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Iqac.csic.esDRUG REPOSITIONING:IDENTIFYING AND DEVELOPINGNEW USES FOR EXISTING DRUGS Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of production to biotechnology companies. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success The biopharmaceutical industry has a problem: output Pharmaceuticals), which contains lovastatin plus has not kept pace with the enormous increases in extended-release niacin for hyperlipidaemia; Gluco- pharma R&D spending (FIG. 1)1. This gap in productivity vance (Bristol-Myers Squib), which contains metformin exists even though pharma companies have invested plus glyburide for diabetes; and Caduet (Pfizer), which prodigious amounts in novel discovery technologies, contains amlodopine plus atorvastatin for hypertension such as structure-based drug design, combinatorial and hyperlipidaemia7,8. The process of finding new uses chemistry, high-throughput screening (HTS) and outside the scope of the original medical indication for genomics2, which were sold on the promise of improv- existing drugs is also known as redirecting, repurposing, ing productivity. For example, many in the industry repositioning and reprofiling8–10.
invested heavily in the idea that HTS technology Repositioning success stories and companies lever- would bring 20-fold improvements in throughput.
aging repositioning strategies are increasing in number.
Well over US $100 million has been invested to date in This review focuses on repositioning and will describe this technology3; so far, it has yielded few products4.
its general advantages over de novo drug discovery and This productivity problem — coupled with world- development; representative repositioning success wide pressure on prices, challenges from generics and stories; hurdles typically encountered during the reposi- ever-increasing regulatory hurdles — has forced many tioning process and approaches for overcoming them; drug developers to become more creative in finding new the strategies applied by several biotech companies uses for, and improved versions of, existing drugs5,6. For using this approach to drug development; and the rela- example, extended- or controlled-release formulations tive merits of pursuing repositioning approaches inside of marketed drugs have improved drug attributes, pharmaceutical or biotech companies.
such as dosing frequency — for example, once-a-daymethylphenidate (Concerta; ALZA) for attention-deficit Faster development times and reduced risks
and hyperactivity disorder — and side-effect profiles — Attempts to reduce pharmaceutical research and devel- Dynogen Pharmaceuticals,
Inc., 31 St James Avenue,
for example, extended-release oxybutynin (Ditropan opment timelines are often associated with increasing Suite 905, Boston,
XL; Johnson & Johnson) and transdermal oxybutynin risk. However, drug repositioning offers the possibility of Massachusetts 02116, USA.
patch (Oxytrol; Watson), both for overactive bladder.
escaping the horns of this dilemma. Specifically, develop- Correspondence to T.T.A.
Drug developers are also creating new product opportu- ment risk is reduced because repositioning candidates e-mail:
nities by combining therapeutically complementary have often been through several stages of clinical devel- firstname.lastname@example.org
drugs into one pill — for example, Advicor (Kos opment and therefore have well-known safety and VOLUME 3 | AUGUST 2004 | 6 7 3
thereby increasing urethral resistance and protectingagainst leakage of urine. Preclinical studies showed that duloxetine potentiated the excitatory effects of sero- tonin and noradrenaline on sphincter motor neurons11.
The Lilly group therefore proposed that duloxetine might be useful in the treatment of stress urinary incontinence (SUI), a condition characterized by episodic loss of urine associated with sharp increases in intra-abdominal pressure (for example, when a person laughs, coughs or sneezes). It is commonly seen inwomen who have experienced several child births and 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 is caused by a weakening of the pelvic floor, which inturn compromises the angle of the bladder neck responsible for maintaining normal continence. As a Total approvals (including priority and standing review)Original INDs received (commercial) result, SUI was largely considered to result from ananatomical defect, and it was widely thought that SUI Figure 1 | The growing productivity gap in the biopharmaceutical industry. Despite
would not respond to any drug therapy. Instead, SUI is enormous increases in spending in novel technologies over the last several years, R&D productivityhas actually decreased since the mid-1990s, as measured either by the number of new drugs treated with incontinence pads or adult diapers, pelvic approved per dollar spent or by the number of original Investigational New Drug (IND) applications floor Kegel exercises and surgery (for example, ure- received by the US FDA from commercial sources per dollar spent.
thropexy or sling procedures). However, clinical trials inwomen showed that duloxetine was an effective therapyfor treatment of SUI12, and so Lilly decided to develop pharmacokinetic profiles. Shorter routes to the clinic duloxetine for both SUI and depression. In September are also possible because in vitro and in vivo 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 costs, to be removed from the pathway to the market(FIG. 2). As such, repositioning can offer a better risk- Third time’s the charm for dapoxetine. Dapoxetine is a
versus-reward trade-off compared with other drug selective serotonin-reuptake inhibitor (SSRI) that was originally developed by Lilly as adjunct therapy for anal- These advantages have not escaped the notice of gesia, and discontinued for portfolio reasons. Dapoxetine venture capital firms seeking near-term, high-value exits was then considered as a follow-on antidepressant to for their companies. For venture capitalists in 2004, it is fluoxetine. However, the rapid onset and short half-life of hardly possible to invest in a therapeutics company the compound did not allow for once-daily dosing, an neurons in the central nervoussystem and in the enteric without drug candidates in or near clinical trials because absolute must for any competitive antidepressant, and it of the positive reception received by such companies was again passed over. Fluoxetine was subsequently out- from the public equity markets. Indeed, repositioning licensed to GenuPro, where one of us (K.B.T), who was offers the opportunity to quickly create such a pipeline, then Chief Scientific Officer of GenuPro, proposed that a that affect the action ofserotonin are commonly used and repositioning companies are having little trouble common side effect of SSRIs — that is, delayed ejacula- tion — could be turned into a therapeutic benefit in menwith premature ejaculation, a disorder that is a problem Case studies
for more than 20% of men in the United States13.
A novel ‘below the belt’ use for duloxetine. Duloxetine
Furthermore, it was proposed that duloxetine’s rapid neurotransmitter contained in a specific subpopulation of (Cymbalta and Duloxetine SUI; Eli Lilly) blocks the reup- onset and short half-life would be a pharmacokinetic take of both SEROTONIN and NORADRENALINE in the synaptic advantage for ‘as needed’ treatment, which led to the cleft. The Neuroscience Division of Eli Lilly discovered filing of a METHOD-OF-USE (MOU) PATENT. After obtaining this compound in the late 1980s as a part of its efforts Phase II proof of concept for premature ejaculation, the peripheral autonomicnervous system.
to find an improved version of fluoxetine (Prozac), GenuPro out-licensed dapoxetine in 2001 to ALZA Lilly’s highly successful drug for depression. One of us Corporation (now a part of Johnson & Johnson), where (K.B.T.) was a member of Lilly’s Neuroscience Division it is now in Phase III clinical development for premature during the time that duloxetine was being developed ejaculation. Johnson & Johnson is currently estimating for depression and reasoned that drugs with duloxe- peak sales of dapoxetine to approach US $750 million14.
a method of use (for example, amethod of treating disease X, tine’s mechanism of action might also increase urethral sphincter tone and decrease detrusor activity. Serotonin The fall and rise of thalidomide. It is remarkable that
and noradrenaline, although best known for their thalidomide could ever have a comeback after its tragic effects on mood, were also known to have significant beginning. Thalidomide was originally marketed in need thereof). The exclusionaryright is limited to the particular activity in the spinal cord and, specifically, to exert an 1957 in Germany and England as a sedative and targeted excitatory effect on urethral sphincter motor neurons, specifically to pregnant women to treat morning sickness.
6 7 4 | AUGUST 2004 | VOLUME 3
De novo drug discovery and development• 10–17 year process• <10% overall probability of success • Ex vivo and in vivo• High throughput Drug repositioning• 3–12 year process• Reduced safety and pharmacokinetic uncertainty Figure 2 | A comparison of traditional de novo drug discovery and development versus drug repositioning. a | It is well
known that de novo drug discovery and development is a 10–17 year process from idea to marketed drug72. The probability of success
is lower than 10%37. b | Drug repositioning offers the possibility of reduced time and risk as several phases common to de novo 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.
It was later shown that thalidomide is an inhibitor of Without the fortuitous presence of the banned drug tumour-necrosis factor-α (TNF-α)17; and that AIDS in a hospital’s medicine cabinet, thalidomide might not patients suffered as much as leprosy patients from the have been revived. Thalidomide was next used to treat inappropriate production of TNF-α16, which was known the condition erythema nodosum laprosum (ENL), an to be involved both in the development of AIDS-related agonizing inflammatory condition of leprosy character- mouth ulcers and cachexia in these patient popu- ized by large, persistent, painful boils and inflammation lations16. But it was Kaplan’s 1993 discovery that thalido- so severe it often leads to blindness. Cases of ENL are mide suppresses the activation of latent HIV type I that now well managed as a result of thalidomide’s new use.
sparked the interest of the company Celgene and led to The discovery of thalidomide’s activity in ENL could the subsequent approval of the drug under the trade not have been more accidental16. In 1964, physician name Thalomid in 1998 for use in treating ENL16.
Jacob Sheskin in the University Hospital of Marseilles In 1994, researchers at Children’s Hospital in Boston was desperate to treat a critically ill ENL patient whose discovered that thalidomide had anti-angiogenic proper- pain had been so great that he had not slept for weeks.
ties that made it a candidate in oncology, and also began As a last resort, Sheskin used the only drug in the hospi- to explain its dramatic effects in limb development in tal’s infirmary that he believed might help the patient the human foetus18. Celgene acquired the rights to sleep. Thalidomide not only allowed the patient a night’s Children’s Hospital’s thalidomide MOU patent in 1998.
VOLUME 3 | AUGUST 2004 | 6 7 5
as they did not want to give the pills back! By 2003,sildenafil had annual sales of US $1.88 billion and nearly 8 million men were taking sildenafil in the Identifying repositioning opportunities
So where exactly do the ideas for repositioning and the actual repositioning candidates come from? Ideas for repositioning can come from serendipitous observations(for example, sildenafil)22; from novel, informed insights(for example, duloxetine)11; or from technology platformsestablished to identify repositioning opportunities (for example, CombinatoRx’s cHTS system26). Once therepositioning idea has been generated, and the proposed approach scientifically validated, then a commerciallyviable target product profile for a candidate can be gener- ated and a search conducted to identify compounds withthe desired characteristics. This search often involves a review of the public and subscription-based information Risk (α target validity, drug-like properties and the development pathway) sources (for example, company websites, intellectualproperty (IP)5 and scientific databases5, and FDA Figure 3 | The risk-versus-reward trade off between different drug development strategies.
Summary Bases of Approval and so on) to identify can- Drug repositioning offers one of the best risk-versus-reward trade-off of the available drugdevelopment strategies. It can offer lower risk than in-licensing strategies because repositioning didates within the generic and branded pharmacopoeia candidates have often been through several stages of development and may even be marketed and also the pipelines of pharmaceutical companies.
entities. In addition, repositioning offers the possibility of high rewards because of shorter times However, discovering and validating the repositioning to market and higher possibility of differentiation as compared with in-licensing and reformulation idea and identifying the actual repositioning candidate strategies.*For example, rare diseases or diseases primarily incident in developing nations; is just the beginning of the repositioning process.
government regulations have been enacted to reduce risk and/or raise potential reward for Market analyses, IP and regulatory diligence, and the some small markets, for example, by conferring Orphan Drug status on certain drugs.
formulation of new development plans, are all as mucha part of the repositioning process as they are for de novodrug discovery and development. The same is true for Celgene recorded 2002 sales of US $119 million for selling the opportunity within one’s own company.
Thalomid, 92% of which came from off-label use of the However, challenges associated with obtaining access drug in treating cancer, primarily multiple myeloma19,20.
and commercial rights to repositioning candidates can Sales reached US $224 million in 200321. The lesson from the thalidomide story is that no drug is everunderstood completely, and repositioning, no matter Due Diligence: ‘is this dog gonna hunt?’
how unlikely, often remains a possibility.
The next hurdle in the repositioning process is to evalu-ate the candidate’s potential for attaining a competitive An ineffective angina drug with an interesting side effect.
product profile in an attractive market with a reasonable Pfizer was seeking a drug for angina when it originally COST OF GOODS SOLD (COGS). Part rigorous analysis and part created sildenafil (Viagra) in the 1980s. As an inhibitor crystal-ball gazing, market analysis involves three key (COGS). The expense a companyincurs to manufacture a drug of phosphodiesterase-5 (PDE5), sildenafil was intended elements: developing a detailed understanding of the to relax coronary arteries and therefore allow greater current market; predicting what the market will look coronary blood flow. The desired cardiovascular effects like when the repositioning candidate launches; and were not observed on the healthy volunteers tested at asking whether the market is large and growing rapidly, the Sandwich, England, R&D facility in 1991–1992.
and/or whether it will support premium pricing.
However, several volunteers reported in their question- Once a competitive product profile in an attractive naires that they had had unusually strong and persistent market is identified, it must then be evaluated against the erections. Pfizer researchers did not immediately realize candidate’s known PHARMACODYNAMIC, PHARMACOKINETIC that they had a blockbuster on their hands, but when a and safety profiles. It is also important to understand on biological systems. In otherwords,‘the study of what the member of the team read a report that identified PDE5 what the candidate’s potential COGS might be. Has as a key enzyme in the biochemical pathway mediating production already been scaled to multi-kilogram levels? erections, a trial in impotent men was quickly set up22. A If not, does its current synthetic route involve a reason- large-scale study carried out on 3,700 men worldwide able number of steps? Can its drug substance be formu- The study of the rates of themovements of drugs within with erectile dysfunction between 1993 and 1995 con- lated into drug product in a way that allows for attractive firmed that it was effective in 63% of men tested with the lowest dose level and in 82% of men tested with the The due diligence process can be one of the most highest dose23. Of note, in many of these studies22, Pfizer’s challenging steps in the repositioning process, because it researchers had difficulties retrieving unused sample of is almost impossible to gain a complete understanding study of what the body does tothe drug.’ the drug from many subjects in the experimental group of these issues; this can be because the data were never 6 7 6 | AUGUST 2004 | VOLUME 3
Table 1 | Repositioned antidepressant drugs
(trade name; originator)
(trade name; repositioner)
Approved as Wellbutrin for depression in 1996 (REF. 39) and as Zyban smoking cessation in 1997 (REF. 39). Worldwide sales in 2003 for Wellbutrin were US $1.56 billion and US $125 million for Zyban41.
Currently in Phase III. If approved, it would be the first approved agent for premature ejaculation. Peak sales are projected to reach US $750 million42.
Simultaneously in development for depression and SUI. Projected worldwide peak sales are US $800 million in SUI and US $1.2 billion in depression43.
Approved 6 July 2000 in the United States for use in premenstrual dysphoric disorder44. Sold in January 2003 to Galen, US $60 million of revenue reported by September 2003.
Marketed as Ixel for depression in Europe and Japan*; currently in Bought in acquisition of Knoll Pharmaceuticals in 2001. Approved 24 November 1997 in the United States for the management of obesity.
*Source: Company news: deals. BioCentury 2 Feb 2004; available from http://www.biocentury.com. ‡Source: Edelson, S. Strategy: Cypress — the channel’s the thing.
BioCentury 12 Jan 2004; available from www.biocentury.com. MOA, mechanism of action; NSRI, non-selective serotonin-reuptake inhibitor; SSRI, selective serotonin-reuptake inhibitor; SUI, stress urinary incontinence.
collected, because the data that are available do not Without these measures, it is difficult to determine, for directly address issues specific to the new indication or example, whether a 50% reduction in incontinence because necessary data are not available in the public episodes or a 2-minute delay in ejaculation is meaningful record. Indeed, if the availability of public data is lim- ited, which is often the case, then the current or origi- In addition, the reduced risk offered by well-known nal developer of the compound must be approached safety and pharmacokinetic profiles of the repositioning to obtain the needed information. This can be a deli- candidates can be offset by the lack of a clinically vali- cate process, to say the least. For older compounds, dated mechanism of action. Furthermore, even basic even if the data are available, it might not meet current data on toxicology or pharmacokinetics that were col- lected for the repositioning candidate in the originalindication might be unacceptable due to the changes Clinical development challenges
in regulatory standards. However, such pioneering The reduced risks and development times associated efforts can pay off handsomely: achieving first-in-class with repositioning can sometimes come at a price.
status can allow for a significant head start on the com- Success stories such as sildenafil occurred in therapeutic petition, as exemplified by the roughly five-year head areas in which drug therapy was unavailable or inconve- start that Pfizer’s sildenafil had on Lilly and ICOS’s nient: no oral drug had even been tested for erectile dys- tadalafil (Cialis) and GlaxoSmithKline and Bayer’s function. In the case of duloxetine, SUI was not thought to be treatable with drug. For dapoxetine, premature There have also been instances in which the timing of ejaculation was not widely recognized as a medical dis- regulatory review of the original and repositioned indi- order. What makes the development path for such indi- cations overlap. Needless to say, such circumstances cations challenging is that they require novel designs for can cause headaches for both the developers and regu- clinical trials. For example, criteria for patient inclusion latory agencies. As an example, duloxetine’s NEW DRUG in trials of premature ejaculation needed to define a APPLICATIONS for depression and SUI were filed within maximal time to ejaculation as an entry criterion, even about a year of each other with different sections of the though the Diagnostic and Statistical Manual IV does FDA. Typically, if the same drug is being considered by not stipulate ejaculation time in its definition of a time two different sections, the FDA creates an ‘oversight com- limit. In addition, it was important to ensure that a single mittee’ to coordinate the two. However, in this case, the NEW DRUG APPLICATION(NDA). An application to the US partner was maintained throughout the duration of the vastly different responses coming from the two sets of study to prevent partner-induced changes in ejaculatory FDA reviewers posed a significant challenge for Lilly29.
latency. Novel study endpoints and efficacy measures must also be developed. In the case of duloxetine for IP issues particular to repositioning
studies, human clinical trials ofan Investigational New Drug SUI, dapoxetine for premature ejaculation and sildenafil Both blessings and unique challenges surround IP issues for erectile dysfunction, it was necessary to develop associated with repositioning. On the plus side, new IP psychometric instruments to measure patient-perceived in the repositioned indication can create substantial benefit; that is, the Incontinence Quality of Life12, the value for the repositioner, particularly if the candidate Premature Ejaculation Questionnaire27, and the Inter- has never received marketing approval. However, of an approved NDA before UScommercialization.
national Index of Erectile Function28, respectively.
because the candidate is usually not new to the scientific VOLUME 3 | AUGUST 2004 | 6 7 7
Table 2 | Repositioned neurological drugs (not including anti-depressants)
(trade name; originator) (trade name; repositioner)
Approved by FDA in 2002 for ADHD44. Reached US $370 million in sales in 2003 (REF. 45), is projected to achieve US $1.15 billion annually by 2007 (REF. 43).
Originally marketed as a general sedative and anti-emetic (dopamine receptor (Thorazine; (Thorazine; SmithKline) agent. After Paris surgeon Heri Laborit observed in 1952 that it had a tranquilizing effect, SmithKline marketed it for that indication and it became a standard element of psychiatric care, used to treat 50 million patients during the next 12 years*.
marketed in 1960s (REF. 47) and now approved in many countries for mild to moderate Alzheimer’s disease48.
Corus is reformulating lidocaine for use as inhalation treatment for oral corticosteroid-dependent asthma. This programme, known as Corus-1030, is in Phase II trials in the UnitedStates and Europe‡,§. In a non-trial setting at Mayo Clinic over four years, inhaled lidocaine was well tolerated, all but one patient continued treatment, and 47 out of 49 patients were able to stop corticosteriod use49.
Marketed for Parkinson’s disease since 1997; currently in SmithKline idiopathic restless leg syndrome Phase III for idiopathic restless leg syndrome. Worldwide sales reached US $162 million in 2003.
Racemic tofisopam has been sold for over two decades in Europe and Asia for anxiety disorders. A Phase II trial in irritable bowel syndrome began in June with the R-enantiomer (dextofisopam)50.
*WGBH. A Science Odyssey: People and Discoveries; website of the television programme (http://www.pbs.org/wgbh/aso/thenandnow/humbeh.html) accessed 19 Apr 2004.
‡Source: Clinical news: clinical status. 5 May 2003; available from www.biocentury.com. §Source: Clinical news: clinical status. BioCentury 22 Dec 2003; available fromwww.biocentury.com. ADHD, attention-deficit hyperactivity disorder; MOA, mechanism of action; NSRI, non-selective serotonin-reuptake inhibitor.
community, prior art might exist that can render a loss. In addition, companies developing drugs in combi- repositioning idea unpatentable. For similar reasons, nation might be able to obtain new COM IP. This is the pre-existing patents might also exist that could impede development strategy that CombinatoRx is pursuing and commercialization of the repositioned drug.
the one that Dynogen used to create DDP200, which is The process of defending repositioned drugs against being developed for overactive bladder. Finally, obtaining competitors can be particularly challenging, even more exclusive marketing approval in new geographic markets than is the case with de novo drug discovery and develop- can also be effective in keeping out competition. For ment. Two general cases must be considered: either the instance, in the United States, drugs can rely on six- COMPOSITION-OF-MATTER (COM) IP on the compound of month, three-, five- or seven-year marketing exclusivity interest is held by another party; or the compound is off- awarded under 21 U.S.C. § 505(b)(2) for FDA approval of patent and therefore generic. In the former case, a deal a new indication in a paediatric population30, for a known must be struck to license or acquire that IP, and there are compound for a new indication31, a new chemical several strategies for dealing with the latter case.
entity32, or in a orphan population33, respectively.
If the repositioning candidate is off-patent, then the repositioner can rely on novel MOU protection or simply Potential intra-organizational hurdles
a ‘use’ patent to provide substantial barriers to entry if A repositioning programme must endure the same the drug has never been marketed. For example, many intra-organizational Darwinian struggle that every repositioned drugs are either on the market (for example, development programme endures for access to corpo- atomoxetine (Strattera; Eli Lilly)) or are in development rate resources. For an internal repositioning candidate (for example, duloxetine, dapoxetine and milnacipran to enter development, it not only has to clear the typical (TABLE 1)) that rely or plan to rely on MOU patents for development ‘fitness’ hurdles, but it might also have to protection because their COM patents have expired or compete against itself. For example, a repositioning pro- gramme using a previously discontinued internal com- In addition, companies can invent new formulations, pound might encounter resistance from those who were dosage forms, drug combinations or geographic strategies involved in discontinuing the drug’s initial programme.
that create new barriers to entry. Still other companies, Furthermore, an additional indication can trigger con- such as Sepracor, Sention and Vela Pharma, are devel- cern on the part of the of the original development team oping isometrically pure enantiomers with fewer side regarding resource allocation, safety, pricing differences effects or better efficacy than the corresponding racemic and patient perceptions. An example of the latter would mixtures. New dosage forms can themselves be a source be a concern about taking duloxetine, a psychiatric acid or particular formulationof an agent.
of new IP, as in the case of Propecia, Merck’s drug for hair medicine, for an incontinence problem, and vice versa.
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Table 3 | Repositioned non-neurological drugs
(trade name; originator)
(trade name; repositioner)
Currently in Phase II trials for prevention of colon and breast cancer43. Pfizer intends to also test celecoxib for use in Barrett’s oesophagus, actinic keratosis, bladder cancer and ankylosing Originally developed for use against West African trypanosomiasis52 and also explored for antitumour effects53. Originally approved for the treatment of enlarged prostate in 1992, Propecia (with a fivefold lower dose), approved in 1997 for the treatment of hair loss54, had worldwide sales of US $239million in 2003 (REF. 55).
Inversine was originally launched in the 1950s, and was one of the first orally active antihypertensives on the US market.
It is currently used off label for Tourette syndrome and Targacept has a low-dose version of mecamylamine undergoing Mifepristone was first synthesized in 1980 at Roussel-Uclaf in France as an oral abortifacient. First approved in France in 1988, it was only approved in the United States in 2000 (REF. 73). It has been used experimentally in cancer (for example, meningioma),endometriosis and Cushing syndrome. Corlux has been fast-tracked by the US FDA as a treatment for psychotic major depression. It is now in Phase III clinical testing and is also being considered for bipolar depression.
Originally developed for hypertension56; repositioned for both male pattern baldness and erectile dysfunction57. Rogaine was approved in 1998 for the treatment of hair loss58 and hadworldwide sales of US $162 million in 1996 (REF. 59).
The US FDA approved the TAXUS system on 4 March 2004 (REF. 60).
Preliminary worldwide net sales during the first quarter were Phentolamine is used for the short-term control of hypertension in patients with pheochromocytomas. When delivered intraocularly, phentolamine inhibits pupil dilation, an action that might allow it to be used for the treatment of impaired night vision, which can occur following LASIK surgery62.
Revenue of US $922 million in osteoporosis in 2003 (REF. 63), with US $1.5 billion in annual revenue projected by 2007 (REF. 43).
Viagra, the first approved drug for male erectile dysfunction, achieved worldwide sales of US $1.88 billion in 2003 (REF. 51).
Tadalafil transferred to ICOS after GSK did not see any potential in the initial indication areas62. L aunched in August, 2003. Sales in 2003 reached US $203.3 million64.
Approval by the US FDA in 1998 for cutaneous manifestations of erythema nodosum leprosum in leprosy65. It is now widely used to treat multiple myeloma and Celgene is now seeking US FDA approval for this indication. Thalomid sales reached US Johnson & Johnson noticed that Topamax caused weight loss in overweight drug recipients. However, the side-effect profile was unacceptable using the initial formulation*. TransForm Pharmaceuticals received an approvable letter for a novel crystalline form of Topamax in late 2003‡, then signed a licensing Originally developed in 1964 in oncology and was found, in 1985 to be a potent drug for AIDS§. Became the first drug approved for treatment of HIV in 1987. Worldwide sales of US $100 million *Source: Maggos, C. Product development: formulation fix for Topamax. BioCentury 11 Feb 2002; ; available from www.biocentury.com. ‡Source: Company news: regulatoryJohnson & Johnson. BioCentury 25 Nov 2003; available from www.biocentury.com. §Source: AIDS Healthcare Foundation versus GlaxoSmithKline PLC et al. No. 02-5223TJH (http://www.aidshealth.org/newsroom/news/news_archive/N110702A.htm). ADHD, attention-deficit hyperactivity disorder; AIDS, acquired immune deficiencysyndrome; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GSK, GlaxoSmithKline; HIV, human immunodeficiency virus;MOA, mechanism of action; PDE, phosphodiesterase; SERM, selective oestrogen receptor modulator; TNF, tumour-necrosis factor.
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Table 4 | Biopharmaceutical companies repositioning drugs for neurological disorders
Milnacipran, an antidepressant licensed from Pierre Fabre that is on the market for depression in Europe and Japan as Ixel, is in Phase III for fibromyalgia syndrome67.
their diagnoses and also animal models of fibromyalgia syndrome*.
DDP200, a proprietary combination of two generic neurological drugs which show statistically significant synergy in two in vivo models of overactive bladder, will be starting Phase IIa trials in overactive bladder in 2H:04.
Dynogen has filed an IND application with the US FDA in 2004 for DDP225, a clinical stage antidepressant licensed from Mitsubishi Pharma Corporation which Dynogen is repositioning for diarrhoea-predominant IBS.
C105, a stereoisomer of a known drug for a non-cognition related therapeutic indication, has received an Orphan Drug designation for a memory-related condition and is currently in Phase II. SN104, a proprietary component of a currently approved drug, has completed Phase I trials for attentiondeficit disorder68.
Dextofisopam, the R enantiomer of tofisopam, which has been sold in Europe and Asia for over two decades for anxiety-related conditions, is in Phase II for irritable bowel syndrome. Low-dose cyclobenzaprine has completed Phase II clinical trials for fibromyalgia syndrome.
S-tofisopam, the S-enantiomer of tofisopam, is in Phase I for a variety of symptoms associated with menopause||.
*Source: Company web site: www.dynogen.com; accessed 15 Feb 2004. ‡Source: Company web site: www.cypressbio.com; accessed 15 Feb 2004. §Source: Companyweb site: www.velapharm.com; accessed 13 Feb 2004. CNS, central nervous system; IBS, irritable bowel syndrome; IND, Investigational New Drug.
It is not necessarily easier when a drug comes in from Gaining access to repositioning candidates
outside. Here the inevitable conflict of judgment between Even after overcoming all of the above obstacles, gaining internal and external candidates can be encountered9, access to the repositioning candidate’s patent estate which are often driven by biases against any drug ‘not and data package might at best be challenging and at worst impossible. Only a few pharmaceutical compa- Again, we can use the duloxetine experience as case nies will even consider out-licensing their discontinued in point. When one of us (K.B.T.) originally proposed programmes. Within big pharma, only Eli Lilly and that an agent with duloxetine’s mechanism of action GlaxoSmithKline have dedicated out-licensing efforts, could be useful for the treatment of SUI, it was met with with Lilly having out-licensed more than fifty com- a high degree of scepticism. Specifically, there were pounds in the past six years34 and GlaxoSmithKline using many, both inside and outside of Lilly, who felt that SUI its discontinued programmes as a ‘currency’ for making could not be treated with a drug because SUI resulted venture capital-like investments in biotech companies35.
from an anatomical defect. However, during the course Big pharma companies that do not actively out- of seven years, sceptics were converted into advocates license discontinued programmes cite long lists of reasons as further data supporting the use of duloxetine in why they take this position: “It is expensive to gather all SUI became available and a development path for SUI of the required data”; “it is better for the organization to direct all of its resources towards internal efforts”;“people Finally, the new indications of repositioned drugs usually do not get promoted for getting rid of com- are often ones that have been overlooked in the past. If pounds”; “no one wants to be responsible for out- this is the case, then there might not be a lot of famil- licensing a blockbuster”; “the Company is concerned iarity with the new indication and there might even be about liability issues”. Clearly these are real issues.
disbelief, either within the organization or the medical Indeed, in our experience, some pharmaceutical compa- community at large, that the reposition indication will nies will not even pull the paperwork for a compound actually be addressing a disease or that the mechanism unless the initial licensing fee will be US $1 million or of action of the repositioning candidate represents a more. But there are many strategies for managing these viable approach to treating it. However, history shows concerns, such as including ‘buy back’ options in the that such challenges can be overcome, as exemplified licensing deal and applying accounting methods that by drugs successfully repositioned for what were once involve placing discontinued compounds to a non-basis overlooked or unrecognized diseases; these include asset pool and capitalizing the associated expenses34. In attention-deficit hyperactivity disorder, fibromyalgia the end, good relationships between those seeking to syndrome, hair loss, irritable bowel syndrome, male erec- license in a compound and their counterparts at the tile dysfunction and premenstrual dysphoric disorder pharmaceutical company they approach often make the difference between success and failure9.
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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 picked up. The same type of executive who would Simplistically viewed, the advantage of being a work well in a pharmaceutical company can also be an technology-based company is the greater likelihood of excellent candidate for a repositioning effort.
making discoveries that can be protected with patent Venture-backed start-ups applying repositioning claims. The disadvantage lies in the longer development strategies can be classified as those repositioning drugs times and increased costs of developing these new for either neurological or non-neurological disorders products from the beginning. The advantage of the and those using a technology platform or relying on indication-focused approach, by contrast, is that it has expertise within a particular therapeutic area to make the potential to move the compounds very quickly decisions on repositioning opportunities (TABLES 4,5).
through clinical trials on the basis of previously collected An example of a technology-based start-up is Com- data. However, these approaches sometimes lack the abil- binatoRx, which uses HTS and other technologies to dis- ity to generate data able to support patent claims. Hybrid cover proprietary combinations of known compounds approaches can enjoy the best of both worlds, building with novel therapeutic activity (TABLE 5). Companies on their indication-based repositioning successes to Table 5 | Biopharmaceutical companies repositioning drugs for non-neurological disorders
Biomed 101, a cytokine inhibitor acquired from Searle in 1997, and Biomed 510, an omega interferon recombinant protein acquired from Boehringer Ingelheim in 1998, are in Phase I for renal cell carcinoma and hepatitis C, respectively.
in 1999, is in Phase III for breast cancer.
Collaborations with ALZA and Nobex69.
Funded research programmes with Eli Lilly, AstraZeneca human cell lines that report the activity of specific disease-associated pathways.
Quinamed, a synthetic–organic compound with demonstrated antitumour and anti-viral properties, has completed Phase I/II studies. Ceflatonin, a natural-product with demonstrated clinical activity against haematological malignancies, is in Phase II clinical trials for chronic myelogenous leukaemia and myelodysplastic syndrome, and expects to begin trials in acute myeloid leukaemia this year70,71.
CRx-026, a sedative and antibiotic combination product, is in Phase I/II for cancer. CRx-119 and CRx-139, low-dose cell-based phenotypic assays to identify steroids plus ‘enhancer’ molecule, is in Phase I for rheumatoid arthritis||. Research collaborations with Sosei and able attack multiple disease pathways§.
SOU-001 originally failed efficacy standards in Phase II col aborations to discover new applications or a cardiovascular-related disease is in Phase I for in urinary incontinence. Several collaborations with Western biotechnology companies where each company is applying its own proprietary technology to Sosei’s library**.
*Source: Company web site: www.biomedicinesinc.com; accessed 15 Feb 2004. ‡Source: Company web site: www.chemgenex.com; accessed 15 Feb 2004. §Source:Company web site: www.combinatorx.com; accessed 15 Feb 2004. ||Source: Calkins, K. Emerging company profile: CombinatoRx: the art of the nonobvious. BioCentury25 Nov 2003; available from www.biocentury.com. ¶Source: Company news: deals. BioCentury 20 Oct 2003; available from www.biocentury.com. #Source: Company website: www.sosei.com; accessed 13 Feb 2004. **Source: Company web site: www.sosei.com; accessed 13 Feb 2004.
VOLUME 3 | AUGUST 2004 | 6 8 1
takeover targets. The benefit is likely to become even Box 1 | Sosei’s novel reposition strategy
more pronounced once the biotech-based repositioning Founded in 1990, Sosei Co. Ltd. is meeting the enormous demand for repositioning
model has been validated by some approvals. Pharma candidates by sourcing the Japanese pharmacopoeia. As of late 2003, Sosei had obtained
companies might find it more efficient and lucrative to non-Japanese rights to more than 2,000 compounds already marketed in Japan and an
own the repositioning engine rather than sharing rights additional 50 unmarketed compounds out of Japanese pharmaceutical companies that
and royalties. It is easy to imagine each of the remaining are thought to be drug 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
their indication of choice — but exclusivity is assigned on a first-come, first-served basis.
At the same time, Sosei in-licenses compounds from outside of Japan and markets them
in its home market. Finally, Sosei has used its own drug development expertise to
During the past several years, there has been a surge of reposition SOU-001, a drug that had reached Phase II trials in a cardiovascular indication
interest in repositioning. Both pharmaceutical and but was repositioned by Sosei and taken through pivotal trials in stress urinary
biotech companies have recognized the advantages of incontinence. Part out-licenser, part in-licenser and part drug developer, Sosei has found
repositioning, and activity in the area has increased favour with investors, raising more than US $27 million in its history from both
dramatically. There are a number of examples in which international and Japanese venture capital groups. The company filed for an Initial
serendipity or directed efforts have led to successful Public Offering on the Tokyo Stock Exchange in June, 2004.
launches in new indications. The strategy is economi-cally attractive when compared with the cost of drug generate the revenue needed to develop early-stage development based on de novo drug discovery and compounds that take advantage of their technological development. Unique challenges are associated with expertise. However, the number of opportunities for repositioning strategies, which demand creative approaches and great dedication on the part of drugrepositioners inside and outside pharmaceutical compa- A question of venue
nies. Institutional bias often militates against developing As we have seen, repositioning is an increasingly popular a drug in a new indication in the same pharmaceutical strategy in both biotech and pharmaceutical companies.
company in which the drug was developed for the initial But which venue — pharma or biotech — is the most indication. But for those outside of big pharma, the appropriate for repositioning? We believe that the challenge is equally great. Without a sense of trust answer is self-evident: pharmaceutical companies based on a long-term relationship, pharmaceutical might own most of the raw material for repositioned executives could be reluctant to make the deals with drugs, but the initiative and insight to screen them for outside companies that are required to create out- novel uses usually comes from biotech companies.
Furthermore, like regulatory agencies, pharmaceutical The current boom in repositioning raises an exis- companies have not traditionally been organized tential question about the approach: when the obvious along lines conducive to repositioning.
candidates for repositioning have been exhausted, will By contrast, biotech companies would seem to pos- anything be left to reposition? Fortunately, the number sess the ideal combination of incentives to pursue new of potential indications for repositioned drugs exceeds indications for existing drugs given their level of entre- the current screening capacity of most companies.
preneurship, motivation (succeed or die) and institu- Although the boom will consume the most obvious tional flexibility. In the short-term, then, biotech is the candidates, it is likely that repositioning opportunities place to look for the fastest-moving repositioning stories.
will continue to present themselves, albeit possibly at a In the long term, repositioning in biotech could lower rate. Those companies that have sufficient bio- become a mergers-and-acquisitions game. Given that logical and technological expertise should be able to pharmaceutical companies are gobbling each other up, develop early-stage discovery compounds to fill their as well as acquiring product-oriented biotech compa- pipelines while still taking advantage of repositioning nies, to fill their yawning productivity gap, the best strategies. The full potential of the existing pharma- biotech repositioning efforts are likely to be attractive copoeia will not be unleashed for a long time to come.
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Çocuk Saðlýðý ve Hastalýklarý Dergisi 2005; 48: 257-265 Çocukluk çaðýnda metabolik sendrom Þükrü Hatun1, Filiz Çizmecioðlu2 Kocaeli Üniversitesi Týp Fakültesi 1Pediatri Profesörü, 2Pediatri Uzmaný SUMMARY: Hatun Þ, Çizmecioðlu F. (Department of Pediatrics, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.) Metabolic syndrome in childhood. Çocuk Saðlý