Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

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

To: tuck who wrote (295)	2/22/2006 11:23:20 AM
From: tuck	Read Replies (2) \| Respond to of 566

[Preliminary data from PI for R788 for RA & ITP] >>SOUTH SAN FRANCISCO, Calif., Feb. 22 /PRNewswire-FirstCall/ -- Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL - News) today announced preliminary data from a Phase I double-blind, placebo controlled trial to investigate the safety and pharmacokinetics of R788, an oral syk kinase inhibitor, in combination with methotrexate in rheumatoid arthritis (RA) patients. The data demonstrated that R788 was well tolerated when given in combination with methotrexate and had no significant adverse pharmacokinetic interactions. The company also announced plans to initiate separate clinical efficacy studies with R788, in RA and in Immune Thrombocytopenic Purpura (ITP), in the second half of 2006. "New, effective therapeutic options in RA are greatly needed since current treatments have potentially significant limitations," stated Elliott B. Grossbard, M.D., senior vice president of medical development at Rigel. "We are pursuing R788 in autoimmune diseases such as RA and ITP because it has been shown to be a potent and selective inhibitor of syk kinase, which may play a key role in autoimmune diseases." The Phase I study enrolled patients verified to suffer from RA and who were receiving methotrexate treatment. There were no unanticipated adverse events and pharmacokinetic analysis suggests that there is no adverse interaction with the two agents. About R788 R788 is a novel, oral syk kinase inhibitor that blocks the activation of mast cells, macrophages and B cells that promote swelling and an inflammatory response. It is being developed initially to treat RA. Phase I trial results have demonstrated that R788 is well-tolerated and showed good pharmaceutical properties. Earlier Phase I studies generated valuable pharmacokinetic/pharmacodynamic data establishing a strong correlation between drug plasma levels and the inhibition of the drug target. In preclinical studies, Rigel's compound greatly diminished the swelling and tissue destruction associated with RA. In addition, in a murine model of ITP, the drug increased platelet counts significantly. Rheumatoid Arthritis: Current Treatments and Market Opportunity Approximately 2.1 million people in the U.S. suffer from RA and the worldwide market for innovative RA drugs is projected to reach $10 billion by 2008. RA is a chronic inflammatory disease that affects multiple tissues, but typically produces its most pronounced symptoms in the joints. It is often progressive and debilitating, preventing people from living a symptom-free life. Ultimately the chronic inflammation of joints leads to the destruction of the soft tissue and erosion of the articular surfaces of the bone. The current treatment options for RA have potentially significant side effects and other shortfalls, including gastrointestinal complications and kidney damage. Some RA patients currently receive multiple drugs depending on the extent and aggressiveness of the disease. Most RA patients require some form of DMARD -- including methotrexate, an anti-cancer agent, or TNF-blocking agents such as Enbrel®. The TNF-blocking agents only inhibit the inflammatory mediator TNF, and are all delivered via injection. Rigel believes that there is a significant opportunity for an oral DMARD that can be used earlier in the course of the disease, preventing its progression prior to major bone and cartilage destruction; this is the product goal for R788 in RA.<< snip Cheers, Tuck

To: tuck who wrote (295)	9/3/2006 1:15:43 PM
From: tuck	Read Replies (2) \| Respond to of 566

>>J Pharmacol Exp Ther. 2006 Aug 31; [Epub ahead of print] R406, an Orally Available Syk Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation. Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Balloum M, Qu K, Herlaar E, Lau A, Young C, Wong BR, Lovell S, Sun T, Park G, Argade A, Jurcevic S, Pine P, Singh R, Grossbard EB, Payan DG, Masuda ES. Rigel, Inc. Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune-complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 as a potent inhibitor of IgE- and IgG-mediated activation of Fc receptor signaling (EC50 for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate LAT in mast cells and BLNK/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (Ki = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils, and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-in-human study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.<< Not free, but at least adds an EC50 number for those interested. "reverse passive Arthus reaction" At first I thought this might be an obscure and difficult sexual position, but if so, it's only for rats, from what I can gather. Google wasn't much help. Rick? Edit: Definition of Arthus Reaction: Local inflammatory response due to deposition of immune complexes in tissues. One type of Immune Complex Initiated Hypersensitivity (Type III) reactions. Allergic Bronchopulmonary Aspergillosis ( ABPA ), Chronic obstructive pulmonary disease and Farmer's lung are examples of an arthus reaction. Still not sure what the reverse passive variant is about. Cheers, Tuck