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The widely-discussed antibody cocktail, ZMapp, is finally going to be tested under standardized, controlled conditions for its safety and efficacy in Ebola virus disease-infected patients in Liberia and, potentially, the United States.
Late Friday, the NIH National Institute of Allergy and Infectious Disease (NIAID) announced the launch of a randomized trial in up to 200 patient volunteers with confirmed Ebola virus infections.
The two-arm study will compare supportive standard of care with or without three intravenous infusions of ZMapp spaced three days apart. This is the same dosing regimen published in Nature that protected 18 of 18 monkeys when given up to five days after experimental infection.
LeafBio, the commercial arm of San Diego-based Mapp Biopharmaceutical, announced concomitantly that the FDA had approved their IND for this trial. The three antibodies that comprise ZMapp target both distinct and overlapping parts of the Ebola virus glycoprotein (GP) that it uses to infect humans.
Read more - Ebola 'Secret Serum': Small Biopharma, The Army, And Big Tobacco
With the cooperation of the Liberian government, volunteers will primarily be drawn from adults and children of any age in Liberia who have been infected with the Ebola virus.
The trial will also include health care workers from anywhere in West Africa who are transported to the U.S. for treatment as well as any adults or children in the U.S. who contracted through secondary transmission from infected individuals.
Study sites will include Ebola treatment centers in Monrovia, Liberia that are currently staffed by health professionals from the U.S. Public Health Service and in U.S. at the NIH Clinical Research Unit in Bethesda, Maryland.
Other U.S. sites will be considered if necessary, such as Emory University Hospital, the University of Nebraska Medical Center, and the Walter Reed National Military Medical Center in Bethesda.
A very high statistical barrier to ZMapp efficacy
Again, patients in both control and ZMapp groups will received the optimized standard of care that has evolved for treating Ebola virus disease: intravenous fluids, balancing electrolytes, maintaining oxygen status and blood pressure, and treating other infections if they occur.
While this treatment in the control group is certainly the most ethical way to conduct the study, it also presents a high bar for demonstrating the effectiveness of ZMapp. Eight of the ten Ebola-infected patients treated in the U.S. survived, and the two that died had advanced disease at the time of treatment: Thomas Eric Duncan, the Liberian national who traveled to Texas but was originally turned away when presenting with symptoms, and Dr. Martin Salia, a Maryland physician who contracted the disease while caring for patients in his native Sierra Leone.
Medical missionary, Nancy Writebol, with her husband, David, speaking to the press at the Charlotte,... [+]
Almost all of the U.S.-treated patients also received some other experimental drug, including ZMapp. So, we don't know what the actual survival rate will be with supportive care alone, but it may well still be in the range of 80%. It's certain to be much higher than in the challenged healthcare settings in West Africa. And the higher the control survival rate, the better ZMapp must perform to show a statistical benefit.
Because the study isn't blinded to the caregivers, investigators will monitor the progression of patients in real-time. If ZMapp does appear to be providing an additional margin of protection, it will then be added to the control group and then subsequent patients may receive one of several other drugs or therapies under investigation, as in this list from NIAID:
- Tekmira siRNA from Tekmira Pharmaceuticals Corp., based in Burnaby, British Columbia
- Favipiravir from Toyama Chemical Co. LTD, based in Tokyo
- Convalescent or post-immunization plasma collected from recent Ebola infection survivors. It is possible that this category could potentially be expanded to include plasma donors who have participated in Phase 1 Ebola vaccine clinical trials and whose plasma shows high neutralizing activity against the virus.
- BCX4430 from BioCryst, based in Durham, North Carolina
- AVI-7537 from Sarepta, based in Cambridge, Massachusetts
Conversely, if ZMapp doesn't prove more effective than control after evaluating 100 patients per arm, NIAID says they'll continue to individually evaluate each of the treatments above.
But will there be enough Ebola-infected patients in Liberia in the U.S. for the study to proceed?
Despite the news from Liberia, it's not too late to try
While the West African Ebola outbreak isn't as widespread as in the summer and fall of 2014, 99 news cases of Ebola infections were reported in Guinea, Sierra Leone, and Liberia last week.
(Note: Those number are when considering only natural outbreaks, not incidences due to laboratory exposures, or asymptomatic Reston virus episodes.)
On one hand, none of those new cases were in Liberia. In fact, it's Sierra Leone where the disease appears to be regaining a foothold, with 65 of those 99 new cases. Guinea accounts for the other 33 new cases.
But, on the other hand, Liberia has counted 10 new cases in the last 21 days. Liberian President Ellen Johnson Sirleaf met with President Obama in Washington this week to stress the continued need for support to eradicate the disease.
Will Liberia's success preclude full evaluation of ZMapp? The primary ZMapp study sites are in the country with the greatest success of the three. And President Johnson Sirleaf's goal is for Liberia to have zero cases by April 15.
So what happens then? In NIAID's statement announcing the trial, this statement appears:
"Given the current decline in the number of new Ebola cases in Liberia, study investigators anticipate the need for flexibility in the conduct and design of the trial to address the changing nature of the outbreak in West Africa. Consideration will also be given to other sites in the outbreak region that express interest."
Did lack of patients cause another trial to be stopped?
In late January, the antiviral drug company, Chimerix, announced that it would discontinue Liberian trials of its broad spectrum antiviral drug, brincidofovir (BCV), in patients with Ebola virus disease. The Wellcome Fund had originally supported a 140-patient open-label BCV to be conducted by researchers at the University of Oxford and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) at the Médicins Sans Frontières-operated ELWA 3 Ebola Treatment Centre in Monrovia.
But the company reported then that disease incidence had slowed to the point that only a "handful" of patients could be recruited over the three weeks since the study was formally initiated. Their withdrawal from the study was taken by much of the international media as indicating that the Ebola crisis in West Africa had passed.
That may not be the full reason for the Chimerix decision. The small North Carolina-based company, lacking any approved product, has already generated impressive Phase 2 trial data supporting anticipated regulatory filings for BCV against adenovirus and cytomegalovirus (CMV), when ongoing Phase 3 trials are complete.
In contrast, the potential for brincidofovir's efficacy against Ebola virus was far less developed, driven only by cell culture experiments with the virus in a CDC drug screening campaign whose results were only made public in October 2014.
ZMapp: a government-small business biomanufacturing accomplishment
The speed at which ZMapp has gone into production for this trial is impressive. According to Mapp Biopharmaceutical, the antibody cocktail was only conceived in January 2014, deriving from individual Ebola antibody efforts supported by the Canadian and U.S. governments and Defyrus, Inc., a Toronto-based life sciences and biodefense company.
Since 2011, work had been independently undertaken at the Public Health Agency of Canada's National Microbiology Laboratory in Winnipeg, led by Gary Kobinger, MD, to generate antibodies that could prevent Ebola infections in monkeys and stall its advancement after infection.
But when combined with one of the antibodies developed by Mapp Biopharmaceutical, a new cocktail was created that has proven in non-human primates to have the greatest possible utility against Ebola infections in humans.
Other drugs already tested in monkeys must be given within 24 hours of an experimental infection. But ZMapp has proven 100% effectiveness when given up to five days after experimental infection (with the 1995 Kikwit Ebola virus), a much more likely scenario to be encountered with human patients.
In September, LeafBio/Mapp received a $25 million grant from the U.S. Biodefense Advanced Research and Development Authority (BARDA) to produce enough bulk product to initiate potential Phase 1 studies and the current Phase 2 trial. The antibodies are produced in a Australian species of tobacco plant at Kentucky Bioprocessing Inc., a subsidiary of Reynolds American. BARDA's own fill finish and manufacturing network provided the final product.
Prior to this trial, ZMapp had been used in nine Ebola victims under emergency protocols, including the first two U.S. medical missionaries in Liberia who were infected in July 2014, Kent Brantly, MD, and Nancy Writebol. Both were subsequently transported to Emory University Hospital and were the first two Ebola victims who were treated, and survived, on U.S. soil.
When these cases were reported in detail in the New England Journal of Medicine, the authors cautioned that they were unable to conclude how much, or even if, the ZMapp treatment influenced their survival.
Existing supplies of ZMapp were reported to have been exhausted in August 2014, a month after Brantly and Writebol were treated.
Sidebar
For those interested in the precise technical details of the antibody combination and individual contributions of Mapp Biopharmaceutical and the Public Health Agency of Canada's National Microbiology Laboratory in Winnipeg, here's an introductory paragraph from a paper in the Proceedings of the National Academy of Sciences where the antibodies were evaluated by Dr. Erica Ollman Saphire's team at The Scripps Research Institute for how they bound the Ebola glycoprotein:
"Key components of two of the most efficacious mAbs cocktails, titled MB-003 (MappBio) including antibodies c13C6, h13F6, and c6D8 (27) and ZMAb (Defyrus) including antibodies c1H3, c2G4, and c4G7 (22), have been recently combined and are being developed for human use as a cocktail named ZMapp (24). The mAb components of ZMapp include c13C6, c2G4, and c4G7. Each of these antibodies was raised in vaccinated mice (28, 29), chimerized into human IgG1 scaffolds (21, 27, 30, 31), and are currently being mass produced in tobacco plants (31)." [The reference numbers refer to the list here at PNAS.]
Hence, ZMapp is two-thirds Canadian-generated intellectual property.
