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Everything old is new again
Viagra. Everyone's heard of it. Everyone knows what it does. But most people probably don't realize that sildenafil citrate began its life intended for another purpose before it was repurposed into the blockbuster that it is today. When the compound was found to be unsuccessful as an anti-hypertensive agent in Phase I trials, Pfizer Inc. found success in switching the drug to the treatment of erectile dysfunction.
Long before that success, other compounds have gone on to other lives; a commonly cited example is thalidomide, originally used as a sedative to treat morning sickness in pregnant women, and then went on to be used as a treatment for multiple myeloma and erthema nodosum leprosum. Another success: finasteride, originally approved for benign prostate hyperplasia, now also approved to treat male pattern baldness as the active ingredient in Propecia.
"Broadly speaking, drug repurposing or drug repositioning alludes to the development of existing drugs or pro-drugs for new indications, not necessarily related to the original disease focus. In general, these drugs have probably failed in late-stage clinical trials by lacking in efficacy or safety, or have problems associated with commercial strategies, patent expiration or geographic expansion," explains business research and consulting firm Frost & Sullivan Analyst Cecilia E. Cauwenberghe.
Companies have likely invested millions of dollars and countless hours in the development process. Bringing completely new drugs to market, through all the stages of human trials and regulatory approvals, can take years. Inherent in this process is risk.
"A repositioned drug has the same chances of success as an original drug in meeting efficacy end points. There is nothing inherently different about repositioned drugs to make them less able to succeed due to efficacy," says Dr. Andreas Persidis, co-founder and CEO of Biovista Inc., a private drug development services company that is headquartered in Charlottesville, Va. "However, they lack the risks of original drugs, which is a major advantage of repositioning."
And, adds Frost & Sullivan Technical Insight Research Analyst Ruplekha Choudhurie,
"Toxicity studies; absorption, distribution, metabolism and excretion (ADME) studies; and other important criteria, are already assessed during clinical trials for the drug. Hence, time—usually a couple of years to understand the drug metabolism, safety and tolerance—can be saved. Similarly, clinical trials to understand the drug efficacy have to be carried out while repurposing, while the other parameters need not be reassessed. This is a good option, as thousands of dollars spent on clinical trials can be saved."
How are they chosen?
According to Cauwenberghe, two main selection criteria for drug repurposing candidates can be cited: known compounds with new targets in the first place, and known mechanisms with new indications in the second place.
"Eli Lilly's raloxifene hydrochloride, Evista, is an example," she says, "as this drug was conceived as an osteoporosis therapeutic agent, with its initial steps in clinical trials related to breast cancer therapies. Similarly, Genzyme's plerixafor (Mozobil) was recognized primarily as an inhibitor of HIV infection, and finally was launched as a hematopoietic stem cells mobilizer, particularly related to novel advances in the treatment of multiple myeloma. Cypress Bioscience's milnacipran (Savella) was initially thought of as an antidepressant, and later repurposed by Laboratoires Pierre Fabre as Joncia for the treatment of fibromyalgia. Another example is GlaxoSmithKline's paroxetine hydrochloride (Paxil), which was originally launched as an immediate-release formulation, then later licensed for the treatment of major depression and anxiety disorders. GlaxoSmithKline's ropinirole and Boehringer Ingelheim's pramipexole were both originally developed for the treatment of Parkinson's disease; however, posterior findings derived in their development as a repurposed compound for the treatment of restless leg syndrome."
Trends that drive the repositioning phenomenon
According to Persidis, four key trends are paving the path in drug repositioning.
First, the patent cliff: This means that companies have to find new applications and products more quickly than the 10 to 12 years a new drug takes to come to market, and repositioning allows that to happen.
Second, generics pressures: Generics companies are becoming more aggressive, and they are also entering the new drug arena themselves (e.g., Teva acquiring Cephalon). This means that both pharmas and generics companies are looking to repositioning as a way to distance themselves from each other.
Persidis also cites productivity and innovation.
"Repositioning allows an increase in Phase II starts leading to more drugs entering the clinic at any given time," he says. "In addition, repositioning may reveal new biology in a disease, leading to innovation in therapeutic approaches. A good example is Gleevec, whose previously unexpected off-target pharmacology has led to it being tried in a number of non-cancer indications, including spongyloarthritis and others."
Last, Persidis says, but certainly on par with the other factors, are competitor adjacency threats.
"Competitor adjacency threats drive companies to not only add new compounds to their pipelines, but indicate when a savvy company reacts to what its competition is doing with a new twist on an old compound. Several companies are doing both," he explains. "These strategies are complimentary. However, there are still major companies that do not include systematic repositioning as part of their strategy, and I believe this makes them vulnerable to competitors repositioning their drugs instead."
"A good example is Enbrel, which was repositioned by BDC in sciatica, and then acquired by Cephalon for about $40 million upfront and about $200 million in milestones in 2009-2010," he adds. "Amgen, the owner of Enbrel, does not have rights now in the use of their drug in this new major market, and this vulnerability is prevalent in a number of well-known companies, because they seem to choose to ignore the possibility that another group may be able to find something about their drug that they didn't know."
What are the good disease targets?
Frost and Sullivan's Choudhurie singles out two targets for further growth in repurposing; both diseases are complex and treatments for both are highly sought-after around the globe.
"Obesity is a complex metabolic disorder, and drugs usually used for obesity fall into different categories which target the disease in different ways," she says. "Similarly, other complex diseases that don't have just one target can provide a good opportunity for drug repositioning. Oncology is another disease area where drug repositioning activity has been very high."
Not without impact is the rising tide of medical needs in the aging baby boomer population. Choudhurie's Frost & Sullivan colleague Cauwenberghe says it's hard to choose targets specifically, but we can generalize about impacts in the future.
"Regarding more appropriate disease targets, actually an in-depth prediction of the most benefited disease areas is uncertain, as well as the impact of new technologies over drug repositioning approaches." she says. "Nonetheless, a notable expansion of the aging population, as well as cancer, pain, diabetes, metabolic, cardiovascular and neurological diseases, including Alzheimer's and Parkinson's, can be remarked.
"On the other hand," she points out, "rare diseases have been also targeted through numerous projects."
Choudhurie agrees: "Another advantage of repositioning is that diseases with a high unmet need can be targeted with these drugs that are already in the market," she says.
"In orphan diseases, the driver is to find a therapy as quickly as possible, no matter what the approach," adds Persidis. "Repositioning is now recognized as a major potential contributor to this, which is why there is a dedicated NIH effort."
Some are not as exuberant about the potential of this method of discovery for attacking rare diseases. Again, limited resources juxtaposed against a small population who can benefit makes the math sometimes tricky, even if expensive early steps have been taken.
Over at the Sanford Burnham Medical Research Institute, officials promote the work of their organization, which takes on these orphan causes in a unique way.
"Regrettably, pharmaceutical companies are not likely to engage in drug repositioning efforts for rare childhood diseases," the institute's representatives say. "This is in part due to the smaller patient populations and challenges in running clinical trials in these indications. In addition, competition with generic drugs makes this effort commercially unviable, in spite of its great potential to benefit human health. Even if companies were motivated to engage in these efforts, it is very difficult for the pharmaceutical industry to perform the type of screens Sanford-Burnham is doing because of their limited access to patient samples."
Failures … or opportunities?
There is not always a direct path to success. Not every repositioning effort is a clear winner.
"A recent example of a not successful one is Dimebon, a cough suppressant that was repositioned in Alzheimer's disease by Medivation and Pfizer, but failed to meet its Phase III end-points," says Persidis. "However, there is believed to be more extensive pharmacology on this drug, creating important possibilities for it to be rescued and re-repositioned in other diseases."
To be sure, rapid technological advances and new business strategies in the recent past have changed the game rapidly since the time of thalidomide.
Says Cauwenberghe: "On that note, it is important to highlight the fact that during the past five years, innovation in the biopharmaceutical industry has helped counter rising development costs, and stagnant product output has become a leading cause for drug repurposing."
With little new on drug companies' plates for one reason or another, new therapies have to come from somewhere.
"Two other relevant reasons rely on the need to expand product pipelines with new projects, as well as the increasing of the pool of potential compounds abandoned due to strategic reasons," she adds.
New technologies and methods for sharing information play a large role.
"Companies have been encouraged to emerge from another perspective, by expanding their technology platforms for identifying new indications," Cauwenberghe explains. "This has led to the success of several projects committed to the development of proprietary pipelines of candidates, while reducing the related risks and timelines in further clinical development. Moreover, current business models and technology platforms promote the public generation of proof-of-concept clinical data to share efforts for repositioning purposes."
An example of those new business models is the one being developed by Transparency Life Sciences (TLS), which is developing repurposed drugs based on an open-innovation and crowdsourcing model.
Now beginning work with Stanford University, the company will examine developing the blood pressure medicine lisinopril for multiple sclerosis (MS). Preclinical data showing how lisinopril works through autoimmune and inflammatory mechanisms to reduce paralysis and blindness in animal models of MS has shown promise.
The relatively new company introduced its crowdsourcing model in beta on Jan. 31, and is inviting interested individuals to participate in the design of the protocol for a Phase II trial of lisinopril in MS. It hopes that opening up the study design in this way will allow for collaboration in ways not before thought possible.
"The paradigm shift around drug repositioning necessarily derives a change in the current business models utilized by pharmaceutical and biotechnology industry," concludes Cauwenberghe. "In particular, pharmaceutical companies have to face the challenge to transform their blockbuster model toward a more accurate, flexible and cost-effective model that involves the development of therapeutics for new prospect indications. Indeed, a myriad of small companies have started to play new roles in the biopharmaceutical market. Their innovative capacity, as well as their constant nutrition with academic fields, becomes these companies as strategic players, leading to a novel trend of M&A activities and licensing agreements."