Ebola: Behind the experimental drugs

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As Canada prepares to ship out as many as 1,000 doses of an experimental Ebola vaccine, it is also preparing to hand off to international medical experts the gut-wrenching decisions about who in West Africa will receive an injection that could protect against the deadly virus – or cause unanticipated and dangerous side effects.

Here is an explainer behind the vaccine:

THE DRUGS

ZMapp:

Perhaps the most widely mentioned drug during the current Ebola outbreak is a serum developed by a San Diego-based company called Mapp Biopharmaceutical Inc.

The drug, called ZMapp, is a still-experimental Ebola treatment that functions in a similar way to some vaccinations. Usually, vaccinations work by exposing the body to a small quantity of some virus, prompting the immune system to produce antibodies. However, in the case of especially aggressive and fast-moving diseases such as Ebola, that process can be too time-consuming. Instead, ZMapp delivers the antibodies directly to the body. The drug is a cocktail of three antibodies – two of which latch on to the virus and attack it directly, while the third one alerts the immune system to the presence of the virus. In early trials, ZMapp has shown positive results. Perhaps most important, the drug also has a relatively wide window of effectiveness. In animal studies in Winnipeg, the drug was administered to non-human primates that had been infected between one and three days earlier – with very successful results, according to Erica Ollmann Saphire, a professor with the California-based Scripps Research Institute and an expert on viral hemorrhagic fever pathogenesis. Indeed, even in some cases where the disease had progressed to the hemorrhagic fever stage, some subjects could still be saved.

TKM-Ebola:

Another potentially effective treatment for the Ebola virus is being developed by a pharmaceutical company called Tekmira Pharmaceuticals Corp., based in Burnaby, B.C.

The drug, called TKM-Ebola, attacks the genetic material of the virus – and while testing is still far from complete, it has shown positive results.

For years, Tekmira worked on the drug in association with researchers at Boston University, and using research funding provided in part by the U.S. Department of Defense as part of a $140-million contract.

The basis of the treatment is a mechanism called Ribonucleic acid interference, or RNAi. Drugs based on RNAi try to shut down genes responsible for certain disease. The RNAi mechanism itself has been well-studied by biologists for years. To produce the Ebola drug, however, Tekmira combined the RNAi treatment with its proprietary mechanism designed to deliver the treatment to disease sites.

In early-stage testing, the drug showed significant potential. In a preclinical study published in The Lancet, researchers found that non-human primates could be protected from an otherwise lethal dose of the virus using the TKM-Ebola treatment.

Vaccine:

An Ebola vaccine, generally, functions in a manner similar to many other vaccines. In essence, the body is given a small taste of the virus. This prompts the immune system to produce antibodies to fight the small infection, and as a result the subject is protected from full-blown iterations of the virus in the future.

There are myriad researchers in the U.S. and Canada working on such vaccines, and many have shown signs of progress. In one study completed by an American pharmaceutical company, animals given an Ebola vaccine before the onset of infection had a 100-per-cent protection rate. In some cases the vaccine managed to stop the virus even when administered shortly after an infection.

But because the vaccines have had almost no testing at all on human subjects, it is unclear whether the promising results will translate. A vaccine would also be of slightly limited use, compared with other treatments, in helping those stricken during the current Ebola outbreak, in part because it is often difficult to determine when a patient was infected, and the vaccine's effective window of treatment appears to be smaller than that of drugs such as ZMapp.

THE MANUFACTURERS

Zmapp:

Mapp Biopharmaceutical Inc. barely existed on the public radar before the recent Ebola outbreak. However, the company's drug, ZMapp, generated massive public attention after it was used to treat two American patients who fell ill with the Ebola virus. Since then, Mapp has been inundated with requests for the drug – requests the company is largely unable to meet because, until the outbreak, ZMapp was still in early experimental stages.

Zmapp is not entirely the work of the San Diego pharmaceutical firm. The drug is in part a joint effort with a small Canadian company called Defyrus Inc., which provided some of the antibodies used in the treatment.

After initially speaking openly about the development of the drug, the makers of ZMapp have shied away from providing much more information.

"The available supply of ZMapp has been exhausted," the company said in a terse statement this week. "We have complied with every request for ZMapp that had the necessary legal/regulatory authorization. It is the requestors' decision whether they wish to make public their request, acquisition, or use of the experimental drug."

Contacted by the Globe, Larry Zeitlin, president of Mapp, declined to comment.

TKM-Ebola:

Since its Ebola treatment came under the public spotlight at the start of the current Ebola epidemic, Tekmira Pharmaceuticals Corp. has seen its stock price take a roller-coaster ride – jumping on Monday on news that the company may have a viable Ebola treatment, and then dropping again later in the week as the initial investor euphoria died down.

In July, the U.S. Food and Drug Administration put a hold on Tekmira's Ebola treatment program trials. But as the outbreak grew, the regulatory body eased that restriction to allow for the treatment to be administered to patients with suspected or confirmed cases of the virus.

Keen not to raise expectations (nor inflate its share price) without ironclad evidence that the treatment works, Tekmira has played down the potential widespread use of its drug in the outbreak.

"Our therapeutic, TKM-Ebola, is currently an unapproved agent and the regulatory framework to support its use in Africa has not yet been established," the company said on Wednesday. "Given the severity of the situation, we are carefully evaluating options for use of our investigational drug within accepted clinical and regulatory protocols."

A Tekmira representative said the company has no further comment about its Ebola treatment at this time.

Vaccine:

A number of companies and researchers around the globe are working on Ebola vaccines, but perhaps the epicentre of development and distribution at the moment is in Canada.

A vaccine that Canada is offering to send to Ebola-stricken countries was developed at the National Microbiology Laboratory in Winnipeg, which is part of the Public Health Agency of Canada and is the centre of Ebola-related research in this country. The lab has in its possession about 1,500 doses of the vaccine, known as VSV-EBOV, all of which were produced in Germany. Canada has offered to donate as many as 1,000 doses, keeping the remainder in Canada for research or for distribution in the unlikely event that Ebola turns up in Canada.

Although Canada still holds the intellectual property rights to the vaccine, it has licensed the rights to develop it to an Iowa-based company that said Wednesday it planned to step up production of the vaccine. Gary Kobinger, the chief of special pathogens at the National Microbiology Laboratory, said he expected a second batch – over and above those sitting in the Winnipeg lab – could be produced in two or three months.

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THE PROCESS

ZMapp:

So far, ZMapp has been administered to at least three patients. Two American health workers who became infected with the virus are now in a medical facility in Atlanta, and appear to be showing signs of progress. A third patient, a 75-year-old Spanish priest, died. In another case, medical officials decided not to give the untested drug to another doctor, who subsequently succumbed to the disease. It is uncertain how effective the drug would have been in treating the patient.

This week, the World Health Organization decided that the drug, despite being far from fully tested, could ethically be used as possible treatment in the Ebola outbreak. Since that time, the makers of ZMapp have quickly exhausted their supply of the drug, giving it away for free to a number of parties, including the government of Liberia, which planned to treat several infected doctors with the medication.

Mapp Biopharmaceutical is now scrambling to make more doses of the treatment, as demand far outstrips supply. The antibodies used in the drug are grown inside modified tobacco plants, and that process is usually slow. Now the company is trying to work with a number of partners to speed up production considerably.

TKM-Ebola:

Unlike ZMapp, Tekmira's Ebola treatment has yet to reach infected patients. However the company is not ruling out a move similar to Mapp Biopharmaceutical's that would provide its drug to outside parties.

Tekmira chief executive officer Mark Murray said on Wednesday that the company is closely monitoring the Ebola outbreak, and has had discussions with multiple government and NGO representatives, as well as those from the World Health Organization.

These discussions may result in an appropriate "framework" by which Tekmira could provide its investigational drug, but Mr. Murray cautioned that "there can be no assurance that … an appropriate framework will be found."

Even if Tekmira reaches an agreement to make its drug available, it is unclear how much supply the company has, and how quickly it can produce TKM-Ebola. Company executives have said only that they "have an inventory" of the drug, without giving more details. Tekmira is also exploring how much time it would take to make more than the current inventory, but would offer no more specific a timeline than to say the process would likely take "months."

Vaccine:

Canada will soon begin providing doses of the Ebola vaccine to the World Health Organization, after Ottawa approved the move earlier this week. The majority of Canada's supply of the vaccine will go to the WHO – about 1,000 doses – with a small batch remaining in the country in case an instance of the disease shows up in Canada. Ottawa is also sending about $185,000 to the WHO to aid in other efforts to fight the outbreak.

It is difficult to estimate how far the vaccine will go, in part because it may be used in many cases as a form of treatment, rather than vaccination, which requires a different dosage. As with other forms of treatment, it will likely take a few months to make more of the vaccine. However the government has licensed its vaccine to some outside drug makers, who are also working on producing more doses.

There are other challenges that are likely to come up only after the vaccine is used on human patients – chiefly, it is unclear whether the vaccine's positive results in animal tests will carry over to human subjects. There is also the thorny ethical issues of which patients will get the doses.

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THE WINNIPEG LAB

A nondescript building in Winnipeg is probably not the first thing Canadians picture when they think of Ebola, the brutal virus that has killed more than 1,000 people in West Africa in the worst-ever outbreak of the virus. But the National Microbiology Laboratory in Winnipeg is the Canadian epicentre of research into Ebola and its cousin, the Marburg virus.

Part of the Public Health Agency of Canada – the co-ordinating body set up after the SARS crisis in 2003 – the NML is an infectious disease surveillance and research lab that employs more than 400 people and boasts high-level containment labs for humans and animals in a single building.

Scientists connected to the NML developed the experimental Ebola vaccine that Canada has promised to ship to West Africa.

The research group, led by Gary Kobinger, chief of special pathogens at the NML, also developed two of three monoclonal antibodies in an experimental Ebola treatment called ZMapp, which was given to three westerners – two Americans, who are reportedly recovering, and a Spanish priest who has since died.-Kelly Grant