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Ebola Outbreak: A Plea To Think Far Beyond The Norm By Adegboyega Oyelere

August 18, 2014

It is now prudent for the medical authorities in countries most ravaged by the current Ebola virus pandemic to take a lead in investigating other more readily available alternatives to ZMapp.

In the current outbreak, the Ebola virus has moved beyond its north-eastern-central African hot-spots, raging uncontrollably in many West African countries. The ensuing epidemic, regarded as the worst to date, has claimed more than a thousand victims. The lack of therapeutic intervention (approved) for Ebola has made infection a near death sentence as close to 90 % of its victims succumb to the virus. Recognizing the threat it poses to global health, the World Health Organization (WHO) has recommended the use of unauthorized drugs to fight Ebola. In making this declaration, WHO assistant Director General Dr. Marie-Paule Kieny said, "In the special circumstances of this Ebola outbreak it is ethical to offer unregistered interventions as potential treatments or prevention,"

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Ebola patient being treated by a medical team

Most attention has been given to one experimental drug in particular - a serum called ZMapp. The buzz around ZMapp is justified due to the encouraging effects it has shown on two US citizens who came down with Ebola virus while working as medical missionaries in Liberia. Unfortunately, the third patient treated with ZMapp, Father Miguel Pajares, did die of complications from Ebola.  One key limitation to the general use of ZMapp is its short supply. It appears the entire ZMapp stock has been exhausted at the time WHO made the recommendation.

The WHO recommendation of the use of unauthorized drugs in the fight against Ebola came with a clause – drugs proven safe and effective in monkeys. The phrase “effective in monkeys” most certainly mean proven efficacious in monkey model of Ebola. It is not clear how many drugs have been tested in monkeys as this information is not commonly available in public domain. Additionally, it is less certain if any of these drugs will be available for immediate distribution to those who need them the most.    

If the “proven safe” part of WHO recommendation clause is extended to studies which aimed at repurposing Food and Drug Administration (FDA) approved drug for Ebola therapy, then the work of Johansen et al is of significant relevance [Johansen et al FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection, Sci Transl Med 2013, 5, 190ra79].  The authors performed an in vitro (test tube only experiments) screen of FDA approved drugs and identified two drugs – clomiphene and toremifene as potent inhibitors of Zaire Ebola virus. To obtain further evidence of anti-Ebola activity, the authors challenged in vivo mouse infection model of the virus with these drugs. They found that 50 % and 90% of the mice treated with toremifene and clomiphene respectively survived. Encouraged by their finding, Johansen et al opined that clomiphene and toremifene are “immediately actionable class of approved drugs that can be repurposed for treatment of infections caused by filovirus such as Ebola virus and Marburg virus”.

It is important to clarify that drug treatment in the experiments performed by Johansen et al started after only 1 h of exposure of mice to the virus.  Moreover, it will be utterly reckless to tout this result as an indicator of efficacy in human Ebola virus infection as there are copious data that indicate drugs which show early promise in murine model of diseases eventually turned worthless in human trials. Nevertheless, clomiphene and toremifene have one alluring quality – they are in use in the clinic. Clomiphene (brand name Clomid) and toremifene (brand name Acapodene) are selective estrogen receptor modulators (SERMs) approved for treatment of infertility and metastatic breast cancer respectively. These drugs may not be subject to supply shortage that has bedeviled ZMapp.  

In addition to stressing the need for adherence to strict criteria, including full transparency and informed consent, WHO declaration included a plea about the “moral obligation to collect and share all data generated” when unauthorized drugs are used to treat Ebola patients. Perhaps, it is now prudent for the medical authorities in countries most ravaged by the current Ebola virus pandemic to take a lead in investigating other more readily available alternatives to ZMapp. The study by Johansen et al and possibly many more not identified by this author could form the foundation for such investigation. Though there is no guarantee that any of the lead drugs from these studies will work, the alternative is far less appealing. These are desperate times, it is better to try than wait for an experimental drug that may not be available any time soon. 

Finally, I want to clearly state that I am neither a medical doctor nor a virologist. I write this piece out of my heartfelt desire to bring to fore any information that may potentially help curb the current Ebola virus outbreak or at least give those exposed to the deadly virus a fighting chance, no matter how infinitesimally small that odd may be.

A. Oyelere writes from Marietta Georgia, USA ([email protected])