Drug Repurposing and Repositioning: Workshop Summary (2014)

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Introduction and Themes of the Workshop¹

Drug development can be time-consuming and expensive. Recent estimates suggest that, on average, it takes 10 years and at least $1 billion to bring a drug to market (Paul et al., 2010). Given the time and expense of developing drugs de novo, pharmaceutical companies have become increasingly interested in finding new uses for existing drugs (a process referred to as drug repurposing or repositioning)² (for an overview of this topic, see Barratt and Frail, 2011).

Finding a new use for an existing compound holds many appeals. Typically the safety, efficacy, and toxicity of an existing drug have been extensively studied, and, therefore, data have already been accumulated toward gaining approval by the U.S. Food and Drug Administration (FDA) for a specific indication. Because data have already been acquired, repurposing a drug can save time and money compared with the process of developing a drug de novo; repurposed drugs are generally approved in shorter timeframes (3 to 12 years) and at about 60 percent of the typical development cost (Ashburn and Thor, 2004; Chong and Sullivan, 2007). While approximately 10 percent of new drug applica-

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¹The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, are not necessarily endorsed or verified by the Institute of Medicine, and should not be construed as reflecting any group consensus.

²Drug repurposing is the use of an approved drug or a drug under development for a different indication than that for which it was originally developed. Drug repositioning has recently been used to describe the novel use of a drug that was previously discontinued for development. For the purposes of this workshop summary, drug repurposing and repositioning are used interchangeably.

tions gain market approval, it is estimated that nearly 30 percent of repurposed drugs are approved, which gives companies a significant market-driven incentive for finding ways to repurpose existing drugs (Ashburn and Thor, 2004; Kaiser, 2011).

Historically, drug repurposing has been largely an unintentional, serendipitous process that took place when a drug was found to have an off-target effect or a previously unrecognized on-target effect that could be used for identifying a new indication. Perhaps the most recognizable example of such a successful repositioning effort is sildenafil. Originally developed as an anti-hypertensive, sildenafil, marketed as Viagra^® and under other trade names, has been repurposed for the treatment of erectile dysfunction and pulmonary arterial hypertension. Viagra^® generated more than $2 billion worldwide in 2012 (Pfizer, 2013) and has recently been studied for the treatment of heart failure (Bishu et al., 2011). Another drug, thalidomide, was essentially removed from the market after its connection to serious fetal limb defects was discovered (Kim and Scialli, 2011). However, recent research has shown it to be an effective treatment for leprosy and multiple myeloma (Huang et al., 2011).

These and other success stories have prompted pharmaceutical companies to add repurposing projects to their research portfolios and the National Institutes of Health (NIH) to test an award program for identifying new uses for existing molecules (Thayer, 2012). In addition, technological advances and the increasing availability of genomic data and computational systems have resulted in new methods to systematically identify both drug targets and pathways for linking drugs with secondary—and sometimes seemingly unrelated—indications (Sirota et al., 2011).

Given the widespread interest in drug repurposing, the Roundtable on Translating Genomic-Based Research for Health of the Institute of Medicine (IOM) hosted a workshop on June 24, 2013, in Washington, DC, to assess the current landscape of drug repurposing activities in industry, academia, and government. Stakeholders, including government officials, pharmaceutical company representatives, academic researchers, regulators, funders, and patients, were invited to present their perspectives and to participate in workshop discussions. Box 1-1 lists the goals of the workshop.³ As several of the individual workshop speakers noted, many of the drug repurposing strategies they discussed are broadly applica-

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³The workshop agenda, speaker biographical sketches, full statement of task, and list of registered attendees can be found in Appendixes A–D, respectively.

ble across disciplines, inclusive of, but not specific only to genomics. For example, improving access to compounds and data, encouraging collaborative efforts, dedicating teams to repurposing (as highlighted in Chapter 2) and using high-throughput screening technologies, gaining a better understanding of disease mechanisms, employing collaborative models, and data sharing techniques (discussed in Chapters 3 and 4) were examined as potential strategies to increase the success of drug repurposing efforts. While genomics could be an extremely useful enabler of many of these approaches, these strategies are not specific only to the field of genomics.

WORKSHOP THEMES

The high failure rate of drugs in development and the fact that most drugs have multiple indications are powerful arguments for repurposing and repositioning. Chapter 2 of this workshop summary explores this reasoning within the current state of the science. Industry, academic, and governmental perspectives are presented, with an extended discussion of Marfan syndrome as an example of the ways in which these stakeholder roles overlap during the development process. Though orphan drugs are used by relatively few patients, they can still be profitable for companies and have been a major target of repurposing and repositioning efforts. Barriers to drug repositioning are also discussed, including reluctance to explore alternate indications, the need to update clinical regulatory documents, and considerations relating to the limited patent life of repurposed drugs.

In Chapter 3 the roles of new tools and technologies in drug repurposing are considered; the discussion includes a look at genomics-based technologies that have enabled the identification of new indications for

drugs as well as screening technologies that can generate new ideas about targets and drugs. This chapter also examines the vast new stores of publicly available data that can accelerate the discovery process for repurposing drugs. There is a description of new collaborative models that combine the strengths of pharmaceutical companies, biotechnology companies, academic researchers, venture capitalists, and others. These models call for, among other elements, enhanced coordination and communication to engage patients and clinicians during the drug development process.

Chapter 4 addresses the question of whether the value proposition for companies is sufficient for them to pursue repurposing as a profitable business opportunity. Although returns on research and development (R&D) investments have been declining in the pharmaceutical industry, the investigation of new targets and mechanisms for existing drugs with known safety profiles may add value to the business model and bring more therapies to market for patients. Governmental incentives for drug development are also discussed, but they may not always provide the most attractive business opportunity for pharmaceutical companies. Finally, the drug development process is considered, with a particular focus on the idea that disease indications need to be re-evaluated throughout the discovery, development, and life-cycle management of a compound.

Chapter 5 presents research and policy initiatives that have been undertaken to encourage repurposing activities; such initiatives often take the form of partnerships involving academic researchers, companies, and government agencies. The strategy of crowdsourcing candidate compounds for repurposing is discussed in the context of how it can generate ideas about new mechanisms of action and potential applications. The release of information about potential compounds for repurposing is emphasized in a discussion about the goal of striking a balance between confidentiality and providing sufficient information to attract the best research proposals. Finally there is a discussion of how a trusted intermediary often participates to spur collaboration and to provide the infrastructure needed for institutions to work together.

In Chapter 6 the role that genomics plays in drug repurposing is considered, along with other potential research tools such as the electronic medical record (EMR). Barriers to drug repurposing are discussed, including the sharing of drug data, return on investments, and intellectual property concerns. This last chapter also outlines the potential roles that academia, industry, government, regulators, and patient advocacy groups can play in improving repurposing collaboration. Individual workshop

speakers and many participants who spoke stated that drug repurposing has the potential to change the lives of patients by providing another path for drug development.

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