Fast Track on Drug for Ebola Has Faltered

As Ebola raged through West Africa last summer, an experimental drug was tried for the first time on two American aid workers in Liberia who were gravely ill with the virus. Both recovered, one of them rapidly. Though it could not be said for sure that the drug, ZMapp, was responsible, patients and doctors began clamoring for it. But there was enough to treat only a handful of patients. Federal officials vowed to produce more.

Six months later, very little has been produced, diminishing the chances that the drug can be used to treat large numbers of patients in the current outbreak, which appears to be ebbing.

The delays show some gaps in preparedness and have frustrated biodefense and infectious disease experts.

“I think it’s inexcusable that they haven’t moved on it,” said Dr. Philip K. Russell, a retired major general who once ran the United States Army Medical Research and Development Command. “They’ve had months.”

Government officials announced on Thursday that a clinical trial to test whether ZMapp is effective would begin in Liberia, probably within three weeks. But that trial will involve at most 150 patients, the officials said.

Efforts to procure more of the drug have run into snags, according to federal officials, researchers and biotechnology executives. The Department of Health and Human Services asked for proposals to produce more of it to be submitted by November, but so far, no contracts have been awarded.

Facilities that Health and Human Services created, at a cost of hundreds of millions of dollars, expressly for rapidly manufacturing drugs or vaccines in a public health emergency are not being used to produce ZMapp yet. The same is true, with one exception, of facilities the Department of Defense invested in to build the capacity for rapid response.

Thomas W. Geisbert, an Ebola expert at the University of Texas Medical Branch in Galveston, said ZMapp and another drug also in short supply, called TKM-Ebola, were the most promising potential treatments for Ebola based on their effectiveness in treating monkeys.

“Make more of them. We know they work,” he said. “If I were exposed to the virus, those are the two things I would want.”

The government is now working with two leading biotechnology companies, Genentech and Regeneron Pharmaceuticals, and reports rapid progress. Regeneron executives say that not only can they produce ZMapp, but they have also come up with drug candidates that might be even better.

Federal officials defend their performance. “We feel with our partners that we’ve made significant progress in the Ebola crisis,” Robin Robinson, who is in charge of biodefense procurement for Health and Human Services, said in a news conference on Thursday.

By government contracting standards, the effort might be moving at a lightning pace, just not fast enough for the epidemic. And problems unique to ZMapp have made it difficult to expect mass production. The drug is owned by a tiny company, Mapp Biopharmaceutical of San Diego, which has few resources of its own. ZMapp was in a very early stage of development when the outbreak began, and Mapp was not producing more because it had all it needed for early studies.

ZMapp is a combination of three antibodies, which are immune system proteins that can home in on a virus and neutralize it. Partly because it had little money, Mapp chose to manufacture the antibodies in genetically modified tobacco plants. That seemed to be a less expensive way to get small quantities of the drug than the usual biotechnology industry method of producing antibodies in genetically engineered animal cells grown in stainless steel vats.

But there are not many factories that can produce proteins in tobacco, limiting how much can be made now.

A research arm of the Defense Department gave money several years ago to help set up facilities to produce vaccines rapidly in tobacco in the event of a pandemic. At least one of the centers passed a “live fire” test in 2012, producing 10 million doses of a flu vaccine in a month.

But vaccines require a lot less material than antibodies. And after being formed, the tobacco production centers have had to drum up business to remain staffed and ready, and they have not always been able to do so.

Production of ZMapp began in August at one of these facilities, Kentucky BioProcessing, which is now owned by Reynolds American, the cigarette company. That output is slated for the clinical trials beginning next month.

The Biomedical Advanced Research and Development Authority, or Barda, which is the biodefense procurement agency in Health and Human Services run by Dr. Robinson, decided to seek additional production. It turned to three centers it had set up on its own to provide rapid production of drugs and vaccines in an emergency.

Two of the centers, one run by Texas A&M University and the other by the biotech company Emergent Biosolutions, submitted proposals by the Nov. 10 deadline. The third, run by Novartis, which is getting out of the vaccine business, did not.

But those centers had no experience manufacturing using tobacco. So they had to work with the tobacco facilities that the Defense Department had financed.

Dr. Russell, the retired Army biodefense official, said Barda might have saved time by dealing directly with the tobacco companies but probably felt a need to justify its investment in its own centers. Others say dealing with centers it was already familiar with allowed Barda to move faster.

Still, no contracts have been awarded. Some industry executives say Barda found the bids too high. While Emergent, Texas A&M and Barda say the proposals are still under evaluation, Barda is exploring alternatives.

The initial plan was to have the other centers produce ZMapp using the same technology employed by Kentucky BioProcessing. But another tobacco facility, Caliber Biotherapeutics, could not reach an agreement with Kentucky BioProcessing on licensing the technology, said a federal official who spoke on the condition of anonymity because contract discussions are continuing. Moreover, this official said, Kentucky felt it could not devote manpower to helping Caliber when it was scrambling to produce ZMapp on its own.

So Barda is now letting tobacco production companies use their own technology. Dr. Robinson said in the news conference that the agency might go through the Defense Department, which has standing contracts with these facilities, to procure the drug. One company that has produced the antibodies in tobacco is Medicago, , which declined to comment.

Barda is also working with Genentech and Regeneron to see if the antibodies can be manufactured in Chinese hamster ovary cells, or CHO cells, the biotechnology industry’s usual method. There is a lot of capacity available for such production.

Regeneron executives said they had developed CHO cells that can produce the ZMapp antibodies. But they have also developed their own antibodies that the company says bind to the virus more tightly and have better pharmaceutical properties.

Since both sets of antibodies are probably at least somewhat different from ZMapp, they will have to be first tested in monkeys. That will happen soon, but it will delay their possible use in people.

Dr. Robinson said hundreds or thousands of treatment courses made in tobacco could be available by the end of the year. And thousands of doses made in CHO cells could be available by then. Barda’s rapid response centers could be enlisted to help manufacture using CHO cells, he said.

But it is possible that the outbreak will be over by then. In West Africa, trials have begun of other drugs that do not yet have the same results in monkeys as ZMapp but that would be available in large quantities should they prove effective.

Dr. George D. Yancopoulos, chief scientific officer of Regeneron, said the crisis had pointed up shortcomings in biodefense. “Nobody is really prepared,” he said. “Nobody in the world has rapid response capabilities.”

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