R E V I E W S
`
`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
`has not kept pace with the enormous increases in
`pharma R&D spending (FIG. 1)1. This gap in productivity
`exists even though pharma companies have invested
`prodigious amounts in novel discovery technologies,
`such as structure-based drug design, combinatorial
`chemistry, high-throughput screening (HTS) and
`genomics2, which were sold on the promise of improv-
`ing productivity. For example, many in the industry
`invested heavily in the idea that HTS technology
`would bring 20-fold improvements in throughput.
`Well over US $100 million has been invested to date in
`this technology3; so far, it has yielded few products4.
`This productivity problem — coupled with world-
`wide pressure on prices, challenges from generics and
`ever-increasing regulatory hurdles — has forced many
`drug developers to become more creative in finding new
`uses for, and improved versions of, existing drugs5,6. For
`example, extended- or controlled-release formulations
`of marketed drugs have improved drug attributes,
`such as dosing frequency — for example, once-a-day
`methylphenidate (Concerta; ALZA) for attention-deficit
`and hyperactivity disorder — and side-effect profiles —
`for example, extended-release oxybutynin (Ditropan
`XL; Johnson & Johnson) and transdermal oxybutynin
`patch (Oxytrol; Watson), both for overactive bladder.
`Drug developers are also creating new product opportu-
`nities by combining therapeutically complementary
`drugs into one pill — for example, Advicor (Kos
`
`Pharmaceuticals), which contains lovastatin plus
`extended-release niacin for hyperlipidaemia; Gluco-
`vance (Bristol-Myers Squib), which contains metformin
`plus glyburide for diabetes; and Caduet (Pfizer), which
`contains amlodopine plus atorvastatin for hypertension
`and hyperlipidaemia7,8. The process of finding new uses
`outside the scope of the original medical indication for
`existing drugs is also known as redirecting, repurposing,
`repositioning and reprofiling8–10.
`Repositioning success stories and companies lever-
`aging repositioning strategies are increasing in number.
`This review focuses on repositioning and will describe
`its general advantages over de novo drug discovery and
`development; representative repositioning success
`stories; hurdles typically encountered during the reposi-
`tioning process and approaches for overcoming them;
`the strategies applied by several biotech companies
`using this approach to drug development; and the rela-
`tive merits of pursuing repositioning approaches inside
`pharmaceutical or biotech companies.
`
`Faster development times and reduced risks
`Attempts to reduce pharmaceutical research and devel-
`opment timelines are often associated with increasing
`risk. However, drug repositioning offers the possibility of
`escaping the horns of this dilemma. Specifically, develop-
`ment risk is reduced because repositioning candidates
`have often been through several stages of clinical devel-
`opment and therefore have well-known safety and
`
`Dynogen Pharmaceuticals,
`Inc., 31 St James Avenue,
`Suite 905, Boston,
`Massachusetts 02116, USA.
`Correspondence to T.T.A.
`e-mail:
`tashburn@dynogen.com
`doi:10.1038/nrd1468
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 3 | AUGUST 2004 | 6 7 3
`
`Medac Exhibit 2034
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
`
`

`
`thereby increasing urethral resistance and protecting
`against 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 in
`women who have experienced several child births and
`is caused by a weakening of the pelvic floor, which in
`turn compromises the angle of the bladder neck
`responsible for maintaining normal continence. As a
`result, SUI was largely considered to result from an
`anatomical defect, and it was widely thought that SUI
`would not respond to any drug therapy. Instead, SUI is
`treated with incontinence pads or adult diapers, pelvic
`floor Kegel exercises and surgery (for example, ure-
`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
`duloxetine for both SUI and depression. In September
`of 2003, Lilly received an ‘approvable’ letter from the
`US FDA to market duloxetine as Duloxetine SUI. If
`approved, it will be the first pharmacological treatment
`for SUI, and Lilly is currently anticipating worldwide
`sales of Duloxetine SUI to approach US $800 million
`within four years of launch8.
`
`Third time’s the charm for dapoxetine. Dapoxetine is a
`selective serotonin-reuptake inhibitor (SSRI) that was
`originally developed by Lilly as adjunct therapy for anal-
`gesia, and discontinued for portfolio reasons. Dapoxetine
`was then considered as a follow-on antidepressant to
`fluoxetine. However, the rapid onset and short half-life of
`the compound did not allow for once-daily dosing, an
`absolute must for any competitive antidepressant, and it
`was again passed over. Fluoxetine was subsequently out-
`licensed to GenuPro, where one of us (K.B.T), who was
`then Chief Scientific Officer of GenuPro, proposed that a
`common side effect of SSRIs — that is, delayed ejacula-
`tion — could be turned into a therapeutic benefit in men
`with premature ejaculation, a disorder that is a problem
`for more than 20% of men in the United States13.
`Furthermore, it was proposed that duloxetine’s rapid
`onset and short half-life would be a pharmacokinetic
`advantage for ‘as needed’ treatment, which led to the
`filing of a METHOD-OF-USE (MOU) PATENT. After obtaining
`Phase II proof of concept for premature ejaculation,
`GenuPro out-licensed dapoxetine in 2001 to ALZA
`Corporation (now a part of Johnson & Johnson), where
`it is now in Phase III clinical development for premature
`ejaculation. Johnson & Johnson is currently estimating
`peak sales of dapoxetine to approach US $750 million14.
`
`The fall and rise of thalidomide. It is remarkable that
`thalidomide could ever have a comeback after its tragic
`beginning. Thalidomide was originally marketed in
`1957 in Germany and England as a sedative and targeted
`specifically to pregnant women to treat morning sickness.
`
`Expenditure (US $ billion)
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`R E V I E W S
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`Number of INDs received/
`
`NDAs approved
`
`1990
`
`1991
`
`1992
`
`1993
`
`1994
`
`1995
`
`1996
`
`1997 1998 1999 2000 2001 2002 2003
`
`Total worldwide R&D expenditures
`Total approvals (including priority and standing review)
`Original INDs received (commercial)
`
`Figure 1 | The growing productivity gap in the biopharmaceutical industry. Despite
`enormous increases in spending in novel technologies over the last several years, R&D productivity
`has actually decreased since the mid-1990s, as measured either by the number of new drugs
`approved per dollar spent or by the number of original Investigational New Drug (IND) applications
`received by the US FDA from commercial sources per dollar spent.
`
`pharmacokinetic profiles. Shorter routes to the clinic
`are also possible because in vitro and in vivo screening,
`chemical optimization, toxicology, bulk manufacturing,
`formulation development and even early clinical
`development have, in many cases, already been com-
`pleted and can therefore be bypassed. In sum, these
`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-
`versus-reward trade-off compared with other drug
`development strategies (FIG. 3).
`These advantages have not escaped the notice of
`venture capital firms seeking near-term, high-value exits
`for their companies. For venture capitalists in 2004, it is
`hardly possible to invest in a therapeutics company
`without drug candidates in or near clinical trials because
`of the positive reception received by such companies
`from the public equity markets. Indeed, repositioning
`offers the opportunity to quickly create such a pipeline,
`and repositioning companies are having little trouble
`raising venture rounds9.
`
`Case studies
`A novel ‘below the belt’ use for duloxetine. Duloxetine
`(Cymbalta and Duloxetine SUI; Eli Lilly) blocks the reup-
`take of both SEROTONIN and NORADRENALINE in the synaptic
`cleft. The Neuroscience Division of Eli Lilly discovered
`this compound in the late 1980s as a part of its efforts
`to find an improved version of fluoxetine (Prozac),
`Lilly’s highly successful drug for depression. One of us
`(K.B.T.) was a member of Lilly’s Neuroscience Division
`during the time that duloxetine was being developed
`for depression and reasoned that drugs with duloxe-
`tine’s mechanism of action might also increase urethral
`sphincter tone and decrease detrusor activity. Serotonin
`and noradrenaline, although best known for their
`effects on mood, were also known to have significant
`activity in the spinal cord and, specifically, to exert an
`excitatory effect on urethral sphincter motor neurons,
`
`SEROTONIN
`Also known as a 5-hydroxy-
`tryptamine (5-HT), a chemical
`neurotransmitter contained in
`a specific subpopulation of
`neurons in the central nervous
`system and in the enteric
`nervous system. Because changes
`in serotonin levels in the brain
`can alter mood, medications
`that affect the action of
`serotonin are commonly used
`to treat depression.
`
`NORADRENALINE
`A catecholamine
`neurotransmitter contained in
`a specific subpopulation of
`neurons in the central nervous
`system and in sympathetic
`post-ganglionic neurons of
`the peripheral autonomic
`nervous system.
`
`METHOD-OF-USE PATENT
`(MOU). A patent containing
`one or more claims directed to
`a method of use (for example, a
`method of treating disease X,
`comprising administering a
`therapeutically effective amount
`of product Y to a subject in
`need thereof). The exclusionary
`right is limited to the particular
`use claimed.
`
`674 | AUGUST 2004 | VOLUME 3
`
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`
`Page 00002
`
`

`
`a
`
`b
`
`De novo drug discovery and development
`• 10–17 year process
`• <10% overall probability of success
`
`Target discovery
`
`• Expression analysis
`• In vitro function
`• In vivo validation;
`for example,
`knockouts
`• Bioinformatics
`
`Discovery & screening
`Discovery
`• Traditional
`• Combinatorial
`chemistry
`• Structure-based
`drug design
`Screening
`• In vitro
`• Ex vivo and in vivo
`• High throughput
`
`Lead optimization
`
`ADMET
`
`Development
`
`Registration
`
`• Traditional
`medicinal
`chemistry
`• Rational
`drug design
`
`• Bioavailability and
`systemic exposure
`(absorption,
`clearance and
`distribution)
`
`• Must start clinical
`testing at Phase I
`(Phase I/II for
`cancer)
`
`• United States
`(FDA)
`• Europe (EMEA
`or country-by-
`country)
`• Japan (MHLW)
`• Rest of world
`
`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
`
`Compound
`identification
`
`• Targeted
`searches
`• Novel insights
`• Specialized
`screening
`platforms
`• Serendipity
`
`Compound
`acquisition
`
`• Licensing
`• Novel IP
`• Both licensing
`and novel IP
`• Internal sources
`
`Development
`
`Registration
`
`• May start at
`preclinical,
`Phase I or
`Phase II stages
`• Ability to
`leverage existing
`data packages
`
`• United States
`(FDA)
`• Europe (EMEA
`or country-by-
`country)
`• Japan (MHLW)
`• Rest of World
`
`R E V I E W S
`
`Market
`
`Market
`
`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
`billed as “completely safe” — although the disaster that
`followed led to the introduction of the drug law
`known as the ‘Arzneimittelgesetz’, which requires that
`proof of safety be established for pharmaceuticals sold
`in Germany15,16. Taking the drug as indicated led to
`severe skeletal birth defects in at least 15,000 children
`born to mothers who had taken thalidomide during
`the first trimester of their pregnancies. Marketing in the
`initial indication went on until 1961, by which time
`the drug was being marketed to thousands of patients
`in 46 countries16.
`Without the fortuitous presence of the banned drug
`in a hospital’s medicine cabinet, thalidomide might not
`have been revived. Thalidomide was next used to treat
`the condition erythema nodosum laprosum (ENL), an
`agonizing inflammatory condition of leprosy character-
`ized by large, persistent, painful boils and inflammation
`so severe it often leads to blindness. Cases of ENL are
`now well managed as a result of thalidomide’s new use.
`The discovery of thalidomide’s activity in ENL could
`not have been more accidental16. In 1964, physician
`Jacob Sheskin in the University Hospital of Marseilles
`was desperate to treat a critically ill ENL patient whose
`pain had been so great that he had not slept for weeks.
`As a last resort, Sheskin used the only drug in the hospi-
`tal’s infirmary that he believed might help the patient
`sleep. Thalidomide not only allowed the patient a night’s
`
`sleep; it also healed the patient’s sores and eliminated his
`pain. Sheskin then conducted a double-blind study of
`thalidomide in Venezuela, and of 173 patients treated
`92% were completely relieved of their symptoms16. A
`World Health Organization-sponsored follow-up study
`on 4,552 ENL patients showed that a full 99% of
`patients enjoyed a complete remission in less than two
`weeks16. Thalidomide is still the primary, indeed the
`only, drug used to treat ENL16. Female ENL patients
`who receive thalidomide also go on two forms of birth
`control before being prescribed the drug.
`It was later shown that thalidomide is an inhibitor of
`tumour-necrosis factor-α (TNF-α)17; and that AIDS
`patients suffered as much as leprosy patients from the
`inappropriate production of TNF-α16, which was known
`to be involved both in the development of AIDS-related
`mouth ulcers and cachexia in these patient popu-
`lations16. But it was Kaplan’s 1993 discovery that thalido-
`mide suppresses the activation of latent HIV type I that
`sparked the interest of the company Celgene and led to
`the subsequent approval of the drug under the trade
`name Thalomid in 1998 for use in treating ENL16.
`In 1994, researchers at Children’s Hospital in Boston
`discovered that thalidomide had anti-angiogenic proper-
`ties that made it a candidate in oncology, and also began
`to explain its dramatic effects in limb development in
`the human foetus18. Celgene acquired the rights to
`Children’s Hospital’s thalidomide MOU patent in 1998.
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 3 | AUGUST 2004 | 6 7 5
`
`Page 00003
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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
`nearly 8 million men were taking sildenafil in the
`United States alone24,25.
`
`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 platforms
`established to identify repositioning opportunities
`(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
`review of the public and subscription-based information
`sources (for example, company websites, intellectual
`property (IP)5 and scientific databases5, and FDA
`Summary Bases of Approval and so on) to identify can-
`didates within the generic and branded pharmacopoeia
`and also the pipelines of pharmaceutical companies.
`However, discovering and validating the repositioning
`idea and identifying the actual repositioning candidate
`is just the beginning of the repositioning process.
`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
`selling the opportunity within one’s own company.
`However, challenges associated with obtaining access
`and commercial rights to repositioning candidates can
`be unique to the process.
`
`Due Diligence: ‘is this dog gonna hunt?’
`The next hurdle in the repositioning process is to evalu-
`ate the candidate’s potential for attaining a competitive
`product profile in an attractive market with a reasonable
`COST OF GOODS SOLD (COGS). Part rigorous analysis and part
`crystal-ball gazing, market analysis involves three key
`elements: developing a detailed understanding of the
`current market; predicting what the market will look
`like when the repositioning candidate launches; and
`asking whether the market is large and growing rapidly,
`and/or whether it will support premium pricing.
`Once a competitive product profile in an attractive
`market is identified, it must then be evaluated against the
`candidate’s known PHARMACODYNAMIC, PHARMACOKINETIC
`and safety profiles. It is also important to understand
`what the candidate’s potential COGS might be. Has
`production already been scaled to multi-kilogram levels?
`If not, does its current synthetic route involve a reason-
`able number of steps? Can its drug substance be formu-
`lated into drug product in a way that allows for attractive
`delivery and release characteristics?
`The due diligence process can be one of the most
`challenging steps in the repositioning process, because it
`is almost impossible to gain a complete understanding
`of these issues; this can be because the data were never
`
`R E V I E W S
`
`High
`
`Repositioning
`
`De novo
`
`Proteins
`
`In licensing
`
`Reformulting
`
`Low
`
`Small markets*
`
`Rewrad (α time to market, differentiability and revenue)
`
`High
`Low
`Risk (α target validity, drug-like properties and the development pathway)
`
`Figure 3 | The risk-versus-reward trade off between different drug development strategies.
`Drug repositioning offers one of the best risk-versus-reward trade-off of the available drug
`development strategies. It can offer lower risk than in-licensing strategies because repositioning
`candidates have often been through several stages of development and may even be marketed
`entities. In addition, repositioning offers the possibility of high rewards because of shorter times
`to market and higher possibility of differentiation as compared with in-licensing and reformulation
`strategies.*For example, rare diseases or diseases primarily incident in developing nations;
`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.
`
`Celgene recorded 2002 sales of US $119 million for
`Thalomid, 92% of which came from off-label use of the
`drug in treating cancer, primarily multiple myeloma19,20.
`Sales reached US $224 million in 200321. The lesson
`from the thalidomide story is that no drug is ever
`understood completely, and repositioning, no matter
`how unlikely, often remains a possibility.
`
`An ineffective angina drug with an interesting side effect.
`Pfizer was seeking a drug for angina when it originally
`created sildenafil (Viagra) in the 1980s. As an inhibitor
`of phosphodiesterase-5 (PDE5), sildenafil was intended
`to relax coronary arteries and therefore allow greater
`coronary blood flow. The desired cardiovascular effects
`were not observed on the healthy volunteers tested at
`the Sandwich, England, R&D facility in 1991–1992.
`However, several volunteers reported in their question-
`naires that they had had unusually strong and persistent
`erections. Pfizer researchers did not immediately realize
`that they had a blockbuster on their hands, but when a
`member of the team read a report that identified PDE5
`as a key enzyme in the biochemical pathway mediating
`erections, a trial in impotent men was quickly set up22. A
`large-scale study carried out on 3,700 men worldwide
`with erectile dysfunction between 1993 and 1995 con-
`firmed that it was effective in 63% of men tested with
`the lowest dose level and in 82% of men tested with the
`highest dose23. Of note, in many of these studies22, Pfizer’s
`researchers had difficulties retrieving unused sample of
`the drug from many subjects in the experimental group
`
`COST OF GOODS SOLD
`(COGS). The expense a company
`incurs to manufacture a drug
`product for sale. Often includes
`labour, materials, overhead and
`depreciation associated with the
`manufacturing process.
`
`PHARMACODYNAMICS
`The study of therapeutic and/or
`toxic effects that pharmaco-
`logically active substances have
`on biological systems. In other
`words,‘the study of what the
`drug does to the body’.
`
`PHARMACOKINETICS
`The study of the rates of the
`movements of drugs within
`biological systems as affected
`by absorption, distribution,
`metabolism and elimination
`(ADME). In other words,‘the
`study of what the body does to
`the drug.’
`
`676 | AUGUST 2004 | VOLUME 3
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`
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`
`Table 1 | Repositioned antidepressant drugs
`Generic
`Original indication
`New indication
`(MOA)
`(trade name; originator)
`(trade name; repositioner)
`Bupropion
`Depression
`Smoking cessation
`(enhancement
`(Wellbutrin;
`(Zyban; GlaxoSmithKline)
`of noradrenaline GlaxoSmithKline)
`function)
`Dapoxetine
`(SSRI)
`
`Premature ejaculation
`(N/A; Johnson & Johnson)
`
`Analgesia and depression
`(N/A; Eli Lilly)
`
`R E V I E W S
`
`Comments
`
`Approved as Wellbutrin for depression in 1996 (REF. 39) and as Zyban
`for smoking cessation in 1997 (REF. 39). Worldwide sales in 2003
`for Wellbutrin were US $1.56 billion and US $125 million for Zyban41.
`
`Duloxetine
`(NSRI)
`
`Fluoxetine
`(SSRI)
`
`Depression
`(Cymbalta; Eli Lilly)
`
`Stress urinary incontinence
`(Duloxetine SUI; Eli Lilly)
`
`Depression
`(Prozac; Eli Lilly)
`
`Premenstrual dysphoria
`(Sarafem; Eli Lilly)
`
`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 September2003.
`Marketed as Ixel for depression in Europe and Japan*; currently in
`Fibromyalgia syndrome
`Depression
`Milnacipran
`(N/A; Cypress Biosciences) Phase III trials‡.
`(Ixel; Pierre Fabre Médicament)
`(NSRI)
`Obesity (Meridia; Abbott)
`Bought in acquisition of Knoll Pharmaceuticals in 2001. Approved
`Depression (Sibut;
`Sibutramine
`24 November 1997 in the United States for the management of obesity.
`Boots Company)
`(NSRI)
`*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
`directly address issues specific to the new indication or
`because necessary data are not available in the public
`record. Indeed, if the availability of public data is lim-
`ited, which is often the case, then the current or origi-
`nal developer of the compound must be approached
`to obtain the needed information. This can be a deli-
`cate process, to say the least. For older compounds,
`even if the data are available, it might not meet current
`regulatory standards.
`
`Clinical development challenges
`The reduced risks and development times associated
`with repositioning can sometimes come at a price.
`Success stories such as sildenafil occurred in therapeutic
`areas in which drug therapy was unavailable or inconve-
`nient: no oral drug had even been tested for erectile dys-
`function. In the case of duloxetine, SUI was not thought
`to be treatable with drug. For dapoxetine, premature
`ejaculation was not widely recognized as a medical dis-
`order. What makes the development path for such indi-
`cations challenging is that they require novel designs for
`clinical trials. For example, criteria for patient inclusion
`in trials of premature ejaculation needed to define a
`maximal time to ejaculation as an entry criterion, even
`though the Diagnostic and Statistical Manual IV does
`not stipulate ejaculation time in its definition of a time
`limit. In addition, it was important to ensure that a single
`partner was maintained throughout the duration of the
`study to prevent partner-induced changes in ejaculatory
`latency. Novel study endpoints and efficacy measures
`must also be developed. In the case of duloxetine for
`SUI, dapoxetine for premature ejaculation and sildenafil
`for erectile dysfunction, it was necessary to develop
`psychometric instruments to measure patient-perceived
`benefit; that is, the Incontinence Quality of Life12, the
`Premature Ejaculation Questionnaire27, and the Inter-
`national Index of Erectile Function28, respectively.
`
`Without these measures, it is difficult to determine, for
`example, whether a 50% reduction in incontinence
`episodes or a 2-minute delay in ejaculation is meaningful
`to the patient.
`In addition, the reduced risk offered by well-known
`safety and pharmacokinetic profiles of the repositioning
`candidates can be offset by the lack of a clinically vali-
`dated mechanism of action. Furthermore, even basic
`data on toxicology or pharmacokinetics that were col-
`lected for the repositioning candidate in the original
`indication might be unacceptable due to the changes
`in regulatory standards. However, such pioneering
`efforts can pay off handsomely: achieving first-in-class
`status can allow for a significant head start on the com-
`petition, as exemplified by the roughly five-year head
`start that Pfizer’s sildenafil had on Lilly and ICOS’s
`tadalafil (Cialis) and GlaxoSmithKline and Bayer’s
`vardenafil (Levitra).
`There have also been instances in which the timing of
`regulatory review of the original and repositioned indi-
`cations overlap. Needless to say, such circumstances
`can cause headaches for both the developers and regu-
`latory agencies. As an example, duloxetine’s NEW DRUG
`APPLICATIONS for depression and SUI were filed within
`about a year of each other with different sections of the
`FDA. Typically, if the same drug is being considered by
`two different sections, the FDA creates an ‘oversight com-
`mittee’ to coordinate the two. However, in this case, the
`vastly different responses coming from the two sets of
`FDA reviewers posed a significant challenge for Lilly29.
`
`IP issues particular to repositioning
`Both blessings and unique challenges surround IP issues
`associated with repositioning. On the plus side, new IP
`in the repositioned indication can create substantial
`value for the repositioner, particularly if the candidate
`has never received marketing approval. However,
`because the candidate is usually not new to the scientific
`
`NEW DRUG APPLICATION
`(NDA). An application to the US
`FDA to market a new drug in the
`United States that contains data
`gathered during the animal
`studies, human clinical trials of
`an Investigational New Drug
`(IND) and also data on
`chemistry, manufacturing and
`controls (CMC). Every new drug
`since 1938 has been the subject
`of an approved NDA before US
`commercialization.
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 3 | AUGUST 2004 | 6 7 7
`
`Page 00005
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`

`
`R E V I E W S
`
`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
`(NSRI)
`(N/A; Eli Lilly)
`(Strattera; Eli Lilly)
`
`Chlorpromazine
`(dopamine receptor
`blockade46)
`
`Anti-emetic/antihistamine Non-sedating tranquillizer
`(Thorazine;
`(Thorazine; SmithKline)
`Rhone-Poulenc)
`
`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
`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*.
`Originally marketed in 1960s (REF. 47) and now approved in
`many countries for mild to moderate Alzheimer’s disease48.
`
`Alzheimer’s disease
`(Reminyl; Johnson &
`Johnson)
`Oral corticosteroid-
`dependent asthma
`(N/A; Corus Pharma)
`
`Polio, paralysis and
`Galantamine
`(acetylcholinesterase anaesthesia
`inhibition)
`(Nivalin; Sopharma)
`Lidocaine
`Local anaesthesia
`(sodium channel
`(Xilocaine; AstraZeneca)
`blockade)
`
`Ropinirole
`(dopamine-2
`agonism)
`
`Hypertension
`(N/A; SmithKline
`Beecham)
`
`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 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.
`Marketed for Parkinson’s disease since 1997; currently in
`Parkinson’s disease and
`idiopathic restless leg syndrome Phase III for idiopathic restless leg syndrome. Worldwide
`(Requip and Zepreve;
`sales reached US $162 million in 2003.
`GlaxoSmithKline)
`Irritable bowel syndrome
`(N/A; Vela Pharmaceuticals)
`
`Tofisopam
`(unclear)
`
`Racemic tofisopam has been sold for over two decades in Europe
`Anxiety-related conditions
`and Asia for anxiety disorders. A Phase II trial in irritable bowel
`(Grandaxin & Seriel;
`syndrome began in June with the R-enantiomer (dextofisopam)50.
`EGIS Pharmaceuticals)
`*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
`repositioning idea unpatentable. For similar reasons,
`pre-existing patents might also exist that could impede
`commercialization of the repositioned drug.
`The process of defending repositioned drugs against
`competitors can be particularly challenging, even more
`than is the case with de novo drug discovery and develop-
`ment. Two general cases must be considered: either the
`COMPOSITION-OF-MATTER (COM) IP on the compound of
`interest is held by another party; or the compound is off-
`patent and therefore generic. In the former case, a deal
`must be struck to license or acquire that IP, and there are
`several strategies for dealing with the latter case.
`If the repositioning candidate is off-patent, then the
`repositioner can r