Finding new uses for approved drugs continues to produce important therapeutics, particularly for disorders where no animal model, physiologic abnormality, biochemical pathway, or molecular target has been identified. Repurposing allows human investigation early in the process of drug discovery. In addition to providing new treatments, repurposing can be an important tool in dissecting complex disorders, discovering molecular targets, and unraveling disease processes. In recent years, an increasing number of pharmaceutical development programs have been focusing on the development of new therapeutics based on existing agents, so a brief overview of this endeavor, along with some classic and recent examples, seems timely.
The illusion that molecular target-based drug design would yield a vast treasure of new drugs for central nervous system (CNS) disorders, cardiovascular disease (CVD), metabolic disorders, and cancer was shattered by the realization that the human genome encodes fewer than 30,000 proteins. The low number of druggable targets was only the beginning of the problem. Each protein has to perform diverse functions in different cells and at different stages of development, so agents that are potent and specific can still have off-target effects on nonaffected organs or on developing or replenishing tissues. In practice, certain drugs that affect more than one target at different potencies can be more effective or better tolerated than highly potent and specifically targeted agents. Repurposing drugs often starts with the premise of therapeutic effect and tolerability, so the dissection of mechanism is typically backfilled after critical path activities like formulation and dose-finding.
New markets for repurposed drugs could be the key to research and development productivity while existing products lose patent protection, and managed care and government payors have stopped reimbursing for new premium brands that are only “me-too” products or control-release drugs that only improve compliance. Depending on the amount of existing human exposure data, repurposing an existing drug has the potential to eliminate or reduce preclinical testing and early clinical trials, and cut some of the estimated 10–15 years, and the more than $1 billion it takes to bring a new chemical entity to market. Repurposing also reduces the risk of late-stage product failure from unexpected toxicity. Repurposing is breathing new confidence into an industry whose research managers have been trained to fail fast.
Repurposing drugs is particularly important in the treatment of CNS disorders, CVD, metabolic disorders, and cancer. Pathological processes in these conditions are carried out by proteins and processes that differ from their normal counterparts only in a subtle way such as the level or pattern of expression. Sometimes these subtleties are only discovered by anecdotal observations of patients or patients reporting unexpected therapeutic benefits, and the repurposing activity depends on improving the formulation or optimizing a treatment regimen. In contrast, molecular target-based screening and rational drug design remain the standard for targeting infectious agents (i.e., HIV and HCV) because the pathogen’s targets are either unique or sufficiently different from their human homologues so as to increase the likelihood of developing specific inhibitors.
Reflecting the appeal of drug repurposing, 2012 witnessed several conferences for researchers, including the 2nd Annual Drug Repositioning & Indications Discovery Conference in San Francisco in October, and the World Drug Repositioning Congress in Washington, D.C. in December. A few years ago, no such conferences existed. Additionally, initiatives related to drug repurposing are growing. For example, in spring 2012, eight major drug firms joined the National Center for Advancing Translational Sciences (a division of NIH) to create the Discovering New Therapeutic Uses for Existing Molecules program.
Many drug repurposing projects are supported by the FDA’s intention to encourage innovation without creating duplicate work under the 505(b)(2) provision. Filing a New Drug Application (NDA) under the 505(b)(2) provision allows a sponsor to rely, in part, on FDA’s earlier findings of safety and/or effectiveness for the previously approved drug, therefore simplifying the drug development pathway, allowing for a less expensive development program and faster access to market.