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Life-Saving Cancer Drugs Not Approved by the FDA

September 2007

By William Faloon and Donna Pogliano

For the past 27 years, Life Extension has identified life-saving medications that languished too long in the FDA’s archaic approval process.

When effective new drugs are delayed, the inevitable consequence is needless human suffering and death. An equally insidious problem is the chilling effect bureaucratic roadblocks have on the development of better drugs that might actually cure the disease.

Just imagine the difficulty of raising the tens of millions of dollars needed to get a new cancer drug into the approval pipeline when prospective investors see the FDA deny a drug with documented efficacy, as was done recently with Provenge®. (Refer to page 7 for the complete story of the FDA’s denial of Provenge®.)

Another problem with the FDA’s unpredictable approval pattern is the outrageous cost of the cancer drugs that actually make it to market. Classes of cancer drugs (like anti-angiogenesis agents) that Life Extension long ago advocated are finally approved. The problem is that the out-of-pocket cost of these new drugs can exceed $12,000 per month. The media has reported on heart-wrenching stories of cancer patients who choose to die rather than send their families into bankruptcy from paying these costs.

It’s easy to point fingers at drug companies for charging such extortionist prices, but the harsh reality is that getting these medications approved by the FDA is so costly and risky that the high prices can arguably be justified by the hideously inefficient drug approval process that now exists.

In this article, we review a few of many drugs that have been shown to be effective against cancer, but are not yet approved by the FDA. While there are dozens of anti-cancer drugs in various stages of the approval process, the sad truth is that thousands of compounds with anti-cancer activity will never be submitted for FDA approval due to lack of patentability, lack of investor funding, or just plain unwillingness to deal with today’s cancer bureaucracy.

It has become brutally apparent that the system of drug approval needs a radical overhaul. We have some specific proposals at the end of this eye-opening article.

Each day, about 1,500 Americans perish from cancer. Each day, over 3,000 Americans are diagnosed with this dreaded disease.1 While the general population is relatively ignorant about medicine, virtually everyone knows that a cancer diagnosis means exposure to therapies that produce miserable—if not lethal—side effects. The public is also aware that in too many cases, government-approved therapies fail to cure the disease.

Promising Ovarian Cancer Drug—Still Not Approved!

Back in August 2003, Life Extension wrote about phenoxodiol, a drug that appeared effective in treating ovarian and other cancers. Ovarian cancer kills more than 15,000 women each year in the US alone.1

What makes this type of cancer so insidious is that there are few early warning signs, meaning the disease is usually well advanced when diagnosed. About 80% of ovarian cancer patients present with advanced-stage disease. There is a high rate of relapse after first-line chemotherapy, with less than 10-15% of patients who initially respond to chemotherapy remaining in remission.2 Relapsed cases are often resistant to other chemotherapy agents, leaving them without options for further treatment.3

In May 2003, an announcement emanating from the Yale University School of Medicine stated that phenoxodiol induced 100% cell death in ovarian cancer cell lines, including those cells resistant to chemotherapy drugs such as Taxol® and carboplatin.4 While a number of studies of phenoxodiol are currently underway, it remains unapproved.

In early November 2004, the FDA granted fast-track status to phenoxodiol so that Marshall Edwards, Inc., a subsidiary of Novogen, Limited, could become eligible for accelerated marketing approval programs through the FDA.2 The intended use was to benefit ovarian cancer patients who had become resistant or refractory to chemotherapy agents. The FDA acknowledged that these ovarian cancer patients face a life-threatening condition, and that phenoxodiol demonstrates potential to address their unmet need for a medication that can restore chemosensitivity.

The Problem with “Accelerated Drug Approval”

The FDA usually restricts access to experimental cancer drugs to those patients who have already failed all currently approved conventional therapies. This creates a major obstacle, since new drugs that might cure cancer or induce durable remissions if used in earlier stages may be ineffective in advanced stages of the disease.

The reason that it is so difficult to kill advanced-stage, chemotherapy-resistant cancer cells is that these cells have already mutated and acquired multiple survival mechanisms. These advanced-stage cancer cells are thus extremely difficult to eradicate with other therapies. What surprised researchers at Yale is that phenoxodiol killed all ovarian cancer cells (in the laboratory setting), regardless of their resistance to chemotherapy agents.4

Killing cancer cells in a Petri dish is the first step to identifying potential anti-cancer drugs. The greater challenge is getting these same drugs to function effectively in the human body. By restricting clinical testing of phenoxodiol only to advanced cancer patients (who have already failed anti-cancer treatments such as surgery, radiation therapy, and/or one or more chemotherapy agents), a bureaucratic hurdle is erected that precludes optimal evaluation of the drug, i.e., testing it in early-stage cancer, when drug resistance is most likely minimal or absent.

While the FDA seems to have acknowledged the potential of phenoxodiol as early as the year 2004, and despite the fact that clinical trials reveal no significant adverse side effects, ovarian cancer patients are still waiting for the approval of this drug.5

Since phenoxodiol is only being tested in advanced-stage cancer patients, scientists may never know if it would be effective in early-stage cases.

Phenoxodiol Has Multiple Mechanisms of Action

Phenoxodiol was discovered when scientists were studying the anti-cancer properties of soy genistein plant extracts. The scientists used data collected from this research to synthesize (and patent) phenoxodiol, which is a genistein analog. There are both oral and intravenously administered versions of phenoxodiol.

Phenoxodiol functions via several unique mechanisms to induce cancer cells to undergo programmed cell death (apoptosis). Normal cells undergo apoptosis in a controlled manner so they can be replaced with healthier-functioning cells. Cancer cells, on the other hand, have undergone genetic mutations that prevent them from self-destructing. The ultimate goal of a cancer therapy is to induce malignant cells to undergo apoptosis, instead of indefinitely proliferating out of control.

Phenoxodiol works via several mechanisms, including altering a signal pathway in cancerous cells that prevents them from undergoing apoptosis (programmed cell death). These findings indicate that the drug could be successful at treating many types of cancer. The study in which researchers at Yale showed how phenoxodiol kills cancer cells was published in the May 1, 2003, issue of Oncogene, but advanced-stage cancer patients still have to apply to enter a clinical trial to have any chance of accessing it, and of course entry slots into such clinical trials are extremely limited.4

Life-Saving Cancer Drugs Not Approved By The FDA: What You Need to Know

• Due to the FDA’s inefficient drug approval process, many promising cancer therapies are never approved, resulting in needless suffering and death.

• In the past 10 years alone, scientists have developed therapies that may help fight difficult-to-treat malignancies such as ovarian and prostate cancers, as well as osteosarcoma, leukemia, and melanoma. Because these therapies have not yet been approved by the FDA, however, they are only available to a lucky few who are able to enroll in clinical trials.

• Even those who enroll in clinical trials have no guarantee that they are receiving a potentially life-saving therapy. Most clinical trials for cancer require that some participants receive a worthlessplacebo—an almost guaranteed death sentence.

• The FDA’s current system of drug approval is clearly in need of a major overhaul.

• By contacting your Representative and two Senators, you can help promote change in the FDA’s outdated system of drug approval. It only a takes a few minutes to take action, but these efforts might one day save your life—or the lives of your loved ones.

Phenoxodiol Studies in Ovarian Cancer

Preliminary results of a clinical trial conducted at the Cleveland Clinic found that more than half of the 10 patients tested using phenoxodiol showed some response.6 Each of these patients had different types of advanced cancer that did not respond to chemotherapy. The researchers also tested phenoxodiol in mice and found that when dosed at 20 mg/kg every day for six days there was a three-fold reduction in tumor mass compared with a control group. No side effects were noted.

In a May 2006 report published in the International Journal of Cancer, phenoxodiol was acknowledged by researchers in Australia as an agent that directly inhibits the proliferation of tumor cells by inducing apoptosis and disrupting the process of cell division. In addition, their in vivo angiogensis study demonstrated that phenoxodiol may also have the ability to combat the other process that drives tumor growth, namely, angiogenesis, the stimulation of the vasculature that provides the tumor with its blood supply.7

Another study published in October 2006 by Australian researchers in Cancer Chemotherapy and Pharmacology used a dose-escalating study on a small number of human cancer patients to find the maximum tolerated dose and toxicity of phenoxodiol.5 They found that toxicity was minimal, and a maximum tolerated dose was never reached. Despite the fact that most of the 21 patients they treated had advanced cancers with progressive disease, they noted that at least one patient responded to treatment with stabilization of disease status for six months before further progression. As noted earlier, cancer patients with advanced-stage disease are unlikely to respond well to any therapy.

In the case of ovarian cancer, the high mortality rate arises not only because of difficulties with detecting the disease in its early stages when symptoms are not apparent, but also due to the widespread development of chemoresistance.3 One of the major areas of study involving phenoxodiol concerns its potential as a chemosensitizing agent in the treatment of ovarian cancer.

In January 2005, Oncology Research reported that in laboratory studies conducted at Yale, phenoxodiol increases the effectiveness of docetaxel (Taxotere®) by at least 100 times.8 In other words, when the researchers measured the effect on human ovarian cancer cells previously found to be resistant to docetaxel, the synergistic effect of phenoxodiol combined with docetaxel allowed for the use of only 1/100th of the amount of docetaxel, which proved to be as effective as the standard dose of docetaxel alone. This potential for the reduction of dosage in standard chemotherapy agents could result in a dramatically improved quality of life for patients undergoing chemotherapy due to the reduction in chemotherapy’s toxic side effects.

Co-administration of phenoxodiol with standard chemotherapy agents also allows for the administration of both agents at lower doses, while retaining significant anti-tumor activity compared with mono-therapy, according to researchers at Yale who reported on a new chemotherapy study in the April 2007 issue of Cancer Biology and Therapy.9 Their report states that they have previously shown that phenoxodiol is able to sensitize epithelial ovarian cells to pacitaxel, carboplatin, gemcitabine, and docetaxel. In previously conducted in vitro studies and in their current in vivo studies in mice, it was demonstrated that in over half of the cell lines tested (which were previously determined to be resistant to a newer chemo drug called topotecan), pretreatment with phenoxodiol demonstrated a clear therapeutic advantage.

A report on phenoxodiol research conducted at New Zealand’s leading medical research facility was released on May 1, 2007. The research included laboratory studies and Phase II clinical trials on human subjects with resistant ovarian cancer.10 Professor Michael Berridge, PhD, calls phenoxodiol a novel drug and cites its unique mechanism of action, which is not exhibited by other anti-cancer drugs currently in use. Phenoxodiol is described as an agent that works by targeting a specific protein that occurs only on cancer cells and inducing their destruction. Since this particular protein does not occur on healthy cells, they suffer no damage from phenoxodiol. Dr. Berridge notes that phenoxodiol is the first compound to operate via this signal disruption pathway. This class of drugs will be called “Multiple Signal Transduction Inhibitors,” or “MSTRs.”

While over 1,000 women perish each month from ovarian cancer, the drug remains bogged down in the lengthy FDA approval process. A multi-national Phase III clinical trial is finally underway at 60 sites in the US, Europe, and Australia. Called the OVArian TUmor REsponse study, or OVATURE, it is recruiting recurrent or persistent advanced patients with ovarian, fallopian tube, or primary peritoneal cancers.11 Preliminary results from the trial are expected within 18 months—meaning 22,000 American women and countless other women throughout the world might needlessly die from ovarian cancer who should have been allowed to access phenoxodiol before they developed advanced disease.

The FDA’s Drug Approval Quagmire

Before the efficacy of a drug can be tested, the FDA first mandates that Phase I studies be conducted in which advanced cancer patients are given low doses of a new drug to verify safety. The dose is usually so small that the drug has no chance of curing end-stage cancer victims. In the case of phenoxodiol, five Phase I human trials were completed in 2003, and the side effects shown were few if any.

Under today’s antiquated system, a new drug cannot be marketed until it has been thoroughly investigated in clinical trials. These trials can take many years to complete. The results of these numerous trials are then submitted in a New Drug Application to the FDA. The FDA sends these results to a committee for review. The committee may then ask for more studies, reject the application, or recommend that the drug be approved. The FDA then takes the committee’s report and decides whether to approve the drug as safe and effective. This can happen quickly, or drug approval can become bogged down in the FDA’s regulatory quagmire. Until the FDA reaches its final verdict, no marketing of the drug can take place. It can take ten to twenty years after a promising cancer drug has been discovered before the FDA may approve it, e.g., VM-26® or teniposide (Vumon®) for childhood leukemia, small cell lung cancer, and malignant brain tumors. One reason for this long delay is that after the drug has been discovered, money has to be raised to fund the clinical studies, and negotiations have to be completed to get approval for the study design itself.

Phenoxodiol Delays Progression of Prostate Cancer

Phenoxodiol is also being tested for the treatment of prostate cancer, beginning with hormone-refractory (advanced) prostate cancer patients. It is hoped that when phenoxodiol and other drugs in its class are eventually developed, tested, and approved, they will also be useful in the treatment of early-stage prostate cancer.

In November 2005, it was reported that in Phase IB/IIA clinical trials, phenoxodiol was demonstrated to significantly delay tumor progression in late-stage, hormone-refractory prostate cancer patients.12 The anti-tumor effect was dose dependent with the two highest dosages, 200 and 400 mg, given three times a day for 21 days with the next 7 days without treatment, proving to be the most effective. The study conducted in Australia was scheduled to end after 24 weeks, but due to the unexpected extended survival and lack of toxicity (which might have limited the use of the drug), the trial was extended to 90 weeks and beyond. The lead investigator noted that phenoxodiol provided a significant anti-tumor effect in patients whose disease has progressed to the point where it is normally unresponsive to treatment, with a few patients experiencing reductions in PSA of 50% or greater from baseline and many patients experiencing dramatic extension of PSA doubling times.

American oncologists who specialize in the treatment of prostate cancer were very excited by these findings and the potential for phenoxodiol to impact the treatment of both early- and late-stage prostate cancer patients, and very interested in studying the ability of phenoxodiol to restore sensitivity to standard chemotherapy agents in end-stage prostate cancer patients.13 The potential of phenoxodiol in the treatment of hormone-refractory prostate cancer that is resistant to chemotherapy resulted in the FDA’s approval of fast-track status for this use in early 2005, but prostate cancer patients note that there has been a significant delay in the investigations needed to win approval. The Novogen Phase I trial being conducted on solid tumors may potentially enroll prostate cancer patients, but as of this date, it appears that no other significant trials are underway.13

Press releases have indicated that due to financial constraints the company that holds the patent rights to phenoxodiol has had to defer further studies relating to prostate cancer patients and to restrict its clinical trials to ovarian cancer. Given the apparent efficacy of phenoxodiol in prostate cancer, such obstruction to further study and/or access of phenoxodiol to patients with life-threatening diseases should be considered criminal. The fault lies not with the company, but with the FDA.

Phenoxodiol and Melanoma

Australian researchers are also targeting human melanoma cells using phenoxodiol to induce apoptosis. This work will try to pinpoint the mechanisms by which specific proteins of the apoptosis cascade are affected.

In January 2007, Yale researchers reported in the Journal of Translational Medicine that pretreatment with phenoxodiol can sensitize melanoma cells to carboplatin, a currently available chemotherapy agent. This research has promising implications for use in the treatment of metastatic melanoma, and most probably for any malignancy where carboplatin has shown activity, such as ovarian, breast, prostate, testicular, lung, and other cancers.14

Phenoxodiol and Squamous Cell Carcinoma

Oral phenoxodiol is being tested at Yale in Phase IB in patients with squamous cell carcinomas of the cervix, vagina, or vulva, and in adenocarcinoma of the cervix.15 The study will assess phenoxodiol as monotherapy in these patients, and examine its safety and tolerability. The intravenous form of phenoxodiol continues to be used in Phase IB/IIA ovarian and other gynecological cancer clinical trials at Yale as a chemosensitizing agent in combination with various chemotherapy regimens. The patients under study have recurrent disease resistant to platinum or taxane-based chemotherapy.15