With Ebola cases petering out, will trial of the drug ZMapp run out of time?

TORONTO -- Moments after the first person treated with ZMapp started receiving the experimental Ebola drug he could feel effects which suggested it was working.

Dr. Kent Brantly's soaring temperature abated within 15 minutes. Ninety minutes after the infusion started, the American doctor was able to walk to the bathroom for the first time in a day and a half, Brantly recounts in the new book "Called for Life," which he wrote with his wife Amber.

Brantly's recovery from what his doctors believed was death's doorstep was widely credited to the drug ZMapp, an antibody cocktail designed at Canada's National Microbiology Laboratory in Winnipeg.

But a year later, a clinical trial set up to prove whether the drug is actually effective has yet to come up with a conclusion.

And with new Ebola cases occurring at a rate of two or three a week at this point, it's unclear if an answer can be arrived at before the unprecedented West African outbreak is finally extinguished.

"It will be very hard to have a definite answer on the value of a drug which has been considered as promising," Dr. Marie-Paule Kieny, the World Health Organization's point person for development of Ebola vaccines and drugs, says of the current situation.

Dr. Clifford Lane, charged with overseeing Ebola clinical trials for the U.S. National Institute for Allergy and Infectious Diseases, acknowledges enrolling enough cases to complete the trial is a challenge at this point.

Still, Lane hopes the trial will not be the equivalent of a hung jury. "I have to say I would like us to get to a result because I'd like to know what this drug does."

Hopes have long been high for ZMapp, a combination of three different human antibodies that fight the Ebola virus. Two of the antibodies were isolated and cloned by scientists at the Winnipeg lab while the third was developed by researchers at the U.S. Army Medical Research Institute of Infectious Diseases in Frederick, Md.

Both labs had created unique versions of a three-antibody cocktail, both of which showed promise when tested in non-human primates. But the Winnipeg group worked to optimize the approach by testing various combinations of the six antibodies to identify the mixture that worked best.

The antibodies are grown in genetically modified tobacco plants, a process that doesn't allow for rapid development of ZMapp. When Ebola exploded in West Africa in the spring and early summer of 2014, there were fewer than a dozen treatment courses available.

Those were quickly used to try to save the lives of health-care workers like Brantly who were infected while working in Ebola clinics. Most survived, though an elderly Spanish missionary died before he could receive the full treatment.

By late winter enough ZMapp had been made to start a clinical trial to try to determine if the drug was as effective as the recoveries would suggest.

But massive international efforts to bring the outbreak under control were paying off. Over the course of this spring and summer, case counts fell to a few dozen a week and then to the current weekly tallies of fewer than a handful.

Lane says nearly 60 people have been enrolled in the trial so far, with Ebola patients randomly assigned to get either supportive care -- the standard treatment -- or supportive care plus ZMapp.

The trial's Data and Safety Monitoring Board has taken periodic looks at the data to date, and they will do so again next week. The fact that these outside experts haven't stopped the trial tells us two things.

The first: ZMapp hasn't yet been shown to be a statistically better treatment than supportive care. If it was clear the drug was effective it would be unethical to withhold it and the trial would have been ended.

The second: The drug hasn't been shown not to work either. A study of another drug, TKM-Ebola, was stopped when its Data and Safety Monitoring Board concluded there was no hope giving it to more people would show it was effective.

"The fact that the study is ongoing indicates there is hope that the product (ZMapp) will work," Kieny says.

Lane says he had anticipated that an answer would be found when the trial had enrolled somewhere between 40 and 100 Ebola patients. The better a drug works, the faster an answer becomes clear.

Some researchers who are rooting for the drug worry that the trial design may be making ZMapp look less effective than they believe it to be. They argue ZMapp cannot save Ebola patients who are too far along in the disease, so enrolling them in the study makes it harder to see if and how well the drug works.

Lane flips that argument around.

Yes, anyone who can be given an infusion can be enrolled in the trial, he says, noting the sickest have the most to gain if ZMapp is effective.

But patients who are less sick may survive with supportive care alone, he says. If ZMapp only shortens their hospital stays, it would likewise be hard to prove that the drug increases the chances of survival.