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In monkeys, Zmapp works against advanced Ebola, researchers report

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By Anette Breindl
Science Editor

Researchers reported Friday that in primates, the experimental antibody cocktail Zmapp could reverse Ebola disease in monkeys when it was administered up to five days after infection, at a point where the animals were severely ill.

"We could rescue some of the animals that had advanced disease," senior author Gary Kobinger of the Public Health Agency of Canada told reporters at a press conference announcing the findings. "The level of improvement was . . . beyond my own expectations."

In previous studies testing a different experimental Ebola drug, TKM-Ebola, the treatment was administered only an hour after infection – although the same authors found that a drug targeting the related Marburg virus was still effective when administered several days after infection. (See BioWorld Today, Aug. 20, 2014.)

Asked how the five-day time period relates to a natural human infection, Kobinger said that "in nonhuman primates, at day five, they are on average three days away from death. If you translate that to a human – and this is very speculative, I just want to highlight that . . . but if you extrapolate you get to a number that would be day nine to day 11."

Kobinger said the work, which was published online in Nature on Aug. 29, 2014, "gives you the explanation of how we got to Zmapp," Mapp Biopharmaceuticals Inc.'s three-antibody mixture.

At the outset of the study, there were a total of six candidate antibodies. The team went through initial studies in mice, then on to guinea pigs and ultimately monkeys, to identify "the best cocktail among the monoclonal antibodies we had" – the current version of Zmapp.

The antibody cocktail tested in the paper was tested against monkeys with the Kikwit strain of Ebola, but also showed activity against the Zaire strain that is behind the current outbreak.

Based on the findings now published in Nature, a phase I trial of the cocktail is scheduled for early 2015. Because the drug is being developed under the FDA's two-animal rule, in a best-case scenario the cocktail could be approved by the summer of 2015.

In the meantime, as the largest Ebola outbreak on record continues in Western Africa, with 3,069 recorded cases and 1,552 deaths reported as of Aug. 28, when the World Health Organization (WHO) released a sobering Ebola Response Roadmap that warned the true caseload from the current outbreak was likely two to four times higher than the recorded cases, and could ultimately exceed 20,000.

The WHO's stated goal of the roadmap is "to stop Ebola transmission in affected countries within six to nine months and prevent international spread."

But the agency warned that the current outbreak "continues to evolve in alarming ways, with the severely affected countries, Guinea, Liberia and Sierra Leone, struggling to control the escalating outbreak against a backdrop of severely compromised health systems, significant deficits in capacity, and rampant fear."

Several patients infected during that outbreak have been administered Zmapp under compassionate-use rules. Two Americans that were treated with Zmapp are expected to make a full recovery. (See BioWorld Today, Aug. 4, 2014.)

A Liberian doctor and a Spanish priest, meanwhile, have both died despite receiving Zmapp.

That 50 percent death rate is the same that is being observed in the larger outbreak. But "the problem is, it was not done in the context of a trial," Kobinger stressed, making it next to impossible to draw any sound conclusions from the fates of the treated individuals.

The priest, in particular, died before he could receive a full three-dose course of treatment. He received only one dose, an amount that Kobinger thought would be insufficient to fight the virus.

"We have never tried," he said. But in the primate experiments, "my guess is that one dose would not save the animal."

Age and comorbidities would also be expected to play a role in how well a patient could fight off the virus. "Our animals are always in the young adult part of their life," Kobinger pointed out.

If the trials go well, the biggest bottleneck may turn out to be the production of monoclonal antibodies. The antibodies that make up the Zmapp cocktail are produced in tobacco plants and, for now, production capacity is limited to 20 to 40 doses per month, although that could be increased by adding new production facilities.

The scarcity of the antibodies harkens back to the early days of penicillin, when the drug was so precious it was recycled from the urine of treated patients. Unfortunately, the closest thing to such recycling – treating acutely ill patients with the serum of individuals who have managed to recover from an infection – did not appear to be an effective approach for treating Ebola when it was tested in earlier outbreaks.

The two doses of Zmapp left from the treatment of the priest, however, have been used to treat additional British patients.

"There is a movement to produce more," Kobinger said, "but I can't say how it's going to fall into place in the next few months. . . . The only thing I know now is that there is nothing left."