San Diego, CA, December 4, 1998 -- Signal Pharmaceuticals today announced the successful completion of preclinical studies demonstrating the ability of two series of compounds to safely and effectively inhibit bone resorption in animal models of osteoporosis. The drug leads belong to a new class of small molecule compounds termed selective estrogen receptor modulators (SERMs), also referred to as 'designer estrogens.' SERMs are designed to mimic the positive effects of estrogen by inhibiting bone loss in postmenopausal women, while avoiding some of estrogen's adverse effects such as increased risk of breast and uterine cancer. Moreover, studies have demonstrated that some SERMs, such as Zeneca's tamoxifen (NolvadexTM) and Eli Lilly's raloxifene (EvistaTM), also have anti-estrogenic effects and therefore can be effective in preventing and treating breast cancer. Signal researchers are presenting data from successful preclinical studies at the joint meeting of The American Society for Bone and Mineral Research and The International Bone and Mineral Society being held in San Francisco, California, December 1-6.
Signal evaluated the efficacy of its novel SERMs in a rodent model of post-menopausal osteoporosis. Left untreated, these animals lose bone mass and eventually develop advanced stages of osteoporosis due to the loss of estrogen function. In the study, two series of drug leads were tested in parallel with estrogen and raloxifene for their ability to inhibit bone resorption. The study concluded that Signal's drug leads were twice as effective as raloxifene in preventing bone loss, at doses equal or less than raloxifene's therapeutic dose. In a separate study, these compounds also demonstrated superior safety, when compared with raloxifene, tamoxifen and estrogen, with regard to potential cancer risks in reproductive tissues. These drugs, if successfully developed, would provide clinicians with an alternative, non-estrogen treatment for osteoporosis that also would minimize some of the adverse effects associated with estrogen replacement therapy, including an increased risk for certain cancers.
Signal's President and CEO, Alan J. Lewis, Ph.D. commented, "Signal's integrated target and drug discovery capabilities allowed us to progress from lead discovery to lead development and in vivo efficacy in under a year. This is an impressive accomplishment given the complexity of this field of research. We believe these drug leads represent the 'third generation' of SERMs, combining the bone-protective effects of estrogen with a potentially improved safety profile."
Osteoporosis is an age-related disease that occurs primarily in post-menopausal women due to loss of estrogen. The disease is characterized by persistent loss of bone mass and afflicts more than 28 million people in the U.S. and over 200 million people worldwide, approximately 80% of whom are women. Estrogen-replacement therapy remains the primary treatment for pre- and post-menopausal women at risk for osteoporosis. However, this traditional hormone replacement therapy carries with it an increased risk of breast and uterine cancer. In December of 1997 the U.S. Food and Drug Administration (FDA) approved marketing of Eli Lilly's raloxifene, the first SERM with estrogen-like effects prescribed for the prevention of osteoporosis. While raloxifene represents an important advance in hormone replacement therapy for post-menopausal women, the drug is less potent than estrogen in inhibiting bone loss and does not prevent hot flashes.
Signal is developing new classes of small molecule drugs that potently and selectively control the mechanisms of bone disease at the level of gene function. Previously, Signal researchers identified a non-classical, estrogen-mediated gene regulation pathway that plays a fundamental role in regulating bone loss in women following menopause. In May of 1998, Signal was awarded a $750,000 Phase II SBIR grant from the National Institute of Diabetes and Digestive and Kidney Diseases to advance the Company's estrogen-mediated gene regulation program, including the preclinical development of novel classes of anti-resorptive SERM drugs for the treatment of osteoporosis. To expedite the discovery and validation of these drugs, Signal also developed a proprietary in vitro human bone model system that mimics the actual physiological environments of bone formation and bone resorption. The Company used this human bone model system, along with its high throughput screening and medicinal chemistry capabilities, to identify the two series of drug leads reported on today.
Signal has expanded its SERM gene regulation program to target and treat other estrogen-mediated diseases, particularly cancer. The Company recently completed a series of in vitro studies, both independently and in collaboration with the National Cancer Institute (NCI), that evaluated the anti-tumor effects of several newly discovered SERM drug leads. Both studies demonstrated significant anti-cancer effects in breast, renal, prostate and certain other tumor-types. These compounds are undergoing further evaluation at Signal and the NCI.
Signal Pharmaceuticals, Inc. is an integrated target and drug discovery company focused on identifying new classes of small molecule drugs that regulate genes and the production of disease-causing proteins. The Company applies advanced cellular, molecular and genomic technologies to map gene-regulating pathways in cells and to identify proprietary molecular targets that activate or deactivate genes and result in disease. Signal is advancing the application of genomics beyond identifying and elucidating the functions of genes to designing novel classes of disease-modifying drugs that selectively regulate the activation of disease-causing genes. The Company conducts its target and drug discovery programs both independently and with its five collaborative partners: Ares-Serono, Roche Bioscience, Nippon Kayaku, the Organon pharmaceutical division of Akzo Nobel and The DuPont Pharmaceutical Company.
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