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Everything old is new again
April 2012
EDIT CONNECT
SHARING OPTIONS:
Viagra. Everyone's heard of it.
Everyone knows what it does.
But most people probably don't realize that sildenafil citrate began its life
intended for another purpose before it was
repurposed into the blockbuster that
it is today. When the compound was found to be unsuccessful as an
anti-hypertensive agent in Phase I trials, Pfizer Inc. found success in
switching the drug to the treatment
of erectile dysfunction.
Long before that success, other compounds have gone on to
other lives; a
commonly cited example is thalidomide, originally used as a
sedative to treat morning sickness in pregnant women, and then went on to be used
as a
treatment for multiple myeloma and erthema nodosum leprosum. Another
success: finasteride, originally approved for benign prostate hyperplasia, now
also approved to treat male pattern baldness as the active ingredient in
Propecia.
"Broadly
speaking, drug repurposing or drug repositioning
alludes to the development of existing drugs or pro-drugs for new indications,
not necessarily related
to the original disease focus. In general, these drugs
have probably failed in late-stage clinical trials by lacking in efficacy or
safety, or have
problems associated with commercial strategies, patent
expiration or geographic expansion," explains business research and consulting
firm Frost & Sullivan Analyst Cecilia E.
Cauwenberghe.
Companies have likely invested millions of dollars and
countless hours in the
development process. Bringing completely new drugs to
market, through all the stages of human trials and regulatory approvals, can
take years. Inherent
in this process is risk.
"A repositioned drug has the same chances of success as an
original
drug in meeting efficacy end points. There is nothing inherently
different about repositioned drugs to make them less able to succeed due to
efficacy,
" says Dr. Andreas Persidis, co-founder and CEO of Biovista Inc.,
a
private drug development services company that is headquartered in
Charlottesville, Va. "However, they lack the risks of original drugs, which is
a major advantage of repositioning."
And, adds Frost & Sullivan Technical Insight Research
Analyst Ruplekha Choudhurie,
"Toxicity studies; absorption, distribution, metabolism and
excretion (ADME) studies; and other important
criteria, are already assessed
during clinical trials for the drug. Hence, time—usually a couple of years to
understand the drug metabolism, safety and
tolerance—can be saved. Similarly,
clinical trials to understand the drug efficacy have to be carried out while
repurposing, while the other parameters
need not be reassessed. This is a good
option, as thousands of dollars spent on clinical trials can be saved."
How are they chosen?
According to Cauwenberghe, two main selection criteria for
drug repurposing candidates can be cited: known compounds with new targets in
the
first place, and known mechanisms with new indications in the second place.
"Eli Lilly's raloxifene hydrochloride, Evista, is an
example," she says, "as this drug was conceived as an osteoporosis therapeutic
agent, with its initial steps in clinical trials related to breast
cancer
therapies. Similarly, Genzyme's plerixafor (Mozobil) was
recognized primarily
as an inhibitor of HIV infection, and finally was launched as a hematopoietic
stem cells mobilizer, particularly related to novel
advances in the treatment
of multiple myeloma. Cypress
Bioscience's milnacipran (Savella) was initially
thought of as an antidepressant, and later repurposed by Laboratoires Pierre
Fabre as Joncia for the
treatment of fibromyalgia. Another example is
GlaxoSmithKline's
paroxetine hydrochloride (Paxil), which was originally
launched as an immediate-release formulation, then later licensed for the
treatment of major
depression and anxiety disorders. GlaxoSmithKline's
ropinirole and Boehringer Ingelheim's pramipexole were both originally
developed for the treatment of Parkinson's disease; however, posterior
findings
derived in their development as a repurposed compound for the treatment of
restless leg syndrome."
Trends that drive the
repositioning phenomenon
According to Persidis, four key trends are paving the path
in drug repositioning.
First, the patent cliff: This means that companies have
to
find new applications and products more quickly than the 10 to 12 years a new
drug takes to come to market, and repositioning allows that to
happen.
Second, generics pressures: Generics companies are becoming
more aggressive, and they are
also entering the new drug arena themselves (e.g., Teva acquiring Cephalon). This
means that both
pharmas and generics companies are looking to repositioning as
a way to distance themselves from each other.
Persidis also
cites productivity and innovation.
"Repositioning allows an increase in Phase II starts leading
to more drugs entering the clinic at any given time," he says. "In addition,
repositioning may reveal new biology in a disease, leading to innovation
in therapeutic
approaches. A good example is Gleevec, whose previously unexpected off-target
pharmacology has led to it being tried in a number of
non-cancer indications,
including spongyloarthritis and others."
Last, Persidis says, but
certainly on par with the other
factors, are competitor adjacency threats.
"Competitor adjacency threats drive companies to
not only
add new compounds to their pipelines, but indicate when a savvy company reacts
to what its competition is doing with a new twist on an old
compound. Several
companies are doing both," he explains. "These strategies are complimentary.
However, there are still major companies that do not
include systematic
repositioning as part of their strategy, and I believe this makes them
vulnerable to competitors repositioning their drugs instead.
"
"A good example is Enbrel, which was repositioned by BDC in
sciatica, and then acquired by
Cephalon for about $40 million upfront and about
$200 million in milestones in 2009-2010," he adds. "Amgen, the owner of Enbrel,
does not have rights
now in the use of their drug in this new major market, and
this vulnerability is prevalent in a number of well-known companies, because
they seem to
choose to ignore the possibility that another group may be able to
find something about their drug that they didn't know."
What are the good
disease targets?
Frost and Sullivan's Choudhurie singles out two targets for
further growth in repurposing; both diseases are complex and
treatments for
both are highly sought-after around the globe.
"Obesity is a complex metabolic
disorder, and drugs usually
used for obesity fall into different categories which target the disease in
different ways," she says. "Similarly, other
complex diseases that don't have
just one target can provide a good opportunity for drug repositioning. Oncology
is another disease area where drug
repositioning activity has been very high."
Not without impact is the rising tide of medical needs
in
the aging baby boomer population. Choudhurie's Frost & Sullivan colleague Cauwenberghe
says it's hard to choose targets specifically, but we
can generalize about
impacts in the future.
"Regarding more appropriate disease targets, actually an
in-depth prediction of the most benefited disease areas is uncertain, as well
as the impact of new technologies over drug repositioning approaches."
she
says. "Nonetheless, a notable expansion of the aging population, as well as
cancer, pain, diabetes, metabolic, cardiovascular and neurological
diseases,
including Alzheimer's and Parkinson's, can be remarked.
"On the other hand," she
points out, "rare diseases have
been also targeted through numerous projects."
Choudhurie
agrees: "Another advantage of repositioning is
that diseases with a high unmet need can be targeted with these drugs that are
already in the market,"
she says.
"In orphan diseases, the driver is to find a therapy as
quickly as possible, no matter what the approach," adds Persidis.
"Repositioning is now recognized as a major potential contributor to this,
which is why there is a dedicated NIH effort."
Some are not as exuberant about the potential of this method
of discovery for attacking rare diseases. Again, limited
resources juxtaposed
against a small population who can benefit makes the math sometimes tricky,
even if expensive early steps have been taken.
Over at the Sanford Burnham Medical
Research Institute,
officials promote the work of their organization, which takes on these orphan
causes in a unique way.
"Regrettably, pharmaceutical companies are not likely to engage
in drug repositioning efforts for rare childhood
diseases," the institute's
representatives say. "This is in part due to the smaller patient populations
and challenges in running clinical trials in
these indications. In addition,
competition with generic drugs makes this effort commercially unviable, in
spite of its great potential to benefit
human health. Even if companies were
motivated to engage in these efforts, it is very difficult for the
pharmaceutical industry to perform the type of
screens Sanford-Burnham is doing
because of their limited access to patient samples."
Failures … or
opportunities?
There is not always a direct
path to success. Not every
repositioning effort is a clear winner.
"A recent example of a not
successful one is Dimebon, a
cough suppressant that was repositioned in Alzheimer's disease by Medivation
and Pfizer, but failed to meet its Phase III
end-points," says Persidis.
"However, there is believed to be more extensive pharmacology on this drug,
creating important possibilities for it to be
rescued and re-repositioned in
other diseases."
To be sure, rapid technological advances and new
business
strategies in the recent past have changed the game rapidly since the time of
thalidomide.
Says Cauwenberghe: "On that note, it is important to
highlight the fact that during the past five years, innovation in the
biopharmaceutical
industry has helped counter rising development costs, and
stagnant product output has become a leading cause for drug repurposing."
With little new on drug companies' plates for one reason or
another, new therapies have to come from somewhere.
"Two other relevant reasons rely on the need to expand
product pipelines with new projects, as
well as the increasing of the pool of
potential compounds abandoned due to strategic reasons," she adds.
New technologies and methods for sharing information play a
large role.
"Companies have been encouraged to emerge from another
perspective, by expanding their technology platforms for identifying new
indications,"
Cauwenberghe explains. "This has led to the success of several
projects committed to the development of proprietary pipelines of candidates,
while
reducing the related risks and timelines in further clinical development.
Moreover, current business models and technology platforms promote the public
generation of proof-of-concept clinical data to share efforts for repositioning
purposes."
An
example of those new business models is the one being
developed by Transparency Life Sciences (TLS), which is developing repurposed
drugs based on an open-innovation and crowdsourcing model.
Now beginning work with Stanford University, the company
will examine developing the blood pressure medicine lisinopril for multiple
sclerosis
(MS). Preclinical data showing how lisinopril works through
autoimmune and inflammatory mechanisms to reduce paralysis and blindness in
animal models
of MS has shown promise.
The relatively new company introduced its crowdsourcing
model in beta on
Jan. 31, and is inviting interested individuals to participate
in the design of the protocol for a Phase II trial of lisinopril in MS. It
hopes that
opening up the study design in this way will allow for collaboration
in ways not before thought possible.
"The paradigm shift around drug repositioning necessarily
derives a change in the current business models utilized by
pharmaceutical and
biotechnology industry," concludes Cauwenberghe. "In particular, pharmaceutical
companies have to face the challenge to transform
their blockbuster model
toward a more accurate, flexible and cost-effective model that involves the
development of therapeutics for new prospect
indications. Indeed, a myriad of
small companies have started to play new roles in the biopharmaceutical market.
Their innovative capacity, as well as
their constant nutrition with academic
fields, becomes these companies as strategic players, leading to a novel trend
of M&A activities and
licensing agreements."
Code: E041230 Back |
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