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Two New Protease Inhibitors Approved By FDA: NIAID Research Was Pivotal to Development of New Class of Drugs

Date: April 1, 1996
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

In March, the Food and Drug Administration (FDA) approved the second and third of a new class of drugs called protease inhibitors. Protease inhibitors are compounds that block the protease enzyme of HIV, thereby preventing the production of infectious viral particles. Other anti-HIV drugs known as nucleoside analogues (AZT, ddI, ddC, d4T, 3TC) target a different viral enzyme, reverse transcriptase.

Ritonavir (Norvir, Abbott Laboratories) received full approval for use alone or in combination with nucleoside analogue medications such as AZT in patients with advanced HIV disease. Early work on discovery of protease inhibitors at Abbott was partially supported through NIAID's National Cooperative Drug Discovery Groups for Treatment of HIV (NCDDG-HIV).

Ritonavir also received accelerated approval for patients with less advanced HIV disease. Accelerated approval is a regulatory mechanism under which FDA grants conditional marketing approval for a product based on improvements in laboratory markers such as CD4+ T cell counts, with the stipulation that information on clinical endpoints such as disease progression or mortality subsequently be obtained in these patients.

Indinavir (Crixivan, Merck) received accelerated approval for monotherapy and combination therapy for the treatment of HIV infection in adults when therapy is warranted. FDA based its approval for indinavir on data showing that the drug improves laboratory markers such as CD4+ T cell counts and viral load in patients at various stages of disease.

A number of studies suggest that protease inhibitors, especially when given in combination with other drugs, can provide significant benefits to HIV-infected people," says Anthony S. Fauci, M.D., NIAID director. "The concept and feasibility of protease inhibitors grew in part out of NIAID-supported basic research, and is an excellent example of research supported by government and industry, working together to benefit patients."

NIAID-supported basic research was pivotal to:

  • The discovery and definition of the importance of the HIV protease enzyme.
  • The definition of the structure of the HIV protease enzyme.
  • The development of assays to measure the inhibition of the HIV protease enzyme.

"NIAID-supported research set the stage for a number of companies to do what the pharmaceutical industry does best: identifying and developing specific medications and ultimately bringing them to market," says Jack Killen, M.D., director of the NIAID Division of AIDS. "Now, with the potent activity of protease inhibitors well-established, NIAID is working with several companies on other research opportunities."

Central to the FDA approval of the new protease inhibitors were data presented at the 3rd Conference on Retroviruses and Opportunistic Infections in Washington, D.C., in late January. Abstracts from this conference are available on the internet at

Studies of Ritonavir

Among these studies, Abbott scientists presented data from an ongoing phase III clinical trial of ritonavir that enrolled more than 1,000 antiretroviral-experienced HIV-infected patients with 100 or fewer CD4+ T cells per cubic millimeter (mm3) of blood (abstract LB6a). In this study, mortality after six months for HIV-infected patients receiving a combination of ritonavir and standard therapy was approximately 43 percent lower than for patients receiving standard therapy alone.

In a separate, open-label study, untreated HIV-infected individuals with CD4+ T cell counts below 250/mm3 received a triple combination of ritonavir plus AZT and ddC. Study investigators noted marked increases in CD4+ T cell counts and significant decreases in viral load in 21 patients who tolerated treatment for at least six months (abstract 285).

"Although these findings are very encouraging, they do not indicate if ritonavir will be clinically beneficial when used long term or in patients with less advanced disease," says Dr. Fauci. "Continued follow-up and additional studies are necessary to answer these questions."

Adverse events associated with ritonavir treatment have included diarrhea, nausea, vomiting, weakness, tingling, liver inflammation, elevation of lipid levels and taste disturbance, according to the FDA. The drug should not be used with many highly metabolized medications; physicians and patients are advised to read the package label closely to assure that potentially severe drug interactions are avoided.

Studies of Indinavir

At the Washington meeting, Merck-supported scientists presented new data from studies involving indinavir, alone and in combination with nucleoside analogues. In one small study, the combination of indinavir, AZT and 3TC dramatically reduced the amount of HIV in the bloodstream of antiretroviral-experienced patients with initial CD4+ T cell counts between 50 and 400 cells/mm3 (abstract LB7). After 12 weeks of treatment with this triple combination, levels of HIV decreased in 22 of 25 patients to amounts that could no longer be detected by a currently available test. Nine of 22 patients taking indinavir alone also achieved this result. Similar results were seen in a small number of patients who had reached the 24-week point in the ongoing trial.

In another study, of 78 AZT-naive individuals with CD4+ T cell counts below 500/mm3, 60 percent of patients taking the combination of indinavir, ddI and AZT had levels of HIV that were reduced to undetectable levels after 24 weeks (abstract 200).

"Further research will help determine whether these dramatic reductions in viral burden will translate to clinical benefit," says Dr. Fauci. "I want to stress that reducing the level of virus to the point that it can no longer be detected does not indicate that a patient is cured or that the virus has been completely destroyed."

Adverse reactions associated with indinavir therapy have included flank pain, blood in urine or kidney stones, which together have occurred in about 2 to 4 percent of patients in current trials. Patients taking indinavir are encouraged to drink water regularly to maintain hydration. Drug interactions with rifabutin and ketoconazole have been reported.

The first licensed protease inhibitor, saquinavir (Invirase, Hoffmann La Roche), was approved for use in conjunction with nucleoside analogues by the Food and Drug Administration in December 1995. Pivotal to the approval of saquinavir were data from an NIAID-sponsored clinical trial known as AIDS Clinical Trials Group (ACTG) 229.

In addition to the three companies with licensed protease inhibitors, several other companies have similar products in advanced stages of clinical development.

"As newer and more powerful anti-HIV therapies become available, and we further define the optimal use of currently licensed drugs, we move closer to our goal of prolonging the disease-free state in HIV-infected people," says Dr. Fauci.