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European Biopharmaceutical Review
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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
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- Better efficacy of already existing drugs
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- Better therapeutic profile (modifying effects versus
symptomatic) |
- A better side effects profile
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- Better dosing or scheduling
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- A lower cost than existing therapies
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| For the industry |
- Lower development costs and time
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- Patent life extension when applicable
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- Longer life cycle management and return on investment
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- Lower risk in the development (better success rate)
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- Possibility to recover previously failed compounds
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| For the health system |
- Maximise the value of products in the market
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- Faster approval safety process
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- Get access to new applications at lower costs
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- Identification and coverage of unmet medical needs
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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 |
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| Rational scientific approach |
| Technology platforms |
- In silico computerised systems
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- Databases of clinical side effects
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Complementary technologies (a mix of the above)
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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
- Dimasi JA, Risks in new drug development: approval success rates for investigational drugs, Clin Pharmacol Ther 69(5): pp297-307, 2001
- Reichert JM, Trends in development and approval times for new therapeutics in the United States, Nat Rev Drug Discovery 2(9): pp695-702, 2003
- Reichert JM and Valge-Archer VE, Development trends for monoclonal antibody cancer therapeutics, Nature Reviews Drug Discovery 6(5): pp349-356, 2007
- Chong CR and Sullivan Jr DJ, New uses for old drugs, Nature 448 (7,154): pp645-646, 2007
- Tobinick EL, The value of drug repositioning in the current pharmaceutical market, Drug News Perspect 22(2): pp119-125, 2009
- Tartaglia LA, Complementary new approaches enable repositioning of failed drug candidates, Expert Opin Investig Drugs 15(11): pp1,295-1,298, 2006
- Campàs C, Drug repositioning summit: finding new routes to success, Drug News Perspect 22(2): pp126-128, 2009
- 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
- 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
- Keiser MJ et al, Predicting new molecular targets for known drugs, Nature 08506: pp1-8, 2009
- 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
- Ashburn TT and Thor KB, Drug repositioning: identifying and developing new uses for existing drugs, Nature Reviews 3: pp673-683, 2004
- Hunter J, Is open innovation the way forward for big pharma?, Nature Reviews 9: p87, 2010
- 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
- Barton CL, Drug Repositioning Strategies, Innovative strategies to boost pipeline productivity, Business Insights Report, 2007
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