Ebola Therapy From an Obscure Biotech Firm Is Hurried Along
By ANDREW POLLACKAUG. 6, 2014
Share This Page
Inside special isolation units at an Atlanta hospital on Wednesday, Kent Brantly and Nancy Writebol, the two Americans infected with Ebola in West Africa, appeared to be responding to an experimental medicine devised by an obscure biotechnology company with ties to the Defense Department.
In West Africa, the estimated death toll from the outbreak kept rising, to 932, by the latest official count.
How and why Dr. Brantly and Ms. Writebol received the drug, ZMapp, is one of the many mysteries surrounding what has been called a “secret serum,” including the big one: Does it really work? The Americans are the only two patients who have been treated with the medicine, out of perhaps thousands who might have benefited so far, raising old questions about who does — and does not — have access to medications, including experimental drugs.
But the San Diego-based Mapp Biopharmaceutical, the primary developer of the drug, was consumed Wednesday with how to manufacture more of it with an eye to providing the drug to more patients, probably in the form of clinical trials.
Photo
A Reynolds American plant in Owensboro, Ky., makes ZMapp inside the leaves of tobacco plants, but production is very limited. Credit Kentucky Bioprocessing, via European Pressphoto Agency
“It’s absolutely overwhelming,” Larry Zeitlin, the president of Mapp, said in an interview Wednesday. “We are discussing with the F.D.A. the right path to make the drug available to people as quickly and safely as possible,” he added, referring to the Food and Drug Administration.
There were signs that efforts to increase production were beginning. Caliber Biotherapeutics, a Texas company established with funding from the Defense Department to respond to biological threats, has received inquiries from the government about whether it could help manufacture ZMapp, said R. Barry Holtz, the company’s chief science and technology officer.
The World Health Organization said it would convene a panel of medical ethicists early next week to explore the use of the experimental treatment in the outbreak in West Africa. Currently, neither ZMapp nor any other medicine or vaccine is approved for treatment of the virus, but there are several experimental options under development.
How quickly the drug could be made on a larger scale will depend to some extent on the tobacco company Reynolds American. It owns the facility in Owensboro, Ky., where the drug is made inside the leaves of tobacco plants. David Howard, a spokesman for Reynolds, said it would take several months to scale up.
Mapp was started in 2003 by Dr. Zeitlin and Kevin J. Whaley. They have worked together for many years, starting at Johns Hopkins University, on research that uses crops to produce immune system proteins to treat diseases in people.
Dr. Whaley, the chief executive of Mapp, and Dr. Zeitlin have not spoken much publicly since the news of the treatment broke on Monday, saying they are too busy and want to avoid the limelight. The privately held company has only nine people and has been financed solely by government grants and contracts, they said.
They say that major decisions on how to proceed are in the hands of public health authorities.
“We definitely would like to ramp up to have an impact on the Ebola epidemic,” Dr. Whaley said. But he added, “We’re not decision makers on many of these issues. There are regulatory and legal issues that have to be addressed.”
The drug had never before been tried in people, though it and some predecessor drugs had been tested in monkeys, showing some effectiveness. Mapp was only now gearing up to start the larger animal toxicity studies typically needed before testing it in humans, with an eye to doing the first human safety studies in healthy volunteers next year. For that reason there were very few doses available when the Ebola outbreak started.
Now the company is trying to move faster and it is likely the drug will be tested in patients rather than healthy volunteers.
ZMapp uses an approach called passive immunotherapy. Instead of having a vaccine stimulate the immune system to make antibodies that attack the virus, passive immunotherapy simply supplies the antibodies to the patients. For some infectious diseases, these antibodies are extracted from the blood of patients who have survived the infection and presumably have effective antibodies.
ZMapp instead consists of antibodies that are made by exposing mice to a key Ebola protein and harvesting their antibodies. Those antibodies are then genetically modified to make them more like human antibodies and therefore less likely to provoke an immune reaction if injected into people.
Photo
Nancy Writebol Credit SIM International, via European Pressphoto Agency
The gene for each antibody is then introduced into the leaves of tobacco plants using a system developed by Icon Genetics, a German company. The leaves then produce the antibody.
In one study published last year, three out of seven monkeys treated with antibodies developed by Mapp survived being infected with Ebola, even though treatment did not start until four days after the infection. Both animals in the control group died. The treatment worked even better in another study when begun earlier after exposure to the virus.
It turns out another tiny company, Defyrus, based in Toronto, was independently developing a similar treatment with the Public Health Agency of Canada.
The companies agreed to combine the best of their antibodies into a single cocktail called ZMapp, which is what the two American aid workers received. The data for ZMapp in monkeys has not been published but is said to be substantially better than for the predecessor drugs.
Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said it was “too early to make any conclusions about how effective this intervention is,” since it was tested in only two people.
Still, there is interest in scaling it up.
Continue reading the main story Video
Why Ebola Patients Are Rejecting Care
Amid the deadliest Ebola virus outbreak in history, doctors are fighting the disease and also local populations’ fear of medical treatment.
Video Credit By Carrie Halperin on Publish Date July 27, 2014. Image CreditSamuel Aranda for The New York Times
Monoclonal antibodies produced by pharmaceutical companies for use in treating cancer or other diseases are typically made in genetically engineered cells of mammals grown in vats. But Mapp chose to use plants instead because large quantities can potentially be produced more quickly and cheaply.
About 15 years ago, it was thought that genetically engineered crops would be widely used to produce human proteins for use as drugs. When Dr. Whaley and Dr. Zeitlin were both researchers at Johns Hopkins University in 1998, they published a paper with Monsanto scientists about a soybean genetically engineered to produce an antibody against genital herpes. But that idea has largely been abandoned, especially when it comes to using food crops, because of concerns that drugs produced in crops might inadvertently get into someone’s cornflakes.
Even so, research has continued, funded by the Defense Department, on quickly producing proteins in tobacco plants that are grown inside buildings.
“You can start making protein within a matter of days,” said Robert L. Erwin, president of iBio, another company that is working on this technology.
Still, it seems that this product will take several months to produce in any quantity. The capacity of the Kentucky facility is small, meant to support only the small scale human safety tests that Mapp had been planning. The tobacco plants have to be grown for about a month before they can be infected with the antibody gene and the proteins have to be harvested and purified.
“Starting from zero and going to 60 is not so easy, but once you’re at sixty you can keep going at that rate,” Dr. Whaley said. He would not say how many doses could be made and how quickly.
Photo
Kent Brantly Credit Samaritan's Purse, via Associated Press
Dr. Fauci of the infectious diseases institute said officials had been told it would be a moderate amount even after several months. “You’re not talking about thousands of doses or even hundreds of doses,” he said.
But there are some other companies that can also make drugs in tobacco, including Caliber, which has a larger capacity than the Kentucky facility. So the government is exploring using them to supplement production.
“We told them we have the capacity and are ready,” said Dr. Holtz of Caliber. He said that together Caliber and the Kentucky facility of Reynolds could produce large quantities in six months.
Dr. Michael V. Callahan, an infectious disease specialist at Massachusetts General Hospital who has responded on the ground to Ebola outbreaks, said the use of ZMapp for the two Americans raised some concerns given the limited existing supply. “What was the prioritization that allowed these patients to be treated?” he said.
According to the Department of Health and Human Services, the reason was that Samaritan’s Purse, the organization that employed one of the aid workers, contacted the Centers for Disease Control, which in turn referred them to National Institutes of Health, which in turn referred them to Mapp.
Doing clinical trials in Africa will likely require approvals from authorities there. And treating large numbers of patients with ZMapp, which needs to be given intravenously, could be difficult.
“What can you give in an austere treatment environment where there is very little nursing care?” asked Dr. Callahan. Authorities, along with the San Diego biotech company, are trying to figure it all out. Dr. Zeitlin said, “We’re kind of in uncharted territory here.”
Second Drug Is Allowed for Treatment of Ebola
By ANDREW POLLACKAUG. 7, 2014
The Food and Drug Administration helped clear the way on Thursday for a second experimental drug to be tried by people in Africa stricken with the Ebola virus.
The drug, being developed by Tekmira Pharmaceuticals of British Columbia, was in the initial phase of human testing, which is on healthy volunteers, when the F.D.A. last month halted the trial because side effects were observed.
Tekmira announced that the F.D.A., while still saying the drug, called TKM-Ebola, should not be given to healthy volunteers, was now allowing its use to treat patients actually infected with the virus.
“We have been closely watching the Ebola virus outbreak and its consequences, and we are willing to assist with any responsible use of TKM-Ebola,” Mark Murray, the chief executive of Tekmira, said in a statement. “The foresight shown by the F.D.A. removes one potential roadblock to doing so.”
He said the company was evaluating options for use of the drug, which is being developed under a $140 million contract from the Defense Department.
•
Ebola Therapy From an Obscure Biotech Firm Is Hurried AlongAUG. 6, 2014
The drug works by shutting off genes of the virus using a technique called RNA interference. Earlier this week there were reports that a different experimental medicine, made by Mapp Biopharmaceutical of San Diego, appeared to be helping two American aid workers who had been stricken by the disease. Mapp and federal agencies are looking to provide that drug, called ZMapp, to sick people in Africa.
But supplies of both ZMapp and TKM-Ebola are limited. And there are various other obstacles, such as regulatory ones, to be surmounted before the drugs can be used in Africa.
by ROTMANLUV 2023-07-08, 17:34
