefit compared to conventional care regimens (CCR) in higher-risk MDS patients. The median overall survival advantage for azacitidine -treated patients compared to CCR-treated patients in this, the largest clinical trial in MDS, was 9.4 months (24.4 months vs. 15 months; 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). These data, along with results from 18 additional studies of azacitidine, are being presented at the 49th Annual Meeting and Exposition of the American Society of Hematology (ASH) in Atlanta.
"As the only hypomethylating agent, and, in fact, the only drug to have shown an improvement in overall survival, we believe azacitidine now stands alone as the standard of care for higher risk MDS patients," said Patrick J. Mahaffy, president and chief executive officer of Pharmion. "In addition to the unprecedented improvement in overall survival, 45 percent of patients on azacitidine achieved transfusion independence compared to 11 percent on CCR, and for patients on azacitidine, the median time to transformation to AML during the treatment period was 26 months, compared to 12 months for patients on CCR therapy. These data provide further evidence of the substantial benefit that azacitidine provides to higher-risk MDS patients in prolonging their lives. "
"The data from this trial further confirm that azacitidine should be considered first-line therapy for patients with higher-risk MDS," said Pierre Fenaux, M.D., principal investigator of the Phase 3 study, Professor of Haematology at the University of Paris, and Head, Department of Clinical Haematology, Hopital Avicenne, France. "The results from this trial are robust and clinically meaningful and represent an important advance in the treatment of higher-risk MDS patients."
Professor Fenaux will deliver an oral presentation titled "Azacitidine (AZA) Treatment Prolongs Overall Survival (OS) in Higher-Risk MDS Patients Compared with Conventional Care Regimens (CCR): Results of the AZA-001 Phase III Study" (Abstract 817) on Tuesday, December 11, 2007 at 7:30 a.m. Eastern time. Professor Fenaux presented data from this study this morning at a media briefing sponsored by ASH.
The primary objective of this multi-centre, international, randomized, open-label, parallel-group, Phase 3 trial was to demonstrate superiority in survival of azacitidine versus CCR in higher-risk MDS patients. The study evaluated 358 higher-risk MDS 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 azacitidine (N=179; 75 mg/m2/day SC for seven consecutive days every 28 days) or CCR for the treatment of MDS. Patients assigned to CCR could receive either BSC alone (N=105), low-dose cytarabine (LDAC; N=49), or standard chemotherapy (StdChemo; N=25). Median number of cycles for azacitidine was nine; for the CCR arm, the median number of cycles was as follows: BSC seven cycles, LDAC 4.5 cycles and StdChemo one cycle.
With a median follow-up of 21.1 months, azacitidine demonstrated a statistically significant overall survival advantage over CCR (24.4 months vs. 15 months; stratified log rank p=0.0001). At two years, azacitidine 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 azacitidine arm, compared to six months in the CCR arm (log rank p=0.01).
Treatment with azacitidine was well tolerated, demonstrating a safety profile consistent with previous experience.
"Azacitidine is the first drug to have demonstrated an overall survival advantage in MDS, which is a considerable breakthrough in this treatment area, " said Professor Ghulam Mufti, Head of Department, Professor of Haematological Medicine at Kings College, London. "It is also the first epigenetic therapy to demonstrate survival benefit in any cancer, indicating it is an exciting area of research for which we hope to see many more developments in the future."
Azacitidine 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, azacitidine became the first drug approved by the FDA for the treatment of patients with FAB (French-American-British) classification Myelodysplastic Syndromes (MDS). The FDA approved azacitidine, the first in a new class of drugs called demethylation agents, for treatment of all five FAB MDS subtypes. These subtypes include: refractory anaemia (RA) or refractory anaemia with ringed sideroblasts (RARS) if accompanied by neutropenia or thrombocytopenia or requiring transfusions; refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukaemia (CMMoL).
Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal haematopoietic 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 azacitidine. Azacitidine was approved for IV administration in January 2007.
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 mechanisms involved. The silencing of key cell cycle control genes and tumour suppressor genes through these two mechanisms of epigenetic regulation has been demonstrated in vitro and in vivo in haematological malignancies and in solid tumours. These key growth control genes can be re- expressed in cancer cells when DNA hypermethylation is reversed by azacitidine. The epigenetic approach to cancer therapy is that rather than using molecules that kill both normal, and tumour 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. MDS affects approximately 40,000-50,000 people in the United States and 75,000-85,000 patients in Europe. 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 leukaemia (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 haematologic 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
Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumours.
In clinical studies, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anaemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leucopoenia (48.2%), diarrhoea (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 azacitidine 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.
Azacitidine may cause foetal harm. While receiving treatment with azacitidine, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with azacitidine should not nurse.
Pharmion is a leading global oncology company uniquely focused on acquiring, developing and commercializing innovative products for the treatment of haematology 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, azacitidine, a DNA demethylating agent. For additional information about Pharmion, please visit the company's website at http://www.pharmion.com.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, including summary statements relating to the interim or preliminary results of clinical trials involving azacitidine. 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. Preliminary results may not be confirmed upon final analysis of the detailed results of a trial and additional information relating to the safety, efficacy or tolerability of azacitidine may be discovered upon further analysis of clinical trial data and upon review and analysis of additional clinical trial data from this or other clinical trials. 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 September 30, 2007, its Annual Report on Form 10-K for the year ended December 31, 2006 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.
Contact: Breanna Burkart or Anna Sussman, Directors, Investor Relations and Corporate Communications, both of Pharmion Corporation, +1-720-564-9144 or +1-720-564-9143, Web site: http://www.pharmion.com; On-Site Media Contacts: Kevin Loth, Director, Professional Relations, Pharmion Ltd, +44-7900-980-823, Joanne Wunder, Ogilvy Public Relations, EU, +44-7801-082-574