Gay Men's Health Crisis: Treatment Issues - Volume 5 no. 4, May 15, 1991
Garance Franke-Ruta

New Approaches

Several new and exciting approaches to inhibiting HIV are now under observation. For example, drugs called protease inhibitors are in development by a number of firms, including Hoffmann-La Roche, Smith-Kline Beecham, Upjohn, Abbott, Lilly Research Labs, and Merck, Sharpe and Dohme.

Roche Products has begun the first human trial of a protease inhibitor in England in order to examine the pharmacology of the drug. Protease inhibitors have a different target on HIV during the HIV-replication cycle, than other antiviral drugs. Nucleoside Analogues (AZT, ddI and ddC) function by stopping HIV from copying its genetic information onto that of the cell it has infected. This action then stops the virus from reproducing within the new cells it has infected.

Protease inhibitors -- instead of interrupting HIV when it first invades a healthy cell -- interrupt a later stage of the HIV production cycle. More specifically, protease inhibitors interefere with certain natural cell substances, called enzymes, which tailor-make the precursor virus particles that form new HIV.

Other drugs aim at specific genes of HIV. These genes have a variety of functions. One, called the tat gene, plays an important role in controlling reproduction of HIV [1]. New drugs that inhibit tat are under investigation by Hoffman-La Roche and competitor company, Smith Kline and French. The Hoffmann-La Roche tat inhibitor recently completed a phase I nine-person, single-dose safety study at Johns Hopkins University in Baltimore, Maryland. Further trials have been "put on hold," while Hoffmann-La Roche "aggressively seeks a partner company" to co-sponsor further multiple dose studies, said Paul Oestreicher, a company representative. The decision is financial and not based on scientific data. In the meantime, Hoffmann-La Roche is committed and moving ahead on ddC and protease inhibitor development, he said.

Other novel approaches to treating HIV have also caught fire recently. Drugs, prescribed for distinct medical conditions, such as N-acetylcysteine (NAC), an inexpensive, relatively non-toxic medication routinely used to treat bronchitis, and pentoxifylline, prescribed for people with poor blood circulation to the legs, are finally receiving serious consideration. Both these agents work by mediating the effects of a protein, called tumor necrosis factor (TNF). This particular protein is elevated in many people with HIV. TNF is believed to increase production of HIV, antagonize the affects of AZT and may be linked to wasting syndrome by stimulating the breakdown of fat.

What's in a Name?

Two new drugs which inhibit HIV at the same stage, but in a different manner as AZT, have entered Phase I testing. These drugs block the action of an enzyme called reverse transcriptase (RT) which helps the virus copy its own genetic material into the mechanism of the cell it has infected, in order to make more virus. Infected cells are transformed into virtual "virus factories." Without the RT enzyme, HIV cannot infect new cells. These new reverse transcriptase inhibitors agents are BIRG (made by Boehringer Ingelheim) and the so-called "L" drugs -- L-679,639 and L-679,661 (made by Merck, Sharpe and Dohme). The rest of this article will focus on these drugs.

The "Boehringer Drug"

BIRG inhibits HIV in the test tube, and shows little toxicity against uninfected human cells at up to 8,000 times the dose necessary to inhibit HIV [2]. The majority of BIRG's antiviral activity appears to be dependent on its ability to inhibit RT. BIRG shows activity against HIV-1 only, but not against HIV-2. BIRG also does not appear to have activity against SIV or FeLV, two viruses found in monkeys and felines, respectively, which are often used as models for HIV. Several other human, viral, and animal enzymes are also unaffected by the drug.

In the test tube, Dr. Douglas Richman has found that BIRG has anti-HIV activity in blood taken from patients who have developed resistance to AZT. In addition, there appears to be a synergistic effect in the test tube when AZT and BIRG are used together. In other words, AZT and BIRG have a stronger anti-HIV effect together than each drug has when used singly.

In monkeys and chimpanzees, an oral form of the drug was well absorbed. BIRG has a half-life in animals of over 24 hours (it takes more that 24 hours for half of the drug administered to clear from the bloodstream). Its long half-life means that frequent dosing will probably not be necessary. Other animal studies using oral administration indicate that the drug can effectively reach the brain, an important consideration in patient's with HIV dementia.

BIRG is a derivative from a class of drugs called benzodiazepines, drugs used to treat anxiety, like Valium. Studies in mice have shown that BIRG does increase sleeping. Because of these promising test tube and animal studies, BIRG received a disproportionate amount of media attention in the fall of 1990. The excitement can be attributed in part to the fact that the drug appears to be relatively specific, as compared to nucleoside analogues, like AZT, ddI and ddC. This fact means that BIRG could be less toxic.

Now, five months later, the phase I single-dose study has been completed, and the phase II protocols are under review. BIRG will have to be studied in a phase I trial that looks at longer-term dosing before it can be moved into the comparative or pediatric study trials planned through the ACTG.

Plans for future trials of BIRG include two studies through the AIDS Clincial Trials Group (ACTG). ACTG trial 164 will be an open-label (participants will know what and how much drug they are recieving), dose-escalating study of BIRG alone, or in combination with AZT. The trial is for HIV-infected people with T4 counts under 400, and will seek to enroll 72 people. Trial 164 will determine the safety and tolerance of BIRG, as well as the compound's antiviral activity.

A pediatric study is also planned for BIRG. ACTG trial 165 will be an open-label study of single, increasing doses of the compound in children with symptomatic HIV infection. Boehringer Ingelheim has made a commitment to develop the drug in children and adults at the same time. Usually adult studies are completed before the initiation of pediatric trials.

Late-breaking reports reveal that no more than twelve people have yet received BIRG in single doses. A comparison study with AZT has not yet been started, because a safety study is needed first, and development seems to be going slowly. For more information see AIDS Treatment News Issue 125.

History of the Drugs Called "L"

Merck took the AIDS communities by surprise with the initiation of trials in the U.S. of the so-called "L" drugs. As it turns out, Merck had been working on AIDS research since 1986. The company has focused on the development of antiviral agents, as well as a vaccine to prevent HIV infection, in collaboration with a company called Repligen.

In 1989, Merck researchers noted that one of the compounds from their laboratory had significant activity against the RT enzyme of HIV-1. This discovery came after two years of screening approximately 23,000 compounds. Versions of the anti-HIV compound which would make the best drug candidates were then synthesized.

Two promising compounds, L-697,639 and L-697,661, were synthesized in April 1990. The compounds were tested against multiple T-cell lines and human peripheral blood lymphocytes. According to the "informed consent" for one of the phase I studies (a document which explains the pros and cons of the trial to participants), "Animal testing (primarily in rats and monkeys) with L-697,639 has revealed that the drug appears to be generally well tolerated and safe over a broad range of dosing, although certain mild toxicities have been identified." The toxicities are mild elevations of certain liver enzymes and injury to some cells of the liver [3].

No other serious toxicities have yet been identified during extensive testing with this drug. The data from animal and test tube studies has been submitted for publication.

Later in 1990, Merck conducted phase I safety trials at undisclosed sites in Europe whcich enrolled approximately 40 HIV-negative, paid volunteers. Some of these volunteers were on drug for as long as ten days. According to the pharmaceutical company, the preliminary studies indicated that the two "L" drugs were well-tolerated over this short period of time. Long-term toxicities are still unknown.

In December of 1990, Merck opened a phase I study of L-697,639 at the National Institutes of Health (NIH) in Bethesda, Maryland. This trial examined absorption of the drug in the body and side effects in 24 asymptomatic people with T4 counts over 500. It looked at the absorption of single-doses of oral drug. However, L-697,639 had poor absorption and distribution of the drug to body tissue. Further study of this particular compound is not anticipated.

Phase I testing of another L drug, "L-679,661", began in February to examine the saftey and absorption of single-doses of the drug. Sixteen asymptomatic HIV-positive people with T4 counts over 500 were enrolled. Doses ranged from 25 mg to 500 mg. Preliminary results of these studies showed no significant toxicities. The drug was well absorbed.

L-679,661 was selected as a candidate for further studies. Phase II, double-blind, placebo-control trials are already underway. These phase II trials are being conducted at two sites -- the National Institute of Allergy and infectious Disease (NIAID) at the NIH in Maryland and the University of Alabama at Birmingham (UAB). The trials will seek to collect initial information on how well the drug works. The NIAID study at the NIH is for people with T4 counts over 200.

Thirteen patients have already enrolled, and the study plans to recruit a total of 75 participants. The trial consists of five arms: one group of participants will receive 25 mg of drug twice a day; another will receive 100 mg of drug three times a day; the third group will receive 500 mg of drug twice a day. The fourth group will receive 500 mg of AZT alone, and the last group of participants will receive only placebo. After 12 weeks of the trial, those participants receiving AZt alone or placebo will be randomized to receive one of the doses of the "L"-drug. Participants are being informed in the informed consent that they may receive placebo for twelve weeks, which is sub-standard treatment. The UAB study contains an arm for people with T4 counts under 200, and no placebo will be used.

Discussions among Merck, the NIH, and the AIDS Clinical Trials Group have been initiated regarding pediatric trial. It is hoped that such trials will begin this summer, when further information about the drug is available. Also on the discussion table is larger-scale adult trial.

For more information about the NIAID trial call 1-800-772-5464. The contacts are Donna O'Neill at ext. 312, Susan Haneiwich at ext. 403, and Marilyn Decker at ext. 306. Due to a large number of interested parties, enrollment into the UAB trial will be prioritized according to previous involvement in other UAB trials and regional proximity. For more information call (205) 934-9999.

Conclusion

If history is any indication, these drugs have a long journey ahead of them. But there are indications that at least Merck is moving full speed ahead. People anxiously await trial results and, ultimately, access to these drugs, if they prove efficacious. At this point, the only way to try these drugs is by enrolling in a clinical trial.

Treatment Issues has heard reports that efforts are being made to create bootleg copies of the new RT inhibitors. Potential users of these products should bear in mind that there is no solid information about their efficacy, long-term safety, or interactions other drugs often used by PWAs.

References:

1. Rosen CA et al. Tat and Rev: positive regulators of HIV gene expression. AIDS 4(6):499-509, 1990. 2. Merluzzi VJ et al. Inhibition by a non-nucleoside reverse transcriptase inhibitor. Science 250:1411-1413, 1990. 3. L-drug Informed Consent Form, 1991.

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