New Anti-AIDS Drugs Win FDA Panel’s Backing
Ushering in an era of more powerful drugs to fight AIDS, a Food and Drug Administration advisory committee Tuesday recommended approval of the first in a new generation of anti-AIDS compounds.
AIDS researchers have been very excited about the potential offered by the new compounds, which are known as protease inhibitors. They are believed to be many times more potent than the most prescribed current AIDS therapies, called nucleoside analogs, which include AZT, DDI and DDC.
Protease inhibitors are “a class of drugs that are the most active agents we have seen to date,” FDA Commissioner David A. Kessler said. The new compound, known as saquinavir, would be the first of a new family of drugs that target the underlying HIV infection. Nucleoside analogs also target the infection, but differently.
The hope in prescribing one or more of the anti-viral drugs is not to cure the disease, because researchers currently believe that is impossible, but to control it by suppressing the onset of AIDS symptoms and thereby prolong life--much as diabetes and hypertension are controlled through a regimen that includes drugs.
The eight-member panel voted its endorsement 6 to 1 with one abstention. The agency is not bound by advisory panel recommendations, but typically gives them great weight in the final decision. In the case of saquinavir, FDA officials have indicated they are leaning toward licensing the drug quickly.
The panel recommended using the drug in combination with a nucleoside, such as AZT or DDC. The hope is that the drugs will hit the virus at two different stages of its reproductive cycle in the body, and have more impact.
This goes along with current belief among most AIDS researchers that the virus may be vulnerable to a “cocktail” approach--using new combinations of drugs. The nucleoside analogs attack the virus early in its replication cycle, while protease inhibitors target the virus in its late stages.
Many researchers have abandoned the concept of HIV as a simple infection that can be treated with a single drug. Instead, they are increasingly looking at the cancer model, where a single tumor is aggressively bombarded with a series of drugs, each exploiting a different weakness of the cancer cells.
The panel said saquinavir appeared to have the most dramatic impact in patients who had not taken nucleoside analogs. Yet clinical trials also indicated that saquinavir had little effect in patients when not taken jointly with a nucleoside, and recommended against use of saquinavir as a single drug.
The committee expressed serious reservations about the drug’s poor “bioavailability”--the extent to which it is absorbed by the body--and the possibility that patients could develop resistance to the drug and to future protease inhibitors.
The drug is manufactured by Hoffmann-La Roche Inc. of Nutley, N.J., and will be marketed under the brand name Invirase.
Saquinavir is one of six protease inhibitors currently under study in humans. Despite its promise, it is regarded by experts as the weakest of the group because of its absorption problems. The company is working on an improved formulation, but it has not yet been studied in patients.
“Is this drug inferior to what we’ll see down the road? Yes,” Kessler said. “Is it inferior to anything else available today? No. . . . It is a first step.”
Roche is further along in clinical trials than other companies testing protease inhibitors. The company submitted its application for approval in September, and the FDA put it on a fast track toward a decision.
In recent years, the agency has moved rapidly--in months, rather than years--to license drugs for AIDS, cancer or other conditions that are life-threatening, or for which there are no other drugs available.
In its willingness to speed such drugs to the market, the FDA often has acted on preliminary evidence without proof that the drugs delay disease and improve survival.
Protease inhibitors work by interfering with the activity of proteinase, an enzyme critical to HIV replication. Laboratory studies have indicated that blocking this enzyme could alter the virus produced, resulting in the replication of new, harmless viruses instead of HIV.
Nucleoside analogs have proved only modestly effective and are plagued by severe side effects because they interfere with other cellular enzymes similar to the viral enzyme they target.
In contrast, the viral enzyme protease, which is important in HIV replication, is unlike enzymes in human cells. Researchers believe the drug will not affect the function of normal cells.
Protease inhibitors have been shown in human trials to sharply reduce the body’s load of HIV, and enhance the number of CD4 cells--the critical immune system cells that are the main target of the virus.
Patients treated with combination therapies including saquinavir showed greater increases in CD4 cells and greater reduction of HIV load than patients given treatments that did not include the drug.
In some cases, the HIV load as measured in the blood was reduced up to 99% and CD4 cells, a measure of the immune system’s strength, increased by up to 100 cells per cubic millimeter of blood, the company said. But the FDA cautioned that for most patients, the boost in CD4 cells was between 30 and 40.
Panel members and experts who spoke to the committee expressed concerns that patients will develop a resistance to protease inhibitors and that using one could render the patient resistant to all such drugs, so-called “cross-resistance.”
Thus, if saquinavir is approved, AIDS patients could face a dilemma in deciding whether to take it, particularly since other protease inhibitors still in development appear to be more powerful.
“It’s not an ideal drug,” said Martin Delaney, founder of Project Inform. “If patients have run out of options, they should be able to take it. But if they’re stable . . . it may pay to wait.”
John S. James, an AIDS activist who edits a publication called AIDS Treatment News, reflected the prevailing view, however, when he told the committee: “Some people do not have time to wait for other options. They should not be denied access to a protease inhibitor now. Resistance or other problems with saquinavir, unless they are very severe, should be handled by warnings on the labeling, not by denying access.”
