NIH on government role in funding development of Protease Inhibitors

[James Love <love@cptech.org>]

http://www.niaid.nih.gov/factsheets/protease.htm
March 1996, US NIH fact sheet:


  Two New Protease Inhibitors Approved by FDA

NIAID research was pivotal to development of new class of drugs

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 anti­HIV
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 
(NCDDG­HIV).

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 www.idsociety.com.

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 HIV­infected 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 24­week 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 NIAID­sponsored 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 anti­HIV therapies become available, and we
further define the optimal use of currently licensed drugs, we move
closer to our goal of prolonging the disease­free state in HIV-infected
people," says Dr. Fauci.



NIAID, a component of the National Institutes of Health, supports
research on AIDS, tuberculosis and other infectious diseases as well as
allergies and immunology.

Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services
March 1996


-- 
James Love, Director, Consumer Project on Technology
I can be reached at love@cptech.org, by telephone 202.387.8030,
by fax at 202.234.5176. CPT web page is http://www.cptech.org