Ligand Discusses New Compounds That Modulate Androgen Receptor Actions At Endocrine Society Meeting.

SAN DIEGO--(BW HealthWire)--June 25, 1998--

Designer Therapies Targeting Androgen Receptor Close to Human Trials

Scientists at Ligand (LYE-gand) Pharmaceuticals Incorporated (NASDAQ:LGND) announced today the discovery of new tissue-selective male hormone-based compounds targeting the androgen receptor (AR).

This research will be presented tomorrow at a symposium titled, "New Insights into the Pharmacology of Steroid Receptors," during the annual meeting of The Endocrine Society in New Orleans.

Through the application of its proprietary intracellular receptor technology, Ligand has developed a series of selective androgen receptor modulators (SARMs) that specifically interact with the androgen receptor and display agonist, antagonist or partial agonist properties. These structurally novel, non-steroidal, orally active, small-molecule drug candidates have demonstrated in vivo efficacy in an animal model. They also exhibit selectivity equivalent or superior to existing therapies, and show potential to have reduced undesired side effects.

The AR is a key molecular target for the development of drugs that can improve the treatment of a wide range of endocrine disorders and oncological diseases affecting both men and women. Anti-androgens have a role in the treatment of prostate cancer, benign prostatic hyperplasia (BPH), hirsutism, androgenic alopecia (male-pattern baldness) and acne. Androgen agonists are important in treating hypogonadism (a condition characterized by low levels of circulating androgens), age-associated androgen deficiency (affecting both men and women) and muscle-wasting disorders (such as those seen in AIDS, cancer and other major wasting diseases).

Currently prescribed AR antagonists have significant side effects. Among them are negative impact on libido, elevation in endogenous serum androgens, breast tenderness and diarrhea. Ligand's advanced AR antagonists have shown efficacy in animal models of prostate cancer, hirsutism and acne, and appear to have no negative impact on male reproductive behavior in rats.

Other SARMs studied by Ligand with agonist properties have shown good activity in restoring muscle mass in a hypogonadal model while showing a reduced impact on prostate gland growth.

"Based on the encouraging data we are seeing with our SARMs, we will evaluate which of the disease areas offer the best clinical and business opportunities, and expect to begin clinical trials with a novel AR antagonist next year," said Andres Negro-Vilar, M.D., Ph.D., Ligand's senior vice president, Research and chief scientific officer.

Androgen Discovery Complements Research in Progesterone and Estrogen

Earlier this month, The Journal of Medicinal Chemistry published data about Ligand's discovery of the first non-steroidal, tissue-selective progesterone agonist mimic, which, in an animal model, blocks endometrial hyperplasia in the uterus without concomitant breast-cell stimulation. This discovery may have applications in the development of advanced molecules for hormone replacement therapy.

Ligand has been involved in estrogen-related research with its partner, Wyeth-Ayerst Research, the pharmaceutical division of American Home Products (NYSE:AHP). In March, Wyeth-Ayerst filed an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA) for the compound TSE-424, a tissue selective estrogen. Wyeth-Ayerst Research is developing TSE-424 for the treatment of post-menopausal osteoporosis, which was one of the results of its collaboration with Ligand.

Other Research Shows Advances with Retinoids in Diabetes and Breast Cancer

Another study presented by Ligand scientists at a symposium titled, "Orphan Receptors and Metabolic Disease," held by The Endocrine Society showed that compounds binding the RXR-receptor, such as Ligand's retinoid Targretin(R), may block the progression of type II diabetes, the most common form of the disease. Previous studies with Targretin in diabetes have demonstrated its potential to treat the condition, but did not evaluate the effect on disease progression.

Targretin may also provide clinical benefits in the treatment of breast cancer. In pre-clinical animal studies, Targretin, added to tamoxifen therapy, caused a complete or partial regression in 94 percent of tamoxifen-resistant primary breast tumors versus a 33 percent complete or partial regression in tamoxifen-resistant primary breast tumors that continued on high-dose tamoxifen but did not receive Targretin. A study published in the February issue of Cancer Research showed that Targretin caused complete regression in 72 percent of breast cancer tumors in a proven rat model -- more than twice the efficacy shown by tamoxifen. The study was the first to compare the treatment potential of the two drugs individually, and as combination therapy. Tamoxifen resulted in complete regression in 33.3 percent of tumors.

Additional previous research (Cancer Research, December 1996) demonstrated that Targretin is equally as effective as tamoxifen at preventing breast cancer in this animal model. Tamoxifen is currently the most commonly prescribed breast cancer therapy in the world.

Targretin is a synthetic retinoid analogue discovered by Ligand scientists which selectively activates a subclass of retinoid receptors called retinoid X receptors (RXRs) which play an important role in cellular activities.

Since 1989, Ligand Pharmaceuticals Incorporated has established a leadership position in gene transcription technology, particularly intracellular receptor (IR) technology and Signal Transducer and Activators of Transcription (STATs). Ligand has applied IR and STATs technology to the discovery and development of small molecule drugs to enhance therapeutic and safety profiles and to address unmet patient needs in cancer, women's and men's health and skin diseases, as well as osteoporosis, metabolic, cardiovascular and inflammatory diseases.

This news release may contain 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 Targretin(R), or any compound in Ligand's or any of its partners' pipelines, will be successfully developed, that results of in vivo studies will be predictive of results in early- or late-stage human trials or that they will be supportive of initial or subsequent regulatory filings or approvals, that additional proposed indications will have results in subsequent clinical trials supportive of regulatory filings, that regulatory filings will be made on a timely basis, or at all, that regulatory approvals will be granted, that patient and physicians' acceptance of any products will be achieved, that final results of human clinical trials will be consistent with any interim results, or that final results will be supportive of regulatory approvals required to market products. Ligand undertakes no obligation to update the statements contained in this press release after the date hereof.

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    CONTACT:  Ligand Pharmaceuticals Incorporated
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