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Drug Repurposing

Finding new uses for approved drugs and shelved drug candidates is gaining steam as a pharmaceutical development strategy

by Ann M. Thayer
October 1, 2012 | A version of this story appeared in Volume 90, Issue 40

Credit: Maggie Bartlett/NHGRI
The National Human Genome Research Institute’s Chemical Genomics Center has compounds available for repurposing studies.
These are 96-well, 384-well and 1,536-well plates use with robotic screening by the Chemical Genomics Center.
Credit: Maggie Bartlett/NHGRI
The National Human Genome Research Institute’s Chemical Genomics Center has compounds available for repurposing studies.

This fall, at least three conferences will bring together researchers to discuss how finding new uses for known drug compounds can be a strategy for both clinical development and business growth. A few years ago, no such conferences existed. The attendee lists show that interest is widespread among large pharmaceutical companies, small biotech firms, government agencies, academic groups, and nonprofit organizations alike.

Although the practice is called by many names—repurposing, repositioning, reusing, and rediscovery—the goal is finding ways to deploy approved drugs or abandoned clinical candidates in new disease areas. “Three key drivers make this very attractive,” says Richard K. Harrison, scientific director at the business information firm Thomson Reuters. “The cycle times are shorter, the development costs are less, and the success rates are higher.”

Repurposers have a leg up because they are working with compounds that have been approved or at least put through millions of dollars’ worth of preclinical and early clinical testing. As a result, repurposing can get drugs to the market cheaper and faster than de novo research and development, Harrison says. Moreover, whereas 10% of new molecular entities make it to the market from Phase II clinical trials and 50% from Phase III, the rates for repurposed compounds are 25% and 65%, respectively.

A few thousand drug candidates are estimated to languish in pharma company cold storage, and the number only grows as more compounds fail in development or get dropped for business reasons. Companies, academics, and nonprofit groups are reapplying drug discovery technologies to get these compounds off the shelf. Commercial groups see an opportunity for profits, and nonprofits see an efficient way to treat neglected diseases or address unmet medical needs.

But obstacles can crop up along the way, even after the initial challenge of identifying and acquiring good drug prospects. Although others may have completed much of the preclinical work, developers still have to fulfill regulatory requirements. How much of that they can complete with existing data depends on the extent of change in a drug, its formulation, and its use.

Repurposing “is still drug development, and there is always a large amount of risk associated with it,” Harrison says. “Whether it is repositioning or new drug discovery, you still have to make sure you understand the science, the disease, and the patient population.”

In broad terms, repurposing isn’t new. Pharma companies have always created variations of their existing products, such as new formulations or combination products. Some companies reposition compounds during development, usually at the earlier stages. Other times, serendipitous clinical effects—such as those that made sildenafil a candidate for erectile dysfunction after it failed in trials as an angina treatment—can redirect efforts.

Credit: Saint Louis University
Medicinal chemist Megh Singh contributes to R&D at the Center for World Health & Medicine.
This is a photo of medicinal chemist Megh Singh at the Center for World Health and Medicine at Saint Louis University.
Credit: Saint Louis University
Medicinal chemist Megh Singh contributes to R&D at the Center for World Health & Medicine.

Some pharma companies look at new compounds from the start as potential treatments for multiple diseases, says Karen Lackey, head of medicinal chemistry at Roche. “You’ll start with some biological rationale for a particular target but, in the lifetime of a project, you basically repurpose on your way to the clinic because you are looking for the best possible disease indications.”

Because biological systems overlap, researchers may share compounds that fail in one disease with researchers working in other areas, she says. Although safety is always a concern, side effects or toxicity in one application may not be an issue when a drug is delivered differently or at a different dose. In fact, “what’s a side effect for one disease could be the disease indication for another,” Lackey points out.

Other companies shy away from repurposing efforts after approval because of what they might uncover. Merck & Co.’s experience with Vioxx is a cautionary tale, points out David P. Cavalla, founder of Cambridge, England-based Numedicus, which provides services around repurposing. After getting approval for the drug as an analgesic, Merck began testing it for treating colon polyps. Cardiovascular issues that arose had to be reported to regulators and scuttled the blockbuster entirely.

Credit: Food & Drug Administration
This table shows drugs approved by FDA for common diseases that are also approved for orphan diseases.
Credit: Food & Drug Administration

Many large companies also will not consider repurposing a drug once it is in Phase III or near approval, because they “don’t want to upset the apple cart,” says Aris Persidis, president of Biovista, a Charlottesville, Va.-based company that identifies compounds for repurposing through mechanism-of-action analytics. “Once a drug is approved, they may look at it again further on in time, but they will typically look only at indications within strategic areas of interest to them.”

Revisiting shelved compounds is an undertaking without much downside and one that can help companies feeling the pressures of expiring patents, high costs, and low productivity. Some firms have cut back on early R&D and have made repurposing a part of their core business. These factors, along with the time and cost benefits, make it “a great time to do repositioning,” Harrison says. “There is a greater emphasis now as companies try to squeeze more revenue out of their existing assets.” Thomson Reu­ters expects that drug repositioning will generate up to $20 billion in sales this year.

Seizing the opportunity, this spring eight major drug firms joined the National Center for Advancing Translational Sciences (NCATS) to create the Discovering New Therapeutic Uses for Existing Molecules program. The companies together contributed 58 compounds that advanced in clinical studies but were unsuccessful in their original therapeutic indication or not pursued for business reasons. The list of compounds, many of which come from abandoned neuroscience programs, was posted in June.

NCATS, which is part of the National Institutes of Health, hopes the availability of these advanced compounds will encourage researchers to turn them into drugs for diseases that lack treatments. Researchers can submit proposals outlining how they would explore a specific hypothesis related to the use of a compound in a disease area. In 2013, NCATS plans on providing up to $20 million to fund several two- to three-year cooperative research grants.

The NCATS program has garnered praise but also debate. One issue is around government support of corporate product development. In the program, a research partner will own new intellectual property (IP) that it generates, but the company that owns the compound will have the first right to develop it. Other concerns center on whether there’s any chance of finding something that pharma R&D has missed, especially when it involves screening compounds in unrelated diseases.

Roche, which is not an NCATS member, has taken a different approach to repurposing. As a first step, it interviewed researchers company-wide to compile a set of more than 350 compounds. “By putting them all together, we are remaining agnostic about the disease area and are more focused on the fact that they are all high-quality compounds that you could repurpose if you found a good disease association,” Lackey says.

“Many times, early biological investigations trying to understand a disease are mired by the fact that you don’t have good enough quality compounds to do the studies,” Lackey adds. “Using advanced compounds to understand the biology means that you take a lot of questions off the table,” such as those about safety, pharmacology, and bioavailability.

Roche next wants to find external researchers with skills and expertise in disease biology who can propose well-thought-out experiments. These studies must provide “meaningful answers that could link a compound with a patient population,” Lackey says. But rather than trying to match an experiment or target to a single compound beforehand, “we think it is a better approach to run experiments on the whole set,” she adds.

Lackey believes this less-engineered approach could lead to more opportunities. Collaborators will first get the compounds and their molecular weights. If they uncover any interesting findings, more information will be shared. Roche and the partner will then agree to the next steps, which might include publishing results, further experimentation, and a development plan.

“The goal is to actually find products and projects that benefit patients,” Lackey says. They may include rare or orphan diseases where potential partners “would have sophisticated enough disease biology with a patient population in mind and clearly are motivated to find a drug that modulates a particular disease.”

It’s not yet known whether NCATS’s, Roche’s, or even another approach to repurposing is superior, “but I have a feeling that scientific approaches will probably win out over serendipity,” Harrison says. “Programs that have a well-defined patient population and truly understand the disease are going to be more successful than those that don’t,” he says, pointing to Novartis’ Ilaris, which the Food & Drug Administration approved in 2009.

Novartis tried to develop the interleukin- 1β (IL-1β) blocking antibody as a rheumatoid arthritis treatment but stopped in Phase II trials. “A couple of very smart researchers knew that there was a rare disease called Muckle-Wells syndrome in which patients were genetically predisposed to high levels of IL-1β,” Harrison says. Though the patient population was very small, the researchers pushed for clinical trials and saw a rapid and sustained 97% response rate.

“They were able to show great success, and Novartis got approval for a minor indication and now is going after additional indications,” Harrison says. “Sometimes it takes a good researcher understanding the science behind a disease and really pushing forward to get the repurposing to happen.”

While big drug companies repurpose to get their money’s worth from the compounds they discover, nonprofits such as the Center for World Health & Medicine (CWHM) at Saint Louis University are pursuing a different goal. Founded in 2010 by former Pfizer scientists, the group sees repurposing as a way to tackle neglected and rare diseases.

CWHM scientists are using their pharma background and knowledge of advanced drug molecules to go after disease targets, Executive Director Peter G. Ruminski says. “We have worked with pharma to try to have them provide compounds for us to test in our preclinical models.” To access patient populations, CWHM collaborates with academic and disease-focused nonprofit groups.

CWHM scientists were familiar, for example, with cell surface proteins thought to play a role in vaso-occlusion, pain, and organ damage associated with sickle cell disease. They are now looking to repurpose a marketed angioplasty drug that targets these same proteins. Working in cooperation with a major company, they hope to soon start Phase II clinical trials.

Although there are an estimated 7,000 orphan or rare diseases—each of which affects fewer than 200,000 people—only about 350 therapies to treat them are approved. Still, orphan drugs were a $50 billion market in 2011, according to Thomson Reuters. The products can move through approval quickly, bring high prices, and enjoy seven years of market exclusivity by law.

Because of the small patient populations involved, the best way to interest a big pharma company in repurposing one of its compounds for an orphan application is to come bearing good information, Ruminski advises.

“If you present them with something that looks very solid and promising, you might have a potential development partner or they might be willing to share their clinical data package,” he says. For the pharma company, it’s a chance to recoup an investment in a compound. “It is like getting free research if somebody actually stumbles across an alternative indication,” he points out.

CWHM and others repurposing for rare and neglected disease are looking for access to compound databases and libraries or are creating their own. Unlike the very large investigational compound libraries kept and sometimes shared by pharma companies, the newer libraries are focused on approved or advanced clinical compounds. FDA’s Rare Disease Repurposing Database identifies promising approved drugs. And NIH has a pharmaceutical collection that it makes available through the Therapeutics for Rare & Neglected Diseases program.

CWHM is among the nonprofit groups, companies, and universities participating in the consortium called WIPO Re:Search. Through the program, the World Intellectual Property Organization has created a database of available IP assets—including compounds, technology, and regulatory data—to support research on neglected tropical diseases. CWHM has taken advantage of channels and agreements set up by WIPO to talk with a few pharma companies about sharing data, advanced clinical molecules, or even small diverse libraries, Ruminski says.


Separately, Ruminski is trying to get funding to build an international clinical compound repository to house as many compounds as possible in one place. “We are trying to create something that’s a one-stop shop,” he says. Many marketed and clinical drug compounds can be bought from research chemical suppliers. At the same time, CWHM scientists and collaborators in China and South Africa are synthesizing as many as they can.

“We’ll find a way to get them all made, even if it takes several years,” Ruminski says. Last year, he reached out to university chemistry departments in a pilot program. As part of their advanced organic chemistry courses, students at Regis University, in Denver, and Gonzaga University, in Spokane, Wash., helped make compounds. “As soon as we reach a critical mass, we’ll start making compounds available for researchers to screen,” he says.

Another nonprofit that sees promise in repurposing is Cures Within Reach, formerly known as Partnership for Cures. “It’s our belief that drug repurposing is the fastest, safest, most affordable way to solve medical problems, especially in those rare and neglected diseases where the economics of new drug development makes it almost impossible for the for-profit sector,” says Bruce E. Bloom, president and chief scientific officer of CWR.

The Chicago-based nonprofit is supported by companies, foundations, and private individuals. Partners include more than 50 academic and other research institutions at which it funds $1 million to $2 million in research annually. CWR has helped launch seven drug- or device-based “rediscovery research” treatments, has 18 projects in progress, and has 31 new ones ready to start.

CWR focuses primarily on approved compounds because they are already on the market, deemed safe, and plentiful. “It is much easier to do a project where we don’t have to get support from a pharma company than when we do,” Bloom says. “Getting failed compounds from a pharma company has tremendous legal, intellectual, publication, and other complexities built into it.”

With an approved drug as its starting point, CWR can often quickly move into a relatively low-cost pilot human clinical trial to see if a drug might work. “We can buy a drug and test it, and the drug company can’t stop us,” Bloom explains. “We still may need approval from an institutional review board and sometimes from FDA in order to do the repurposing.”

A good example of the projects CWR likes to take on involved finding a therapy for autoimmune lymphoproliferative syndrome. ALPS is an often deadly childhood blood disease in which white blood cells accumulate in the organs and lead to a host of immune and other problems.

Several years ago, the causative gene was identified, which led to an understanding of the pathway involved and pointed directly to a particularly promising drug, Bloom says. CWR provided funding to University of Pennsylvania physician David T. Teachey to create a mouse model of the disease for testing the transplant rejection drug rapamycin. A six-patient trial showed that the drug was very effective against ALPS.

The project took about three years, and CWR spent about $25,000 funding the mouse model and about $135,000 on the clinical trial. “At that point, we published the results,” Bloom says. Armed with this information, doctors can choose to prescribe the drug “off-label”—that is, for a use other than the one for which it was approved. Although drug companies can’t promote off-label use, physicians can legally prescribe drugs this way. They do so at a rate of roughly 20% of all prescriptions in the U.S., according to Bloom.

“Our main focus is to find a drug, raise the money, test the drug in patients, publish the results, and then give physicians the opportunity to figure out how they might use it in their clinical practice,” Bloom explains. “We primarily, but not always, stop at that point, knowing that we have introduced something into the marketplace that has enough scientific credibility that people can make a good decision.”

To find leads for repurposing, CWR relies often on clinical observations, such as side effects or changes in a patient’s condition when taking a drug for another disease. “We spend a fair amount of our time polling the clinicians and scientists we work with,” Bloom says, and searching for anecdotal information in the literature and case reports. The information can be valuable if it is reproducible and consistent from patient to patient, he adds. It also can provide more insight than can be learned in the lab because it comes from actual human experience.

In addition to big pharma and nonprofits, small firms are trying to cash in through repurposing. As for any small drug discovery operation, success depends on attracting investors and partners, says Hermann A. M. Mucke, founder of Vienna-based H.M. Pharma Consultancy.

Some firms offer technology-based services, others develop their own drug pipelines, and still others license-in drugs or clinical candidates from larger firms, Mucke says.

Working in the other direction, some small firms identify ideas and develop projects to license to others, he says. For example, Japan’s Sosei and its British partner Vectura developed an inhaled form of the old antiulcer drug glycopyrronium. Novartis licensed the compound in 2005 and recently got approval in Europe for its use in chronic obstructive pulmonary disease.

In vitro and in vivo screening methods are popular among small firms, as are bioinformatic approaches to identify opportunities. “If they have the structure of a target, they run it against a database of known structures to see if they can find any interaction that has not been described before,” Mucke says. Using information in the public domain, other firms rely on chem­informatics, text analysis, patent landscaping, and other data-mining methods alone or in combination with screening.

“Our strategy is always to go to the patents first,” Mucke says about his own firm’s approach. Patents can provide complete information on a compound’s chemistry and pharmacology but are an underused resource. “You also can immediately exclude what would not work for IP reasons,” he adds. Knowing this avoids wasted effort and allows for a more focused follow-on search of the scientific literature.

Managing IP is an important aspect of the drug repurposing business. Anyone can patent a new use, dosage, or formulation. But the holder of a use patent can still be blocked by a composition-of-matter patent on the compound itself.

One way around this roadblock is to strike a deal with the holder of the composition-of-matter patent, Mucke says. On the other hand, if the patent is set to run out within a few years, a company can use the waiting time to complete clinical development and launch a repurposed product to coincide with the patent expiration.

With patent protection on a new use, the patent holder can then block others, even the originator company, from repositioning its drug for the new indication, Biovista’s Persidis says. Repurposed drugs can “make money to the same degree as a brand-new drug,” he contends.

Repurposing is a way to open new markets for successful drugs or recoup investments in failed ones, Persidis says. “It’s a very powerful growth argument but a defensive strategy as well.” Despite the fact that drug companies may think they know everything about their compounds, he notes, they clearly missed something when “a smart person in a virtual garage operation can figure out that their drug is good in some other disease.”

Novelty of repurposed drugs varies with therapeutic area and biological target pairing.SOURCE: H.M. Pharma Consultancy
This table shows how novel repurposing is depending on the indication and target pairings. KW: drug repurposing~reformulation
Novelty of repurposed drugs varies with therapeutic area and biological target pairing.SOURCE: H.M. Pharma Consultancy

Many firms avoid repurposing generic drugs, even if they can find novel and patentable uses. If the repurposed drug works using available formulations and doses, it will likely compete with low-cost generics prescribed off-label. “You would never be able to commercialize it and make any money,” Numedicus’ Cavalla says. His firm helps academic and pharma collaborators with scientific, legal, and business repurposing strategies.

To see where the potential value lies, the industry divides projects into different classes based on how unique the drug and target interaction is. The class offering the most novelty is off-target pharmacology—finding a new target in a new disease with an old drug. “When repurposing is done right, you have maximum separation between the new indication and the original one,” Persidis says.

Novartis’ cancer drug Gleevec is an example, he explains. Although designed to be very specific for its then-known target, later studies found new targets in several diseases. With the right questions, “repurposing can lead you to find unanticipated targets in biology, and it is very, very powerful in this sense,” he says.

A somewhat less novel class, but one still scientifically and clinically important, is on-target repurposing—hitting a known target in a new disease. “Five years ago, we might not have had an assay sensitive enough to pick up expression of a target in new tissue,” Persidis says. Being able to dissect the function of drugs, targets, and diseases with new technologies is why there is “so much excitement these days around repurposing,” he says.


Although excited about repurposing, at least one small company, Melior Discovery, is sticking with older technology to find its drug candidates.

As Chief Executive Officer Andrew G. Reaume notes, the drug industry’s discovery paradigm has shifted in recent years to identifying targets, finding compounds to hit them, and then optimizing leads. Before this, industry relied more on in vivo phenotypic screening, intuition, and serendipity.

But the industry hasn’t gotten any better at predicting valid targets or developing successful candidates, Reaume argues. As its repurposing strategy, the company has moved away from target- or hypothesis-driven methods, which it sees as based on incomplete knowledge about complex biological systems. Instead, he says, “we are using unbiased in vivo pharmacology screening to finding otherwise unpredicted activity.”

“It is not a matter of throwing the science to the wind and saying we don’t really care how it works; we do,” Reaume explains. “It’s just that we are starting with the observations first and then developing hypotheses afterward.” Melior’s phenotypic screening platform incorporates more than 40 in vivo disease models that cover an array of therapeutic areas.

“We work with models that have stood the test of time,” Reaume says. By multiplexing the models, Melior can screen faster with less compound, making the overall process more cost-effective than it would be on a stand-alone basis.

“Most of the new biology we uncover is an on-target effect,” he says, rather than “small-molecule promiscuity,” where one compound affects many different targets. “Accordingly, we tend not to pick our compounds from classes that have been extremely well vetted,” he adds.

Melior works with pharma partners that can provide compounds, maybe 10 to 20 at a time, with extensive clinical information. Working through databases and other publicly available information, the firm also identifies clinically tested compounds that weren’t abandoned for safety reasons and aren’t protected by composition-of-matter patents.

Melior’s screening approach is expensive, Reaume acknowledges, but it’s warranted because the company is working with high-value compounds. “We are not screening thousands of compounds in chemical libraries but rather compounds that have been in Phase II or III trials with tens of millions of dollars invested in them and, accordingly, we use very high quality, more expensive, and lower throughput screening models.”

Regardless of the specific approach, starting from already studied drugs may prove to have benefits in both the for-profit and nonprofit worlds. Being able to develop drugs faster and at less cost could have an economic impact and also deliver new medicines for unmet medical needs.

Repurposing is not risk-free, Mucke cautions. Although compounds poised for repurposing may have more favorable druglike properties, and the risk of safety may be lower than for untested ones, they must still be shown to work. And despite the industry’s best efforts, drug candidates—repurposed or not—have the potential to fail in late-stage clinical trials and even after reaching the market.

Still, Mucke sees a huge potential to make good use of what drug researchers have already discovered and are not exploiting. “There are hundreds of possibilities still open where we don’t need to construct, design, identify, or screen anything new,” he says. “We just need to go into our chemical libraries, our papers, and our patents and see what is hanging around.”


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