Being Alive Newsletter - March 1999
Chris Griffin

Presentations at the Retrovirus Conference in Chicago last month focused on the ongoing development and testing of relatively new compounds. These included studies of drugs in the protease inhibitor class-(ABT-378 and AG-1776)-and in the NNRTI (non-nucleoside reverse transcriptase inhibitor) class-(AG-1549 and DMP-961/DMP-963). Of all these new drugs, only Abbot's ABT-378, which has been anticipated for some time, has been investigated in clinical trials.

Novel Protease Inhibitors

ABT-378 (Abbott Labs). This drug has been expected for some time to be one of the most powerful protease inhibitors developed so far. At the time of last year's Conference it had been tested only in vitro (in test tube) and in rats; in those tests it was shown to be ten times more potent than ritonavir (Norvir).

A year later we have the results of human clinical trials of ABT-378. One group of researchers presented the results of a study involving 101 patients who had never taken any anti-retrovirals prior to the start of the trial. These people received 24 weeks of ABT-378 (200 or 400 mg BID) in combination with low dose ritonavir (100 or 200 mg BID) and d4T/3TC.

At entry, patients had a median viral load of approximately 70 000 and CD4 of approximately 350. At 24 weeks, HIV in more than 90% of these participants was undetectable. CD4 cells increased by about 160 cells. Furthermore, side effects were few and no patient discontinued from study due to ABT-378 side effects. This is the lead product in a group of second generation protease inhibitors with apparently little cross-resistance to the first generation of PIs.

Abbott reports that ABT-378 has a synergistic effect when used with ritonavir. Resistance profiles suggest that people with extensive exposure to previous PIs should remain at least partially sensitive to ABT-378, and people previously treated with saquinavir should remain wholly sensitive.

AG-1776 (Agouron Pharmaceuticals).

Data from in vitro studies of AG-1776 were presented at the Conference. This novel protease inhibitor shows activity comparable to other potent PIs and is active against all strains of HIV, including HIV-2. It appears highly synergistic with ritonavir (Norvir), indinavir (Crixivan) and nelfinavir (Viracept). One study showed that all strains of HIV had remarkable susceptibility to AG-1776, suggesting minimal cross-resistance with other PIs. Clinical trials are planned soon.

A New NRTI (Nucleoside Reverse Transcriptase Inhibitor) FTC.

Dr. J. Delehanty reported on an experimental nrti called FTC. Triangle Pharmaceuticals is developing this drug that is similar to, but more potent than, Epivir (3TC). FTC will be able to have a dosing of once daily. Results of a Phase I/II study indicate that a dose of 200 mg will be used.

New NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors) AG-1549. In vitro studies of AG-1549 demonstrate that this novel NNRTI shows minimal cross-resistance to other nnrtis.

DMP-961 and DMP-963.

Researchers presented results from in vitro studies of two other candidate NNRTI compounds-DMP-961 and DMP-963. These new compounds similarly showed excellent activity, specifically against resistant virus. In addition, each of these two drugs has a prolonged half-life, meaning they would remain active in the blood stream for a substantial period of time, increasing the likelihood of ease of administration.

A New Fusion Inhibitor

T-20. Last year we reported on a promising new approach to the attack on HIV: a drug called T-20 (pentafusamide), a fusion inhibitor developed by a company called Trimeris, Inc. This genetically-engineered peptide is designed to target a specific step in the process by which HIV attaches to cells in the course of infecting that cell. A year ago it had already been shown to reduce viral load substantially, and it was not expected to have cross-resistance with our current batch of treatments. Therefore, T-20 was hoped to be highly effective in people who had been heavily treated with HAART and were experiencing drug failure and viral rebound.

This year's Conference included the results of clinical human studies of T-20, and indeed its earlier promise was borne out. T-20 was shown to produce a dramatic and profound reduction of viral load. In a Phase II clinical trial, T-20, which uses a novel mechanism to inhibit HIV, was given to 78 HIV+ people for 28 days.

Patients who received the higher doses of T-20 experienced a 90% reduction in viral load, according to Dr. Joseph Eron of the University of North Carolina at Chapel Hill. Calling the findings "impressive," he pointed out that the average number of anti-HIV medications that had not worked for the patients in the trial was nine, including an average of three protease inhibitors. He also noted that the subjects' average baseline viral load was 100 000 copies, which is a "difficult hurdle for any drug when administered as a single agent."

Only 3% of patients had to discontinue the drug. Most patients developed a mild-to-moderate skin irritation at the site of the injection or infusion.

(One disappointing note: after several weeks on monotherapy many people experienced a rebound of viral load; therefore, researchers have concluded that T-20 will probably have to be used in combination with other anti-HIV agents.)

Last year we said that this drug may not be especially practical for anyone other than those with literally no other options, because it was expected to be given by continuous intravenous infusion. In early clinical trials it was administered via a small computerized pump with a flexible catheter, something used successfully in diabetes treatment. But more recently it has been administered also as a sub-cutaneous (under the skin) injection, which most people found more acceptable.

"An unexpected positive outcome from this trial was the demonstration that twice-daily injections may be a feasible method to deliver T-20 on a chronic basis," Dr. M. Ross Johnson, Trimeris CEO, commented. Targeted levels of T-20 were obtained and sustained using the twice-daily injection method, which "expands our options for administering T-20," Dr. Johnson concluded.

Trimeris announced recently that it had secured fast-track status from the Food and Drug Administration for T-20. The FDA grants fast track status, an expedited approval process, for a drug that could significantly improve treatment for a serious or life-threatening disease.

Other Drugs Under Investigation

Several other drugs that are in the earliest stages of investigation were mentioned at the Conference. These include:

**other fusion (or entry) inhibitors: AR 177 (zintevir), AMD-3100, FP-21399, and PRO542;

**new NRTIs (nucleoside reverse transcriptase inhibitors): BCH-10652 and DFC;

**new NNRTIs: GW420867x and Calanolide B; a new protease inhibitor: BMS-232632 (once daily dosing likely).

In Conclusion

It is heartening that new compounds are now arriving in early clinical and pre-clinical studies that offer ease of administration, few side effects, and little cross-resistance to current agents. It may be too early to adequately assess the promise of these drugs: it remains to be seen whether they will bear out their promise once they are administered to large numbers of patients. But there's little doubt a once meager anti-HIV arsenal is expanding at a pace that makes a vision of AIDS as chronic and manageable rather than life-threatening as realistic as has been wished.

990310
BA990303

ÆGIS is made possible through unrestricted grants from Roxane Laboratories, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

Copyright © 1999 - Being Alive. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. Subscription lists are kept confidential. Being Alive, 621 N. San Vicente Blvd., West Hollywood, CA 90069 TEL: 310.289.2551; FAX: 310.289.9866; Email: BeiAlive@aol.com  http://www.beingalivela.org/