Date: 06 Mar 94 03:30 PST Subject: AIDS TREATMENT NEWS #194 AIDS TREATMENT NEWS #194, March 4, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Merck Protease Inhibitor: Viral Resistance Suspected, Large Trials on Hold AZT May Reduce the Risk of Maternal Transmission of HIV Thymosin Alpha 1: Sustained T-Helper Count Rise in Three-Drug Combination Isis 5320: New Combinatorial Approach to Drug Development ***** Merck Protease Inhibitor: Viral Resistance Suspected, Large Trials on Hold by John S. James Protease inhibitors, a new kind of AIDS drug, work differently than any approved or available treatment; they block an enzyme, the HIV protease, which is produced by the virus and required for it to reproduce. About a dozen pharmaceutical and biotechnology companies are now developing different protease inhibitors. One of them, code-named L- 735,524 (usually called L-524), being developed by Merck and Co., has shown very good ability to suppress HIV activity in people, for about three months. But when the trial was continued beyond that, a sensitive blood test (for HIV RNA) showed that viral activity later returned; after about six months on the drug, the virus was about as active as when treatment began. Merck researchers suspect that the virus became resistant to the drug, but they do not know for sure. After seeing this disappointing result, Merck called off plans for a large trial, which could have started as early as March and given the drug to hundreds of people. Instead, Merck will increase the dose of L-524 in its ongoing small trial (known within the company as Protocol 006), and also begin other small trials to test the drug in combination with other antivirals -- probably AZT, and also in a triple combination with AZT and ddI. Meanwhile, researchers will continue laboratory studies of the virus from the volunteers who have already been treated. On February 24 Merck held a meeting with treatment activists, including a number of volunteers who are taking L-524, to explain the trial results and the company's changing plans; this writer attended that meeting by telephone. This article describes some of the information presented, which may be important for understanding L-524 and other drugs as well. (Merck also explained its results to reporters from the Wall Street Journal and the Philadelphia Inquirer; both papers published articles on February 25.) [Note: Do not confuse the Merck protease inhibitor, L-524, with the Hoffmann-La Roche protease inhibitor, Ro 31-8959. Large trials of the Ro 31-8959, which will involve several thousand volunteers, are now beginning, as described in our previous issue, AIDS TREATMENT NEWS #193. Also, do not be confused by the terminology: the words "protease" (used by Merck) and "proteinase" (used by Roche) are the same. [The Roche trials, which will recruit a total of about three thousand volunteers, are going forward even though "reduced sensitivity" to Ro 31-8959 has also been found. Why would the companies respond differently to data suggesting that viral resistance had developed? There are several possible reasons. First, Roche is ahead of all other companies in human trials of its protease drug; early human results were first presented at the International Conference on AIDS, in June 1993. This means that Roche has had time to study the problem; while Merck, which has only observed the apparent resistance to its drug since January 1994, wants to understand what is happening better before giving L-524 to hundreds of people. Also, a drug can be useful even if resistance develops (as it does eventually with almost all drugs); and Roche has an incentive to preserve its major advantage in protease inhibitors, its lead in human trials. But Merck is seeking a major advance, not just a "me too" drug comparable to what Roche is developing. For the first three months, L-524 looked like it might be such an advance; when it failed to hold up later, Merck decided to learn how to use the drug better, before beginning large trials. (Merck has other protease inhibitors which work better in the laboratory than L-524, but they are not yet ready for human studies.)] The Blood Tests: P24 Vs. HIV RNA Protocol 006 was first designed to last for 12 weeks, and to test for antiviral activity of L-524 in humans primarily by using a blood test to measure the level of a protein, called p24, which is produced by HIV. But scientists are becoming increasingly disenchanted with the p24 blood test (even the newer 'ICD' version, which Merck is not using). Although this test can show if a drug has antiviral activity in patients, long-term studies are finding that it does not predict which patients will do well in the future. The p24 blood test is inherently unreliable, because the result depends not only on the amount of p24, but also on the amount of antibody against p24 which the patient's immune system is producing. Because of this concern, Merck researchers decided to also measure the concentration of HIV RNA in the blood. This new viral test is not affected by the antibody, so it can be a more reliable measure of viral activity. (For background, see "Better Viral Tests: Interview with Mark B. Feinberg, M.D., Ph.D.," AIDS TREATMENT NEWS #186, November 5, 1993.) The RNA test is new and difficult to perform, however, and because of technical difficulties the results can vary from day to day even in the same laboratory. To help control this variability, blood samples were frozen so they could be tested together in the same batch. In Protocol 006, no one has yet taken L-524 for more 18 weeks; but Merck has data from a handful of people at 24 weeks, from a small phase I study (Protocol 004) which started earlier. RNA data are not yet available from Protocol 006. But Protocol 004 found that the results of the p24 and HIV RNA tests were comparable for the first four weeks, but then became fundamentally different. Within two weeks of beginning treatment, the p24 had decreased by about 60 to 70 percent of its starting value; then it continued to decrease until it became undetectable in most of the volunteers. Then it remained largely undetectable, although there was a slight rise eventually. The HIV RNA was tested only at baseline (before treatment began) and at every two weeks up to 24 weeks, but samples were only run in batches at four weeks and then again after 20-24 weeks. During the first four weeks, RNA dropped in parallel to p24. However, the assays conducted at 20-24 weeks revealed that RNA had begun to rise back at the 12-week time point, and by 24 weeks had returned to baseline levels -- apparently because the drug was no longer controlling HIV. Patients seemed to do well, showing weight gain and T-helper count increases during the period that the virus appears to have been controlled; but with only a handful of patients tested, it is too early to know if the patients benefited as a result of the drug. If the new test for HIV RNA were not available, everything else would suggest that L-524 looked very good. Why did the two tests give different results? Merck researchers suspect that the drug initially suppressed the virus, allowing the levels of antibodies against the p24 protein to become very high. Later, when viral activity returned, these high antibody levels prevented the p24 from being detected. But the test for HIV RNA showed that the drug was no longer stopping the virus. Trial Design and Drug Approval Requirements Protocol 006 is comparing L-524 to an AZT control; after the trial had begun (in October 1993), it was extended from a 12- week to a 24-week trial. This change angered some of the volunteers, who expected to have to be on the blinded study for only 12 weeks, after which they could switch to "open label" L-524. Merck acknowledged that there had been communication problems; clearly the volunteers should have been told by the investigators before entering the study that an extension was possible, and should have been told about the extension as soon as it was officially approved. (Another issue is that Merck has only given a summary of the study protocol, not the protocol itself, to the volunteers. Most pharmaceutical companies do not release their protocols to the public or the volunteers in the trial; however, the U.S. National Institutes of Health usually does.) The evolution of Protocol 006 illustrates some of the requirements for drug development and approval today. It began as a 12-week study because the FDA would not approve a design which called for giving the drug to people for longer than animals had received it in toxicology tests. As the data from the first 12 weeks came in, the drug looked like it was working well; and Merck knew that the FDA would require a 24- week trial in order to count toward drug approval. Instead of losing time by starting over with a new 24-week trial, Merck asked the FDA for permission to extend Protocol 006 for another 12 weeks. Since there was enough animal experience by then, permission was granted. (As it turned out, this trial will not count toward approval in any case, due to the disappointing 24-week results.) If L-524 had worked in the six-month trial, what else would have been needed for approval? Usually the FDA requires two controlled studies before a new drug can be approved. The expectation today is that if a new kind of anti-HIV drug works much better than anything else known at six months (but as measured only by blood tests, without proof of clinical benefit to patients), the FDA would require the company to begin a second study (which would measure clinical benefit, and therefore could take two years or more to complete) before the drug could be approved. But while this second study would have to be started, it would not necessarily have to be finished before drug approval. Future Research Plans Because HIV mutates very rapidly, Merck researchers suspect that it may be necessary to completely stop the virus in order to prevent drug-resistant strains from emerging. L-524 did not do this in the doses given (up to 400 mg every six hours). It seems likely that some viral mutation, probably already present in the volunteers before treatment began, may give HIV a low-level resistance to the drug; Merck researchers believe there is probably no more than a four- fold reduction in sensitivity (meaning that the drug would still work if the dose could be increased, by no more than four times). And even if resistance cannot be overcome by increasing the dose it might be greatly delayed by combining two or more drugs with different mechanisms of action -- a strategy which has been used very effectively against tuberculosis and other infectious diseases. While new trials of L-524 are being designed, virological studies are being done to confirm that viral resistance is the problem, and to find what mutation or mutations are responsible. (Drugs can lose effectiveness due to mechanisms other than viral resistance -- for example, there can be changes over time in how the body processes the drug.) But low-level resistance is more difficult than high-level resistance to test in the laboratory; therefore, these studies could take months to complete. Comment: The Past and the Future Merck has shown consistent commitment to AIDS research, top quality science, competent operational planning of the drug- development process, and openness to the interested public -- a rare combination in research today. It has kept its AIDS program going despite serious setbacks. These began tragically in December 1988, when Dr. Irving S. Sigal, senior director of molecular biology at the Merck Research Laboratories, and the world's leading expert on the structure of the HIV protease, was killed in the bombing of the airliner over Lockerbie, Scotland. Other setbacks were the failure of an early protease inhibitor when it caused biliary obstruction in dogs in toxicology tests, and the failure of L-661, a reverse-transcriptase inhibitor, due to rapid development of high-level viral resistance. Merck's determination to get it right before going into large trials is a welcome change from the usual approach of allowing one's research efforts to become focused on treatments which clearly do not work very well and never will. But there is also concern in the community that Merck may abandon a drug which is better than anything else and could be useful, if it does not fit with the corporate goal of a home run. We do need to plan carefully for the possibility that we may not be able to stop HIV completely at this time. And when combination treatment is needed, the obvious drugs to add are the approved antiretrovirals: AZT, ddI, and ddC. But the search should not stop there. Other treatment approaches, aimed at reducing the activation of HIV, should also be considered. These include LTR inhibitors, tat inhibitors, certain immune suppressive therapies, certain anti-inflammatories, and therapies based on providing or blocking certain cytokines. Also, there are other immune- based treatment possibilities, which seek to restore or enhance the immune system's natural ability to control HIV for years -- which it does far better than any known drug. This whole cluster of approaches has received far too little attention and support. But there are some treatments which, while still experimental, could feasibly be tried now as part of a combination regimen with L-524. And if it is true that L-524 shuts down HIV in people more completely than any other known treatment, even if only temporarily, then it could be used to answer some important AIDS research questions, for example: * In persons with very low T-helper counts, will the immune system recover on its own (without special immune reconstitution treatment) if the virus is stopped? * In those with early HIV infection (for example, with T- helper counts over 500), would the drug work for a much longer time, since there is little viral replication and therefore little opportunity for resistant HIV variants to evolve? * Could the drug be used as a temporary antiviral "cover" during certain therapies (such as IL-2 treatment) which otherwise can cause a temporary increase in HIV activity? * Is it feasible to increase the "trough" level of the drug (the lowest concentration in the body between doses, when resistant virus has the most chance to emerge) by a time- release formulation, or by more frequent administration, in addition to increasing the total dose? In another area, a major challenge for 1994 and 1995 will be learning how to use the new viral tests, both for drug development and for individual patient care. (These are still research tests, not yet regularly available to physicians.) Merck's results suggest that the key to controlling HIV infection may be to reduce viral activity to a low level -- and then keep it low indefinitely, which is more difficult. The right treatment may be whatever works -- antivirals, immune-based treatments, drugs to reduce viral activation, various combination treatments, life-style changes, even "alternative" treatments where the mechanism of action may be unknown. Effective strategies may be very different for different patients -- and for the same patient at different times. As better viral tests become more widely available, it will be feasible to develop "libraries" of treatment strategies, all of which work at certain times for certain patients, but do not work at other times. Patients will be periodically tested for viral activity, and whatever treatments are necessary will be used to keep the activity down. As the treatment strategies, guidelines for their use, and viral tests all improve, it may become possible to control the disease indefinitely, even without a single treatment that works for everybody. ***** AZT May Reduce the Risk of Maternal Transmission of HIV by Rae Trewartha On February 21 the U.S. National Institutes of Health issued a Clinical Alert announcing that AZT greatly reduced the risk of HIV transmission from pregnant women to their babies, according to preliminary results of the Federally-sponsored trial ACTG 076; those who received the drug in the trial were only a third as likely to transmit HIV to their children as those who did not. As a result, AZT will be offered to all currently enrolled pregnant women who remain in the study, and also offered to their babies for the first 6 weeks of life. It is also planned to follow all the infants who participated in the study "to monitor for the possible development of unknown late effects of study treatment." The NIH points out that "there are currently 10-20,000 HIV- infected children and approximately 7,000 infants born annually to HIV-infected women in the United States; it is estimated that by the year 2000, ten million children will have been infected globally." Consequently, there are immense implications arising from these preliminary trial results in regard to the future standard of care for HIV-infected pregnant women and their infants. As Peter Vink, M.D., the doctor in charge of the site for this trial at the University of Maryland School of Medicine in Baltimore, put it, "Until this time there has been no equivalent to the clean needle or condom for the pediatric population." Here we review the background to the trial and discuss some of the implications for future care which arise in relation to the preliminary trial results. This study, which began in April 1991, was conducted by the Pediatric AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases (NIAID) in collaboration with the National Institute of Child Health and Human Development (NICHD), and the Institut National de la Sant et de la Recherche Mdicale (INSERM) and Agence Nationale de Recherches sur le SIDA (ANRS), France. There were 35 NIAID sponsored sites, 15 NICHD sponsored sites, and 9 centers in France. Eligible patients were HIV-infected women who were between 14 and 34 weeks pregnant; had had no antiretroviral treatment, and had no clinical signs indicating their need for AZT as part of their medical care, during their current pregnancy; and had baseline T-helper cell counts greater than 200. The women received either AZT or placebo during the trial and neither the researchers or the women knew which treatment arm the women had been randomly assigned to. While they were pregnant the mothers were given oral doses of AZT and they also received it intravenously during labor. They were seen frequently throughout their pregnancy and delivery, and for 6 weeks after giving birth. They were also carefully assessed for evidence of drug toxicity, HIV-disease progression, and fetal well-being. The babies began receiving AZT syrup 8-12 hours after they were born and for the following 6 weeks; they were carefully monitored until they were eighteen months old and were defined as HIV infected based on one positive viral culture. The preliminary results of the trial showed that 8.3 per cent of babies were infected when both mothers and babies received AZT, compared to 25.5 per cent of babies when the mothers and babies had received a placebo. There was no difference in birth defects between the two arms of the study and the rate was the same as that for the population at large. Burroughs Wellcome points to the same results from the pregnancy register, which it established with the Centers for Disease Control to document the use of AZT in pregnant women when AZT was first released in 1987. While hemoglobin levels were slightly lower for children in the AZT group these were not significant enough to require transfusion and all resolved themselves several weeks after completion of AZT therapy. AZT was well tolerated by the mothers; of the 477 women enrolled in the trial, only six discontinued therapy due to perceived toxicity (three in the AZT group and three in the placebo group). While these results are certainly encouraging, there are still many questions HIV-infected women who are pregnant, or contemplating pregnancy, will need to consider in collaboration with their caregivers -- this is not a cure, eight per cent of babies are still infected and until more data is available we do not know if there are any signs which may indicate which women are at most risk from giving birth to infected babies. Dr. Vink hails the results of this trial as "tremendously exciting" but expresses cautions for future standards of care. First, there is no conclusive evidence to indicate whether babies are infected in the uterus or during the birth process -- and whether babies whose mothers deliver precipitously (and are thus unable to receive AZT intravenously during labor) may be at greater risk of infection than babies whose mothers are able to receive intravenous AZT. Secondly, he points out that it is imperative that the babies receive their first dose of AZT as soon as possible after birth, are kept on their AZT regimen for the first 6 weeks of their lives, and have their health regularly monitored. In addition, there is no evidence as to whether AZT would work as well if the mothers were to become pregnant on subsequent occasions. Rebecca Denison of WORLD (Women Organized to Respond to Life- Threatening Diseases, a monthly newsletter written by and for HIV-positive women to address concerns specific to women and HIV disease; WORLD can be contacted at P.O. Box 11535, Oakland, CA 94611, 510/658-6930) sees these preliminary results as, "Wonderful if they hold up and there are indeed no major side effects." She cautions, however, that women who are contemplating pregnancy and have much higher T-helper cell counts than the average for the women in the trial (which was 586) may want to know more about whether they should take AZT and how taking AZT would affect their own health. She is concerned that there could be a danger that the health of the mothers may not be considered to the same degree as that of the babies. Laura Thomas of ACT UP San Francisco agrees, pointing out that we really know very little about the pregnancies of well HIV-positive women and that until we have more research in this area it is difficult for women to make informed choices on the use of AZT in pregnancy. For instance, it may be that healthy women, or women whose pregnancies are carefully monitored, are less at risk for transmitting the virus to their babies anyway. There is no data available so far to tell us whether the women who had the highest viral loads were most at risk for transmitting the virus. Another area of concern is the one surrounding the testing of pregnant women for HIV. Ms. Denison pointed out that many women already sign a form for an array of tests, HIV just being one of them, when they first become pregnant, without being aware of the implications of a positive HIV result and without receiving pre-test counseling. She and Dr. Vink both expressed the hope that the trial results would not lead to mandatory testing, but they also noted that, given supportive counseling, most women are happy to be tested if they know a positive result could lead to better care and a healthier pregnancy. While HIV-positive women now have more hope that transmission of the virus to their babies is preventable, the preliminary results of this study still leave many questions unanswered, particularly for women anxious to weigh the risks before deciding whether or not to become pregnant. However, as the Clinical Alert from the National Institute of Allergy and Infectious Diseases (NIAID) notes, "If a pregnant woman is infected with HIV, the therapy evaluated in this protocol may be of substantial benefit to her infant. These findings should therefore be considered in formulating policies or standard of care recommendations regarding counseling and testing of HIV-infection status of pregnant women, as well as in the assessment and obstetrical care of individual women." This leaves a major concern, though, as to how AZT will reach those pregnant women who need it but are unable to afford it and, of course, as Ms. Denison notes, many of the babies being born to HIV-infected women are born to women in countries where even basic health care is the exception rather than the rule; for them AZT is not even likely to be an option. [Note: For copies of NIAID's ACTG 076 Questions & Answers, the Clinical Alert, and the press release, call the AIDS Clinical Trials Information Service, 800/TRIALS-A.] ***** Thymosin Alpha 1: Sustained T-Helper Count Rise in Three-Drug Combination An Italian study has found that a three-drug combination of AZT, alpha interferon, and thymosin alpha 1 resulted in a large increase in T-helper cell count, sustained for at least 18 months, in patients who started with a T-helper count between 200 and 500. However, only a handful of patients received the treatment in this small, preliminary study; and no one in either the treatment or the control arms progressed to AIDS, so there is no proof yet that the treatment resulted in clinical benefit. A larger study has started in Italy. Thymosin alpha 1, a thymic hormone which affects the maturation of T-cells, has been developed primarily as a treatment for hepatitis B and C; in the U.S., it is an orphan drug being developed by Alpha 1 Biomedicals, Inc., of Bethesda, Maryland. It was first considered as a possible AIDS treatment at least ten years ago. In the new study, volunteers were given 500 mg per day of AZT, 2 million units of natural human alpha interferon (Wellferon) intramuscularly twice weekly, and 1 mg of thymosin alpha 1 subcutaneously twice weekly. Of the seven patients who completed one year of the three-drug treatment, the average T-helper count went from 309 before treatment to 496 after treatment. This difference was statistically significant (p = 0.029), meaning that it would have been unlikely to have occurred by chance alone. Five of these patients continued treatment through 18 months on the three drugs; their average T-helper counts increased by 50 between month 12 and month 18. (This difference was not statistically significant, however, since the standard deviation of both averages was over 200.) Incidentally, the two-drug combinations of AZT plus alpha interferon, or AZT plus thymosin alpha 1, seemed to work much less well than the three-drug combination, although better than AZT alone. Reference Garaci E, Rocchi G, Perroni L, and others. Combination treatment with zidovudine, thymosin alpha 1, and interferon-alpha in human immunodeficiency virus infection. INTERNATIONAL JOURNAL OF CLINICAL & LABORATORY RESEARCH. 1994; volume 24, pages 23-28. ***** Isis 5320: New Combinatorial Approach to Drug Development by John S. James Isis 5320 is a new anti-HIV agent developed by Isis Pharmaceuticals, of Carlsbad, California. It is much too early to know whether this potential drug will be useful in AIDS treatment; not even complete animal toxicology data is yet available. What is most interesting now is the unusual method of drug development by which this substance was created. Isis Pharmaceuticals is best known as a leading developer of antisense technology. Antisense drugs are designed to target particular genes and selectively block them, without affecting other genes. Genetic information is contained in a long sequence of four different chemical "building blocks," called nucleotides, which make up the genetic code. Antisense drugs provide an exactly complementary sequence to a unique part of the target gene, so that the drug will bind to and affect only to that gene. (The nucleotides used by the body would not work well in pharmaceuticals, however; therefore chemists have created four artificial building blocks, which correspond to the four natural ones, to use in assembling antisense drugs. Different antisense technologies use different sets of four chemicals for building the drugs.) For more information on antisense drugs for HIV and for CMV, see AIDS TREATMENT NEWS #185, October 15, 1993, and #187, November 19, 1993. Isis 5320 is not an antisense drug, however; it was developed by a different approach, called combinatorial drug discovery. Isis is only one of the companies exploring this kind approach. It has the advantage of being able to use the four building blocks it had already created for making antisense drugs -- and its expertise in the related chemistry-- in this new way. Its scientists already know that the resulting drugs (produced as sequences of these four) can work in the human body. In combinatorial drug development, "libraries" of thousands of different potential drugs are created at random, in one batch. If the library as a whole shows the desired activity as a drug, various techniques are used to determine which one or more of the chemicals is responsible. That chemical can then be synthesized in pure form for further testing. This approach has at least two advantages. First, thousands of potential drugs can be screened in one test. And also, the mechanism of action of the drug does not matter -- which means that an effective drug can be found even if it works in a way not expected by the researchers, or in a new way which is unknown. Isis 5320 was discovered as follows. First, researchers decided to look at sequences eight units long; there are exactly 48 (65,536) such sequences. These sequences were prepared in sixteen different libraries, each containing 4,096 sequences; these libraries were tested against HIV in the laboratory. (Each library was created by holding two of the eight positions fixed, and allowing the other six to vary at random.) By various chemistry and virology, and some intelligent guess work, one particular sequence -- Isis 5320 -- was selected for development as a potential HIV treatment. The next scientific step was to find the mechanism of antiviral action of Isis 5320; when this substance was first identified, the researchers did not know how it might work. It was found to target a part of the virus called the V3 loop, preventing HIV from binding to and entering uninfected cells. Usually the V3 loop would not be selected as a target for drug development, because it varies greatly among different HIV strains. But there always seem to be certain chemical similarities, which may be essential for it to work properly, and which are apparently targeted in this case. Isis 5320 has been tested against a number of clinical and drug-resistant strains of HIV, and the concentration required for 50 percent viral inhibition is 0.2 to 2.0 micromolar. What may be most important here is the early practical demonstration of combinatorial drug development in AIDS. References Wyatt JR, Vickers TA, Roberson JL and others. Combinatorially selected guanosine-quartet structure is a potent inhibitor of human immunodeficiency virus envelope-mediated cell fusion. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. February 1994; volume 90, pages 1356-1360. Also see Background Information for Isis 5320, prepared by Isis Pharmaceuticals, for a less technical introduction. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. 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