Subject: Merck Setback Shows Problems Of AIDS Drugs Date: Published: 11/26/91 (131 lines) Source: Wall Street Journal. Copyright Dow Jones & Co. Inc. Medicine: Merck Setback Shows Problems Of AIDS Drugs ---- By Marilyn Chase Staff Reporter of The Wall Street Journal While scores of researchers and companies press their search for new weapons against the AIDS virus, Merck & Co., in a sobering setback, has dropped a promising drug it had rushed into clinical trials less than a year ago. Merck's drug, L 661, has encountered the same problem that limits the effectiveness of Wellcome PLC's AZT: The AIDS virus mutates and becomes resistant. Merck discovered in recent weeks that seven out of seven patients develop resistance to its drug after just six to 12 weeks of treatment. AZT -- the drug first approved against the virus -- can extend the lives of its users as much as two years. "We hoped it wouldn't happen," a Merck spokesman said. "Our researchers were quite disheartened." The recent spate of celebrities stricken by the AIDS virus has renewed public interest in AIDS drugs, but the Merck experience suggests the search for new and better treatments will continue to be difficult. Work by Merck scientists and others indicates that patients who become resistant to L 661, also will be resistant to similar compounds like BIRG 586, made by a U.S. Unit of Boehringer Ingelheim International G.m.b.H., and the TIBO drug of Johnson & Johnson's Janssen Pharmaceutica unit. Two AIDS activists, Bill Bahlman and Michael Becker of ACT UP, called the findings "extremely disappointing." That disappointment is all the sharper because Merck announced the trial's launch with great fanfare 11 months ago, after "heroically fast" lab work. The company says it hasn't abandoned the concept of using an alternate drug, L 229, in combination with AZT. But the resistance problem means such drugs will probably never make it as single agents, according to the spokesman. "The lesson here is that one needs to target drugs as specifically as possible to sites on the virus that aren't likely to mutate," says Jerome Groopman, a researcher at New England Deaconess Hospital in Boston. He warned researchers to be wary of drugs that work against just one AIDS strain -- such as HIV-1 and not HIV-2 -- as did the troubled compounds. But Robert Yarchoan of the National Cancer Institute -- who has played a role in the development of AZT and its sister compounds DDI and DDC -- cautions fellow researchers against becoming "paralyzed by potential difficulties." He adds: "It's important we not get obsessed with these things to the point that drugs get blocked from going into clinical tests." Currently, there are 60 clinical trials in progress. One reason for Dr. Yarchoan's optimism is the "exciting approach" offered by a class of drugs called protease inhibitors -- drugs designed to block a protein that's essential to the virus's life cycle. Roche Holding Ltd.'s Hoffmann-La Roche Inc. unit is testing one such compound in Europe, and other companies are hard at work on similar drugs. They include a SmithKline Beecham PLC unit, Abbott Laboratories, Vertex Pharmaceuticals Inc. and others. The big problem with protease inhibitors is that they require many steps to manufacture and tend to be broken down by the acids in the digestive system -- making oral formulation a problem. A prime target on the AIDS virus is the gene known as TAT, which makes a protein that accelerates the replication of the virus. Roche has developed an "anti-TAT" drug that has shown promise in early studies, but that the company plans to spin off to a developer it hasn't disclosed yet. Several groups are trying to target TAT proteins in another way, by using gene therapy to flood the body with copies of an AIDS viral protein called TAR to which the TAT protein sticks. Groups at Memorial Sloan-Kettering Cancer Center in New York and the National Institutes of Health are investigating whether sopping up TAT with TAR could, in effect, gum up the machinery of HIV's reproduction, and thus slow the lethal infection. Another type of gene therapy -- known as antisense because it would cancel the instructions of viral genes to make certain proteins -- is being pursued by a number of companies including Applied Biosystems Inc., Gilead Sciences and Hybridon Inc. While the goal of prevention remains more distant, vaccines are already being tested as a major strategy for boosting the immune systems of people already infected with the virus. Several groups are expanding efforts to test vaccines made by MicroGeneSys Inc., Immune Response Corp., Genentech Inc. and others. A brand-new trial shortly will test whether human growth hormone -- so far approved only to treat dwarfism in children -- could also stimulate immunity and combat the severe wasting in AIDS. "There's data from rodent studies that if you give growth hormone to mice, you can increase the number of CD4 cells" in the immune system, says Dr. Yarchoan. Thomas Merigan of Stanford University recently found that the protein IL-2 can raise levels of immune system cells in the body, and he hopes to build on such findings to "fine tune" the use of substances that strengthen the immune system. Two relative newcomers to the AIDS drug business also have appeared: UniRoyal Chemical Co. with its compound UC38, and Stanford's husband and wife team of Leonard and Lenore Herzenberg, with their compound called NAC. Many researchers say the best short-term hope for treatment lies in combinations of AZT and DDI or DDC. In the long term, many doctors are counting on the protease inhibitor drugs. But most admit they see no miracle on the horizon. "The reality is that there isn't anything we've heard that is earth-shattering," says Donald Abrams, a researcher at the University of California at San Francisco. "As we draw to the end of 1991, there's not some secret powerful weapon out there." When a new drug such as L 661 fails, according to the Merck spokesman, "there's a sense of hopelessness, but it doesn't last long." --- Corrections & Amplifications MERCK & Co. has a major program to develop an anti-AIDS drug known as a protease inhibitor. In yesterday's edition, Merck's name was inadvertently omitted from a list of companies participating in this field. (WSJ Nov. 27, 1991) [This article is made available here by Dow Jones Co. for the personal and non-commercial use of callers to this bbs, in the hope that it will be of some help to those who are suffering from the disease and others who are seeking to help them.]