Repurposing Challenges: Conceptualization of a Research Agenda

Christopher P. Austin
National Center for Advancing Translational Sciences
National Institutes of Health

epurposing,” or finding a new therapeutic use for a drug other than the indication for which it was originally intended or used, is a tantalizingly simple concept. The pleiotropic nature of drug targets dictates that most drugs will have effects on more than one pathway, cell type, organ, or disease. And the evolutionary gene family organization of the human genome means that most drugs will have effects on multiple structurally related targets.

While this pleiotropy and polypharmacology can lead to undesired adverse clinical events, it can also lead to unanticipated clinical benefits for diseases other than the one it was initially intended to treat. The history of medicine—and particularly my own specialty of neuropsychiatry—is replete with examples of drugs developed for one indication being found to be useful for another. And the advent of collections of approved drugs amenable to facile screening against cellular or model organism-based models of human diseases have spawned in the last decade thousands of reported novel activities for drugs already in clinical use. Such drugs often already have an extensive safety profile and thus offer a much more rapid development course, leapfrogging years of optimization, toxicity testing, and chemistry, manufacturing, and controls (CMC).

The clinical need for repurposed drugs is also enormous. Of the approximately 7,000 diseases that affect humans, only about 5 percent have any regulatorily approved treatment, and at the current rate of new indication approvals about 2,000 years will pass before every human disease has a treatment. This raises an important public health question about repurposing: What percentage of currently untreatable diseases could be ameliorated by a drug in the current pharmacopeia? The answer to that question would have a profound impact not only on health but also on the number of disorders that would require a new molecular entity (NME) to be developed to treat them—a much longer and more expensive process than repurposing.

So why, in light of these positive genomic, biological, regulatory, and medical factors, have so few of the drugs identified as potential repurposing candidates found their way into routine clinical use? This is a question my colleagues and I at NCATS have been working on since our Center’s founding eight years ago, and we have taken a variety of approaches to it.

Perhaps the most well-known is our “New Therapeutic Uses” program, which is a collaboration with pharmaceutical companies to find new indications for investigational compounds that had been shown to be safe in humans but did not have efficacy for the original indication, or were not pursued for business reasons. Importantly, those compounds often still have patent protection, so there is a potential commercial route to development if a new therapeutic use is found. This approach is sometimes referred to as “rational repurposing,” because it is based on matching a compound’s target or mechanism-of-action with knowledge of targets implicated in a disease. While this program has been remarkably successful at creating partnerships and performing preclinical and clinical trials of investigational assets, to our knowledge none of the repurposing projects to date has led to a new drug or indication approval.

Complementing this rational, or opportunistic, approach is the NCATS Pharmaceutical Collection (NPC), a comprehensive virtual and physical library of every small molecule compound ever approved for human use in major markets worldwide, the majority of which no longer have patent protection, i.e., are “off-patent.” Our hope in creating the NPC was to “systematize serendipity,” allowing identification of potential repurposing opportunities without prior knowledge of the target being acted on (which may be different from the known target of the drug) or the pathophysiology of the disease. The NPC has now been screened in over 200 different disease assays in collaboration with disease experts around the world, with results deposited in a public database, PubChem. While these projects identify interesting and potentially useful compounds, none has progressed all the way to regulatory approval and/or routine clinical use. Though some of this lack of clinical translation simply reflects the time since the screen was performed, analysis of the results of the first 10 years of the NPC demonstrates that most compounds failed to progress beyond reports of initial screening results, animal model testing, or (in a few cases) early stage clinical trials.

Our hypothesis when starting these two programs was that the reason more repurposed drugs were not reaching clinical use was primarily scientific, and therefore the solution was to generate more data. It is now clear that that hypothesis was incorrect, or at best incomplete.

A foundational lexical problem is that repurposing is used to describe at least four different scenarios with different roadblocks that require different solutions:

  1. Experimental assets (of any modality) that have never been approved for human use due to development discontinuation for efficacy, toxicity, or business reasons, but which have remaining patent life.
  2. Therapeutics that are currently approved for one or more indications but have potential uses in others and have remaining patent life protecting their use.
  3. Assets that have exhausted their patent protection but are not currently marketed because they were either never approved or were withdrawn.
  4. Therapeutics that are off-patent but currently manufactured by generic companies, approved for certain indications, and available by prescription from healthcare providers.

While repurposing each of these categories of therapeutics presents its own challenges, experience has demonstrated that the most numerous opportunities, and the most numerous difficulties, lie in the fourth group, the off-patent drugs. Given the time limitation of patent protection, most of the drugs ever approved for human use are past their exclusivity period. A rough estimate is that about 80 percent of currently available pharmaceuticals are off-patent for at least one indication in one major market. A definitive percentage is difficult to obtain, given variations in patent protection for various formulations and indications in different markets. (Note the use of the term “off-patent” here rather than “generic;” the terms are often used interchangeably but the latter has specific regulatory meaning. The correct appellation is “off-patent.”) The market price of most of these therapeutics is quite low, making them attractive from a cost-containment point of view.

Repurposing Drugs: Four Scenarios Requiring Different Solutions
Therapeutic assets (of any modality) with remaining patent life but never approved for human use
Therapeutics with remaining patent life that are currently approved for one or more indication(s) but have potential use in others
Therapeutic assets with no patent life that are not currently marketed because they were either never approved or were withdrawn
Therapeutics with no patent life currently manufactured by generic companies, approved for certain indications, and available by prescription from healthcare providers

This brings us back to our original question: What percentage of currently untreatable diseases could be ameliorated by a drug in the current pharmacopeia? And why has there been so little successful off-patent repurposing? Given that most indications/diseases currently have no approved treatment, virtually all drugs likely have applications to disease indications other than those for which they are currently labelled, and those treatments would be inexpensive and immediately available if identified and utilized.

After screening in cells and testing in animal models, off-patent drug repurposing faces a litany of roadblocks to clinical utilization, including disease- and population-specific toxicology; GMP-compliant manufacturing of active pharmaceutical ingredients (API) and finished dosage forms for clinical studies; availability and adequacy of a Drug Master File or equivalent; funding for testing therapeutic hypotheses in humans; funding for clinical trials to satisfy regulatory, payor, and physician evidentiary requirements; and drug availability of low-margin, off-patent drugs. Solving one of these problems in isolation will not solve the overall problem. Clearly, a holistic, system-wide approach is needed.

Roadblocks to Repurposing Therapeutics
Evaluating preclinical efficacy in new indication
Evaluating disease and population-specific toxicology
GMP-compliant manufacturing (APIs and dosage forms for clinical studies)
Availability/adequacy of a Drug Master File or equivalent
Funding for clinical trials testing therapeutic hypotheses
Funding for clinical trials to satisfy regulatory, payor, and physician evidentiary requirements
Cost/benefit of development

As a start to exploring these questions and developing a research agenda to address them, NCATS and its Cures Acceleration Network Review Board (CANRB) partnered with the FDA and the Reagan-Udall Foundation to hold a two-day workshop in Bethesda, Maryland on December 5-6, 2019, entitled “Repurposing Off-Patent Drugs: Research and Regulatory Challenges.” Over 300 attendees from various communities attended, including the basic, translational, clinical, patient, data science, economist, drug owner, funder, investor, regulatory, legal, manufacturing, and payor communities. A meeting report that describes the discussion and suggested actions is currently being developed. It was clear that the off-patent repurposing dilemma typifies the kind of “tragedy of the commons” problem that aligns with NCATS’ mission of solving system-wide, translational scientific and operational problems that span across diseases, disciplines, and sectors.

In order to break the logjam of repurposing, NCATS will need to consider a much broader research agenda than it has to date. Attendees were enthusiastic and cautiously optimistic that with a stepwise, data-driven, multi-sector, coordinated, and experimental but bold approach, the promise of off-patent repurposing for patient and public health can at last be realized.