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Drug repositioning offers an alternative path to drug development
Researchers at the US drug group Pfizer’s Sandwich research center while working on an angina treatment found a compound by the name of Sildenafil, which failed to work. It seemed as if it was the end of the road for the compound; however, the drug did have a fascinating side-effect. Three days after the male volunteers were administered the pill, they got a prolonged erection. Gradually, the treatment was refined and the time was shortened. It was branded as Viagra and immediately became a blockbuster-a great cure for erectile dysfunction. The tiny blue pill is prescribed to millions of men all over the world even today and this made Pfizer richer by $2billion in sales a couple of years back. Finding new uses for obsolete drugs is a thriving business as major pharmaceutical companies struggle to come up with new innovative drugs.
There are more than 7000 unsolved diseases and ironically there are thousands of generic drugs that can be repositioned to help patients suffering from those diseases.
Built from knowledge from anecdotal evidence, bioinformatics and scientific discoveries, drug repositioning research can result in affordable and rapid development of innovative medical solutions. After the identification of a drug repurposing opportunity, a major issue is whether the clinical trial should emphasize on supporting a path to physician off-label use or commercialization. The direction of focus is based on the entity that supports the clinical trial development. These entities are either philanthropic or commercial.
When thinking about the results, commercial entities (financial investors, biotech, pharma) normally focus on shareholder and financial value. Philanthropic entities (government, individual philanthropists, foundations, patient advocacy groups), on the other hand, emphasize on patient impact.
Three key issues to evaluate
Before a commercial body moves forward with a drug repurposing clinical trial, it has to evaluate three major issues.
Firstly, there has to be the possibility of considerable financial gains. Some important factors that contribute to the financial potential include patent protection, manufacturing exclusivity and market exclusivity. If exclusivity/patent is possible, the commercial entity has to gather extra information to find out the potential ROI of the clinical trial. Lastly, the entity has to determine whether the specific opportunity matches its portfolio and adheres to its business objectives.
The decision process for philanthropic entities is different. They might begin with the same evaluation as done by commercial entities to determine if a regulatory approval path and clinical trial could yield robust ROI and profits. If so, they would hunt for a commercial partner who could possibly bring the repurposed drug to the market. However, if the ROI is weak, they can take the help of concessionary impact investors in funding these clinical trials and other associated expenses
Some companies with the hope of recouping returns on their investments are looking to reposition existing drugs that are still under patent like those that were shelved following unsuccessful trials. Since resources have been devoted to these unacknowledged therapies, manufacturers see value in revamping them for a new indication. Craig Wegner, head of AstraZeneca’s Emerging Innovation, says that a lot of risks and costs associated to drug development have already been surpassed.
Data mining and bioinformatics for identifying repositioning candidates and potential targets
One of the important challenges in finding future therapeutic indications lies in picking the therapeutic target to test a drug of interest. There is a growing body of evidence that points to the fact that a huge number of medications interact randomly with biological elements outside their targets, also referred to as off target effects. Comprehending such interactions of existing medications is of crucial interest in pharmaceutical research, both for providing insight into the side effects of a drug and also discovering its innovative therapeutic uses. The challenge, however, remains in identifying these targets in a way that also provides vital information on how the drug can be used to its ultimate benefit.
Rapid advances in proteomic, genomic, functional, and structural analysis of the known targets have allowed the discovery of drugs, combination therapies, multi-target agents along with pharmacogenetic responses and examination of target and off-target toxicity.
Information on therapeutic targets can be publicly accessed from databases like Potential Drug Target Database, DrugBank, SuperTarget, and Therapeutic Target Database. These databases augment each other to supply target and drug profiles. One common approach for target identification is the fact that they are not driven by hypothesis nor do they focus on one pure target. In fact, they cover multiple targets and quite often involve pathway-based or in vivo techniques.
Methods like network analysis and systems biology are used to identify druggable targets. These techniques integrate cell biology and biochemistry with physiology and genetics in addition to computational biology and bioinformatics to get holistic information of biological systems at the organ/tissue, cellular, and organism levels. Numerous algorithms can be used in identifying hidden traits common to successful targets, which can eventually be applied across upcoming target landscape in order to forecast the success level. Some of the popular ligand knowledge bases that are popularly used in the discovery of drugs include MDL Drug Data Report, World Drug Index, Aureus Pharma and Jubilant Biosys (India) to name a few.
After having identified the targets, the hunt for promising compounds involve a thorough review of subscription-based and public information like company websites, scientific databases, and intellectual property (IP). These sources help in identifying candidates within the branded and generic pharmacopoeia. Some of the databases that keep a close watch on clinical programs right from the process of target identification to the development phase include Prous, Adis Insight, Trial Tove, and the Investigational Drug Database. These databases provide in-depth information on websites, conferences, patents and additional materials. The other way to identify potential candidates is by using FDA’s Orange Book, which recently cited IDMap, a java-based software that allows researchers to match chemicals with possible drug targets, thus saving a huge chunk of time querying huge databases.
The Butte Lab in California uses the notion that if two diseases have similar therapies, other medications that are presently used in reversing one of the two can also offer treatment for the other.
Compound Libraries
Gaining admittance to repositioning candidates can turn out to be an onerous task or at worst unattainable. However, private agencies and the government in some developed nations have taken special initiatives to create chemical libraries of present medications and provide them for screening to researchers all over the world. The largest known accessible library of existing medications is the Johns Hopkins Clinical Compound Screening Initiative. Launched in 2002, it boasts of more than 3100 existing drugs, with a major portion of them having being approved by the FDA and out of patent restrictions. These drugs are now being screened by many collaborators on a variety of diseases like HIV, cancers, angiogenesis, and malaria.
Conclusion
Irrespective of whether a clinical trial is funded by a philanthropic or commercial entity, drug repositioning offers an alternative path to drug development in order to build medical solutions to unmet patient requirements. Finding future therapeutic indications for existing drugs is a strong healthcare strategy even when there is a dearth of commercialization potential. This holds true for neglected or rare disease populations, where commercialization can be pretty challenging. A wide scale implementation of repurposing strategies in the near future will provide an immense opportunity to let loose the potential of the pharmacopeia and result in a win-win situation for the patients and the private and public sectors worldwide.