The World Health Organization's (WHO) assistant director general, Marie-Paule Kieny, announced on August 12 that the agency would allow the use of unregistered therapies and vaccines to thwart the Ebola Zaire virus epidemic in West Africa. The WHO stressed, however, the importance of obtaining informed consent, maintaining confidentiality, preserving dignity, involving the community, and ensuring the release of safety and efficacy data to the wider scientific community. Several biotech companies stepped up to offer experimental treatments, although all had insufficient supplies to offer more than a trickle of therapeutic options.

Ebola treatments and vaccines have only been tested in animal models, with Tekmira's drug the only exception. Credit: CARL DE SOUZA/AFP/Getty Images/Newscom

Several days before the WHO announcement, San Diego–based Mapp Biopharmaceuticals had provided its Ebola treatment, ZMapp (MB-003) to two US health workers and a Spanish priest who had been infected with the virus in Liberia. As Nature Biotechnology went to press, the aid workers, who had returned to the US, were recovering, but the Spanish priest had succumbed to infection.

ZMapp is a cocktail of three monoclonal antibodies (mAbs) developed from work carried out at the US Army Medical Research Institute for Infectious Diseases in Frederick, Maryland, in the 1990s (Science 287, 1664–1666, 2000). The current cocktail is a collaboration between Mapp, another San Diego–based startup LeafBio, biodefense company Defyrus of Toronto, and the Winnipeg, Manitoba–based level-4, National Microbiology Laboratory at the Public Health Agency of Canada, all largely funded by the US Department of Defense and the National Institutes of Health (NIH). The three mAbs target nonoverlapping Ebola virus epitopes (the mucin-like domain as well as the 6D31 and core epitopes of glycoprotein 1). They are murine mAbs engineered with human constant regions and manufactured in transgenic Nicotiana benthamiana tobacco lacking plant-specific N-glycan residues. By August 11, there was not much ZMapp to go around; the company announced it had given free of charge all the product it had in stock—enough to treat only six people. The company is currently gearing up to produce up to 50 treatment courses by the end of the year, enough for a small safety study.

The same month, Vancouver, British Columbia–based Tekmira Pharmaceuticals also announced it was making available its experimental drug TKM-Ebola after the US Food and Drug Administration (FDA) lifted a clinical hold on a phase 1 trial initiated in January in which volunteers had suffered several adverse events. Tekmira is the only company to have advanced an Ebola program as far as the clinic—all other companies with active programs are in the preclinic (Table 1).

Table 1 Ebola treatments and vaccines in preclinical development
Full size table

TKM-Ebola has previously proved protective in non-human primates injected with an otherwise lethal dose of Ebola virus. Rather than a cocktail of mAbs, TKM-Ebola is a mixture of three intravenously injected 2′-O-methyl modified G/U short interfering RNA (siRNA) oligos targeting Ebola Zaire virus transcripts encoding polymerase L protein, viral protein 24 (VP24) and VP35. The siRNAs are packaged in Tekmira's stable nucleic acid-lipid particle (SNALP) technology, comprising synthetic cholesterol, dipalmitoyl phosphatidylcholine, 3-N-((ω-methoxy poly(ethylene glycol)2000)carbamoyl)-1,2-dimyrestyloxy-propylamine and cationic 1,2-dilinoleyloxy-3-N,N-dimethylamino propane. Although the company declined to respond to Nature Biotechnology's request for an interview, it disclosed in August that it was still not clear whether “an appropriate framework for the use of this product will be found” in the West Africa outbreak.

Elsewhere, Cambridge, Massachusetts–based Sarepta Therapeutics (formerly AVI Biopharma) also urged federal officials to make its oligo drug AVI-7537 available. Sarepta's drug is a mixture of two positively charged, phosphorodiamidate morpholino antisense oligos containing piperazine moieties along the backbone that target VP24 and VP35 transcripts. The company says the drug has been on hold since 2012 when funding from the US government dried up, but it has enough doses of the intradermally injected drug to treat about two dozen patients. The treatment has not yet completed a phase 1 trial, but it has shown cure rates of 60–80% in Ebola-infected rhesus monkeys.

Given the meager amounts of all these experimental treatments available, health authorities have been turning to more traditional small-molecule therapeutics, such as Birmingham, Alabama–based BioCryst's nucleoside analog BCX4430, and preventative approaches, such as vaccines (Table 1). The Canadian government has offered WHO up to 1,000 doses of an experimental Ebola vaccine using epitopes similar to those targeted by ZMapp. This adenoviral vector vaccine, developed by scientists at the Public Health Agency of Canada and licensed to US company BioProtection Systems, a unit of Ames, Iowa–based Newlink Genetics, has never been tested in humans. The company has stepped up manufacturing to allow human trials to begin quickly. NewLink has a contract with the US Defense Threat Reduction Agency to fund preclinical studies, including the manufacturing of clinical material.

Thus far, the Mapp, Tekmira and BioProtection Systems products have been approved for emergency use through the FDA's animal rule, which allows laboratory animal data to be used to show efficacy when human trials are not logistically or ethically feasible. This emergency rule was passed in 2002, in the wake of a series of anthrax attacks in the US. Its latest version allows the agency to approve drugs “to prevent or ameliorate serious or life threatening conditions” to be used as countermeasures, before the threat exists, because approval is based on efficacy testing in animals and safety testing in humans only. Recently, approval was given for Johnson & Johnson's Levaquin (levofloxacin) for plague, and for GlaxoSmithKline's raxibacumab for inhalation anthrax (Nat. Biotechnol. 31, 8, 2013). Last month, the FDA also authorized a reverse transcriptase (RT)-PCR diagnostic assay for Ebola Zaire, developed by the Department of Defense, after the Department of Health and Human Services announced that it had determined that “the Ebola virus presents a material threat against the US population, sufficient to affect national security.”

Numerous other Ebola treatments are in various stages of development (Table 1), predominantly through government-funded biodefense programs. “Without federal agencies, in particular NIH [US National Institutes of Health] and the Department of Defense, having put large amounts of dollars into Ebola research, I can't imagine we would be anywhere as close to potential treatments as we are today,” says Thomas Geisbert, a professor and expert in Ebola at the University of Texas Medical Branch at Galveston.

Investors have long been wary of supporting high-risk pathogen programs. “If you look at Ebola and Marburg [viruses] from a commercial market point of view it is not perceived as being of high value even though we have an $18-million contract with [NIH] and we have worked on filoviruses for a number of years,” says Paul Chaplin, president and CEO of Kvistgaard, Denmark–based Bavarian Nordic, which is working on an Ebola treatment. “In fact if you look at the investment analysts who evaluate our company, you will see that none of them include our filovirus program in their valuation models.”

It remains to be seen whether the West African Ebola outbreak will change the attitude of private investors or reinvigorate government interest in supporting companies developing filovirus treatments. In the meantime, the clamor for investigational treatments will likely intensify. The epidemic is already the worst on record; 1,176 cases had been confirmed by August 12 with 660 deaths. The toll, however, may be even higher: on August 13, WHO reported 2,127 suspected and confirmed cases and 1,145 lives claimed by the outbreak across Guinea, Liberia, Nigeria and Sierra Leone.