Duramed acquires rights to improved tamoxifen manufacturing process

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Duramed Pharmaceuticals, Inc. (Cinncinati, OH) has obtained an exclusive option to purchase the rights to an improved tamoxifen synthesis process from Generic Biologicals Ltd. (GBL; Oxford, UK), a UK-based product development company. Under the terms of the agreement, milestone payments will be made by Duramed to GBL based on the 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 opportunity to further commercialize the improved drug, including the production and marketing of a branded finished pharmaceutical product. Duramed will have exclusive rights to this technology in the United States, Canada and Mexico; GBL will receive royalties on North American sales of Duramed.

Tamoxifen, which has been used for 25 years for the treatment of patients with advanced breast cancer, was recently approved by the United States Food and Drug Administration (FDA) for prophylactic use in patients at risk. genetics to develop breast cancer. Tamoxifen has thus obtained the distinction of being the first drug approved for the prevention of cancer.

GBL’s patent pending synthetic process produces a purer form of Z-tamoxifen. Currently available tamoxifen preparations contain a low level (0.3%) of the E-isomer impurity of tamoxifen, which may be associated with an increased risk of endometrial cancer due to the estrogenic properties of the isomer E. Oddly, at a time when many racemic drugs are still marketed and even under development, tamoxifen is one of the few drugs in the US Pharmacopoeia for which there is a limit on the amount of a single positional (E- vs. Z) isomer which may be present. Researchers believe that E-depleted tamoxifen will significantly reduce the risk of endometrial cancer associated with tamoxifen treatment, 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 reduce 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 reversed.

E. Thomas Arington, President and CEO of Duramed, commented: “This new Z-tamoxifen, identified by our subsidiary Duramed Europe, solves a major health problem through improved science and may add depth to Duramed’s long-term pharmaceutical portfolio. The GBL synthesis process creates a significantly purer form of tamoxifen which should eliminate a major drawback of the current drug product. The development of a new drug product using this synthetic process has the potential to have long-term health benefits for women. Duramed is looking for a partner to collaborate on this project.

While Duramed could not comment on proprietary aspects of the new process, it likely involves a more selective synthesis of the drug and possibly one or more downstream processing steps to remove the unwanted E-isomer. According to Sidney Goldstein, vice president of science and technology at Duramed, the active Z-isomer of tamoxifen is anti-estrogenic while the E-isomer is estrogenic. This raises significant concerns for long-term prophylactic treatment in women at risk of developing breast cancer but who are otherwise healthy. “The RDP [Physician’s Desk Reference] for tamoxifen, suggests that the increase in endometrial cancer is due to the estrogenic properties of tamoxifen. If you remove the E isomer, you will reduce this activity. The new preparation of tamoxifen reduces the E-isomer to less than 0.015%, which is our lowest current detection level. ”

However, it remains to be clinically demonstrated whether this will result in clinical benefit for women taking tamoxifen for long periods of time. “We are interested in starting clinical trials on this idea with the right business partner,” Goldstein said. “But it’s safe to assume that right now, if you’re a patient with a choice of two drugs, you would probably be taking the purer product compared to standard tamoxifen.”

The players

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

Second, GBL believes that new drugs are needed in specific market areas where current treatments can only poorly, if at all, meet a major therapeutic need. Products in this category are longer term targets in the market.

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

By Angelo DePalma

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


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