By Suzanne Elvidge
Drug development is a long, complex, costly, and high-risk business. According to the Tufts Center for the Study of Drug Development, drug development from discovery to U.S. approval takes about 15 years on average and costs over $1 billion, and only 3 in 10 drugs on average make enough revenue to sustain R&D.
“A number of studies have shown that in the last 10 to 15 years, while R&D spending has steadily increased, the number of drugs making it to the market has not followed pace,” says Andreas Persidis, Ph.D., CEO, Biovista. Biovista is a business intelligence products and services company that has developed a technology platform to use existing knowledge to support systematic discovery, which has applications in drug repositioning.
Because of the decline in drug launches, drug development companies are under increasing pressure to reduce costs and shorten development timelines through a range of different approaches, including improving processes and protocols, moving more toward collaboration, and licensing and drug repositioning.
AN INTRODUCTION TO DRUG REPOSITIONING
Drug repositioning, also known as drug repurposing, drug reprofiling, or therapeutic switching, is the process of developing existing molecules for new indications. Candidates for repositioning fall into four key groups, explains David Cavalla, Ph.D., founder of Numedicus. “These include marketed drugs that are still under patent or patents that have expired, drugs that have moved through development and fallen at clinical or regulatory hurdles, and stereoisomers or metabolites of existing compounds. Another approach is to make a small change in the molecular structure — this provides stronger patent protection but still reduces the risk of failure.” Cavalla founded Numedicus in 2008 to provide collaborative services to companies seeking novel uses for existing drugs.
THE OPPORTUNITIES FOR DRUG REPOSITIONING
Drug repositioning is a growing field, with many companies looking to exploit its potential. “Generic companies are aware that as pharma pipelines decline, there will be a fall in the number of molecules coming off patent, so they are using drug repositioning to create new markets. Pharmaceutical companies are using drug repositioning to extend the life cycles of marketed products, creating new patents and defending themselves against generic competition, and to salvage the investment in failed or failing drug candidates. Finally, entrepreneurs are creating new drug repositioning companies to provide a service,” says Ken Phelps, president and CEO, Camargo Pharmaceutical Services. Phelps founded Camargo in 2003 as a strategic partner in drug development, including drug repositioning.
“Many older drugs and drug candidates in development have never been fully explored. These can be looked on as resources, as they already have stores of valuable preclinical and clinical data on toxicity, safety, and dosing,” says Steven Flostrand, MBA, business development director, Marco Polo Pharmaceuticals. “From a commercial perspective, with the era of ‘easy’ discoveries seemingly over, it makes sense to revisit existing drugs to ensure that we are making the best possible use of them.” Marco Polo Pharmaceuticals, founded in 2008, specializes in geographic repositioning — developing existing drugs for new markets.
THE DRUG REPOSITIONING PROCESS
The first step in the process is to carry out a thorough market assessment and identify market needs. This should also include a prediction of the market needs by the time of launch and a review of the patent position and potential IP issues. “Just because there is a potential new use for a drug does not mean it will be a commercial proposition,” says Cavalla.
Once the analysis has confirmed a potential market, the company needs to select the product target based on a number of specific criteria, including therapeutic area and financial measures, such as ROI, time to profit, and investment requirements.
The next step is to select the development candidate. Drug repositioning candidate discovery can be serendipitous, based on interesting but “off topic” responses to drugs. Another route is to use drugs that have already received approval elsewhere. “Marco Polo Pharmaceuticals primarily sources patent-expired drugs from other markets, such as Russia, which haven’t been commercialized outside these markets. We then conduct proof-of-concept trials to develop new indications and reinforce the dossier to include studies that are required to register internationally,” says Flostrand. “We focus on the major CNS (central nervous system) diseases: schizophrenia, depression, and epilepsy. Our first clinical trial, for VLB-01, an epilepsy compound originally developed in Russia, started in January 2010.”
Companies such as Biovista use a mechanism-of-action (MoA) comparison approach to identify compounds, targets, and diseases for repositioning development projects. “An advantage to this approach is that it addresses not only the benefit but also the risk profile of a compound. While the toxicity of a repositioning candidate is usually adequately characterized, being able to predict its adverse effect profile is an important capability that can help select the best candidate,” says Persidis.
Companies can also use in-house libraries for in silico, in vitro, or in vivo screening against new or existing targets. “Sistemic’s approach sits between in vitro and in silico screening, providing detailed information about the biological effects of the compound while positioning it against a proprietary range of knowledge bases that classifies the compound according to therapeutic area, drug class, subclass, and even mechanism of action,” says Chris Hillier, Ph.D., CEO, Sistemic.
The technology platform at Sistemic, founded by Hillier in 2008, is based on microRNA profiles and correlates profiles of compounds against its proprietary knowledge base. “The technology is also appropriate for de novo discovery, but the commercial opportunity in drug repositioning was very strong, because it can provide simultaneous data on indication, efficacy, and toxicology. This is a very good option in terms of cost, time, and maximization of asset value,” says Hillier.
After candidate selection, the company needs to collate data from the literature, originators, and the regulatory authorities and use this to formulate a development plan to fill in any gaps in the data. The company presents this at the pre-IND (investigational new drug) meeting, where the authorities provide feedback on any additional studies required. The company can then move through preclinical and clinical development, much as with any other drug in development, and submit for approval.
Repositioned marketed drugs can receive approval from the FDA in the United States through a type of NDA (new drug application) known as the 505[b] application. This can use the FDA’s existing data to reduce the number of trials required and does not require a “right of reference” from the original applicant (repositioned pipeline drugs will use the standard 505[b] route). The EMEA Article 10 of Directive 2001/83/EC is a similar approach in Europe.
Phelps led one of the first 505[b] drug submissions in the mid-1990s. “I saw that this route could provide options both to large pharmaceutical companies struggling with their pipelines and to new players in the drug marketplace.”
THE ADVANTAGES OF DRUG REPOSITIONING
The key advantage of the drug repositioning approach is that it reduces the time, cost, and risk compared with de novo development. As well as providing an advantage to companies, it also provides an advantage to patients, because it reduces the overall cost by rescuing the investment in failed drugs and makes safer and more effective drugs available. “Drug repositioning is a means of obtaining better health outcomes without the massive investments and long time frames associated with traditional drug development. As such, it is both commercially and socially attractive,” says Flostrand.
Recouping existing investments
“Many pharma companies have drug libraries of well-characterized compounds that are gathering dust and losing value as assets, whether it’s through failures in development or a change in therapeutic focus. Repositioning these for a different therapeutic purpose allows the patent clock to be reset and lets the company recoup some of its development costs,” says Hillier.
Saving time and money
Drug repositioning is generally a faster process than de novo development because it can rely on existing data, including efficacy and toxicity studies. “For a company that takes drugs from target discovery to the market, developing an NCE (new chemical entity) can take 10 to 17 years, depending on indication. For a drug repositioning company, the development process from compound identification to launch can be around 3 to 12 years,” says Cavalla.
Persidis adds that de novo development of a single compound to reach a point that it can enter clinical trials typically takes three to four years and will cost around $10 to $20 million. “Generally, of three to five drugs that reach this point, only one will move into phase 2 trials, making a total of $40 to $80 million spent. The cost of identifying a repositioning candidate that already has phase 1 data varies but could be as low as $2 to $3 million and could take just one to two years, which gives two or more years of additional market exclusivity and significantly greater profits.”
The amount of time saved will depend on the amount of data publicly available on the compound, the stage of its development, and the length of trials required for the specific therapeutic target selected, as well as the amount of formulation required, particularly if this involves a change in route of administration. “At a minimum, a strong phase 2 proof-of-concept study can lead directly to phase 3 trials and commercialization in a few years, though in practice there is almost always additional information required, particularly if there is a change in the dosing and administration or if the MOA [mechanism of action] for the new indication is not well characterized,” says Flostrand.
The time taken to develop a repositioned drug also will depend on the indication targeted — developing a drug for a new chronic indication will take longer than for a new acute indication, and both will take longer than simply improving a drug’s efficacy, safety, ease of dosing, or dosing frequency in the original indication.
Drug repositioning is a significantly lower risk than de novo development, certainly from a scientific or clinical perspective. “Because it deals with compounds whose safety profiles are already known, it significantly reduces this risk of drug development,” says Persidis. “We wanted to help people make discoveries at a higher rate and in a more predictable way, rather than just depending on the ‘eureka’ moment, by promoting access to seemingly disparate but ultimately very relevant prior knowledge. Our platform was very well-suited for drug repositioning because it allowed us to look at the drug’s efficacy as well as the unwanted side effects,” Persidis explains.
Phelps adds, “For the improvements to existing marketed drugs, we know what needs to be changed and generally, how to make these improvements. Very few 505[b] projects fail due to a science issue — most are due to money or markets.”
“In classical drug development, everyone is chasing ‘first-in-class,’ which does provide a high reward, but is very high risk. It’s still possible to get a ‘first-in-class’ with drug repositioning, even with an old drug, because it may represent a new mechanism applied to a new indication. Revatio (sildenafil) for pulmonary hypertension is an example of this,” states Cavalla.
THE CHALLENGES IN DRUG REPOSITIONING
There are a number of challenges for companies repositioning drugs, some unique to this process and others common to any form of drug development. In the development of a drug for a completely new indication, drug repositioning cannot avoid the potential risk that the drug will not be effective in late-stage clinical trials, especially if it has not previously moved further forward than preclinical development.
Drug repositioning can be based on marketed drugs that are off patent. This means that the active ingredients are easily available. However, if the dose required is similar to the dose used for an existing indication, physicians may simply choose to use the generic form, which is likely to be cheaper than the newly available, and possibly higher cost, branded repositioned drug. “Because of this, it is important for a repositioned drug to have a difference in presentation. This may be a difference in delivery system or formulation, or a significant difference in dose — for example, Merck & Co launched the 5-alpha reductase inhibitor finasteride as Proscar for benign prostatic hyperplasia and then relaunched it as Propecia, at a significantly reduced dose and under a new patent, for male pattern baldness,” says Cavalla.
Access to data can have an impact on drug repositioning timelines. Companies that are developing a compound that they have not originated will need access to a competitor’s data or will have to rely on public domain data. This dependence on publicly available data can have its pitfalls. “If the company relies wholly on using public databases for their in silico screening, then there is a risk that their discovery may be found simultaneously by others,” says Hillier.
It may be harder for drug repositioning companies to get funding, as some investors have been burned by project failures, and others may be more familiar with traditional drug development and so are unsure how to value repositioning projects, especially as existing financial models don’t work.
PATENTS IN DRUG REPOSITIONING
In order to get a return on investment, companies need to ensure that their repositioned drug will have at least some patent protection. Drug repositioning candidates that are still in development may have composition of matter patents, depending on how far into development they are and how long they have been on hold. Companies developing off patent drugs or drugs with patents close to expiry have to rely on data protection, method of use patents, or patents related to formulation technologies. Manufacturers launching drugs have some protection against generic competition through data exclusivity, which provides 3 to 11 years of data protection after launch, depending on the market.
Thalidomide: A Drug Repositioning Success Story
Thalidomide has a tragic history. In the 1950s and early 1960s physicians used it as a painkiller, tranquilizer, and to treat morning sickness in pregnant women, under the impression that drugs could not cross the placenta into the developing fetus. The drug caused birth defects including malformed limbs, known as phocomelia. The drug affected children in 46 countries, including Germany, the United Kingdom, and the United States.
Following renewed research, thalidomide showed efficacy in leprosy and cancer. Celgene in-licensed the drug in 1992 and received approval for its use as THALOMID in erythema nodosum leprosum in 1998 and multiple myeloma in 2006, though prescribing is very strictly controlled.
Thalidomide also has anti-inflammatory and antiangiogenic effects, and researchers are studying the agent in a wide range of inflammatory diseases and cancers, as well as macular degeneration and tuberculosis.