COMPOUND Q UPDATE

Our previous issue included a last-minute report on a so-called "unofficial study" of Compound Q -- actually a treatment program and data monitoring project -- organized by San Francisco's Project Inform and including over 30 patients and nine physicians in four U.S. cities (San Francisco, Los Angeles, New York, and Miami/Ft. Lauderdale), using a version of the drug which is in common use in China. Probably no single story in the AIDS epidemic has generated as much coverage in San Francisco's major daily newspapers, the San Francisco Chronicle and San Francisco Examiner. Some of the information released by the San Francisco press is available nowhere else. Local press coverage has been even-handed and mostly sympathetic, despite vociferous opposition from some researchers in the official Compound Q study at San Francisco General Hospital. (A spokesperson for the California Medical Association took a middle position, describing the doctors involved as "respected physicians in the community working desperately to provide effective treatment and care," but expressing serious concern about phase I -- dosage or safety -- studies being conducted outside of a university medical center).

We believe that a loud debate "for" or "against" the unofficial study would be unproductive, the wrong issue for furthering the common fight against AIDS. The better question is what can we learn from this extraordinary response to an extraordinary situation. What can we learn about the drug, and also about how to improve the official system of authorized research, to get faster and better answers not only for AIDS but for other diseases as well?

Project Inform and others involved in this treatment program want to wait until it is finished, probably 30 to 60 days, to make a full report. This article is based on news already released but not widely available outside the San Francisco area.

Background

AIDS TREATMENT NEWS covered Compound Q in its issues of January 13, April 21, May 5, and June 16; the last issue went to press late and contained a news flash dated June 28. The active ingredient of Compound Q is a protein called trichosanthin, extracted from the root of a Chinese cucumber. The plant extract must be highly purified before injection; otherwise it is highly toxic and could be fatal. In the test tube, trichosanthin works by selectively killing macrophages infected with HIV. Infected macrophages are believed to be the major reservoir of the virus in the body.

In China, trichosanthin is used to induce abortion, because it selectively kills "trophoblast" cells, which line the uterus during pregnancy. It is also used to treat choriocarcinoma, a cancer of these cells, and may be better for this purpose than any treatment available in the U.S.

Dr. Hin-Wing Yeung, a scientist from Hong Kong, suggested trichosanthin as an AIDS treatment, based on earlier development of the drug by researchers in Shanghai. Michael McGrath, M.D., at San Francisco General Hospital, first thought that the drug might kill every macrophage in the body -- a radical but possible treatment, as macrophages are normally replaced. In laboratory tests, he unexpectedly learned that it killed only those cells infected with HIV.

The Unofficial Study

About three months ago, before Project Inform was involved with Compound Q, scattered groups of persons with AIDS, especially one group in Florida, had been able to obtain supplies of the drug from China. Because this drug is more dangerous than other non-approved AIDS treatments, the effort was made to obtain some answers quickly about its safety and efficacy through a highly professional treatment and data-monitoring program, before patients were harmed by self-medication or other improper use.

At a press conference on June 28, Martin Delaney of Project Inform explained the unofficial study, and the reason it was done. We edited his comments for length:

"This treatment use (of Compound Q) is no different from things like it that have been going on for the last five years.
What is different is that the media has turned this into a highprofile event.

"Several points guided us and made us feel compelled to organize this treatment program. One was impending community use of this drug. Like other drugs before it -- like ribavirin, AL 721, dextran sulfate -- patients have ways to get these drugs into the country legally. When there is hope about new drugs, patients begin distributing and using them. Unfortunately, widespread distribution and use has often taken place before we had any sense of whether the drugs were safe, or whether they worked.

"For example, in 1985 when ribavirin started coming into the U. S. from Mexico, Project Inform was formed to ask the medical community to set up prospective data monitoring on patients using that drug. Nobody did so, and three years went by of use of that drug, and the government ultimately concluded that it was not useful, and might even be harmful in some patients. That's not an intelligent way to run an epidemic.

"Now Compound Q is perhaps the most hopeful drug, but also maybe a very toxic drug. Patients legitimately within their rights are preparing to use it. Once again we have the specter of hundreds if not thousands of people using a drug that we do not know is safe or effective. Once again, it will take years to get the answer by the standard methods.

"A hundred and fifty people a day are dying now because of bureaucratic delays, because of inability to access important drugs that are tied up in the pipeline. A good example is the drugs DDI and DDC; their promise has been known since 1986. The official researchers have now finished phase I testing on them, and now they are telling us it will be two to two and a half more years before efficacy tests are confirmed. AIDS patients don't have that long to live. That's beyond the life expectancy of most patients.

"We're already two and a half years into Compound Q, as scientists learned the basic facts about it two and a half years ago, and kept the information from us while there was a good equivalent drug in China, a drug that had been used there for nearly two decades.

"It is true that the ongoing official study of Compound Q might have been done in six or nine months -- but it would not provide the answers we needed to guide community use. It will give limited answers about certain doses of the drug, one administration only, in certain patients. We have to answer to an entire community of people who are going to use the drug in any way they see fit, unless guidance is given.

"It is not OK, it is not acceptable morally, to just turn our backs and say, "You guys shouldn't do it," and feel that we've done our job. We have to give guidance, if people are going to have access to these drugs -- and they do have that access, whether we want it or not.

"We also had experience going into this from people in Florida. We were not the first ones to use Compound Q in a clinical study. More than a dozen people in Florida had already used the (Chinese) drug for HIV, before we even began talking about doing what we are doing now. So we had considerable human experience before going in.

"What did we do? First we talked to people working on importation. We asked them this time, let's not distribute the drug, let's not sell it to people. Instead, let's try to channel it into controlled clinical use, rather than the old system which
was pass it out and see what happens.

"We then collaborated to design a carefully controlled clinical process under which patients would be treated. This is not technically a study, it is a treatment program. People call it a study because of the extent of scientific processes being used to collect data from it. But the primary goal is treatment, not research.

"For the protocol design, we called upon a researcher who had run the research on another drug similar to trichosanthin, called ricin-A, which has been used in more than a thousand patients and is in the same family as trichosanthin. We used her help in putting this protocol together, along with the experience of the physicians involved. So the data gathering, the study part of what we are doing, was based on an existing FDA-approved study of the drug ricin-A; it is not something we made up.

"We also created an elaborate consent process to protect the patients and the physicians alike.

"We then shared the protocol with other interested physicians, pulled together a team of four groups in four cities, looking to treat about 60 patients."

(The next section of the statement, omitted here, concerned legal implications.)

"Baseline data was collected from all patients. Most of them already had more than a year of extensive laboratory work. After a complete workup, the patients were infused with a reasonable quantity of the drug -- the smallest amount used for any purpose in China. It is a fraction of the dose used in China with cancer patients. It is a midpoint in the dose range proposed for the trials at San Francisco General Hospital; in another week they will have exceeded our dose. Our dose is the midpoint of expected therapeutic doses based on laboratory data -- and the dose used by more than a dozen patients in Florida. It is a fifth of the dose that we've seen some patients use self-medicated.

"Basic safety precautions were followed. The criteria for entrance to this study were the criteria we lifted from San Francisco General's study. The same precautions were taken. Each patient was administered a test dose of the drug in a tiny quantity, to look for allergic reactions. They were followed for a 24 hour period of hospitalization, with vital signs taken constantly. They were in the physician's office nearly daily for the following week.

"Elaborate data gathering is going on, just as in a formal clinical study. 14 full physicals, 14 complete work ups, blood chemistry, urinalysis, sedimentation rates, P24 antigen and antibodies, complete cellular immunity, all of what is being done in virtually every AIDS clinical study in the country.

"Additional safety precautions include use of standard adverse experience reporting forms that are approved by FDA, standard side-effect ratings from FDA-approved studies, and complete tracking of concomitant medications used. There is nothing missing here in what has been done.

"The outcome to date is that the vast majority of the more than 30 patients who have been treated in our treatment program have tolerated the drug very well.

"We seem to have made an interesting, perhaps major discovery about the effect of the drug on patients with HIV infection of the brain. Two patients experienced mental confusion, which cleared up in one to two weeks. And as you all know one patient entered a coma, a coma that lasted no more than 24 hours and was in the process of complete resolution when the incident occurred about a week later when the patient died.

"This patient vomited in his sleep and inhaled some of the vomit, and had to be resuscitated. The evidence at the scene suggested that the resuscitation process was quite successful, his vital signs had returned to normal. However, the patient had a living will, an agreement which called for no heroic measures, which the family interpreted this as being, and the family asked that the tube be pulled. It was the opinion of physicians on site that had that not been the case, the patient could well be alive today. We cannot say at this point if the problem was related to the drug or not.

"At this time we are not making statements about whether the drug is working. We have seen some interesting lab measures. But it would be irresponsible scientifically to say that therefore the drug is working. It will take time, to follow these patients for a longer period and see if these results hold up. It would give the wrong signal to our community to say we've concluded that the drug works. We need more information before people should start using this drug. The buyers' clubs and other groups that work with patients are completely cooperative with this; nobody is interested in endangering anyone.

"As to the future, there are questions we set out to answer here to protect our community; we intend to get the answers to those questions. The FDA has not shut us down; we do not know whether they will try to or not. We think where we should go is cooperation; we would like to collaborate, share our data with the people in San Francisco General Hospital and the Food and Drug Administration. That was the intention all along; and until the incident last week, they shared in that intention. We had discussed sharing data submissions, about the interaction of our data with theirs. It was only after this very unfortunate death that people headed for the hills.

"We intend to present our data to the Food and Drug Administration, the National Institutes of Health, and the medical journals. If the data suggests that the drug is useful, we will fight for early access to it on behalf of AIDS patients. And whatever the outcome, we will continue to press for faster action. It is unconscionable to accept five and a half years' typical time for the development of drugs for AIDS, when patients have an average lifespan of only two years. We have fought long and hard battles in Washington to improve this process, we think progress is being made, but it isn't being made fast enough."

Neurological Side Effects: Bad News or Good?

As Delaney mentioned in the press conference above, a handful of patients with dementia or other evidence of HIV infection of the brain suffered neurological side effects -- a period of mental confusion lasting one to two weeks for two patients, or a coma lasting less than 24 hours for one other.

Although no one knows for sure, it seems likely that the neurological effects may be evidence that the drug is doing its job -- not a sign of toxicity.

What Delaney had heard from experts familiar with the study is that HIV does not infect neurons in the brain, but rather glial cells -- supporting cells which the body can replace. The neurological effects seem to be a temporary result of killing a large number of infected cells at one time. If so, Compound Q might prove helpful for persons with HIV brain infection. It may need to be given in smaller doses at first, to control the side effects.

Further studies will be needed to answer this question. Meanwhile, because of the unknowns and risks involved, physicians are screening patients for evidence of HIV brain infection, because of the increased risk of treating them with Compound Q until more is known.

The Future

The unofficial Compound Q study will end in 30 to 60 days. Until the results are reported, we will not know whether the drug is useful for treating AIDS or HIV, or not.

Readers should realize that there are other side effects, dangers, and precautions not touched on in this article. No one should use Compound Q without expert medical supervision.

What lessons have been learned? Medically, the unofficial study has taught researchers more in the last few weeks about Compound Q as a human treatment for HIV than had ever been learned before. And according to Delaney, the official study at San Francisco General Hospital has already used this information to skip some of its low test doses, which are now unnecessary. One result of the unofficial study, therefore, is that the official trials will produce results sooner -- a major purpose of the unofficial treatment program all along.

Even more importantly, the unofficial Compound Q study is demonstrating that it is possible to get useful results quickly, if a research project is organized for that purpose. How is Project Inform's program getting useful results in only four or five months, while official trials take five years or longer to do the same?

A look at specifics of the trials will show part of the answer. The official Compound Q was kept secret for at least a year and a half, between May 29, 1987 when the patent application was filed for anti-HIV use of trichosanthin, and January 3, 1989 when the patent was granted. During this time a new method for extracting the drug from the Chinese cucumber root was developed. Then after the patent was granted, it took six months to get phase I tests going; and these tests are slow because phase I tests were designed for new chemical never given to humans before. The Chinese experience was ignored.

In contrast, the unofficial study used the drug and medical information already existing in China. It proceeded immediately with a dose well known in human use and projected, based on laboratory data, to be therapeutic for HIV. By doing so, instead of developing a new patentable technology requiring new animal tests and phase I human trials, it avoided two years or more of delay. Note that this study could have been carried out two years ago, exactly as it is being done today, if the anti-HIV use of trichosanthin had not been kept secret during that time. As far we know, the intervening two years of official research added little or nothing to the unofficial study, which is based on pre-existing medical technology from China, not on the new technology created during the patent hiatus.

After the patent was granted on January 3 of this year, there was little media interest until April 15, 1989, when an article on Compound Q (also called GLQ 223) was published in the Proceedings of the National Academy of Sciences.

Another delay in the official research track is illustrative. After the patent was granted in January, it took some time for Genelabs, the developer of Compound Q, to get an IND (Investigational New Drug approval, meaning approval to test the drug in humans) from the FDA. We cannot know the full story of this delay, but we do know that at one point a San Francisco TV reporter called the FDA to ask why the IND had not been granted for this drug, and was told that the FDA had no application for the IND on file! Genelabs said that it had applied. Because of a misunderstanding, each party was waiting for the other. Apparently the FDA believed that what Genelabs had submitted was only a draft, not an official application -- while Genelabs thought it had applied and was waiting for approval to begin the clinical trial at San Francisco General Hospital. We are all lucky that a chance call from a reporter straightened out this snafu, which had put the entire world's research program for one of the two most promising AIDS drugs on hold.

This kind of problem seems surprising only to the uninitiated. In our three years of covering AIDS treatment research, we have seen such mindless delays happen again and again. The difference is that usually there is no public interest in the details of the process, and nobody there to make the call or do what else may be needed to straighten the problem out.

For too long the public has accepted a stock answer that clinical research is going as fast as possible, that the delays are caused only by the requirements of good science. But analysis of what is actually happening shows that the system can be vastly improved.

In the field of industrial quality assurance, there are trained, professional specialists to solve just this kind of problem. If a company is taking too long to get its products developed, for example, it can hire experts to analyze what is happening and suggest solutions. Typically the problems are due to flaws in the system, not to faults of the individuals involved, as no one person alone may have the power and resources to produce results. Instead, the system must be improved, by identifying the problems and correcting them. Academic experts in quality assurance can and should be invited onto the team to examine how trials might be organized to get faster results, consistent with good science.

The unofficial study of Compound Q organized by Project Inform is now producing the most important results -- practical information about whether, when, and how to use the drug -- about ten times faster than the official research system has been able to do so, either for Compound Q or for other drugs.

Admittedly there are greater risks to the patients in an accelerated study. Some patients want a role in making this decision, however, in balancing the risks of using a new treatment against the risks of doing nothing. Some may also want to contribute to the benefit of others, realizing that tens of thousands of lives are likely to be saved if an accelerated study shows unequivocally that a drug is helpful, months or years ahead of the official trials.

The take-home lesson, we believe, is not to blame individuals, on either side. Nor do we believe that the official system, with its safeguards and protections for research subjects, should be abandoned. Instead, we should reform the official system of clinical trials to make it faster and more efficient. If this can be done, there should be no need for bypassing the system in the future.

The right approach to reform is a win-win approach. Nobody's interest needs to be sacrificed -- and certainly the quality of scientific workmanship need not be reduced. Instead, careful, professional analysis and negotiation can find intelligent ways to make the system work better.

Who can implement this approach? Ultimately the only force which can do so is a professional consensus in the medical and research communities. Without that consensus, no one else -- not the AIDS community, not the FDA, the NIH, the White House, or the pharmaceutical industry -- can make it happen.

What if the consensus is not there? Physicians and scientists prize their independence; no one can tell them what to do. But we can appeal to their intelligence. The AIDS community can investigate and analyze exactly what is happening, and illuminate precisely what the problems are, what their consequences are, and what should be happening instead. Usually we cannot implement the reforms by ourselves. But we can make the problems and the opportunities for improvement so obvious that they cannot be ignored.