Teaching Old Drugs New Tricks
Could existing drugs be repurposed as a shortcut to treating Ebola?
After testing around 2600 approved drugs and active molecular probes for activity against the Ebola virus, researchers have identified 80 FDA-approved drugs that could be promising (1). Of particular interest are bepridil, an angina treatment that is no longer sold in the US, and the antidepressant sertraline. Both drugs were able to protect against Ebola in mice – survival rates for mice infected with Ebola were 70 percent and 100 percent when treated with sertraline and bepridil, respectively. We spoke with Gene Olinger, co-author of the study and formerly a researcher at the US Army Medical Research Institute of Infectious Diseases, to find out more about the potential of drug repurposing.
How did you get involved?
I was asked to move from vaccine development to drug development for viral haemorrhagic fever viruses like Ebola. The focus was on finding medical countermeasures that could be quickly deployed during an outbreak. We wanted to use the live virus as a phenotypic screening tool to increase the chances we would find a direct antiviral. We started with a variety of small (<10,000) compound libraries and I quickly realized that with the development costs and timeframe, this was likely to be less than fruitful. We also realized that during an outbreak we would need answers quickly. The idea of repurposing drugs with known human clinical safety profiles was compelling.
Did the results surprise you?
We were hopeful about the results, but were surprised by both the number and diversity of compounds that had activity! Some, like ion transport, made sense biologically, but others were more surprising. We are still trying to dissect if these unexpected drugs are functioning through their known mechanism of action for their indication(s) or some off-target effect. The results provide a starting point to understand critical host–pathogen interactions and a lot of basic science questions.
How promising is the antiviral activity identified?
The drugs have adequate potency as antivirals. For an acute infection like Ebola, however, the ability to change the course of disease once symptoms develop is going to be difficult. Thus, we think combinations may be required. The library data may also provide insights into chemistry that may allow for novel drug development and thus increase potency.
What are the next steps?
Next steps are to assess the drugs individually in prophylactic and post-exposure conditions in guinea pig models and in the more rigorous nonhuman primate models of disease. We are also completing a combination assessment where we have identified synergistic combinations.
How is an approved drug typically repurposed?
A clinician could simply prescribe a drug “off-label”. In addition, the 505(b)(2) New Drug Application process has been used for repurposing. This is a common method to reposition existing drugs. There are advantages and disadvantages (both commercial and scientific) when it comes to repurposing. For rare and neglected diseases, it is a key area of interest that is gaining traction.
- L. M. Johansen et al., “A Screen of Approved Drugs and Molecular Probes Identifies Therapeutics with Anti–Ebola Virus Activity”, Sci. Transl. Med., 7 (290), 290ra89 (2015).
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