After many years of talking about it, the patent cliff isfinally with us in a big way. Startingwith Pfizer's Lipitor this coming November, Big Pharma is projected to losemore than $60 billion in the next five to six years from drugs that will losepatent protection to generics.
Naturally, the industry hasn't been standing still. Mergersand acquisitions and buyouts have been one "quick-fix" way to bolstercompanies' drying pipelines. Carpet-bombing patent practices have been anotherway to enrich one's intellectual property (IP) estate. Recently, many Big Pharmacompanies are officially entering the generics market, which only a few yearsago they were happy to leave to competition.
However, all of these temporary "pain relievers" do notcreate real shareholder value and do not address the root cause of these woes,which is none other than our innovation deficit. In other words, despiteincreasing dollar spending on R&D, we are not discovering enough new, safeand efficacious new chemical entities (NCEs), nor is our understanding ofbiology, disease and drug mechanisms-of-action (MoAs) improving fast enough andin a way that creates a fertile knowledge foundation for the development ofthese 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 asefficient as it should be.
At the heart of the present pharma industry predicament is aknowledge-generation and management problem. This is no revelation to anyoneinvolved in the industry, so what are the options?
One recent trend has been to "recycle" existing knowledgeand IP. The thinking is simple and goes something like this: "If we can'tgenerate enough new knowledge, maybe we should re-examine what we already knowto see if there are any hidden gems already in one's possession."
This is exactly what drug repositioning (DR, also known asdrug reprofiling and drug repurposing) is all about. It assumes that manyexisting pharmacological compounds, having made it to market or not, may showefficacy in more than one therapeutic area (TA)—and as a minimum in at leastone additional TA than that for which it was originally developed. Companiesthen proceed to look for these alternate indications.
Drug repositioning is not new, and there are many examplesof successfully repositioned drugs from the past. Thalidomide is a good exampleof a repurposed drug. In 1964, Jacob Sheskin at the University Hospital ofMarseilles was trying to treat insomnia in a patient suffering from erythemanodosum leprosum (ENL) when he ran out of options. In a last-ditch attempt, heused thalidomide, which he believed might be effective as a sedative. Not onlydid thalidomide allow the patient to sleep, but simultaneously healed his sores.This effect was corroborated in follow-up clinical trials, which establishedthalidomide as a primary treatment for ENL. Finasteride (Proscar) is anotherinteresting example. Originally approved for the treatment of benign prostatehyperplasia, it was subsequently found to be effective against male-patternbaldness.
Impressive though they are, most of these examples have beenpredominantly serendipitous affairs. What is now needed for the industry is forthis to occur on a systematic basis. If drug repositioning could occur on asystematic basis, this would be seen as a reliable tool that can be usedmultiple times to support management in go/no-go decisions on company assets oreven 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 thatwould advance from Phase II to Phase III clinical trials were, in fact,repositioned drugs.
There are also very good scientific reasons why drugrepositioning is valuable, with recent research showing how an existing drug(such as Gleevec, ibuprofen, certain antidepressants and others) can have animpact on more than one disease that share certain characteristics at themechanistic level. Pharmaceutical companies are taking increasing notice ofthis, as reusing an existing drug with proven safety to start a new clinicaldevelopment program is much cheaper and less risky than creating an entirelynew drug. This strategy makes sense within the context of portfoliodevelopment, being relevant not only for the drugs that are slated to bedeveloped internally, but also for the ones that are on the shelf and are beingexplored for out-licensing.
Like many processes, drug repositioning can be practiced ina variety of ways. For example, one can develop mathematical models of diseasesand/or biological systems and use these to simulate the effect of selecteddrugs in that disease. Alternatively, one can select a set of animal modelsthat are deemed predictive enough of disease progression in humans and usethose to assess the potential of any asset (drug or compound) of interest as arepositioning candidate.
Another way is to use existing scientific literature andother resources, once again to identify repositioning opportunities, based onthe broad understanding of what is known about the drug or the disease ofinterest. Done properly, this last approach has a distinct advantage as itminimizes assumptions, which in a discovery context can be the mother of all missedopportunities. It can also support "bidirectional repositioning," meaning thatone 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 TAof interest.
Literature-driven repositioning, moreover, has the potentialfor a much broader impact on the industry since its techniques, possiblycombined with other tools such as cheminformatics and molecular bindingsimulations, could be used to render de-novodiscovery as a systematic process. This would be the final of a three-stageevolutionary process, the first stages of which we are already beginning towitness.
In the first stage, repositioning is no longer aserendipitous event, but becomes more of a systematic process, increasinglyused by pharma companies to fill their pipelines and ensure the appropriateexploitation of existing IP. In the second stage, examples of which are alreadytaking place, repositioning is applied to compounds at their earlierdevelopment phases. In other words, repositioning becomes part of a drug's life-cyclemanagement process. This will become very important as companies attempt toprotect themselves from what we call "competitor adjacency moves," which arenothing more than the "usurping" of IP estate from less-than-vigilant IPowners.
One ultimately expects that the opportunities forrepositioning using existing knowledge will have run their course, and the needto discover novel chemistry and novel MoAs will resurface. At that point, someof the tools and techniques developed for drug repositioning will be used forNCE discovery, as well as for better understanding of biology itself.
Given these factors, repositioning will be useful to thelife sciences industry in three ways in the years to come: it will help developnew/better therapies to address medical needs, it will help develop newtechniques to make discoveries on a systematic basis and finally, as aconsequence of the above, it will help make drug development more efficient.
We expect drug repositioning to increasingly impactstrategic decision-making. As the Enbrel story shows, one company's oversightcan be another company's opportunity. Enbrel is the Amgen anti-TNF drug that was repositioned by BioassetsDevelopment Corporation (BDC) to Sciatica before its patent expiration. BDC wassubsequently bought by Cephalon, itself now in advanced buyout discussions withTeva. What this incident tells us is that one can no longer feel safe andremain complacent, even when it comes to assets still under patent protection. Stronglysupported method-of-use patents can be granted to competitors forcing theoriginal owner to either cede the specific area, or come to some arrangementwith 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 companiesthat, while owning the application of a certain compound to a number of diseaseareas, in practice do not have "full possession" of their know-how, meaning theyare unsure for which of these areas to further develop their asset. Applyingrepositioning analysis on these known disease areas could help prioritize themfor the drug owner.
It seems that drug repositioning is here to stay and willhave a definite role to play in the years to come. It has started withrepositioning of generics on a systematic basis and will soon rapidly evolve tosupport 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 supportstrategic IP management and protect composition-of-matter IP holders againstcompetitor "adjacency moves." In the longer term, literature-driven drugrepositioning could become one of the tools supporting de-novo discovery. These are extremely exciting prospects forsomething 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 technologydevelopment teams at European corporations in the engineering, software andtelecommunications fields. He is also an expert reviewer and evaluator for theEuropean Commission and the Austrian government in the areas of IT and the lifesciences, serves on a number of expert advisor panels on knowledge technologiesand is a frequent presenter at international fora.