Tat Inhibitor Trials Cancelled; Business Reasons Cited

In a serious setback to AIDS treatment development, Hoffmann-La Roche Inc. indefinitely postponed trials of its tat inhibitor (code named RO 24-7429), the only such drug in development. Researchers at Johns Hopkins University in Baltimore, where the trial was about to begin, were described as shocked by the news, which they received by phone on April 29. Hoffmann-La Roche has issued no written statement about the decision, which has received almost no media coverage.

The Johns Hopkins team, probably the world's experts on the drug since they conducted preclinical studies and a small single-dose human trial there, are reluctant to speak publicly but have insisted that there was no medical or scientific reason to stop the trial. Paul Oestreicher, Ph.D., spokesperson for Hoffmann-La Roche, also acknowledged that there was no scientific reason to stop the trial. He said the company decided that, after a review of its entire antiviral program, it will pursue the development of ddC and a protease inhibitor while it "aggressively" seeks a partner (another pharmaceutical company) to continue tat antagonist development. Dr. Oestreicher said that Hoffmann-La Roche is open to a wide range of potential business arrangements (to continue development of the potential tat drug), including co-development or licensing.

Importance of the Drug

The Hoffmann-La Roche tat inhibitor is the only drug developed with its mode of action -- interfering with the protein produced by the tat gene of HIV, which is essential for viral replication. Since this drug could potentially offer a new kind of therapeutic alternative, it may increase the treatment options available, and also provide an excellent candidate for use in combination therapy.

The drug is also important because researchers believe that a successful tat inhibitor would have specific action against KS (Kaposi's sarcoma), besides its anti-HIV effect. In addition, Johns Hopkins researchers had previously discovered that the tat protein causes immune suppression in laboratory cell cultures, similar to the immune suppression seen in AIDS; they published this finding in Science, December 22, 1989.

An effective tat inhibitor would also have a unique business advantage -- one reason researchers thought Hoffmann-La Roche was especially interested in this drug. If such a drug is effective against KS, then it could bypass the unworkable HIV-drug pipeline full of other antivirals waiting to be compared to AZT. It could be approved as a KS treatment without such comparison, and then physicians could also use it "off label" for treating HIV in patients without KS. Such a drug might become a standard AIDS therapy before its rivals get approved, giving it a momentum hard for other drugs to overcome. (There are efforts to clear the drugjam, through proposals such as surrogate markers, or conditional approval. But the acceptance of these reforms is not assured.)

Background

"Tat" (an abbreviation for "transactivator") is a gene in HIV. This gene produces a protein which turns on other HIV genes, greatly increasing the activity of the virus. Without tat, HIV is largely or totally inactive. The Hoffmann-La Roche drug is believed to stop this protein from working.

Some researchers have questioned whether the Hoffmann-La Roche drug is really a tat inhibitor. It is a benzodiazepine derivative, chemically similar to other potential AIDS drugs (such as Merck's L-661, or Boehringer Ingelheim's BI-RG-587) which inhibit reverse transcriptase, not tat; therefore, it is possible that this drug could be effective against HIV by other than the tat mechanism. If so, it might still be an important AIDS drug, but without the unique advantages of a tat inhibitor. Some people suspect that Hoffmann-La Roche may have stopped the trial because of doubts about whether the drug is in fact a tat inhibitor. (We consider it doubtful that Hoffmann-La Roche would have made a mistake about the mechanism of action, since methods for testing tat activity have been published, and only persons working with the company, not the skeptics on this issue, have full access to the laboratory test results.)

The tat protein is also believed to have a major role in the development of KS; it could not be the sole cause, however, as KS can develop without HIV. A human trial of the drug as a KS treatment had been discussed for next autumn in Los Angeles.

The reason the KS trial had been scheduled to start later than the HIV trial was to allow an animal test first -- an attempt to treat human KS in mice. But the animal study could not be run because the mice had not developed KS yet. Only the laboratory of Robert Gallo, M. D., at the U. S. National Cancer Institute, has been known to have the KS mouse model, which it first reported some years ago. Apparently Hoffmann-La Roche decided to redevelop this model elsewhere.

Comment

For months there has been concern among some AIDS treatment activists that Hoffmann-La Roche might pull out of its new- generation AIDS drug development if ddC proved unexpectedly difficult or expensive. The company now has over 3,000 people on its expanded-access ddC program -- which is costly because of the labor and record-keeping involved, even though the drug itself costs almost nothing. (In addition, about two thousand people may be using "underground" ddC obtained from chemical-industry sources, where ddC has been available for years.) The drug is not especially attractive as a single therapy, but it is an important option for thousands of persons who cannot successfully use AZT.

The expanded-access program originally required paperwork burdensome enough that many physicians could not enroll their patients, because they did not have the time required to fill out the forms. The paperwork burden led to a boycott against Hoffmann-La Roche, first approved by ACT UP/New York on February 11, 1991. The boycott had largely been settled before the tat drug trials were stopped, as the paperwork problems had eased; and Hoffmann-La Roche claims that it had no effect on the company's business. But such boycotts, if supported by the medical community, can be a serious threat to pharmaceutical companies, because hospital, laboratory, and other medical personnel can divert millions of dollars of business to competitors, in cases where equivalent products are available. ACT UP/New York had distributed detailed boycott packets, and claimed that hundreds of physicians were refusing to prescribe Hoffmann-La Roche pharmaceuticals or laboratory services. (One unpublished advertisement, professionally prepared for medical
journals and sent to the company by ACT UP/New York, shows a morgue with two sheet-covered bodies, under the headline, "Thanks to Roche, a lot of people with AIDS don't have it anymore.")

We cannot read the minds of Hoffmann-La Roche executives, but it is hard to see how stopping the Johns Hopkins trial now would make business sense if the company wanted to find a partner to develop the product. The drug, if it works, would have much greater value after the study than before, because this trial would have produced the first human efficacy information ever for this drug. (We asked Dr. Oestreicher about this, and he replied that the trial was stopped now to allow the partner a role in designing new studies.)

Another reason in favor of continuing was the ethical issue of stopping a trial for business reasons after the sponsor had already given the drug for the first time to volunteers, who had therefore undergone the risk of taking a new chemical never given to humans before. (It is our understanding that no efficacy information was collected from this earlier single-dose study.)

Yet stopping the trial now would make business sense if the purpose was to avoid being pressured into another expanded-access program, with its resulting expense and possible threat to non- AIDS-related products. Without a trial, the data to support the public demand for such a program will never come into existence. Unfortunately, if this scenario is correct, then the prognosis for continuing the trial by finding a future partner is not good -- unless responsibility could be transferred to an entity willing to finance such a program, or to one clearly unable to do so. Since such business negotiations are almost always secret, the public will not know what is happening with a drug on which, in the future, thousands of lives may depend.

This case illustrates the long-range problem of disincentives to pharmaceutical companies built into the current system of clinical trials. Once companies begin trials, they may incur millions of dollars in costs, which they might never recover. The tat inhibitor is unusual in that development was stopped so late, for a unique and potentially valuable drug. Other drugs which would have been developed, if the disincentives were not so severe, never get out of the laboratory, and we do not hear about them.

At this time there seems to be little chance to convince Hoffmann-La Roche to continue the trial, not even to fill the gap until an acceptable partner is found. It might be possible for the AIDS community to help in locating a potential partner.

Meanwhile, what AIDS TREATMENT NEWS can do is to make available all information we can find about this drug. Persons associated with the project have become even more secretive since the trial was cancelled than they had been before. We would like to hear from anyone with information about this drug, the research so far, the cancellation of the trials, or medical or scientific reaction to the cancellation. Anyone willing to talk on or off the record, or who knows someone who might, could call John S. James at 415/255-0588, or write to AIDS TREATMENT NEWS, Attn.: tat, P. O. Box 411256, San Francisco, CA 94141.

Acknowledgement: Garey Lambert, reporter for the Baltimore Alternative, provided major assistance with this article.