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European Biopharmaceutical Review

Drug Reprofiling

 

Systematic, bioinformatics-driven reprofiling offers an enticing way for companies to gain new value from old drugs. While approaches to this common goal vary, the initial results look promising. ‘Drug alchemists’ are those people or companies who transform the modern basic metals of the pharmaceutical industry – generic drugs – into the new gold – new patents. This activity is usually called reprofiling, being a clear reference to the change of the drug profile; or repositioning/repurposing, referring to the change of a drug purpose. For some authors and from a strict linguistic point of view it is better to use the term ‘repositioning’ if the drug has already been launched to the market and still active, and ‘reprofiling’ for those drugs that were withdrawn from the market but are now intended for recycling, re-activated and relaunched a new purpose and for new targets. In this article, we will use the term ‘reprofiling’ for both cases; to give a new value to the drugs whose original worth has diminished, or to resurrect drugs that have never had sufficient value to survive in a highly competitive environment in the first place.

Drug alchemists are using numerous strategies, and the nature of those strategies and methods can be used to classify them into different categories. The first possible parameter to take into account when classifying drug alchemists is the quantity of experiments they conduct. This may span from the bruteforce strategies based on a huge number of experiments carried out, understanding this as a high throughput method needing considerable processing power, to those more rational methods including in-depth analysis of accumulated data and knowledge on the drug and the indication. Following intuition, it seems better to choose the rational method over the brute-force strategy, but ultimately this is not such a simple choice, as we will see later. There are many other ways to classify drug alchemists. For instance, the further parameter for classification could be the importance of ‘water’ in their methods. In this case we differ in silico strategies from ‘water-dependent’ strategies, where using the wet lab is essential. The final validation needs to take place in an animal model, but here we are mainly focused on finding the most appropriate strategy to obtain exploitable reprofiling results, and not on the validation process.

Another parameter used in classifying drug alchemists takes into account their objective. From that point of view, there are both drug-focused alchemists, centered on drug transformation; and also indication-focused alchemists, centered on finding new indications for already existing drugs. Drug-focused alchemists strive to transform the chemical structure of a drug by adding, removing or modifying parts of the drug structure, fine-tuning it in order to increase its efficacy. On the other hand, indicationfocused alchemists are searching for any drug that can be helpful in treating a specific indication, regardless of the fact that the drug was previously used to treat different indications to the one they want to treat, supporting the theory that one drug can be successfully applied to multiple targets.

What is the best strategy? It is difficult to say. Most people think the best approach is the one that ensures the highest efficiency and security level for a particular indication, and this could be true from the patient’s point of view, but the picture changes slightly when looking through the business prism of biotech and pharma companies. Market value must be considered alongside efficiency and security requirements as an incentive to increase the product exploitability. Therefore, we should definitely include the market value of the reprofiling findings as an extra parameter.

Many companies use a combination of the aforementioned strategies, albeit to a different extent, to benefit from their synergy and to develop more marketable drugs with increased value. Are these strategies acceptable from a commercial point of view? If we take into account the new patents resulting from the reprofiling they seem so, but if the result is to have more new drugs launched to the market, the answer is not so clear. Nobody can be sure whether these strategies are good or not; we can only say that all these strategies are still not good enough.

 

In reality, companies often combine all the aforementioned strategies, even when they seem to be incompatible at first sight. This was the case with CombinatoRx, an indication-focused American company that was combining brute-force with ‘water-dependent’ strategies. Logically, if you use brute-force methods in your research and, subsequently, waterdependent methods, a very expensive and time-consuming process could result; or to put it in other words, it will not ensure a competitive edge since the costs of drug development are much higher than the drug’s market value. On the other hand, CombinatoRx’s strategy of focusing the search on combinations of drugs, instead of a single drug to treat a specific indication, was a good approach in terms of market value. Why? Because obtaining the patent and increasing the market share is simpler and less risky for a drug combination than for a new single drug. Unfortunately, CombinatoRx went bankrupt in 2010, but paradoxically, it obtained a very large number of patents. However, this whole business model can be improved by optimising the process and the company’s working strategy.

One of the most promising new strategies in enhancing the understanding of biological mechanisms is based on the systems biology approach. Systems biology suggests that instead of accumulating a huge amount of information about the drug or indication, it would be more advisable to manage less information but also to include information about the cell or even the entire human if possible as it is a specific context for the drug action. This is an in silico approach which is becoming increasingly popular lately and is being used by companies such as Biovista, E-Therapeutics, PharNext, Anaxomics, SOM Biotech, Chrono RX, and others. Using systems biology as an holistic approach ensures a more dynamic perspective, allows peripheral vision in drug research and development, and provides a new, ‘alchemical’ insight into opportunities that have not been noticed before.

Is this the best avenue for reprofiling? We should not forget that Viagra is an unexpected, off-target realignment of an antihypertensive drug; in fact its main value is obtained from its original adverse event, the penis erection. Not all companies are as lucky and intelligent when analysing their results as Pfizer was with Viagra. Intuition tells us that, eventually, a rational method is better or at least more cost- and time-effective, and as a result more successful in reprofiling. At any rate, common sense and alertness should be a decisive factor that will distinguish the success from the failure for drug alchemists.


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Jordi Naval Chamosa is Co-Founder and CEO of Anaxomics. Previously, he was the Global Head of Post-Marketing Trials and Managing Director Southern Europe for RPS Inc, a leading global CRO, where he coordinated global clinical research activities across different therapeutic areas. From 1998 to 2008, Jordi was Founder and CEO at Infociencia, a leading Spanish CRO, where he managed a team of more than 120 specialists. Jordi has a BSc in Pharmacy and Biochemistry, and an MSc in molecular vaccines. 

José Manuel Mas is Co-founder of Anaxomics. José Manuel is currently Head of Collaborative Research Department at RPS Inc, collaborating with universities and other companies in the discovery of new drugs. He is also Co-Founder and Scientific Advisor in the area of systems biology for Anaxomics. José Manuel was a Founder, and from 1998 to 2008 a Technical Director at Infociencia. He has a degree in Biochemistry, an MSc in Biotechnology and a PhD in Biocomputing, specialising in protein structure, drug design and systems biology. José Manuel holds two patents and has written more than 30 scientific papers.

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