Industry Voices: What's Old Is New Again--A Prescription for Drug Repurposing

By Joe Cornicelli, Fraser McIntosh and Erik Rocheford, Discovery Research Services, Charles River

Joe Cornicelli

Only one in 10,000 compounds under active investigation makes it to market, and less than 20% of drugs entering Phase II clinical trials succeed. Moreover, drugs have an average development timeline of 10 years and cost at least $1 billion each to produce. What if there were a way to repurpose drugs, either those on the market or those abandoned along the way, saving the otherwise wasted time and money?

Last week, the Institute of Medicine released a 118-page report on drug repurposing, noting that many pharmaceutical companies are salvaging failed compounds and seeing whether these drugs might have other indications, particularly after an "increasing number of previously shelved compounds" have been repurposed. The report also cited the NIH's New Therapeutic Uses award program as another encouraging sign for this field.

There are a number of approaches to drug repurposing, but these are ultimately an expedition into uncharted territory. Scientists have to justify examining a compound in a different disease state, so they often make a hypothesis based on possible associations between mechanisms. At the end of the day, making associations is often a stretch and, even when hypotheses are accurate, scientists still need to test them in vivo. Phenotypic screening, however, just might be able to engineer the serendipity that drug repurposing needs.

Fraser McIntosh

Phenotypic screening involves testing agents of interest directly in relevant animal models across a number of therapeutic areas. This screening method has potential to discover new biology and could make the process of drug development more efficient by shortening development timelines. With the appropriate choice of animal models, it's possible to determine whether a candidate has efficacy in another disease state and ultimately to accelerate clinical development.

While all other approaches rely on testing the candidate compound in systems where the target for the candidate is known and its mechanism is established, in vivo phenotypic screening is target- and disease-agnostic. In other words, it's unbiased. At once, it can assess activity in a pathway or disease-relevant model with all the complexities of working in the whole organism. 

Relevant animal models are key because they account for all of the complexities of demonstrating efficacy in an intact organism. Variables such as absorption, distribution, metabolism and delivery of the test article to the relevant target all have to be overcome to show activity. 

Erik Rocheford

Some of the best indicators of drug repurposing's power come from studies on diabetes and inflammation. For example, salsalate, a drug used to treat inflammation associated with rheumatic conditions, has shown promising success for Type 2 diabetes patients. The standards of care for Type 2 diabetes consistently attacked obvious targets of the disease for years until salsalate challenged the status quo. This anti-inflammatory drug has already shown efficacy in improving markers of glycemic control in Type 2 diabetic patients.

But not every class of drugs lends itself easily to phenotypic screening at first. Cancer compounds, for example, might require a more measured approach because scientists have to consider a number of different diseases lumped under the moniker of oncology. But many other disease areas are ripe for this tactical approach. And there is already ample evidence that phenotypic screening will yield new indications. If we look at the off-label uses of currently approved medications as an indication of the chance for success, then our odds look promising considering that about 20% of all drugs are prescribed for indications other than the approved indication or indications. For cardiovascular medications and anticonvulsants, the estimate for alternative use is about 80%!

Phenotypic screening could make the process of drug development more efficient by shortening development timelines. The possibilities are endless, and animal models are elevating drug repurposing's potential. Look around. Think differently. What's old may be new again.


Joe Cornicelli, Ph.D., F.A.H.A., is the director of inflammation and cardiovascular pharmacology services for Charles River and has over 22 years of experience in drug discovery and development. In 2007, Dr. Cornicelli joined Discovery Research Services at Charles River, where he is responsible for directing discovery efforts for the assessment of potential therapeutics for inflammatory and cardiovascular disorders. Dr. Cornicelli is a Fellow of the American Heart Association.

Fraser McIntosh, B.Sc., is the director of discovery services at CRL in Montreal and has over 23 years of experience in drug discovery and development across different disease areas. Prior to working at Charles River, Fraser led teams at AstraZeneca responsible for developing novel respiratory and inflammation therapeutics, then moved to Canada in 2006 to lead AstraZeneca's in vivo pharmacology pain division.

Erik Rocheford, M.S., is a study director in discovery research services and has over 9 years of experience in drug discovery and development. He oversees all aspects of in vivo studies and provides guidance on study design, data interpretation, and troubleshooting for academic, biotech and industry clients. Prior to joining Charles River in 2012, his focus at Novartis Institute for BioMedical Research was in Type 2 diabetes, obesity and metabolic disease states, with specific training in in vivo animal models focusing on lipid synthesis and oxidation, insulin resistance, obesity, and the kinetics of dietary carbohydrate and lipid intermediates.