Nancy A. Melville

June 05, 2015

LEIPZIG, Germany ― The spread of Ebola is slowing, which is good news for everyone except perhaps those who are trying to develop new treatments, experts said here at the 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID).

The unexpected scarcity of human patients left to enroll in clinical trials — as opposed to the millions who as recently as last fall had been projected to be infected — adds to a series of stumbling blocks that have hindered efforts to develop an effective treatment.

"This is a tough situation," said Martin Howell Friede, PhD, a scientist with the World Health Organization's (WHO's) Essential Medicines and Health Products Division, in Geneva, Switzerland. "As public health official, you see these numbers go down and you say, 'Yes! We're getting control of it.' But as a product development researcher, when you see the counts going up again, you say, 'Yes! We can enroll some more patients.' The reality is that now, enrollment is down to one or none per week," he said, and as a result, clinical trials are having to compete for the few available patients that are available.

However, the process has been highly competitive from the start, Dr Friede said.

"Within weeks of the declaration of the Ebola epidemic, more than 250 possible drugs were proposed for clinical trials — far more than there were clinical trial sites available set up with the resources necessary to conduct the trials," he explained.

The choices of drugs suitable for being prioritized in clinical trials were narrowed down by a WHO committee and were based on key criteria, including supportive preclinical evidence, which settled on drugs that had evidence of curing Ebola in nonhuman primates.

Priority Drugs

Among them is ZMapp (Mapp Biopharmaceutical, Inc), a drug cocktail comprising three monoclonal antibodies made in plants, which is being studied in a clinical trial at sites in the United States and Sierra Leone. Only seven patients are enrolled in the trial so far. Even if more patients become available, supplies are limited, with only 15 courses of treatment produced every 6 weeks.

TKM100803 (Tekmira Pharmaceuticals Corp) is being studied in five patients, who were expatriated on compassionate grounds in phase 1 safety trials in the United States, and in 10 patients (to date) in a phase 2 efficacy trial in Sierra Leone.

With so few patients available in recent months, studies have had to rely on historical controls, but those figures are unreliable owing to the fluctuating mortality rates, Dr Friede said.

"You're comparing the mortality rate to what was known before you started the trial, but that rate has been going up and then going down, so even the effort to compare a drug to historical data is becoming very hard," he said.

Unprecedented Strides in Vaccines

Meanwhile, efforts to develop an Ebola vaccine are moving full speed ahead, at an entirely unprecedented pace that speaks of the science community's ability to rapidly mobilize when not faced with insurmountable obstacles.

"We have conducted vaccination progress in record-breaking time," Dr Friede told Medscape Medical News.

"It usually takes 10 years to develop a vaccine, and we have gone from nothing to conducting phase 1 trials for an Ebola vaccine within 6 to 8 weeks," he said. "The community became engaged, and it was all hands on board, with universities, industry, the general population, and everyone stepping up."

In addition, regulators worked to streamline the process.

"There was an enormously rapid turnaround from all the regulators and ethics committees; financing was available, and people moved forward with the products available rather than requesting a return to the drawing board to solve issues such as temperature sensitivity, etc," Dr Friede explained.

The leading candidate that has emerged for vaccines is rVSV-ZEBOV — a recombinant vesicular stomatitis virus being developed by NewLink Pharmaceuticals, PHAC, and Merck Pharmaceuticals.

Phase 1 data on the vaccine were published in April in the New England Journal of Medicine, and the vaccine is already in phase 2 and phase 3 trials in Guinea and Sierra Leone.

The Canadian government has donated 800 vials of the new vaccine to the WHO.

Other vaccine candidates include Chimp-Adeno–ZEBOV, which is being developed by GlaxoSmithKline, and Ad26-ZEBOV Prime and MVA-ZEBOV boost, being developed by Johnson & Johnson.

As part of the phase 1 trial for rVSV-ZEBOV, the WHO is currently vaccinating frontline health workers. It is using a ring vaccination approach when a new case is identified, in which all of the people around the new case are vaccinated. The goal in the trial is to vaccinate 190 rings.

"Hopefully, there will be enough cases in the unvaccinated to enable a statistically significant evaluation of efficacy, but only time will tell," said Dr Friede.

In the 15 months or so since the first case of Ebola caused the death of a 2-year-old child, there have been 26,593 cases and 11,005 deaths from the disease, said Dina Pfeifer, MD, of the WHO's Quality, Safety and Standards Division in the Department of Immunization, Vaccines and Biologicals, in Geneva, Switzerland, who also spoke at the session.

Risk for Second Outbreak Remains

Despite the encouraging development of the outbreak being declared over in Liberia, there may be more grappling with the disease in the future.

"The estimation is that there is a 50% chance of a second Ebola outbreak in western Africa in the next 2 years," she said.

Dr Pfeifer told Medscape Medical News that the troubling estimation reflects the realistic challenges of the Ebola virus.

"Ebola may easily strike back and continue to linger for a while," she said.

"Unless the human-animal interface is not capped, risk of another outbreak remains, as repeated outbreaks in equatorial Africa teach us," she explained.

A multitude of measures will be essential in avoiding the kind of delays that prompted widespread criticism of the WHO, including criticism from a United Nations panel, for its initial response to the outbreak.

The immensity of the outbreak, which was the largest Ebola epidemic in history, caught many in the response community off guard.

"Rapid response can influence size and duration of an outbreak, and it requires an effective early reporting system," Dr Pfeifer said.

"It requires laboratory capacity for quick confirmation of an outbreak, trained clinicians and auxiliary staff to manage patients safely, good understanding of triage and isolation measures, and no compromises in infection prevention and control measures at healthcare facilities," she said.

"WHO was overwhelmed, as were all other responders," Dr Chan said. "The demands on WHO were more than 10 times greater than ever experienced in the history of this organization."

That kind of unexpected scenario, however, is precisely what public health officials should really be preparing for, Dr Friede said in his talk.

"Our hope is that next time we will be more prepared," he said, "but the concern is that the next time it might be something else that we in fact know absolutely nothing about."

Dr Friede and Dr Pfeifer are employees of the WHO.

33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Presented May 15, 2015.


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