Pharmion Corporation announced that the US Food and Drug Administration (FDA) has granted Fast Track designation for oral Azacitidine in the treatment of Myelodysplastic Syndromes (MDS).
Fast Track programmes are designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Fast Track emphasizes the critical nature of close, early communication between the FDA and sponsors. The benefits of Fast Track include scheduled meetings to seek FDA input into development plans, and the option of submitting a New Drug Application in sections rather than all components simultaneously. These meetings can help the FDA and sponsors reach early agreement on design of the clinical efficacy studies that will be needed to support approval.
The FDA stated that Fast Track designation was granted for oral Azacitidine for MDS because Azacitidine is approved to treat all subtypes of MDS, and because it will potentially provide a safer, more comfortable, more convenient and more efficient route of administration of Azacitidine.
"We are extremely enthusiastic about working closely with Pharmion to drive the development of oral Azacitidine," said Dr. Hagop Kantarjian, chair of the department of leukaemia at the University of Texas M.D. Anderson Cancer Center. "Vidaza has now demonstrated a unique and profound survival benefit in higher-risk MDS, and we think oral Azacitidine may provide significant benefit in treating lower risk forms of MDS as well. We are delighted that the FDA shares our view that its development should be expedited. The opportunity to explore the biological and clinical consequences of continuous oral dosing of Azacitidine is particularly exciting, since we know that DNA remethylation occurs between cycles of intermittent parenteral therapy. Effects of continuous Azacitidine dosing on tumou RNA, another potential azacitidine target, will also be explored for the first time."
Pharmion currently markets the parenteral formulation of azacitidine, known as Vidaza (azacitidine for injection) for the treatment of patients with Myelodysplastic Syndromes (MDS). In January 2007 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. Earlier this month, Pharmion announced topline results from the largest study ever conducted in higher-risk MDS, which demonstrated a significant improvement in survival for patients treated with Vidaza. In the primary endpoint analysis, Vidaza treatment was associated with a median survival of 24.4 months versus 15 months for those receiving conventional care regimens, an improvement of 9.4 months (p<0.0001).
Pharmion is exploring oral Azacitidine's utility in the treatment of MDS and other cancers where demethylation may provide an anti-tumour effect. Oral Azacitidine is the subject of a Phase 1 multi-center, open label dose escalation trial that will assess the maximum tolerated dose, dose limiting toxicities and safety of a seven day, multi-cycle oral dosing regimen of oral Azacitidine in patients with MDS and AML. In addition, the trial will examine pharmacokinetics and pharmacodynamic effects of orally administered Azacitidine, as compared with parenteral Vidaza.
An oral dosage formulation of Azacitidine, in addition to the more desirable and convenient route of administration, would enable the evaluation of a low-dose regimen that could maximize demethylation and gene re-expression, as well as the evaluation of long-term or maintenance therapy.
Vidaza was the first drug approved for the treatment of all five subtypes of myelodysplastic syndromes (MDS), including refractory anemia (RA), 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).
Vidaza 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 Vidaza.