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Biotech / Medical : Agouron Pharmaceuticals (AGPH) -- Ignore unavailable to you. Want to Upgrade?

To: Steve Fancy who wrote (4386)	5/27/1998 1:36:00 PM
From: Peter Singleton	Respond to of 6136

fyi, below is a post from Yahoo which was in response to someone's question on PNU-140690 ... I took a look on Altavista for information on PNU-140690. Looks like it's in PI/II studies, and is targeted at anti-viral resistant patients. It's in the clinic with indinavir (Crixivan) resistant patients. PNU also published pre-clinical results in November showing in vitro potency against ritonavir (Norvir) resistant virus. Norvir and Crixivan are structurally similar and display similar resistance patterns, so it looks like PNU is testing it in the largest market for PI resistant patients, folks that have failed Crixivan. Note: in vitro potency against strains resistant to another PI does not guarantee in vivo potency ... Btw, PNU-140690 is a derivative of coumarin (warfarin), a generic anti-coagulant. A couple of links are below: Altavista query: altavista.digital.com /* didn't copy over properly from yahoo post Info on ABT-378 and PNU-140690, with info on PNU's clinical plan. Note target market is definitely patients who've failed prior PI therapy from natap.org Additionally, Abbott's second generation protease, ABT-378, is currently in phase II in HIV infected individuals. ABT-378 appears to have a relatively unique resistance profile, based on in vitro research done to date. It did not appear to have a mutation at position 82, which is important for IDV and RTV resistance. ABT-378 will be used with a small dose of RTV because the addition of ritonavir greatly enhances the PK profile of ABT-378. In vitro ABT-378 appears to suppress virus with some limited degree of ritonavir resistance (possibly up to 25 fold RT resistance ). As soon as possible, Abbott hopes to start trials with ABT-378 for individuals who1ve failed protease therapy. As well, Upjohn's new protease, PNU-140690, may offer some effectiveness against protease resistant virus.ÿUpjohn has just started recruiting for a small study evaluating the effectiveness of PNU-140690 in individuals who have failed protease therapy. In one arm indinavir or ritonavir failures will receive PNU140690. The second arm is for individuals who have experience with multiple protease inhbitors. Individuals will receive PNU140690 if they've failed their current protease therapy and had previous protease therapy. The objective is to make a preliminary observation if individuals who've filed protease inhibitors will be sensitive to PNU140690. If all goes well, the hope is that by this Summer a larger study will begin exploring PNU140690's effectiveness for individuals who have failed protease therapy. ÿ Other info on the compound: aegis.com (AW) AIDS Therapies: New Upjohn Protease Inhibitor Kills Ritonavir-Resistant HIV AIDSWEEKLY Plus, Monday, December 15, 1997. Daniel J. DeNoon, Senior Editor ------------------------------------------------------------------------ A new protease inhibitor, currently in early clinical studies, is effective against HIV strains resistant to ritonavir (Norvir, Abbott). The drug, code named PNU-140690, is a third-generation non-peptidic derivative of coumarin. It is a sulfonamide- containing 5,6-dihydro-4-hydroxy-2-pyrone. In vitro studies show that PNU-140690 is equally effective against ritonavir-sensitive and ritonavir-resistant strains of HIV-1. Moreover, the new drug has additive-to-moderately- synergistic effects in combination with ritonavir - even against ritonavir-resistant virus. "These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protease inhibitor such as ritonavir," wrote Upjohn researchers K.-T. Chong and P.J. Pagano in the journal Antimicrobial Agents and Chemotherapy ("In Vitro Combination of PNU-140690, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, with Ritonavir against Ritonavir-Sensitive and -Resistant Clinical Isolates," Antimic Ag Chem, 1997;41(11):2367-73). Development of PNU-140690 was announced at the 1996 International Conference on AIDS by Upjohn researcher S. Thaisrivongs. "The third-generation non-peptidic compounds were identified in the dihydropyrone class, [with] potent inhibition of HIV protease (K; 0.05 nM), high antiviral activity (IC[50]= 50 nM in HIV-1[IIIB] infected H9 or MT4 cells; IC[50]= 30 nM in HIV-1[JRCSF] infected PBMC; and IC[90] (median)= 0.3 (micro)M against a panel of 10 AZT-resistant clinical HIV isolates in PBMC)," Thaisrivongs and colleagues wrote in their presentation abstract. "In an assay medium with added 75 percent human plasma, there was an approximately half-a-log-unit increase in the IC[50] value. After oral administration to dogs (C[max]= 26 (micro)M at 10 mg/kg), the bioavailability was 40 percent." The corresponding authors for this study are K.-T. Chong and P.J. Pagano, Infectious Diseases Research, Pharmacia & Upjohn Inc., Kalamazoo, Michigan 49001.