YSM Issue 86.1

PHARMACOLOGY
FEATURE
Match, Manipulate, Medicate:
Old Drugs Targeted for New Use
BY ANDREW QI
In 1993, scientists working for pharmaceutical giant Pfizer faced
a conundrum. Their new wonder drug, the product of years of
intense and costly research, failed to show any effectiveness in treating
patients with angina pectoris, a common cause of severe chest
pain. Then named UK-92,480, the drug was destined to be shelved.
If it were not for the keen observation that some patients reported
sustained erections as a side effect of their treatment. The researchers
were baffled at first but then realized the opportunity on their
hands. Five years later, UK-92,480 gained FDA approval as an oral
treatment for erectile dysfunction and was released to the market.
Today it has been rebranded as sildenafil — or Viagra — and has
become a windfall for Pfizer.
Could other failed drugs find their own stories of serendipity?
Certainly, finding novel uses for failed drugs is not a new idea. Aside
from Viagra, a number of well-known drugs had originally been
developed for other purposes, such as Rogaine, which had started as
a drug for high blood pressure, and AZT, the anti-HIV drug that was
originally supposed to be a cancer drug. In each case, advances in our
understanding of diseases and human biology led researchers back
to the past, repurposing old drugs based on a better understanding
of their mechanisms of action.
Sildenafil, better known as Viagra: the little blue pill that
began its career as heart medication. Courtesy of The New
York Times.
Pharmaceutical companies have taken an interest in reviving their
failed drugs. From their perspective, drug development is a risky
business. Bringing a drug from the lab to the clinic typically takes 13
years and an investment of around $1 billion, with a 95 percent risk
of failure. Some drugs may not be structurally suitable for efficient
mass production, some show dangerous side effects, and some simply
do not work against the target disease. In total, around 30,000 drugs
have been shelved by pharmaceutical companies over the past three
decades, and some of these failed drugs have shown new promise
for treating other diseases. Because they have already been tested in
humans, details about their production, dosage, and toxicity are readily
available, which can expedite the process of developing new disease
treatments. Instead of starting from scratch, successful repurposing
of even a few drugs could save companies substantial costs and time.
The National Institute of Health is soliciting applications to
investigate new applications for drugs shelved by pharmaceutical
corporations. Courtesy of the Medical College of Wisconsin.
A new development in drug retargeting strategies has been the
creation of drug libraries that allow receptor sites to be matched up
with pre-existing chemical compounds. Last year, Dr. Elias Lolis,
Professor of Pharmacology at the Yale School of Medicine, and Dr.
Michael Cappello, Professor of Pediatrics, Microbial Pathogenesis,
and Public Health at the Yale School of Medicine, jointly published
a paper detailing how this approach can be applied to treating hookworm
infestations. Previous research had suggested that hookworms
manipulate the human immune system by mimicking a key human
regulator with their own protein, AceMIF. Together, Lolis and Cappello’s
research teams screened a chemical library of almost a thousand
FDA-approved compounds for possible drugs that could inhibit
AceMIF activity, effectively preventing a hookworm from shutting
down the human immune response. From this study, they were able
to identify two potential anti-hookworm drugs previously tested for
other purposes: sodium meclofenamate, an anti-inflammatory drug,
and furosemide, a diuretic.
Recently, the National Institute of Health, through their National
Center for Advancing Translational Sciences (NCATS), launched a
massive $20 million program to reopen research into 58 drugs shelved
by various pharmaceutical companies. Worth up to $2 million each,
these grants will be awarded to proposals from academics, non-profit
groups, and biotechnology corporations investigating novel applications
for these failed drugs. Even this effort, however, has not been
without controversy. Some, like former Pfizer President John LaMattina,
have criticized the NCATS undertaking, claiming that companies
themselves have already taken similar rediscovery initiatives.
Others worry about potential intellectual property issues that may
impede the process to push the repurposed drug through to the
clinic. Companies may be hesitant to sacrifice any measure of intellectual
property rights of their compounds, which are central to their
value. On the other hand, without patent protection, researchers will
have a difficult time convincing companies to continue developing
off-patent drugs and bring them to market. Although advances in
both biological understanding and computational technology offer
exciting possibilities for old drugs, the road to the clinic remains
long and treacherous.
www.yalescientific.org January 2013 | Yale Scientific Magazine 27