Published in the Bulletin of Experimental Treatments for AIDS April 1999 issue, by the San Francisco AIDS Foundation.

April 1999 Table of Contents

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New Anti-HIV Drugs in Development

By Liz Highleyman

What's Happening in the Research Pipeline?  

In the past three years several new anti-HIV drugs have been approved by the Food and Drug Administration (FDA), including drugs belonging to two new classes, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors. This flurry of approvals followed a period of intensive research in the mid-1990s during which few new drugs were placed on the market.  

The cycle appears to have shifted once again. Glaxo Wellcome's new protease inhibitor, amprenavir (Agenerase), just received FDA approval on April 15, 1999; only one other drug is expected to receive approval in the coming months--adefovir dipivoxil (Preveon), Gilead Science's nucleotide analog.

Still, several new compounds are in earlier stages of laboratory and clinical testing. This may shift the focus of HIV positive people and their advocates once again toward clinical trials, as they seek new drugs without the side effects, interactions, resistance problems, and inconvenience of existing anti-HIV therapies. (See two related articles in this issue, "Current Challenges to HIV Research" and "Volunteering for Clinical Trials".)

The following is a brief summary of new compounds currently undergoing testing. Results from early studies of these drugs have been presented at medical conferences during the past year. The following by no means constitutes an exhaustive list of all new anti-HIV drugs in development. 

The Next Nucleosides  

These days less research is devoted to developing new nucleoside analogs. However, there is a place for new drugs in this class, especially for people whose HIV is resistant to existing members of the class. 

One new drug that bears watching is BCH10652, also known as dOTC. This drug is a cytidine analog and is related to 3TC. A phase I study reported at the 6th Conference on Retroviruses and Opportunistic Infections (CROI) this past February showed that BCH10652 is active against HIV in vitro and appears to have some efficacy against 3TC-resistant strains. Based on pharmacokinetic results, once-daily dosing should be possible.  

PZT is a phosphonated nucleoside analog that is structurally related to AZT. A phase I/II study in Russia of 42 treatment-naive participants showed that the drug's anti-HIV activity is similar to AZT's, but its side effects appear to be milder.   

Numerous New NNRTIs  

NNRTIs are well represented among new drugs in development. At the 12th World AIDS Conference last summer in Geneva, results were presented on S1153, an experimental new NNRTI that was subsequently purchased by Agouron and renamed AG1549. A phase I trial tested seven different doses of the drug in 54 participants who were taking no other antiretroviral therapy. Researchers reported that the drug has good bioavailability and anti-HIV activity ten times greater than that of nevirapine or delavirdine. Two or more mutations may be needed to confer resistance to AG1549.

Results reported at the February CROI indicate that AG1549 is active against HIV, including some strains that have single NNRTI-resistance mutations, and somewhat active against strains that have two or three NNRTI-resistance mutations.

Reports were presented at the same conference on two new NNRTIs from DuPont Pharmaceuticals, DMP961 (also known as DPC961) and DMP963 (DPC963). These drugs have an anti-HIV potency similar to that of efavirenz (Sustiva) in laboratory studies, and they appear active against HIV strains with some NNRTI-resistance mutations, and somewhat active against HIV strains with two resistance mutations. Pharmacokinetic studies in monkeys indicate that the compounds have good bioavailability.  

Another CROI study reported by researchers from Pharmacia & Upjohn showed that the company's new NNRTI, PNU142721, is effective in vitro against some strains of HIV that are resistant to existing drugs in its class.  Glaxo Wellcome's GW420867X has shown activity against HIV in early studies. It has good bioavailability that should allow once-daily dosing. The drug's in vitro resistance profile appears similar to that of efavirenz. Also like efavirenz, the drug's side effects include vivid dreams. GW420867X is the successor to Hoechst-Bayer's related compound HBY097, which is no longer being developed.  

Triangle Pharmaceuticals' new NNRTI, MKC442, has shown anti-HIV activity in adults in early clinical trials. Researchers presented results of reproductive and developmental studies at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this past September. Birth defects including anencephaly (defective brain development) were seen in a small number of infant monkeys whose mothers took the drug. No adverse fetal effects were reported in rats or mice given the drug, although birth weights were lower than normal.  

Another new NNRTI that bears watching is calanolide A.

Protease in the Pipeline  

Researchers presented results at CROI of early laboratory and clinical studies of Agouron's second-generation protease inhibitor, AG1776. The drug showed activity both in vitro and in vivo against several strains of HIV. In laboratory studies, AG1776 appears effective against some HIV strains that have mutations that would likely make them resistant to indinavir, nelfinavir, and/or other approved protease inhibitors.  

At both ICAAC and CROI, reports were presented on Bristol-Myers Squibb's new compound, BMS232632. This protease inhibitor appears more potent in laboratory studies than currently approved drugs in its class. In randomized clinical trials of HIV negative volunteers who were given doses of 100-1,200 mg daily, the drug was well tolerated and had good oral bioavailability, which may allow for once-daily dosing.

However, the drug appears to have considerable cross-resistance with other protease inhibitors.  In January Merck and Company announced that it will soon initiate clinical trials of its second-generation protease inhibitor, which it did not identify by name. The company hopes that the new drug will have a less complex regimen--preferably once daily without food requirements--than its currently approved protease inhibitor, indinavir (Crixivan), which must be taken three times daily on an empty stomach or with a fat-free snack.

Is Fusion the Future?  

All currently approved anti-HIV drugs inhibit one of two HIV enzymes, reverse transcriptase (the nucleoside analogs and NNRTIs) or protease (the protease inhibitors). Several pipeline drugs are aimed at novel targets; most notable are a new class of drugs called fusion inhibitors. Fusion inhibitors interfere with the binding of HIV to a host cell, the first step in infection. The first fusion inhibitor, Trimeris' T-20, is already well along in clinical studies (see BETA, January 1999).  

Trimeris is also developing a second fusion inhibitor based on a conserved region of HIV called peptide 2. The new compound blocks fusion of HIV with the envelope of the host cell. The peptide 2 drug has been shown in laboratory tests to be active against several strains of HIV, including one that is resistant to T-20. In tests using mice, the drug blocked infection of several different types of cell. 

At the February CROI a poster report was presented on another candidate fusion inhibitor, PRO542. This agent is a genetically engineered form of a human antibody. Researchers hope that it can inhibit HIV infection by blocking host cell receptors.

In early clinical studies, PRO542 appears to be well tolerated; like T-20, it must be given by injection.  Certain strains of HIV must bind with the host cell's CXCR4 co-receptors to gain entry into the cells. Met-SDF1 is a modified form of SDF1, a human molecule that naturally binds with CXCR4. By binding with CXCR4, the modified met-SDF1 prevents the receptor from binding with HIV. The compound has shown some anti-HIV activity in laboratory studies.  

Finally, there are several other fusion or entry inhibitors in early stages of development. AMD-3100, which was reported on at CROI and at the World AIDS Conference, is a member of a new class of agents called bicyclams, which also block the CXCR4 co-receptor. The drug was studied in 12 HIV negative persons, and appears to be well tolerated. Not surprisingly, AMD-3100 is only active against so-called "T-tropic" strains of HIV, which use the CXCR4 co-receptor ("M-tropic" strains use a different co-receptor called CCR5). 

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DeClerq, E. Bicyclams: a class of highly potent anti-HIV drugs that block viral entry into the cell at the chemokine receptor CXCR4. Antiviral Therapy 3 (Suppl. 5): 13. 1998.

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Page last updated 1 June 1999