To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Potential for New Combination of Investigational Anti-HIV Drugs URL: http://www.pslgroup.com/dg/196AE.htm Doctor's Guide January 26, 1997
WASHINGTON, Jan. 26, 1997 -- Preliminary data released today suggest that the combination of the investigational antiretroviral agents 1592U89 and 141W94 may be an effective treatment for human immunodeficiency virus (HIV) infection. Initial results from an ongoing small Phase I/II clinical trial have shown that five of seven patients treated with this combination for four weeks experienced drops in HIV viral load to below the limits of detection (400 copies/mL) for the measurement assays used. The median maximum decrease in viral load for the seven patients was 2.08 logs. (Undetectable viral load does not mean viral eradication as patients may still have virus in their systems.) In addition, the average increase in infection-fighting CD4 cells among these patients after four weeks was 79 cells/mm3. At the time these data were gathered, the trial had enrolled a total of nine patients. Two patients prematurely discontinued the study due to adverse events -- one due to nausea and one as a result of complaints of rash and speech difficulties. Early indications suggest nausea is the most commonly reported adverse event with this combination. 1592 is a nucleoside analogue reverse transcriptase inhibitor and 141 is an HIV protease inhibitor. Both compounds are being developed by Glaxo Wellcome. The preliminary data from this small Phase I/II study were presented today at the conclusion of the Fourth Conference on Retroviruses and Opportunistic Infections. "While it would be extremely premature to draw any conclusions based on such early results in such a small number of patients, we are encouraged by these initial reports," said Richard Kent, M.D., vice president and director of worldwide clinical research for Glaxo Wellcome (NYSE: GLX). "Larger clinical trials of these compounds in a variety of combinations and in various patient populations are ongoing and we are working as quickly as possible to learn what their optimal role in therapy will be." In a separate poster presentation, scientists reported information on the in vitro, anti-HIV activity of combinations of 1592 and 141. The combination of 1592 and 141 was found to be highly synergistic in this in vitro model reinforcing the rationale for evaluating this combination in clinical studies. 1592 was discovered and is being developed by Glaxo Wellcome. The rights to related technology and compounds used in the manufacture of 1592 resulting from research by Dr. Robert Vince, et al., were licensed to Glaxo Wellcome by the University of Minnesota in 1992. 141, also known as VX-478, was discovered by scientists at Vertex Pharmaceuticals and was subsequently licensed to Glaxo Wellcome for development. Additional Presentations Related to 1592 or 141 -- Additional analyses of a recently reported 12 week dose ranging study of 1592 as monotherapy were conducted to better understand the potential for the development of resistance to this compound. In this dose ranging study, patients were treated for four weeks with either 200 mg, 400 mg, or 600 mg three times, daily, or 300 mg twice daily, as monotherapy, followed by eight weeks of treatment in which either Retrovir(R) (zidovudine; AZT) or placebo was added to their 1592 regimen. Reductions in viral load ranging from 1.5 to 2.2 logs were observed after four weeks of monotherapy with 1592 at the dosing levels studied, as well as average increases of 79 to 127 CD4 cells over baseline. These viral load decreases and CD4 increases were sustained following the eight week add-on portion of the trial. Researchers concluded that the continued suppression of viral load indicated that significant resistance to 1592 had not generally occurred after 12 weeks of therapy. While some patients who received 12 weeks of 1592 alone (add on therapy was placebo) developed resistance mutations, the combination of 1592 with Retrovir appeared to prevent the selection of these mutations over the course of the trial. These data are consistent with in vitro observations which indicate that multiple mutations in HIV reverse transcriptase are required to confer modest reductions in 1592 susceptibility. -- Researchers reported an analysis of HIV genotype and phenotype during four weeks of dose escalating monotherapy with 141. A total of 42 patients enrolled in the study which found a linear correlation between inhibitor plasma trough levels and reduction in viral load. The median maximum changes from baseline calculated for viral load showed a range of 1.95 log reduction to .58 log reduction for the highest dose (1200 mg twice daily) and lowest dose (300 mg twice daily) respectively. Similarly, CD4 cell increases ranged from llO cells/mm3 over baseline in the highest dose group to 64 cells/mm3 over baseline in the lowest dose group. Although a few patients, particularly at lower doses, showed some rebound in viral load at week four, no consistent pattern of drug resistance mutations were observed. Therefore, researchers concluded that the significant antiviral activity, generally good tolerability and favorable dosing regimen (twice daily dosing with no food effect), along with a lack of key resistance mutations arising in early monotherapy make this compound a good candidate for further clinical investigation. --------------------------------------------------------------------------------------------- Copyright © 1999 P\S\L Consulting Group Inc. All rights reserved. Republication or redistribution of P\S\L content is expressly prohibited without the prior written consent of P\S\L. P\S\L shall not be liable for any errors, omissions or delays in this content or any other content on its sites, newsletters or other publications, nor for any decisions or actions taken in reliance on such content. --------------------------------------------------------------------------------------------- This news story was printed from *Doctor's Guide to the Internet* located at http://www.docguide.com --------------------------------------------------------------------------------------- Return to News Story Page This site is maintained by webmaster@pslgroup.com Please contact us with any comments, problems or bugs. All contents Copyright (c) 1998 P\S\L Consulting Group Inc. All rights reserved.