Italian pharmacy online: cialis senza ricetta medica in farmacia.
DRUG REPOSITIONING:IDENTIFYING AND DEVELOPINGNEW USES FOR EXISTING DRUGS
Biopharmaceutical companies attempting to increase productivity through novel discovery
technologies have fallen short of achieving the desired results. Repositioning existing drugs for
new indications could deliver the productivity increases that the industry needs while shifting
the locus of production to biotechnology companies. More and more companies are scanning the
existing pharmacopoeia for repositioning candidates, and the number of repositioning success
The biopharmaceutical industry has a problem: output
Pharmaceuticals), which contains lovastatin plus
has not kept pace with the enormous increases in
extended-release niacin for hyperlipidaemia; Gluco-
pharma R&D spending (FIG. 1)1. This gap in productivity
vance (Bristol-Myers Squib), which contains metformin
exists even though pharma companies have invested
plus glyburide for diabetes; and Caduet (Pfizer), which
prodigious amounts in novel discovery technologies,
contains amlodopine plus atorvastatin for hypertension
such as structure-based drug design, combinatorial
and hyperlipidaemia7,8. The process of finding new uses
chemistry, high-throughput screening (HTS) and
outside the scope of the original medical indication for
genomics2, which were sold on the promise of improv-
existing drugs is also known as redirecting, repurposing,
ing productivity. For example, many in the industry
repositioning and reprofiling8–10.
invested heavily in the idea that HTS technology
Repositioning success stories and companies lever-
would bring 20-fold improvements in throughput.
aging repositioning strategies are increasing in number.
Well over US $100 million has been invested to date in
This review focuses on repositioning and will describe
this technology3; so far, it has yielded few products4.
its general advantages over de novo
drug discovery and
This productivity problem — coupled with world-
development; representative repositioning success
wide pressure on prices, challenges from generics and
stories; hurdles typically encountered during the reposi-
ever-increasing regulatory hurdles — has forced many
tioning process and approaches for overcoming them;
drug developers to become more creative in finding new
the strategies applied by several biotech companies
uses for, and improved versions of, existing drugs5,6. For
using this approach to drug development; and the rela-
example, extended- or controlled-release formulations
tive merits of pursuing repositioning approaches inside
of marketed drugs have improved drug attributes,
pharmaceutical or biotech companies.
such as dosing frequency — for example, once-a-daymethylphenidate (Concerta; ALZA) for attention-deficit
Faster development times and reduced risks
and hyperactivity disorder — and side-effect profiles —
Attempts to reduce pharmaceutical research and devel-
Inc., 31 St James Avenue,
for example, extended-release oxybutynin (Ditropan
opment timelines are often associated with increasing
Suite 905, Boston,
XL; Johnson & Johnson) and transdermal oxybutynin
risk. However, drug repositioning offers the possibility of
Massachusetts 02116, USA.
patch (Oxytrol; Watson), both for overactive bladder.
escaping the horns of this dilemma. Specifically, develop-
Correspondence to T.T.A.
Drug developers are also creating new product opportu-
ment risk is reduced because repositioning candidates
nities by combining therapeutically complementary
have often been through several stages of clinical devel-
drugs into one pill — for example, Advicor (Kos
opment and therefore have well-known safety and
VOLUME 3 | AUGUST 2004 | 6 7 3
thereby increasing urethral resistance and protectingagainst leakage of urine. Preclinical studies showed that
duloxetine potentiated the excitatory effects of sero-
tonin and noradrenaline on sphincter motor neurons11.
The Lilly group therefore proposed that duloxetine
might be useful in the treatment of stress urinary
incontinence (SUI), a condition characterized by
episodic loss of urine associated with sharp increases in
intra-abdominal pressure (for example, when a person
laughs, coughs or sneezes). It is commonly seen inwomen who have experienced several child births and
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
is caused by a weakening of the pelvic floor, which inturn compromises the angle of the bladder neck
responsible for maintaining normal continence. As a
Total approvals (including priority and standing review)Original INDs received (commercial)
result, SUI was largely considered to result from ananatomical defect, and it was widely thought that SUI
Figure 1 | The growing productivity gap in the biopharmaceutical industry.
would not respond to any drug therapy. Instead, SUI is
enormous increases in spending in novel technologies over the last several years, R&D productivityhas actually decreased since the mid-1990s, as measured either by the number of new drugs
treated with incontinence pads or adult diapers, pelvic
approved per dollar spent or by the number of original Investigational New Drug (IND) applications
floor Kegel exercises and surgery (for example, ure-
received by the US FDA from commercial sources per dollar spent.
thropexy or sling procedures). However, clinical trials inwomen showed that duloxetine was an effective therapyfor treatment of SUI12, and so Lilly decided to develop
pharmacokinetic profiles. Shorter routes to the clinic
duloxetine for both SUI and depression. In September
are also possible because in vitro
and in vivo
of 2003, Lilly received an ‘approvable’ letter from the
chemical optimization, toxicology, bulk manufacturing,
US FDA to market duloxetine as Duloxetine SUI. If
formulation development and even early clinical
approved, it will be the first pharmacological treatment
development have, in many cases, already been com-
for SUI, and Lilly is currently anticipating worldwide
pleted and can therefore be bypassed. In sum, these
sales of Duloxetine SUI to approach US $800 million
factors enable several years, and substantial risks and
costs, to be removed from the pathway to the market(FIG. 2). As such, repositioning can offer a better risk-
Third time’s the charm for dapoxetine.
Dapoxetine is a
versus-reward trade-off compared with other drug
selective serotonin-reuptake inhibitor (SSRI) that was
originally developed by Lilly as adjunct therapy for anal-
These advantages have not escaped the notice of
gesia, and discontinued for portfolio reasons. Dapoxetine
venture capital firms seeking near-term, high-value exits
was then considered as a follow-on antidepressant to
for their companies. For venture capitalists in 2004, it is
fluoxetine. However, the rapid onset and short half-life of
hardly possible to invest in a therapeutics company
the compound did not allow for once-daily dosing, an
neurons in the central nervoussystem and in the enteric
without drug candidates in or near clinical trials because
absolute must for any competitive antidepressant, and it
of the positive reception received by such companies
was again passed over. Fluoxetine was subsequently out-
from the public equity markets. Indeed, repositioning
licensed to GenuPro, where one of us (K.B.T), who was
offers the opportunity to quickly create such a pipeline,
then Chief Scientific Officer of GenuPro, proposed that a
that affect the action ofserotonin are commonly used
and repositioning companies are having little trouble
common side effect of SSRIs — that is, delayed ejacula-
tion — could be turned into a therapeutic benefit in menwith premature ejaculation, a disorder that is a problem
for more than 20% of men in the United States13.
A novel ‘below the belt’ use for duloxetine.
Furthermore, it was proposed that duloxetine’s rapid
neurotransmitter contained in a specific subpopulation of
(Cymbalta and Duloxetine SUI; Eli Lilly) blocks the reup-
onset and short half-life would be a pharmacokinetic
take of both SEROTONIN and NORADRENALINE in the synaptic
advantage for ‘as needed’ treatment, which led to the
cleft. The Neuroscience Division of Eli Lilly discovered
filing of a METHOD-OF-USE (MOU) PATENT. After obtaining
this compound in the late 1980s as a part of its efforts
Phase II proof of concept for premature ejaculation,
the peripheral autonomicnervous system.
to find an improved version of fluoxetine (Prozac),
GenuPro out-licensed dapoxetine in 2001 to ALZA
Lilly’s highly successful drug for depression. One of us
Corporation (now a part of Johnson & Johnson), where
(K.B.T.) was a member of Lilly’s Neuroscience Division
it is now in Phase III clinical development for premature
during the time that duloxetine was being developed
ejaculation. Johnson & Johnson is currently estimating
for depression and reasoned that drugs with duloxe-
peak sales of dapoxetine to approach US $750 million14.
a method of use (for example, amethod of treating disease X,
tine’s mechanism of action might also increase urethral
sphincter tone and decrease detrusor activity. Serotonin
The fall and rise of thalidomide.
It is remarkable that
and noradrenaline, although best known for their
thalidomide could ever have a comeback after its tragic
effects on mood, were also known to have significant
beginning. Thalidomide was originally marketed in
need thereof). The exclusionaryright is limited to the particular
activity in the spinal cord and, specifically, to exert an
1957 in Germany and England as a sedative and targeted
excitatory effect on urethral sphincter motor neurons,
specifically to pregnant women to treat morning sickness.
6 7 4
| AUGUST 2004 | VOLUME 3
drug discovery and development• 10–17 year process• <10% overall probability of success
• Ex vivo
and in vivo
• High throughput
Drug repositioning• 3–12 year process• Reduced safety and pharmacokinetic uncertainty
Figure 2 | A comparison of traditional de novo drug discovery and development versus drug repositioning. a
| It is well
known that de novo
drug discovery and development is a 10–17 year process from idea to marketed drug72. The probability of success
is lower than 10%37. b
| Drug repositioning offers the possibility of reduced time and
risk as several phases common to de novo
discovery and development can be bypassed because repositioning candidates have frequently been through several phases of
development for their original indication. ADMET, absorption, distribution, metabolism, excretion and toxicity; EMEA, European
Medicines Agency; FDA, Food and Drug Administration; IP, intellectual property; MHLW, Ministry of Health, Labour and Welfare.
No regulatory approval was required — the drug was
sleep; it also healed the patient’s sores and eliminated his
billed as “completely safe” — although the disaster that
pain. Sheskin then conducted a double-blind study of
followed led to the introduction of the drug law
thalidomide in Venezuela, and of 173 patients treated
known as the ‘Arzneimittelgesetz’, which requires that
92% were completely relieved of their symptoms16. A
proof of safety be established for pharmaceuticals sold
World Health Organization-sponsored follow-up study
in Germany15,16. Taking the drug as indicated led to
on 4,552 ENL patients showed that a full 99% of
severe skeletal birth defects in at least 15,000 children
patients enjoyed a complete remission in less than two
born to mothers who had taken thalidomide during
weeks16. Thalidomide is still the primary, indeed the
the first trimester of their pregnancies. Marketing in the
only, drug used to treat ENL16. Female ENL patients
initial indication went on until 1961, by which time
who receive thalidomide also go on two forms of birth
the drug was being marketed to thousands of patients
control before being prescribed the drug.
It was later shown that thalidomide is an inhibitor of
Without the fortuitous presence of the banned drug
tumour-necrosis factor-α (TNF-α)17; and that AIDS
in a hospital’s medicine cabinet, thalidomide might not
patients suffered as much as leprosy patients from the
have been revived. Thalidomide was next used to treat
inappropriate production of TNF-α16, which was known
the condition erythema nodosum laprosum (ENL), an
to be involved both in the development of AIDS-related
agonizing inflammatory condition of leprosy character-
mouth ulcers and cachexia in these patient popu-
ized by large, persistent, painful boils and inflammation
lations16. But it was Kaplan’s 1993 discovery that thalido-
so severe it often leads to blindness. Cases of ENL are
mide suppresses the activation of latent HIV type I that
now well managed as a result of thalidomide’s new use.
sparked the interest of the company Celgene and led to
The discovery of thalidomide’s activity in ENL could
the subsequent approval of the drug under the trade
not have been more accidental16. In 1964, physician
name Thalomid in 1998 for use in treating ENL16.
Jacob Sheskin in the University Hospital of Marseilles
In 1994, researchers at Children’s Hospital in Boston
was desperate to treat a critically ill ENL patient whose
discovered that thalidomide had anti-angiogenic proper-
pain had been so great that he had not slept for weeks.
ties that made it a candidate in oncology, and also began
As a last resort, Sheskin used the only drug in the hospi-
to explain its dramatic effects in limb development in
tal’s infirmary that he believed might help the patient
the human foetus18. Celgene acquired the rights to
sleep. Thalidomide not only allowed the patient a night’s
Children’s Hospital’s thalidomide MOU patent in 1998.
VOLUME 3 | AUGUST 2004 | 6 7 5
as they did not want to give the pills back! By 2003,sildenafil had annual sales of US $1.88 billion and
nearly 8 million men were taking sildenafil in the
Identifying repositioning opportunities
So where exactly do the ideas for repositioning and the
actual repositioning candidates come from? Ideas for
repositioning can come from serendipitous observations(for example, sildenafil)22; from novel, informed insights(for example, duloxetine)11; or from technology platformsestablished to identify repositioning opportunities
(for example, CombinatoRx’s cHTS system26). Once therepositioning idea has been generated, and the proposed
approach scientifically validated, then a commerciallyviable target product profile for a candidate can be gener-
ated and a search conducted to identify compounds withthe desired characteristics. This search often involves a
review of the public and subscription-based information
Risk (α target validity, drug-like properties and the development pathway)
sources (for example, company websites, intellectualproperty (IP)5 and scientific databases5, and FDA
Figure 3 | The risk-versus-reward trade off between different drug development strategies.
Summary Bases of Approval and so on) to identify can-
Drug repositioning offers one of the best risk-versus-reward trade-off of the available drugdevelopment strategies. It can offer lower risk than in-licensing strategies because repositioning
didates within the generic and branded pharmacopoeia
candidates have often been through several stages of development and may even be marketed
and also the pipelines of pharmaceutical companies.
entities. In addition, repositioning offers the possibility of high rewards because of shorter times
However, discovering and validating the repositioning
to market and higher possibility of differentiation as compared with in-licensing and reformulation
idea and identifying the actual repositioning candidate
strategies.*For example, rare diseases or diseases primarily incident in developing nations;
is just the beginning of the repositioning process.
government regulations have been enacted to reduce risk and/or raise potential reward for
Market analyses, IP and regulatory diligence, and the
some small markets, for example, by conferring Orphan Drug status on certain drugs.
formulation of new development plans, are all as mucha part of the repositioning process as they are for de novo
drug discovery and development. The same is true for
Celgene recorded 2002 sales of US $119 million for
selling the opportunity within one’s own company.
Thalomid, 92% of which came from off-label use of the
However, challenges associated with obtaining access
drug in treating cancer, primarily multiple myeloma19,20.
and commercial rights to repositioning candidates can
Sales reached US $224 million in 200321. The lesson
from the thalidomide story is that no drug is everunderstood completely, and repositioning, no matter
Due Diligence: ‘is this dog gonna hunt?’
how unlikely, often remains a possibility.
The next hurdle in the repositioning process is to evalu-ate the candidate’s potential for attaining a competitive
An ineffective angina drug with an interesting side effect.
product profile in an attractive market with a reasonable
Pfizer was seeking a drug for angina when it originally
COST OF GOODS SOLD (COGS). Part rigorous analysis and part
created sildenafil (Viagra) in the 1980s. As an inhibitor
crystal-ball gazing, market analysis involves three key
(COGS). The expense a companyincurs to manufacture a drug
of phosphodiesterase-5 (PDE5), sildenafil was intended
elements: developing a detailed understanding of the
to relax coronary arteries and therefore allow greater
current market; predicting what the market will look
coronary blood flow. The desired cardiovascular effects
like when the repositioning candidate launches; and
were not observed on the healthy volunteers tested at
asking whether the market is large and growing rapidly,
the Sandwich, England, R&D facility in 1991–1992.
and/or whether it will support premium pricing.
However, several volunteers reported in their question-
Once a competitive product profile in an attractive
naires that they had had unusually strong and persistent
market is identified, it must then be evaluated against the
erections. Pfizer researchers did not immediately realize
candidate’s known PHARMACODYNAMIC, PHARMACOKINETIC
that they had a blockbuster on their hands, but when a
and safety profiles. It is also important to understand
on biological systems. In otherwords,‘the study of what the
member of the team read a report that identified PDE5
what the candidate’s potential COGS might be. Has
as a key enzyme in the biochemical pathway mediating
production already been scaled to multi-kilogram levels?
erections, a trial in impotent men was quickly set up22. A
If not, does its current synthetic route involve a reason-
large-scale study carried out on 3,700 men worldwide
able number of steps? Can its drug substance be formu-
The study of the rates of themovements of drugs within
with erectile dysfunction between 1993 and 1995 con-
lated into drug product in a way that allows for attractive
firmed that it was effective in 63% of men tested with
the lowest dose level and in 82% of men tested with the
The due diligence process can be one of the most
highest dose23. Of note, in many of these studies22, Pfizer’s
challenging steps in the repositioning process, because it
researchers had difficulties retrieving unused sample of
is almost impossible to gain a complete understanding
study of what the body does tothe drug.’
the drug from many subjects in the experimental group
of these issues; this can be because the data were never
6 7 6
| AUGUST 2004 | VOLUME 3
Table 1 | Repositioned antidepressant drugs
(trade name; originator)
(trade name; repositioner)
Approved as Wellbutrin for depression in 1996 (REF. 39) and as Zyban
smoking cessation in 1997 (REF. 39). Worldwide sales in 2003
for Wellbutrin were US $1.56 billion and US $125 million for Zyban41.
Currently in Phase III. If approved, it would be the first approved
agent for premature ejaculation. Peak sales are projected to reach US $750 million42.
Simultaneously in development for depression and SUI.
Projected worldwide peak sales are US $800 million in SUI and US $1.2 billion in depression43.
Approved 6 July 2000 in the United States for use in premenstrual
dysphoric disorder44. Sold in January 2003 to Galen, US $60 million of revenue reported by September 2003.
Marketed as Ixel for depression in Europe and Japan*; currently in
Bought in acquisition of Knoll Pharmaceuticals in 2001. Approved
24 November 1997 in the United States for the management of obesity.
*Source: Company news: deals. BioCentury
2 Feb 2004; available from http://www.biocentury.com. ‡Source: Edelson, S. Strategy: Cypress — the channel’s the thing.BioCentury
12 Jan 2004; available from www.biocentury.com. MOA, mechanism of action; NSRI, non-selective serotonin-reuptake inhibitor; SSRI, selective serotonin-reuptake inhibitor; SUI, stress urinary incontinence.
collected, because the data that are available do not
Without these measures, it is difficult to determine, for
directly address issues specific to the new indication or
example, whether a 50% reduction in incontinence
because necessary data are not available in the public
episodes or a 2-minute delay in ejaculation is meaningful
record. Indeed, if the availability of public data is lim-
ited, which is often the case, then the current or origi-
In addition, the reduced risk offered by well-known
nal developer of the compound must be approached
safety and pharmacokinetic profiles of the repositioning
to obtain the needed information. This can be a deli-
candidates can be offset by the lack of a clinically vali-
cate process, to say the least. For older compounds,
dated mechanism of action. Furthermore, even basic
even if the data are available, it might not meet current
data on toxicology or pharmacokinetics that were col-
lected for the repositioning candidate in the originalindication might be unacceptable due to the changes
Clinical development challenges
in regulatory standards. However, such pioneering
The reduced risks and development times associated
efforts can pay off handsomely: achieving first-in-class
with repositioning can sometimes come at a price.
status can allow for a significant head start on the com-
Success stories such as sildenafil occurred in therapeutic
petition, as exemplified by the roughly five-year head
areas in which drug therapy was unavailable or inconve-
start that Pfizer’s sildenafil had on Lilly and ICOS’s
nient: no oral drug had even been tested for erectile dys-
tadalafil (Cialis) and GlaxoSmithKline and Bayer’s
function. In the case of duloxetine, SUI was not thought
to be treatable with drug. For dapoxetine, premature
There have also been instances in which the timing of
ejaculation was not widely recognized as a medical dis-
regulatory review of the original and repositioned indi-
order. What makes the development path for such indi-
cations overlap. Needless to say, such circumstances
cations challenging is that they require novel designs for
can cause headaches for both the developers and regu-
clinical trials. For example, criteria for patient inclusion
latory agencies. As an example, duloxetine’s NEW DRUG
in trials of premature ejaculation needed to define a
APPLICATIONS for depression and SUI were filed within
maximal time to ejaculation as an entry criterion, even
about a year of each other with different sections of the
though the Diagnostic and Statistical Manual IV does
FDA. Typically, if the same drug is being considered by
not stipulate ejaculation time in its definition of a time
two different sections, the FDA creates an ‘oversight com-
limit. In addition, it was important to ensure that a single
mittee’ to coordinate the two. However, in this case, the
NEW DRUG APPLICATION(NDA). An application to the US
partner was maintained throughout the duration of the
vastly different responses coming from the two sets of
study to prevent partner-induced changes in ejaculatory
FDA reviewers posed a significant challenge for Lilly29.
latency. Novel study endpoints and efficacy measures
must also be developed. In the case of duloxetine for
IP issues particular to repositioning
studies, human clinical trials ofan Investigational New Drug
SUI, dapoxetine for premature ejaculation and sildenafil
Both blessings and unique challenges surround IP issues
for erectile dysfunction, it was necessary to develop
associated with repositioning. On the plus side, new IP
psychometric instruments to measure patient-perceived
in the repositioned indication can create substantial
benefit; that is, the Incontinence Quality of Life12, the
value for the repositioner, particularly if the candidate
Premature Ejaculation Questionnaire27, and the Inter-
has never received marketing approval. However,
of an approved NDA before UScommercialization.
national Index of Erectile Function28, respectively.
because the candidate is usually not new to the scientific
VOLUME 3 | AUGUST 2004 | 6 7 7
Table 2 | Repositioned neurological drugs (not including anti-depressants)
(trade name; originator) (trade name; repositioner)
Approved by FDA in 2002 for ADHD44. Reached US
$370 million in sales in 2003 (REF. 45), is projected to achieve US $1.15 billion annually by 2007 (REF. 43).
Originally marketed as a general sedative and anti-emetic
(dopamine receptor (Thorazine; (Thorazine; SmithKline)
agent. After Paris surgeon Heri Laborit observed in 1952 that
it had a tranquilizing effect, SmithKline marketed it for that indication and it became a standard element of psychiatric care, used to treat 50 million patients during the next 12 years*.
marketed in 1960s (REF. 47) and now approved in
many countries for mild to moderate Alzheimer’s disease48.
Corus is reformulating lidocaine for use as inhalation treatment
for oral corticosteroid-dependent asthma. This programme,
known as Corus-1030, is in Phase II trials in the UnitedStates and Europe‡,§. In a non-trial setting at Mayo Clinic over four years, inhaled lidocaine was well tolerated, all but one patient continued treatment, and 47 out of 49 patients were able to stop corticosteriod use49.
Marketed for Parkinson’s disease since 1997; currently in
SmithKline idiopathic restless leg syndrome Phase III for idiopathic restless leg syndrome. Worldwide
sales reached US $162 million in 2003.
Racemic tofisopam has been sold for over two decades in Europe
and Asia for anxiety disorders. A Phase II trial in irritable bowel
syndrome began in June with the R-enantiomer (dextofisopam)50.
*WGBH. A Science Odyssey: People and Discoveries
; website of the television programme (http://www.pbs.org/wgbh/aso/thenandnow/humbeh.html) accessed 19 Apr 2004.
‡Source: Clinical news: clinical status. 5 May 2003; available from www.biocentury.com. §Source: Clinical news: clinical status. BioCentury
22 Dec 2003; available fromwww.biocentury.com. ADHD, attention-deficit hyperactivity disorder; MOA, mechanism of action; NSRI, non-selective serotonin-reuptake inhibitor.
community, prior art might exist that can render a
loss. In addition, companies developing drugs in combi-
repositioning idea unpatentable. For similar reasons,
nation might be able to obtain new COM IP. This is the
pre-existing patents might also exist that could impede
development strategy that CombinatoRx is pursuing and
commercialization of the repositioned drug.
the one that Dynogen used to create DDP200, which is
The process of defending repositioned drugs against
being developed for overactive bladder. Finally, obtaining
competitors can be particularly challenging, even more
exclusive marketing approval in new geographic markets
than is the case with de novo
drug discovery and develop-
can also be effective in keeping out competition. For
ment. Two general cases must be considered: either the
instance, in the United States, drugs can rely on six-
COMPOSITION-OF-MATTER (COM) IP on the compound of
month, three-, five- or seven-year marketing exclusivity
interest is held by another party; or the compound is off-
awarded under 21 U.S.C. § 505(b)(2) for FDA approval of
patent and therefore generic. In the former case, a deal
a new indication in a paediatric population30, for a known
must be struck to license or acquire that IP, and there are
compound for a new indication31, a new chemical
several strategies for dealing with the latter case.
entity32, or in a orphan population33, respectively.
If the repositioning candidate is off-patent, then the
repositioner can rely on novel MOU protection or simply
Potential intra-organizational hurdles
a ‘use’ patent to provide substantial barriers to entry if
A repositioning programme must endure the same
the drug has never been marketed. For example, many
intra-organizational Darwinian struggle that every
repositioned drugs are either on the market (for example,
development programme endures for access to corpo-
atomoxetine (Strattera; Eli Lilly)) or are in development
rate resources. For an internal repositioning candidate
(for example, duloxetine, dapoxetine and milnacipran
to enter development, it not only has to clear the typical
(TABLE 1)) that rely or plan to rely on MOU patents for
development ‘fitness’ hurdles, but it might also have to
protection because their COM patents have expired or
compete against itself. For example, a repositioning pro-
gramme using a previously discontinued internal com-
In addition, companies can invent new formulations,
pound might encounter resistance from those who were
dosage forms, drug combinations or geographic strategies
involved in discontinuing the drug’s initial programme.
that create new barriers to entry. Still other companies,
Furthermore, an additional indication can trigger con-
such as Sepracor, Sention and Vela Pharma, are devel-
cern on the part of the of the original development team
oping isometrically pure enantiomers with fewer side
regarding resource allocation, safety, pricing differences
effects or better efficacy than the corresponding racemic
and patient perceptions. An example of the latter would
mixtures. New dosage forms can themselves be a source
be a concern about taking duloxetine, a psychiatric
acid or particular formulationof an agent.
of new IP, as in the case of Propecia, Merck’s drug for hair
medicine, for an incontinence problem, and vice versa.
6 7 8
| AUGUST 2004 | VOLUME 3
Table 3 | Repositioned non-neurological drugs
(trade name; originator)
(trade name; repositioner)
Currently in Phase II trials for prevention of colon and breast
cancer43. Pfizer intends to also test celecoxib for use in Barrett’s
oesophagus, actinic keratosis, bladder cancer and ankylosing
Originally developed for use against West African
trypanosomiasis52 and also explored for antitumour effects53.
Originally approved for the treatment of enlarged prostate in
1992, Propecia (with a fivefold lower dose), approved in 1997
for the treatment of hair loss54, had worldwide sales of US $239million in 2003 (REF. 55).
Inversine was originally launched in the 1950s, and was one
of the first orally active antihypertensives on the US market.
It is currently used off label for Tourette syndrome and Targacept
has a low-dose version of mecamylamine undergoing
Mifepristone was first synthesized in 1980 at Roussel-Uclaf in
France as an oral abortifacient. First approved in France in 1988,
it was only approved in the United States in 2000 (REF. 73). It has
been used experimentally in cancer (for example, meningioma),endometriosis and Cushing syndrome. Corlux has been fast-tracked by the US FDA as a treatment for psychotic major depression. It is now in Phase III clinical testing and is also being considered for bipolar depression.
Originally developed for hypertension56; repositioned for both
male pattern baldness and erectile dysfunction57. Rogaine
was approved in 1998 for the treatment of hair loss58 and hadworldwide sales of US $162 million in 1996 (REF. 59).
The US FDA approved the TAXUS system on 4 March 2004 (REF. 60).
Preliminary worldwide net sales during the first quarter were
Phentolamine is used for the short-term control of
hypertension in patients with pheochromocytomas. When
delivered intraocularly, phentolamine inhibits pupil dilation, an action that might allow it to be used for the treatment of impaired night vision, which can occur following LASIK surgery62.
Revenue of US $922 million in osteoporosis in 2003 (REF. 63), with
US $1.5 billion in annual revenue projected by 2007 (REF. 43).
Viagra, the first approved drug for male erectile dysfunction,
achieved worldwide sales of US $1.88 billion in 2003 (REF. 51).
Tadalafil transferred to ICOS after GSK did not see any
potential in the initial indication areas62. L aunched in August,
2003. Sales in 2003 reached US $203.3 million64.
Approval by the US FDA in 1998 for cutaneous manifestations
of erythema nodosum leprosum in leprosy65. It is now widely
used to treat multiple myeloma and Celgene is now seeking
US FDA approval for this indication. Thalomid sales reached US
Johnson & Johnson noticed that Topamax caused weight loss
in overweight drug recipients. However, the side-effect profile
was unacceptable using the initial formulation*. TransForm
Pharmaceuticals received an approvable letter for a novel
crystalline form of Topamax in late 2003‡, then signed a licensing
Originally developed in 1964 in oncology and was found, in 1985
to be a potent drug for AIDS§. Became the first drug approved
for treatment of HIV in 1987. Worldwide sales of US $100 million
*Source: Maggos, C. Product development: formulation fix for Topamax. BioCentury
11 Feb 2002; ; available from www.biocentury.com. ‡Source: Company news: regulatoryJohnson & Johnson. BioCentury
25 Nov 2003; available from www.biocentury.com. §Source: AIDS Healthcare Foundation versus GlaxoSmithKline PLC et al
. No. 02-5223TJH (http://www.aidshealth.org/newsroom/news/news_archive/N110702A.htm). ADHD, attention-deficit hyperactivity disorder; AIDS, acquired immune deficiencysyndrome; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GSK, GlaxoSmithKline; HIV, human immunodeficiency virus;MOA, mechanism of action; PDE, phosphodiesterase; SERM, selective oestrogen receptor modulator; TNF, tumour-necrosis factor.
VOLUME 3 | AUGUST 2004 | 6 7 9
Table 4 | Biopharmaceutical companies repositioning drugs for neurological disorders
Milnacipran, an antidepressant licensed from Pierre Fabre
that is on the market for depression in Europe and Japan as
Ixel, is in Phase III for fibromyalgia syndrome67.
their diagnoses and also animal models of fibromyalgia syndrome*.
DDP200, a proprietary combination of two generic
neurological drugs which show statistically significant
synergy in two in vivo
models of overactive bladder, will be
starting Phase IIa trials in overactive bladder in 2H:04.
Dynogen has filed an IND application with the US FDA in
2004 for DDP225, a clinical stage antidepressant licensed
from Mitsubishi Pharma Corporation which Dynogen is repositioning for diarrhoea-predominant IBS.
C105, a stereoisomer of a known drug for a non-cognition
related therapeutic indication, has received an Orphan Drug
designation for a memory-related condition and is currently
in Phase II. SN104, a proprietary component of a currently
approved drug, has completed Phase I trials for attentiondeficit disorder68.
Dextofisopam, the R enantiomer of tofisopam, which has
been sold in Europe and Asia for over two decades for
anxiety-related conditions, is in Phase II for irritable bowel
syndrome. Low-dose cyclobenzaprine has completed
Phase II clinical trials for fibromyalgia syndrome.
S-tofisopam, the S-enantiomer of tofisopam, is in Phase I
for a variety of symptoms associated with menopause||.
*Source: Company web site: www.dynogen.com; accessed 15 Feb 2004. ‡Source: Company web site: www.cypressbio.com; accessed 15 Feb 2004. §Source: Companyweb site: www.velapharm.com; accessed 13 Feb 2004. CNS, central nervous system; IBS, irritable bowel syndrome; IND, Investigational New Drug.
It is not necessarily easier when a drug comes in from
Gaining access to repositioning candidates
outside. Here the inevitable conflict of judgment between
Even after overcoming all of the above obstacles, gaining
internal and external candidates can be encountered9,
access to the repositioning candidate’s patent estate
which are often driven by biases against any drug ‘not
and data package might at best be challenging and at
worst impossible. Only a few pharmaceutical compa-
Again, we can use the duloxetine experience as case
nies will even consider out-licensing their discontinued
in point. When one of us (K.B.T.) originally proposed
programmes. Within big pharma, only Eli Lilly and
that an agent with duloxetine’s mechanism of action
GlaxoSmithKline have dedicated out-licensing efforts,
could be useful for the treatment of SUI, it was met with
with Lilly having out-licensed more than fifty com-
a high degree of scepticism. Specifically, there were
pounds in the past six years34 and GlaxoSmithKline using
many, both inside and outside of Lilly, who felt that SUI
its discontinued programmes as a ‘currency’ for making
could not be treated with a drug because SUI resulted
venture capital-like investments in biotech companies35.
from an anatomical defect. However, during the course
Big pharma companies that do not actively out-
of seven years, sceptics were converted into advocates
license discontinued programmes cite long lists of reasons
as further data supporting the use of duloxetine in
why they take this position: “It is expensive to gather all
SUI became available and a development path for SUI
of the required data”; “it is better for the organization to
direct all of its resources towards internal efforts”;“people
Finally, the new indications of repositioned drugs
usually do not get promoted for getting rid of com-
are often ones that have been overlooked in the past. If
pounds”; “no one wants to be responsible for out-
this is the case, then there might not be a lot of famil-
licensing a blockbuster”; “the Company is concerned
iarity with the new indication and there might even be
about liability issues”. Clearly these are real issues.
disbelief, either within the organization or the medical
Indeed, in our experience, some pharmaceutical compa-
community at large, that the reposition indication will
nies will not even pull the paperwork for a compound
actually be addressing a disease or that the mechanism
unless the initial licensing fee will be US $1 million or
of action of the repositioning candidate represents a
more. But there are many strategies for managing these
viable approach to treating it. However, history shows
concerns, such as including ‘buy back’ options in the
that such challenges can be overcome, as exemplified
licensing deal and applying accounting methods that
by drugs successfully repositioned for what were once
involve placing discontinued compounds to a non-basis
overlooked or unrecognized diseases; these include
asset pool and capitalizing the associated expenses34. In
attention-deficit hyperactivity disorder, fibromyalgia
the end, good relationships between those seeking to
syndrome, hair loss, irritable bowel syndrome, male erec-
license in a compound and their counterparts at the
tile dysfunction and premenstrual dysphoric disorder
pharmaceutical company they approach often make
the difference between success and failure9.
6 8 0
| AUGUST 2004 | VOLUME 3
Biotech approaches to repositioning
focused on specific therapeutic areas, such as Cypress
Repositioning stories have historically not been an area
Biosciences and Sention (TABLE 4), use their extensive
of great interest to venture capitalists, but they are now
knowledge in particular diseases to be more oppor-
becoming increasingly attractive opportunities as thera-
tunistic than pharmaceutical companies and claim
peutics companies of all sizes, from start-ups backed by
rights to molecules that others would not expect to be
venture capitalists to publicly traded pharmaceutical
active in the new indications. Sosei and Dynogen do
and biotech companies, are now in favour of adopting
not fall neatly into either of these categories. Sosei
this approach (TABLES 4,5). In addition, venture investors
acquires molecules from the Japanese pharmacopoeia
have lately become disenchanted by the long time lines
and Japanese pharma companies that have proven safe,
and high development costs associated with de novo
and then makes them available for screening by com-
covery and development. Indeed, development time
panies interested in repositioning (BOX 1). Dynogen is
lines have improved only slightly36 and costs have risen
using a hybrid repositioning strategy as one way to
dramatically37, despite promising technological innova-
build its pipeline. This strategy uses a technology
tions in combinatorial chemistry, HTS and genomics.
involving predictive pharmacological models of geni-
Furthermore, people are the stock in trade of venture
tourinary and gastrointestinal disorders coupled with a
capital start-ups as much as products. Cherry picking of
deep understanding of the neuro-pathophysiology of,
excellent people from large pharmas has become easier
and clinical development challenges associated with,
as merger and acquisition activity in the industry has
picked up. The same type of executive who would
Simplistically viewed, the advantage of being a
work well in a pharmaceutical company can also be an
technology-based company is the greater likelihood of
excellent candidate for a repositioning effort.
making discoveries that can be protected with patent
Venture-backed start-ups applying repositioning
claims. The disadvantage lies in the longer development
strategies can be classified as those repositioning drugs
times and increased costs of developing these new
for either neurological or non-neurological disorders
products from the beginning. The advantage of the
and those using a technology platform or relying on
indication-focused approach, by contrast, is that it has
expertise within a particular therapeutic area to make
the potential to move the compounds very quickly
decisions on repositioning opportunities (TABLES 4,5).
through clinical trials on the basis of previously collected
An example of a technology-based start-up is Com-
data. However, these approaches sometimes lack the abil-
binatoRx, which uses HTS and other technologies to dis-
ity to generate data able to support patent claims. Hybrid
cover proprietary combinations of known compounds
approaches can enjoy the best of both worlds, building
with novel therapeutic activity (TABLE 5). Companies
on their indication-based repositioning successes to
Table 5 | Biopharmaceutical companies repositioning drugs for non-neurological disorders
Biomed 101, a cytokine inhibitor acquired from Searle in 1997,
and Biomed 510, an omega interferon recombinant protein
acquired from Boehringer Ingelheim in 1998, are in Phase I
for renal cell carcinoma and hepatitis C, respectively.
in 1999, is in Phase III for breast cancer.
Collaborations with ALZA and Nobex69.
Funded research programmes with Eli Lilly, AstraZeneca
human cell lines that report the activity of specific disease-associated pathways.
Quinamed, a synthetic–organic compound with
demonstrated antitumour and anti-viral properties, has
completed Phase I/II studies. Ceflatonin, a natural-product
with demonstrated clinical activity against haematological
malignancies, is in Phase II clinical trials for chronic myelogenous leukaemia and myelodysplastic syndrome, and expects to begin trials in acute myeloid leukaemia this year70,71.
CRx-026, a sedative and antibiotic combination product,
is in Phase I/II for cancer. CRx-119 and CRx-139, low-dose
cell-based phenotypic assays to identify
steroids plus ‘enhancer’ molecule, is in Phase I for
rheumatoid arthritis||. Research collaborations with Sosei and
able attack multiple disease pathways§.
SOU-001 originally failed efficacy standards in Phase II
col aborations to discover new applications
or a cardiovascular-related disease is in Phase I for in urinary
incontinence. Several collaborations with Western
biotechnology companies where each company is applying
its own proprietary technology to Sosei’s library**.
*Source: Company web site: www.biomedicinesinc.com; accessed 15 Feb 2004. ‡Source: Company web site: www.chemgenex.com; accessed 15 Feb 2004. §Source:Company web site: www.combinatorx.com; accessed 15 Feb 2004. ||Source: Calkins, K. Emerging company profile: CombinatoRx: the art of the nonobvious. BioCentury
25 Nov 2003; available from www.biocentury.com. ¶Source: Company news: deals. BioCentury
20 Oct 2003; available from www.biocentury.com. #Source: Company website: www.sosei.com; accessed 13 Feb 2004. **Source: Company web site: www.sosei.com; accessed 13 Feb 2004.
VOLUME 3 | AUGUST 2004 | 6 8 1
takeover targets. The benefit is likely to become even
Box 1 | Sosei’s novel reposition strategy
more pronounced once the biotech-based repositioning
Founded in 1990, Sosei Co. Ltd. is meeting the enormous demand for repositioning
model has been validated by some approvals. Pharma
candidates by sourcing the Japanese pharmacopoeia. As of late 2003, Sosei had obtained
companies might find it more efficient and lucrative to
non-Japanese rights to more than 2,000 compounds already marketed in Japan and an
own the repositioning engine rather than sharing rights
additional 50 unmarketed compounds out of Japanese pharmaceutical companies that
and royalties. It is easy to imagine each of the remaining
are thought to be drug candidates
38. These compounds form the basis for no fewer than
five or ten big pharma companies having its own in-
17 collaborations with US and European biotech companies. At the outset, these
house repositioning effort driven by a former biotech
collaborations are non-exclusive — each partner can screen the entire library for hits in
their indication of choice — but exclusivity is assigned on a first-come, first-served basis.
At the same time, Sosei in-licenses compounds from outside of Japan and markets them
in its home market. Finally, Sosei has used its own drug development expertise to
During the past several years, there has been a surge of
reposition SOU-001, a drug that had reached Phase II trials in a cardiovascular indication
interest in repositioning. Both pharmaceutical and
but was repositioned by Sosei and taken through pivotal trials in stress urinary
biotech companies have recognized the advantages of
incontinence. Part out-licenser, part in-licenser and part drug developer, Sosei has found
repositioning, and activity in the area has increased
favour with investors, raising more than US $27 million in its history from both
dramatically. There are a number of examples in which
international and Japanese venture capital groups. The company filed for an Initial
serendipity or directed efforts have led to successful
Public Offering on the Tokyo Stock Exchange in June, 2004.
launches in new indications. The strategy is economi-cally attractive when compared with the cost of drug
generate the revenue needed to develop early-stage
development based on de novo
drug discovery and
compounds that take advantage of their technological
development. Unique challenges are associated with
expertise. However, the number of opportunities for
repositioning strategies, which demand creative
approaches and great dedication on the part of drugrepositioners inside and outside pharmaceutical compa-
A question of venue
nies. Institutional bias often militates against developing
As we have seen, repositioning is an increasingly popular
a drug in a new indication in the same pharmaceutical
strategy in both biotech and pharmaceutical companies.
company in which the drug was developed for the initial
But which venue — pharma or biotech — is the most
indication. But for those outside of big pharma, the
appropriate for repositioning? We believe that the
challenge is equally great. Without a sense of trust
answer is self-evident: pharmaceutical companies
based on a long-term relationship, pharmaceutical
might own most of the raw material for repositioned
executives could be reluctant to make the deals with
drugs, but the initiative and insight to screen them for
outside companies that are required to create out-
novel uses usually comes from biotech companies.
Furthermore, like regulatory agencies, pharmaceutical
The current boom in repositioning raises an exis-
companies have not traditionally been organized
tential question about the approach: when the obvious
along lines conducive to repositioning.
candidates for repositioning have been exhausted, will
By contrast, biotech companies would seem to pos-
anything be left to reposition? Fortunately, the number
sess the ideal combination of incentives to pursue new
of potential indications for repositioned drugs exceeds
indications for existing drugs given their level of entre-
the current screening capacity of most companies.
preneurship, motivation (succeed or die) and institu-
Although the boom will consume the most obvious
tional flexibility. In the short-term, then, biotech is the
candidates, it is likely that repositioning opportunities
place to look for the fastest-moving repositioning stories.
will continue to present themselves, albeit possibly at a
In the long term, repositioning in biotech could
lower rate. Those companies that have sufficient bio-
become a mergers-and-acquisitions game. Given that
logical and technological expertise should be able to
pharmaceutical companies are gobbling each other up,
develop early-stage discovery compounds to fill their
as well as acquiring product-oriented biotech compa-
pipelines while still taking advantage of repositioning
nies, to fill their yawning productivity gap, the best
strategies. The full potential of the existing pharma-
biotech repositioning efforts are likely to be attractive
copoeia will not be unleashed for a long time to come.
Landers, P. Drug industry’s big push into technology falls
This article provides a brief overview of the
A detailed article on various strategies, including
short. Wall Street J.
A1 & A8 (2004).
strategies that companies are using to make drugs
drug repositioning, that biopharmaceutical
This article provides background on the industry’s
easier and more convenient to take and to extend
companies are taking to reduce development risk
technology-driven attempts to improve productivity.
patents. Several products that have benefited from
and time to market.
Usdin, S. Industry development: pipeline or flatline?
these approaches are also described.
10. Stuart, M. Rediscovering existing drugs. Start-Up 9
Hensley, S. Drug makers’ ‘combos’ treat two disorders with
Moving beyond the genome projects. Nature Biotechnol.
one pill. Wall Street J.
A brief review of the approaches that several biotech
, 1234–1238 (1996).
Kerber, R. Old drugs, new life. Boston Globe
C1 & C4
companies, such as Cypress Biosciences, Ocularis
Horrobin, D. F. Realism in drug discovery — could Cassandra
Pharma, and Ascend Therapeutics, are taking to
be right? Nature Biotechnol. 19
, 1099–1100 (2001).
Provides background on several successfully
reformulate and reposition existing drugs.
Editorial. Colonizing therapeutic space: the overlooked
repositioned drugs and companies that are
11. Thor, K. B. & Katofiasc, M. A. Effects of duloxetine,
science of drug husbandry. Nature Rev. Drug Discov. 3
leveraging repositioning as a drug development
a combined serotonin and norepinephrine reuptake inhibitor,
on central neural control of lower urinary tract function in the
Zimmerman, R. New ways to take old drugs help patients
Longman, R. Pharmaceutical strategies: jumpstart to
chloralose-anesthetized female cat. J. Pharmacol. Exp.
extend patents. The Wall Street J.
B1 & B3 (2004).
products. In Vivo 22
, 17 (2004).
, 1014–1024 (1995).
6 8 2
| AUGUST 2004 | VOLUME 3
12. Norton, P. A., Zinner, N. R., Yalcin, I., Bump, R. C. &
37. Gilbert, J., Henske, P. & Singh, A. Rebuilding big pharma’s
Boston Scientific. Boston Scientific announces FDA
Duloxetine Urinary Incontinence Study Group. Duloxetine
business model. In Vivo 21
, 73–80 (2003).
approval for its TAXUS Express2 paclitaxel-eluting coronary
versus placebo in the treatment of stress urinary
Provides an overview of the economic challenges
incontinence. Am. J. Obstet. Gynecol. 187
, 40–48 (2002).
the biopharmaceutical industry’s productivity
13. Lauman, E. O., Paik, A. & Rosen, R. C. Sexual dysfunction
problem is causing and proposes a new,
in the United States: prevalence and predictors. JAMA 281
interconnected, four-pronged approach for
addressing these problems.
a&acceptedWarning=PR> (4 March 2004).
PPD. PPD acquires Lilly’s patents for dapoxetine; adjusts
38. Stuart, M. Sosei’s drug re-profiling strategy: a three-way
Boston Scientific. 8-K filing [online], <http://ccbn.
street. Start–Up 21
, 6 (2003).
Center for Drug Evaluation and Research. Approval
15. Ärzteschaft, A. d. D. Der Beitrag der deutschen Ärzteschaft
zu verbesserter Arzneimittelsicherheit und rationaler
Arzneiverordnung in den achtziger Jahren. 2004, The
Contribution of German Physicians to Improved Drug Safety
GlaxoSmithKline. 1997 Annual Report [online],
Longman, R. Jumpstart to products. In Vivo
and Rational Drug Regulation in the Eighties (2003).
16. Brynner, R. & Stephens, T. Dark Remedy: The Impact of
Eli Lilly. January 29, 2004 8-K. Indianapolis: Eli Lilly, 2004.
Thalidomide and Its Revival as a Vital Medicine
GlaxoSmithKline. Announcement of 2003 annual results
8-04-22/04-00.pdf, accessed February 13, 2004.
17. Sampaio, E. P., Sarno, E. N., Galilly, R., Cohn, Z. A. &
Icos Corp. ICOS Corporation reports results for 2003 [online
Kaplan, G. Thalidomide selectively inhibits tumor necrosis
42. PPD. PPD acquires Lilly’s patents for dapoxetine; adjusts
press release], <http://www.corporate-
factor-α production by stimulated human monocytes.
earnings guidance for 2003 [online PPD press release],
J. Exp. Med. 173
, 699–703 (1991).
18. D’Amato, R., Loughnan, M. S., Flynn, E. & Folkman, J.
Celgene Pharmaceuticals. Thalomid history [online],
Thalidomide is an inhibitor of angiogenesis. Proc. Natl Acad.
43. SG Cowen. Pharmaceutical Industry Pulse
Sci. USA 91
, 4082–4085 (1994).
Celgene Pharmaceuticals. Celgene Corporation reports
19. Tsao, A. Thalidomide’s surprising act IV. Business Week
Center for Drug Evaluation and Research. CDER new and
record operating performance in fourth quarter and full-year
generic drug approvals: 1998–2004 [online],
2003 with strong revenue growth and profits [online press
20. Ratner, M. L. Celgene backs into biotech. In Vivo 15
Eli Lilly. 8-K filing [online], <http://www.shareholder.com/
Cypress Bioscience. Fribromyalgia syndrome: minacipran
Celgene. Celgene Corporation reports record operating
Parkinson’s Information Exchange Network Online.
Phase III trial [online], <http://www.cypressbio.com/corp/
performance in fourth quarter and full-year 2003 with strong
Parkinson’s list drug database: chlorpromazine/Thorazine
revenue and profit [online], <http://ir.celgene.com/phoenix.
Ratner, S. Sention Inc: improving memory consolidation.
November 34–36 (2002).
Sopharma. Nivalin [online], <http://www.bpg.bg/nivalin/
22. Kolata, G. U. S. approves sale of impotence pill; huge
market seen. NY Times (New York)
Janssen Pharmaceuticals. Reminyl consumer home page
23. Haltmaier, H. K., A. Potenz aus dem Labor: Die Erektionspille
[online] <http://www.us.reminyl.com/> (2004).
VIAGRA (‘Potency from the Lab: The Erection Pill Viagra’)
Pongdee, T., Frigas, E. & Hunt, L. W. Nebulized lidocaine is
(Rowohlt Taschenbuch Verlag GmbH, Reinbek bei
the drug of choice for severe steroid-dependent asthma.
Am. Coll. Allergy Asthma Immunol. Ann. Mtg
Reichert, J. M. Trends in development and approval times
24. Pfizer. Pfizer 8-K filing [online], <http://www.pfizer.com/
Barclay, L. New medical therapy briefs: irritable bowel
for new therapeutics in the United States. Nature Rev. Drug
syndrome [online], <http://www.centerwatch.com/
, 695–702 (2003).
25. Renaud, R. C. & Xuereb, H. Erectile-dysfunction therapies.
73. Women’s Health Action Trust. Events report: RU486
Nature Rev. Drug Discov. 1
, 663–664 (2002).
Pfizer. Pfizer 8-K filing [online], <http://www.pfizer.com/
26. Ostrov, B. F. Renewed life for old drugs. San Jose Mercury
Bacchi, C. J., Nathan, H. C., Hutner, S. H., McCann, P. P. &
A brief overview of drug repositioning with
Sjoerdsma, A. Polyamine metabolism: a potential
descriptions of successful repositioning efforts,
therapeutic target in trypanosomes. Science 210
We would like to thank L. A. Asinas, M. Boshar, L. R. Brettman,
including thalidomide, Viagra, Botox, Mifepristone,
S. Dickman, G. Kaplan, S. A. Holmes, S. B. Landau, J. D.
Celebrex and Vioxx.
Pegg, A. E. Polyamine metabolism and its importance in
Leander, R. C. Lorette and H. E. Wendler for helpful discussions in
27. Thor, K. B. Methods of using rapid-onset selective serotonin
neoplastic growth as a target for chemotherapy. Cancer
reuptake inhibitors for treating sexual dysfunction.
, 759–774 (1988).
CenterWatch. Newly Approved Drugs – Propecia (Merck).
28. Rosen, R. C. et al
. The international index of erectile function
The authors declare competing financial interests: see Web version
(IIEF): a multidimensional scale for assessment of erectile
dysfunction. Urology 49
, 822–830 (1997).
Merck & Co. Other financial disclosures, fourth quarter 2003
Pharmaceutical Industry Pulse
. October (2003).
Erickson, D. Emerging company profile: Pharmagene PLC.
September 23–28 (1999).
The following terms in this article are linked online to:
Resource Informagen. Pharmacia & Upjohn, Inc. [online],
34. Ratner, M. L. In-licensing: still a difficult model. Start-Up 8
35. Dawson, H. GSK ventures: recycling R&D assets. In Vivo
Pharmacia & Upjohn. Hair loss news: FDA Advisory
Europe Rx 2
, 30 (2003).
Committee recommends rogaine extra strength for OTC
Pharmaceutical Industry Profile 2004:
36. Tufts Center for the Study of Drug Development. Outlook
This report describes major R&D efficiency,
rogaine/rogaine_extra_strength_approval.cfm> (July 27,
Tufts Center for the Study of Drug Development:
regulatory, biotechnology and prescription drug
policy trends in the pharmaceutical and
Pierson, R. Merck hair-loss pill seen as future blockbuster.
US Food and Drug Administration:
Indian Express (Bombay)
(24 Dec 1997).
Access to this interactive links box is free online.
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EFEKTIFITAS TISU BASAH ANTISEPTIK SEBAGAI ALTERNATIF CUCI TANGAN BIASA DALAM MENURUNKAN JUMLAH BAKTERI TELAPAK TANGAN ABSTRAK Infeksi saluran cerna disebabkan oleh konsumsi makanan dan minuman yang terkontaminasi mikroorganisme, cuci tangan tidak memadai dapat menyebabkan makanan terkontaminasi mikroorganisme, terutama yang berasal dari tinja. Penularan fecal oral bisa dikurangi dengan berbagai
Ethical issues involving children 1. Preamble Children have unique ethical characteristics, as they are the only class of people who may be discriminated against legally. As minors they are judged not capable of running their own affairs, which are left to adults, normal y parents, to act as guardians for them. Historical y children have had minimal legal rights, with their paren