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Biotech / Medical : Rigel Pharmaceuticals, Inc. (RIGL) -- Ignore unavailable to you. Want to Upgrade?

To: kenhott who wrote (285)	12/1/2005 1:05:50 PM
From: LJM	Respond to of 566

I think you make some valid points re: SYK, given how the market threw RIGEL in the cellar. I found this early RIGL publication re: SYK target. Disclosure: I own a very small amount of this one but clearly am disappointed. Targeting Syk as a treatment for allergic and autoimmune disorders. Wong BR, Grossbard EB, Payan DG, Masuda ES. Expert Opin Investig Drugs. 2004 Jul;13(7):743-62. Recent advances in our understanding of allergic and autoimmune disorders have begun to translate into novel, effective and safe medicines for these common maladies. Examples include an anti-IgE monoclonal antibody recently approved for severe asthmatics and the TNF-alpha antagonists that have demonstrated their ability to suppress rheumatoid arthritis, Crohn's disease and other chronic inflammatory processes. However, protein therapies are difficult and expensive to develop, manufacture and administer. Clearly, there is also a need for small-molecule inhibitors of novel targets that have safe and effective characteristics. Syk is an intracellular protein tyrosine kinase that was discovered 15 years ago as a key mediator of immunoreceptor signalling in a host of inflammatory cells including B cells, mast cells, macrophages and neutrophils. These immunoreceptors, including Fc receptors and the B-cell receptor, are important for both allergic diseases and antibody-mediated autoimmune diseases and thus pharmacologically interfering with Syk could conceivably treat these disorders. In addition, as Syk is positioned upstream in the cell signalling pathway, therapies targeting Syk may be more advantageous relative to drugs that inhibit a single downstream event. Syk inhibition during an allergic or asthmatic response will block three mast cell functions: the release of preformed mediators such as histamine, the production of lipid mediators such as leukotrienes and prostaglandins and the secretion of cytokines. In contrast, commonly used antihistamines or leukotriene receptor antagonists target only a single mediator of this complex cascade. Despite its expression in platelets and other non-haematopoietic cells, the role of Syk in regulating vascular homeostasis and other housekeeping functions is minimal or masked by redundant Syk-independent pathways. This suggests that targeting Syk would be an optimal approach to effectively treat a multitude of chronic inflammatory diseases without undue toxicity.

To: kenhott who wrote (285)	12/5/2005 12:27:17 PM
From: tuck	Read Replies (1) \| Respond to of 566

Did you in fact listen to the CC? I would recommend doing so. It seems to be more of a matter of potency & perhaps formulation (relating to various matters of PK/PD such as bioavailability, concentration, and so on) of the compound than validity of the target. This suggests follow-on compounds -- one of which is supposed to be 30x more potent -- have a decent chance. Further, the biology of RA is very different, and the compound aimed at it is systemic, while R112 for rhinitis was not. No, I think the target is fine, but the first shot on goal just went wide. Now, comments regarding how early the pipe is are nevertheless on target. We'll hear more about that on the 15th. I haven't attempted a valuation analysis, but if lots of people are thinking that Syk is a bad target, then Rigel may have been beaten up a bit too much. Cheers, Tuck