REVIEWS

DRUG REPOSITIONING:
IDENTIFYING AND DEVELOPING
NEW USES FOR EXISTING DRUGS
Ted T. Ashburn and Karl B. Thor
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
stories is increasing.
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-day
methylphenidate (Concerta; ALZA) for attention-deficit Faster development times and reduced risks
Dynogen Pharmaceuticals, 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.
e-mail:
Drug developers are also creating new product opportu- ment risk is reduced because repositioning candidates
[email protected] nities by combining therapeutically complementary have often been through several stages of clinical devel-
doi:10.1038/nrd1468 drugs into one pill — for example, Advicor (Kos opment and therefore have well-known safety and

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600 35 thereby increasing urethral resistance and protecting

against leakage of urine. Preclinical studies showed that
30
500 duloxetine potentiated the excitatory effects of sero-
Number of INDs received/

Expenditure (US $ billion)

25 tonin and noradrenaline on sphincter motor neurons11.
NDAs approved

400
The Lilly group therefore proposed that duloxetine
20
300 might be useful in the treatment of stress urinary
15 incontinence (SUI), a condition characterized by
200
10
episodic loss of urine associated with sharp increases in
intra-abdominal pressure (for example, when a person
100 5 laughs, coughs or sneezes). It is commonly seen in
0
women who have experienced several child births and
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 is caused by a weakening of the pelvic floor, which in
turn compromises the angle of the bladder neck
Total worldwide R&D expenditures
Total approvals (including priority and standing review)
responsible for maintaining normal continence. As a
Original INDs received (commercial) result, SUI was largely considered to result from an
Figure 1 | The growing productivity gap in the biopharmaceutical industry. Despite anatomical defect, and it was widely thought that SUI
enormous increases in spending in novel technologies over the last several years, R&D productivity would not respond to any drug therapy. Instead, SUI is
has 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 in
women showed that duloxetine was an effective therapy
for 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 screening, 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 within four years of launch8.
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
SEROTONIN development strategies (FIG. 3). originally developed by Lilly as adjunct therapy for anal-
Also known as a 5-hydroxy- These advantages have not escaped the notice of gesia, and discontinued for portfolio reasons. Dapoxetine
tryptamine (5-HT), a chemical venture capital firms seeking near-term, high-value exits was then considered as a follow-on antidepressant to
neurotransmitter contained in
for their companies. For venture capitalists in 2004, it is fluoxetine. However, the rapid onset and short half-life of
a specific subpopulation of
neurons in the central nervous hardly possible to invest in a therapeutics company the compound did not allow for once-daily dosing, an
system and in the enteric without drug candidates in or near clinical trials because absolute must for any competitive antidepressant, and it
nervous system. Because changes of the positive reception received by such companies was again passed over. Fluoxetine was subsequently out-
in serotonin levels in the brain from the public equity markets. Indeed, repositioning licensed to GenuPro, where one of us (K.B.T), who was
can alter mood, medications
that affect the action of
offers the opportunity to quickly create such a pipeline, then Chief Scientific Officer of GenuPro, proposed that a
serotonin are commonly used and repositioning companies are having little trouble common side effect of SSRIs — that is, delayed ejacula-
to treat depression. raising venture rounds9. tion — could be turned into a therapeutic benefit in men
with premature ejaculation, a disorder that is a problem
NORADRENALINE
Case studies for more than 20% of men in the United States13.
A catecholamine
neurotransmitter contained in A novel ‘below the belt’ use for duloxetine. Duloxetine Furthermore, it was proposed that duloxetine’s rapid
a specific subpopulation of (Cymbalta and Duloxetine SUI; Eli Lilly) blocks the reup- onset and short half-life would be a pharmacokinetic
neurons in the central nervous take of both SEROTONIN and NORADRENALINE in the synaptic advantage for ‘as needed’ treatment, which led to the
system and in sympathetic cleft. The Neuroscience Division of Eli Lilly discovered filing of a METHOD-OF-USE (MOU) PATENT. After obtaining
post-ganglionic neurons of
the peripheral autonomic
this compound in the late 1980s as a part of its efforts Phase II proof of concept for premature ejaculation,
nervous 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
METHOD-OF-USE PATENT (K.B.T.) was a member of Lilly’s Neuroscience Division it is now in Phase III clinical development for premature
(MOU). A patent containing
during the time that duloxetine was being developed ejaculation. Johnson & Johnson is currently estimating
one or more claims directed to
a method of use (for example, a for depression and reasoned that drugs with duloxe- peak sales of dapoxetine to approach US $750 million14.
method of treating disease X, tine’s mechanism of action might also increase urethral
comprising administering a sphincter tone and decrease detrusor activity. Serotonin The fall and rise of thalidomide. It is remarkable that
therapeutically effective amount and noradrenaline, although best known for their thalidomide could ever have a comeback after its tragic
of product Y to a subject in
need thereof). The exclusionary
effects on mood, were also known to have significant beginning. Thalidomide was originally marketed in
right 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
use claimed. excitatory effect on urethral sphincter motor neurons, specifically to pregnant women to treat morning sickness.

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a De novo drug discovery and development

• 10–17 year process
• <10% overall probability of success

Target discovery Discovery & screening Lead optimization ADMET Development Registration
Discovery
• Expression analysis • Traditional • Traditional • Bioavailability and • Must start clinical • United States
• In vitro function • Combinatorial medicinal systemic exposure testing at Phase I (FDA)
• In vivo validation; chemistry chemistry (absorption, (Phase I/II for • Europe (EMEA
for example, • Structure-based • Rational clearance and cancer) or country-by- Market
knockouts drug design drug design distribution) country)
• Bioinformatics Screening • Japan (MHLW)
• In vitro • Rest of world
• Ex vivo and in vivo
• High throughput
2–3 years 0.5–1 years 1–3 years 1–2 years 5–6 years 1–2 years

Drug repositioning
• 3–12 year process
• Reduced safety and pharmacokinetic uncertainty
b
Compound Compound
identification acquisition Development Registration

• Targeted • Licensing • May start at • United States

searches • Novel IP preclinical, (FDA)
• Novel insights • Both licensing Phase I or • Europe (EMEA
• Specialized and novel IP Phase II stages or country-by- Market
screening • Internal sources • Ability to country)
platforms leverage existing • Japan (MHLW)
• Serendipity data packages • Rest of World

1–2 years 0–2 years 1–6 years 1–2 years

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 drug
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.
in 46 countries16. 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.

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as they did not want to give the pills back! By 2003,

sildenafil had annual sales of US $1.88 billion and
Rewrad (α time to market, differentiability and revenue)

De novo nearly 8 million men were taking sildenafil in the

High Repositioning
United States alone24,25.
Proteins
Identifying repositioning opportunities
In licensing
So where exactly do the ideas for repositioning and the
Reformulting 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 platforms
established to identify repositioning opportunities
Low Small markets* (for example, CombinatoRx’s cHTS system26). Once the
repositioning idea has been generated, and the proposed
approach scientifically validated, then a commercially
viable target product profile for a candidate can be gener-
ated and a search conducted to identify compounds with
the desired characteristics. This search often involves a
Low High review of the public and subscription-based information
Risk (α target validity, drug-like properties and the development pathway) sources (for example, company websites, intellectual
Figure 3 | The risk-versus-reward trade off between different drug development strategies.
property (IP)5 and scientific databases5, and FDA
Drug repositioning offers one of the best risk-versus-reward trade-off of the available drug Summary Bases of Approval and so on) to identify can-
development 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
some small markets, for example, by conferring Orphan Drug status on certain drugs. Market analyses, IP and regulatory diligence, and the
formulation of new development plans, are all as much
a 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 be unique to the process.
from the thalidomide story is that no drug is ever
understood 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
COST OF GOODS SOLD
Pfizer was seeking a drug for angina when it originally COST OF GOODS SOLD (COGS). Part rigorous analysis and part

(COGS). The expense a company created sildenafil (Viagra) in the 1980s. As an inhibitor crystal-ball gazing, market analysis involves three key
incurs to manufacture a drug of phosphodiesterase-5 (PDE5), sildenafil was intended elements: developing a detailed understanding of the
product for sale. Often includes to relax coronary arteries and therefore allow greater current market; predicting what the market will look
labour, materials, overhead and
coronary blood flow. The desired cardiovascular effects like when the repositioning candidate launches; and
depreciation associated with the
manufacturing process. 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.
PHARMACODYNAMICS However, several volunteers reported in their question- Once a competitive product profile in an attractive
The study of therapeutic and/or naires that they had had unusually strong and persistent market is identified, it must then be evaluated against the
toxic effects that pharmaco-
logically active substances have
erections. Pfizer researchers did not immediately realize candidate’s known PHARMACODYNAMIC, PHARMACOKINETIC
on biological systems. In other that they had a blockbuster on their hands, but when a and safety profiles. It is also important to understand
words,‘the study of what the member of the team read a report that identified PDE5 what the candidate’s potential COGS might be. Has
drug does to the body’. 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-
PHARMACOKINETICS
The study of the rates of the large-scale study carried out on 3,700 men worldwide able number of steps? Can its drug substance be formu-
movements of drugs within with erectile dysfunction between 1993 and 1995 con- lated into drug product in a way that allows for attractive
biological systems as affected firmed that it was effective in 63% of men tested with delivery and release characteristics?
by absorption, distribution, the lowest dose level and in 82% of men tested with the The due diligence process can be one of the most
metabolism and elimination
(ADME). In other words, ‘the
highest dose23. Of note, in many of these studies22, Pfizer’s challenging steps in the repositioning process, because it
study of what the body does to researchers had difficulties retrieving unused sample of is almost impossible to gain a complete understanding
the drug.’ the drug from many subjects in the experimental group of these issues; this can be because the data were never

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Table 1 | Repositioned antidepressant drugs

Generic Original indication New indication Comments
(MOA) (trade name; originator) (trade name; repositioner)
Bupropion Depression Smoking cessation Approved as Wellbutrin for depression in 1996 (REF. 39) and as Zyban
(enhancement (Wellbutrin; (Zyban; GlaxoSmithKline) for smoking cessation in 1997 (REF. 39). Worldwide sales in 2003
of noradrenaline GlaxoSmithKline) for Wellbutrin were US $1.56 billion and US $125 million for Zyban41.
function)
Dapoxetine Analgesia and depression Premature ejaculation Currently in Phase III. If approved, it would be the first approved
(SSRI) (N/A; Eli Lilly) (N/A; Johnson & Johnson) agent for premature ejaculation. Peak sales are projected to reach
US $750 million42.
Duloxetine Depression Stress urinary incontinence Simultaneously in development for depression and SUI.
(NSRI) (Cymbalta; Eli Lilly) (Duloxetine SUI; Eli Lilly) Projected worldwide peak sales are US $800 million in SUI and
US $1.2 billion in depression43.
Fluoxetine Depression Premenstrual dysphoria Approved 6 July 2000 in the United States for use in premenstrual
(SSRI) (Prozac; Eli Lilly) (Sarafem; Eli Lilly) dysphoric disorder44. Sold in January 2003 to Galen, US $60 million of
revenue reported by September 2003.
Milnacipran Depression Fibromyalgia syndrome Marketed as Ixel for depression in Europe and Japan*; currently in
(NSRI) (Ixel; Pierre Fabre Médicament) (N/A; Cypress Biosciences) Phase III trials‡.
Sibutramine Depression (Sibut; Obesity (Meridia; Abbott) Bought in acquisition of Knoll Pharmaceuticals in 2001. Approved
(NSRI) Boots Company) 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- to the patient.
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-
regulatory standards. lected for the repositioning candidate in the original
indication 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 vardenafil (Levitra).
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-
NEW DRUG APPLICATION limit. In addition, it was important to ensure that a single mittee’ to coordinate the two. However, in this case, the
(NDA). An application to the US partner was maintained throughout the duration of the vastly different responses coming from the two sets of
FDA to market a new drug in the study to prevent partner-induced changes in ejaculatory FDA reviewers posed a significant challenge for Lilly29.
United States that contains data
latency. Novel study endpoints and efficacy measures
gathered during the animal
studies, human clinical trials of must also be developed. In the case of duloxetine for IP issues particular to repositioning
an Investigational New Drug SUI, dapoxetine for premature ejaculation and sildenafil Both blessings and unique challenges surround IP issues
(IND) and also data on for erectile dysfunction, it was necessary to develop associated with repositioning. On the plus side, new IP
chemistry, manufacturing and psychometric instruments to measure patient-perceived in the repositioned indication can create substantial
controls (CMC). Every new drug
since 1938 has been the subject
benefit; that is, the Incontinence Quality of Life12, the value for the repositioner, particularly if the candidate
of an approved NDA before US Premature Ejaculation Questionnaire27, and the Inter- has never received marketing approval. However,
commercialization. national Index of Erectile Function 28, respectively. because the candidate is usually not new to the scientific

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Table 2 | Repositioned neurological drugs (not including anti-depressants)

Generic Original indication New indication Comments
(MOA) (trade name; originator) (trade name; repositioner)
Atomoxetine Parkinson’s disease ADHD Approved by FDA in 2002 for ADHD44. Reached US
(NSRI) (N/A; Eli Lilly) (Strattera; Eli Lilly) $370 million in sales in 2003 (REF. 45), is projected to achieve
US $1.15 billion annually by 2007 (REF. 43).
Chlorpromazine Anti-emetic/antihistamine Non-sedating tranquillizer Originally marketed as a general sedative and anti-emetic
(dopamine receptor (Thorazine; (Thorazine; SmithKline) agent. After Paris surgeon Heri Laborit observed in 1952 that
blockade46) Rhone-Poulenc) 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*.
Galantamine Polio, paralysis and Alzheimer’s disease Originally marketed in 1960s (REF. 47) and now approved in
(acetylcholinesterase anaesthesia (Reminyl; Johnson & many countries for mild to moderate Alzheimer’s disease48.
inhibition) (Nivalin; Sopharma) Johnson)
Lidocaine Local anaesthesia Oral corticosteroid- Corus is reformulating lidocaine for use as inhalation treatment
(sodium channel (Xilocaine; AstraZeneca) dependent asthma for oral corticosteroid-dependent asthma. This programme,
blockade) (N/A; Corus Pharma) known as Corus-1030, is in Phase II trials in the United
States 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.
Ropinirole Hypertension Parkinson’s disease and Marketed for Parkinson’s disease since 1997; currently in
(dopamine-2 (N/A; SmithKline idiopathic restless leg syndrome Phase III for idiopathic restless leg syndrome. Worldwide
agonism) Beecham) (Requip and Zepreve; sales reached US $162 million in 2003.
GlaxoSmithKline)
Tofisopam Anxiety-related conditions Irritable bowel syndrome Racemic tofisopam has been sold for over two decades in Europe
(unclear) (Grandaxin & Seriel; (N/A; Vela Pharmaceuticals) and Asia for anxiety disorders. A Phase II trial in irritable bowel
EGIS Pharmaceuticals) 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 from
www.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-
are close to expiring. gramme using a previously discontinued internal com-
In addition, companies can invent new formulations, pound might encounter resistance from those who were
COMPOSITION-OF-MATTER
PATENT
dosage forms, drug combinations or geographic strategies involved in discontinuing the drug’s initial programme.
(COM). A patent containing that create new barriers to entry. Still other companies, Furthermore, an additional indication can trigger con-
one or more claims directed such as Sepracor, Sention and Vela Pharma, are devel- cern on the part of the of the original development team
to a composition of matter oping isometrically pure enantiomers with fewer side regarding resource allocation, safety, pricing differences
or product per se, such as a
small molecule, protein, nucleic
effects or better efficacy than the corresponding racemic and patient perceptions. An example of the latter would
acid or particular formulation mixtures. New dosage forms can themselves be a source be a concern about taking duloxetine, a psychiatric
of an agent. of new IP, as in the case of Propecia, Merck’s drug for hair medicine, for an incontinence problem, and vice versa.

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Table 3 | Repositioned non-neurological drugs

Generic Original indication New indication Comments
(MOA) (trade name; originator) (trade name; repositioner)
Celecoxib Osteoarthritis and adult Familial adenomatous Currently in Phase II trials for prevention of colon and breast
(cycloxygenase-2 rheumatoid arthritis polyposis, colon and cancer43. Pfizer intends to also test celecoxib for use in Barrett’s
inhibition) (Celebrex; Pfizer) breast cancer oesophagus, actinic keratosis, bladder cancer and ankylosing
(Celebrex; Pfizer) spondylitis51.
Eflornithine Anti-infective Reduction of unwanted Originally developed for use against West African
(ornithine (N/A; Bristol-Myers Squibb) facial hair in women trypanosomiasis52 and also explored for antitumour effects53.
decarboxylase (Vaniqa; Women First
inhibition) HealthCare)
Finasteride Benign prostatic hyperplasia Hair loss Originally approved for the treatment of enlarged prostate in
(5-α-reductase (Proscar; Merck) (Propecia; Merck) 1992, Propecia (with a fivefold lower dose), approved in 1997
inhibition) for the treatment of hair loss54, had worldwide sales of US $239
million in 2003 (REF. 55).
Mecamylamine Moderately severe to severe ADHD Inversine was originally launched in the 1950s, and was one
(nicotinic receptor essential hypertension and (N/A; Targacept) of the first orally active antihypertensives on the US market.
antagonism) uncomplicated cases of It is currently used off label for Tourette syndrome and Targacept
malignant hypertension has a low-dose version of mecamylamine undergoing
(Inversine; Layton BioScience) Phase II testing for ADHD.
Mifepristone (RU486) Pregnancy termination Psychotic major Mifepristone was first synthesized in 1980 at Roussel-Uclaf in
(glucocorticoid (Mifeprex; Danco depression France as an oral abortifacient. First approved in France in 1988,
receptor type II Laboratories) (Corlux; Corcept) it was only approved in the United States in 2000 (REF. 73). It has
antagonism) 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.
Minoxidil Hypertension Hair loss Originally developed for hypertension56; repositioned for both
(β-adrenoceptor (N/A; Pharmacia & Upjohn) (Rogaine; Pharmacia & male pattern baldness and erectile dysfunction57. Rogaine
blockade) Upjohn (now Pfizer)) was approved in 1998 for the treatment of hair loss58 and had
worldwide sales of US $162 million in 1996 (REF. 59).
Paclitaxel Cancer Restenosis The US FDA approved the TAXUS system on 4 March 2004 (REF. 60).
(disrupts normal micro- (Taxol; National Cancer (TAXUS Preliminary worldwide net sales during the first quarter were
tubule dynamics by Institute/ Express; Angiotech/ approximately US $216 million61.
promoting the poly- Bristol-Myers Squibb) Boston Scientific)
merization of tubulin)
Phentolamine Hypertension Impaired night vision Phentolamine is used for the short-term control of
(α-adrenoceptor (Regitine; Novartis) (Nyxol; Ocularis Pharma) hypertension in patients with pheochromocytomas. When
antagonism) 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.
Raloxifene Breast and prostate cancer Osteoporosis Revenue of US $922 million in osteoporosis in 2003 (REF. 63), with
(SERM) (Evista; Eli Lilly) (Evista; Eli Lilly) US $1.5 billion in annual revenue projected by 2007 (REF. 43).
Sildenafil Angina Male erectile dysfunction Viagra, the first approved drug for male erectile dysfunction,
(PDE5 inhibition) (N/A; Pfizer) (Viagra; Pfizer) achieved worldwide sales of US $1.88 billion in 2003 (REF. 51).
Tadalafil Inflammation and Male erectile dysfunction Tadalafil transferred to ICOS after GSK did not see any
(PDE5 inhibition) cardiovascular disease (Cialis; Eli Lilly & ICOS) potential in the initial indication areas62. L aunched in August,
(N/A; GlaxoSmithKline) 2003. Sales in 2003 reached US $203.3 million64.
Thalidomide Sedation, nausea and Cutaneous manifestations Approval by the US FDA in 1998 for cutaneous manifestations
(TNF-α inhibition) insomnia of moderate to severe of erythema nodosum leprosum in leprosy65. It is now widely
(Contergan; erythema nodosum used to treat multiple myeloma and Celgene is now seeking
Chemie Grunenthal) leprosum in leprosy and US FDA approval for this indication. Thalomid sales reached US
multiple myeloma $224 million in 2003 (REF. 66).
(Thalomid; Celgene)
Topiramate Epilepsy Obesity Johnson & Johnson noticed that Topamax caused weight loss
(state-dependent Na (Topamax; (N/A; Johnson & Johnson) in overweight drug recipients. However, the side-effect profile
channel blockade, Johnson & Johnson) was unacceptable using the initial formulation*. TransForm
GABA stimulation Pharmaceuticals received an approvable letter for a novel
and kainate/ crystalline form of Topamax in late 2003‡, then signed a licensing
AMPA antagonism*) agreement with J&J62.
Zidovudine Cancer HIV/AIDS Originally developed in 1964 in oncology and was found, in 1985
(reverse- (N/A; Burroughs Wellcome) (AZT/Retrovir; GSK) to be a potent drug for AIDS§. Became the first drug approved
transcriptase for treatment of HIV in 1987. Worldwide sales of US $100 million
inhibition) in 2003.
*Source: Maggos, C. Product development: formulation fix for Topamax. BioCentury 11 Feb 2002; ; available from www.biocentury.com. ‡Source: Company news: regulatory
Johnson & Johnson. BioCentury 25 Nov 2003; available from www.biocentury.com. §Source: AIDS Healthcare Foundation versus GlaxoSmithKline PLC et al. No. 02-5223
TJH (http://www.aidshealth.org/newsroom/news/news_archive/N110702A.htm). ADHD, attention-deficit hyperactivity disorder; AIDS, acquired immune deficiency
syndrome; 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.

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Table 4 | Biopharmaceutical companies repositioning drugs for neurological disorders

Company Therapeutic Approach Comments
(location) focus
Cypress Bioscience, Inc. Functional Leverages expertise in the Milnacipran, an antidepressant licensed from Pierre Fabre
(San Diego, California) somatic pathophysiology underlying that is on the market for depression in Europe and Japan as
syndromes functional somatic syndromes and Ixel, is in Phase III for fibromyalgia syndrome67.
and pain their diagnoses and also animal
models of fibromyalgia syndrome*.
Dynogen Pharma- Genitourinary Leverages its knowledge of the nexus DDP200, a proprietary combination of two generic
ceuticals, Inc. and between neurology and genitourinary neurological drugs which show statistically significant
(Boston, Massachusetts gastrointestinal and gastrointestinal disorders, as synergy in two in vivo models of overactive bladder, will be
and Durham, North disorders well as its predictive pharmacology starting Phase IIa trials in overactive bladder in 2H:04.
Carolina) models to make informed decisions Dynogen has filed an IND application with the US FDA in
on potential research and development 2004 for DDP225, a clinical stage antidepressant licensed
candidates‡. from Mitsubishi Pharma Corporation which Dynogen is
repositioning for diarrhoea-predominant IBS.
Sention, Inc. Memory Applies a whole-animal assay system C105, a stereoisomer of a known drug for a non-cognition
(Providence, Rhode impairment and that identifies genes and proteins related therapeutic indication, has received an Orphan Drug
Island) other CNS involved in memory consolidation designation for a memory-related condition and is currently
disorders and then identifies known drugs which in Phase II. SN104, a proprietary component of a currently
modulate these targets69. approved drug, has completed Phase I trials for attention
deficit disorder68.
Vela Pharmaceuticals, IBS, fibromyalgia, ‘Rediscovers’ drugs by re- Dextofisopam, the R enantiomer of tofisopam, which has
Inc. (Lawrenceville, anxiety, formulating de-prioritized been sold in Europe and Asia for over two decades for
New Jersey) menopausal compounds, seeking expanded anxiety-related conditions, is in Phase II for irritable bowel
symptoms geographic approval for drugs syndrome. Low-dose cyclobenzaprine has completed
with limited distribution and Phase II clinical trials for fibromyalgia syndrome.
exploring possible uses across S-tofisopam, the S-enantiomer of tofisopam, is in Phase I
multiple therapeutic areas§. 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: Company
web 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
invented here’. 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
became more clearly defined. 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
(TABLES 1–3). the difference between success and failure9.

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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 dis- 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 these disorders.
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

Company Therapeutic Approach Comments
(location) focus
BioMedicines, Inc. Oncology and ‘Redirected development’ of Biomed 101, a cytokine inhibitor acquired from Searle in 1997,
(Emoryville, hepatitis compounds bought or licensed from and Biomed 510, an omega interferon recombinant protein
California) pharmaceutical companies*. Biomed 777/ acquired from Boehringer Ingelheim in 1998, are in Phase I
Atamestane, acquired from Schering AG for renal cell carcinoma and hepatitis C, respectively.
in 1999, is in Phase III for breast cancer. Collaborations with ALZA and Nobex69.
Bionaut Cancer and Leverages its Sentinel Pathway Reporter Funded research programmes with Eli Lilly, AstraZeneca
(Cambridge, inflammation System which consists of a library of and Biogen.
Massachusetts) human cell lines that report the activity
of specific disease-associated pathways.
ChemGenex Oncology Uses gene-expression analysis, cellular Quinamed, a synthetic–organic compound with
Therapeutics screening systems and computational demonstrated antitumour and anti-viral properties, has
Inc. (Menlo Park, medicinal informatics software to completed Phase I/II studies. Ceflatonin, a natural-product
California) recognize chemical structures with with demonstrated clinical activity against haematological
unique attributes‡. 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.
CombinatoRx, Inc. Oncology, Leverages a high-throughput combination CRx-026, a sedative and antibiotic combination product,
(Boston, inflammation, screening system in conjunction with is in Phase I/II for cancer. CRx-119 and CRx-139, low-dose
Massachusetts) respiratory, meta- cell-based phenotypic assays to identify steroids plus ‘enhancer’ molecule, is in Phase I for
bolic and infectious combinations of existing compounds rheumatoid arthritis||. Research collaborations with Sosei and
diseases able attack multiple disease pathways§. DanioLabs¶.
Sosei Co., Ltd. Multiple Uses an extensive network of biotech SOU-001 originally failed efficacy standards in Phase II
(Tokyo, Japan) collaborations to discover new applications or a cardiovascular-related disease is in Phase I for in urinary
for a library of pre-commercialization incontinence. Several collaborations with Western
stage compounds licensed from biotechnology companies where each company is applying
various Japanese pharma companies#. 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 web
site: www.sosei.com; accessed 13 Feb 2004. **Source: Company web site: www.sosei.com; accessed 13 Feb 2004.

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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 candidates38. 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 company it has acquired.
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 Conclusions
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
hybrid approaches might be limited. approaches and great dedication on the part of drug
repositioners 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. licensing opportunities.
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.

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