The litany of problems that beset the pharma-ceutical industry continues unabated1. Thetotal cost of bringing a new drug to market

was recently calculated at a staggering $2.558 bil-lion2. Some have argued that this is a gross over-esti-mation, and a more ‘conservative’ value is $1.778billion3! The average time required from drug dis-covery to launch remains at an eye-watering 12-15years4. Approval of new chemical and biologicalentities, and hence a measure of productivity remainsrelatively static, but Research and Development

(R&D) spending continues to climb4-6. Furthermore,stratospheric risk is associated with bringing a drugto market. Initial screening of compound libraries(104-106), leads to a single compound that only hasan ~8% chance of successfully traversing the clinicaltrials gauntlet7. Even then, the value and quality ofthe end product has been questioned, with ‘seriousconcerns raised about the industry’s integrity andtransparency involving safety and efficacy’3. Unfortunately, the ‘Wagon of Woe’ for pharma-

ceutical companies does not end once a drug reaches

By Dr StephenNaylor and Judge M.Schonfeld

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Therapeutic Drug Repurposing, Repositioning and Rescue

The pharmaceutical industry is still beleaguered by escalating costs, stagnantproductivity and protracted timelines as it struggles to bring therapeutic drugsto market. This situation has been compounded by a ravenous generic drugsector, and patients that have morphed into a discerning consumer population.The growing interest, activity and productivity in Drug Repurposing, DrugRepositioning and Drug Rescue (DRPx) appears to offer some encouragementin finding solutions to the myriad of problems the pharmaceutical companiesmust overcome. Here we describe the current status of DRPx, discuss theemerging consensus on terminology and describe the tools, technologies andapproaches utilised in DRPx. This perspective is augmented by consideration ofthe companies that provide services and platform technologies for DRPxdiscovery and development, as well as examples of approved DRPx drugscurrently on the market. We also discuss the value and challenges associatedwith undertaking DRPx and its impact on the pharmaceutical sector as well aspatients and the healthcare system.

Part 1: Overview

market8. Generic drugs continue to offer significantcompetition, and now capture ~70% of prescriptionswritten in the USA3. Also, ‘patent cliff’ expirations(2001-2016) have been calculated to cost $245.5 bil-lion in lost sales for the pharmaceutical industry tothe generics market9. Finally, there is a morphinglandscape dictated by more stringent regulatoryoversight, demands for mechanism-of-action-baseddrug discovery and development (DDD) and apatient population driven by the advent of person-alised medicine and a consumer mentality8,10. Thishas left the pharmaceutical sector scrambling foravenues of opportunity to minimise risk, reducecosts, and fill their pipelines with safe and efficaciouscandidate drugs. A series of endeavours that maydeliver on addressing such needs include DrugRepurposing, Repositioning, and Rescue. Thesestrategies, and others, have been used in order tocombat the current limited productivity of the phar-maceutical industry, and they are all summarised inFigure 111. Drug Repurposing, also commonly referred to

as Drug Repositioning or Drug Rescue, emergedprimarily in the early 1990s as a viable alternativeto conventional de novo DDD. The terminology(see below) usually refers to the process of identi-fying new indications for existing drugs, aban-doned or shelved compounds and candidatesunder development. Barrett has noted that “it isan attractive way to maximise return on prior andcurrent preclinical and clinical investments inassets that were originally designed with differentpatient populations in mind”12. In this article wefocus on Drug Repurposing/Repositioning/Rescue(DRPx), and do not address drug reformulation,dosage, delivery mechanisms and combinationtherapies.

Definitions of drug repurposing,repositioning and rescueCurrently, DRPx endeavours play an increasing rolein the DDD efforts of the pharmaceutical industry.It is estimated that the DRPx process accounts formore than 30% of new drugs and vaccinesapproved by the US FDA in recent years13. In addi-tion Aris Persidis, President and Co-Founder ofBioVista, has calculated that DRPx now generates$500 Billion (~25% of annual revenue) for thepharmaceutical industry14. This impact has createda flurry of new activity and interest in DRPx. Forexample, a new journal dedicated to DRPx entitledDrug Repurposing, Repositioning & Rescue hasjust been launched15, a book on the subject pub-lished12, a series of annual conferences inaugurat-ed16 and a workshop sponsored by the Institute ofMedicine (National Academy of Sciences) held inWashington DC last year17.Unfortunately, the evolutionary process associat-

ed with a nascent and/or revitalised discipline isoften embodied by chaos, confusion and circumlo-cution, as evidenced by the similarities experiencedin the Biomarker18 and Companion Diagnostic19

sectors. Thus, as might be expected, the lexicon ofthis field is still in flux and there are competing, yetinconsistent ‘synonyms’ for Drug Repositioningthat include Repurposing, Rescue, Retargeting andReprofiling. More recently there has been a con-certed attempt to bring some ontological structurein this area11,20. It is now suggested that DrugRepurposing should be used as a catch-all termthat includes ‘all the redevelopment strategiesbased on the same chemical structure of the thera-peutically active ingredient as in the original prod-uct’11. Mucke has stated that “repurposingdescribes the general concept of branching thedevelopment of an active pharmaceutical ingredi-ent, at any stage of the life cycle and regardless ofthe success or misfortune it has encountered so far,to serve a therapeutic purpose that is significantlydifferent from the originally intended one”20. Drug Repositioning is defined more specifically

as the process of finding a new indication for anapproved drug20. If the pharmacological frame-work, such as the pathway or target is the same asfor the original indication then it is referred to asOn-Target Repositioning. Approximately 80% ofDrug Repositioning efforts have occurred throughthis route. The more novel Off-TargetRepositioning is used as the descriptor when themechanism of action, pathway or target is differentfrom the original indications12,21. Finally, DrugRescue refers to a system of developing new usesfor chemical and biological entities that previously

Figure 1Potential drug

repurposing strategies

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were investigated in clinical studies but not furtherdeveloped nor submitted for regulatory approval,or had to be removed from the market for safetyreasons20.

DRPx organisations and initiativesMost of the larger pharmaceutical companiescontinue to embrace DRPx efforts in either a for-mal or ad hoc manner. The one exceptionappears to be Merck. It remains cautious becauseof the experience with its NSAID Rofecoxib(brand name Vioxx). In 2000-01 the companycarried out a series of studies to determine ifRofecoxib was efficacious in slowing down theonset of Alzheimer’s Disease, as well as prevent-ing colon polyps (APPROVe Trial). In both theseDRPx studies the drug manifested safety issues,including adverse cardiovascular events(APPROVe Trial only). Ultimately, this led to thewithdrawal of the drug from the market in200422. In contrast, other companies, such asRoche, view candidate compounds from apolypharmacological perspective as a potentialtreatment for multiple diseases. They start outwith a rationale for a particular target, but willrepurpose during the lifetime of the project if thedata indicates a different direction should betaken23. Roche formalised its DRPx approach byannouncing an arrangement with the BroadInstitute in 2012. It agreed to provide 300 of itsfailed compounds in order to let the BroadInstitute screen them for potential new uses24. Other large pharma companies that have dedi-

cated internal resources to DRPx include Novartis(New Indications Discovery Unit), BayerHealthcare Pharmaceuticals (Common MechanismResearch group) and TEVA announced in 2013 thecreation of its ‘New Therapeutic Entity’ initiative.Pfizer, on the other hand, recently closed its DRPxIndications Discovery Unit based in St Louis, butjoined the National Center for AdvancedTranslational Sciences (NCATS) TherapeuticDiscovery Program. The NCATS initiative waslaunched in 2012 and was NIH funded to find newuses for therapeutic compounds shelved or aban-doned by pharmaceutical companies. In this pro-gramme, eight pharmaceutical companies –AbbieVie, AstraZeneca, Bristol Myers Squibb,Lilly, GlaxoSmithKline, Sanofi-Aventis, Janssenand Pfizer – have collectively made 58 of theircompounds available for DRPx. A similar initia-tive was announced by the Medical ResearchCouncil (MRC) in a partnership arrangement withAstraZeneca in the UK. This programme wasexpanded to include Cancer Research UK late last

Drug Discovery World Winter 2014/15

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year and allows unprecedented access toAstraZeneca’s compound library.A vibrant interest in DRPx has garnered sub-

stantial growth in this sector, and resulted in theemergence of a number of dedicated private corpo-rations that are listed in Table 1. These companiescover the gamut of capabilities and offer every-thing from consulting services, such as HMPharma, to marketed drug products courtesy ofNeXeption, SEEK Group and Sosei. Many of the

companies listed in Table 1 provide fee-for-servic-es, offer platform technologies (includes databasesand/or technologies) for discovery and develop-ment in DRPx, and in some cases have their ownpipeline of DRPx compounds. BioVista is one such company that offers and

provides all of these competencies and is widelyregarded as a pioneer of dedicated DRPx efforts.The company was founded in 1996 by the Persidisbrothers, and has headquarters in both the USA

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Table 1: Corporations, Non profits and government agencies with a primary focus in DRPx. Focus Area 1= Consulting; 2= Services; 2*= Compoundsavailable for DRPx evaluation; 3= DRPx database and/or platform 4= Pipeline of DPR compounds; 5=DRPx marketed drugs; 6= Offer funding for DRPxprojects and drug candidates

ORGANISATION CURRENT LEADERSHIP WEBSITE LOCATION FOUNDED FOCUSAREA

A. CorporationsAnaxomics Jose Manuel Mas PhD www.anaxomics.com Barcelona, Spain 2013 2,3BioVista Aris Persidis PhD www.biovista.com Charlottesville, VA, USA 1996 2,3,4Camargo Pharma Ken Phelps www.camargopharma.com Cincinnati, OH, USA 2003 2Celentyx Nicholas Barnes MD www.celentyx.com Birmingham, UK 2006 2,3,4CureHunter Judge Schonfeld www.curehunter.com Portland, OR, USA 2003 2,3Epsilon 3 Karl Altenhuber www.epsilon-3.com Vienna, Austria 2014 1,2GVK Bio Manni Kantipudi www.gvkbio.com Hyderabad, India 2001 2,3HM Pharma Hermann Mucke PhD www.hmpharmacon Vienna, Austria 2000 1,2Kailash BioSciences Alisa Wright www.kailashbio Bloomington, IN, USA 2014 2*Intellimedix Jim Richards www.intellimedix.com Atlanta, GA, USA 2014 2,3Marco Polo Pharma Mondher Toumi MD www.marcopolo-pharma.com Paris, France 2008 4Mellior Andrew Reume PhD www.meliordiscovery.com Exton, PA, USA 2005 2,3,4nPharmakon Dmitri Rebatchouk PhD www.npharmakon.com Piscataway, NJ, USA 2008 2,3,4NeXeption Stephen Tullman www.nexeption.com Malvern, PA, USA 2011 5NovaLead Supreet Dashpande www.novaleadpharma.com Pune, India 2010 3,4Numedicus David Cavalla PhD www.numedicus.co.uk Cambridge, UK 2008 1,3NuMedii Gini Deshpande PhD www.numedii.com Palo Alto, CA, USA 2011 3PharmaKure Farid Khan PhD www.pharmakure.com Manchester, UK 2013 3,4Quantacea Ivaylo Penchev www.quantacea.eu Sofia, Bulgaria 2012 3ReDiscovery LifeSci. Daniel Behr MBA www.rediscoveryls Cambridge, MA, 2014 3,4Revive Therapeutics Fabio Chianelli www.revivethera.com Vaughan, ON, Canada 2012 4Re-Pharm Robert Scoffin DPhil www.re-pharm.com Cambridge, UK 2011 2,3,4Seachange Pharma Nicholas Hodge PhD www.seachangepharma.com San Jose, CA, USA 2009 2,3Sistemic Jim Reid www.sistemic.co.uk Glasgow, UK 2010 2,3SEEK Gregory Stoloff MEc www.seekacure.com London, UK 2004 4,5Switch Biotec Stefan Schulze PhD www.switch-biotec.com Conway. AR, USA 1997 3,4SOM Biotech Raul Insa PhD/MD www.sombiotech.com Barcelona, Spain 2009 3,4Sosei Takaya Fujii MBA www.sosei.com/en Tokyo, Japan 1990 3,4,5Therametrics Raffaele Petrone www.therametrics.com Stan, Switzerland 2007 2,3,4TONIX Seth Lederman MD www.tonixpharma.com New York, NY, USA 2007 4Transparency LS Tom Sablinski MD/PhD www.transparencyls.com Online presence only 2010 2,4

B. Non-profitCWHM Peter Ruminski MS www.cwhm.org St. Louis, MO, USA 2010 2Cures Within Reach Bruce Bloom JD/DDS www.cureswithinreach.org Chicago, IL, 2005 2,3,6GlobalCures Vidula Sukhatme MS www.global-cures.org Newton, MA, USA 2004 2WIPO Re:Search www.wipo.int/research/en 2011 2

C. GovernmentNCATS Chris Austin MD www.ncats.nih.gov Bethesda, MA, USA 2012 2*,6MRC/AstraZeneca Chris Watkins www.mrc.ac.uk Cambridge, UK 2011 2*,6

(Charlottesville, Virginia) and Europe (Athens,Greece). It provides services to the pharmaceuticalindustry but also has a DRPx discovery platformentitled the Clinical Outcome Search Space(COSS). This computational biology platformintelligently searches a database of pharmacologi-cally active compounds, while simultaneously link-ing them with mechanism of action, adverse eventsand human target information. In addition thecompany has its own DRPx pipeline with candi-date compounds in neurodegeneration, epilepsy,oncology and CNS disease. Another company witha robust DRPx pipeline is Therametrics (Stans,Switzerland). It has 19 DRPx pipeline candidates,predicated on its ‘unique bio-mathematical tech-nology research platform’ which utilises Graph-Network Theory. Based on business and regulato-ry considerations, they are primarily focused inOrphan Disease areas such as sarcoidosis and idio-pathic pulmonary fibrosis, but also have com-pounds in clinical trials for COPD, Tuberculosisand excessive angiogenesis. Melior Discovery has taken a more conventional

approach to DRPx utilising in vivo animal models todetermine safety and efficacy of potential drug can-didates. It employs approximately 45 validated ani-mal models covering a wide range of disease states.The theraTRACE animal model platform was piv-otal in the DRPx discovery of MLR-1023, an oralinsulin sensitiser being developed for treatment oftype II diabetes. Late last year the companyannounced that it had received FDA protocolapproval for a Phase II trials and also its first mile-stone payments from its licensing partner BukwangPharmaceuticals (Seoul, South Korea). In contrast,Transparency Life Sciences is taking a new, as yetunproven, approach to DRPx discovery and devel-opment. It sources its DRPx drug candidates “fromthe hundreds of distressed clinical-stage compoundsthat have potential for rescue or repositioning”. Theapproach of the company is based on three princi-ples of; i) crowdsourcing-in order to enable all par-ticipant stakeholders to contribute to the design ofthe company’s clinical trials; ii) leveraging advancesin information technology and mobile health; andiii) transparency throughout the developmentprocess to build credibility with diverse stakehold-ers. It is attempting to develop a portfolio of drugcandidates, retaining ownership stakes in each whilesoliciting foundations and government grants,crowdfunding, and other potential funding opportu-nities. At present it is evaluating Naltrexone inCrohn’s disease; Lisinopril for multiple sclerosis;Pioglitazone in Parkinson’s Disease, Metformin inprostate cancer and Kiacta in sarcoidosis.

Experimental DRPx requires physical access to acollection of approved drugs. In the past this hascreated considerable obstacles to successful DRPxendeavours. Last year Kailash Biosciences openedits doors and currently offers “480 SmartCompounds of drugs which have regulatoryapproval for human use and have been selected fortheir diverse pharmacological properties and theirscarcity”. Compounds are offered either in a 96-well plate (60 compounds per well) or individualvial format. The company intends to expand itsoffering to more than 3,600 approved and specialinterest compounds in 2015. A number of otherchemical library companies such as Enzo LifeSciences (Plymouth Meeting, PA, USA), PrestwickChemicals (Washington DC, USA) and SpectrumMicrosource (Gaylordsville, CT, USA) also offersmall libraries containing 500-1,000 compoundsthat are approved or off-patent drugs. (Since thesecompanies offer a suite of other services and prod-ucts they are not included in Table 1.) Also, in2011 the NIH Chemical Genomics Center phar-maceutical collection was created and a pro-gramme initiated25. This is a screening service forcollaborators to access and assess this approveddrug library using a wide range of assays, and thusfind new repositioning candidates for a multitudeof diseases particularly, rare, neglected and orphandiseases. This effort is now managed by NCATSand the library now consists of ~2,500 approved,small molecule compounds, as well as an addition-al 1,000 investigational molecular entities.Corporations are pursuing DRPx efforts for a

multitude of reasons but are primarily driven bythe need to generate revenues. However, non-prof-its such as Cures Within Reach (CWR) are pursu-ing somewhat different goals (see Table 1B). DrBruce Bloom, Founder and President of CWR, stat-ed that: “Drug Repurposing is a very safe, fast andaffordable way to create new medical treatments,especially in those rare and neglected diseaseswhere the economics of new drug developmentmakes it challenging for the for-profit sector, or forthe payers.”26 This Chicago-based entity has abroad partnership base consisting of academic andresearch institutions. It helps finance DRPx collab-orative efforts, and has to date facilitated thelaunch of 10 new DRPx drugs. In 2015 it rolledout its new CureAccelerator Platform. Dr Bloomhas stated that “CWR is scaling up the repurposingrevolution through the CureAccelerator web plat-form to find repurposing ideas ready for the clinic,raise the money for the clinical trials, and test therepurposed drugs, devices and nutraceuticals inpatients. Then publish the results to give physicians

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the opportunity to determine how they might usethese repurposed solutions in clinical practice.”26

The platform connects patient groups, industry,researches and funding sources all interested in theDRPx process, and aims to facilitate the dialoguebetween them. In a similar manner, the Center for World Health

& Medicine (CWHM) is focused on DRPx candi-date compounds, but with interest in neglected andrare diseases primarily impacting patients inDeveloping World countries. This organisationwas founded in 2010 by a group of former Pfizerresearchers and access compounds from a varietyof sources to evaluate in their pre-clinical models.Currently they have ongoing DRPx projects inchildhood diarrhoea, tuberculosis, malaria, sicklecell disease and a number of rare diseases such asidiopatheic pulmonary fibrosis. CWHM is one of anumber of non-profit, company and academicgroups participating in the consortium World

Intellectual Property Organization (WIPO)Re:Search programme. WIPO Re:Search has creat-ed a database of available IP assets including regu-latory data, technology and compounds to supportresearch on neglected diseases, and much of thiseffort is in the form of DRPx investigation. Finally,it should be noted that a number of non-profitpatient advocacy and disease foundations supportefforts in DRPx focused on their particular area ofdomain expertise. For example the CHDIFoundation provides guidance, reagents and fund-ing to help companies carry out DRPx activities oncandidate compounds as potential therapeutictreatments for Huntingdon disease. While all theseefforts are noteworthy, they are usually only a partof other substantial efforts and therefore are notincluded in Table 1.DRPx is a complex, multi-factorial component

process. It requires a myriad of tools, technologiesand skilled collaborators to ensure success in the

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Table 2: Drugs approved for new indications after being subjected to DRPx

DRUG NAME ORIGINAL INDICATION NEW INDICATION YEAR PHARMA COMPANY

Amitripyline Antidepressant Neuropathic pain 2005 AstraZeneca Amphotericin B Antifungal Leishmaniasis 1997 NeXstar PharmaAspirin Inflammation, Pain Anti-platelet, heart attack, stroke Various VariousAzathioprine Rheumatoid Arthritis (RA) IBD, MS, organ transplants Various VariousBimatoprost Glaucoma Eyelash growth 2008 AllerganBleomycin Antibiotic Cancer 1973 Kayaku/BMSBromocriptine Parkinson’s Disease Type II diabetes 2009 NovartisBuprenorphine Pain Drug treatment 2002 Reckitt-BenckiserBupropion Antidepressant Smoking cessation 1997 GSK

Weight-loss (combi-therapy) 2014 Orexigen/TakedaCanakinumab Rheumatoid Arthritis (RA) Muckle-Wells Syndrome 2009 NovartisClofazime Tuberculosis Leprosy 1986 GeigyColchicine Gout Familial mediterranean fever 2009 URL PharmaColesevelam LDL-lowering Type II diabetes 2008 Daiichi-SankyoCrizotinib Lymphoma NSCLC 2011 PfizerCycloserine Tuberculosis CNS disorders Various VariousCyclosporine Organ transplant rejection Psoriasis, RA 1997 NovartisDapoxetine Antidepressant Premature ejaculation 2004 J&JDimethyl Fumarate Psoriasis MS 2013 Biogen IDECDonepezil Alzheimer’s Disease Dementia 2006 Eisai/PfizerDoxepin Antidepressant Atopic dermatitis 2003 VariousDuloxetine Depression & GAD Stress urinary incontinence 2004 Lilly

Fibromyalgia 2008 LillyPain 2010 Lilly

Eflornthine Cancer Hirsutism 2000 GilletteSleeping sickness 1990 Aventis

Etanercept Rheumatoid Arthritis (RA) Plaque psoriasis 2004 Amgen/PfizerEverolimus Organ rejection Various cancers Various NovartisFinasteride Hypertension Benign prostate hyperplasia 1992 Merck

Male pattern baldness 1997 MerckFluoxetine Antidepressant PMDD 2002 Lilly Gabapentin Seizure Postherpetic neuralgia 2004 Parke DavisGalantamine Chronic fatigue syndrome Alzheimer’s Disease 2001 Various Gemcitabine Anti-viral Various cancers Various Lilly

creation of a ‘new’ drug. In order to facilitate suchefforts a series of Open Source initiatives and mod-els have been created, and some have beendescribed above. This allows for efficient sharingof resources, data, compounds and drugs, com-pound libraries and screening platforms to “cost-effectively advance old drugs and/or candidatesinto clinical redevelopment”27. Open Sourceresources continue to be developed and madeavailable and include numerous database and datamining capabilities such as DrugBank, PotentialDrug Target Database, Therapeutic TargetDatabase, SuperTarget, PubChem, ChEMBL,ChemSpider, IDMap, Open Phacts and PROMIS-CUOUS. These and other capabilities are describedin detail elsewhere13,27,28.

DRPx discovery – tools & methodsHistorically, numerous DRPx drugs have been dis-covered through serendipitous routes. They

include drugs that were tested fortuitously for newindications such as Buproprion (Brand NameZyban) for smoking cessation, and Thalidomidefor leprosy and multiple myeloma. In addition thelist includes candidate compounds or drugs whereobservations of unexpected side-effects in ongoingclinical trials led to the successful development of,for instance, Sildenfil (brand name Viagra) fortreatment of erectile dysfunction (ED) andMinoxidil (brand name Rogaine) for hair loss.Table 2 lists a number of compounds and drugsthat were subjected to DRPx efforts and approvedfor new indications. A bedrock principle of the pharmaceutical

industry used to be the ‘one drug-one target’ para-digm. However, the high attrition rate of com-pounds in late stage clinical trials due to poor effi-cacy indicated that this model was flawed. Today itis clear that ‘drug promiscuity’, also referred to aspolypharmacology, is widespread29. Indeed it was

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Table 2 (continued): Drugs approved for new indications after being subjected to DRPx

DRUG NAME ORIGINAL INDICATION NEW INDICATION YEAR PHARMA COMPANY

Glycopyrronium Anti-ulcer COPD 2005 Sosei/Novartis Histrelin Prostate cancer Precocious puberty 2007 Endo Pharma Hydroxychloroquine Malaria Lupus, rheumatoid Various Various Ibuprofen Inflammation, pain OA, RA, headache, migraine Various VariousImatinib CML GIST 2012 Novartis

ALL 2013 NovartisImfliximab Autoimmune diseases Crohn’s Disease 1998 JanssenIproniazid Tuberculosis Antidepressant 1958 VariousLomitapide Hypercholesterimia HoFH 2012 Aegerion PharmaMethotrexate Cancer Psoriasis, RA 2001 Barr LabsMinoxidil Hypertension Hair Loss 1988 UpjohnMilnacipran Antideprressant Fibromyalgia 2009 Forest PharmaMiltefosine Cancer Leishamaniasis 2014 ZentarisNaltrexone Opiod/alcohol addiction Weight-loss (combi-therapy) 2014 Orexigen/TakedaOnabotulinumtocin Facial spasm Cervical dystonia 2000 Allergan

Chronic migraine 2010 AllerganFacial cosmetics 2012 Allergan

Paclitael Various cancers Stent restenosis prevention Various VariousParoxetine Antidepressant Menopausal hot flashes 2013 GSKPertuzumab Various cancers HER-2 + breast cancer 2013 GenetechPlerixafor AIDS/HIV Lymphoma & multiple myeloma 2008 GenzymePramipexole Parkinson’s Disease Restless leg syndrome 2006 BoehringerPregabalin Anticonvulsant, neuropathic pain Fibromyalgia 2007 PfizerPropranolol Hypertension Migraine, angina, tremors Various VariousRetinoic Acid Acne Acute myeloid leukaemia 1995 Hoffman La RocheRaloxifene Osteoporosis Breast cancer 2007 LillyRituximab Various cancers Rheumatoid Arthritis 2004 IDECRopininole Parkinson’s Disease Restless leg syndrome 2005 GSKSildenafil Angina Erectile dysfunction 1998 Pfizer

PAH 2005 PfizerSunitinib GIST and RCC Pancreatic tumors 2010 PfizerThalidomide Anti-nausea Leprosy 1998 Celgene

Multiple myeloma 2006 CelgeneZidovudine Cancer HIV/AIDS 1987 Burroughs

recently reported that the average drug promiscu-ity rate is ~6-7.5 targets/approved drug30. Suchpharmacological properties are a pre-requisite forDRPx efforts to be viable, but it also suggested thata more rational approach to the identification ofDRPx candidates is possible. In that regard a vari-ety of tools and technologies have been developedthat determine and/or identify: i) compounds thatmodulate specific disease phenotypes, ii) identifynew drug-target interactions, iii) define new rolesfor existing targets, or iv) find new disease path-ways. Many of these technologies were developedand used in conventional DDD, but have also nowbeen routinely applied to DRPx discovery andinclude high-throughput screening (HTS) and largescale kinase inhibitor assays12,17,31. It has been suggested that DRPx discovery should

be considered from a drug-centric, target-centric anddisease-centric perspective12,17,21,31. However, thetwo predominant outcomes in DRPx discovery areeither i) a known candidate compound/drug inter-acting with a new target, or ii) known target map-ping to a new disease indication. Methods and toolsutilised in DRPx discovery to identify such possibil-ities include in vitro and in vivo (cell/organ/tissue/animal) phenotype model screening, HTS, HighContent Screening (HTC), Chemoinformatics,Bioinformatics, as well as Network and SystemsBiology12,13,17,30. These approaches are used inconjunction with available information on knowntargets, drugs, biomarkers of disease, and path-ways/networks of disease that can ultimately lead toaccelerated timelines in the discovery and develop-ment of DRPx candidate drugs.In a thoughtful analysis, Jin and Wong have fur-

ther sub-classified methods into approaches predi-cated on available information and elucidatedmechanisms13.The sub-classification of methodsconsists of:

i) Screening-based: Examples include off-label druguse and phenotype screening. These approachesoffer flexibility but typically do not include biolog-ical/pharmacological information and do not pro-vide mechanism of action (MOA) insight.Information content output is poor. This includesoff-label drug use, phenotype screening using HTSand HCS.ii) Target-based: examples include HTS, HTC andin silico screening of libraries. Targets typically linkto MOA, and provide rapid screening capability ofcompound libraries. Information content output ispoor. This includes phenotype screening(HTS/HCS) as well as in silico screening (dockingand ligand screening studies).

iii) Knowledge-based: examples include variousbioinformatic and chemoinformatic approaches.Since the information input is high, the DRPx pre-diction is more accurate than screening and target-based approaches. Information content output ismoderate. This includes drug-target predictions,adverse event reporting, clinical trial informationand disease pathway analysis.iv) Signature-based: Examples include individualgene/protein/metabolite signatures from diseaseomics data. These approaches are more likely touncover off-target and disease mechanisms.Information content output is moderate to high.This includes connectivity maps linking diseaseswith drugs and genome-wide association studies(GWAS). v) Pathway/network-based: Example includesavailable signalling or metabolic pathway, and pro-tein interaction networks to reconstruct specificdisease pathways. This allows the narrowing downof a large number of proteins to a small specificdisease-related network. Information content out-put is high. This includes differential disease omicsand reconstruction of disease pathways to identifykey targets. vi) Targeted mechanism-based: Example includesintegrated omics data with signalling pathway andprotein interaction networks. This is a powerfulapproach to delineate MOA for a drug treatmentof a specific disease. Information content output isextremely high. This includes determining similari-ty networks between drugs and disease.

This systematic approach allows one to identifywhich method to use predicated on the availableinformation. All this is summarised in Table 3, andexplained in more detail elsewhere13. A compre-hensive overview and details of existing DRPxmethods can be found in a variety of other pub-lished works on the subject12,13,17,21,28,31.Numerous challenges still exist to execute on

cost-effective DRPx efforts. For instance, Jin andWong stated that: “To test a large number of dis-eases for a specific drug or a large number of drugsfor a specific disease, it is difficult to unify theneeded computational approaches because theavailable information for different diseases ordrugs varies. For example, to use target-basedmethods to reposition drugs for 100 diseases, onewould have to know the biomarkers or availablepathways for each of these diseases. The knowl-edge needed for this type of drug repositioningmight be unavailable or difficult to derive from theliterature or available databases.”13

However, one DRPx company has taken such an

References1 PriceWaterhouseCoopers-Pharma 2020. i) The Vision; ii)Virtual R&D; iii) Marketing theFuture; iv) ChallengingBusiness Models; v) TaxingTimes Ahead; vi) Supplying theFuture vii) Introducing thePharma 2020 Series.http://www.pwc.com/gx/en/pharma-life-sciences/pharma2020/index.jhtml.2 Cost to Develop and WinMarketing Approval for a NewDrug Is $2.6 Billion.TuftsCSDD. http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study.3 Paul, SM et al. How toImprove R&D Productivity: thePharmaceutical Industry’sGrand Challenge. NatureReviews: Drug Discovery, 9,203-214 (2010).4 Deloitte Centre for Healthsolutions. Measuring theReturn from PharmaceuticalInnovation 2014. Turning aCorner? http://www2.deloitte.com/content/dam/Deloitte/uk/Documents/life-sciences-health-care/measuring-the-return-from-pharmaceutical-innovation-2014.pdf.5 Gavura, S. What Does aNew Drug Cost? Part II TheProductivity Problem.http://www.sciencebasedmedicine.org/what-does-a-new-drug-cost-part-ii-the-productivity-problem.6 Hay, M et al. ClinicalDevelopment Success Ratesfor Investigational Drugs.Nature Biotech. 32, 40-51(2014).7 Cook, D et al. LessonsLearned from the Fate ofAstra-Zeneca’s Drug Pipeline:A Five Dimensional Network.Nature Reviews: DrugDiscovery. 13, 419-431 (2014).8 Naylor, S. NostraPharmusRevisitied: A Future of SplendidIsolation or MultilevelParticipation forPharmaceutical Companies.Drug Discov. World. SummerSupplement, 24-26 (2010).

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approach. CureHunter Inc (Portland, Oregon)utilises an Integrated Systems Biology platformwhich effectively synthesises all the data andknowledge acquired from the methods describedabove (i-vi screening to targeted mechanism) toproduce a clinical outcome database (see Table3D). This database is structured for autonomousprediction of new disease indications for any givendrug, biomarker, or active biological agent. Theplatform consists of five modules:

i) Controlled source knowledge module: USNational Library of Medicine archive (USNLM)from 1809-current (continuously updated).ii) Data acquisition module: High precision clinicalefficacy variable text mining capability using apurpose-built semantically intelligent NaturalLanguage Processor.iii) Array module: All data is arrayed into a drug-disease-outcome relationships database where eachrelation is an empirically weighted contributor toclinical efficacy.iv) Analysis module: Using Network GraphTheory and a suite of algorithms to determine themost centric and similar components of clinicalefficacy for all diseases.v) Prediction module: Answer system analyticsautomation layer with graphic user interface (GUI)for real-time output of new indications with highprobability of clinical success prediction.

The CureHunter platform facilitates the captureand automated DRPx analysis of all of publishedbiomedical knowledge (in the USNLM) demon-strating a functional role in the clinical efficacypotential of more than 250,000 active biologicalmolecules, markers, mechanisms and drugs operat-ing in more than 11,600 disease states. Each yearthis self-updating system has added close to onemillion new records to its master clinical outcomedatabase so that the system constantly learns andupdates its predictive analyses in real time. Thusthe design and operation of the CureHunter enginealso solves one of the major problems facing theDRPx community, namely the need to cost-effec-tively utilise the ever-increasing flow of data andforward integrate new research for successive yearsof discovery. It is interesting to note that the systemis effectively a ‘push-button’ DRPx engine.

DRPx drugsApproximately 80 examples of DRPx drugs havebeen approved and launched as therapeutic agentsfor new indication(s) in the USA and Europe32.The origin of such DRPx candidates is varied but

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can be loosely grouped into one of the followingcategories: i) Compounds from academic and pub-lic sector labs that were never commercialised; ii)Compounds already in a clinical development thatdemonstrated polypharmacology; iii) Shelved com-pounds – failed to demonstrate efficacy in Phase IIor III clinical trials; iv) Drugs that were discontin-ued for commercial or safety reasons; v) Drugsclose to patent expiry or competition from gener-ics; vi) Drugs with incremental new indications-known as Line Extension; vii) Drugs available indeveloping markets but not commercialised in the

USA/Europe/Japan (sometimes referred to asGeographical/Transnational DRPx). A poster-child for DRPx, and an example of a

shelved drug candidate, is Sildenfil. This compoundis a potent inhibitor cGMP-phosphodiesterase 5, anenzyme known to regulate blood flow. Sildenfil wasbeing evaluated in clinical trials for the treatment ofangina. However, the trials were suspended after itwas demonstrated that the compound manifestedpharmacokinetic properties that were inconsistentwith the prolonged control necessary for the treat-ment of angina. By happenstance, during the

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FIELD TYPE METHOD/CATEGORY APPROACHES USED/OUTPUTS

A. Drug-centric

Off-Label Blinded serendipity Clinical decision

Phenotype screen Blinded screening HTS/HCS

Phenotype screen Target-based screening HTS/HCS

Chemical structure Target-based chemoinformatics In silico screening

Drug-target interactions Knowledge-based bio/chemoinformatics Drug-target predictions

Clinical trials data (adverse events) Knowledge-based bioinformatics Correlation analysis for drug similarity

Approved drug-adverse event Knowledge-based bioinformatics PCA for drug similarity

B. Target-centric

Pathways Knowledge-based bioinformatics Disease mechanism

Omics data Signature-based bioinformatics Primarily gene signatures

Genetics data Signature-based bioinformatics GWAS

Pathway/omics data Pathway/network biology Disease pathways

C. Disease-centric

Drug omics data Signature-based bioinformatics Connectivity maps

Drug omics data Signature bioinformatics/networks Gene signature & community structure

Disease/drug omics data Signature-based bioinformatics Differential signatures

Drug omics, disease pathway & proteininteraction networks

Target mechanism-based & network biology Target pathway elucidation

D. Clinical outcome-centric

Drug/omics/pathway/networks & systems Target mechanism-based & diseasepathways/networks

Differential clinical outcome database

Patient reportage Web & EMR-based Association databases

Table 3: Approaches to DRPx. Methods, tools and outcomes. Adapted from Jin and Wong13

clinical trial, researchers noted an unexpected side-effect that led to the development and approval ofthe compound for previously untreatable, erectiledysfunction (ED) in 1998. Ironically, the original‘poor’ pharmacokinetic properties of Sildenfil actu-ally made it an ideal drug for ED therapy.Subsequently, Sildenfil was also found to be effec-tive in the treatment of pulmonary arterial hyper-tension and was approved for use in the USA in2005, but is marketed under the brand nameREVATIO. Other examples of drug candidates thatlacked efficacy in the original clinical trial but weresuccessfully repurposed include Canakinumab,Pertuzumab and Finasteride. In the case ofFinasteride, this was originally evaluated for hyper-tension, but was ultimately repurposed for bothbenign prostate hyperplasia (BPH) as well as malepattern baldness (MPB), and in both cases was anon-target repurposing endeavour. Table 2 providesa summary of this data as well as a list of otherapproved DRPx drugs that includes their originalindication and new indication(s).A limited number of drugs have failed after their

post-market launch, but then subsequently subject-ed to successful DRPx. The most well-knownexample of such a strategy is the ‘notorious’ drugThalidomide. It was originally marketed as a seda-tive and antiemetic and had an inhibitory effect onmorning sickness, common in pregnant women.Unfortunately, the drug had a teratogenic effect onthe foetus and many children were born withdeformed limbs and faces. The drug was with-drawn from the market in 1962. Further studiesrevealed that the drug also appears to inhibitTumor Necrosis Factor-Alpha signalling and it wassubsequently approved for the treatment of erythe-ma nodosum leprosum, a painful skin condition ofleprosy in 1998 and Multiple Myeloma in 2006.The drug is currently under evaluation for an addi-tional 30 other new indication treatments. As discussed above, drug promiscuity is now

well-recognised, and any one drug can affect morethan a single pathway, which can ultimately lead tonew indications for drug candidates or existingdrugs. Thalidomide is an example of off-targetDRPx. Other drug candidates that have been sub-ject to successful off-target DRPx includeCrizotinib and Imatinib. Crizotinib is a proteinkinase inhibitor that binds within the ATP-bindingpocket of target kinases. It was originally tested foranaplastic large cell lymphoma as a MET-kinaseinhibitor. However it was subsequently approvedby the FDA in 2011 for the treatment of non-smallcell lung cancer where the ALK-oncogene was thetarget. In addition, Imatinib (brand name Gleevec),

a small molecule BCR-abl tyrosine kinase inhibitor,was originally approved for treatment of chronicmyelogenous leukemia (CML). The drug was fur-ther approved by the FDA in 2002 for use inpatients with gastrointestinal tumours (GIST), andagain in 2012 for removal of KIT-positive tumoursafter surgery in order to prevent the reoccurrenceof the tumour. In both cases the MOA involvedoff-target c-kit and PDGF-RA.There are numerous examples of on-target

DRPx, and include such popular drugs asDuloxetine (brand name Cymbalta), Everolimus(brand name Zortress), Sunitinib (brand nameSutent) and the first anti-retroviral Zidovudine(brand name Retrovir, also known as AZT).Sunitinib is an example of a drug-centric DRPxcase. The drug was originally approved for treat-ment of GIST and renal cell carcinoma (RCC) as areceptor tyrosine kinase inhibitor. It was subse-quently subjected to DRPx and approved for treat-ment of pancreatic neuroendocrine tumour in2010. Everolimus is an example of a target-centricapproach. This drug is used as an immunosuppres-sant in the post-treatment of organ transplantpatients, and inhibits the mammalian target ofrapamycin. The target was subsequently identifiedas an important candidate in numerous other dis-eases and the drug was approved for kidney cellcancer (2009), astrocytoma (2010), metastaticpancreatic neuroendocrine tumour (2011) andHER-2(-) breast cancer (2012). As an interestingaside, the compound was also approved for use inconjunction with a drug-eluting stent as animmunosuppressant to prevent restenosis.Duloxetine is a reported example of a DRPx wherethe pathway was determined to be important inother diseases. The drug is a mixed serotonin/nor-epinephrine reuptake inhibitor (SNRI.) It was ini-tially approved for the treatment of depression andgeneral anxiety disorder (GAD), but was repur-posed for fibromyalgia (2008) and musculoskeletalpain (2010). However, the pathway and mecha-nism of action for its analgesic properties has sub-sequently been suggested to act via a sodium chan-nel blocker and not the SNRI pathway34. A finalexample of an on-target DRPx effort involvesZidovudine. This drug is a nucleoside analoguereverse-transcriptase inhibitor that was subjectedto DRPx and became the first antiretroviralapproved for the treatment of HIV/AIDS. It wasoriginally evaluated as an anticancer agent in the1960s, since the prevailing theory at the time wasthat most cancers were caused by environmentalretroviruses. Needless to say the original cancertesting proved to be unsuccessful.

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9 Accenture Life Sciences.Beyond the Patent Cliff-Signsof Recovery in BioPharma’sNew Normal.http://www.accenture.com/SiteCollectionDocuments/PDF/Accenture-Life-Sciences-Beyond-The-Patent-Cliff-Signs-Of-Recovery-in-Biopharmas-New-Normal.pdf.10 Kessel, M. Restoring thePharmaceutical Industry’sReputation. Nature Biotech.32, 983-990 (2014).11 Murteira, S, Ghezaiel, Z,Karray, S and Lamure, M. DrugReformulations andRepositioning inPharmaceutical Industry andits Impact on Market Access:Reassessment ofNomenclature. Journal ofMarket Access & Health Policy1: 21131 – http://dx.doi.org/10.3402/jmahp.v1i0.21131(2013).12 Barratt, MJ and Frail, DE(Eds). Drug Repositioning:Bringing New Life to ShelvedAssets and Existing Drugs.John Wiley & Sons, Hoboken,NJ, USA. (2012). 13 Jin, G and Wong, STC.Toward Better DrugRepositioning: Prioritizing andIntegrating Existing Methodsinto Efficient Pipelines. DrugDis. Today 19, 637-644 (2014).14 Persidis, A. PersonalCommunication. Data to bepublished in Drug RepurposingRescue & Repositioning.(2015).15 Persidis, A and Mucke,HAM (Eds). Drug Repurposing,Rescue & Repositioning.http://www.liebertpub.com/overview/drug-repurposing-rescue-brand-repositioning/627.16 Lederman, S. DrugRepurposing RekindlesPromise. GEN. January 30th2013. http://www.genengnews.com/gen-articles/drug-repurposing-rekindles-promise/4710/?kwrd=Drug%20Repositioning.

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Value and challenges of DRPxThe tribulations of the pharmaceutical industryhave been discussed already in this article. Thedevelopment and successful execution of wellthought-through DRPx strategies can help alleviatesuch problems and add significant value to phar-maceutical company pipelines as well as to patients,the ultimate end-users of these products. The spe-cific issues that contribute to DRPx value include:

i) Cost savings: Previously, Persidis has suggestedthat the cost “to relaunch a repositioned drug aver-ages $8.4 million”35. This appears to be a ratherconservative estimation and may be more applica-ble to simple, line-extension DRPx cases. We esti-mate that the cost is ~$300 million, assuming thatthe DRPx candidate has to undergo Phase II andPhase III clinical trials. This is predicated on themodel proposed by Paul et al3, but still representsan ~85% saving, compared to the $1.778 billioncost of a de novo DDD drug. ii) Time savings: A commonly-cited assumption isthat DRPx can reduce the conventional DDDprocess by 3-5 years. We estimate a cycle time of~6.5 years for a DRPx drug, again based on themodel of Paul and co-workers3. However, there areexamples of even more rapid DRPx approvals.Crizotinib was investigated as a DRPx drug basedon its ALK-inhibiting properties. It was approvedfor the new indication of NSCLC treatment in justfour years31.iii) Productivity/risk: The attrition rate of drugcandidates subjected to the conventional DDDprocess is ~95%. Much of this failure is caused bya compound’s lack of safety (~45% failure in PhaseI) and efficacy (~65% failure rate in Phase II)3.These poor success rates place tremendous pres-sure on the drug pipeline and hence pharmaceuti-cal company productivity. Since DRPx drugs havebeen either approved or shown to be safe in latestage trials, they can enter the pipeline at the effi-cacy stage, thus significantly decreasing the failure-rate probability and increasing the chances for asuccessful launch. It has been reported that 25% ofDRPx drugs successfully make it from Phase II tomarket launch in contrast to only 10% for con-ventional DDD drugs. The probability of successincreases to 65% for DRPx drugs moving Phase IIIto market (only 50% for DDD drugs)23. In addi-tion it is estimated that there are at least 2,000failed drug candidates available that could beexploited through a DRPx strategy, and this num-ber increases by 150-200 compounds per year, pro-viding an ample pipeline of opportunity36.iv) Market potential: The market potential for a

DRPx drug is determined by the same marketforces as a conventional DDD drug and includesdrug differentiation, market need, patient accept-ance, marketing strategy and Intellectual Property(IP) position35. Thus a DRPx drug has the samepossibility to achieve blockbuster status as a denovo derived drug. A recent example of a DRPxblockbuster drug is dimethyl fumarate (brand nameTecfidera) from Biogen IDEC. It was approved fora new indication to treat multiple sclerosis (MS) in2013 and achieved revenue sales of >$2.5 billionworldwide in 2014. This represented ~30% of totalrevenues for Biogen IDEC last year.v) Intellectual Property: DRPx can help in patentlife elongation and thus aid in prolonging lifecyclemanagement of product portfolios. Persidis hasargued that a successful DRPx strategy can signifi-cantly cushion the patent cliff dilemma faced bythe pharmaceutical industry35. In part this can beachieved because it is possible to “obtain verystrong patent protection for a new use of an exist-ing drug whose composition of matter patents arestill running, if that new use is not covered andproven in the original patent”.vi) Patient/health system: The advent of person-alised medicine has fuelled the transition of patientsto consumers19b. This has led to a more demandingcustomer-base that requires a better, cheaper, per-sonalised product. DRPx efforts have impacted sig-nificantly on orphan, rare and neglected diseases12,as well as providing therapeutic efficacy wherenone existed previously (eg Sildenfil). Consumerneeds, in the form of cheaper, faster, safer, more effi-cacious drugs across the entire drug spectrum, arebeing considered and contemplated with the morewidespread adoption and use of DRPx.

On the other hand it is also important to recog-nise that DRPx still requires an element of discov-ery and development. These undertakings bringinherent risk and it is important that one compre-hensively understands the science, disease, patientpopulation, regulatory, business and IP issues asso-ciated with any specific DRPx initiative. Forinstance, new Phase I clinical trials may be requiredif the DRPx candidate is an old drug and the orig-inal safety data does not meet current regulatorystandards. Plus, safety issues can still present prob-lems for a potential new indication. For example,Buproprion, a drug originally approved for thetreatment of depression, was subject to DRPxefforts in the treatment of obesity. These studiesinvolving the individual drug were ultimatelyunsuccessful due to adverse events observed in theclinical trials31. However, the drug was ultimately

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17 Beachy, SH, Johnson, SG,Olson, S and Berger, AC (Eds).Drug Repurposing and DrugRepositioning-WorkshopSummary. National AcademiesPress, Washington DC, USA(2014).18 Naylor, S. Overview ofBiomarkers in Disease, DrugDiscovery and Development.Drug Discov. World. SpringEdition: 21-30 (2005).19a Naylor, S and Cole, T.Overview of CompanionDiagnostics in thePharmaceutical Industry. DrugDiscov. World. Spring Edition:67-79 (2010). b Naylor, S andCole, T. CompanionDiagnostics in thePharmaceutical Industry: Part IIBusiness Models Drug Discov.World Summer Edition: 61-68(2010).20 Mucke, HAM. A NewJournal for the DrugRepurposing Community. DrugRepurposing, Rescue &Repositioning 1, 3-4 (2014).21 Sekhon, BS. RepositioningDrugs and Biologics;Retargeting Old/Existing forPotential New TherapeuticApplications. J. Pharm. Educ.Res. 4,1-15 (2013). 22 Sukkar, E. Still Feeling theVioxx Pain. Pharm. J.September 14th, 2014.http://www.pharmaceutical-journal.com/news-and-analysis/feature/still-feeling-the-vioxx-pain/20066485.article.23Thayer, AN. DrugRepurposing. Chem. & Eng.News 90, 15-25 (2012).24 Fierce Biotech. Roche andBroad Band Together to BringFailed Drugs Back from theDead. http://www.fiercebiotech.com/story/roche-broad-band-together-bring-failed-drugs-back-dead/2012-11-28.25 Huang, R et al. The NCGCPharmaceutical Collection: AComprehensive Resource ofClinically Approved DrugsEnabling Repurposing andChemical Genomics. ScienceTranslational Medicine 3,80ps16.doi:10.1126/scitranslmed.3001862 (2011).

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approved as a combination therapy withNaltrexone in late 2014 and is marketed under thebrand name Contrave (see Table 2). Another obvious challenge is that the efficacy of

a DRPx drug must be demonstrated. Clearly theDRPx drug must have superior, differential proper-ties from existing drugs already being marketedand sold in the same class. Otherwise it will be sub-ject to the same regulatory scrutiny as a conven-tional drug, which could have a significant impacton its forward progress. Any lack of differentiationor clear efficacy can obviously lead to the DRPxtrial being abandoned. For example, Sunitinib wasoriginally approved for treatment of GIST andRCC, but failed in a multitude of other cancer tri-als due to efficacy issues31. A final consideration ofobstacles and hurdles that can confront the unwaryis IP and (original) drug ownership issues. Thesecan be complex and troublesome as one attemptsto navigate the DRPx process. Such issues, as wellas business and regulatory matters, will be consid-ered and discussed in detail in our subsequent man-uscript on this subject37.

ConclusionsThe continued rising costs, combined with the cat-astrophic failure rates of de novo DDD have driv-en the pharmaceutical industry towards someexploration of DRPx strategies and their potential.This has been augmented somewhat by the well-documented problem of the ‘Patent Cliff’, as wellas the more aggressive stance taken by Genericcompanies as they look to infiltrate the conven-tional DDD sector. However, implementation of asuccessful DRPx strategy is not a simple undertak-ing. The skills and expertise required are consider-able and range across a number of different disci-plines. They include the need to access compoundsand information, determine the disease area offocus and implement a well thought-through busi-ness and IP strategy. The successful execution of aDRPx business model can result in a pipeline thathas an increased number of Phase II-level com-pounds, as well as lead to new innovations in dis-ease aetiology and pathway/network biology. Itcan also address what Persidis labels the competi-tor adjacency threat. He was recently quoted as

Continued from page 6026 Bloom, B. Cures WithinReach. PersonalCommunication.27 Allarakhia, M. Open sourceApproaches for theRepurposing of Existing orFailed Candidate Drugs:Learning From and Applyingthe Lessons Across Diseases.Drug Design Develop. Ther. 7,753-766 (2013).28 Loging, W.Cheminformatic/BioinformaticAnalysis of Large CorporateDatabases: Application to DrugRepurposing. Drug Dis.Today8, 109-116 (2011).29 Haupt, VJ, Daminelli, S andSchroeder, M. DrugPromiscuity in PDB: ProteinBinding Site Similarity Is Key.PLoS ONE 8, (2013).http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065894.

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stating that: “Competitor adjacency threats drivecompanies to not only add new compounds totheir pipelines, but indicate when a savvy companyreacts to what its competition is doing with a newtwist on an old compound.”38

There are numerous factors that contribute to thefeasibility and viability of DRPx. They include accessto voluminous amounts of scientific and clinicallycurated data, the large number of potential drug can-didates that could be made available, lead time fromproof-of-concept to Phase II is short, and infrastruc-ture needed to undertake DRPx can be limited. Thefuture appears bright for DRPx, but there are a num-ber of issues impacting the future that need to be con-sidered and include; i) how to maximise the genera-tion of ideas through open source partnerships thatincludes academia, industry, non-profits and govern-ment agencies; ii) better design of clinical trials andpatient selection; iii) electronic medical records needto be more fully integrated into the study of patientoutcomes and therapeutic effectiveness as well asutilised in a systematic role in DRPx selectionprocesses; iv) key stakeholders such as FDA/EMA,payers, patient advocacy groups should play a moresubstantial role; and vi) automation and updatingcapability should be key review factors for commer-cial organisations seeking to prioritise adoption ofDRPx methods and stay competitive over time.Highly automated semantically intelligent systemscan reduce data capture errors and bioinformaticsworkloads dramatically.The numerous benefits of DRPx are clear and

well documented12,17,35. If this is so transparentthen why is the pharmaceutical industry so slow onthe DRPx uptake and in many cases only practic-ing on an ad hoc basis? It is possible that theentrenched, silo-structured, pharmaceutical com-panies are not conducive corporate structures forDRPx. In addition there appears to be a sentimentthat DRPx is not an endeavour that produces inno-vative research and outcomes35. Such attitudesneed to change and the pharmaceutical industryneeds to be more embracing of this exciting, inno-vative and productive series of approaches. Wide-scale implementation of smart DRPx strategiescould unleash a torrent of productive activity thatenhances pharmaceutical company performancesand provides significant opportunities for all thestakeholders including the public and private sec-tors as well as those ‘demanding’ patients!

AcknowledgementsWe would like to thank Dr Bruce Bloom (CWR),Daniel Behr (ReDiscoveryLS), Ed Kahn (CWR &

ReDiscoveryLS), Dr Herman Mucke (HM Pharma)and Dr Aris Persidis (BioVista) for all their help viaconversation and/or correspondence in the prepara-tion of this manuscript. DDW

Dr Stephen Naylor is a Founder, Chairman andCEO of MaiHealth Inc, a systems/network biologylevel diagnostics company in the health/wellnessand precision medicine sector.

Judge M. Schonfeld is Founder, CEO and CSO ofCureHunter Inc, a company with a purpose-builtplatform to carry out DRPx. In addition the com-pany produces scientific publications, analyticaltools and provides web-based access to their clinicaldisease outcome databases for clinical evidence-based medicine and new drug development research.

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30 Hu, Y and Bajorath, J.Monitoring Drug PromiscuityOver Time. F1000Research 3,(2014), Last updated: 05 JAN2015. http://f1000research.com/articles/3-218/v2 .31 Li, YY and Jones, SJM. DrugRepositioning for PersonalizedMedicine. Genome Medicine 4,27-41 (2012).32 Murteira, S, Millier, A,Ghezaiel, Z and Lamure, M.Drug Reformulations andRepositioning in thePharmaceutical Industry andTheir Impact on MarketAccess: RegulatoryImplications. Journal of MarketAccess & Health Policy 2,(2014) http://dx.doi.org/10.3402/jmahp.v2.22814 .33 Padhy, BM and Gupta, YK.Drug Repositioning: Re-Investigating Existing Drugs forNew Therapeutic Indications. J.Postgrad. Med. 57,153-60(2011).34Wang, S-Y, Calderon, J andWang GK. Block of NeuronalNa+ Channels by theAntidepressant Duloxetine in aState-Dependent Manner. PainMedicine 113, 655-665 (2010). 35 Persidis, A. The Benefits ofDrug Repositioning. DrugDiscov. World Spring Edition:9-12 (2011).36 Knowledge-Based DrugRepositioning to Drive R&DProductivity. ThompsonReuters (2012).http://thomsonreuters.com/products/ip-science/04_038/drug-repositioning-cwp-en.pdf.37 Naylor, S, Kauppi, DM andSchonfeld, JM. TherapeuticDrug Repurposing,Repositioning, and Rescue: PartII- Regulatory, IntellectualProperty and BusinessConsiderations. Drug Discov.World In Press (2015).38 See Sirk, K. Everything Oldis New Again. Drug Discov.News 10, (2014).http://www.ddn-news.com/index.php?newsarticle=6045.