FDA Grants Fast-Track Designation for Phenoxodiol for Recurrent Ovarian Cancer

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FDA Grants Fast-Track Designation for Phenoxodiol for Recurrent Ovarian Cancer

WASHINGTON, DC -- November 4, 2004 -- Marshall Edwards, Inc., (Nasdaq: MSHL)(LSE AIM: MSH) 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."

About phenoxodiol
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.
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.

About the current study
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.



References:

1. Kamsteeg M et al., 2003. Phenoxodiol -- an isoflavone analog -- induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22:2611.

2. Cheng JQ et al., 2002. Drug Resist Update 5, 131.

3. Sapi E et al., 2004. Resistance of ovarian carcinoma cells to (Taxotere) docetaxel is XIAP dependent and reversible by phenoxodiol. Oncology Research (In Press)

4. National Cancer Institute Common Toxicity Criteria (CTC version 2)



SOURCE: Marshall Edwards, Inc.

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Patients with recurrent ovarian cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. Currently, physicians select a drug and must wait about six months to see whether it is effective on a particular patient. For many cancers, especially after a relapse or when a particular treatment is ineffective, more than one standard treatment exists.

All the rigorous clinical trials that have been identified are the "best" treatments for the "average" patient. This has been referred to as the lowest common denominator theory of cancer treatment. But cancer is not an "average" disease. Cancer is far more heterogeneous in response to various individual drugs than are bacterial infections.

The heterogeneity of human cancer is shown both by the fact that some patients derive great benefit from treatments which fail to help (and often harm) the majority of patients who receive the treatment. And many patients fail to benefit from 1st line chemotherapy, only to derive great benefit from 2nd or even 3rd line chemotherapy. These patients should have received the correct treatment the first time around. The earlier in the course of the disease that the most active treatment is given, the better the result for the patient.

Chemosensitivity testing can help physicians predict whether a patient will respond to a specific drug, much like they test bacteria for sensitivity to antibiotics, called Bacterial Culture and Sensitivity Testing. Chemosensitivity testing is an attempt to do something similar for cancer. Fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. It is highly desirable to know what drugs are effective against your particular cancer cells before highly-toxic agents are systemically administered to your body.

It is true that what happens in the lab is not necessrily what happens in the patient. Individual testing of patients are not scale models of chemotherapy in the patient, anymore than the barometric pressure is a scale model of the weather. But it's always more likely to rain when the barometer is falling than when it is rising, and chemotherapy is more likely to work in the patient when it kills the patient's cancer cells in the laboratory. It's no different than any other medical test in this regard.

Assay-testing is based on a biological principle that when a drug is effective, it will induce apoptosis (cell death) in the cancer cell. If the cancer cell is resistant to a drug, apoptosis will not occur. Assay-testing for apoptosis will determine whether a drug kills the tumor. Chemosensitivity testing (assay-testing) can take the guesswork out of cancer treatment. Patients with refractory cancer and have very limited time left, six months can feel like an eternity when they may have to start a whole new course of treatment if the original treatment proves ineffective.

The cell culture assay tests provide much more powerful prognostic information. They tell you that a given form of treatment has an above average probability of being associated with a clinical response and/or with being associated with above average survival. Likewise, they indicate that given treatment is associated with a below average probability of response and/or survival.