Drug Repurposing and Repositioning: Making New Out of Old

Given the high cost of new drug development, pharmaceutical companies, researchers, and other organizations are looking for innovative ways to reduce time and costs. Drug repurposing and repositioning hold some answers.

Companies, such as Sanofi and Astellas Pharma, have recently announced external partnerships and increased internal focus on drug repurposing and repositioning. Drug repurposing refers to studying drugs that are already approved to treat one disease or condition to see if they are safe and effective for treating other diseases. Drug repositioning refers to taking a pharma pipeline compound already shown to be safe for human use and finding new indications that can be studied to expand a compound's value. Industry estimates place the market for repurposed drugs at $24.4 billion in 2015 with projections that it could reach $31.3 billion in 2020. So how are pharmaceutical companies, researchers, and other organizations responding? DCAT Value Chain Insights (VCI) examines recent developments.

Drug repurposing/repositioning: making the old new
Drug repurposing generally refers to studying a drug already approved to treat one disease or condition to see if they are safe and effective for treating other diseases, according to The National Center for Advancing Translational Sciences, part of the National Institutes of Health (NIH), US Department of Health and Human Services. Repositioning refers to studying a drug-like compound already tested safe for human use, Both repurposing and repositioning can be used to reduce the costs and time in developing drugs since information is available on their pharmacology, formulation, and potential toxicity, thereby allowing new candidate therapies to be ready for clinical trials more quickly, speeding their review by the US Food and Drug Administration (FDA) and, gaining possible approval.

The need to come up with cost-effective solutions to bring new drugs to market is underscored by recent estimates for drug development. An analysis issued by the Tufts Center for the Study of Drug Development earlier this year estimates that the average cost to develop and gain marketing approval for a new drug is $2.558 billion. The $2.558 billion figure per approved compound is based on estimated average out-of-pocket costs of $1.395 billion and time costs (expected returns that investors forego while a drug is in development) of $1.163 billion. The analysis was based, in part, on information provided by 10 pharmaceutical companies on 106 randomly selected drugs that were first tested in human subjects globally from 1995 to 2007.

Given the high cost of drug development, repurposing and repositioning drugs offers the potential benefit of saving time and money. A 2013 workshop, Drug Repurposing and Repositioning, held by the Roundtable on Translating Genomic-Based Research for Health, Board on Health Sciences Policy, Institute of Medicine, offered some promising statistics. It is estimated that repurposed drugs generally are approved in much shorter timelines (3-12 years) and at about 60% of the cost of typical development. While approximately 10% of new drug applications gain market approval, repurposed drugs approach approval rates near 30%.

There are several well-known examples of repurposed and repositioned drugs. The first is sildenafil, the active ingredient in Pfizer's Viagra, a drug approved to treat erectile dysfunction (ED). This compound originally failed in development for hypertension, but during clinical studies the ED “side effect” was noted and developed. Viagra was further repurposed by Pfizer, under a different dosing schedule, as Revatio for use in pulmonary arterial hypertension. Another example, is thalidomide, which was originally developed to treat morning sickness in pregnant women in the 1950s and was later withdrawn due to causing birth defects. Thalidomide is a chiral drug and was developed as a racemic mixture. It was later found that one enantiomer (the (R)-(+)-enantiomer) was effective against morning sickness and the other entantiomer (the (S)-(-)-enantiomer) caused teratogenic effects (1). Thalidomide was later successfully developed by Celgene into a drug to treat leprosy and multiple myeloma. Thalidomide was approved by the FDA in 1998 to treat leprosy and in 2006 to treat multiple myeloma.

Inside the market
Drug repurposing and repositioning offers commercial benefits. The global market for drug repurposing reached nearly $24.4 billion in 2015 and could reach $31.3 billion in 2020, reflecting a five-year compound annual growth rate (CAGR) of 5.1%, according to a recent analysis by BCC Research, a Wellesley, Massachusetts-based market research firm. The US, which dominated the market, totaled about $13.7 billion in 2015 and is forecast to reach nearly $17.9 billion by 2020, demonstrating a five-year CAGR of 5.4%. The non-U.S. market is expected to increase to nearly $13.4 billion by 2020 from $ 10.6 billion in 2015, with a CAGR of 4.7%.

“The current environment for drug development is putting increased pressure on manufacturers to find innovative ways to supplement the development of new molecular entities,” says BCC Research analyst Shalini S. Dewan, in commenting on the study. “Drug repositioning has accounted for approximately 30% of the newly approved drugs by the FDA in recent years. Advances in the methods available for drug repurposing will also impact the growth of the repurposed drug market. With new technologies like in silico drug repositioning, the development of repurposed drugs can take place faster and more cost efficiently than typical drug discovery and development.”

Several large pharmaceutical companies have recently announced external partnerships specifically for drug repurposing. Earlier this year, Sanofi, through its specialty care subsidiary, Sanofi Genzyme, formed a research agreement with Recursion Pharmaceuticals, a Salt Lake City, Utah-based biotechnology company, for use of Recursion's drug-repurposing platform to identify new uses for Sanofi's clinical-stage molecules across dozens of genetic diseases. Recursion generates human cellular models of many diseases and uses computer vision to extract thousands of morphological measures at the level of individual cells. Molecules are then screened for their ability to rescue phenotypic defects associated with each disease. Recursion has already used the platform to generate an internal pipeline of candidates for a handful of genetic diseases, with a lead asset nearing an investigational new drug application for the treatment of cerebral cavernous malformation.

In June 2016, Astellas Pharma, which in 2015 formed an internal unit focusing on drug repurposing, formed a strategic collaboration with Excelra, an Indian informatics company. The collaboration is focused on identifying novel therapeutic indications for a number of undisclosed Astellas' shelved pharma assets. Under the deal, Astellas will have access to Excelra's proprietary drug repurposing platform (GRIP), which is a combination of a proprietary repurposing database, repurposing algorithms, analytics tools, and a visualization engine. The collaboration is focusing on identifying mechanism of actions using drug-disease-target relationships to identify alternative indications for existing assets.

The drug repurposing pact with Excelra was the third drug repurposing pact announced by Astellas since December 2015. In December 2015, Astellas formed a pact with Biovista, a privately held biotechnology company based in Charlottesville, Virginia, which finds novel uses for existing drugs. The collaboration is focused on identifying new indications for a number of undisclosed Astellas compounds using Biovista’s Clinical Outcome Search Space technology. In January 2016, Astellas formed a research collaboration with NuMedii, a Palo Alto, California-based informatics company formed from the research laboratory of Stanford University professor, Atul Butte, to identify new indications for a number of undisclosed Astellas compounds using NuMedii's technology. These collaborations followed recent restructuring by Astellas in 2015, which included establishing a new Drug Repurposing & Application Management unit to upgrade its activities in this area, which had previously been addressed by individual units within the company's Drug Discovery Research organization at the level of therapeutic areas or functions.

Other companies are forming external partnerships in drug repurposing. Allergan formed a pact with NuMedii in September 2015 for the discovery of new treatments for psoriasis. Under the terms of the agreement governing the research alliance, NuMedii will provide Allergan with proprietary, de-risked therapeutic candidates for psoriasis that are compatible with the 505b2 drug development regulatory pathway. NuMedii and Allergan may select and evaluate lead candidates in proof-of-concept disease models for potential further development. The 505(b)(2) new drug application pathway was created by the Hatch-Waxman Amendments of 1984, with 505(b)(2) referring to a section of the Federal Food, Drug, and Cosmetic Act. An 505(b)(2) NDA contains full safety and effectiveness reports but allows at least some of the information required for NDA approval, such as safety and efficacy information on the active ingredient, to come from studies not conducted by or for the NDA applicant.

Market drivers and challenges
So what are the opportunities and challenges in the drug repurposing and repositioning market? There are several factors driving growth, according to the BCC analysis. The increased worldwide incidence of cardiovascular and autoimmune diseases and central nervous system disorders has increased demand of repurposed drugs, a trend that should continue over the forecast period. Other key drivers include advancements in technologies, including computational tools such as bioinformatics, chemoinformatics, network biology and system biology. An increase in chronic diseases, a rapidly growing elderly population, and rising healthcare costs are driving the market, as well.

Factors restricting the market include dependence on the public data for the chemical structure and other information about the drug molecule, a lack of funding opportunities and the lack of trained professionals. Because drug repurposing is a relatively new approach, many small-scale manufacturers may be unfamiliar with the regulatory requirements involved in the repurposing of drugs, according to the BCC analysis. However, with new technologies, such as in silico drug repositioning, the development of repurposed drugs can take place faster and more cost-efficiently. In silico drug repositioning uses public databases and bioinformatics tools to identify interaction networks between drug and protein targets.

Finding solutions
One organization seeking to facilitate researchers engaged in generic and proprietary drug repurposing is Cures Within Reach, a Chicago-based non-profit organization founded in 2005 from the private foundation, Goldman Philanthropic Partnerships, with the name Partnership for Cures. Cures Within Reach changed its name in 2012 to highlight that many “new” repurposed treatments are potentially only one proof-of-efficacy clinical study away from off-label use and/or further clinical development toward commercialization for the new indication. The organization now has 80 partners from philanthropy, academia, patient advocacy, and the pharmaceutical and biotechnology industry. Cures Within Reach has raised funds for and overseen more than 50 drug repurposing research projects that have created 12 repurposed therapies that are either being used off-label by physicians and patients or are undergoing larger confirmatory clinical trials toward commercialization. In 2015, the organization launched CureAccelerator, an interactive online platform for repurposing research. The platform was built with a grant from the Robert Wood Johnson Foundation and is used to connect researchers, funders, clinicians, the biomedical industry, and patient groups.

Drug repurposing proof-of-efficacy research is the focus of Cures Within Reach. The research supported by Cures Within Reach must target an unsolved disease, repurpose at least one human approved medical asset, have the potential to improve patient lives in three to five years, cost less than $250,000, and be published in a peer-reviewed journal. Cures Within Reach focuses on three main areas related to repurposing, explains Amy Conn, Director of Advancement, Cures Within Reach. Its main focus is to launch proof-of-efficacy studies of approved drugs or devices to support off-label use and/or clinical development in a new disease indication. A second focus is to create infrastructure and incentives to bring funders, researchers, clinicians, industry, patients, and others together to generate more repurposing, and the third is to create new economic engines to bring more funding to generic and proprietary drug repurposing.

Such efforts can focus on various ways in which an older drug may be “repurposed,” explains Ms. Conn. For example, the repurposing may combine an older drug or a combination of older drugs with a newer drug to increase the newer drug's effectiveness. The repurposing may combine a drug with a non-drug treatment option, such as radiation, to make the non-drug treatment work better, or combine a non-drug treatment option with an available drug to make the drug work better. The repurposing can test combinations of available drugs that are not currently prescribed together, but are already used in a specific disease, to see if the combination works better in that disease. The repurposing might also change drug dosage, formulation, or method of administration for existing drugs, which would improve outcomes by improving disease management, increasing patient adherence, or reducing side effects.

There are government programs assisting industry and non-profits, such as Cures Within Reach, with drug repurposing. The NIH's National Center for Advancing Translational Sciences is one government source of funding for drug repurposing. It anticipates allocating $4.3 million in fiscal year 2016 for pre-clinical research projects that are based on repurposing existing drugs or biologics. Its aim is to issue 10 to 15 awards in support of studies that establish the rationale for a clinical trial. Pre-clinical studies funded through this initiative will serve as “use cases” to demonstrate the utility of an independent crowdsourcing effort or of a computational algorithm to predict new therapeutic uses of an existing drug or biologic. The goal of an individual project must be to explore the potential new use of an existing investigational therapeutic or one already approved by FDA to treat another disease.

1. I. Agranat, H. Caner, J. Caldwell, “The Thalidomide Tragedy: The Myth of a Missed Opportunity,” Nature Reviews Drug Discovery 1, 753-768 (2002).

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