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Amid efficacy questions, a Japanese antiviral drug is also being evaluated to combat the deadly disease

The World Health Organization (WHO), the health department of the United Nations (UN), revealed on Friday that the Ebola virus (EBOV) epidemic that's gripped central Africa has now claimed over 1,400 lives.  Adding to the bad news, supplies of the experimental drug ZMapp have reportedly been exhausted and a recent death of a ZMapp-treated doctor is increasing questions of the drug's efficacy, as health workers in Africa desperately search for a way to treat -- or at least stop the spread of -- the deadly virus. 

I. ZMapp -- an Exotic Treatment Option

ZMapp is a monoclonal antibody produced in plants, and then humanized.  Antibodies are large Y-shapped proteins that the human body uses to tag "antigens" surface chemicals on hostile invaders such as viruses and bacteria.  More specifically, in this case the antibodies are thought to tag strains of the Ebola family of viruses (EBOVs), including the most prevalent and deadly titular strain, the Ebola virus (EBOV) (aka Zaire virus, or Zaire ebolavirus).

Ebola colorized
The Ebola virus is cutting a wake of destruction across Central Africa. [Image Source: AP]
 
The ZMapp effort was formed by the merger of two attempts to produce monoclonal antibody serums via genetically modified organism (GMOs).  The first serum was MB-003, formulated by San Diego, Calif.-based Mapp Biopharmaceutical, Inc. and its commerical sister-firm LeafBio.  Both Mapp and Leafbio were funded [PDF] in part by grants from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRID).  The second serum was ZMAb, made by Toronto-based Defyrus Inc., a startup funded in part by grants from a Public Health Agency of Canada (PHAC) grant.

Both Defyrus and Mapp/LeafBio are tiny, very young firms; Defyrus was found in 2008, Mapp in 2003.  Defyrus has six employees, Mapp has nine.  Both companies look to use purified antibodies from GMOs to try to boost a patients' defense against disease which currently have no cure.  Because of this, both companies fall under the so-called "biodefense" category as they could provide a novel tool to combat rare deadly diseases -- a highly coveted weaponizable class of pathogens.

The ZMapp cocktail is produced by infecting Nicotiana benthamiana, a close relative of cigarette tobacco, with a virus similar to the target viral agent.  The tobacco plants are grown at the U.S. and Canadian companies' German partner firm, Icon Genetics.  Leaves are grown in small batches at Icon Genetic's greenhouse.  Genes are introduced into the plants via recombinant bacteria administered by eyedroppers.

ZMapp nicotine leaves
Leaves are picked at a Icon Genetics greenhouse in Germany and readied for extraction.
[Image Source: Reuters]

The crop responds to the infection by producing antibodies.  After the harvest, workers much grind the leaves and carry out a set of hand extractions and purifications.

Via this costly, slow process a batch of serum is made.  The antibodies are "humanized" either using recombinant DNA in the plant or via scaffold or rodent reporcessing -- processes that make these immune proteins compatible with the human body, despite coming from a highly different source organism.

Hand extraction
Defyrus and Mapp/LeafBio must painstakingly extract and mix the proteins for each batch of ZMapp by hand.
[Image Source: Reuters]

Humanized monoclonal antibodies are being considered for novel forms of cancer treatment, as well as for combatting rare and understudied diseases.  The fundamental idea in both cases is to get nature to do medical researchers' dirty work at a much faster speed.  The downside is that these treatments get very expensive as the process is very new.  Purification and humanification technologies are far from achieving the levels needed to achieve the production associated with common antibiotics and vaccines.  And many of the formulations -- including ZMapp -- have not gone through clinical trials, and at this point can be considered at best educated guesses.

II. Great Expectations

At first it perhaps appeared to the overly hopeful observer that ZMapp might be a magic bullet for the EBOV.  After Mapp and Defyrus received a rare exemption from the U.S. Food and Drug Administration (FDA) allowing experimental treatment of patients with a drug that has yet to undergo clinical trials, the ZMapp formula was used to treat two Americans.  
The lucky potentially lucky recipients of the expensive experimental cocktail were Kent Brantly, a 33-year-old doctor, and Nancy Writebol, a 59-year-old aid worker.  Both the patients became infected while trying to assist in combating the current EBOV outbreak in Central Africa.

ZMapp
Both American patients treated with ZMapp recovered fully. [Image Source: Bloomberg]

Treated at Emory University Hospital near Atlanta, Georgia, both patients made remarkable recoveries.  Closely monitored by teams of doctors and provided an ample supply of sterile fluids to keep them hydrated, both of these ZMapp-treated patients made full recoveries. Recently, after a quarantine they were allowed to go home to family members in the U.S. after being deemed no longer contagious.  Dr. Brantly cheered that his recovery with the help of ZMapp was "miraculous."

Cheered by the results, further purchases of ZMapp were made to treat an infected Spanish missionary and African doctors.  The serum was also given to 
three African doctors treating patients in Liberia who had become infected with EBOV.  After receiving doses of ZMapp all three doctors subsequently showed signs of a "remarkable" recovery, according to local officials.

But the optimism was dampered somewhat when Rev. Miguel Pajares, a 75-year-old missionary, died despite receiving treatment with ZMapp.  Rev. Pajares was treated at the state of the art Carlos III Hospital in Madrid, Spain, but neither the cutting edge medical center nor the ZMapp was able to save his life.

More bad news arrived this week when Liberia's Dr. Abraham Borbor -- one of the African doctors who received ZMapp -- took a turn for the worse and died, after appearing poised to make a full recovery.  News of the death was shared to various outlets by Liberian Information Minister Lewis Brown.  The loss of Dr. Borbor was a major blow as he was the Deputy Chief Medical Doctor of the leading medical institution in hardest hit African nation, Liberia.  Dr. Borbor's age was not widely reported, but he appears to be middle-aged.
 
Dr. Borbor
Dr. Abraham Borbor, a top medical doctor in Liberia, died this week, despite being one of only three Africans to receive treatment with the expensive drug ZMapp. [Image Source: Dailly Mail]

The latest development calls into question to some extent the efficacy of ZMapp, as thus far 2 patients treated with it have died, while two have made full recoveries.  Further complicating the issue is that supplies of ZMapp have run out, so there can be no more additional tests for now.  Mapp/LeafBio and Defyrus are working to prepare more doses, but they may not be ready until a few months from now, given the lengthy grow time need to make small batches of the treatment.

Some will surely point to potential differences the condition and treatment of patients who were given ZMapp and died versus those who lived.  Both of the patients who made full recoveries were younger than 65 and were treated at modern medical institutions.  Of those who died, the Liberian doctor was treated at a top regional facility, but without some of the advanced amenities of a European or Amerian hospital.  The Spanish priest's age, meanwhile, is being attributed as a factor in that case for the lack of success.

III. Now It's Toyama's Turn

Greater mortality rates for the infection are estimated to be around 55 percent, according to BBC News.  And that brings to bear the elephant in the room. Other factors aside, the survival rate for ZMapp treated patients isn't significantly higher.

ZMapp
The scant supply of ZMapp has been exhausted without conclusive results. [Image Source: Getty Images]

At the end of the day, though, we're back to where we started.  ZMapp may indeed be useful in combatting the disease, but it remains highly expensive and slow to produce.  Worse, critics and proponents at best have educated speculation and anecdotal cases studies to rely upon when trying to determine its efficacy.  ZMapp may "work" to some extent; or it may have little impact on the course of the disease versus other factors.  At this point there simply isn't enough evidence to determine which is the case.

But if ZMapp can't stop Ebola, what can?  The answer may lie in other experimental drugs, such as T-705, an antiviral drug marketed under the name Avigan.  This new antiviral is produced by Japan's Toyama Chemical Comp., Ltd., which recently became a subsidiary of Fujifilm Holdings Corp. (TYO:4901).  Avigan has been through limited clinical trials with other viruses.  It is currently approved of to treat influenza in Japan.

Avigan action
Avigan, an inhibitor of viral RNA polymerases, is being tried as an alternative to ZMapp.
[Image Source: Fujifilm]

No one knows if it will be able to similarly slow EBOVs, but Japan has already cleared red tape to allow it to ship worldwide -- with or without WHO approval.  Avigan is currently being tested on William Pooley, a 29-year-old British volunteer, who returned home after contracting EBOV as a relief worker.  He's being treated in isolation at a London, UK hospital.

Should Avigan pan out, the big upside is that unlike ZMapp, it could potentially be produced at much higher volume and far more quickly.  Indeed, Fujifilm and Toyama Chemical sound eager to do so.  But care must be taken as thus far other less exotic antivirals have had little success at combatting EBOV.  The worst case scenario would be for afflicted nations to purchase large stocks of the antiviral, only to find in an inaffective treatment.

Meanwhile the disease marches on, unchecked in the worst-hit nations of Liberia and Sierra Leone.  The latest statistics from the WHO lists 2,615 infections and 1,427 deaths for the latest outbreak -- a infection count higher than the past 20 EBOV outbreaks combined.
 
Ebola Spread
The death toll from the epidemic has topped 1,400. [Image Source: CDC]


The good news is that Nigeria -- Africa's most populous nation -- has thus far managed to constrain EBOV disease occurences to a dozen or so cases.  Of the five deaths in Nigeria, all have been related to those who came in contact with an American-born citizen of Liberia who traveled to Nigeria after becoming infected with EBOV in his home country.

But in Liberia, particularly, the situation remains grim.

Sources: WHO, BBC News





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