Major Proteinase Inhibitor Trials to Begin

Two large-scale trials of the Hoffmann-La Roche proteinase
inhibitor Ro 31-8959 -- seeking 1200 volunteers for a U. S.
study, and approximately 1800 others for a separate international
study -- are now beginning. Proteinase inhibitors are a new kind
of anti-HIV drug, fundamentally different from AZT, ddI, ddC,
d4T, etc., because they target a different step in the HIV life
cycle. Ro 31-8959 is the proteinase inhibitor which is furthest
ahead in human trials; it was tested in people in small studies
last year. The new trials will be the first large human studies
of a proteinase inhibitor.

[Note on terminology: The words "protease" and "proteinase" are
interchangeable; "protease" seems to have slightly more common
usage, and is generally the form preferred in AIDS TREATMENT
NEWS. But Hoffmann-La Roche consistently uses "proteinase"; we
followed its usage here, because this article refers only to the
Roche drug.]

Of the two trials now beginning, one is in the U. S., and
the other is international, including the U. S.

The U. S. trial, which will take place in 40 sites
throughout the country, is now open at a number of those sites.
Volunteers must have used AZT previously, but no other
antiretroviral, and currently have a T-helper count between 50
and 300. They will be randomly assigned to one of four treatment
arms: Ro 31-8959 alone, ddC (HIVID) alone, and combination
treatment combining Ro 31-8959 (at two dose levels) and HIVID.
This study will last for at least 12 months of treatment, and
will compare the treatment regimens by using "clinical endpoints"
of disease progression and survival; it will also investigate
possible resistance to Ro 31-8959, and try to validate the
usefulness of laboratory markers (certain blood tests) for
measuring disease progression and the possible benefits of
treatment.

The international study, due to begin in late February or in
March, will seek 1,800 volunteers, at sites in North America,
South America, Europe, and Australia; 600 of the 1800 will be in
the U. S. Volunteers must have T-helper counts between 50 and
300; but, opposite to the U. S. study, they must not have
previously used AZT (or any other antiretroviral treatment). This
study will also assign patients at random to one of four
treatment regimens, but it will compare the proteinase inhibitor
with AZT, not with ddC. (The four arms are Ro 31-8959 alone,
AZT alone, and Ro 31-8959 (two doses) in combination with AZT.)
This study will last for at least 18 months of treatment. A
total of 90 sites (for both the U. S. and the international
study) will be enrolling volunteers.

Comment

Ro 31-8959 is considered one of the leading proteinase
inhibitors at this time. Its unique advantage is that it is
further along in clinical trials than the other proteinase
inhibitors, and it appears to be well tolerated and to have
antiviral activity in humans. Its major disadvantage is that it
is difficult and expensive to manufacture.

This trial may be difficult to fill, because the
restrictions on prior antiretroviral treatment will exclude many
volunteers. (This is especially true for the international
trial, which is seeking 600 U. S. volunteers with T-helper count
between 50 and 300 who have not taken any antiretroviral
treatment so far -- and who are willing to take AZT as well as
the experimental drug in this trial.)

A common issue in clinical trials (including early trials of
Ro 31-8959) concerns continued access to the drug after the trial
has ended. According to Roche spokesperson Gail Levinson, if the
drug is found to be safe and active it will be provided to
patients in these phase III trials (and also to those in the
phase II trial ACTG 229, which has tested Ro 31-8959 in
combination with other drugs, and is now ending). Roche has not
stated this in writing, however.

Proteinase inhibitors will be in the news during 1994 and
1995, as more clinical trials get underway. These drugs work
very well in laboratory tests, but only the earliest human data
is available. Concerning Ro 31-8959, early human results
reported last summer, at the International Conference in Berlin,
showed significant but not spectacular antiviral activity,
without serious side effects. We will know more when the results
of ACTG 229 are released, probably in the second quarter of 1994;
this study tested Ro 31-8959 in various combinations with other
antiretrovirals, in 300 volunteers.

For more information on either trial, including contact
information for a site in your area, call Hoffmann-La Roche at
800/526-6367.