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Guest Commentary: Every drug deserves a second chance
After many years of talking about it, the patent cliff is finally with us in a big way. Starting with Pfizer's Lipitor this coming November, Big Pharma is projected to lose more than $60 billion in the next five to six years from drugs that will lose patent protection to generics.
Naturally, the industry hasn't been standing still. Mergers and acquisitions and buyouts have been one "quick-fix" way to bolster companies' drying pipelines. Carpet-bombing patent practices have been another way to enrich one's intellectual property (IP) estate. Recently, many Big Pharma companies are officially entering the generics market, which only a few years ago they were happy to leave to competition.
However, all of these temporary "pain relievers" do not create real shareholder value and do not address the root cause of these woes, which is none other than our innovation deficit. In other words, despite increasing dollar spending on R&D, we are not discovering enough new, safe and efficacious new chemical entities (NCEs), nor is our understanding of biology, disease and drug mechanisms-of-action (MoAs) improving fast enough and in a way that creates a fertile knowledge foundation for the development of these NCEs. To say there has been no progress at all would be an overstatement, but the process is slow, and one cannot help but feel this process is not as efficient as it should be.
At the heart of the present pharma industry predicament is a knowledge-generation and management problem. This is no revelation to anyone involved in the industry, so what are the options?
One recent trend has been to "recycle" existing knowledge and IP. The thinking is simple and goes something like this: "If we can't generate enough new knowledge, maybe we should re-examine what we already know to see if there are any hidden gems already in one's possession."
This is exactly what drug repositioning (DR, also known as drug reprofiling and drug repurposing) is all about. It assumes that many existing pharmacological compounds, having made it to market or not, may show efficacy in more than one therapeutic area (TA)—and as a minimum in at least one additional TA than that for which it was originally developed. Companies then proceed to look for these alternate indications.
Drug repositioning is not new, and there are many examples of successfully repositioned drugs from the past. Thalidomide is a good example of a repurposed drug. In 1964, Jacob Sheskin at the University Hospital of Marseilles was trying to treat insomnia in a patient suffering from erythema nodosum leprosum (ENL) when he ran out of options. In a last-ditch attempt, he used thalidomide, which he believed might be effective as a sedative. Not only did thalidomide allow the patient to sleep, but simultaneously healed his sores. This effect was corroborated in follow-up clinical trials, which established thalidomide as a primary treatment for ENL. Finasteride (Proscar) is another interesting example. Originally approved for the treatment of benign prostate hyperplasia, it was subsequently found to be effective against male-pattern baldness.
Impressive though they are, most of these examples have been predominantly serendipitous affairs. What is now needed for the industry is for this to occur on a systematic basis. If drug repositioning could occur on a systematic basis, this would be seen as a reliable tool that can be used multiple times to support management in go/no-go decisions on company assets or even entire disease programs.
Pfizer seems to already be down this path. In March 2008, the company declared that approximately 50 to 60 percent of its assets that would advance from Phase II to Phase III clinical trials were, in fact, repositioned drugs.
There are also very good scientific reasons why drug repositioning is valuable, with recent research showing how an existing drug (such as Gleevec, ibuprofen, certain antidepressants and others) can have an impact on more than one disease that share certain characteristics at the mechanistic level. Pharmaceutical companies are taking increasing notice of this, as reusing an existing drug with proven safety to start a new clinical development program is much cheaper and less risky than creating an entirely new drug. This strategy makes sense within the context of portfolio development, being relevant not only for the drugs that are slated to be developed internally, but also for the ones that are on the shelf and are being explored for out-licensing.
Like many processes, drug repositioning can be practiced in a variety of ways. For example, one can develop mathematical models of diseases and/or biological systems and use these to simulate the effect of selected drugs in that disease. Alternatively, one can select a set of animal models that are deemed predictive enough of disease progression in humans and use those to assess the potential of any asset (drug or compound) of interest as a repositioning candidate.
Another way is to use existing scientific literature and other resources, once again to identify repositioning opportunities, based on the broad understanding of what is known about the drug or the disease of interest. Done properly, this last approach has a distinct advantage as it minimizes assumptions, which in a discovery context can be the mother of all missed opportunities. It can also support "bidirectional repositioning," meaning that one can use this method to identify new TAs for an existing drug of interest, as well as identify the most appropriate drug (or drug combination) for any TA of interest.
Literature-driven repositioning, moreover, has the potential for a much broader impact on the industry since its techniques, possibly combined with other tools such as cheminformatics and molecular binding simulations, could be used to render de-novo discovery as a systematic process. This would be the final of a three-stage evolutionary process, the first stages of which we are already beginning to witness.
In the first stage, repositioning is no longer a serendipitous event, but becomes more of a systematic process, increasingly used by pharma companies to fill their pipelines and ensure the appropriate exploitation of existing IP. In the second stage, examples of which are already taking place, repositioning is applied to compounds at their earlier development phases. In other words, repositioning becomes part of a drug's life-cycle management process. This will become very important as companies attempt to protect themselves from what we call "competitor adjacency moves," which are nothing more than the "usurping" of IP estate from less-than-vigilant IP owners.
One ultimately expects that the opportunities for repositioning using existing knowledge will have run their course, and the need to discover novel chemistry and novel MoAs will resurface. At that point, some of the tools and techniques developed for drug repositioning will be used for NCE discovery, as well as for better understanding of biology itself.
Given these factors, repositioning will be useful to the life sciences industry in three ways in the years to come: it will help develop new/better therapies to address medical needs, it will help develop new techniques to make discoveries on a systematic basis and finally, as a consequence of the above, it will help make drug development more efficient.
We expect drug repositioning to increasingly impact strategic decision-making. As the Enbrel story shows, one company's oversight can be another company's opportunity. Enbrel is the Amgen anti-TNF drug that was repositioned by Bioassets Development Corporation (BDC) to Sciatica before its patent expiration. BDC was subsequently bought by Cephalon, itself now in advanced buyout discussions with Teva. What this incident tells us is that one can no longer feel safe and remain complacent, even when it comes to assets still under patent protection. Strongly supported method-of-use patents can be granted to competitors forcing the original owner to either cede the specific area, or come to some arrangement with the owner of the repositioned drug.
There are additional variations to this theme. For example, as a result of past patent practices, there are a number of pharma companies that, while owning the application of a certain compound to a number of disease areas, in practice do not have "full possession" of their know-how, meaning they are unsure for which of these areas to further develop their asset. Applying repositioning analysis on these known disease areas could help prioritize them for the drug owner.
It seems that drug repositioning is here to stay and will have a definite role to play in the years to come. It has started with repositioning of generics on a systematic basis and will soon rapidly evolve to support life-cycle management decisions for drugs still under patent protection, as well as product development in the OTC space.
We also expect drug repositioning type analyses to support strategic IP management and protect composition-of-matter IP holders against competitor "adjacency moves." In the longer term, literature-driven drug repositioning could become one of the tools supporting de-novo discovery. These are extremely exciting prospects for something that started out as a small collection of serendipitous events.
Andreas Persidis is co-founder and CEO of Biovista Inc.
Persidis has a PhD. artificial intelligence. He has built technology development teams at European corporations in the engineering, software and telecommunications fields. He is also an expert reviewer and evaluator for the European Commission and the Austrian government in the areas of IT and the life sciences, serves on a number of expert advisor panels on knowledge technologies and is a frequent presenter at international fora.