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European Biopharmaceutical Review

Drug Repositioning: Filling the Gap

Raúl Insa at SOM Biotech highlights the various approaches to finding new uses for existing drugs

Drug repositioning is the process of developing new indications for existing drugs or biologics, and is also known as drug repurposing, reprofiling, retasking, redirecting or even therapeutic switching. There has been increased interest in drug repositioning due to sustained high failure rates and the costs involved in attempts to bring new drugs to market (1). It is well known that it may cost more than $800 million to discover and develop a new medical entity, with a required wait for regulatory approval of between 10 and 17 years (2,3). The old and new drug discovery technologies, such as structure-based drug design, combinatorial chemistry, or high-throughput screening have not delivered as expected, and while hopes rest on the promise of cellular therapy (stem cells), proteomics or genomics, the pharmaceutical industry and the healthcare authorities must maximise the products that are already on the market (4). Drug repositioning offers real, valuable advantages. Many of these have been discussed elsewhere recently, but some considerations have to be addressed, as drug repositioning is not the ultimate solution to improving or curing human diseases (5).

DRUG REPOSITIONING APPROACHES

The methodology of discovering a new use of a given drug is not standard. The ultimate proof-of-concept to screen a drug for a new indication would be to perform a Phase II clinical trial for each of the possible indications, but the economic cost and risk for the population make this impractical. The new uses or indications have to be induced through non-clinical evidence which will justify the later, obliged, clinical validation. In Drug repositioning value proposition, a list of drug repositioning approaches or ways that have been used to discover new drug applications are described. Some illustrative examples include:

 Drug repositioning value proposition
 For the patients
  •  Medical efficacy where none existed previously
  •  Better efficacy of already existing drugs
  •  Better therapeutic profile (modifying effects versus
           symptomatic)
  •  A better side effects profile
  •  Better dosing or scheduling
  •  A lower cost than existing therapies
 For the industry
  •  Lower development costs and time
  •  Patent life extension when applicable
  •  Longer life cycle management and return on investment
  •  Lower risk in the development (better success rate)
  •  Possibility to recover previously failed compounds
 For the health system
  •  Maximise the value of products in the market
  •  Faster approval safety process
  •  Get access to new applications at lower costs
  •  Identification and coverage of unmet medical needs


New Methods of Administration

This includes the improvement in a dosing regimen or a new formulation, for example paclitaxel (a chemotherapeutic cancer agent that has been reprofiled for restenosis by stent elution) or rivastigmine (which has been reformulated into a transepidermal patch to reduce the daily schedule and side effects). Some new formulations of a drug for the same indication may not be considered as ‘repositioning’, as this will improve compliance, dosing, effectiveness or safety, but within the same label use. Methods of administration may solve a problem, but do not always discover a new indication for a given drug.

Serendipity

This word refers to fortuitous discoveries made while looking for something unrelated. Despite the fact that many repositioned proposals come from the scientific rational, it is still the case that serendipitous observations by the enduser (usually physicians) are the most common source of real applications. This was the case for one of the most famous reprofiled drugs: sildenafil from angina and hypertension to male erectile dysfunction.

Rational Scientific Approach

This approach requires an in-depth understanding of both normal human physiology and the pathophysiology of a given disease. Drugs that modulate fundamental molecular pathways and have an impact on multiple organ systems, such as cytokines, growth factors, immunomodulators, and so on, are particularly well-suited to repositioning. The strongest observation to this approach is that it is based on known facts, so it will never predict unknown or non-obvious activities. There are many examples that fit in this category, including finasteride (a 5α-reductase inhibitor indicated for benign prostate hyperplasia and reprofiled to male baldness), botulinum toxin A (a neurotoxic protein used for blepharospasm and cervical dystonia and redirectioned to cosmetic anti-wrinkle use), imatinib (a tyrosine kinase inhibitor approved for a specific type of leukaemia and reprofiled for a variety of malignances) or monoclonal antibodies targeted to specific factors (bevacizumab and rituximab).

Technology Platforms

This category includes in silico computerised systems, databases of clinical side effects, in vitro screenings (binding, genome expression, receptorome platforms, flow-cytometry and so on) and non-invasive imaging or in vivo focused platforms with animal models. Due to the fact that these platforms allow large screening, they are usually based on the ‘fishing’ concept of looking for unknown, or unexpected, results.

No single current technology is powerful enough to provide the confidence to pursue expensive clinical trials. A portfolio of complementary technologies must be assembled to provide independent confirmation of the original technology’s finds (6).

A NEW DISCIPLINE THAT’S ALREADY HERE

The discipline of reprofiling has promoted the growth of many dedicated companies devoted to this task. Some of them are based on an in silicoproprietary platform such as SOM Biotech, Aureus Pharma, Prous Institute, Bio-Modelling Systems, NovaLead Pharma and Arachnova Therapeutics, among others. This approach, which relies on different technologies and bioinformatics solutions, is generally less intense in time and economic resources than other experimental approaches (8-11).

Other companies’ research is based on in vitro screening technologies, such as Switch Biotech, Retrogenix, BioVista, Bionaut, ChemGenex and DanioLabs (VasTox), or ex vivo technologies, as is the case for Vivia Biotech or Sosei. Other groups have a different approach, like Melior Discovery, which focuses on in vivo animal models, Ore Pharmaceuticals, which subcontracts specific technologies for later development, or CombinatoRx, which identifies mixtures of existing compounds (12).

A more classical approach, in terms of new formulations and delivery systems, is followed by companies such as AGI Therapeutics and ICO Therapeutics. Large pharmaceutical companies have also expanded their approaches in order to maximise the value of their own pipeline through drug repositioning.

And finally, but equally as important, is the contribution to research of public centres and universities. Washington University, for example discovered the new use of rapamicin for brain tumours, Verona University uncovered the use of imatinib for diabetes type II, and Virginia University used sildefanil as a cardiac protective agent.

CONCLUSION

So, why is drug repositioning uncommon within large pharma companies? There are different levels of barriers. One of the strongest is the historical organisation of the pharmaceutical industries around new chemical entities. A culture based on acceptance of the long development times and the high costs associated with drug discovery can be threatened by a method that can significantly reduce both parameters. The second barrier is that the expertise needed for drug repositioning is not the same as the expertise needed to discover new chemical entities, not because of a lack of training, but as a result of ‘NIH’ syndrome. NIH refers to ‘notinvented- here’, an attitude of many brilliant scientists that blocks them from receiving new ideas or approaches from an open innovation environment (13).

Drug repositioning also needs broad knowledge and a cross-disciplinary perspective of the organ systems of the body as a whole. This holistic approach may deliver ideas essential to the discovery of new drug uses. Of course, this only applies to rational drug development, as serendipity will still be among us for a long time with its unexpected observations.

 Drug repositioning techniques
 Serendipity
 Methods of administration
  •  New formulation
  •  New dosing regimen
 Rational scientific approach
 Technology platforms
  •  In silico computerised systems
  •  Databases of clinical side effects
  •  In vitro screenings
  •  Non-invasive imaging
  •   In vivo disease models
 Complementary technologies (a mix of the above)


There are more than 9,900 active pharmaceutical ingredients that are administerable to humans (14). Before leaving some of them on the shelves because of a lack of efficacy in the first intended indication, repurposing should be a must. Fortunately, the number of companies that have followed this rule is increasing, and includes Bayer, Roche, Merck, Organon, Eli Lilly, Pfizer and Novartis (14). Every broad-focused, research-based pharmaceutical company should include drug repositioning as one of its primary disruptive innovation strategies, while keeping an open mind towards the different disciplines listed above.

References
  1. Dimasi JA, Risks in new drug development: approval success rates for investigational drugs, Clin Pharmacol Ther 69(5): pp297-307, 2001
  2. Reichert JM, Trends in development and approval times for new therapeutics in the United States, Nat Rev Drug Discovery 2(9): pp695-702, 2003
  3. Reichert JM and Valge-Archer VE, Development trends for monoclonal antibody cancer therapeutics, Nature Reviews Drug Discovery 6(5): pp349-356, 2007
  4. Chong CR and Sullivan Jr DJ, New uses for old drugs, Nature 448 (7,154): pp645-646, 2007
  5. Tobinick EL, The value of drug repositioning in the current pharmaceutical market, Drug News Perspect 22(2): pp119-125, 2009
  6. Tartaglia LA, Complementary new approaches enable repositioning of failed drug candidates, Expert Opin Investig Drugs 15(11): pp1,295-1,298, 2006
  7. Campàs C, Drug repositioning summit: finding new routes to success, Drug News Perspect 22(2): pp126-128, 2009
  8. Dubus E, Ijjaali I, Barberan O and Petitet F, Drug repositioning using in silico compound profiling, Future Med Chem 1(9): pp1,723-1,735, 2009
  9. Schneider P, Tanrikulu Y and Schneider G, Self-organizing maps in drug discovery: compound library design, scaffold-hopping, repurposing, Current Medicinal Chemistry 16: pp258-266, 2009
  10. Keiser MJ et al, Predicting new molecular targets for known drugs, Nature 08506: pp1-8, 2009
  11. Sato T, Matsuo Y, Honma T and Yokoyama S, In silico functional profiling of small molecules and its applications, J Med Chem 51: pp7,705-7,716, 2008
  12. Ashburn TT and Thor KB, Drug repositioning: identifying and developing new uses for existing drugs, Nature Reviews 3: pp673-683, 2004
  13. Hunter J, Is open innovation the way forward for big pharma?, Nature Reviews 9: p87, 2010
  14. Chong CR and Sullivan DJ, New uses for old drugs, Nature448(9): pp645-646, 2007 15. Barton CL, Drug Repositioning Strategies, Innovative strategies to boost pipeline productivity, Business Insights Report, 2007
  15. Barton CL, Drug Repositioning Strategies, Innovative strategies to boost pipeline productivity, Business Insights Report, 2007

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Dr Raúl Insa is the CEO and co-founder of SOM Biotech, a startup biopharmaceutical company established in the Science Park of Barcelona and specialising in drug repositioning through an in silico solution. He has worked for more than 20 years in multinational pharmaceutical companies, such as Parke-Davis (now Pfizer), UCB Pharma, Uriach Group (now Palau Pharma) and ISDIN (from Esteve Group). Raúl received his medical training and his PhD in Clinical Neurology at the University of Alicante, Spain, an MBA from ESADE Business School in Barcelona, an Executive Education Program from IESE, Barcelona, and has attended biotech leadership programmes at Harvard Business School.
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