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European Biopharmaceutical Review

An Alternative Path to Drug Discovery

Biopharmaceutical firms and small specialised companies with novel discovery technologies are arm-in-arm as they search for new indications to failed drugs as well as currently marketed products.

In the past few years there has been an increased interest in drug reprofiling due to sustained high failure rates and the rising costs involved in attempts to bring new drugs to the market (1). Developing a new chemical entity (NCE) – from discovery to market – is currently estimated to cost billions of dollars (2). With regulatory approval timelines of between 10 and 17 years, there is not much time left for market exclusivity to recover the investment made by the developers.

The repurposing or repositioning of already approved pharmacotherapies for other uses is considered by the industry to be a less risky enterprise than de novo drug discovery. Preclinical and clinical development will be sped up if no new safety studies are needed. In addition, the repositioning opportunity can also be considered for candidates that failed in any preclinical or clinical phase, which could allow an unexpected return of investment, especially if the drug failed in late development.

Big Pharma and small specialists have identified this business opportunity and the economical potential of drug repurposing with major advantages including: cost savings in the discovery, development and clinical phase; acceleration of the drug development process; patent life extension; the possibility to recover previously failed compounds; and the de-risking benefits. Thus, repurposing of approved drugs is widely accepted by the industry and encouraged by worldwide regulatory agencies.

Drug Repositioning Methods

There is no standard path for discovering new uses for drugs, but several valid pathways may be followed. Generally, when actively searching for a new use of a drug (such as nonserendipitous reprofiling) the potential new use will first be validated through non-clinical evidence, which will justify the later, obliged, clinical validation. Different approaches to discovering new drug applications include:

Marketing Strategy or Commercial Extension
This includes new formulation, different strengths or the improvement in a dosing regimen to treat the same or different pathologies. Duloxetine and Milnacipran are examples of this type of repurposing: Duloxetine from depression to urinary incontinence and pain, and Milnacipran from depression to fibromyalgia.

Duloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), first developed and launched in 2004 by Lilly as a treatment for major depressive disorders.The list of approved uses of this drug has not stopped growing since its initial approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In the EU alone, it is used for the treatment of diabetic peripheral neuropathic pain, anxiety, stress and urinary incontinence. In 2008 it also gained FDA approval for generalised anxiety disorder and fibromyalgia and then in November 2010 was authorised for use in the management of chronic musculoskeletal pain.This is an example of a successful reprofiling of a blockbuster drug, although one could argue that it merely represents a classic example of logical line extensions since all marketed indications share the same mechanism of action.

Milnacipran (Ixel and Savella), a mixed SNRI similar to Duloxetine, was developed and launched by the French company Pierre Fabre in 1997 for the treatment of major depressive episodes. It is currently marketed as Ixel for this indication in over 45 countries worldwide including several European countries, Japan and Mexico, but not the US. Under a North American license from Pierre Fabre, Cypress Bioscience and Forest Laboratories have reprofiled Milnacipran for the treatment of fibromyalgia, a chronic syndrome of diffuse musculoskeletal pain with tenderness at specific locations, often associated with persistent fatigue, cognitive and mood disorders, joint stiffness and insomnia. In January 2009, the FDA approved Milnacipran – under the brand name Savella – for the treatment of this disease.However, the EMA refused its marketing authorisation due to an unfavourable risk:benefit ratio.

The fact that antidepressants are widely used to treat symptoms other than depression,many of which fit into a general category of pain, as well as the fact that both Milnacipran and Duloxetine remained in the market for their original indications, could be seen as a reprofiling borderline case between true drug repurposing and mere label extensions.

Scientific Approach
This approach requires an in-depth understanding of the pharmacology and human pathophysiology of a given disease.This also includes data mining approaches and identification of overlooked opportunities by studying the pharmacology, mechanism of action and the biological target of existing drugs.

Rifaximin (Xifaxan) is a semisynthetic, rifamycin-based, non-systemic antibiotic. The FDA firstly approved it for the treatment of traveller’s diarrhea in 2004 and then for hepatic encephalopathy in 2010, but there are still more potential uses for it. A recent study suggests that treatment with Rifaximin relieves symptoms for some sufferers of irritable bowel syndrome (IBS). According to the data currently available, Rifaximin could be repositioned as the first treatment for IBS that targets the underlying cause of the condition, rather than just treating the symptoms. Current treatments, including anti-diarrheal and anticonstipation medications, solely target the symptoms of IBS and work only as long as people continue taking the drugs.This research seems to show that antibiotics work for patients with IBS, suggesting the intestinal microbiota has a role in causing this condition.

In March 2010, the FDA approved Polidocanol (Asclera), a sclerosing agent from the German company Chemische Fabrik Kreussler, indicated to treat uncomplicated veins and reticular veins in the lower extremities. In the last few years it has also been under investigation for the treatment of several tendinopathies such as Achilles tendinopathy, where neovessels are observed representing an increased capillary blood flow at the point of pain. Recent studies using injections of the sclerosing substance polidocanol in the Achilles tendon have shown promising clinical results. It is now just a matter of time to see whether this new indication will be approved by the regulatory agencies (3-5).

Serendipity
Fortuitous discoveries can be made while looking for something unrelated. Despite the fact that many repositioned proposals come from scientific rational, it is still the case that serendipitous observations by the end-user (patient and/or physician) are the most common source of new applications. Apart from the well-known case of sildenafil (Viagra), there are similar cases of drug repurposing through serendipity.

Bimatoprost (Lumigan, Allergan) is an ophthalmic synthetic prostamide analog, developed by Allergan for the treatment of open angle glaucoma and ocular hypertension. It was launched as eye drops in the US and EU in 2001 and 2002, respectively. Lumigan and other prostaglandin-like drugs lower intraocular pressure by increasing the uveoscleral outflow of aqueous humour (6).The ability of Bimatoprost to affect eyelash growth was first detected in clinical trials, where it was initially considered an adverse side effect.This serendipitous observation eventually led to the FDA approval of Latisse (Allergan) for the treatment of eyelash hypotrichosis in December 2008. Latisse is an ophthalmic solution of Bimatoprost for topical administration on the eyelid margins, thereby retaining efficacy in promoting eyelash growth and strength without other side effects observed when used as eye drops, such as conjunctival hyperaemia (7).

Technology Platforms

This category includes in silico screening computational platforms, toxicological and clinical side effect databases, in vitro screening, targeted high-throughput screening (HTS) and high-content screening among others.

Although Big Pharma also makes use of these technologies at several stages of drug development, including drug life cycle management, several small specialised companies have arisen with drug reprofiling and technology development as their core business. These small companies are becoming the ‘new players’ in the drug development scenario, as most of them were only founded recently (see Table 1). It is still early to compare which will prove to be the best approach, although some promising data has come out using in silico platforms. The pipeline of these small companies is growing quickly. Collaborations, partnering and deals with big pharmaceutical companies are also increasing accordingly and proofof- concept for many Phase 2 clinical trials are currently ongoing with results expected soon.We do hope it is only a matter of time until we see new drug applications based on successfully repurposed drugs coming from projects fully generated by technology platforms.



Conclusion

It is clear that diverse business and technology strategies are being used in order to successfully bring reprofiled drugs to market. The number of approaches and tools used to find new indications for compounds is rapidly increasing, particularly at the level of technology platforms. Big pharmaceutical companies are increasingly partnering with universities and small technological companies that can boost the identification of new uses of their failed drug candidates, such as in the field of neglected and rare diseases (9). We will need a few years to reap the rewards of these partnering efforts and technological advances, such as in silico reprofiling, but it will undoubtedly be exciting to follow up, as we will hopefully witness an increased use of old drugs for new concepts.

References
  1. Dimasi JA, Risks in new drug development: approval success rates for investigational drugs, Pharmacol Ther 69(5): pp297-307, 2001
  2. DataMonitor, Pharmaceutical key trends 2011 – pharmaceutical industry infrastructure overview: pharma innovates, diversifies and contains cost in order to grow profits, ref HC00062-008, 2011
  3. Ohberg L and Alfredson H, Ultrasound guided sclerosis of neovessels in painful chronic Achilles tendinosis: pilot study of a new treatment, Br J Sports Med 36(3): pp173-175, 2002
  4. Alfredson H and Ohberg L, Sclerosing injections to areas of neovascularisation reduce pain in chronic Achilles tendinopathy: a double-blind randomised controlled trial, Knee Surg Sports Traumatol Arthrosc 13(4): pp338-344, 2005
  5. Willberg L, Sunding K, Ohberg L, Forssblad M, Fahlström M and Alfredson H, Sclerosing injections to treat midportion Achilles tendinosis: a randomised controlled study evaluating two different concentrations of Polidocanol, Knee Surg Sports Traumatol Arthrosc 16(9): pp859-864, 2008
  6. Smid DS, Role of prostaglandins and specific place in therapy of bimatoprost in the treatment of elevated intraocular pressure and ocular hypertension: a closer look at the agonist properties of bimatoprost and the prostamides, Clinical Ophtalmology 3: pp663-670, 2009
  7. Cohen JL, Enhancing the growth of natural eyelashes: the mechanism of bimatoprost-induced eyelash growth, Dermatologic Surgery 36: pp1,361- 1,371, 2010
  8. Hermann AM Mucke, Insight Pharma Reports, Drug Repositioning: extracting added value from prior R&D investments, Cambridge Healthtech Institute, July 2010
  9. Ekins S, Williams AJ, Krasowski MD and Freundlich JS, In silico repositioning of approved drugs for rare and neglected diseases, Drug Discovery Today 16(7/8): pp298-310, 2011


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Núria Gavaldà joined SOM BIOTECH in June 2010. She has a PhD in Biological Sciences from the University of Barcelona specialised within the Neuroscience field. She was also the Coordinator of Histology in the Faculty of Medicine for two years, before spending five years as a Research Associate at Cardiff University, UK, where she also obtained Project Management qualifications. Email: gavalda@sombiotech.com

Núria Reig joined the company in October 2010. She obtained a PhD in Biochemistry and Molecular Biology at the University of Barcelona and completed a four-year period of post-doctoral research in immunology and bacterial pathogenesis at the University of Geneva and EPFL, Switzerland. Núria has also worked at Xigen, a small biotech company in Lausanne, as a senior scientist in the Discovery/Exploratory Inflammation Unit, participating in the early development of antiinflammatory peptide drugs. Email: reig@sombiotech.com

Marc Centellas joined the company in January 2011. He is a BSc in Pharmacy from the University of Barcelona and has worked for more than nine years in pharmaceutical companies such as Grupo Ferrer, Palau Pharma (Uriach Group), Alcon (now Novartis) and Ceva Santé Animale, developing strong background in regulatory affairs and quality and project management. Marc also received a Business Administration and Pharmaceutical Marketing postgraduate qualification at the University of Barcelona and the Univeristat Politécnica de Catalunya. Email: centellas@sombiotech.com
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Núria Gavaldà
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Núria Reig
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Marc Centellas
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