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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Andrew H who wrote (11948)	12/1/1997 6:40:00 PM
From: Henry Niman	Respond to of 32384

Andy, LGND has been including brief descriptions about PPARs and TZDs since their 1994 or 1995 Annual Report. The alliance (which began in 1992) targets atherosclerosis and LGND has selected compounds but I'm not sure if they are TZDs (and they may be more specific for PPAR alpha than PPAR gamma). GLX is supposed to put one or two compounds into the clinic next year, and LGND has included a program for more specific TZDs (for PPAR gamma) in their alliance with LLY. Ron Evans discovered natural ligands (prostaglandins) for PPARs several years ago.

To: Andrew H who wrote (11948)	12/1/1997 6:46:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Andy, Herre's a few words on PPARs under the "Cardiovascular" section of LGND's on-line Annual Report: Exciting discoveries in the cardiovascular program area have facilitated expansion of Ligand's drug development focus into additional therapeutic areas. Early in 1996, Ligand scientists, in collaboration with scientists from Institute Pasteur de Lille, published new information in the Proceedings of the National Academy of Sciences defining the promoter of the human leptin gene. Patent claims connected with this work have been filed on behalf of Ligand. In addition, the role of the PPAR (peroxisome proliferator-activated receptor) family of IRs in the regulation of key genes in diabetes, obesity and cardiovascular disease has been further elucidated. Discovery progress in both of these areas culminated in the creation of a program targeting metabolic diseases. (see pages 12-15.) The collective use of research information from several different labs at Ligand allows us to expand our discovery efforts and demonstrates the importance of Ligand's scientific critical mass and our ability to achieve synergies across different therapeutic platforms.

To: Andrew H who wrote (11948)	12/1/1997 6:51:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's more info from the "Metabolic Disease" section of the Annual Report: Scientists have known for several years that retinoids that bind the RXR family deliver their therapeutic effects through partnered intracellular receptors (IRs). However, more recently researchers have discovered that RXRs are necessary or "obligate" partners in these IR pairs through all tissues. These IR pairs consist of one RXR and one of a variety of other IRs, such as RARs, PPARs (peroxisome proliferator-activated receptors), or thyroid hormone receptors. While RXRs are widely expressed, their IR partners are more discreet, being expressed in selective tissues, such as liver, fat or muscle. As a result, compounds that bind RXRs offer the unique potential to be broadly active compounds that can treat a variety of metabolic diseases. In animal models of type II diabetes, RXR agonists appear to stimulate the physiological pathways responsive to RXR-PPAR receptor partners expressed in key target tissues that are involved in glucose metabolism. As a result, a discrete set of genes is activated in these tissues resulting in a decrease in serum glucose levels, triglycerides and insulin. Developing drugs that utilize this unique mechanism of action may offer more 'gentle' therapies than conventional insulin-stimulating drugs. RXR Heterodimer Biology Once activated, RXR receptors exist as a heterodimer complex, partnered with a variety of other intracellular receptors (IRs). RXR receptors can act as obligate partners with these IRs, resulting in potential clinical utility in type II diabetes, other metabolic diseases or cancer depending on their partner. Nature Article on RXRs in Diabetes Early in 1997, Ligand scientists published an article in the journal Nature discussing the antidiabetes activity of RXR compounds such as TargretinTM and ALRT268, another potent, RXR-selective agonist (an ALRT compound). The antidiabetic activity of Targretin and ALRT268 were compared in two well-studied rodent models (ob/ob and db/db mice) with a second generation thiazolidinedione (TZD) (a new class of antidiabetes drugs which are potent PPAR agonists) and a control group. There were 15 mice in each treatment group. Glucose, triglycerides and insulin levels were monitored throughout the duration of the treatment. Studies performed indicate that both Targretin and ALRT268 decreased blood glucose by approximately 40%. Targretin reduced triglycerides by 30% and insulin by 20%. ALRT268 reduced insulin levels by more than 50% compared to control animals. Targretin, as a single agent, was as effective as TZD, and additive therapeutic effects were obtained when it was administered with TZD. Co-administration of ALRT268 and TZD decreased blood glucose levels by nearly 50%. Targretin maintained its antidiabetic activity and was well-tolerated during the course of therapy. These data suggest that Targretin and ALRT268 may be promising oral therapeutics for treatment of type II diabetes. Sidebar RXR Heterodimer Biology Once activated, RXR receptors exist as a heterodimer complex, partnered with a variety of other intracellular receptors (IRs). RXR receptors can act as obligate partners with these IRs, resulting in potential clinical utility in type II diabetes, other metabolic diseases or cancer depending on their partner. Oral TargretinTM in Phase II Human Clinical Trials in Diabetes A Phase II multi-center trial in type II diabetes in Europe was initiated with Targretin Oral Capsules in the first quarter of 1997. US trials are expected to begin in 1997. The clinical studies have two main objectives: to study the safety and tolerability of different dose levels of Targretin in type II diabetic patients, and to determine the potential for this RXR-agonist to have positive metabolic effects on carbohydrate and/or lipid metabolism in this population. If Phase II studies are successful Ligand expects to enter full development on a registration track during 1998. Ligand's goal is to initiate a significant pharmaceutical partnership in type II diabetes in 1997 to conduct this development and subsequent commercialization. A New Tool For Identifying Novel Obesity Drugs Ligand's basic research programs in gene signal transduction and intracellular signaling have yielded exciting findings that may provide new drug discovery tools for identifying novel drugs for the treatment of obesity. In collaboration with researchers from the prestigious Institute Pasteur de Lille, Ligand's scientists discovered the region of DNA, called the promoter, that is responsible for controlling expression of the protein leptin by the human obesity gene, or leptin gene. Leptin, or ob protein, plays a key role in controlling appetite and metabolism. The identification of the leptin promoter is significant because it provides a vehicle for researchers to identify novel small molecule drugs that modulate the leptin gene's expression, and in turn, treat obesity. The Company is now integrating this promoter into its proprietary high throughput screening assays to identify new drug candidates that can be administered orally, unlike proteins which require injection. To protect its proprietary rights to this genetic tool, Ligand submitted a patent application to the US Patent and Trademark Office covering this and related inventions.