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Thursday, 22 November 2001 Phenoxodiol Explanatory Notes Anti-cancer drug development has had a lot of theories and targets. The search is ongoing for the class of compounds that will offer stabilisation of a broad range of cancers. The research area now favoured for cancer treatment is a group of drugs known as signal transduction inhibitors (STI). Some breakthroughs in this area are already evident for example Novartis has the drug Gleevec now on the market. This STI works in a small sub-class of cancers, but the ultimate STI which operates across the cancer spectrum is still to be finally tested and marketed. Novogen has the first and only STI in human trials which is active against the crucial signal transduction enzyme sphingosine kinase(SK). The drug is called phenoxodiol and is now in human trials in cancer patients at the Cleveland Cancer Clinic in Ohio USA. In November 2001, the interim results of a concurrent trial in Sydney Australia were released at the Miami cancer conference. These results included the facts that phenoxodiol has been non-toxic to the patients, and that although these patients were beyond treatment with any other therapy and were on very low doses, three out of seventeen showed stabilisation of their cancers. And they each had different cancer types. Also in November 2001, the FDA allowed the trial currently underway in Cleveland to be significantly expedited. As a result of the FDA decision phenoxodiol can now be administered to US patients in higher doses sooner than would have been the case under the previous protocol. Here follows a brief summary of the Novogen oncology position In brief: · the oncology drug program is on schedule; · phenoxodiol has demonstrated highly encouraging results in the clinic, and while the current clinical trials are not designed to deliver efficacy, the results to date confirm our belief that phenoxodiol is an effective and exciting anti-cancer agent; · we currently have a range of next generation phenoxodiol compounds with complementary activity to that of phenoxodiol, giving the Company a pipeline of drugs; · the early clinical data with phenoxodiol and the pipeline of oncology drugs being developed reinforces our belief that Novogen owns the most valuable intellectual property and clinical opportunity in the oncology drug field. The field that we are playing in: The Novogen oncology drugs are known as signal transduction inhibitors. Signal transduction inhibition is the dominant area of anti-cancer drug research in medical research and big pharma companies. Signal transduction refers to the chemical communication system within a cell. There are thousands of separate communication systems (like a telephone exchange) within each cell, controlling virtually every function within the cell. Cancer results when certain key systems, mainly ones involved with cell survival and growth, malfunction. The malfunction usually shows up as overactive signalling, causing the cells to divide uncontrollably, to ignore signals to die, and to migrate in a haphazard manner. STIs aim to halt the cancer process by targeting the malfunctioning communication processes. Once the malfunctioning system is knocked out, the cancer cell should no longer be able to divide and to migrate, and usually dies. The theoretical advantage of this approach is that it is far more selective than current methods of radiotherapy and chemotherapy, causing far fewer unwanted side-effects. The challenge to date has been to identify the particular communication systems that are malfunctioning in cancer cells. The key cellular functions of growth and survival are so complicated that they involve dozens, perhaps hundreds, of different pathways. The difficulty has been to determine which of these hundreds of different pathways are malfunctioning. To date, about six different malfunctions have been identified, but this is almost certainly just the tip of the iceberg. Proof-of-concept that STIs can offer safe, effective anti-cancer therapy was presented with the FDAs recent approval of the drug, Gleevec (Novartis), for the treatment of chronic myeloid leukaemia. This previously untreatable cancer has about a 90% response rate to Gleevec, with patients showing a marked response to the drug within days of starting therapy. What is the likely future for STIs? Gleevec is effective because chronic myeloid leukaemia is associated with a single malfunction. Once that malfunction was identified, creating a drug to target the malfunction was a relatively straightforward step. This is known as rational drug design, a process whereby once the chemical structure of the target is known, then it is possible to design another chemical (the drug) to block that target. Outside of chronic myeloid leukaemia, almost all other cancers appear to involve multiple, unrelated malfunctions, and therein lies an inherent problem with the current rational drug design approach. By creating a drug to target a specific malfunction, we limit the action of the drug to that one target. But the common cancers such as lung, breast, prostate, bowel cancer etc. almost certainly are due to a range of malfunctions, meaning that blocking any one malfunction might have some impact on the cancer but not an overwhelming impact. The objective of obtaining a significant impact on cancer cell survival is only likely to come about when a range of critically important malfunctions can be switched off. The strategies generally being discussed for STIs are either the use of multiple STIs designed to target a number of key malfunctions, or the use of STIs to pre-condition cancer patients followed by sub-toxic doses of standard chemotherapies in order to achieve significant depression of the tumour. There is general acceptance that STIs (at least the current ones) are more likely to convert cancer into a chronic disease that fails to grow or grows at a much reduced rate rather than providing full, permanent remission. Where are other companies up to? All the major pharmaceutical companies appear to be developing STI drugs against some of the confirmed malfunctions. Malfunction of the EGFR (epithelial growth factor receptor) pathway has become a common target for rational drug design, as this is a well-described malfunction in many types of human cancer. Two drugs, Herceptin (Genentech) and Iressa (AstraZeneca) are the leaders here and they both show some retardation of growth of certain cancers. Herceptin, for example, is approved for use in women with advanced breast cancer and slows tumour growth to the extent that survival is prolonged about 6 months. Iressa is showing similar effect in a range of other cancers, but again is not expected to go beyond just providing a short- to medium-term extension of survival. A number of other STIs that target other malfunctions are under development, and the early clinical data suggests that their anti-cancer effects vary from clinically irrelevant to moderately effective in certain types of cancer. Overall, the STIs in clinical trials have shown only mild toxicity, suggesting that like Gleevec they can and will need to be given long-term. Flavopiridol belongs to the same general chemical and functional class of drug as phenoxodiol, and has shown in Phase 2 trials to provide some benefit in head & neck cancers. However, flavopiridol is distinctive among STIs in being reasonably toxic and therefore appears unlikely to enjoy widespread use. Where does Novogen sit with the competition? In short, we are very well placed. We have two clear advantages: 1. phenoxodiol and its derivatives are not the result of rational drug design and therefore are not constrained by the narrow spectrum of activity of other STIs. We started with compounds (isoflavonoids) that in Nature are intended to regulate such complex functions within cells as growth and survival. To do this effectively, they have to work across a wide range of important communication processes within the cell. Isoflavonoids therefore provided us with a unique opportunity to start a drug program from chemicals that were multi-acting. In creating phenoxodiol and its derivatives, we simply have enhanced the potencies of the compounds across a range of areas. We already have been able to show that phenoxodiol works on some of the major identified malfunctions (such as EGFR), giving it a spectrum of anti-cancer activity that considerably surpasses existing approved or developing drugs. The closest competitive drug in terms of action to phenoxodiol is one called Flavopiridol (Aventis). 2. phenoxodiol knocks out a key enzyme involved in signal transduction. This key enzyme is known as sphingosine kinase. What makes this enzyme key is that there is increasing evidence to suggest that it regulates many of the processes already identified as malfunctioning in cancer cells. That is, by knocking out this enzyme, it has been proposed that many of the other individual malfunctions would be automatically switched off, making the need to develop a range of individual-acting STIs redundant. At the very least, sphingosine kinase is confirmed as being integral to cell growth and survival and the conversion of a cell to the cancer state appears to require over-activation of sphingosine kinase. In the test tube, knocking out this enzyme effectively kills human cancer cells. That makes sphingosine kinase potentially the most relevant target yet described in order to produce a broad-spectrum anti-cancer response from an STI drug. Phenoxodiol is the first and only sphingosine kinase inhibitor to be tested in humans. Where are we up to with our drug program? Phenoxodiol: Phenoxodiol currently is being evaluated in a Phase 1 and Phase I/II clinical trial program involving 5 trials. These trials are scheduled to conclude progressively over the next 6-8 months. The key objective of Phase 1 trials is to determine how safe the drug is and what side-effects might be expected. Given that sphingosine kinase is such a critically important protein in all cells, both normal and cancer, this obviously is of vital interest to us. But we have a second important objective, and that is to determine how best to use the drug. We know that in order to work, phenoxodiol probably needs to be present in blood at levels no less than about 5 ug/ml. We would assume that the longer we can hold this blood level, then the better the drug will work, but we do not know the minimum time that we need to hold it. The drug has a short half-life (45 minutes) meaning that a single dose (either a single intravenous injection or a single oral dose) would only give meaningful blood levels for about 2 hours. We are developing both an intravenous form and an oral tablet form of phenoxodiol. The intravenous form is being developed as means of delivering high blood levels to patients with advanced cancers in order to achieve maximum effect. The oral form would be used for long-term maintenance therapy. Trials #1, 2 and 3 are using the intravenous dose form. The reason for doing three trials is that we need to build up the intensity of our treatment regime carefully until we confirm that the drug is safe. Trial #1 (Sydney) is almost complete. The early data was presented recently to a cancer conference in Miami and released via the ASX and Nasdaq. This trial used the least intensive treatment regime of a single intravenous injection once weekly. That is, these patients had meaningful blood levels (> 5 ug/ml) of phenoxodiol for only 2 hours each week. Because of such a short period of effective blood levels, we regarded this as a regime that would be highly unlikely to yield any anti-cancer response. Not unexpectedly the drug has proven to be well tolerated, the only toxicities being mild and temporary. But quite unexpectedly, the drug also showed an anti-cancer effect, stopping growth of aggressive tumours in 3/17 patients. Given the relatively low intensity of this treatment regime, this is a highly encouraging outcome. Trial #2 (Sydney) involves giving the drug by continuous intravenous infusion over 7 days followed by 7 days of rest, and then repeating that at least twice. Despite these patients receiving on a weekly basis up to 50x the amount of drug that patients in the first study received, the levels of phenoxodiol in the blood of these patients are still below 5 ug/ml and will not achieve that level until the last 3 patients are started. The number of patients already with stabilisation of tumours has not yet been publicly announced. Trial #3 (Cleveland, USA) involves the same regime as Trial #2 but rises ultimately to a much higher dose. We currently have 10 patients on this study, with the number already showing stabilisation of aggressively growing tumours not yet publicly announced. It is this trial that has received expedition from the FDA to now allow higher doses to be administered to cancer patients sooner than would have been the case under the previous protocol. The patients in Trials #1-3 have advanced cancers across a broad range, excluding leukaemias. The tumours that have responded to phenoxodiol in these trials represent many types including melanoma, pancreatic cancer, renal cancer, adenocarcinoma, and prostate carcinoma. Trial #4 (Sydney) also is using the intravenous formulation and is being conducted in patients with leukaemia. This trial is in the start-up phase and has yet to start the first patient. Trial #5 (Melbourne) is using the oral form of phenoxodiol and is being conducted only in prostate cancer patients. The first patients are now starting on this trial. Phenoxodiol derivatives: We have constructed a number of analogues (or derivatives) of phenoxodiol in order to explore the opportunity of creating drugs with more potent activity against specific cancer types. Two such drugs (NV50 and NV47) have emerged as being more potent than phenoxodiol against selected tumour types and these currently are undergoing pre-clinical studies ahead of clinical trials next year.
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