Market Insight - Drug repositioning: a new strategy for success

The repositioning of drugs for new clinical indications is becoming an increasingly prominent development strategy because it can reduce development risk as well as both the time and investment required to bring a product to market. Previously exclusive to pharmaceutical companies working to expand the applications of their marketed drugs, repositioning (also known as repurposing, reprofiling, therapeutic switching, or developing 'second use' indications) has emerged as an industry in its own right, encompassing both technology and drug companies. Today, companies involved in repositioning are charging for their services, establishing collaborative agreements and using the strategy to develop their own pipelines.

In addition to marketed drugs, compounds that have failed late (Phase II or III) clinical stage development for reasons other than safety or have lost development priority are increasingly undergoing preclinical or clinical testing for new indications.

The economics of drug development is, of course, the principal factor driving this phenomenon. The cost to develop new chemical entities (NCEs) from discovery through clinical trials and regulatory approval continues to rise, while the number of US FDA approvals each year has declined. Other factors include the opportunities provided by new R&D technologies (e.g., drug screening and assay technologies, which can identify unanticipated effects and rationalise the approach), drug formulation and delivery technologies, drug-device combination strategies (to create convergence products), and increased data collection and observation in clinical trials before and after approval.

The degree of the R&D technology deployed ranges from almost none at all – a new indication may be based simply on compelling observations of a desirable side-effect in clinical trials or practice – to very intensive, using sophisticated new technologies. Previously unobserved effects suggestive of efficacy in new indications may be identified by drug screens and assays.

the thalidomide story

Thalidomide is the best known example of successful drug repurposing. The product was marketed in Europe during the late 1950s though the early 1960s as a hypnotic and anti-emetic for the treatment of morning sickness during pregnancy. Approximately 20,000 Americans were exposed to the drug during experimental distribution while its FDA review was ongoing. However, marketing in Europe and distribution in the US were halted after thousands of children were born with severe physical deformities known as phocomelia.

More recently, repurposed indications, based on clinical observations, were initiated (along with regulations to prevent foetal exposure). Thalidomide's first FDA approval came in 1998, for the management of erythema nodosum leprosum, as an orphan drug indication. Since then, thalidomide has shown activity in dermatological, infectious and autoimmune disorders (including ulcerations and wasting syndromes related to HIV infection), Behçet's disease, cutaneous lesions of systemic lupus erythematosus, sarcoidosis and chronic graft-versus-host disease. And after recent studies revealed anti-angiogenic properties, thalidomide was tested in various cancer indications, and FDA approval was granted in 2006 for the primary treatment of multiple myeloma, in combination with dexamethasone.

The thalidomide story encompasses themes that have dominated drug repositioning in the past as well as some of the newer aspects of the strategy. Clinical observation of potentially beneficial effects of thalidomide led to testing for new indications. More recently, scientific testing for new mechanisms of action using the latest technologies identified others. The first FDA approval was for a narrow, orphan drug indication; the earliest indications that followed were for small market applications. Later indications were for larger patient groups and markets.

Repositioning strategies also make use of technologies (e.g., biomarkers) and other methods for selecting patients who are likely to respond to a drug or experience adverse effects. In the case of thalidomide, patient selection requires avoiding women who are pregnant or may become pregnant, which eliminates the potential for the drug's most serious side-effect.

well known cases

Broadly defined, repositioning includes finding new uses for compounds that failed in clinical trials for their original indications and for approved compounds, in new or even the same therapeutic category. By this definition, the developers and marketers of approved drugs routinely reposition their products. Well known repositioned drugs include:

?sildenafil (Pfizer's Viagra): repositioned from hypertension to erectile dysfunction and pulmonary artery hypertension (as Revatio); it has been suggested for use in preventing doxorubicin-induced heart damage in cancer patients;

?rituximab (Biogen Idec/Roche and Genentech's Rituxan/MabThera): marketed for non-Hodgkin's lymphoma and other malignancies and repositioned for rheumatoid arthritis (RA), in combination with methotrexate (another cancer drug also used to treat RA); rituximab is also under study for multiple sclerosis and systemic lupus erythematosus;

?bupropion (GlaxoSmithKline's Wellbutrin): repositioned and rebranded as Zyban for smoking cessation;

?minoxidil (Johnson & Johnson/Pfizer's Rogaine/Regaine): repositioned from hypertension (oral formulation) to baldness and hair loss (topical formulation);

?duloxetine (Lilly's Cymbalta): repositioned from depression to neuropathic pain and stress urinary incontinence (outside the US);

?ropinirole (GlaxoSmithKline's Requip): repositioned from Parkinson's disease to restless leg syndrome.

Once a class of drugs has been successfully repositioned for a new indication, new therapies of that class are often positioned for the alternative indication during their development. For example, anticonvulsants initially developed for epilepsy were repositioned for neuropathic pain and as mood stabilisers for bipolar/mood-swing disorders. Now, many developmental anticonvulsants are evaluated for their potential in these indications in their initial development.

Cancer therapeutics are often positioned during Phase II trials that test their potential in many different indications. Test results are not definitive, however, and the pursuit of new indications continues long after an initial indication is approved.

Some asthma drugs are tested for COPD, and vice versa, if their mechanisms of action suggest they may be effective against both pathophysiologies.

There are many similar examples; repositioning is not a new approach. However, the growing traction of this strategy, the economic factors driving it, the new technologies supporting it, and the many different business models, deal structures, and companies that are emerging in this sector suggest that drug repositioning has become, itself, a bona fide development strategy.

Novel drug-device convergence products may be considered a form of drug repositioning. Angiotech/Boston Scientific developed the Taxus cardiovascular drug-eluting stent, which uses the anticancer drug, paclitaxel, to reduce the rate of restenosis. Such convergence products achieve high local drug concentrations via targeted delivery of small doses, thereby reducing or eliminating serious adverse effects of relatively toxic drugs and expanding their potential indications.

identifying candidates

Observations of unexpected effects in clinical practice or Phases I-IV clinical trials, made by empirical data analysis or noticed by clinicians, has been and remains a useful starting point for identifying drug candidates for repositioning. However, much of the recent interest in this strategy stems from the application of in silico, in vivo, and ex vivo methodologies for rational identification of compounds or combinations of compounds that might not otherwise be expected to demonstrate efficacy. These include proteomic technologies, cellular and tissue assays, animal models of disease, literature and proprietary database searching, and other methods for understanding mechanisms of action and predicting effectiveness (and toxicities and side-effects).

The observational and technological approaches are not exclusive. One of the first steps in the pursuit of a new indication suggested by observation or statistical analysis is to attempt to understand the potential mechanism of effectiveness. Technological approaches can provide mechanistic and other data to supplement the existing preclinical package (which may be out of date and not meet current requirements). Similarly, pursuit of technologically identified new indications ignites a search for relevant clinical observations and empirical data.

Compounds for repositioning include proprietary products from biopharmaceutical companies and marketed generic drugs. Proprietary products include marketed drug and clinical stage compounds that have fallen out of active development for reasons other than safety (e.g., lack of effectiveness in the intended application, superseded in the company's pipeline by newer versions, changes in the company's development or market focus, a small company's inability to fund clinical trials, etc). Completion of Phase I trials that have demonstrated safety – to the satisfaction of relevant regulatory agencies – is the minimum requirement for potential repositioning, although many (possibly most) companies pursuing drug repositioning will evaluate only those opportunities for which significant data from Phase II or Phase III are available.

Various IP strategies are used. Proprietary drugs may or may not have significant time remaining on their composition of matter patent lives. Medical use patents for new indications are the alternative, and are frequently employed. New formulations (e.g., with enhanced drug delivery characteristics) may provide new patent life, although some types may increase clinical trial requirements. Table 1 lists various companies and commercial drug repositioning programmes.

Table 1: Selected drug repositioning programmes and activities*

Company	Approach
Angiotech Pharmaceuticals (Canada)	Repositioned anticancer agent, paclitaxel, in Taxus paclitaxel-eluting stent to reduce the rate of restenosis (with Boston Scientific). Developing Vascular Wrap paclitaxel-eluting mesh surgical implant for vascular graft implants in peripheral vascular disease and haemodialysis. Repositioning anticancer agent, 5-fluorouracil (5-FU) as anti-infective coating on a central venous catheter to prevent catheter-related infections. May have less potential to create resistant super-bugs; intent to file a PMA announced in October 2007.
Arachnova (UK)	Proprietary database for lead identification: CANDI (Compound Analysis for New Drug Indications) database of compounds, mechanisms, and indications. Biological (preclinical) validation is then outsourced.
Aspreva Pharmaceuticals (Canada)	Proprietary screening; focus on less common diseases. Licensed rights to develop autoimmune indications of CellCept (mycophenolate mofetil) from Roche. In Phase III for lupus nephritis and pemphigus vulgaris.
Avanir Pharmaceuticals (US)	Repositioning a formulation of dextromethorphan (plus quinidine to slow enzymatic breakdown; Zenvia) cough suppressant for pseudobulbar affect or involuntary emotional expression disorder or emotional lability. NDA approvable (October 2006); Phase III confirmatory trial ongoing. Also in development for diabetic peripheral neuropathic pain.
BTG (UK)	Focus on neuroscience (pain, symptomatic treatments of neurodegenerative disorders, sleep disorders) and oncology (supportive care). Among the company's partnered programmes are: Campath (Genzyme), Phase III for multiple sclerosis; CB7630 (abirateron; Cougar Biotechnology), Phase II for prostate cancer; Symadex (Xanthus Pharmaceuticals), a FLT3 receptor tyrosine kinase inhibitor in Phase II for breast and colorectal cancer; and ABIO-0801 (Abiogen Pharma), Phase II for anxiety.
Braincells (US)	In-licensing clinical-stage compounds and screening libraries with its neurogenesis platform for CNS indications. Lead drug, BCI-540, was an extensively developed, clinical-stage compound (>700 subjects), in-licensed from Mitsubishi Pharma for repositioning for new CNS indication (depression with anxiety).
Caliper Life Sciences (US; acquired Novascreen Biosciences and Xenogen)	Genomics, proteomics, and computational methods. >800 in vitro assays (e.g., G-protein coupled receptors, kinases, toxicity panels) and >85 in vivo services (e.g., assays targeting disease-related genes, creation of transgenic animals, development of animal models of disease, measurement of phenotypic result).
Celgene (US)	Celgene has developed second-generation analogues of thalidomide, lenalidomide (CC-5013, Revlimid) and CC-4047 (Actimid).
Collegium Pharmaceutical (US)	Drug formulation strategies to enhance clinical benefits of existing drugs, mostly well referenced chemical entities that can be developed under the expedited 505(b)(2) regulatory pathway. Among others, products include COL-007 for fibromyalgia (modified release milnacipran, under agreement with Cypress Biosciences), COL-111 for smoking cessation ([transdermal] bupropion), and COL-132 for sleep apnea (collaboration with BTG, clinical).
Combinatorx (US)	High-throughput screening to identify new indications or patterns of activity of combinations of approved drugs. Four steroid amplifiers in Phase II, testing whether the combination of a reduced-dose corticosteroid with a second compound can enhance anti-inflammatory activity and reduce side-effects. Crx-102, prednisolone (glucocorticoid) + dipyridamole (cardiovascular), demonstrated positive Phase II results in hand osteoarthritis and rheumatoid arthritis. Phase I cancer trial with a combination of chlorpromazine (antipsychotic) and pentamidine (pneumonia).
Cypress Biosciences (US)	In-licensing CNS compounds and repositioning for functional somatic syndromes. Milnacipran, formulated by Collegium, is in a second Phase III trial for fibromyalgia (results expected in 1H 2008), collaboration with Forest Laboratories and Pierre Fabre, the latter of which is conducting a Phase III trial in the EU.
Dynogen (US)	Focusing on candidates with known safety and pharmacokinetic profiles, determined dose ranging, and evidence of efficacy for GI and GU diseases and disorders. DDP733 in Phase IIb for irritable bowel syndrome (IBS) with constipation. DDP225 in Phase II trial for IBS with diarrhoea. DDP200, Phase II-ready for overactive bladder.
Foamix (Israel)	Topical drug and cosmetic delivery, using Foamix Foam and OILGEL platforms.
Hypnion (US; wholly owned by Lilly)	Focus on sleep and wake-alertness disorders and circadian rhythm abnormalities using SCORE-2004 predictive sleep-wake bioassay system for drug discovery.
Kinemed (US)	Drug discovery technology: stable isotope/mass spectrometric measurement of compound's ability to modulate kinetics in central pathways in the etiologies of particular diseases (in live animals and humans). 'Fast-to-Phase II' model for pharmaceutical companies to qualify drug candidates and demonstrate therapeutic activity in humans. Among others, translational research development programmes include reverse cholesterol transport, insulin resistance, and stimulation of neurogenesis (for cognitive and mood disorders).
Melior Discovery and Melior Pharmaceuticals (US)	theraTRACE indications discovery platform for investigation of a compound in multiple in vivo models for various therapeutic areas. Current partners include Pfizer, Immune Control, Cephalon, High Q Foundation, Othera Pharmaceuticals, Merck & Co, and Johnson & Johnson. In addition to fee-for-service repositioning, Melior acquires and develops compounds for its own pipeline. The current focus is the licensing in of Phase II and Phase III compounds discontinued for reasons other than safety. Most advanced programme: MLR-1023, which had reached Phase III trials for gastric ulcer (ca. 1980) and is in development for type 2 diabetes.
Metabolon (US)	Analytical methods and software for biomarker discovery using metabolomics. Mass spectrometric identification of hundreds of named metabolites that are analysed for impact on well documented biochemical pathways.
Ore Pharmaceuticals, formerly Gene Logic (US);	Drug Repositioning and Selection Technology Platform: set of drug evaluation technologies used for finding new development paths for failed, stalled, or de-prioritised clinical-stage drug candidates, prioritising lead candidates, or finding new therapeutic applications of marketed drugs. Current collaborators include Lundbeck, Abbott, Lilly, Organon (Schering-Plough), Roche, Pfizer, Merck Serono, and Solvay. Ore is also developing its own pipeline. Lead candidate: GL 1001 for irritable bowel disease, rights acquired from Millennium Pharmaceuticals, clinical development partner sought. Gene Logic (now Ore) recently sold its genomics database in order to concentrate on repositioning business.
Orexo (Sweden)	Identification of suboptimal characteristics of existing drugs and application of drug delivery technologies (e.g., for quicker onset of action or easier administration).
Organon Biosciences (acquired by Schering-Plough, US)	Repositioning collaboration with Braincells to identify neuroscience applications for compounds formerly in the Organon clinical-stage pipeline. Repositioning collaboration with Gene Logic to identify alternative development pathways for candidates with good safety records that have been de-prioritised or discontinued in Phase II or Phase III. Organon and Gene Logic will become equal owners and may jointly develop and commercialise drug candidates identified for new indications.
Pfizer (US)	Collaboration with Gene Logic, in which Gene Logic is paid fees and will receive a percentage of sales for approved and marketed drugs. Details are not available, although repositioning of an undisclosed compound for potential solid tumour indications has been reported. Collaboration with Melior also underway.
Somaxon Pharmaceuticals (US)	In-licensing for neurology and psychiatry indications. Repositioning the antidepressant and anti-anxiety agent, doxepin (tricyclic antidepressant and histamine H1 receptor antagonist), for insomnia. Four Phase III trials completed.
Sosei (Japan)	Drug Reprofiling Platforms to identify new uses for marketed drugs and marketed drug templates and for drugs that have stalled in Phase II development. Among others, developmental products include SOU-003 (oral vasopressin V2 receptor agonist) for nocturia and nocturial enuresis in the elderly. Safety had already been confirmed in several Phase I trials conducted by licensor, Otsuka. AD 337, an SNRI, is the active single isomer of a racemic drug currently marketed for an indication other than fibromyalgia, which Sosei is pursuing. Phase II proof-of-principle trial is underway in the UK and Australia.
Vectura (UK)	Developing inhaled pharmaceuticals to treat respiratory, neurological, and other diseases. Current partners include Baxter, Boehringer Ingelheim, GlaxoSmithKline, Merck Generics (Mylan), Novartis, Otsuka, Arakis/Sosei, and UCB Pharma.
Vicus Therapeutics (US)	Combining individual, already approved generic drugs for other indications. Focus on cancer supportive care indications, with an initial focus on cachexia. Pursuing both 312.2(b)(1) and 505(b)(2) regulatory approval pathways. Lead product, VT-122, targets multiple inflammatory and other key pathophysiological pathways of cancer cachexia; in Phase II.
*Not inclusive of the many screening, assay and related technology companies, drug delivery companies, and biopharmaceutical companies involved in drug repositioning R&D. Source: Scrip Drug Market Developments

business models

The traditional drug repositioning model is based on the insight and entrepreneurship of small companies, many of which are focused on therapeutic and market niches, often those for which relatively small sales forces are required (e.g., cancer, neurology). These specialty companies license in compounds from mid-sized and major pharmaceutical companies, based largely on clinical observations of new potential indications (e.g., advice from experts). Typically, capital is raised to conduct the Phase II and/or Phase III clinical trials for new indications, after which they may or may not seek a partner for submission of regulatory applications, marketing, and sales. Newer models represent many variations of this theme.

Biopharmaceutical companies: Mid-sized and large biopharmaceutical companies increasingly use drug-repositioning strategies. They may seek access to technologies used for identification of new indications, novel drug delivery/reformulation technologies, particular clinical trial expertise, or marketing and sales presence not available in-house. The types of agreements vary widely. Compounds may be licensed out under fee and sales/royalty agreements, without further participation from the out-licensing company. However, biopharmaceutical companies may secure rights to additional revenue streams by retaining rights to supply approved drugs, or they may retain sole or co-promotion, marketing, and sales rights in specified territories or globally.

Some companies are mining their own marketed drugs and clinical development graveyards through in-house efforts and supplementing that effort with fee-for-service or collaborative agreements with repositioning technology companies. CROs that specialise in clinical areas of interest may be contracted on a fee for service basis or under collaborative, shared-risk agreements. Biopharmaceutical companies are very likely to retain, at minimum, co-promotion and co-marketing rights in therapeutic areas in which they already have marketing staff and sales forces and for drugs with great market potential.

Screening/assay and drug delivery companies: Service companies that provide efficiency and expertise in specialised areas of new-indication identification (for drugs and drug combinations) continue to emerge, and are finding biopharmaceutical company clients that want to outsource this aspect of their R&D. Repositioning companies operate under fee-for-service or collaborative agreements in which they maintain continuing interest in the products on which they work.

Projects may be proposed by the biopharmaceutical company or other companies with proprietary interest. They may also be suggested by independent work conducted by repositioning companies (e.g., they may suggest dose or route of administration or other formulation and delivery changes for use in a new indication). Notably, some of the repositioning service companies are now also developing their own pipelines, such as Braincells, Melior Pharmaceuticals, Ore Pharmaceuticals (formerly Gene Logic), and others.

Speciality companies developing pipelines: These companies get their competitive edge from the huge head start in development gained by in-licensing compounds that are already marketed or have undergone extensive clinical trials. The strategy is to capitalise on the tens of millions of development dollars that have already been invested. In addition to product development companies focused on therapeutic niches, some clinical CROs are developing their own pipelines.

ongoing projects

Well publicised repositioning projects are underway, conducted by both major biopharmaceutical companies and public health institutes. Among others, they include:

?The statin (HMG-CoA reductase inhibitor) class of hypolipidemic drugs undergoing clinical testing for Alzheimer's disease. Virtually all statins are under investigation. A trial with atorvastatin (Pfizer's Lipitor) included extensive collection of data relating to biomarkers;

?The PPAR-gamma agonists, pioglitazone (Takeda/Lilly's Actos) and rosiglitazone (GlaxoSmithKline's Avandia) under study for Alzheimer's disease;

?Tamoxifen, under investigation for bipolar disorder in studies sponsored by the US National Institutes of Health, the Stanley Medical Research Institute, and the National Health and Medical Research Council, Australia. The basis of this repositioning effort is the unique ability of tamoxifen, as a relatively selective protein kinase C inhibitor, to cross the blood-brain barrier;

?The anticancer agent, imatinib (Novartis's Gleevec), under study for rheumatoid arthritis and other inflammatory diseases.

The true economics of drug repositioning will be revealed in the coming years. Potential savings in direct and opportunity costs, and reduced development time and overall time to market are not in dispute. However, the current cost of Phase III trials required for regulatory approval can approach or exceed $100 million for many indications, meaning that failures will remain costly. The hope is that emerging repositioning technologies and data analysis methodologies, combined with other newer drug development technologies (e.g., biomarkers and imaging techniques), will provide rational, effective pathways for the successful development and approval of already available compounds in new indications.

References

1. G Li et al. 'Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease', Neurology, 69(9):878-851, 2007.

2. DL Sparks et al. 'Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial', Acta Neurol Scand Suppl;185:3-7, 2006.

3. Q Jiang et al. ‚The Role of Peroxisome Proliferator-Activated Receptor-gamma (PPARgamma) in Alzheimer's Disease: Therapeutic Implications', CNS Drugs ;22(1):1-14, 2008.

4. CA Zarate Jr et al. 'Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study', Bipolar Disorder, Sep;9(6):561-70, 2007.

5. KK Eklund and H Joensuu. 'Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases', Ann Med; 35(5):362-7, 2003.

Dr Timothy Tankosic is a consultant specialising in neuroscience-based product development. He can be contacted at [email protected].