Duramed Purchases Rights Improved Tamoxifen Manufacturing Process

Duramed Pharmaceuticals, Inc. (Cinncinati, OH) has obtained an exclusive option to purchase rights to an improved tamoxifen synthetic process from Generic Biologicals Ltd. (GBL; Oxford, UK) a United Kingdom-based product development company. Under the terms of the agreement, milestone payments will be made by Duramed to GBL based on successful completion of the drug substance scale-up process, which is expected to be completed within 90 days. With this process Duramed will have the option to pursue commercialization of the improved drug, including production and marketing of a branded finished drug product. Duramed will have exclusive rights to this technology in the United States, Canada and Mexico; GBL will receive royalties on Duramed's North American sales.

Tamoxifen, which has been used for the past 25 years for the treatment of patients with advanced breast cancer, was recently approved by the U.S. Food and Drug Administration (FDA) for prophylactic use in patients with a high genetic risk of developing breast cancer. Tamoxifen thus earned the distinction of being the first approved drug for preventing cancer.

GBL's patent-pending synthetic process yields a purer form of Z-tamoxifen. The currently available preparations of tamoxifen contain a low level (0.3%) of the E-isomer impurity of tamoxifen, which may be associated with an increased risk of endometrial cancer because of the E-isomer's estrogenic properties. Curiously, in an era where many racemic drugs are still marketed and even in development pipelines, tamoxifen is one of only a few drugs in the U.S. Pharmacopeia for which there is a limit on the amount of a single positional (E- vs. Z) isomer that may be present. Researchers believe that E-depleted tamoxifen will greatly reduce the endometrial cancer risk associated with tamoxifen therapy, especially when the drug is prescribed for long-term prophylactic use. In addition to producing purer Z-tamoxifen, GBL's patent-pending process is less complex, which should lower production costs.

The Z-isomer of tamoxifen. In the estrogenic E-isomer the ethyl and phenyl groups on the "left" side of the double bond are switched.

E. Thomas Arington, chairman and chief executive officer of Duramed, commented, "This new Z-tamoxifen, identified through our Duramed Europe subsidiary, addresses a major health problem through improved science and could add depth to Duramed's long-term drug product portfolio. GBL's synthetic process creates a distinctly purer form of tamoxifen that is expected to eliminate a major disadvantage of the current drug product. Development of a new drug product using this synthetic process has the potential for long-term benefits in women's health. Duramed is seeking a partner to collaborate on this project."

Although Duramed could not comment on proprietary aspects of the new process, it probably involves a more selective synthesis of the drug and perhaps one or more downstream processing steps to remove the unwanted E-isomer. According to Sidney Goldstein, Duramed's VP of Science and Technology, the active Z-isomer of tamoxifen is anti-estrogenic while the E-isomer is estrogenic. This raises important concerns for long-term prophylactic treatment in women at risk for developing breast cancer but who are otherwise healthy. "The PDR [Physician's Desk Reference] for tamoxifen, suggests that the increase in endometrial cancer is due to tamoxifen's estrogenic properties. If you remove the E-isomer, you'll reduce this activity. The new tamoxifen preparation reduces the E-isomer to less than 0.015%, which is our current lower level of detection."

Whether this will result in clinical benefit to women taking tamoxifen for long periods of time remains to be shown clinically, however. "We're interested in beginning clinical trials on this idea with the right corporate partner," Goldstein said. "But it's reasonable to assume that right now, if you're a patient given a choice of two drugs, you'd probably take the purer product vs. the standard tamoxifen."

The Players

Generic Biologicals, based in the UK, is a privately held product development company that has two fundamentally independent strategies. The first is to apply novel formulation delivery systems and manufacturing processes to enhance the efficacy and value of existing drugs. Products in this category represent early-to-market license opportunities.

Secondly, GBL believes that novel drugs are needed in specific market areas where current treatments can either only poorly, or in some cases not at all, address a major therapeutic need. Products in this category are longer-to-market targets.

Duramed Pharmaceuticals, Inc. specializes on prescription hormonal therapies and controlled release technology. Since early 1997, Duramed has received approval from the FDA for eight Abbreviated New Drug Applications (ANDAs). Several other applications are in the works. On March 30, 1998, the Company submitted its first New Drug Application (NDA), for its synthetic conjugated estrogens product; on June 15, 1998, Duramed announced that the FDA had completed its preliminary review of the product. When approved by the FDA, the product will be marketed under the brand name Cenestin. The worldwide estrogen replacement market is approaching $2 billion and growing at a rate of 15% per year.

For more information: Sidney Goldstein, vice president, Science and Technology, Duramed, Inc., 5040 Duramed Dr., Cincinnati, OH 45203, USA. Fax: 513-731-6482.