L-524: New Protease Trial Recruiting

A new protease inhibitor developed by Merck Research
Laboratories is beginning its first phase II trial, which
will take place at three East Coast sites.

L-524 (L-735,524) has been in small human trials since
February 1993. In laboratory tests, it gives 95 percent
inhibition of HIV spread in cell cultures at concentrations
of 50 to 100 nanomolar (0.05 to 0.1 micromolar). In people,
anecdotal findings have shown about a 50 percent reduction in
p24 antigen (comparable to AZT), with no viral resistance
found so far. But since only a handful of people have taken
L-524 for more than two weeks, all that can be concluded now
is that more trials are justified. P24 antigen changes
normally happen very quickly; the big question is whether
they are sustained.

The new phase II trial will last six weeks, and may be
extended. It will randomly assign volunteers to three groups:
L-524, 200 mg every six hours; L-524, 400 mg every six hours;
and AZT, 200 mg every eight hours. No toxicities have yet
been found from L-524 in the 400 mg dose; however, some
volunteers given a higher dose (600 mg every four hours)
showed rises in liver-function tests.

Volunteers must by 18-65 years old, with T-helper count below
500 (there is no lower limit). They must not be pregnant.
Creatinine must be less than 1.5 times upper limit of normal,
and liver transaminases and bilirubin less than 2 times upper
limit of normal. Volunteers cannot have previously used any
protease inhibitor. They will be tested and need to have a
positive p24 antigen (at least 25 pg/ml). Before entering the
trial, they will need a 30-day washout of other
investigational drugs, and a two-week washout of AZT, ddI,
and ddC.

For more information, contact the study coordinator at one of
the three trial sites:

* Pitt Treatment Evaluation Unit, University of Pittsburgh,
contact Nancy Mantz, R.N., 412/647-8125.

* AIDS Treatment and Evaluation Unit, University Hospital,
State University of New York at Stony Brook, contact Ruth Ann
Burk, R.N., 516/444-1658.

* Bellevue Hospital Clinical Research Unit, New York
University, New York City, contact Mary Ann Kiernan, R.N.,
212/263-6565.

Comment

Protease inhibitors are generally considered the most
promising class of experimental drugs at this time; they are
being developed by a number of companies. Unlike other
classes of anti-HIV drugs, protease inhibitors are able to
completely shut off viral replication in laboratory tests.
And because the protease is a small enzyme, it should offer
few opportunities for the virus to mutate and develop drug
resistance.

The major problem with protease inhibitors has been getting
them into the body and to the sites where they are needed.
The p24 antigen reduction seen in a few patients so far
suggests that this drug is bioavailable. Similar results have
been seen with a similar protease inhibitor being developed
by Hoffmann-La Roche.

The fact that the p24 antigen result is only comparable to
that of AZT does not necessarily mean that the drug will only
work as well. With protease inhibitors, new virus continues
to be produced by already-infected cells; however, this virus
is immature and not infectious. The p24 antigen test may be
detecting this defective virus, and therefore not giving a
true picture of how well this class of drug is working.