FDA fast tracks investigational anti-cancer drug, phenoxodiol

Nov 4 2004

Marshall Edwards today announced that the U.S. Food and Drug Administration (FDA) has granted the investigational anti-cancer drug, phenoxodiol, Fast Track status for its intended use in patients with recurrent ovarian cancer.

In approving phenoxodiol for fast track status, the letter from FDA stated:

"We are granting fast track designation for the following reasons:

1. Recurrent ovarian cancer that is resistant or refractory to platins and taxanes is a life-threatening condition
2. Phenoxodiol intravenous demonstrates potential to address an unmet medical need by restoring chemo-sensitivity in resistant/refractory ovarian cancer."

The Fast Track application submitted to the FDA contained clinical data including tumor measurements based on radiographic examination. The data are from the current Phase Ib/IIa study where patients with recurrent ovarian and primary peritoneal cancers are receiving phenoxodiol (intravenous dosage form) in combination with paclitaxel in those patients where the cancer is refractory or resistant to taxanes, or in combination with cisplatin where the cancer is refractory or resistant to platinum-based drugs.

Under the FDA Modernization Act of 1997, designation as a Fast Track product means that the drug for the designated indication is eligible for accelerated marketing approval programs. More information on the FDA Fast Track program is available at http://www.fda.gov/cber/inside/fastrk.htm

"We are developing phenoxodiol for the treatment of a wide range of cancers, but for the purpose of this Fast Track Program, we are focusing on its use as a chemo-sensitizing agent in recurrent, late-stage ovarian cancer," said Dr. Graham Kelly, Executive Chairman of Marshall Edwards, Inc.

"Ovarian cancer is one of the most devastating forms of cancer, with half of the women diagnosed with it dying within five years," Dr. Kelly said. "The FDA's decision to accept phenoxodiol into its Fast Track Program reflects the dire need to provide help for women with this deadly disease once they become resistant to standard anti-cancer drugs."

Mr. Christopher Naughton, CEO of Marshall Edwards, Inc., said, "Our goal is to continue the development of phenoxodiol as rapidly as possible for the benefit of ovarian cancer patients. We look forward to working closely with the FDA as we continue the development of phenoxodiol for this and all other indications under development."

Phenoxodiol is an investigational product that regulates signal transduction pathways in cancer cells resulting in the break down of the intra-cellular proteins -- XIAP (X-linked Inhibitor of Apoptosis Protein) and FLIP (Fas Ligand Inhibitory Protein) -- which block the ability of the cancer cell to undergo apoptosis via the death receptor mechanism.(1) While these proteins play a vital role in preventing unintentional cell death in healthy cells, they are over-expressed in many forms of cancer, as well as being associated with the development of resistance to anti-cancer drugs.(2)

Pre-clinical studies have shown that by targeting these anti-apoptotic proteins, phenoxodiol is able to promote death of ovarian cancer cells that are highly resistant to standard anti-cancer drugs, as well as being able to restore sensitivity in these cells to standard anti-cancer drugs such as taxanes.(3)

Phenoxodiol works selectively on tumor cells because of its interaction with the tumor-specific NADH oxidase, which is restricted to cancer cells. Clinical trials to date have revealed no significant drug related adverse side effects.

Phenoxodiol is an investigational drug and, as such, is not approved for marketing in the United States.

Ovarian cancer is the most lethal gynecological malignancy, and the fourth leading cause of cancer related death in women in the United States. The American Cancer Society reports that an estimated 25,580 new cases of ovarian cancer will be diagnosed each year in the United States and 16,090 deaths will occur. The lifetime probability of a woman developing ovarian cancer is 1 in 59. The high mortality is due mainly to the inability to detect early disease, with approximately 80 percent of patients being diagnosed in advanced-staged disease. However, even in those patients diagnosed with Stage I or Stage II disease, the five-year survival rate ranges from 60 to 90 percent depending on the degree of tumor differentiation. Despite treatment advances over the past decade, there has been no advance in overall survival. The reason for this is the high rate of relapse. Of patients who respond to first-line chemotherapy, less than 10 to 15 percent of these will remain in remission, and most relapsed cases are chemo-resistant.

The failure of some ovarian cancers to respond to first-line chemotherapy and the development of resistance to multi-drug therapies represent the major hurdles to effective therapy of ovarian cancer.

The current Phase Ib/IIa study is an open label, randomized study being conducted at two sites (Yale-New Haven Hospital, New Haven, CT, USA, and Royal Women's Hospital, Melbourne, VIC, Australia) and involving women with recurrent ovarian cancer that is either resistant or refractory to taxane- and/or platinum-based drugs. The definition of 'resistant' is disease progression within six months of commencement of drug therapy, and 'refractory' is disease progression while undergoing drug therapy.

Patients are being randomized to one of three treatment groups -- (i) phenoxodiol + cisplatin, (ii) phenoxodiol + paclitaxel, and (iii) paclitaxel only, converting to phenoxodiol + paclitaxel after disease progression has been demonstrated. Phenoxodiol is administered by intravenous infusion on two consecutive days per week and the second drug administered intravenously immediately following the second phenoxodiol administration. Treatment is weekly on a continuous basis until either disease progression or complete response as determined by the absence of detectable disease. There are 20 subjects per treatment group. Phenoxodiol is being administered at a dosage of 3 mg/kg; the dosages of paclitaxel and cisplatin are standard but adjustable to ensure that toxicity is no greater than Grade 1,(4) being the least toxic grade.