Contact:Susan Atkins; Ligand Pharmaceuticals; 619-550-7687
John Bluth; Fleishman-Hillard, Media; 212-265-9150
NATURE STUDY FINDS LIGAND AND ALRT COMPOUNDS INCREASE EFFICIENCY OF INSULIN
BODY: COULD ULTIMATELY DELAY DIABETES
--Targretint Already in Phase II Diabetes Trials --
SAN DIEGO, March 26, 1997 -- A new class of retinoids, acting as insulin sensitizers, could eventually help more than 15 million Americans with diabetes halt progression of the potentially fatal disease, a study in today's issue of the journal Nature concludes.
Researchers at Ligand Pharmaceuticals (Nasdaq: LGND) found that the RXR selective retinoids, Targretint (LGD1069) and ALRT268, enabled diabetic mice to use insulin more efficiently resulting in significantly reduced glucose, insulin and triglyceride levels, important measures of the onset of and abnormalities associated with diabetes.
Using two well-studied mouse models of non-insulin dependent diabetes mellitus (NIDDM or type II diabetes), the investigators compared the anti-diabetic effects of Targretin and ALRT268 to treatment with a second generation member of a new class of recently approved anti-diabetic drugs called thiazolidinediones (TZDs), and with a control group.
"We found that Targretin and ALRT268 reduced glucose levels by approximately 40 percent and that ALRT268 reduced insulin levels by 70 percent," said Dr. Richard A. Heyman, the study's author and Senior Director of Retinoid Research at Ligand. "In addition, both compounds were capable of reducing triglycerides, an important risk factor in cardiovascular disease. In combination with a potent TZD used in this study, RXR agonists reduced the glucose and triglyceride levels even further."
Ligand is developing Targretin in both topical and oral formulations on its own behalf, and Ligand and Allergan are developing the second generation, RXR- selective, preclinical compound ALRT268 on behalf of Allergan Ligand Retinoid Therapeutics, Inc. (ALRT).
Targretin Research Now in Phase II Trials
The positive results reported today in Nature highlight the opportunity for
further expansion of Ligand's retinoid clinical trial program. Last week, the company announced the commencement of clinical human Phase II trials with Targretin for treatment of type II diabetes in Europe. More extensive trials are planned in the United States this year.
"A key question in pharmaceutical research is whether the preclinical results in animal studies, will translate into safety and efficacy in humans," according to AndrÈs Negro-Vilar, Senior Vice President, Research and Chief Scientific
Officer of Ligand Pharmaceuticals, Inc. "Targretin is particularly exciting because, even before the diabetes trial, Ligand has had human clinical trials under way for a wide range of cancers for nearly three years, and results from these trials have already provided evidence that the drug has an acceptable safety profile in cancer patients at high doses," said Dr. Negro-Vilar.
"We are now able to evaluate the safety and efficacy of the drug in this diabetic patient population. We have cautious optimism about the translation of the animal efficacy data because TZDs, which have also shown promise in these animal models, have been translated into human type II diabetes clinical trials, and now a marketed drug ," according to Dr. Heyman.
Insulin Resistance; A Growing Concern
The risk of developing insulin resistance, a deficiency in the body's ability to use insulin efficiently, increases with age and with obesity. Insulin-resistant individuals need more insulin to meet their basic metabolic needs. People with type II diabetes are often severely insulin-resistant and consequently need to produce so much insulin that their insulin-producing cells cannot keep up with their bodies' demands and ultimately fail.
"These animal data show that drugs like Targretin have the potential to delay disease progression in insulin resistant patients with type II diabetes,"Dr. Heyman said.
Diabetes is the fourth leading cause of death by disease in the United States with an estimated annual cost to the economy of $92 billion, according to the American Diabetes Association. Type II diabetes is the most common form of the disease, affecting more than 15 million Americans.
RXR Mechanism of Action
Targretin, a small organic compound discovered by Ligand scientists, selectively activates a subclass of retinoid receptors called retinoid X receptors (RXRs) that play an important role in several cellular activities. ALRT268 is a second generation RXR selective compound owned by Allergan Ligand Retinoid Therapeutics, Inc. Scientists have known for several years that retinoids that bind to the RXR receptors deliver their therapeutic effects by partnering with other intracellular receptors in an activated complex called a heterodimer.
The RXR can partner with several other intracellular receptors with different physiologic effects. One of these partners is peroxisome proliferator activated receptor (PPAR) gamma, a target of the antidiabetic class of drugs, the TZDs.
When the RXR receptor is linked to PPAR gamma receptor which is a target for antidiabetic therapies; the RXR ligand activates the pair and can have an antidiabetic effect. The recently approved TZD is known to exert at least part of its antidiabetic effects through PPAR receptors.
In addition to glucose metabolism, RXRs also play an important role in other cellular activities such as programmed cell death or "apoptosis," a natural
process by which the body eliminates unwanted cells. Topical Targretin is in pivotal Phase III clinical trials for the treatment of cutaneous T-cell lymphoma (CTCL). In addition, Oral Targretin is in pivotal Phase II/III trials for the treatment of CTCL. It is also in Phase II/III trials in lung cancer, and in Phase IIb trials for head and neck carcinoma, Kaposi's sarcoma, ovarian cancer, prostate cancer and renal cell cancer.
Targretin is a compound discovered and developed by Ligand. ALRT268 is a compound of Allergan Ligand Retinoid Therapeutics, Inc. (Nasdaq:ALRIZ), a research and development company formed by Ligand and Allergan, Inc. (NYSE:AGN) to develop retinoid pharmaceutical products. Ligand and Allergan share specific buyback rights to all compounds and assets of ALRT. Ligand owns 100% worldwide rights to Targretin in all indications.
Ligand Pharmaceuticals Inc., founded in 1987, is a leader in gene transcription technology, particularly intracellular receptor (IR) technology, including retinoids like Targretin, 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 and men's health and skin diseases, as well as osteoporosis, metabolic, cardiovascular and inflammatory disease.
Allergan Ligand Retinoid Therapeutics, Inc. was formed in 1994 to discover and develop drugs based on retinoids. Retinoids have a broad range of biological actions, and evidence suggests they may be useful in the treatment of a variety of cancers including leukemias and certain metabolic, skin and eye diseases.
This statement 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 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 is the trademark of Ligand Pharmaceuticals Inc.
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