Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 9 - October, 1993
David Gold

Protease is an enzyme on HIV which is required for the virus to reproduce. The protease enzyme cuts newly produced viral precursors separating the final viral elements (such as p24) in preparation for viral assembly. In laboratory tests, when HIV proteins are not processed by the protease enzyme, virions are non-infectious. A number of pharmaceutical companies, including Merck, Hoffmann-LaRoche, Abbott Laboratories, Monsanto Searle, Vertex and Du Pont Merck, are developing HIV protease inhibitor compounds.

According to Merck researchers, L-735, 524 has demonstrated in laboratory tests that it can strongly inhibit replication of HIV. In fact, they believe that the drug is substantially more potent than RO-31-8059, the protease inhibitor currently in clinical trials and being developed by Hoffmann-LaRoche.

It is hoped that L-735, 524 can either prevent or limit the development of viral resistance to HIV. Historically, the development of HIV protease inhibitors has been slowed by difficulties in insuring sufficient oral bioavailability (that is making sure the body absorbs the drug when it is administered by mouth). Apparently, HIV protease inhibitors are a type of modified peptide which the liver usually eliminates from the body. In the words of Merck scientists, the compounds are "difficult to get into to the body and when they do- they usually don't stay around for too long."

A twelve-day safety and pilot study of L-735, 524 began in June 1993 in HIV positive, P-24 positive patients. Eight patients were given 400mg every six hours (q6h). After the dose appeared safe and tolerable, 600mg q6h was given to another four patients for up to four weeks. However, the 600mg dose appeared to cause some increases in bilirubin levels (a bile pigment level that appears in high levels when the liver is inflamed). These four patients were then given the 400mg dose and have continued on that dosage.

In terms of anti viral activity, early data on this very small number of patients indicate that L-735, 524 was able to achieve p24 reductions in the area of 50 percent on all patients, except one (Merck researchers have found no evidence of L-735, 524 in the blood of this one patient, leading them to believe that he/she was not taking the drug on a regular basis).

The reduction in p24 levels is comparable to that sometimes seen with the initiation of AZT therapy. However, Merck scientists hope that, unlike with AZT or the non-nucleoside reverse transriptase inhibitors, viral resistance will not develop or will develop far more slowly. Nevertheless, officials at the company emphasize that "since the information on anti-viral activity comes from only a few patients given drug for only up to eight weeks in total, we are unable to draw any conclusions about the anti viral effect of L-735, 524 except that we have enough information to proceed with the clinical program."[1]

The Phase I trial will enroll 60 HIV-positive, p24 positive, asymptomatic volunteers with CD4 counts of less than 500 at three sites. The sites will be as follows: NYU Medical Center, NYC (contact Mary Ann Kiernan, RN, 212/263-6565), University of Pittsburgh (contact: Nancy Mantz, RN, 412/647- 8125) and University Hospital, Stony Brook (contact Ruth Ann Burk, RN, 516/444-1658).

Participants will be randomized to one of three arms: 1) L- 735, 524-400mg, q6h, 2) L-735, 524-200mg, q6h, and 3) AZT 200mg, every eight hours (q8h). A two week washout of AZT, ddI or ddC will be required.

In the meeting, Merck officials also discussed the cancellation of the company's non-nucleoside reverse transriptase inhibitor, L 697, 661 and progress on the effort to increase collaboration among drug companies involved in AIDS research. In addition, Merck researchers disclosed that they are working on development of protease inhibitors for cytomegalovirus (CMV) and herpes simplex infections.

1. Standby Statement on HIV Protease Inhibitor L-735, 524, Merck & Co., Inc., September 22, 1993.

Copyright (c) 1993 - GMHC Treatment Issues. Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. Direct Dial: v.34+: 714.248.2836; v.120/ISDN: 714.248.0433 Internet: telnet:aegis.com www: www.aegis.com

931001
GM070903

Copyright © 1993 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011  fredg@gmhc.org  http://www.gmhc.org

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2003. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2003. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .