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Preclinical studies in mouse models indicate RXR-selective retinoid may have utility in treatment of diabetes and prevention/treatment of breast cancer
SAN DIEGO, Sept. 12 /PRNewswire/ -- Scientists from Ligand Pharmaceuticals Inc. (Nasdaq: LGND) today reported preclinical study results at the Bear Stearns conference in New York that indicate Targretin(TM) (LGD1069), one of Ligand's lead retinoid therapeutics, may have utility in treating human type II diabetes and in the treatment or prevention of breast cancer. The preclinical data demonstrated Targretin's (LGD1069) ability to significantly decrease blood glucose, triglyceride and insulin levels in mouse models of human type II diabetes and human obesity. In addition, in a rat model of mammary carcinoma, Targretin (LGD1069) reduced incidence and tumor frequency at least as well as tamoxifen, without the undesirable reduction in mean body weight produced by tamoxifen.
"The ability of Targretin (LGD1069) to provide therapeutic benefits in preclinical animal models of diabetes and breast cancer reinforces the concept that retinoid-based drugs may play a major role in treating a variety of diseases susceptible to intervention through intracellular signaling pathways," according to Andres Negro-Vilar, MD, Ph.D., Ligand Senior Vice President, Research, and Chief Scientific Officer. "We will evaluate Targretin (LGD1069) for treatment of these new indications because they address the needs of large patient populations with few optimal therapeutic alternatives."
Commenting on data presented at the conference, Dr. Richard Heyman, Ligand Director, Retinoid Research, explained: "Our molecular approach to drug discovery, coupled with our extensive understanding of retinoid action, has led us to the identification of an unexpected and novel class of compounds that have promise in new indications."
Preclinical Data In db/db and ob/ob Mouse Models of Diabetes
Data presented by Dr. Heyman indicate Targretin(TM) (LGD1069) may be useful in the treatment of human type II diabetes. Using two mouse models of human type II diabetes (the db/db mouse, and the ob/ob mouse), Targretin (LGD1069) was compared to treatment with a thiazolidinedione (TZD), a member of a new class of investigational antidiabetes drugs, and a control group (15 animals in each treatment group). Animals were treated daily at 3 doses for 14 consecutive days, and glucose, triglycerides and insulin levels were monitored throughout the duration of the treatment.
* Targretin (LGD1069) significantly decreased the levels of blood glucose by 40%, triglycerides by 30% and insulin by 20%, at the termination of the study.
* Targretin (LGD1069) maintained the antidiabetic activity during the course of therapy.
* Targretin (LGD1069), as a single agent, was as effective as TZD.
* Targretin (LGD1069) demonstrated additive therapeutic effects when administered with TZD.
* Targretin (LGD1069) was well tolerated throughout the treatment period.
Non-insulin dependent diabetes mellitus (NIDDM or type II diabetes) is a metabolic disorder affecting primarily adult individuals and is characterized by profound changes in glucose homeostasis and a cascade of associated hormonal and metabolic disturbances. Elevated levels of glucose (hyperglycemia) and triglycerides (hypertriglyceridemia) as well as increases in insulin (hyperinsulinemia) levels due, at least in part, to the ensuing insulin resistance are part of the metabolic profile seen in these patients. Targretin (LGD1069) acts as an insulin sensitizer leading to a significant reduction in hyperglycemia, hypertriglyceridemia and hyperinsulinemia in animal models of NIDDM.
"This suggests that these agents may be effective in the treatment of type II diabetes," according to Dr. Heyman. "Since a key event in the actions of Targretin (LGD1069) is the activation of RXR, this raises the intriguing possibility that these receptors are the molecular target for the antidiabetic action for this class of compounds.
"The translation of these animal models into the human clinical setting is promising based on the observation by others that another class of insulin sensitizer, the thiazolidinediones, decreased hyperglycemia, hyperinsulinemia and hypertriglyceridemia in animal models of NIDDM and appears to be effective in recently conducted early stage human clinical trials of type II diabetes."
Preclinical Data From NMU Rat Model of Mammary Carcinoma
Other data presented by Dr. Heyman indicate Targretin(TM) (LGD1069) may be useful in the treatment or prevention of human breast cancer. In a preclinical study, Targretin (LGD1069) was examined in a carcinogen-induced (i.e. NMU) rat mammary carcinoma model system. Targretin (LGD1069) treatment was compared to treatment with tamoxifen and a control group (15 animals in each group) to determine the retinoid's ability to reduce tumor incidence and tumor frequency. Palpation measurement from week five through week 12 of the study indicated:
* Targretin (LGD1069) decreased incidence of breast tumor formation in Sprague-Dawley rats at least as well as tamoxifen. Animals treated with Targretin (LGD1069) experienced a 90% reduction in breast tumor incidence versus controls. "Incidence" is the percentage of animals which form tumors after administration of the carcinogen. By comparison, tamoxifen reduced tumor incidence by up to 85%.
* Targretin (LGD1069) decreased the number of NMU-induced tumors per animal at least as well as tamoxifen. Control animals had 3.0 tumors per animal. Targretin (LGD1069) reduced the mean number of tumors per animal by 85%. Tamoxifen reduced the mean number of tumors per animal by 75%.
* Targretin (LGD1069) treatment had no dose limiting toxicities, while tamoxifen treatment at higher doses resulted in some dose limiting toxicity including undesirable reduction in mean animal body weight versus control animals.
Targretin (LGD1069) is a small organic compound discovered by Ligand scientists which selectively activates a subclass of retinoid receptors called RXRs which play an important role in several cellular activities. One of these activities is called programmed cell death or "apoptosis," a natural process by which the body rids itself of unwanted cells. Targretin (LGD1069) is being developed by Ligand in both topical and oral formulations. Topical Targretin (LGD1069) is entering pivotal Phase III clinical trials for the treatment of cutaneous T-cell lymphoma (CTCL). In addition, Targretin (LGD1069) oral formulation is entering pivotal Phase II/III trials for the treatment of CTCL and is in Phase II trials in lung cancer, head and neck carcinoma, Kaposi's sarcoma, ovarian cancer, prostate cancer and renal cell cancer.
Ligand Pharmaceuticals Inc., founded in 1987, is a leader in gene transcription technology, particularly intracellular receptor (IR) technology and Signal Transducers and Activators of Transcription (STATs), Ligand applies IR and STATs technology to the discovery and development of small molecule drugs to enhance therapeutic and safety profiles and to address major unmet patient needs in cancer, women's health and skin diseases, as well as osteoporosis, cardiovascular and inflammatory disease.
This statement contains certain forward looking statements by Ligand and actual results could differ materially from those described as a result of factors, including, but not limited to the following. There can be no assurance that: (a) human clinical trials will result from the preclinical studies discussed herein; (b) that the preclinical results described herein will be observed in human patients; (c) that these or any new products under development by Ligand or any of its partners will receive approval from the U.S. Food and Drug Administration or other authorities to market any of these products; (d) that, if approved, there will be a market for the drugs; or (e) that preclinical results will be predictive of any final results.
Targretin (LGD1069) is the trade mark of Ligand Pharmaceuticals Inc.
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SOURCE Ligand Pharmaceuticals. Inc.
CO: Ligand Pharmaceuticals Inc.
ST: California
IN: MTC
SU:
09/12/96 09:17 EDT prnewswire.com |
