This article talks about Yale's role in the development of both
d4T and 3TC. Also, it notes that Yale royalities from d4T
were $34 million in the year ending June 30, 1998, while
BMS reports 1998 revenues of $551 for Zerit for the year
ending December 31, 1998, suggesting a royalty rate for
Yale of under 10 percent.
http://www.med.yale.edu/external/pubs/ym_su98/cover/cov_hunting11.html
Yale Medicine, Summer 1998
Hunting down HIV
Yale research produced two of the current crop of AIDS
drugs and a promising new line of inquiry. It may take a
virus to kill a virus, if genetic approach is proven effective.
By John Curtis
[snip]
Researchers at Yale have played key roles in developing two of
these compounds, the reverse transcriptase inhibitor d4T, known
commercially as Zerit, and 3TC, known as Epivir. Both are key
ingredients of the so-called drug cocktail that has fundamentally
changed the nature of AIDS therapy during the past three years.
[snip]
William Prusoff, Ph.D., professor emeritus of pharmacology, has
spent a 45-year career at Yale investigating potential antiviral and
anticancer compounds, part of the traditional, small-molecule
approach. In the late 1950s he synthesized idoxurine, an analog of
thymidine, which was the first antiviral compound approved by the
FDA for therapy in humans. It was used to treat herpes infection of
the eye. Dr. Prusoff and his long-time collaborator, the late
Tai-Shun Lin, Ph.D., discovered in the 1980s that a thymidine
analog, reported in scientific literature as a poor anticancer agent,
was very effective in slowing the production of HIV. This compound
is known as d4T or stavudine. How does d4T work? "It gets
incorporated into the growing viral DNA chain and synthesis of
proviral DNA is stopped," Dr. Prusoff says. HIV's mechanism for
reproducing is simply turned off.
Bristol-Myers Squibb developed the drug under the trade name
Zerit and brought it to market in 1994. Almost single-handedly, d4T
has boosted Yale's annual patent royalty income nearly tenfold, to
$34 million for the year ending June 30. [AZT, the first medication
shown to slow the progress of HIV, was created by a Burroughs
Wellcome team led by Yale alumnus David W. Barry, M.D. '69, HS
'69-72. (Yale Medicine, Fall 1997)]
[snip]
The combination approach
Two hurdles in AIDS pharmacology are toxicity and drug
resistance. As with cancer chemotherapy, AIDS medications can
make people very sick. For example, d4T can cause peripheral
neuropathy, tingling, numbness and pain in the extremities; ddI can
cause lethal pancreatitis; and AZT is toxic to the bone marrow and
can cause anemia, headaches and nausea. In addition, HIV often
mutates when challenged by a single therapeutic agent, creating
drug-resistant strains of the virus that foil treatment. By prescribing
AIDS drugs in combinations, the physician can reduce individual
dosages and minimize both side effects and the potential for
resistance. "There are dozens of different combinations," Dr. Prusoff
says. "Resistance develops to all of those compounds." Resistance
to d4T has been found with laboratory strains of HIV, but mutant
forms resistant to d4T have not been observed in patients being
treated with d4T, Prusoff says.
Yung-Chi (Tommy) Cheng, Ph.D., the Henry Bronson Professor of
Pharmacology, has worked on a parallel course to Dr. Prusoff.
While Dr. Prusoff found drugs that work against AIDS, Dr. Cheng
has sought ways to reduce their toxicity. Long-term usage, Dr.
Cheng says, leads to a decline in the mitochondrial DNA of certain
organs, affecting their ability to function properly. After a month or
two of use, anti-retroviral agents such as AZT, ddI and DDC can
cause problems in nerves, the pancreas, muscles and the liver.
"If we know the mechanism for the toxicity, we may be able to
prevent the toxicity by either making a new compound or by
combination with other drugs," says Dr. Cheng, whose laboratory
team studies the behaviors of virus-specific proteins in order to
exploit them. "The next question is, 'Can we find a drug that will be
active against the virus but will have no toxicity to the mitochondrial
DNA?' "
That drug turned out to be 3TC, a compound that has positive and
negative forms that mirror one another. Originally synthesized by a
Canadian researcher and identified as an antiviral agent, samples
were sent to Dr. Cheng for study of its toxicity. He found that 3TC's
negative form reduced side effects when used in combination with
AZT. The combination increases 3TC's efficiency at inhibiting
reverse transcriptase, an enzyme HIV uses to reproduce its genetic
material. Dr. Cheng identified 3TC as an agent that would be less
toxic to mitochondrial DNA than DDC, ddI or d4T.
"We are increasing the antiviral effects, decreasing the side effects.
"This may be a key mechanism of the combination protocol against
HIV," he says. "In the meantime we also discovered the same
compound is active against the hepatitis B virus. The results were
very promising." So far, 3TC has been approved for HIV treatment
and is in clinical trials for use against hepatitis B.
[snip]
Thiru
--
Thiru Balasubramaniam
thiru@cptech.org
http://www.cptech.org/thiru