       GMHC Treatment Issues, Volume 10, Number 1 - January 1996
       _________________________________________________________

       Published by Gay Men's Health Crisis, Treatment Education
       129 West 20th Street, New York, NY 10011
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       Contents

       FDA Reform
       New Drugs at theFDA
       New Formulation for an Approved Drug
       Expanded Access and Expanded Trials
       Drugs Under Development
       An Old Drug with a New Use
       Possible Future Drugs

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       The Growing Debate over FDA Reform
       by Derek Link

       Early in the AIDS crisis, when the epidemic's disastrous
scope could not yet be imagined, AIDS activists pressed the Food and
Drug Administration (FDA), the federal agency that regulates the
testing, sale and promotion of drugs, for a faster and more humane
response to this public health emergency. On October 11, 1988,
thousands of AIDS activists from across the nation descended on the
FDA's headquarters in Rockville, Maryland. They demanded faster
approval of new AIDS therapies and focused public attention on the
glacial pace of this federal bureaucracy. Over the last eight years,
AIDS activists have continued to scrutinize the FDA's AIDS
activities, serving as consultants on FDA advisory committees,
issuing critical reports on its operations and winning many
important victories along the way.

       AIDS drugs are now approved faster, and access to them
granted earlier, than anyone thought possible just a few years ago.
Because of pressure and creative ideas from AIDS activists, the FDA
pioneered accelerated approval and expanded access programs. One
need only look at the recent past for a vivid example of the success
of AIDS activists' efforts. Saquinavir, the first of the new
generation of protease inhibitor drugs, was approved in a record
three months, the fastest AIDS drug approval ever. All is surely not
perfect at the FDA, but the agency has made substantial progress.
AIDS activists still have a full regulatory agenda covering such
issues as how best to use the accelerated approval process while
insuring that sufficient information on drugs' actual potential is
generated through post- marketing studies.

       After the Republican landslide in the 1994 Congressional
elections, the new Congress immediately took up the cause of FDA
reform as one of its highest priorities. Accusing the FDA of
murderous delays and inept bureaucracy, the new Congress adopted
much of the confrontational language of AIDS activists in its
debates on the FDA. The similarities between AIDS activists and
Congressional Republicans end with the rhetoric, however. AIDS
activists have helped to organize a national campaign in support of
responsive and efficient drug regulation, but in opposition to
ideological, political attacks on our nation's public health safety
net. Congressional "FDA reform" could halt medical research and
innovation, harm people with serious and life-threatening disease,
and undermine the nation's health.

       A Debate About the Role of Government

       Reform of the FDA, AIDS activists recognized early, was a
problem of policy, management, resources and administration. The FDA
implemented faster drug approvals and expanded access programs
without Congress ever passing a law. This is because the
organization, policies and procedures of the FDA are not established
by Federal law. With wide discretion over drug regulation, the FDA
could approve drugs faster by implementing internal policy changes.
This flexibility is perhaps its greatest asset; it gives the agency
the ability to respond rapidly and in a non-political manner when
public health emergencies, like AIDS, arise.

       Instead of focusing on the management problems at the FDA,
the Republican Congress has set its sites on the Food, Drug and
Cosmetic (FDC) Act itself. The FDC Act gives the federal government
the duty to insure that drugs, biological products and medical
devices are safe and effective for the treatment of specific health
conditions and evidence of that safety and efficacy is accurately
represented to the American people. By seeking to amend fundamental
government authority over drug regulation, the Congress has opened a
debate not on the problems at the FDA but instead on the role of the
federal government in medicine, pharmaceuticals and clinical
research. The FDA can sometimes be frighteningly bureaucratic, but
the FDC Act itself is not an obstacle for drug development. The Act
fosters an environment in which medical innovation grows out of
solid clinical research. People with AIDS, as well as other
life-threatening diseases, need this research more than anyone else
to point the way to effective treatments.

       The FDA regulates the core elements of life, totaling a
quarter of all consumer spending. Any change in the government's
authority over such a large segment of the economy brings out armies
of industry lobbyists, each promoting its own self-interest.
Encouraged by the Republican landslide, FDA-regulated industries and
their advocates initiated a major lobbying and public relations
campaign within a month of the 1994 election.

       Industry and Politics in Congress

       HIMA (the medical device manufacturers group), BIO (the
biotech industry group) and PhRMA (the drug industry group) are the
main industry groups pressing for substantial changes to the Food,
Drug and Cosmetic Act. BIO's president, Carl Feldbaum, told the
National Journal, "We're pushing [FDA reform] very hard. We have a
lot of irons in the fire with the FDA."

       Each of these groups has released FDA reform proposals, and
has dispatched their lobbyists to the Capitol. "I think they'd like
to eviscerate the FDA, but if they can't do that, they'd like to
intimidate the FDA," Henry Waxman, a senior Democrat on the House
Commerce committee and a leading consumer protectionist, told the
National Journal. Right-wing political organizations, with heavy
funding from regulated industries, have gone on the offensive too.
The Washington Legal Foundation (WLF), the Progress and Freedom
Foundation and Citizens for a Sound Economy, are the three most
prominent right-wing advocacy groups working on FDA reform
legislation.

       The WLF has run several full page ads in The New York Times
and Washington Post harshly criticizing the FDA with the tag line,
"The Problem with Health Care in America is the FDA." The WLF
furthermore has filed several lawsuits over FDA regulations, mostly
over the type of marketing strategies pharmaceutical companies can
pursue. The Foundation argues that limiting the claims companies can
make to the applications approved by the FDA is a violation of the
First Amendment's protection of free speech.

       The President of the WLF, Alan Slobodin, temporarily stepped
down from his post to become a senior staff member of the House
Commerce Committee, which has authority over the FDA and will draft
reform legislation in the House. The Lilly Endowment, a foundation
whose funds come from Indianapolis- based drug maker Eli Lilly, gave
the WLF $150,000, making it one of the organization's largest
financial backers.

       The Progress and Freedom Foundation is perhaps the biggest
player among the advocacy groups. The Foundation is closely
associated with House Speaker Newt Gingrich. The Foundation is run
by close Gingrich supporter Jeffrey Eisenach, and handles many of
the Speaker's political activities, including organizing Progress
Report, Gingrich's talk show on National Empowerment Television.
Major industry contributors to the Foundation have included
Burroughs Wellcome, Glaxo, Genzyme, Searle, Johnson & Johnson,
Direct Access Diagnostics (now a Johnson & Johnson subsidiary),
Health South Corporation, Amgen and Solvay. "This was an
organization that looked like it was going to have some influence,
and we wanted to have some influence with them," Lisa Raines, chief
Washington lobbyist for Genzyme, has stated.

       Speaker Gingrich has already interceded on behalf of some of
these Foundation contributors. Last summer, Gingrich urged the FDA
to move faster to approve Luvox, a Solvay drug for
obsessive-compulsive disorders. Gingrich also has urged the FDA to
move faster in approving an HIV home test kit manufactured by Direct
Access Diagnostics. The House Ethics Committee is investigating
Gingrich's relationship to Direct Access Diagnostics, as part of its
overall ethics investigation of the Speaker.

       The Tobacco Industry's Shadowy Role

       Last year, the FDA proposed sweeping new regulations which
would substantially change the way cigarettes are sold in the United
States -- limiting advertising and restricting sales to minors. The
new FDA regulations could have a devastating impact on tobacco
industry profits -- almost all smokers start when they are
teenagers.

       The tobacco industry has responded with a full-scale assault
on the FDA and the FDC Act. On January 2, it submitted to the FDA a
2,000 page document with 45,000 pages of supporting documents
challenging its authority to regulate cigarettes. The industry also
launched an aggressive campaign contribution drive to the Republican
party. In the first half of 1995, the tobacco industry pumped $1.5
million into Republican party coffers, over five times the amount
from the same period in 1994, and a record level contribution of so-
called "soft money" to a political party. In addition the tobacco
industry has sharply increased donations to individual Republican
Congressmen. Most tellingly, Thomas Bliley (R-VA), Chair of the
House Commerce Committee -- the committee responsible for FDA reform
legislation in the House -- received $126,476 from the tobacco
industry, more than any other member of Congress.

       Richard Burr (R-NC), who has received $11,350 from tobacco
interests and also is a Commerce Committee member, wrote in Roll
Call "I cannot understand why the FDA, which cannot efficiently
perform its core mission, should be rewarded with historic
jurisdiction increases [over the tobacco industry]." Although the
tobacco industry has been a driving force that keeps FDA reform high
on the Republican agenda, it has not been publicly identified with
the reform effort. "A veteran tobacco industry hand said that Bliley
has asked companies to lay low for their own benefit and his and
that he doesn't want to be perceived as beating the FDA over the
head because of tobacco. That message has come through loud and
clear," reported the National Journal.

       Preserving Patients' Rights

       In response to the industry-driven assault on the FDA,
patient advocacy groups have joined together in an historic
coalition. The Patients' Coalition, which formed last summer,
includes over 80 leading national organizations from prominent AIDS
groups, such as the American Foundation for AIDS Research and GMHC,
to the American Cancer Society, the National Organization for Rare
Disorders and the National Health Council, which represent the
largest voluntary health organizations in the country.

       The coalition wrote a set of FDA reform principles informed
by the common experiences of all patients with serious and
life-threatening diseases. It also released a policy white paper on
the real problems at the FDA. One much discussed proposal is a
"sunshine law" that would permit the FDA to publicly discuss its
private interactions with drug developers. Currently, companies
frequently complain of FDA delays in processing their drug approval
applications while the FDA refuses any comment on the grounds that
such applications constitute proprietary information.

       The coalition is working together on Capitol Hill and in the
media, trying to ensure that FDA reform legislation serves patients'
true interests. Such diverse patient groups have never worked
together in such an intensive way. They have come together because
all patients need federal regulations that encourage medical
research and innovation while continuing to ensure that drugs are
safe and effective.

       Legislative Maneuvers

       FDA reform legislation has taken much longer to move through
the Congress than many had predicted. Numerous hearings have been
held on FDA reform issues in both the House and Senate during the
first year of the 104th Congress. But legislation has been very slow
to emerge. The Republicans now realize that FDA reform is more
complicated than they first imagined, placing core values into
question, and opening a Pandora's box of competing interests.

       In both the House and Senate, there is no consensus on FDA
reform. Nancy Kassebaum (R-KS), chairwoman of the Senate Labor
Committee -- which has jurisdiction over the FDA in the Senate --
introduced a comprehensive ("Omnibus") FDA reform bill. Sen.
Kassebaum's bill has no co-sponsors, indicating that both industry
advocates and consumer protectionists in the Senate are dissatisfied
with its provisions. The House Commerce Committee has had an even
more difficult time with FDA reform legislation. The House committee
has altogether given up drafting a single, "omnibus" FDA bill.
Instead the Commerce Committee now plans many individual bills on
discrete areas of the FDA's authority. The lack of consensus means
the course and outcome of the FDA reform legislation is
unpredictable and volatile. Individual bills or amendments to bills
could be introduced that radically change the federal government's
authority over drug development and marketing.

       The Congress now anticipates taking up FDA reform early this
year. Sen. Kassebaum plans hearings on her bill over the next few
weeks, and the House could start introducing bills as well. It is
still unclear, though, if the Republicans can move such major
legislation through while budget debates and election campaigns heat
up. In any event, if a bill is eventually passed by Congress, it may
bear little resemblance to the proposals being considered now.

       The Kassebaum Bill

       As the first introduced, Sen. Kassebaum's FDA reform bill
(S.1477) is worth a close look. Written primarily by senior staffer
Jane Williams, the bill is considered a moderate proposal. Sen.
Kassebaum's staff have been open to the concerns and views of the
Patients' Coalition. When a draft of the proposal was circulated
this fall, the coalition sent a detailed analysis, some of which was
incorporated into the final version.

       The bill does reject many of the most radical FDA reform
proposals, and, as Ms. Williams said to a meeting of the coalition,
"it's the best you're going to get." Be that as it may, the bill as
it now stands would harm patients with serious and life-threatening
diseases by undermining incentives for medical research and
innovation.

       The Kassebaum bill establishes that only one efficacy study
of a new drug is necessary to meet the requirement of safety and
efficacy. The FDC Act presently does not define how many studies are
required, but the FDA has interpreted the law to mean that two are
required. On a scientific level, two studies greatly increase the
likelihood of making the correct interpretation of data, especially
when results are ambiguous or marginal. The FDA in any case already
uses a one efficacy study requirement for new drugs if the study is
a large multi-center one, or the drug in question is a high priority
or the results are unambiguous. Without the FDA's discretion over
the number of required studies in drug development, less clinical
research will be performed, reducing the scientific foundation for
new therapies.

       The bill sets strict approval schedules, requiring FDA action
within 120 days on New Drug Applications. Strict time-lines sound
wonderful, but they in fact can slow access to drugs for patients
with serious and life-threatening diseases. If the FDA must approve
everything rapidly, then resources will be pulled away from high
priority approvals, like break- through drugs for serious diseases,
to lower priority approvals, like fourth generation sleeping pills.
The FDA has inadequate resources for every drug to be a high
priority. The FDA must devote more resources and staff time to
reviewing drugs for the sickest patients. This proposal also fails
to acknowledge the FDA's progress. Saquinavir, the first of the new
generation protease inhibitor drugs, was approved in 90 days, for
example.

       The bill also proposes increasing the authority of the FDA's
advisory committees. The FDA maintains a host of independent
advisory committees that review research data and make
recommendations to the agency. The decisions of FDA advisory
committees are not binding on the agency. Sen. Kassebaum's bill
enhances the authority of the advisory committees, making their
decisions binding on the FDA. The bill would also mandate that
representatives of regulated industries be included as members of
the committees, a move which is presently prohibited under
conflict-of-interest regulations.

       The Kassebaum bill ignores ample evidence of the mediocrity
and ineffectiveness of advisory committees. A 1992 study of the FDA
advisory committees by the Institute of Medicine found multiple
problems with them. Well-qualified people often do not serve on FDA
advisory committees because of long time commitments (members serve
two year terms) and low pay for professionals ($150 a day). Sen.
Kassebaum's bill does nothing to fix the recruitment problems for
advisory committees, and instead aggravates it by extending service
to three years. Breakthrough drugs should be evaluated by skilled
FDA scientists and professionals, not mediocre, part- time committee
members.

       The bill's most radical proposal is to create a "presumption
of approvability" for some new drugs. If a drug were approved in the
United Kingdom, it would have an automatic "presumption of
approvability" in the United States. The FDA would have thirty days
to block the automatic approval of the drug in this country. This
proposal ignores some key facts. The United Kingdom has a slower
drug approval process than the United States. Many AIDS drugs --
d4T, 3TC and saquinavir among them -- are not yet approved in the
U.K. Every AIDS drug has been approved first in the U.S.

       The presumption that the U.K. is faster is simply wrong, and
it abrogates the federal government's fundamental responsibility
over the safety and efficacy of drugs marketed in this country. It
also ignores that the U.S. has far fewer drugs withdrawn from the
market for safety reasons than other countries -- just the classic
case of thalidomide.

       The bill also would allow drug companies to promote and
advertise so-called "off-label" uses of their products. Promotion of
off-label uses refers to advertising health claims for a product
that are not approved by the FDA but that are considered part of
standard medical practice. The bill seeks to solve a real problem.
Many drugs -- especially for cancer -- are used in ways that are not
FDA-approved.

       Many drugs have multiple uses, but some are approved for just
a single specific purpose. While many off-label uses of drugs are
standard medical practice, many others are ineffective or harmful.
Sen. Kassebaum's bill would allow marketing of any "medically
accepted" use of a product, without saying what constitutes
"medically accepted." The bill cannot distinguish between legitimate
and harmful off-label uses.

       Advocates for rare diseases are especially concerned about
off-label promotion. They fear Sen. Kassebaum's bill will undermine
the incentives for research into rare diseases created by the Orphan
Drug Act. The Orphan Drug Act establishes financial, tax and patent
incentives for industry to research drugs for rare diseases.

       Many of the drugs used to treat rare diseases are already
approved for other, more common maladies. Say two companies make the
same product, but only one company conducts research into the
product's use in a rare disease. The Orphan Drug Act authorizes the
government to grant the company that did the research an exclusive
right to market the drug for this disease. If adopted, Sen.
Kassebaum's bill may well undermine this exclusivity because any
manufacturer could promote all the "medically accepted" uses of its
drugs, even if the company did not conduct the research on the
orphan indication.

       Patient advocates agree that their goal for off-label drugs
should be to encourage industry and the FDA to work together to
submit data on off-label uses. Applications for secondary
indications should be easier and cheaper to file.

       Preserving the FDC Act

       More broadly, the Patients' Coalition sees the FDC Act as
critical for sustaining the unprecedented era of medical research
and progress, an era in which American science has been preeminent.
The FDC is vital to the nation's, and indeed the world's, health
because its high standards help protect the public against new
therapeutic products backed only by dubious or fraudulent data.

       Congressional meddling with the Act may well end up harming
patients with serious diseases by reducing the amount of medical
information available. Questionable, ill-advised treatment would
become more likely in such circumstances. Many AIDS activists have
pressed for reform of the FDA, but not for changes to the Food, Drug
and Cosmetic Act. These AIDS activists, along with their allies
among patient advocacy groups, are continuing to call for an
efficient and responsible FDA. At the same time, this coalition
considers paramount the preservation of the federal government's
crucial role in drug development and marketing.


       *****************************
       Finding a Place for Cidofovir
       by Theo Smart

       Gilead Sciences has asked the Food and Drug Administration to
approve intravenous cidofovir (brand name: Vistide) as a therapy for
CMV retinitis. Cidofovir's primary advantage is that it need only be
infused into patients on a weekly or biweekly basis compared to once
or twice daily for current medications (ganciclovir and foscarnet).
This dosing schedule furthermore removes the need for the
in-dwelling catheter used with ganciclovir and foscarnet. If
Gilead's application is accepted without modification, cidofovir
would be on a par with the two older drugs and could be administered
either as initial treatment or as a salvage therapy.

       The case for the new drug application rests on data from two
company-sponsored studies. One compares immediate treatment with
cidofovir to deferred treatment. The other is a dose comparison
study.

       The first study enrolled 48 patients with CMV retinitis and
no systemic CMV disease. Retinitis progression was defined as
advancement of the edge of an existing lesion by 750 microns or the
occurrence of a new lesion 750 microns or larger in diameter. Most
of those randomized to deferred therapy experienced progression of
their retinitis after a median 22 days, and were then crossed over
to treatment. Those who received cidofovir immediately and who
remained on treatment throughout the trial did not progress for a
median of 120 days.

       Many patients discontinued the study prior to progression and
were not counted in calculating progression rates. According to
Gilead's Vice President of Clinical Research, Howard Jaffe, M.D.,
though, even if those who discontinued were assumed to have
progressed, the median time to progression would have been
approximately 70 days at worst. The median time to progression had
not yet been reached in the sixteen patients crossed-over to
treatment from the deferred therapy arm, but, again, many patients
have discontinued therapy.

       The dose comparison study includes 100 people with relapsing
CMV retinitis or intolerance to standard therapies. Although an
interim analysis of data from the first sixty patients last April
did not at that time show a statistically significant difference
between the two doses (three mg/kg of body weight vs. five mg/kg),
the median time to first progression was 49 days on the three mg/kg
arm vs. 115 days on the five mg/kg arm. Complete data from this
study should be ready sometime in February -- if there is a
statistically significant difference between the doses, the case for
approval of cidofovir will be stronger.

       One other study and a treatment IND (expanded access) program
provide additional data for the cidofovir application. The SOCA
(Studies of the Ocular Complications of AIDS) network is running a
three arm trial in 90 volunteers comparing two different regimens of
cidofovir and deferred treatment. It is unlikely that any efficacy
data from this study will be ready by the time the FDA reviews
Gilead's application, but some safety data will be available.
Adverse events also are being actively monitored in the treatment
IND program as physicians must submit a report with every two doses
of drug. At press time, 146 patients have re istered in the
protocol. (For TIND information, call 415/573-4700.)

       Toxicity and Drug Interactions

       All three systemic intravenous CMV therapies are toxic. Like
foscarnet, cidofovir can cause irreparable, life-threatening kidney
damage. A few years ago, it appeared too dangerous to be useful as a
systemic therapy until researchers learned that the toxicity could
be attenuated with hydration therapy and four grams of probenecid on
the day of the infusion. (Probenecid helps the kidneys excrete
cidofovir safely. Researchers also reduced the cidofovir regimen.)
Even with probenecid and hydration, the drug at standard dose should
not be administered to patients with proteinuria (high levels of
protein in the urine) or elevated serum creatinine levels, both
indications of kidney impairment. Dose reduction studies are
underway in patients with compromised kidney function.

       Probenecid produces its own side effects, including transient
(lasting one to two days) fevers, nausea and rashes in about fifty
percent of the patients in the Gilead studies. A few patients can
have life-threatening allergic reactions. In the dose-ranging study,
at least two patients required resuscitation and hospitalization
within hours of treatment.

       One had a major drop in blood pressure and the other had a
fever of 104 F, low blood pressure and severe shortness of breath.
Both patients had a history of reactions to sulfa drugs (to which
probenecid is structurally related). Many investigators have been
giving antihistamines along with the probenecid. Discontinuing
pro-benecid or lessening the dose is not an option since cidofovir's
kidney toxicity is so severe.

       There is little drug interaction data available for
cidofovir. There seems to be no interaction with AZT. Interaction
studies with ddI and Bactrim will begin soon, and other studies are
being designed.

       Comparison with Other CMV Drugs

       Some in the community are concerned that if the FDA approves
cidofovir, people may opt to use this drug before the better
characterized ganciclovir or foscarnet because the dosing regimen is
so much easier on patients than the daily regimens and indwelling
catheters of the two older intravenous therapies. But the lack of
studies directly comparing cidofovir to ganciclovir or foscarnet
makes it difficult to determine which drug should be used when.

       The picture is further complicated by the new availability of
oral ganciclovir and the ganciclovir intraocular implants. These two
approaches in combination may represent another attractive option.
The implant would provide the advantages of localized therapy
against CMV retinitis in the treated eye while the oral drug may
provide a cover against breakthrough infections in the uninvolved
eye or elsewhere in the body.

       Hard data on this combination will be available from an
ongoing trial comparing the ganciclovir implant-oral ganciclovir
combination to standard intravenous regimens. In the future,
intraocular injections of cidofovir promises to provide another
effective localized therapy against CMV retinitis. (For a review of
the many new CMV treatments, see the July-August, 1995 Treatment
Issues.)

       The lack of comparative data is not an argument against FDA
approval of cidofovir. Cidofovir appears to show clear clinical
benefit in people who can tolerate it. But unless intravenous
cidofovir is shown to be superior to other CMV therapies, or until
there is more clinical experience with the drug most clinicians will
relegate it to second or third CMV therapy, to be used when other
approaches are failing.

       FDA to Review Two NNRTIs

       Boehringer Ingelheim and the newly combined entity Pharmacia
& Upjohn have announced that they will soon file New Drug
Applications with the FDA this spring for their respective
experimental antiretroviral drugs, nevirapine and delavirdine. Both
drugs are nonnucleoside reverse transcriptase inhibitors (NNRTIs)
that block the action of HIV's reverse transcriptase enzyme (see the
September, 1995 Treatment Issues, pages 8-9). Expanded access
programs for both drugs are also in the works.

       As Treatment Issues went to press, Upjohn announced interim
results from two large clinical studies of delavirdine. The data
form one trial indicate that the combination of delavirdine and AZT
provides more sustained responses in CD4 cell counts and viral load
than either drug alone. In another trial, involving participants
with more advanced disease, delavirdine plus ddI improved on the
response to ddI alone only for several months. The company is now
transforming its AZT plus delavirdine trial to include an
AZT/3TC/delavirdine arm. (Call 800/432-4702.)

       Upjohn believes its data show that even modest 70 percent
(0.5 log) reductions in HIV levels achieved after eight weeks of
treatment are predictive of substantially reduced disease
progression for at least a year. This observation underlines the
importance of mild enhancements delavirdine brings to existing
nucleoside analog therapy. It provides support as well for choosing
treatments on the basis of viral load response.

       The company plans to initiate an expanded access program for
delavirdine that will enroll up to 800 persons per month starting in
March. For more information on the program, call 800/779-0070.

       Boehringer Ingelheim has announced a 2,000 person clinical
endpoint study of nevirapine for people with CD4 counts of 200 or
below. Participants will be randomized to nevirapine or placebo. All
will receive 3TC and may take whatever other nucleoside analogs they
wish in combination with 3TC. For enrollment information call
617/487-9900.

       The company will be meeting with community representatives
over the next few weeks to work out the details for the expanded
access program.

       -- DG

       *************************************************
       New Saquinavir Formulation Enters Clinical Trials
       by Gabriel Torres, M.D.

       Hoffmann La Roche, makers of saquinavir, the first protease
inhibitor to receive FDA approval for treatment of HIV infection,
has just launched a large trial to test a new, more promising
formulation of the drug.

       The old formulation, a hard gelatin capsule with a very low
bioavailability (four percent), has been used in six previous
clinical trials. The drug has displayed an antiviral effect that is
low in comparison to other, soon-to-be-released protease inhibitors
-- at least at the standard 600 mg thrice daily dosage. A study of
high doses of saquinavir (3,600 and 7,200 mg per day) done at
Stanford University did show a substantial improvement in the effect
on HIV levels and CD4 count.

       The new trial will try the soft gelatin capsule at a dose of
1,200 mg taken three times daily, which is predicted to provide
exposures to the drug similar to 7,200 mg/day with the hard gelatin
capsule. The study will be double-blind and placebo-controlled (in a
two to one ratio of people on saquinavir to those on placebo) for
the first sixteen weeks.

       Other concomitant protease inhibitors are excluded, but
participants may take nucleoside analogue therapies as prescribed by
their physicians. They will be required to maintain a constant
anti-HIV regimen for these sixteen weeks. After the first sixteen
weeks, the trial participants will be given the option of open label
therapy with the soft gelatin capsule at the 1,200 mg thrice daily
dose.

       Six hundred volunteers are expected to be enrolled at 35 to
40 centers in the United States. They will be stratified into three
groups by CD4 cell count (0 to 50, 51 to 300 and 301 to 500). One
quarter of the trial group must have plasma HIV levels of greater
than 20,000 copies/ml. The primary endpoints of the study will be
plasma viral load by quantitative PCR and an increase in CD4 cell
count. For the location of trials sites around the country, call
800/TRIALS- A.

       ***********************************
       Expanded Access and Expanded Trials
       by Theo Smart

       NTZ for cryptosporidiosis

       Unimed Pharmaceuticals has announced FDA approval of a
compassionate use program providing very limited access to
nitazoxanide (NTZ), an anti-crypto- sporidial agent currently in
clinical trials (see Treatment Issues, September, 1995, page 14).
The company is also opening a site in San Francisco at the Kaiser
HIV Research Group (investigator: W.J. Fessel, M.D.) to speed the
ongoing American phase II studies of the drug. Meanwhile, the
Mexican licensee of the drug has initiated phase III clinical trials
in that country for people with AIDS-related cryptosporidiosis. Data
from this study should contribute to the eventual application for
FDA approval of NTZ.

       The compassionate use protocol is currently limited to 30
patients until the FDA is provided with additional safety data, but
the size is expected to increase over time. Its purpose is to
provide access to people with cryptosporidiosis who do not qualify
for or cannot enroll in the ongoing study which excludes those who
have other concurrent gastrointestinal infections such as
microsporidiosis. Doctors wishing to enroll their patients in this
protocol can call 800/864-6330. Twenty patients had already enrolled
in this program as of early January.

       AmBisome for Mycoses

An ongoing double blind study of AmBisome, the Fujisawa USA's
liposome-encapsulated version of amphotericin B, is now open to
people with relapsing cryptococcal meningitis (CM) that remains
sensitive to fluconazole (which is used as maintenance therapy).

       Previously, participation in the study had been restricted to
people with primary CM. The study compares AmBisome to standard
amphotericin treatment and currently has 50 patients enrolled. For
information on trial sites, call the government's national
clearinghouse at 800/TRIALS-A. Liposomal versions of amphotericin
are thought to be considerably safer than the unprocessed product
(see Treatment Issues, April, 1994, pages 6, 9-12) A number of
open-label studies have reported positive responses with AmBisome in
people with CM who have failed amphotericin treatment.

       Fujisawa also has opened a general compassionate use program
to provide AmBisome to anyone with systemic fungal infections who is
intolerant to amphotericin or for whom amphotericin would be
contraindicated. The protocol is also open to patients with
candidiasis resistant to the triazole antifungal medications such as
fluconazole. (Maintenance therapy to prevent recurrence may require
once or twice weekly infusions of AmBisome.) For more information,
call Fujisawa's Medical Information Line at 800/727-7003.

       *****************************
       The First Integrase Inhibitor
       by Theo Smart

       The first clinical trials of an HIV "integrase inhibitor,"
Aronex Pharmaceuticals' AR-177, are in progress at San Francisco
General Hospital. Like reverse transcriptase and protease, integrase
is an essential HIV enzyme. It binds to HIV DNA, which is created by
the reverse transcriptase enzyme, and integrates that DNA into the
host cell's chromosomes. AR-177 does not inhibit this integrating
activity (compounds that do so are years away) but rather appears to
keep the enzyme from binding to the newly processed DNA in the first
place.

       The drug is an oligonucleotide (string of nucleotides -- the
building blocks of DNA). Most oligonucleotides cannot be
administered systemically, because they breakdown and rapidly pass
from the body. But AR-177 is unique -- formed by seventeen
nucleotides (mostly guanine), it folds upon itself to form a stable
structure less prone to destruction in the blood. In animal studies,
the compound was not easily metabolized and was excreted very
slowly. Some drug remained in the animals' bodies a week after a
single dose.

       Work on this compound began because similar oligonucleotides
were found to bind to the V3 loop on the HIV envelope protein gp120,
potentially interfering with entry of the virus into cells. But
after adding AR-177 and HIV to cell cultures with HIV, researchers
were still able to detect viral DNA in the cells. Nevertheless, the
drug blocked viral replication, and the HIV DNA within the cells
disappeared after several hours.

       This observation suggested that HIV was getting into cells,
but that AR-177 was keeping the viral DNA from being integrated into
the cell's DNA. Subsequent studies showed that the drug blocked
binding to and early processing of viral DNA by integrase.

       The phase I single dose escalation study of AR-177, directed
by James Kahn, M.D, began in October. The study has reached its
second dose level (1.5 mg/kg of body weight) and has already
achieved blood levels that correlate with activity in laboratory
cell cultures. Higher doses will be evaluated. A subsequent study
evaluating the pharmacokinetics, safety and antiviral effect of
multiple dosing will begin in the second quarter of this year.

       At present, AR-177 is an injectable drug. The company hopes
that the compound's half-life will be long enough to allow for
infrequent dosing. Meanwhile, preliminary data in rodents show that
the drug does have some oral bioavailability. The company is now
studying an oral formulation in primates.


       Testosterone for Wasting

       Unimed Pharmaceuticals is starting a clinical trial of its
new, rub-on testosterone gel in twenty HIV-positive men with wasting
associated with low testosterone levels (hypogonadism). The ten-week
dose comparison study will begin at Beth Israel Hospital in Boston,
and an additional site may be added in San Francisco or Los Angeles.
Call Richard Spark, M.D., at 617/667-2471 if interested.

       Two testosterone patches -- Androderm, marketed by Smith-
Kline Beecham, and Testoderm, from Alza -- already are approved for
use in hypogonadal wasting. Testoderm must be applied to a shaved
scrotum, while Androderm (just approved by the FDA in October) can
be placed anywhere on the body. There is no data available to date
on the use of either patch in people with AIDS, but results from at
least one study should be released within the next few months.

       ******************************************
       A More Practical Therapy for Low Platelets
       by Gabriel Torres, M.D.

       Immune thrombocytopenic purpura (ITP) is a relatively
frequent condition in people with HIV infection. Although most
common early in disease, it can occur at any stage of disease.
"Thrombocytopenia" refers to an abnormally low platelet count,
platelets being the blood cell fragments involved in the clotting
process. Low platelet counts are associated with easy bruising and
spontaneous bleeding, which can be life threatening especially if
the platelet count drops below 20,000 per cubic millimeter of blood.

       Treatment of ITP has been limited in the past by short
duration of response, high cost and sometimes serious side effects
of the available therapies. But a therapy approved last March by the
Food and Drug Administration promises to improve the management of
ITP. This new treatment (brand name: WinRho) utilizes the therapy
that protects against the classic illness that occurs in Rh-positive
babies born to Rh- negative mothers.

       ITP and HIV Infection

       Platelets coated with antibodies are cleared from the body,
mostly by macrophages residing in the spleen and liver. This
phenomenon is seen as the major factor behind ITP during HIV
infection, although the source of the antibodies bound to the
platelets is open to interpretation. In an individual with HIV,
platelets may have particular surface antigens that become the
targets of antiplatelet antibodies that make them targets for
destruction. Platelets also sponge up antibody/antigen complexes as
well as any free antibody floating in the blood, and both of these
are present to a high degree during HIV infection.

       Other factors in thrombocytopenia during HIV infection
include reduced bone marrow production probably due to direct HIV
infection of the megakaryocyte, the precursor stem cell of the
platelet. These cells have CD4 receptors that allow HIV to adhere to
the cells and alter their function. Other factors that may
contribute to decreased platelet production include the low levels
of interleukin-3 and interleukin-6, which serve as growth factors
for megakaryocytes.

       Treatment Options

       Treatment modalities for HIV-related thrombocytopenia include
AZT, corticosteroids, immuno-globulin therapy and splenectomy
(surgical removal of the spleen).

       AZT has been considered the most effective therapy, with 30
to 90 percent of patients responding within twelve weeks of
initiating the drug.1 ddI has also been tried but is much less
effective. The newer antiretroviral agents have not been formally
studied for this purpose, although theoretically they should provide
a similar effect as AZT, by interfering with HIV infection of the
megakaryocyte.

       Corticosteroids can elevate platelet count in 40 to 80
percent of patients yet result in long-term remission in only ten to
twenty percent of patients. They are associated with intolerable
side effects in many people, including further immune suppression,
reactivation of opportunistic infections such as candidiasis, herpes
simplex and tuberculosis and increases in blood glucose, blood
pressure and peripheral edema.1

       Splenectomy offers the most durable response but has some
surgical risks and may increase the risk of infections with such
encapsulated bacteria as pneumococcus, haemophilus influenzae, which
are often effectively removed by the spleen. Patients who are to
under splenectomy should be vaccinated against these two bacteria
prior to surgery.

       Other similar treatment modalities which have been partially
successful include low dose splenic irradiation. Small studies have
shown a 70 percent acute response rate and a durable response rate
of 40 percent.2 This procedure requires total doses of radiation of
approximately 900 to 1,000 centigrays (centijoules per kilogram of
body weight) administered over one month, which allows for some
degree of splenic function to be preserved.

       Finally, immunoglobulin (transfused antibody, also known as
Ig or gammaglobulin) therapy is the quickest therapeutic approach
and is used in cases of very severe thrombocytopenia and prior to
surgery to rapidly lower the risk of bleeding. Immunoglobulins
saturate the receptors on the platelet- trapping macrophages in the
spleen, thus sparing the platelets from destruction.

       The duration of response is only about one to three weeks and
sustained remissions from a single course of treatment occur in less
than ten percent of patients. The cost of immunoglobulin therapy is
about $1,500 to $2,000 per treatment, which makes long-term therapy
prohibitive.

       WinRho

       WinRho, also called anti-D antibody therapy, consists of
concentrated antibodies that bind to the Rh antigen on red blood
cells. WinRho, like broader immuno-globulin therapy, is thought to
act by overloading the reticuloendothelial system by increasing the
number of antibody-coated cells to eliminate. WinRho will lead to
some reduction in the number of red blood cells, but not enough to
cause significant anemia. The treatment will not work in patients
who are Rh- negative or who have had their spleen removed.

       In one study by Bussell and others,3 43 Rh-positive patients
with ITP were treated with WinRho at a dose of 10 mg/kg of body
weight followed by daily doses of 20 mg/kg until either their
platelet count increased to a minimum of 20 to 30,000 per mm3 or
hemoglobin levels decreased greater than 2 gm/dl of blood,
indicating the onset of anemia. The mean platelet increase was
95,000 per mm3, with children having better responses than adults.

       In the largest study to date, 267 patients treated at New
York Hospital/Cornell University between 1987 and 1994, had mean
platelet increases of 76,000 cells. Study participants with HIV had
a poorer response (a mean increase of 49,000 platelets per mm3) than
HIV-negative ones.4 Again, younger patients (less than eighteen
years of age) had a better response than older ones. Changing the
dose of WinRho did not alter the response rate or the decrease in
hemoglobin levels, which were on average 0.8 gm/dl. The HIV-positive
patients had a lower decrease in hemoglobin than the HIV-negative
patients. Concomitant use of AZT affected neither the platelet
response nor the rate of red blood cell clearance. CD4 cell counts
were not adversely affected by the WinRho treatment, nor was there
any other evidence of acceleration of HIV disease progression.

              1 Stricker RB. Hematology-Oncology Clinics of North
       America. Apr 1991; 5(2):249-65.

              2 Calverley DC, Jones GW, Kelton JG. Annals of
       Internal Medicine. Jun 5, 1992; 116(12 pt1):977-81.

              3 Bussel JB et al. Blood. May 1, 1991; 77(5):1884-93.

              4 Scaradavou A et al. American Society of Hematology
       Thirty- Seventh Annual meeting, December 1-5, 1995;
       (abstract).


       ******************************
       HIV Suppressors Found in Cells
       by Theo Smart

       Not long after HIV was identified, many researchers noticed
that it was very difficult to culture the virus from the blood of
many infected people, particularly those free of symptoms.
Investigating this phenomenon, Jay Levy, M.D., of the University of
California San Francisco, determined that activated CD8 lymphocytes
in these cultures were responsible.

       Dr. Levy found that activated CD8 cells from HIV-negative
donors, and SIV-infected primates, also halted the growth of HIV in
cell cultures. This activity was not due to CD8 cells directly
killing HIV-infected cells, as one might expect considering their
commonly accepted antiviral role. Rather, something that these cells
produced, which Dr. Levy referred to as the cell antiviral factor
(CAF), was keeping the virus in check.

       Since proportionally more CD8 cells are required to block the
virus in cultures derived from patients with advanced HIV disease,
Dr. Levy concluded that these CD8 cells were not producing as much
CAF. He reported that CAF could be what is responsible both for the
long period of clinical latency that most people with HIV experience
and for the continued health of many long-term survivors. He also
believes that production of CAF ebbs before CD4 cells become
depleted and people develop symptoms.

       CAF's exact chemical identity proved to be extremely elusive.
Dr. Levy could isolate no one substance secreted by CD8 cells that
could affect this dramatic suppression of HIV. His work languished,
garnering little interest or support from the National Institutes of
Health.

       Last month, Dr. Levy's discovery regained the spotlight, when
two groups separately claimed to have identified CAF. Researchers
from the Paul Ehrlich Institute in Langen, Germany reported in a
letter to Nature (December 7, 1995, page 563) that a cytokine called
lymphocyte chemoattractant factor, or IL-16, has a strong
suppressive effect on HIV. The other team, led by Drs. Paulo Lusso
and Robert Gallo, formerly of the National Cancer Institute, argued
that CAF was not one, but three different substances acting in
concert to keep the virus in check (see Science, Dec. 15, 1995,
pages 1811-5). Dr. Levy, though, does not believe that CAF has truly
been identified by either group.

       IL-16

       Dr. Paul Reinhard Kurth and the other German investigators
have been working with a factor isolated from the CD8 cells of
African green monkeys that suppresses SIV, the monkey virus similar
to HIV. The Germans found that this factor is virtually identical to
human IL-16. However, the observed HIV-suppressive activity of pure
IL-16 was not as dramatic as that of the crude material extracted
from the CD8 cell cultures.

       In a review accompanying the Nature letter, Anthony Fauci,
M.D., director of the National Institute of Allergy Infectious
Diseases, suggested that IL-16 may be working together with other
suppressive factors. How IL-16 works is unknown, but it does bind to
the CD4 receptor and may inhibit CD4 cell activation. At the doses
that Dr. Kurth's group used, IL-16 was not toxic to cells and so
perhaps has some therapeutic potential.

       Chemokines

       Dr. Gallo's team took a CD8 cell line that was particularly
effective at suppressing HIV, removed the actual cells and separated
the remaining substances in the culture. They found three proteins,
previously dubbed RANTES, MIP-1a and MIP-1b, that had potent
anti-HIV activity at nontoxic levels in cell culture. These proteins
belonged to the chemokine family, which heretofore were known to
direct lymphocytes to the site of infection or inflammation.

       The researchers then added antibodies that inactivate the
individual chemokines to the cultures to see which chemokine was
primarily responsible for the CAF activity. Only the antibody to
RANTES seemed to partially reverse some of the suppressive effect.
Yet when antibodies to all three chemokines were added, all of the
anti-HIV activity was eliminated. The scientists observed the same
result when the antibodies were added to cell cultures taken from
people with HIV and concluded that all three of the chemokines are
required to keep the virus under control.

       Dr. Gallo's group is currently running the chemokines through
various in vitro assays to determine which aspect of the viral life
cycle is disturbed by the chemokines. They may act at an early phase
in the viral life cycle, but Dr. Gallo says, "there may be more than
one mechanism of action."

       Natural History

       Dr. Gallo's paper concluded with the suggestion that the
people with HIV should be studied to see whether those who produce
higher levels of these chemokines have a slower rate of disease
progression. Does production ebb as people progress? (Dr. Gallo says
other factors may emerge that reduce the chemokines' effect in
people with progressive disease.)

       Another area to look at is whether vaccine-induced higher
levels correlate with protection against SIV infection in monkeys.
At present, there is little natural history data on the secretion of
chemokines (or IL-16) in people with HIV disease.

       High production of chemo-kines has been noted in a large
number of autoimmune disorders, such as rheumatoid arthritis and
lupus. This observation raises the question of whether people with a
history of such conditions are less likely to become HIV infected,
or, if they do become infected, whether they progress more slowly.

       Researchers have noted that it is extremely unusual to find
HIV and these other conditions together, but there are a few case
studies in the literature. Rather than a slower progression of HIV
disease, a remission of the autoimmune disorders was observed.

       William Blattner, M.D., Deputy Director of the University of
Maryland institute that Dr. Gallo now directs, says, "The first
thing to do is get a better understanding of the way in which these
[chemokines] occur in these different populations. A single marker
may not tell the whole story -- ratios or combinations may be
important. It is possible that there are some suitable populations
for case control studies. Our first approach will be to look at
levels of these markers in patients at different stages of HIV
infection, and whether these markers correlate with protection in
HIV-negative people with continued high-risk exposures. But again,
the initial focus is standardizing the assays."

       Therapeutic Potential

       The extent to which any of these findings will lead to the
development of new therapeutic agents remains to be seen. IL- 16 may
suffer from the same fate as other cytokines that have shown
anti-HIV activity in the lab. Some of these compounds also
concurrently stimulate the production of inflammatory cytokines such
as TNF-a when administered in people, undermining whatever direct
anti-HIV activity they might have had in the test tube. And
generally, administration of the HIV-suppressor cytokines have been
associated with severe side effects.

       The systemic administration of chemokines poses certain
problems. The most established purpose of chemokines is to direct
white blood cells to the sight of the infection. If administered
systemically, immune cells might wander aimlessly, confused by
conflicting signals and be less likely to respond when secondary
infections do occur.

       Administering MIPs alternatively might make common infections
life-threatening by magnifying the amount of inflammation present.
In the lungs, excessive MIP-induced inflammation during pulmonary
infection can lead to suffocation. Added RANTES, meanwhile, could
cause side effects similar to arthritis.

       Nevertheless, the chemokine levels effective in cell culture
"are not showing toxic effects in the animal [rodent] toxicology
studies," says Dr. Gallo. He hopes to administer the chemokines to
green monkeys (the SIV model) within several weeks (although he
notes that delays in the construction of his new institute make it
difficult for him to say for certain).

       Dr. Gallo also believes there may be some way to trigger the
local secretion of chemokines. Presently, Dr. Sergio Romanagni, in
Florence, is conducting experiments to determine how CD8 cells
produce these chemokines, and what factors might stimulate their
secretion.

       Dr. Gallo's team also is manipulating the molecular
structures of the chemokines to determine which subunits are
responsible for the antiviral activity. Altered molecules might be
developed that suppress HIV but do not have the potential side
effects of the whole chemokine molecule.

       Copyright (c) 1996 - GMHC Treatment Issues.  Distributed by
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