The Wall Street Journal - September 28, 1999
Ralph T. King Jr., Michael Waldholz and Thomas M. Burton Staff Reporters of the Wall Street Journal

Resistance is one of the toughest problems doctors treating AIDS patients face.

In some patients who have had long experience with older AIDS drugs, the virus can mutate swiftly, circumventing powerful drugs in a matter of months and causing debilitating symptoms to recur. As a result, new drugs with more long-lasting effectiveness are considered critical as the battle against the disease unfolds.

At a major science meeting here, several drug makers and AIDS researchers presented studies of new drugs and new combinations of existing drugs designed to deal with the troubling rise in resistance among some long-treated patients. DuPont Co., Glaxo Wellcome PLC, Abbott Laboratories and others showcased dozens of studies for the more than 16,000 scientists, doctors and other health-care workers at the conference.

Gilead's study generated interest because its drug works differently than existing medicines. In essence, it is chemically preactivated, making it more effective in a wider range of cells than existing drugs, which undergo more chemical changes inside a cell.

In the study, the company said, 189 patients who had failed other therapies showed no resistance to tenofovir after six months. Moreover, patients suffered no serious side effects even as the drug at the highest dose eliminated more than 80% of the virus from their bloodstreams. In larger studies to begin shortly, the company hopes to show the drug's activity against resistant viruses is sustained.

"This represents an impressive and durable effect," said Robert Schooley, a University of Colorado AIDS expert and chief investigator in Gilead's Phase II trial. "As a doctor, there are a lot of positive features that warrant enthusiasm." One big benefit is that unlike most AIDS drugs, tenofovir need only be taken once daily.

In Nasdaq Stock Market trading Monday, Gilead shares fell $7.75, or 10%, to $69.5625. Investors had bid up the stock in recent months in anticipation of good tenofovir news and high hopes for Tamiflu, an influenza treatment being co-developed with Roche Holding Ltd.

Analysts said the results, reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy, clear up the nagging question of tenofovir's safety. Safety data are closely watched because a similar AIDS drug developed by Gilead known as adefovir triggers kidney problems in some patients. That toxicity has delayed adefovir in the clinic, but Gilead could win regulatory approval to begin selling it by the end of the year.

Introduction of tenofovir is more than a year away, but it could finally put Gilead, based in Foster City, Calif., into the big leagues of biotechnology. "Tenofovir has everything you're looking for," said Caroline Copithorne, an analyst with Prudential Securities Inc. "It has the potential to be a $500 million product."

That will depend in part on competition. Other drug makers are racing to develop drugs that fight resistant strains of the virus. And because AIDS patients currently face a lifetime of drug therapy, tenofovir potency may not be long lasting enough. John Martin, Gilead's president and chief executive, said, "There are bound to be patients somewhere sometime who develop resistance to tenofovir. But we think resistance will be slow to emerge."

In another small study, researchers showed that an experimental drug called T-20 may also be useful in treating patients who have developed resistance. The drug, developed by Trimeris Inc., a small Durham, N.C., company, also works differently from existing medicines; it blocks viruses from entering into cells. In a 16-week test of 55 previously treated patients whose virus appeared to develop resistance to existing drugs, T-20 reduced the levels of virus in the bloodstream of 20 patients to below where it could be detected by the most sensitive tests.

But T-20 will need to be injected by patients twice daily, and producing the drug is expected to be very expensive. Roche, however, recently licensed T-20 and plans to aggressively expand human trials, especially among patients with resistant virus, and to seek less expensive ways to make the drug.

Meanwhile, results of clinical trials on a new Abbott Laboratories AIDS drug show that the medication, called ABT-378, has the effect after 36 weeks of treatment of lowering virus levels, both in patients who haven't previously been treated and in those who have previously failed on other drugs.

The results of two separate Phase II clinical trials on ABT-378 show that the new Abbott "protease inhibitor," used in combination with Abbott's existing protease drug, Norvir, is both potent and well tolerated in both groups of patients, Abbott officials and outside investigators said. (Norvir generically is called ritonavir.)

"ABT-378 with ritonavir demonstrated activity against HIV and a promising tolerability profile in both studies," said Joseph Eron, director of the infectious diseases department at the University of North Carolina in Chapel Hill. After 36 weeks of treatment, 89% of the previously untreated patients with HIV virus had their viral loads reduced below the level of detection after taking the 378-ritonavir combination.

This doesn't necessarily mean the virus has been eradicated, but merely that it isn't detectable. In fact, many scientists believe the virus has become dormant with some of the existing protease drugs, only to mutate and grow again. In a separate Phase II study, 78% of patients who had failed on other AIDS drugs saw their viral loads fall to below detectable levels with the ABT-378/ritonavir combination. In this study, patients took the ABT-378/ritonavir combination for two weeks and then kept taking it in combination with other standard therapy, nevirapine and two nucleoside reverse-transcriptase inhibitors.

Abbott officials said two of 170 patients discontinued the studies because of adverse events related to the ABT-378/ritonavir combination. The most common adverse events in the trials were diarrhea, nausea, lack of strength (asthenia) and headache.
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