The Wall Street Journal - Tuesday, 12 November 1996
Michael Waldholz, Staff Reporter of The Wall Street Journal

He has staved off illness for more than a decade by aggressively cycling through a battery of medications, turning to a new drug each time the virus mutated and overcame an earlier one. "I've taken AZT, DDC, DDI, D4T, 3TC, Saquinavir, Norvir," says Mr. Gendin, the 30-year-old co-founder of a New York mail-order drug company.

"Now I need what's next," he says. "1592 is next." But the potent drug 1592 has been stuck in Glaxo Wellcome PLC's research pipeline for seven years. It now seems unlikely that it will hit the market before mid-1998.

What's taking so long? Glaxo says it didn't recognize the drug's power until recently and now is moving as quickly as it can to complete necessary safety trials and make the drug available. But some critics believe the company is dragging out the development of 1592. After all, development of the powerful AIDS drugs known as protease inhibitors began less than five years ago, and those drugs have been available for almost a year now, extending the lives of thousands of people. The controversy reflects the tremendous demand for new AIDS drugs now that it appears the disease responds, at least temporarily, to treatment.

AIDS activists charge that Glaxo is trying to protect the sales of its two older AIDS drugs, AZT and 3TC. Their combined revenue is expected to hit $600 million this year, double the total in 1995, and could exceed $1 billion in two years. Sales are booming as patients adopt a "cocktail" regimen that combines the two older drugs with one of the new protease inhibitors.

But 1592 is 10 times more powerful than AZT, its chemical and corporate cousin, and it avoids AZT's dangerous side-effects. "Who's going to take AZT if 1592 is available?" asks Martin Delaney, founding director at Project Inform, an AIDS advocacy group.

At the very least, Mr. Delaney and many other AIDS activists contend, Glaxo should make 1592 available immediately to thousands of desperately ill patients under a "compassionate access" program while the drug winds through the long approval process. Virtually every other new AIDS drug has taken that route.

Glaxo officials, saying they haven't gathered enough safety data to do that, deny that they have put commercial considerations before compassion. They concede that work on 1592 and other drugs languished amid the distractions of Glaxo's $14.8 billion acquisition of Wellcome PLC last year. Except for 3TC, all the AIDS drugs in the works were from the Wellcome side. Once Glaxo took over, it didn't offer comparable jobs to most of the top Wellcome research managers who had shepherded 1592 through initial studies. As a result, most of the managers left.

"There were a lot of distractions," says James Rooney, who ran a clinical-studies department at Wellcome before the merger and is now a vice president at Gilead Sciences Inc., Foster City, Calif. "There was a lot of wrestling over new procedures, switching jobs and locations, and uncertainty over which projects would go forward," he says.

The drug 1592 was one of a batch of new chemicals developed in the labs at Wellcome in the late 1980s, when scientists were looking for better versions of AZT. Both drugs, as well as 3TC, belong to a class called nucleosides, which work by blocking an enzyme that is critical to an early phase in the replication of HIV, the virus that causes AIDS.

Wellcome researchers spent several years testing other compounds first. "We had no reason to expect 1592 to be so much more powerful than the others," says Lynn Smiley, director of the company's AIDS clinical trials. Scientists uncovered 1592's antiviral muscle about a year ago, after another experimental drug failed and they began human testing of 1592.

The drug is now in the second of three phases of clinical trials. Glaxo officials say they need another year or more before seeking Food and Drug Administration approval. Because 1592 will be combined with so many other medicines as part of the "cocktail" therapy -- about nine other AIDS drugs are approved or soon will be -- the company must conduct a wider range of safety trials than its earlier drugs required.

"We are very sensitive to the desperation out there from patients who need new drugs," says Stephen LaFon, a Glaxo researcher who helps run tests of the drug. "But we have to balance speed of getting the drug to these few patients and the need to get the best kind of clinical information we can."

That doesn't help patients who have already developed resistance to AZT and other nucleosides. The cocktail approach, by combining three or more drugs that attack different parts of the virus, has been able to reduce HIV to undetectable levels in many patients, allowing the immune system to rebound and fight off deadly infections. But if a patient's HIV has already developed resistance to the AZT-like component, the cocktail will ultimately fail. 1592 could be the new ingredient that would make the cocktail work again.

"You can't just pile a protease drug atop a failing regimen. It won't work," says Martin Markowitz, a research physician at the Aaron Diamond AIDS Research Center in New York.

Demands for the release of 1592 have been growing steadily since this past summer, when Glaxo scientists revealed results of a three-month-long, 80-person study that showed that combining 1592 and AZT was as effective at reducing HIV levels as some three-drug cocktails that included a protease inhibitor. Patient advocates argue that several drugs were released for "compassionate access" based on even fewer test patients than Glaxo has used in studying 1592.

But Glaxo officials say the manufacturing process isn't geared up enough to support widespread distribution right now. Jennifer McMillan, a Glaxo executive who works with AIDS activists, also cites more serious concerns: If 1592 were released now, patients might be less willing to participate in clinical trials because they could, instead, get easy access to free doses of the drug.

Glaxo, surprised by surging demand for 3TC after studies underscored its power, had let 30,000 patients get that drug in a similar program from 1993 to 1995, but it was unable to collect much useful data. "We want to be careful and not repeat that mistake," Ms. McMillan says.

That distresses some people struggling against infection. Spencer Cox, who helps run Treatment Action Group, a New York advocacy group, has watched the HIV levels in his blood rise sharply in recent months as older drugs stopped working and new protease drugs couldn't plug the gap. "I fully understand Glaxo Wellcome's desire for caution," he says. "But I also know I could benefit from 1592 right now. I don't see any reason not to make it available today."

For now, only 175 patients have taken 1592, and only several hundred more will get it when final-stage trials begin sometime next year. That leaves out patients like Mr. Gendin, the 30-year-old New Yorker. He can't take part in Glaxo's expanded trials because such experiments typically use subjects who haven't already developed resistance to earlier drugs. His virus levels have more than doubled in recent months, and Mr. Gendin worries more about HIV outracing his immune system than about any safety problems of Glaxo's experimental drug.

"I have to have" 1592, Mr. Gendin says simply. "I've got nothing to lose."

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From Discovery to Approval

Glaxo Wellcome's new AIDS drug is taking longer to become available than some recently developed AIDS drugs

TIME TO DRUG COMPANY DISCOVERED APPROVAL

1592 Glaxo Wellcome 1989 About nine years* Invirase Hoffmann-La Roche 1989 Six years Crixivan Merck 1992 Four years Norvir Abbott Labs 1993 Three years 141 Glaxo Wellcome (Vertex) 1993 Five years* Viracept Agouron Pharmaceuticals 1994 Three years*

*Anticipated

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