How repositioned drugs can turn failure into success

Only one out of 10 drugs that enter clinical trials make it to market. If car manufacturers only produced one out of 10 cars that entered the assembly line, one would not predict good things for that industry. Pharmaceutical development is its own beast, of course, but we can try to reduce waste by finding new uses for drugs that fail initial clinical trials.

Drug repositioning is the novel use of an existing drug for a different therapeutic indication from which it was originally intended. This approach capitalizes on the fact that approved drugs and many abandoned compounds have already been tested in humans and detailed information is available on their pharmacology, formulation, dose, and potential toxicity. Drug repositioning is supported by the fact that common molecular pathways contribute to many different diseases. For example, pathways involved with diabetes are also altered in Alzheimer’s disease (AD), and various diabetes drugs are now being tested for AD.

A repositioning strategy has many advantages over traditional de novo drug discovery approaches. Repositioned drugs cost less to develop, since the compound has already been extensively researched. Many repositioned compounds have also already demonstrated safety in humans, negating the need for phase I clinical trials.

In many cases the new therapeutic use of a repositioned drug was identified through serendipity, often as a side effect while investigating the hypothesized disease indication. Numerous drugs that have been repositioned, particularly in the neurology field, were done so as a result of a serendipitous observation. For example amantadine, which was intended to treat influenza, was observed to have beneficial effects for a Parkinson’s disease patient. The drug is now solely prescribed for Parkinson’s disease in the United States. Probably the most famous case of drug repositioning is the development of the drug sildenafil, or Viagra®. Originally tested clinically for hypertension, the drug was repositioned for erectile dysfunction upon observation of a certain side effect in clinical trials.  Other examples include:

  • Eflornithine: initially developed to treat cancer, it was later found to be effective against trypanosomiasis (sleeping sickness) and against growth of unwanted facial hair!
  • Rituximab: Primarily developed to treat blood cancers, it was repositioned as a blockbuster drug for rheumatoid arthritis and other autoimmune disorders.
  • Bupropion: For years it was prescribed for depression, but later it was discovered to work in smoking cessation.

Serendipity has been a reliable, albeit unpredictable method of identifying useful drug effects. Typically, drug repositioning approaches attempt to capture some aspect of serendipity, but within a systematic process for drug identification and development.

Drug repositioning approaches can take many forms, from computational to in vitro, cell-based, or in vivo screening systems. New data-driven approaches utilize multiple databases (chemical, pharmacological, medical, genetic) to find gene-disease or drug-disease associations. Such advances in technology can take the luck out of discovering new uses for tested drugs, allowing researchers to create their own serendipity. Cell-based and in vivo systems are used to screen existing drugs for novel interactions or phenotypes in a different therapeutic area. These phenotypic screens can make it possible to find new biological interactions that would not have been predicted by mining existing data.

Repositioning methods have been applied across various therapeutic areas, including neurological and metabolic disorders, inflammation, and cancer. These methods have led to not only new treatments, but also new avenues of research and new hypotheses. The biggest advantage of drug repositioning is that the approval rate for repositioned drugs entering the clinic is approximately 25%, more than double the rate for drugs with no prior clinical exposure. Drug repositioning may not be the complete answer to pharma’s productivity issue, but if it gets a few more cars through the assembly line it’s worth a closer look.

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