[Ip-health] WSJ: Despite Hope, Decade of Delay Afflicts Drug to Prevent AIDS (Amy Nunn)

[K.Shadlen@lse.ac.uk]

Perhaps I'm missing an obvious pt here, or just restating what is already k=
nown.... Last wk there were all sorts of stories in the press about the pos=
sibility that Tenofovir wld be patented in India, much of it re-posted on t=
his list. But if Tenofovir existed in the early 1990s, as it clearly did if=
 the results of a study using the drug on monkeys was published in Science =
in 1995, then the drug should not be eligible for a patent even under India=
's 2005 (amended) patent act. It's a pre-95 drug. Case closed. Why is this =
even a debatable issue?
Ken



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Subject: [Ip-health] WSJ: Despite Hope, Decade of Delay Afflicts Drug to
Prevent AIDS (Amy Nunn)


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Despite Hope, Decade of Delay Afflicts Drug to Prevent AIDS



Company's Caution, Protests Have Slowed Trials of Pill But Pace Is Picking
Up

A Drenching With Fake Blood



By DAVID P. HAMILTON and MARILYN CHASE
May 18, 2006; Page A1

In 1994, University of Washington scientists testing an experimental AIDS
treatment in monkeys made a startling discovery: The drug, tenofovir,
protected the monkeys from getting infected in the first place.

The finding, published in 1995 in the journal Science, was big news to AIDS
researchers. It raised a tantalizing question: Might a simple pill slow or
even halt the spread of the AIDS virus?

Eleven years later, that question remains unanswered. Tenofovir today is a
top-selling AIDS drug for Gilead
<http://online.wsj.com/quotes/main.html?type=3Ddjn&symbol=3DGILD>  Sciences=
 Inc.
-- but only as a treatment for those who already have the disease, not as a
protective measure for people who aren't infected.

The failure of the drug to get more rapid attention as a preventive step
partly reflects the contentious politics of AIDS. Since 2004 protests and
other issues have forced researchers to scrap trials in four nations in Asi=
a
and Africa.

Gilead also has had business reasons for focusing on tenofovir as a
treatment drug. Regulatory hurdles to approval are lower when the people
taking a drug are already sick, and so are legal risks. The company has
sought to avoid being dragged into culture wars over whether an
AIDS-prevention pill might encourage unsafe sex. "We always shied away from
pursuing this ourselves," says Norbert Bischofberger, Gilead's research
chief.

Behind the scenes, however, Gilead research officials have never abandoned
the notion of using tenofovir to block infection by HIV, the AIDS virus. Tw=
o
scientists at the company -- Dr. Bischofberger and Howard Jaffe, formerly a
drug-development executive and now head of the Gilead Foundation -- strove
to advance research and line up third parties to fund clinical trials.

That low-profile strategy may soon bear fruit. Researchers funded by the
U.S. government and others have started new tests of tenofovir in about
5,000 volunteers, most in developing countries. If the trials pan out over
the next three years, a once-a-day prevention pill might help slow the
global AIDS epidemic, although few scientists think tenofovir can completel=
y
halt HIV transmission.

Interest in tenofovir is especially high because efforts to produce an AIDS
vaccine have failed so far. HIV-prevention work with tenofovir "is probably
the most important thing going on in AIDS today," says Martin Delaney, a
longtime AIDS activist based in San Francisco.

Tenofovir's known side effects, including infrequent kidney problems and
bone weakening, could derail the trials if they afflict healthy volunteers.
Another potential roadblock: Some researchers worry that widespread use of
tenofovir alone might spark the emergence of HIV strains resistant to the
drug. Normally tenofovir is used as part of a cocktail of drugs, which
reduces the odds that a resistant virus will evolve.

Even a safe and effective HIV-prevention pill won't be free of controversy,
because it may lead people to abandon the caution that helps keep the virus
in check. Already, anecdotal reports suggest some men on the gay-party
circuit buy tenofovir with Viagra and other party drugs.

Gilead, based in Foster City, Calif., sells tenofovir under the brand name
Viread. It also sells Truvada, a pill combining tenofovir with another AIDS
medicine, emtricitabine or Emtriva. A year's supply of Viread costs about
$5,300 and Truvada about $8,800. The drugs, which together recorded sales o=
f
$441 million in the first quarter of this year, have helped Gilead become a
biotech success, with net income of $814 million in 2005.

The company insists it has no intention of adding to that bottom line by
marketing Viread as a preventive drug. It says the ethical, legal and
regulatory challenges in the U.S. would be too great. If Viread is ever use=
d
as a preventive in poor countries, Gilead says it will supply the drug at
cost -- as it already pledges to do with AIDS treatments.

Gilead's foray into HIV prevention began by accident. In 1991, it acquired
the rights to a new class of antiviral compounds that block an enzyme neede=
d
by the virus to multiply. Gilead chemists tweaked the compounds and produce=
d
several experimental drugs, including tenofovir.

Investigating the drug in infected monkeys presented a problem: At the time=
,
testing virus levels in the blood was a crude process, obscuring whether th=
e
drug was working. Researchers decided instead to test whether tenofovir
shielded healthy macaques from infection with SIV, a simian form of the AID=
S
virus. "Lo and behold, it was completely protective," Dr. Bischofberger
says. Fifteen monkeys were treated with tenofovir, then exposed to SIV. All
remained healthy. Ten monkeys given a placebo became infected within a few
months.

Despite the results, the company was in no position to pursue the findings
in humans. Just eight years old, it had no products or profits. Its focus i=
n
HIV was on winning approval for adefovir, a chemical cousin of tenofovir, a=
s
an AIDS treatment.

Outside the company, researchers were concentrating on other preventive
steps such as an AIDS vaccine or a topical antiviral gel. For a time, Gilea=
d
thought a gel form of tenofovir might be its best hope for HIV prevention.
The Gilead gel blocked simulated sexual transmission of SIV in monkeys. But
work on the gel flagged, although it continues at a slower place. Gilead
says it may soon assign its rights to the tenofovir gel to a nonprofit.

It wasn't until 2001 that interest finally revived in using tenofovir as a
preventive pill. That year, Gilead won Food and Drug Administration approva=
l
for the drug, now named Viread, as a treatment for AIDS patients. (It
dropped adefovir as an AIDS treatment in 1999, after kidney side effects
derailed an FDA application.) In Africa, where AIDS drugs were in short
supply, the epidemic grew catastrophic. Prospects for other prevention tool=
s
looked grim: Efforts to produce a vaccine stalled and a trial of a
spermicide seen as protective showed it actually increased HIV-infection
risk.

"We were really falling on our faces," says Mark Wainberg, an AIDS
researcher at Montreal's McGill University. At a 2001 AIDS meeting in Bueno=
s
Aires, Dr. Wainberg proposed using antiviral drugs such as tenofovir to
prevent HIV.

Inside Gilead, enthusiasm was rising again, led by Dr. Jaffe. He had steppe=
d
down from his research job at the company in 1999 but continued to work
there part-time and promote tenofovir for prevention.

In September, 2001, Dr. Jaffe flew to the Durham, N.C., offices of the
reproductive-health nonprofit Family Health International and sketched the
potential for Viread's use as a preventive pill. "A light bulb went off,"
says Willard Cates Jr., president of the group's Institute for Family
Health. He saw a parallel to the history of contraception, in which the
birth-control pill overtook topical spermicides and condoms in preventing
pregnancy.

John Mellors, a member of Gilead's scientific advisory board and a
University of Pittsburgh AIDS researcher, also heard Dr. Jaffe's prevention
pitch. "We said, 'Go for it,' " Dr. Mellors recalls. "We were frothing at
the mouth."

Things seemed to be coming together. In October, Drs. Jaffe and Cates flew
to Seattle to seek funding for prevention trials from the Bill and Melinda
Gates Foundation. Officials started drawing up plans for studies in
developing countries where HIV infection rates were far higher than in the
U.S. Proving the effectiveness of a preventive drug would likely be faster
in these countries.

Lie-Low Strategy

Gilead was turning down funding requests from all comers -- part of its
lie-low strategy. At the University of California, San Francisco, AIDS
researcher Robert Grant and colleagues were drawing up their own plans for =
a
prevention trial and went straight to Gilead. "'Why not just give us the
money, and we'll do a study?'" Dr. Grant recalls asking. "They said no."

[Viread]Gilead wanted to remain in the wings, bringing together researchers
and outside funders and providing free supplies of pills for trials. All
this, Gilead hoped, might help it avoid the impression that it was seeking
to profiteer from selling its pill in poor countries.

In October 2002, the Gates Foundation announced a $6.5 million grant to
Family Health International for HIV-prevention trials of Viread in Cambodia
and four African nations. The group joined forces the next year with UCSF
researchers, who had received National Institutes of Health funding for
their own trial in Cambodia.

Gilead's hopes that it could fly under the radar were soon dashed. In early
2004, activists in Cambodia's sex trade complained they hadn't been
consulted on the Cambodia trial's planning. In August 2004, they joined
French AIDS activists at a Bangkok AIDS conference, staging noisy
demonstrations.

Activists charged that Gilead would encourage risky behavior among study
participants to ensure infections and get data quickly. Gilead and
researchers deny the charge. The activists also said anyone in the trial wh=
o
ended up infected with HIV should receive a guarantee of lifetime treatment=
.
Demonstrators attacked Gilead's trade booth, dousing displays with buckets
of fake blood.

A few weeks later, Cambodian Prime Minister Hun Sen declared his opposition
to unspecified drug trials in his country, effectively scuttling the Viread
trial. In February 2005, Cameroon backed out of a trial amid claims that
volunteers weren't getting enough medical care. A similar study in Nigeria
then collapsed due to technical problems at local labs. Later, Malawi
cancelled a prevention trial for fear it might give rise to Viread-resistan=
t
HIV.

In Shambles

The program lay in shambles. Only one of the first five study sites is stil=
l
in business, in the Ghanaian port city of Tema. Safety data are expected by
June. But the Ghana trial by itself may not yield statistically convincing
proof of efficacy.

While overseas AIDS activists have blasted Gilead for going too fast, some
doctors in the U.S. fault the pharmaceutical industry for moving too slowly=
.
"The problem since the late 1980s is that these companies are so concerned
about liability they won't promote vaccines or prophylactic drugs," says
Marcus Conant, a San Francisco AIDS physician. He says he has prescribed
preventive Viread to five or six patients who he fears are at high risk of
contracting the virus.

Hope now rests on several trials of Viread or Truvada -- the combination
pill containing Viread -- that have started recently or will do so soon. In
Thailand, CDC researchers have enrolled half of a group of 1,600
intravenous-drug users.

Researchers say they're trying harder to get a commitment of support ahead
of time from government leaders and nonprofit groups in each country. Dr.
Grant of UCSF, who is lead researcher of a Peru trial funded by the NIH,
says: "I'm proud that the community in Peru knew of our plans before NIH
did."

Still unknown is how serious the side effects of Viread will be in people
without HIV. The drug carries a prominent warning on its U.S. label
regarding rare cases of lactic-acid buildup and liver enlargement, which ca=
n
be fatal. Gilead says the warning covers the larger class of drugs that
includes Viread and isn't specific to its drug. None of the drug's problems
were big enough to outweigh the benefit for HIV-positive people, but the
calculation is different for a prevention drug.

Recent research on Viread has led scientists to shift course slightly. A
2005 study showed Viread-treated monkeys eventually became infected after
repeated exposure to a synthetic and particularly virulent form of the
simian virus. The findings suggested that a single drug might not completel=
y
prevent HIV transmission. Even so, Viread slowed the rate of infection,
lessening the chances of getting the virus from a single encounter.

Results were better in a study this year of monkeys taking Truvada. The
combination drug shielded six monkeys even after repeated injections of the
virus. Trials in Botswana and Peru now plan to use Truvada.

In the U.S., researchers have begun enrolling 400 HIV-negative gay men in a
study of Viread. The goal is to test the drug's safety and measure whether
it leads men to engage in more unsafe behavior.

Write to David P. Hamilton at david.hamilton@wsj.com and Marilyn Chase at
marilyn.chase@wsj.com



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