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

To: bob zagorin who wrote (27423)	1/15/1999 10:34:00 PM
From: Henry Niman	Respond to of 32384

bob, Speaking of great posts :-), I think that its time for a LGND review. There are several new (real) handles on this thread as well as Yahoo (although I'm not as sure about the real part over there). As you know, I have been posting on LGND since 1992. Back then Biotech investors did not have a good handle (no pun intended) on the underlying technology, or Biotech business plans. Unfortunately, although the sectored has matured quite a bit, I'm not so sure about the individual investors. Some seem to think that all DR has to do is wave a magic wand and products will instantaneously appear. Unfortunately, products require a good deal of time and money as well as a fair amount of basic research. The time and money eventually pay dividends, but it almost always seems like it takes longer than anticipated. When LGND went public in 1992, their first products were expected to be retinoids and they were expected to hit the market right about now. LGND is on track and they have made a good deal of progress in partnered areas, so I think that its time to give a mini review of the retinoid area, where they have spent the most money and have the most advanced products. LGND scientists and consultants have lead the way in the discovery and characterization of the Retinoid X Receptors (RXRs) and activating ligands (like Panretin, Targretin, LGD1268, and LGD1324). The discovery of Panretin (9-cis retinoic acid) as a natural non-polypeptide hormone, was published in 1992. It was the first non-polypeptide hormone discovered in 25 years. At the time there were six related receptors (3 RARs and 3 RXRs) and Panretin activated all six (hence its name PANretin). Not much was known about the RXRs, and 9 cis retinoic acid was used to help identify functions for RXRs. When activated (by the hormone), the receptors formed heterdulpexes with a wide range of receptors, including PPARgamma, the target of TZDs like Rezulin. Remarkably, LGND was able to move Panretin from discovery to pharmacy shelves in approximately 7 years; quite an achievement. Panretin's target disease is KS as well as APL. Its APL activity is due to its ability to activate RARs, like the FDA approved treatment for APL, Vessinoid (tretinoin, or all trans retinoic acid). When Roche received approval for oral treatment of APL with tretinoin, it was hailed as a major advanced which took over 20 years of research. The side effects were quite extensive and severe, including death from retinoid poisoning and I was impressed with the relatively mild side effects of Panretin and Targretin. LGND developed Targretin, which was targeted toward the RXRs. It was thought that some of the side affects associated with RAR activation would be avoided because Targretin did not activate RARs. As noted in the first post of this thread, in animal models, Targretin was also shown to have applications for the prevention and treatment of breast cancer and type II diabetes. Targretin was effective in treating CTCL, and LGND started Phase II trials to treat type II diabetes in Europe. Although that data has yet to be released, it is my understanding that part of the delay is due to elevated tryclyceride levels associated with high doses of Targretin (which is an effective insulin sensitizer like TZDs such as Rezulin, Avandia, and Actos). Unfortunately, the side effects may be due in part to in vivo metabolism of Targetin into intermediates that do activate RARs, producing some of the side effects associated with retinoids. However, LGND has tinkered with Targretin and come up with second generation rexinoids that are not only specific for RXRs, but they bind more tightly and can thus be used a lower concentrations, which reduces the concentration of metabolites which activate RARs in vivo. Thus, the more potent RXRs can be used at lower concentrations, which would presumably produce few side effects.