DRUG DEVELOPMENT | October 05, 2007 Making Chemo Irresistible
A virtual biopharma has a late-stage cancer drug with an encouraging safety profile that may be able to turn chemo-resistant cancer cells vulnerable.
DANIEL S. LEVINE
In the late 1960s and 1970s, scientists noticed a curious phenomenon. Japanese populations that had lower incidence of breast cancer and prostate cancer in their native lands within a generation of migrating to the United States had rates comparable to populations living here. Large epidemiological studies pointed to diet as the culprit.
Researchers eventually identified a class of substance called isoflavones as a possible player in protecting people against certain cancers. Isoflavones are powerful antioxidants produced by legumes such as soy and chickpeas. As these compounds were examined, laboratory experiments suggested they had anticancer properties. Experiments found isoflavones could steer cancer cells back toward normality. Such compounds could have significant impact on diseases such as ovarian cancer where most patients eventually develop resistance to chemotherapy.
“This was the lead for us,” said Alan Husband, director of research for Marshall Edwards, a subsidiary of Sydney-based Novogen, which has developed a pipeline of synthetic isoflavones. “If you could steer a cancer cell away from being a cancer cell—which is being a cell that fails to die and continues to divide—and start to induce cell death by the natural ways other body cells die, than this would be a major therapeutic opportunity that had never been previously exploited.”
Husband said the problem with using natural isoflavones as a possible cancer therapy is that their level of activity is too low to provide an effective treatment. “You couldn’t give a patient enough to be therapeutically useful in a person with rampant cancer,” he said. But isoflavones’ mechanism of action was intriguing. And, because of its long presence in the human diet, there was confidence that it could be the basis for a cancer drug with a strong safety profile. With that in mind, Novogen began building synthetic isoflavones, molecules based on the structure of isoflavones, but that could have a more potent effect in the body.
The result is a library of compounds led by Phenoxodiol. First synthesized about ten years ago, Phenoxodiol is now in a late-stage trial for patients with chemoresistant ovarian cancer and is also being examined as a treatment for prostate and cervical cancers. Phenoxodiol has received Fast Track status from the U.S. Food and Drug Administration to expedite both ovarian and prostrate cancers. “There really was no safety problem of any significance,” said Husband in reference to data from earlier clinical trials of the drug. “To finally have a safe but effective cancer drug has been the holy grail of medicine. We think we are getting there.”
Researchers at Yale University School of Medicine, who have been involved with the development of the drug and helped design the earlier clinical trials, discovered that in the women with ovarian cancer who initially failed to respond to chemotherapy, when given Phenoxodiol, their cancer cells suddenly died with only a small fraction of the standard dose of chemotherapy.
Gil Mor, associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale University School of Medicine, said he has found that the drug works by inhibiting proteins in cancer cells that shut off their ability to die. By restoring the cell to a more normal state, it allows chemotherapy to damage cancer cells and trigger the process of apoptosis, or cell death.
Mor said the medical community has accepted that there is no single drug to treat cancer and that combination therapies are the answer. But he said the mistake that has been made is to combine toxic drugs with other toxic drugs. Instead, the new approach is to target different molecular pathways involved in cancer, such as with therapies like Phenoxodiol. “You are reversing that condition of immortality into mortality again. That cancer cell then may respond to the chemotherapy,” he said. “We cannot get rid of chemotherapy, but we can use it in a more effective way and with less toxicity.”
Much will depend on the outcome of the pivotal late-stage trial. The company expects to enroll a total of 470 women with advanced chemoresistant ovarian cancer at 60 sites in the United States, Europe, and Australia. Under an agreement with the FDA, the company could halt the trial after the first 95 patients if there is adequate data to apply for approval. That could mean Marshall Edwards files to market the drug as early as 2008. Otherwise, the company expects to be able to do so in 2009. The endpoint of the trial is to establish superior progression-free survival in patients who use Phenoxodiol in combination with chemotherapy compared to patients who use chemotherapy alone.
Marshall Edwards, which operates as a virtual company, has just two employees. It is listed on NASDAQ with about a $180-million market cap. It is incorporated in Delaware as a U.S. corporation, but has no physical offices here. It relies on contract relationships with Novogen and other entities to perform development and plans on entering into a licensing agreement with a major pharmaceutical to commercialize Phenoxodiol.
Brian Rye, director of biotechnology research for Janney Montgomery Scott, which has provided investment banking services to Marshall Edwards and rates its stock a “buy,” said if the late-stage trial confirms the drug’s safety and efficacy, it could provide a chance to lower the toxicity of chemotherapy and make it more effective.
“That strong safety profile is certainly not the hallmark of most cancer therapies that people are familiar with,” said Rye. “On a commercial level, if proven successful in the phase III studies, it should be a pretty successful drug.”
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