By Kim Grahl in Synapse, August 1989 —”SF Physicians Test ‘Compound Q'”
Synapse has obtained an interview with the three San Francisco physicians who have been running an alternative clinical trial of “Compound Q,” a potential treatment for AIDS, challenging procedures for drug testing established by the Food and Drug Administration (FDA).
The group, which consists of Dr. Alan Levin, Dr. Larry Waites, and a third physician who requested anonymity, have been administering injections of an exuact of the root tuber of a Chinese cucumber to AIDS patients, and monitoring their responses.
The extract, known as trichosanthin, GLQ223, or more commonly as “Compound Q,” has been used for years in China to induce abortions and to treat some forms of uterine cancer. Two years ago a contact from the Shanghai Institute, where the drug is made, brought some to Dr. Michael McGrath, a researcher at San Francisco General Hospital (SFGH).
McGrath had just begun been looking for a substance that selectively kills HIV-infected macrophages. And that —according to a paper McGrath published in the April, 1989, Proceedings of the National Academy of Sciences— is precisely what Compound Q does under laboratory conditions.
In May, clinical trials were begun at SFGH following the traditional FDA-approved protocol under the direction of Dr. Paul Volberding. (MacGrath cannot run the trials because he has a financial interest in the success of Compound Q, which is now being produced by Genelabs of Redwood City. His current research is aimed at elucidating the drug’s mechanism of action.) With the publication of MacGrath’s paper, hopes were raised in the community about Compound Q.
Many people with AIDS and their supporters have in recent years become increasingly critical of the established drug-testing procedures, especially the inherent slowness and the widespread use of placebos on patients in control groups. The hopeful news about Compound Q induced members of Project Inform —an advocacy group for people who are HIV positive— to take a radical step: obtaining the drug themselves and testing it outside the academic setting.
According to Alan Levin, the Project Inform representative who obtained the drug from China was “an old Navy helicopter pilot who knows his way around.” Within hours of the time that martial law was declared in May, he managed to obtain a substantial quantity of the drug from the Shanghai Institute and bring it back to San Francisco. Project Inform then supplied Compound Q to people with AIDS, who brought it to Levin and his associates, requesting that they administer it and monitor the results. In this way, the physicians involved have avoided importing a non-approved drug for clinical trials.
Because the Compound Q used in the alternative trial is obtained directly from the Shanghai Institute, it is “at least (as pure) if not more pure” than that purified at Genelabs, according to Levin. He claims that Genelabs sent people to Shanghai Institute to learn how to purify the drug, and then made slight modifications in the procedure. Levin says that the extracts obtained from the two sources are virtually identical.
Levin’s associate, who designed the alternative trial, describes it as a “Dose escalation phase one/phase two study.” In traditional drug testing protocol, such as that governing the current SFGH trial, in phase one the investigators are concerned only with the toxicity of a drug. They administer a very low initial dose and escalate it until they reach a level at which toxic effects are seen in the patient. Only after phase one is completed —which may take months— do the investigators undertake phase two, in which they try to determine the drug’s effectiveness, using a dose only slightly below that al which toxic effects were seen in phase one. Two phases combined The alternative trial combines these phases so that safety and efficacy can be tested from the start. Thus, while the traditional protocol would first give a very small dose to a few people, Levin’s group started off with a larger number of patients (15) and gave them a higher initial dose. The initial dose was equal to that prescribed in China when the drug is used as an aborticant —in other words, they followed the instructions on the label. Their decision to combine phases one and two was influenced, Levin’s associate says, by scientific, ethical and “in part by political considerations.”
According to Levin’s associate, the traditional protocol is somewhat valid for traditional cancer therapeutics. As she points out, because traditional investigators escalate up to the maximum tolerated dose —that is, the dose at which toxicity is first seen — and then drop the dose only slighdy to conduct phase two, many drugs end up being tested and used at very high doses and eventually prove toxic to many patients. Doctors hesitate to use lower doses because the efficacy of the drug has been proven only at the higher dose, and according to Levin’sassociate, it is true that for many cancer therapeutics the higher the dose, the better it is. However, she points out, for other drugs —the “biologies”— scientists are finding that even smaller doses are on the plateau of the dose-response. Thus, she says, there is starting to be a trend to combine the first two phases, so that the efficacy of lower doses can be assessed.
Another departure from convention was the structure of the committee set up to oversee and make decisions concerning the design and progression of the ttial. A traditional study is usually designed and executed by physicians who are primarily academicians, not clinicians. One result of this, Levin contends, is “a group of people setting the standards for medicine who don’t have much contact with the chronically ill.” As practicing clinicians who work with AIDS patients daily, Levin and his colleagues believe that their familiarity with the reallife experience of AIDS patients has prepared them to make a valuable contribution to the process of drug testing. As Larry Waites put it: “We’re empowering the clinical physician to include himself in the process of research and drug development.” In the uaditional protocol, once a trial has been designed, it must be approved by an Institutional Review Board (IRB), whose members include physicians and lay ethicists. Levin’s associate believes that these boards are unethical because they do not include members who would be candidates for the ueatment in question She believes that the perspective and input of such members is crucial to a final decision of whether or not the study design is truly ethical. Thus, their group is composed in part of people with AIDS. Finally, Levin’s group wanted to start at a dose at which there was a chance that Compound Q might be effective. They believe it is wrong to include people in a ttial if the dose that they are given could not possibly help. They started at a dose that was 10 times higher than that administered to the first patients in the SFGH ttial.
The initial treatments were conducted in May in San Francisco, with 15 extremely sick AIDS patients, who were not be expected to live for more than 60 days, according to Levin. Each had a T-helper cell count below 30 per cubic millimeter of blood. [HIV specifically infects and kills T-helper cells, thereby weakening the person’s immune system. Healthy individuals have T-cell counts ranging from 450 to 1,600. As the T- cell count falls, the patient becomes more and more susceptible to opportunistic infections.] The procedure The patients were each given an infusion of Compound Q once a week for three weeks. After this, on Levin’s assessment that the drug was safe, centers in Los Angeles, New York and Miami began treating patients at the same dose. Forty-five patients have now been treated at that dose, and Levin and his associates plan to go up to higher doses. Patients are monitored forp24 antigen, which indicates the rate at which the virus is replicating. According to Levin, initial data shows that in 10 patients in San Francisco who initially had elevated p24 levels , the levels fell by at least 50 percent after three weeks of treatment; in three of the patients, p24 levels fell to undetectable levels. However, in nine of these patients the levels appear to now be going back up in a stepwise fashion; Levin believes that this suggests that the initial dosage must be increased.
Patients treated in Los Angeles did not show a drop in p24 levels. (It is illegal to measure p24 in New York, so results are not available for those patients.) T-cell counts have not gone up; Levin’s associate believes that it is too early to see such an effect if it is to occur at all. They expect to take their data to the FDA this week and to publicly announce results within a few weeks. In addition to the AIDS patients receiving Compound Q in the alternative ttial settings, Levin says that he has anecdotal reports of 15 patients who were treated “in their living rooms” in April. Fourteen are doing very well, he has heard, and one has died of progressive AIDS-related infections. Levin says he is concerned about these and perhaps hundreds of other people with AIDS who are gaining access to Compound Q (which is available in the community) and taking it without advice or monitoring by a physician. Although he believes that most of the lots available in the community arc highly pure extracts attained from Shanghai Institute, he fears that without monitoring, people may be endangering themselves, for example by taking the drug in the wrong doses. “This is exactly the crisis that we are responding to,” he says.
Levin believes that the government and the medical establishment have failed to address the social reality: desperately ill people are not going to wait years to try promising new drugs such as Compound Q; they need information quickly about how to safely and effectively use the drugs. Levin’s associate adds that their group can do a service to the community by “putting a paper into the literature before the long SFGH ttial is completed, so that doctors can deal with a patient that comes to them with a vial of trichosanthin.” She wants doctors to have some information as soon as possible so that they can monitor patients rather than let patients inject themselves and thereby put themselves in danger. The decision to use p24 as an indication of efficacy contrasts with the FDA-approved approach, which, according to Levin’s associate, uses increased survival at the end as the only criteria for having a drug approved. Such a design requires a control group of patients who do not receive the drug and who cannot receive any other treatment. As
Levin’s associate points out, the established way to prove a statistically significant improved survival rate in the patients who have taken the drug, is for a certain number in the control group to die. She believes that this FDA-approved system is unethical, stating, “I don’t think it’s moral to assign people who have fatal illnesses to an arm where you require that they die in order to prove that the other arm is effective.” There are other biochemical parameters, she points out, such as tumor size for cancer patients or p24 levels for AIDS patients, that can be tested as indicators of the disease process. To date, two of the patients who received the initial doses from Levin’sgroup have died. The first patient went into a coma, came out of it and then died shordy afterward of an aspiration. The second man died of progressive Kaposi’s Sarcoma of the lungs. Other patients have experienced minor side effects, including fatigue and pain in their muscles and joints. Three patients experienced short-term dementia which reversed itself. Levin’s group believes that all three patients had evidence of HI V-disease in the brain prior to administration of the drug, which may have made them more susceptible to this complication. The death of the first man and the resulting publicity has reportedly led to the beginning of an investigation by the FDA to determine if Levin’ s group is operating within the bounds of the law. Levin’s associate says she is unsure of what, if anything, the FDA is investigating. She points out that it is not illegal for a patient to import a drug for personal use and take it to a physician who then draws up a treatment plan which includes use of the drug.
The Levin group calls their project a “treatment plan” rather than a clinical trial, which, as they interpret the term, implies FDA approval. They claim that the FDA has known about and been interested in their project since its inception. On Aug. 10, Channel 2 nightly news reported that the FDA “ordered Project Inform to stop the trial.” Synapse spoke to Levin the next morning; he stated that he and his associates “weren’t ordered to do anything.” He says that the FDA has no jurisdiction to tell him how to treat his patients. “There’s nothing that they can do to stop us,” he added.
“This is the beginning of a revolution,” according to Levin. He and his associates believe that their trial, in conjunction with pressure on the FDA from AIDS activists, the National Cancer Institute and other groups, will legitimize new methods of drag testing, including “parallel track” tests. The parallel track approach, which has already won the endorsement of Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, involves making drugs available to the community once they are proven safe (but before they have been proven effective). Regular trials would then be conducted to determine efficacy. Levin and his associates say that they don’t like the air of rivalry surrounding the simultaneous trials of Compound Q. The point is, says Levin, “If this stuff works, we’ve got to get it to the patients. I wouldn’t do it if I thought SFGH was doing it right” His associate adds, “It’s the virus that we ought to be fighting, not each other.”