ZMapp, the experimental drug that may have already have saved a few patients in Africa, is the most effective anti-Ebola therapy yet, according to a recent Nature paper on rhesus macaques monkeys–and some expert observers.
The drug is a cocktail made of the most effective anti-Ebola monoclonal antibodies, concocted by two groups that teamed up for the purpose. The new combo completely protected 18 of 18 monkeys. There is no clinical trial yet, but the World Health Organization has approved compassionate use of experimental drugs like ZMapp in the current African Ebola crisis.
“These are the most promising results of a therapeutic so far,” said immunologist Daniel Bausch to Drug via email. Bausch, head of the U.S. Naval Medical Research Unit Virology and Emerging Infections Department, was uninvolved with the Nature paper. “That does not necessarily mean it is better than others. It is a little farther down the pipeline in terms of testing and results in non-human primates than some other compounds. [But] we will likely need multiple arms in the war against Ebola. ZMapp continues to appear to be a very promising one.”
Immunologist Thomas Geisbert agreed, also via email to Drug: ZMapp is the most effective therapy so far “if you look at the Zaire species of Ebola in nonhuman primates under the conditions being tested.” Geisbert last month published a Science Translational Medicine paper showing a different drug— TKM-Marburg— saved 12 of 12 monkeys with the Marburg virus, a close relative of Ebola. “It does remain to be seen whether it will hold true.”
Word on the drug is so positive that the U.S. government yesterday pledged $24 million to accelerate ZMapp testing and production. Said U.S. Department of Health and Human Services (HHS) Communications Director Gretchen Michael to Drug via email: “It is critical to establish the safety of the product by testing it in humans.”
Clearly works days after symptoms appear
Interestingly, while the above two scientists earlier disagreed whether studies clearly show yet that TKM-Marburg works after symptoms appear, they agree this study establishes ZMapp does. “In these non-human primate experiments, we want to mimic our real-world need to treat people at the times that they would normally come to medical attention, i.e. after a few days of illness, and when virus replication is getting higher,” said Bausch. “It is important to note that in [Ebola] there is a very clear correlation between level of virus and severity of illness. In this experiment they were able to do exactly that, saving the non-human primates up to five days after infection when they were sicker…longer than we’ve seen in previous experiments.”
Furthermore, said Bausch, there is evidence the drug could work even better in humans. “Also note that the time course of disease in these types of experiments is somewhat accelerated relative to what we see in humans,” he said. “This may relate both to genetic differences between species and to the fact that the standard challenge doses for all these types of non-human primate experiments, including this one, are very large, probably much more than what a human usually gets when infected. Considering that, the results are perhaps even more promising when we think of extrapolating the results to humans, in which you’d have a little more time to get the drug into them, and usually have to inactivate a little bit lower level of initial virus inoculum.”
Agreed Geisbert via email, ZMapp is the best so far because the other promising drugs making press recently— TKM Ebola and TKM Marburg— have not been analyzed as extensively. “It is only because we have not tested the TKM Ebola in non-human primates at three days yet, so we don’t know whether it would work then or not….TKM Ebola and TKM Marburg have just not been tested at these later time points yet.”
However, said Geisbert in a commentary accompanying the Nature paper, the ZMapp crews’ work is still a “monumental achievement.” The teams “administered a lethal dose of Ebola virus to three groups of six animals, and then treated them with three doses of ZMapp. The first group received therapy at three, six, and nine days post-infection; the second group at four, seven, and 10 days; and the third group at five, eight, and 11 days. Remarkably, all the animals survived, and were found to have undetectable viral loads by 21 days after infection.”
Defied researcher’s expectations
At a press conference, senior author Gary Kobinger said his group at the Public Health Agency of Canada, and a team at Mapp Biopharmaceutical Inc., decided to get together after each found their own antibodies effective. The resulting three antibodies in the Nature paper work “fantastically well…The level of improvement was at least beyond my own expectation.” The winning cocktail contains two antibodies from the Canadian group; one from Mapp.
Monoclonal antibodies work by targeting, and neutralizing, viruses. Geisbert told Drug that “it should be noted the authors used the Kikwit variant of the virus in these experiments, because the Guinean strain from the current West African outbreak was not available in time for this part of their study. However, they went on to show that ZMapp inhibits replication of the Guinean strain in cell culture.”
Limited availability, but acceleration now likely
One problem: no one knows for sure if the drug will work in humans. Two of seven patients getting ZMapp (via “compassionate use”) have died (one after receiving only one of the three recommended doses). While the other patients are doing well, only controlled clinical trials can absolutely prove drugs effective. And some 40 percent of Ebola patients recover on their own.
Furthermore, while Kobinger noted at the presser that significant doses of the drug may be available by summer 2015, no doses are left now. It can take Mapp’s processing facility— Kentucky Bioprocessing— a month to make 20 to 40 doses “once it’s going,” Kobinger said. (The monoclonals are generated in plants.)
But, he said, other companies may get involved.
On Tuesday, the U.S. HHS’s Biomedical and Advanced Research Development Authority (BARDA) made that possibility more real when it announced ZMapp work would accelerate with a new $24.9 million, 18-month contract with Mapp Biopharmaceutical. The contract offers technical support in both manufacturing and regulatory areas. The goal: FDA approval. Funds may increase to $42.3 million.
“The contract awarded today by BARDA supports improvements in process development that will provide a small amount of the ZMapp product to be used for early stage clinical safety studies and nonclinical studies needed to demonstrate the drug’s safety and efficacy,” Michael told Drug via email. “Working with Mapp Biopharmaceutical, we are exploring whether…other facilities may be able to assist with production of ZMapp. BARDA has performed site visits at other tobacco-plant-based biopharmaceuticals and is evaluating their availability and feasibility in producing the ZMapp product candidate this fall.”
This new Mapp project represents the first BARDA program to help the development of a product fighting viruses prompting viral hemorrhagic fever. BARDA is working with other U.S. agencies to optimize, expand and speed development of Ebola therapeutics and vaccines. Other potential Ebola drugs and vaccines, by other groups, are entering early clinical trials.
Ebola has killed over 1,500 people in four countries since March.