RU 486 Research Forges On, Despite Political Hurdles

Research RU 486 Research Forges On, Despite Political Hurdles Author: MYRNA E. WATANABE Date: January 24, 1994, pp.14 RU 486, discovered more than 10 years ago, is an antiprogestin. Antiprogestins attach to progesterone receptors on the cell membrane in competition with the steroid hormone progesterone. When progesterone binds with a receptor, a cascade of biochemical events leads to DNA transcription. An antiprogestin, once bound to the progesterone receptor, suppresses transcription. In the uterus, this leads to hormonal and biochemical changes that can prevent implantation of a fertilized ovum or, if implantation has occurred, interrupt the pregnancy. Because the uterus is not the only site in the body that has progesterone receptors on its cells, other medical uses of antiprogestins are evident. The most prominent possible uses are in breast or ovarian cancers that may respond by growing in the presence of estrogens and progesterones. RU 486's other potential clinical uses result from its ability to block glucocorticoid receptors in cells throughout the body. They are particularly important in illnesses like Cushing's syndrome, in which the adrenal cortical hormone, cortisol, which affects carbohydrate and protein metabolism, is produced in excessive amounts. G.P. Chrousos, P.W. Gold, Journal of the American Medical Association, 267:1244-1252, 1992. G.P. Chrousos, et al., The Adrenal and Hypertension: From Cloning to Clinic, pages 273-284, eds. F. Mantero, et al., Serono Symposia Series, New York, Raven Press, 1989. M.T. Gomez, G.P. Chrousos, Cushing's Syndrome, Current Therapy in Endocrinology and Metabolism, pages 134-137, ed. W. Bardin, Philadelphia, B.C. Decker, Inc. K.E. Greene, et al., Fertility and Sterility, 58:338-343, 1992. L.M. Kettle, et al., Fertility and Sterility, 56:402-407, 1991. A.A. Murphy, et al., Journal of Clinical Endocrinology and Metabolism, 76:513-517, 1993. It has been a year since President Bill Clinton, in one of his first major acts, called for an import alert on the drug RU 486, commonly called "the abortion pill," to be reconsidered. The alert, imposed by the Bush administration in 1991, allegedly in response to political pressure from conservative and right-to-life groups, prohibits the importation of the drug into the United States for personal use. Since then, agreements have been reached between the drug's French manufacturer, Paris-based Roussel-Uclaf, and the New York-based Population Council to begin clinical trials of RU 486 as an abortifacient in the U.S. Furthermore, the head of Roussel has met with David Kessler, the chief of the U.S. Food and Drug Administration, to discuss the drug. Nonetheless, the ban still remains in effect, until such trials result in FDA approval of the drug. At the time the embargo first went into effect, biomedical researchers in different fields had been studying the drug's promising mechanisms and therapeutic effects in nonabortifacient uses for several years--as a potential treatment for cancer and immune system and neurological disorders, and as a contraceptive. The ban, many of these scientists feared, would have a chilling effect on their studies, limiting availability of the drug and support for their work. But that did not happen, according to many RU 486 researchers, with supplies of the drug and government funding for research remaining essentially unchanged from before the embargo. Given the Clinton administration's supportive attitude, it would have been reasonable to expect that an upsurge in studies and trials might have occurred over the past year. Yet very little new research is being done on the drug in the U.S. and there has not been a significant increase in the modest numbers of projects receiving federal support. Scientists studying the drug, as well as science agency administrators, have several theories on why this is so. A few researchers are concerned that the stigma surrounding the drug because of its abortifacient uses may have carried over to non-abortion-related uses of the compound. Some even worry that this reticence to carry out research may extend to Roussel itself, which is the only source of the drug and a major supplier of research funds for it. And yet still others believe RU 486 is being neglected because it is perceived as a "women's drug," suffering the same lack of federal funding as studies of other women's diseases. On the other hand, some scientists and some agency officials believe that the main reason for the nonproliferation of studies is that similar drugs are showing equal, if not greater, promise. Whatever the case, several investigations with the drug are under way in a variety of biomedical areas. Clinton's call for reevaluating RU 486 opened the way for scientific comment on possible clinical uses of the drug. The Institute of Medicine (IOM) of the National Academy of Sciences was commissioned by the Henry J. Kaiser Family Foundation to write a report on the scientific status of research with RU 486 and similar antiprogestin compounds. The distinguished scientific panel made recommendations for further studies in the report, which is based, in part, on a two-day seminar held in Washington, D.C., last spring and attended by some of the top researchers using RU 486 (M.S. Donaldson, et al., eds., Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda, Washington, D.C., National Academy Press, 1983). The panel concluded that antiprogestins have many potential applications aside from abortion--as contraceptives, in uterine diseases, in breast and ovarian cancers, in Cushing's disease, and against nonmalignant menin-giomas, among others--but needed much additional study. Some of these studies are ongoing and others are just beginning, but they give an indication of extensive medical research potential for a drug that would have been consigned to public obscurity until approval were it not for the abortion controversy. RU 486 (or mifepristone, as it is called generically) and similar antiprogestins interact with progesterone receptors. The effects of these compounds are broad, and indications are that they may be used in treatment of numerous diseases, many unrelated to reproductive function. RU 486 also has a strong antiglucocorticoid effect that makes it useful in treating diseases in which glucocorticoid receptors can be blocked (see accompanying story). Kathryn Horwitz, a molecular endocrinologist at the University of Colorado School of Medicine in Denver and one of the foremost researchers on the role of hormone receptors in breast cancer, explains that breast cancers grow in response to estradiol and progesterone. Antiestrogens, like tamoxifen, are used clinically to inhibit growth of the cancer tissue. Now, Horwitz says, it is important to study the role of antiprogestins, such as RU 486, to complement the suppression of the estrogenic component. She expects that in the future, antiestrogens and antiprogestins could be combined in a treatment regimen. "Right now, we have very little clinical information on the antiprogestins alone," she says. Horwitz is one of a few researchers receiving funding from the National Cancer Institute (NCI) for her studies on breast cancer cells and RU 486. Some clinical evidence of the drug's potential use with breast cancer patients may be forthcoming. A very small test of the drug in women with advanced breast cancer will be conducted at Long Beach Memorial Medical Center in California. The one Phase III clinical trial supported by NCI is a study of the effects of the drug on nonresectable meningioma. Meningiomas are nonmalignant, recurring growths on the meninges, or the covering of the brain, that lead to death. According to Steven Grunberg, who is coordinating the trial and is chief of the hematology and oncology unit at the University of Vermont College of Medicine in Burlington, 70 percent of meningiomas, whether in male or female patients, have high levels of progesterone receptors. RU 486, as an antiprogestational agent, would be able to block the receptors on the tumors, discouraging tumor growth. A pilot study, begun in 1987 while Grunberg was at the University of Southern California, showed positive results. The trial is coordinated through the Southwest Oncology Group (SWOG) in San Antonio, Texas, and institutions throughout the U.S. are participating. In a number of small clinical tests, Samuel S.C. Yen of the University of California, San Diego, has been studying the effects of RU 486 on two very common, nonmalignant, painful conditions related to uterine tissue: endometriosis and leio-myoma. Current pharmaceutical regimens have potentially serious side effects and are therefore limited to the short term; minimally invasive surgery also results in only temporary relief. The only cure is hysterectomy. Thus, a drug that can be administered on a long-term basis with minimal side effects would become the preferred method of treatment. Women treated in trials with RU 486 showed greater improvement than is usually seen with other drugs, Yen says. One of the research projects is based on the drug's effectiveness in promoting uterine contractions. Marilynn Frederiksen, an obstetrician-gynecologist with Northwestern University Medical School in Chicago, has had some success in clinical studies stimulating labor using RU 486 in women carrying dead fetuses. She currently is negotiating with Roussel for a clinical study on the kinetics and efficacy of the drug in inducing labor in cases of stillbirth. RU 486 has several mechanisms of action. One of these is as an antiglucocorticoid. George Chrousos and Lynnette Kaye Nieman of NIH's National Institute of Child Health and Human Development (NICHD) are using RU 486 to treat some patients with a certain subtype of Cushing's syndrome, a disease characterized by excess production of adrenocorticosteroid hormones, such as cortisol. Because glucocorticoids are important in suppression of inflammatory response, Chrousos has used the drug in other basic research on the action of glucocorticoids in humans. The antiglucocorticoid function of the drug has resulted in another clinical study to determine if RU 486 will foster memory improvement in Alzheimer's disease patients. This trial, to total 40 patients, is being carried out by Nunzio Pomara, director of the Geriatric Psychiatry Center of the Nathan Kline Institute for Psychiatric Research in Orangeburg, N.Y., at the New York University School of Medicine, where he is a research associate professor of psychiatry. Pomara explains that in animal studies, high endogenous and exogenous corticosteroid levels have been found to damage the hippocampus. He says that some Alzheimer's patients have increased cortisol levels that cannot be pharmacologically decreased, and many Cushing's syndrome patients--who have high cortisol levels--show signs of cognitive and memory deficits, some even having dementia. Thus, Pomara reasons, blocking glucocorticoid receptors with RU 486 in Alzheimer's patients may decrease damage to the hippocampus. With such fascinating and diverse projects using the drug, the question arises as to why so few projects are being funded by the government. Almost all the researchers contacted for this story believe that the political fallout because the drug's major use is in inducing abortion is, at most, a mild undercurrent in terms of reduced federal support for RU 486 projects. Because the drug is treated as an unproven new drug by FDA, investigators must file an investigational new drug application (IND) in order to obtain supplies of it. But these scientists say that FDA has, by and large, not inhibited their ability to get the drug and has approved their INDs. NCI has been funding basic research on RU 486 for several years. The institute's total support, however, is small. For example, in 1992 the agency disbursed $281,000 in grants; in 1993, $276,000 in grants and $157,000 for the clinical meningioma trial. When asked why NCI is not funding more research with the drug, Michael Friedman, associate director for the Cancer Therapy Evaluation Program at NCI, explains, "There was an important need to evaluate this agent in patients with meningioma and so we were happy to help investigators perform a Phase III study. For breast cancer and other indications, the company, that is, Roussel-Uclaf, showed us all the data they had. Although some patients seem to have benefited from the agent, it looked to be no different than other hormonally active agents." Friedman adds, "We are reevaluating this position regularly so that if new information becomes available, our enthusiasm might change." Ana Murphy, director of the division of reproductive endocrinology at Emory University School of Medicine in Atlanta, who has been studying the drug for endometriosis and fibroids along with UCSD's Yen, has another theory. She believes that RU 486 is being treated as a drug for women, and "there's no money in the budget for a lot of women's diseases." Although some researchers have had very productive experiences working with and receiving funding from Roussel, others fault the drug company. They say that political and economic pressures within the company and from its parent firm, Hoechst AG in Berlin, may be adversely affecting its ability to fund these projects. They also say that other companies, such as Berlin-Teknika in Belgium, have other drugs that may be better than RU 486. Thus, most projects have been funded, at least in part, by researchers' own sources. Yen, optimistically, submitted a grant application to NIH, but he doesn't expect funding because of budgetary problems. Meanwhile, the import ban on personal use that sparked the controversy involving RU 486 will continue until it receives FDA approval. "The FDA's position," according to spokesman Lawrence Bachorik, "is that somebody should submit an NDA [New Drug Application] so we can evaluate the data." Myrna E. Watanabe is a biotechnology consultant based in Yonkers, N.Y.

RU 486 Research Forges On, Despite Political Hurdles

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