AIDS Antivirals: A New Generation

Advances in understanding the life cycle of HIV have quietly led to the development of many potential "designer drugs" for treating HIV disease. Several of the new drugs are now beginning human trials. Because of the advances they represent, we believe there is more hope now than ever before for improvements in AIDS treatment. But optimism should remain cautious, because there have been many disappointments in the past.

At least five of the new drugs have already been given to humans in early tests:

* L-697,661 and L-697,639 (sometimes called the "L- drugs"), developed by Merck & Co. These drugs are of a class called non- nucleoside-analog reverse-transcriptase inhibitors. (This means that they block the viral enzyme reverse transcriptase, but -- unlike AZT, ddC, and ddI -- they are not nucleoside analogs; hopefully they can avoid the toxicity which may be inherent in that class of drugs.) L-697,661 is now recruiting for phase II trials at the National Institutes of Health, near Washington, DC, and also at the University of Alabama in Birmingham (see announcement below).

* A Hoffmann-La Roche tat inhibitor (drug which blocks the protein produced by the tat gene of HIV). Without the tat protein, HIV becomes inactive. This drug is now beginning human trials at Johns Hopkins in Baltimore; we do not have details at this time. Later, the drug may also be tested for specific activity against KS (Kaposi's sarcoma).

* BI-RG-587, being developed by Boehringer Ingelheim Pharmaceuticals, Inc. There has been much interest in this drug since publication of laboratory results in Science, December 7, 1990 (see AIDS TREATMENT NEWS #21, December 21, 1990). Unfortunately, it has recently been learned that there is less human experience to date than had been widely assumed (see BI- RG-587 article, below).

* At least one and probably two companies have conducted early human tests of protease inhibitors (which block another enzyme which is necessary for HIV). Little information is available at this time.

Many other new antivirals have been created by pharmaceutical companies. Some have not reached human testing yet; others are not being actively developed, sometimes because they seem to have no advantage over other drugs ahead of them in the development and regulatory pipeline.

What is notable about these antivirals is that the researchers familiar with them are convinced that they probably will work. Laboratory and animal testing has shown that they do stop the virus, they do get absorbed and into cells where they are needed, and they are nontoxic in animals. The main questions to be answered are whether there is any unexpected toxicity or other problem with human use; and of course doctors need to learn the best ways to use each drug in practice -- dose, schedule, combinations with other antivirals, possible problems with viral resistance, etc.

None of the new drugs is expected to cure AIDS; as with AZT, treatment will have to be continued indefinitely. And no matter how good a drug looks in theory, no one can be sure that it will work until it has proven effective in human use.

One reason for caution is that the last time the research community expressed similar optimism about a new drug -- soluble CD4 -- that drug turned out to be worthless as a treatment. The current situation, however, is different in several ways. The case for soluble CD4 was based largely on theory; for it to work in the body, many things had to happen, and some of them could not readily be tested in advance. By contrast, the mechanism of action of the new drugs is better understood, and more suitable to laboratory and animal tests.

In addition, many new antivirals are now being created, and most of them are very different from each other. Any problem found with one is unlikely to also affect the others. If even one drug works as expected, the result will be a major improvement in treatment for HIV, compared with the current therapy with AZT alone.

Which of the new drugs looks best at this time? It is impossible to tell, because most of the data is secret; even if it were available, only rough and uncertain comparisons could be made from the laboratory and animal results. For the AIDS community, the most important ones now are those which are moving fastest into human trials and (if warranted) FDA approval. By this measure, Merck's L-697,661 is now ahead.

The current system for approval of new drugs by the FDA (which controls how drugs are developed by pharmaceutical companies) is grossly unsuited to the needs of the current situation -- a fact which will increasingly become a public issue. Some of the main problems:

* The current focus is on proving efficacy -- which is not the central issue with the new antivirals. Unless endpoints other than death or disease progression are accepted as good enough for drug approval, years will be wasted arranging for enough people in trials to sicken or die on AZT to provide statistical proof that a new drug works better.

* Combination therapies will almost certainly be better than single drugs for HIV treatment. But combinations are not tested until late in the development process, because the FDA wants proof of single-drug efficacy first, and also because pharmaceutical companies are reluctant to cooperate in testing their rivals' products.

* Major problems can also arise in getting the large organizations involved -- pharmaceutical company, FDA, and often NIH as well -- to work together effectively. There has been little national planning and coordination to see that such problems are worked out.

* Notorious shortages of staff, facilities, and money at the FDA prevent that agency from doing its work efficiently. For example, NDA (New Drug Application) documents are delivered to the FDA in boxes, by truck, because the FDA does not have appropriate computers -- making data analysis very costly in staff time. Pharmaceutical companies would gladly help provide the tools needed, but that would raise issues of control. Apparently the FDA wants to develop the needed systems itself -- a commendable intention, but without resources, little will happen and the current deadlocks will remain.

These are some of the practical problems that will determine how soon the new drugs are tested and made available to those who need them.

AIDS TREATMENT NEWS will focus increasingly on the new generation of antivirals, including those listed above, as more news becomes available. Meanwhile, we will continue to cover what we believe are the most promising of the older treatments -- such as the AZT/ddC (or ddI) combination, or hypericin -- as well as other treatment news of interest to the community.