 DISTRIBUTED BY AEGIS, your online gateway to a world of people, information,
 and resources.  714.248.2836 * 8N1/Full Duplex * v.34
 ****************************************************************************

AIDS TREATMENT NEWS #219, March 24, 1995
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

Protease Inhibitors and Beyond: Interview with David Feigal, 
M.D.

Protease Inhibitors: Merck Plans Larger Trials, Expanded 
Access

Protease Inhibitor Consensus Statement

Mothers March Against AIDS, May 7; Congressional Visits May 8

ICC Trials -- First Study Enrolling


***** Protease Inhibitors and Beyond: Interview with David 
      Feigal, M.D.

by John S. James

David Feigal, M.D., is Director of the Division of Antiviral 
Drug Products of the U.S. Food and Drug Administration. After 
the February 23-24 meeting of the National Task Force on AIDS 
Drug Development, a meeting focused on protease inhibitors, 
we asked Dr. Feigal for his perspective on issues related to 
the current development of these experimental drugs.

Access and Supply Problems

ATN: There is wide agreement that the protease inhibitors, 
despite their known limitations, are the most promising 
single approach to HIV treatment today. Yet it will be some 
time before many patients have access to these drugs. What 
should we as a country do in this situation?

Feigal: At the National Task Force meeting, the companies 
developing protease inhibitors were fairly frank about their 
manufacturing problems; one of the companies even had an 
activist group send in a consulting chemist to verify the 
problems. That shows how generally open they have been. These 
compounds are difficult to produce -- and to make matters 
worse they are not very bioavailable [meaning that a large 
oral dose must be used, so a larger supply must be produced]. 
A company which is manufacturing only a few hundred 
kilograms, which is typical in early drug development, may 
only be able to supply the drug for three or four hundred 
patients, if a year's supply per patient is needed. Many of 
the candidate protease inhibitors require multi-step 
synthesis processes with low yields, and for some of them the 
synthesis takes a long time, and there are other problems 
with scale-up to large quantities. These problems will be 
solved; but it has meant that companies had to make decisions 
to go ahead with a much larger scale of production than is 
usual early in drug development.

This supply problem will pass with time; if these products 
meet their potential, they will be manufactured on a large 
scale, and then this period of poor availability will go 
away. The question is what to do in the meantime -- and how 
get the clinical answers at the same time as we provide the 
product to people who cannot participate, or choose not to 
participate, in clinical trials.

Several suggestions have been proposed, some from the 
companies. One is a tiered approach, to make drug available 
to patients with the greatest need. Very few companies have 
much supply, and even that would be used up very quickly.

This is an area where we could use input from the community. 
What do those affected by HIV think would be the fairest way 
to deal with these problems? In a different area, when 
Betaseron was approved for multiple sclerosis, there was a 
serious supply problem, and a lottery was used to distribute 
it. This was very unpopular; there was much unhappiness about 
using a lottery.

The companies are much aware of the difficulties this limited 
supply creates; and there could be a partnership between the 
community and the companies, to figure out how to distribute 
a drug in very short supply. What about a product that could 
meet less than half the need? The largest supply possibility 
we heard about at the National Task Force was enough product 
for several thousand people; that is not as large as the d4T 
expanded access, or the currently ongoing 3TC expanded 
access. 

There must be some way of cooperatively dividing up these 
scarce drugs; there needs to be a partnership between the 
community that needs the access and the companies. To the 
extent that the companies feel they are being asked [by the 
community] to do things that the FDA would not approve, we 
are happy to get involved. But many of the issues revolve 
around such matters as logistics, and protecting trials. 
These issues are between the company and the community 
affected by the disease more than they involve the FDA. If 
the companies are saying the FDA will not allow wider use of 
the drug at a certain stage of development, then we should 
get involved; it usually will not be true. We have said with 
the proteases for a long time that we would welcome an 
expanded access proposal. Manufacturing remains the real 
problem.

Other Treatment Options

Aside from waiting for the protease inhibitors: I agree with 
your statement that these are the single most promising 
agents to come along. But also, if you look closely at some 
of the combination data now developing [using other drugs 
which are more available], some of these are obtaining 
preliminary results in the same general magnitude as the 
protease inhibitors. Most of them, like the proteases, are 
most effective for patients who have not been pre-treated 
with many other drugs. But some of them were capable of 
getting fairly dramatic drops in viral load and rises in CD4 
count, even in patients who have been on prolonged zidovudine 
[AZT]. So I believe it would be a mistake to focus only on 
the protease inhibitors, particularly since we know that 
resistance to these drugs does develop over time; that is an 
early signal that the protease inhibitors, too, are probably 
going to be most useful in a combination.

ATN: So people should not rule out other options that might 
be available now?

Feigal: I would agree that there are other options now. Most 
of these results I referred to have been presented publicly, 
at the Human Retroviruses and Related Infections conference 
in Washington [January 29 - February 2, 1995]; the 3TC data 
and the nevirapine data were very interesting. Each of these 
has different pluses and minuses, and a different story in 
terms of availability; but these and some others are showing 
fairly similar types of preliminary evidence.

Individual Variation

It is difficult to evaluate these preliminary studies, 
however, because some of them are based on small samples. 
Researchers often find that the most compelling way to 
present their data is to show individual patients' results. 
But there can be much selectivity in picking the best 
responders. There have always been single patients in almost 
any trial who have had dramatic responses at the start of the 
trial.

What is more important is that the average responses are 
better. We do not know yet how good they are in broader 
populations and how long the effects will last, and we still 
do not know how to translate changes in viral load to long-
term clinical outcome. We have had these tests for a short 
period of time.

ATN: I remember that when the AZT trials started, there were 
miracle stories then.

Feigal: There was a patient in the original BW 002 [AZT] 
study who had CD4 count under 50, who went up to a thousand, 
in the first 16 weeks of the study. We attributed this to 
problems with the T-cell test at that time. But even though 
the average difference between the placebo and AZT was only 
40 T-cells in that original trial, there were individuals who 
had very dramatic responses. The same was true for patients 
who started ddC after having been on AZT for periods of time.

There always have been individuals who may have responded 
unusually well to a drug. And just as we have learned about 
the pathogenesis of the disease by studying long-term 
survivors, we would probably learn something about drug 
therapies by taking a look at some of these dramatic 
responders, and seeing what is different about their virus, 
or their drug absorption, their intracellular triphosphate 
levels, etc. Some of the variation might be due to chance, 
but still I think there is potential to learn much about 
therapy from these individuals.

T-Cell Responses

 What is different about the protease inhibitors (compared to 
the gloom we felt a couple years ago, as we looked at 
developing a family of me-too nucleoside analogs) is that we 
have seen people who we thought could not mount much of an 
immune recovery, take their T-cells from under 50 into the 
several hundreds, and sometimes almost back to near-normal 
levels. The caution, of course, is that we do not have enough 
followup to know how much of your immunity is really restored 
by having your counts rise. There have been cases of patients 
who have developed pneumocystis with high CD4 counts 
(although there have always been such cases, even in the 
original pneumocystis trial). Despite such concerns, I still 
think we are on the verge of making some real progress with 
the protease inhibitors, and with drug combinations [with or 
without protease inhibitors included].

Business Incentive Issues

ATN: There is also concern in the community that the rules 
for drug development have made it too difficult for companies 
to justify their financial investment.

Feigal: The businessmen would be better at addressing that 
issue than I. But one clear message that has been sent -- and 
we certainly said it again at the National Task Force meeting 
-- is that we would welcome a good accelerated approval 
package for drugs in new classes. [The FDA's "accelerated 
approval" regulations not only provide drugs sooner to 
patients with serious or life-threatening diseases; they also 
help companies by reducing the investment required before a 
drug begins to generate revenue.]

When accelerated approval was first proposed, there were 
discussions about whether it would be used primarily just to 
approve new drugs in the same class. With a new class of 
drugs, would you have to prove clinical benefit [without 
using accelerated approval] for the first drug, and use 
accelerated approval only for later drugs in the same class? 
But today, so long as the clinical confirmation studies are 
in place, we do think that accelerated approval is a viable 
option [even for the first drug in a new class]. It knocks a 
couple years off of the development time, compared to 
traditional drug development. That allows the companies to 
begin financially recouping their development costs for the 
product at an earlier stage; if they still have patent life 
on the product, they have exclusivity for more years. They 
can continue to do the clinical studies funded in part on 
revenue from the product, rather than having to put more 
money into a product that is not yet generating income. And 
there is also the issue of the cost of money; when companies 
talk about the $250 million that it costs to develop a 
product, about half of that is the cost of money [which is 
reduced by having a faster development track].

Accelerated Approval and 

New Indications

ATN: One of the criticisms I heard at the National Task Force 
hearings is that accelerated approval would work for initial 
approval of a drug, but was not available for additional 
indications [because the need is not as urgent].

Feigal: That is not true; in fact, there are examples where 
we have already used accelerated approval for an additional 
indication. For example, clarithromycin was on the market for 
non-AIDS indications, and we gave it accelerated approval for 
MAC.

Part of the issue here is that the cycle of developing new 
indications is relatively long, compared to the patent life 
of the product. If you look at the time frame, of usually 
taking about a year to design and launch the trial (not just 
FDA time, but the whole time of the community and the 
researchers in setting up a trial), and then enrolling the 
trial for about a year and a half, and then having another 
year of followup, and another half year to write up the 
results if it is a big study, and then another four to six 
months for us to review the results and get the indication 
changed, you are looking at a cycle that can easily run two 
to five years for an additional indication. So one of the 
issues that has been raised in AIDS and in cancer is whether 
that is a standard which results in the drug label not 
keeping up with medical practice. 

Viral Load and Early Approval

The other time that discussion comes up [of whether we will 
always need to have clinical-endpoint studies eventually] is 
the issue of what does it mean to have a validated surrogate 
marker? We, at the FDA, already accept the fact that the 
virus is relevant; and that changes in viral load mean that 
you have an active drug; and that that, along with favorable 
immunologic changes, form a reasonable basis for accelerated 
approval. What we do not know is whether or not you can 
individualize someone's therapy and get a better result by 
changing their therapy as their viral load changes. We do not 
know if early changes in viral load will predict a sustained 
response some years later -- consider the Concorde 
disappointment with the early changes in CD4 count [which 
failed to predict better outcome later]. So we still need 
clinical endpoints to be confirmed. 

But in the future, we might reach the stage where the viral 
load, or some other measure, or some combination measure, is 
so highly predictable that it is a reasonable basis to change 
clinical practice. Then we would be in a situation where we 
are with cholesterol-lowering agents, and anti-hypertensive 
agents; they are not labeled to prevent heart disease or 
stroke, they are labeled to lower cholesterol or to lower 
blood pressure. Right now we would not quite know what a 
label would mean if it said that this drug was indicated to 
lower HIV RNA in the serum. We are still not quite there yet, 
although we are all excited by how promising these measures 
look.

Another consideration is that many of the nasty surprises 
from basing treatment on surrogate markers [such as a 
notorious study of heart drugs, in which two drugs which 
successfully suppressed abnormal heart rhythms also increased 
the chance of death] did not come from the fact that the 
markers were necessarily poor, but from the fact that the 
drug had some other slow, damaging effect that was only 
detectable by doing a clinical study and seeing what the 
actual results were. So I think, for drugs in new classes, we 
eventually need to know how good they are clinically. The 
incentive for the companies is that accelerated approval gets 
them marketing use of their product, at a time when they are 
still pursuing the clinical question. 

Here again we need a partnership with the community; the 
community needs to remain convinced that it is important to 
find out clinically how good these things are, and has to be 
willing to participate in trials. We have passed the era of 
placebo-controlled trials, but we can still learn a lot from 
active-controlled trials, or dose-response trials, and we 
need to have the commitment to do that.

Some companies are discouraged by how difficult it is to 
clinical trials in HIV in the U.S., with the rapidly changing 
therapy, with people discontinuing early in trials because of 
the availability of a new trial or a new expanded access. 
There needs to be that commitment together to find answers. I 
think that commitment is still there; it just gets frayed 
around the edges at times.

FDA Clinical-Trials Workshop

ATN: Kessler mentioned plans to set up a workshop on AIDS 
clinical trials. What issues will this meeting address?

Feigal: The quickest way to organize this meeting may be to 
use the existing advisory-committee mechanism; we can turn 
the meeting into more of a workshop than a hearing. We will 
probably try to do this in late spring or early summer.

A number of questions need to be aired, and relatively 
quickly. For example, what are the most relevant comparison 
arms? That depends on whether you do a traditional standard 
therapy vs. new therapy, or whether you extend that design 
into combinations (which we at the FDA already believe should 
be done more vigorously), or whether you modify it even 
further by taking a treatment-strategy approach, and leaving 
some parts of protocols very wide open, in terms of use of 
concomitant therapies.

Another important area is the role of larger trials, vs. 
smaller, intensive, high-tech trials. This is not an either-
or, but how you best integrate those approaches.

Then there is the question of non-survival clinical 
endpoints. Is it still relevant to use the old CDC 
infectious-disease endpoints? Or are there more efficient 
measures, such as counting them in a weighted fashion, or 
evaluating more than just the first endpoint and also 
counting subsequent ones?

On viral load, there is still much to be learned about which 
viral load markers predict which clinical events, and how far 
into the future do they predict. We know that CD4 counts have 
predicted only for about a year. But we need to take a look 
and see what we can learn, and design further end-point 
research into the trials that are ongoing right now.

There are a number of interesting confirmatory trials 
underway from the past accelerated approvals. The d4T trials, 
the ddC trials, and many of the ACTG studies, will 
potentially give us much data fairly quickly about CD4 
counts, viral load, and clinical events.

We also need continued focus on special populations: the 
design of pediatric trials, the issue of vertical 
transmission, and design for the use of drugs in pregnancy, 
including treating women with advanced disease who are 
pregnant. Some of the newer compounds do not have the 
genotoxic effects that many of the nucleosides have; they may 
be safer for use in pregnancy, even aside from the issue of 
vertical transmission.

I would see this as a two-day workshop to have people present 
designs, and have panels; and probably use the advisory 
committee mechanism at the end to figure out what the 
immediate take-away messages are, and where the Antiviral 
Drug Products Advisory Committee would like to comment -- 
messages that commercial sponsors might pay attention to as 
they are designing trials.

There has been some misunderstandings that the reason that 
large trials are not used, for example, is because the 
sample-size calculations are not done correctly. That may 
happen in some cases, but more often there is disagreement 
among the designers of those trials over whether they are 
ready yet to look for small or moderate effects, or whether 
they are still screening drugs for larger effects. This 
workshop will be a chance to put some of these issues on the 
table and talk about some strategies.

We will not come up with a cookbook. There are many different 
ways to develop drugs; we need to continue to use all the 
ways we can, as we continue to find surprises when we modify 
our designs, or try a different population. For example, we 
are getting a new appreciation that we too rapidly concluded 
that it was hard to benefit patients with very low CD4 
counts.

I think this is an exciting time, as there is a renewed 
interest not only in the proteases, but other combinations of 
non-nucleosides, and the AZT plus 3TC combination, that give 
us some reason to expect that we could make important 
treatment advances if we try some of these new approaches in 
trials.

The Empty Pipeline?

ATN: Many people are saying that after the protease 
inhibitors, the "pipeline" for future development of AIDS 
drugs is empty. How do you see this?

Feigal: It is hard to judge the pipeline. We thought the 
pipeline was fairly empty after many of the non-nucleoside RT 
inhibitors were abandoned three or four years ago; but 
interestingly, the non-nucleoside RT inhibitors are still 
around, and may, at the end of the day, in the right 
combinations, have an important role. The proteases bloomed 
rather rapidly at a time when people though the pipeline was 
largely empty. If it seems empty at times, history shows that 
it is cyclical. 

Many advances that have been made in other fields, in chronic 
infections and malignancies, have been through careful 
construction of rational combination therapies. Even without 
new drugs there is still plenty of work to be done on 
combinations for HIV. For example, 3TC did not look 
attractive before the combination result with AZT; it is 
fortunate that the combination trial got done. 

I do not see the pipeline as being terribly empty.

And there is always the left-field factor. Although we now 
focus a lot on drugs that have a direct antiviral effect, it 
is possible that some of the immunomodulatory therapies, or 
therapies that try to target programmed cell death, or other 
mechanisms of disease pathogenesis, might make a major 
difference, particularly in some combinations. If you look 
more broadly than just the direct antivirals, there is lots 
of work to be done.

ATN: People are concerned that small companies are excluded 
from drug development, because the rules make the process so 
expensive.

Feigal: The possibility of a drug coming out of left field 
does raise the issue of the small-company problem. The 
biggest need of little companies has always been to have big-
company partners, just to keep the business going. A lot of 
how well the little companies do will depend on the big 
companies' interest in investing [which has clearly 
diminished recently, in all of biotech, not just AIDS].

In terms of the FDA's response to small companies, there is 
only one set of laws and regulations, and they apply equally 
to all companies. However, we are given the flexibility to 
interpret and to modify the requirements. We look for 
opportunities to do problem solving with small companies. 
Typically that has involved allowing them to try and get some 
initial evidence of efficacy as efficiently as they can, 
because that is usually the make-or-break for a new product. 
If they say that their compound is an "antiviral," but when 
they give it to someone, it does not affect any parameter 
that they can measure, then probably the substance is not 
worth pursuing as an antiviral. On the other hand, if it is 
dramatically antiviral, the company will probably be able to 
find partners to develop it.

One way we can help speed the development process is to allow 
companies to keep the animal toxicology studies just ahead of 
the human trials, so they do not have to do the whole 
toxicology profile evaluation before they even start in 
humans. The big companies sometimes use that strategy, too; 
although often when they are fairly committed to a product, 
they will do the whole animal workup before they even bring 
it in [to the FDA]. It is case-by-case problem solving; it 
depends on how much is known about the product, and the class 
of products, and how worrisome the potential toxicity. We are 
committed to try to find ways to solve problems with these 
companies, and give them answers quickly. Problem solving and 
rapid review is how we see our role.

ATN: What else was significant at the recent protease-
inhibitor meeting of the National Task Force on AIDS Drug 
Development?

Feigal: Just the ability to get the companies to come and 
talk about drug development, and to talk about their NDA 
(drug approval) filing times in public, was an unusual event; 
some people may not have appreciated that companies do not 
usually like to do that, they sometimes even keep NDA filings 
completely confidential. Kessler [FDA Commissioner David 
Kessler, M.D.] was asked by the community to take a hard look 
at the protease inhibitors and see what could be done. 
Whether the meeting was an overall success or not, there were 
things taken away, including a commitment by Merck to try and 
find expanded access in their drug development, and to do 
pediatric trials. 

The companies are asking us what is the minimum safety 
database [required for approval]. An unfortunate result of 
the supply problem is that we do not have much safety 
experience with some of the protease inhibitors; often there 
are not even three dozen patients who have received the 
product more than three or four months. This issue was 
addressed at the meeting; if we cannot have expanded access 
with ten thousand patients to look at safety [before drug 
approval], what will we settle for? What came out was a 
recommendation for several hundred patients with at least 
half a year or so of exposure and followup. I think that can 
happen relatively quickly, with the studies and the use of 
these compounds already in the pipeline. A good outcome from 
the meeting was preliminary discussion of what the 
requirements should be, what are the parameters. This helps 
the companies in their planning. 

Kessler took the commitment to that meeting very seriously, 
including personally lobbying the companies to get them to 
come forth and talk about these issues fairly frankly. It was 
interesting to me, knowing what they have told the FDA in 
confidence, how willing the companies were willing to be 
frank and open. If they seem to be excited about these 
products, I think it is because of a sincere belief by the 
companies that these could be potentially breakthrough 
products for this disease.

Protease Inhibitors: Merck Plans Larger Trials, Expanded 
Access

by John S. James

Merck and Co. has devoted extraordinary resources and taken 
the lead in overcoming production problems of the current 
generation of protease inhibitors. In mid March it announced 
that its comparative trial and open-label protocol for 
persons with a CD4 (T-helper count) under 50 -- expected to 
start in mid 1995 -- could be expanded from 150 to over 1400 
by the end of 1995. Merck also updated the community on its 
plans for large trials in other groups of patients.

The following phase III studies are currently planned:

* 780 AZT-naive patients, with CD4 counts from 50 to 500, 
will be randomized to MK-639 (the current name of Merck 
protease inhibitor, formerly called L-735,524), AZT, or the 
combination. This one-year trial will look for changes in 
viral load and CD4 count. Screening and enrollment have begun 
in the U.S., Canada, and Europe.

* 540 AZT-experienced patients with CD4 counts from 50 to 500 
will be randomized to MK-639, d4T, or the combination. This 
one-year trial will begin in May in the U.S. and Europe.

* In Brazil, 750 AZT-naive patients, with CD4 count from 50 - 
250, will be randomized to MK-639, AZT, or the combination. 
This study will look for clinical endpoints, but will analyze 
CD4 counts after six months. This study is planned to begin 
in March 1995.

* 90 AZT-experienced patients (with CD4 count between 50 and 
400) will be randomized to MK-639, AZT plus 3TC, or the 
triple combination. Enrollment will begin in April in the 
U.S.

* For those with CD4 count under 50, 300 patients will be 
randomized to MK-639, AZT plus 3TC, or the triple 
combination. Those for whom AZT or 3TC would be medically 
inappropriate will be assigned to receive open-label MK-639. 
After the comparative trial is enrolled, the open-label arm 
will be expanded to allow at least 1400 patients, by the end 
of 1995. This trial will start enrollment in June.

* Another large trial is planned for AZT-experienced 
patients, starting in late 1995. The treatment arms will be 
determined based on results of earlier trials.

Assuming all goes well, Merck plans to file for accelerated 
approval for MK-639. The company currently has no other AIDS 
drugs in development.

For information on enrolling in trials of MK-639, call 
800/379-1332, 8 a.m. to 7 p.m. Eastern time.

Protease Inhibitor Consensus Statement

Note: The following statement was developed by many people, 
collectively calling themselves the Protease Consensus 
Coalition. It has been signed by 61 organizations, including 
ACT UP/New York Treatment and Data Committee, AIDS Project 
Los Angeles, AIDS Research Alliance (formerly Search 
Alliance), AIDS Treatment News, Being Alive (Los Angeles and 
San Diego), Committee of Ten Thousand, Log Cabin Republicans, 
Mothers' Voices, National Association of People with AIDS, 
Project Inform, and the San Francisco AIDS Foundation. Over 
100 individuals have also signed on. Organizations and 
individuals can obtain a copy or sign the statement by 
sending a fax to the Linda Grinberg Foundation, 310/471-4565, 
which is collecting signatures for this project.

Consensus Statement on the Accelerated Approval of 

Protease Inhibitors

* Overview

Access to protease inhibitor drugs now in development 
represents the best hope for delaying disease progression for 
tens of thousands of people living with HIV and AIDS who have 
exhausted the limited benefit from currently approved 
antiviral therapies. As a class, these drugs have 
demonstrated both lower levels of toxicity and significantly 
increased levels of antiviral activity, even in people with 
advanced disease.

The benefit of these drugs may be limited due to the 
development of drug resistance, a problem common to all 
currently approved antiviral compounds. While it may take 
years of additional study to determine the optimal use of 
protease inhibitors, this certainly should not delay prompt 
access to this therapy by people in urgent need and those who 
wish to add them to their arsenal of HIV medications. Any 
further delay in the availability of these drugs is a moral 
affront to the rights of people with HIV/AIDS and their 
healthcare providers.

* Compassionate Use/Salvage Therapy

We demand that both sponsors and the Food and Drug 
Administration take a more compassionate stance and cooperate 
to make promising compounds like these available in "salvage 
programs" after the first evidence of safety and surrogate 
marker activity. These compassionate access programs should 
routinely make drug available, prior to accelerated approval, 
for those people who have failed existing therapies and risk 
near-term danger of death or life-threatening infections.

The development of this class of drug must take into 
consideration its unique ability to provide benefit to the 
acutely compromised segment of the HIV-infected population. 
Availability of salvage strategies is of the highest priority 
for people living with HIV. There is no logical or moral 
reason to withhold these drugs from people with advanced 
illness, people whose lives hang in the balance. Currently, 
the compounds from Abbott, Merck and Roche are qualified, by 
any humane standard, for compassionate use.

* Accelerated Approval

Protease inhibitor compounds should be licensed for 
accelerated approval as soon as possible. FDA approval of 
these compounds should be based on existing regulations 
governing accelerated approval of new drugs for life-
threatening illnesses:

(1) Clear evidence of benefit on surrogate markers has been 
demonstrated;

(2) Principal toxicities have been defined;

(3) Longer-term development plans have been initiated 
designed to determine the drugs' usefulness in promoting 
clinical and survival improvements as part of a medical 
strategy for coping with HIV infection.

These conditions have been met, or nearly met, by a number of 
the existing candidate protease inhibitor compounds, and we 
urge their sponsors to file application for accelerated 
approval no later than the 2nd quarter of 1995. Currently the 
compounds from Abbott, Merck, and Roche qualify by showing 
far superior antiviral activity than any other drug granted 
approval under this regulation.

* Resistance and Drug Interactions

As with all antivirals, the development of drug-resistant 
strains of virus while using these compounds may warrant 
additional considerations. To address this concern, sponsors 
should also be required, prior to accelerated approval, to 
present meaningful data on:

(a) the speed and levels of resistance encountered;

(b) the degree of cross-resistance found with other protease-
inhibitor compounds;

(c) the interaction of the compound with other commonly used 
anti-HIV medications;

(d) bioavailability.

* Summary

Any effort to withhold access to promising protease inhibitor 
compounds is contrary to the interests of HIV-infected 
people, inconsistent with the Accelerated Approval 
regulations, and scientifically unwarranted. The long history 
of the development of the earlier generation of antiviral 
drugs clearly demonstrates that it is possible to continue 
conducting clinical trials of compounds, long after their 
marketing approval.

Mothers March 

Against AIDS, May 7; 

Congressional Visits May 8

Mothers March Against AIDS is organizing a Washington, D.C. 
march on Sunday May 7. "As we march, we will carry large 
photos of our deceased or ill children to show the faces of 
AIDS. We want to impress upon our leaders, our nation, and 
the entire world that we will not tolerate the loss of 
another generation."

And on the following day, Mothers' Voices is organizing 
visits to key members of Congress, especially from the 
following states: Florida, Georgia, Illinois, Kansas, 
Louisiana, Oregon, Texas, and Virginia.

For more information, contact Mothers March Against AIDS, 
212/953-5621; or Mothers' Voices, 212/730-2777.

ICC Trials -- 

First Study Enrolling

by John S. James

The first of a series of trials of the Inter-Company 
Collaboration for AIDS Drug Development (ICC) is now 
enrolling. These trials are particularly important for at 
least two reasons:

(1) The ICC is an association of 15 pharmaceutical companies 
set up to share information and otherwise facilitate the 
testing of drug combinations -- which otherwise can be 
difficult when the drugs are produced by different companies. 
This cooperation allows rational combination treatments to be 
rapidly designed and tested.

(2) The choice of combinations to test is based on analysis 
of all available information about the drugs -- laboratory 
tests, virological analysis, and human experience; some of 
this information is proprietary and has not been released 
publicly outside the ICC. Therefore, the combinations chosen 
from this analysis may be worth considering even for 
treatment outside the trials, when the drugs are available.

The study now enrolling is seeking volunteers with CD4 (T-
helper) counts between 200 and 500, who have NOT previously 
taken AZT.

The current series of planned ICC trials has a master-
protocol design, meaning that the different trials in this 
series will differ little, except for the choice of drugs. 
Each trial will last 48 weeks. It will randomly assign 75 
volunteers each to three different treatment arms. Everyone 
in the trial will receive the same combination of two drugs; 
but one treatment group will receive a third drug in 
addition, another treatment group will receive a different 
third drug, and the third treatment group will receive a 
placebo for the third drug (meaning that they will be treated 
with the basic two-drug combination).

These trials will look for changes in blood tests, especially 
viral load and CD4 count. They will not look for differences 
in clinical endpoints, since few opportunistic infections 
would be expected to occur in these trials.

In the first trial, ICC 001, which is now enrolling patients, 
the two drugs that everyone will receive are AZT (brand name 
Retrovir) and ddC (brand name HIVID). As the third drug, one 
group will receive nevirapine (an experimental non-nucleoside 
reverse-transcriptase inhibitor). Another group will receive 
saquinavir (brand name Invirase, the Hoffmann-La Roche 
protease inhibitor) as its third drug. The third treatment 
group, with the placebo third drug, will be receiving AZT 
plus ddC, which might be more beneficial for those who have 
not taken AZT before than for those who have.

Future ICC Plans

After the first trial is fully enrolled, volunteers will be 
enrolled into the second trial, ICC 002. In this trial, the 
two drugs everyone will receive will be AZT and ddI. One 
group will receive nevirapine as the third drug; another 
group will receive 3TC as the third drug.

We do not know what combinations will be tested later in this 
series.

In addition to this series of trials, the ICC may also 
conduct other trials with a different design. Some of these 
future trials may have fewer patients and may run for less 
than 48 weeks -- since changes in blood work are likely to be 
seen quickly, and changes in clinical outcome will not be 
seen in any case in these studies.

For Information on How to Enroll

The first trial (ICC 001) is being conducted in the cities 
listed below. For more information, you can call the 
coordinating center at PAREXEL International Corporation, 
800/925-AIDS, from 9 a.m. to 5 p.m. Eastern time. Or you can 
call directly to the office of the physician in your city.

Bradenton, FL; Dr. Michael Bach or Dr. Jeffrey Nadler, 
813/753-2949.

Milwaukee, WI; Dr. Barry Bernstein, 414/257-6151.

Sherman Oaks, CA; Dr. Paul Berry, 818/906-6279.

Torrance, CA; Dr. Gildon Beall, 310/222-2365; call the study 
coordinator Sally Kruger, 310/222-3848.

Maitland, FL; Dr. Jeffrey Goodgame, 407/647-6000.

St. Paul, MN; Dr. Keith Henry, 612/221-1280, or Dr. Paul 
Carson, 612/927-1381.

Ft. Lauderdale, FL; Dr. Anthony La Marca, 305/564-4222.

San Francisco, CA; Dr. William Lang, 415/474-4440.

New York, NY; Dr. Donna Mildvan; call Clinical Trials Unit, 
212/420-4519.

Detroit, MI; Dr. Louis Saravolatz, 313/876-2573.

Denver, CO; Dr. Robert Schooley, 303/270-6753.

Atlanta, GA; Dr. Melanie Thompson, 404/876-2317.




***** AIDS TREATMENT NEWS
      Published twice monthly

Subscription and Editorial Office:
   P.O. Box 411256
   San Francisco, CA 94141
   800/TREAT-1-2  toll-free U.S. and Canada
   415/255-0588 regular office number
   fax: 415/255-4659
   Internet: aidsnews@igc.apc.org
Editor and Publisher:
   John S. James
Reader Services and Business:
   Richard Copeland
   Thom Fontaine
   Tadd Tobias

Statement of Purpose:
AIDS TREATMENT NEWS reports on experimental and 
standard treatments, especially those available now. We 
interview physicians, scientists, other health 
professionals, and persons with AIDS or HIV; we also 
collect information from meetings and conferences, 
medical journals, and computer databases. Long-term 
survivors have usually tried many different treatments, 
and found combinations which work for them. AIDS 
Treatment News does not recommend particular 
therapies, but seeks to increase the options available.

Subscription Information: Call 800/TREAT-1-2
   Businesses, Institutions, Professionals: $230/year.
   Nonprofit organizations: $115/year.
   Individuals: $100/year, or $60 for six months.
   Special discount for persons with financial difficulties:
   $45/year, or $24 for six months. If you cannot afford 
   a subscription, please write or call.
   Outside North, Central, or South America, add air mail 
   postage: $20/year, $10 for six months.
   Back issues available.
   Fax subscriptions, bulk rates, and multiple subscriptions
   are available; contact our office for details.
   Please send U.S. funds: personal check or bank draft, 
   international postal money order, or travelers checks. 
   VISA, Mastercard, and purchase orders also accepted.

ISSN # 1052-4207 

Copyright 1995 by John S. James.  Permission granted for 
noncommercial reproduction, provided that our address 
and phone number are included if more than short 
quotations are used.

