Fighting BioTerror
© 2011 FrontLine Security (Vol 6, No 4)

The spraying of the deadly Ebola virus into a crowded subway, for example, could kill or injure hundreds of civilians. Or, as in the movies “Contagion” and “Outbreak,” entire towns might be quarantined and millions infected by a virulent, mutated bat virus or an Ebola-like virus, respectively.

Shocking Lack of Preparedness
Yet the United States – a key target – still lags badly in planning for bio attacks. It must be remembered, of course, that any such attack on the United States could affect Canada as well. Various scientific and government committees have issued “report cards” rating the American preparations as ‘failing’ in many cases, and no ­better than a ‘B’ in others. For instance, in October, the Bipartisan WMD Terrorism Research Centre – a nonprofit orgnization composed of former politicians, retired military officials, and public health experts – released a report entitled 21st Century Biological Threats that gave the United States 15 Fs, 15 Ds, 7 Cs, and 8 Bs (and disturbingly, no As), in areas such as development and dispensing of medical responses, vaccines, and antidotes. The report warns that “the United States is unprepared to respond to a global outbreak of a deadly virus for which we have no medical countermeasures.” A presidential commission on weapons of mass destruction last year gave the U.S. government similarly low rankings.

To cope with the threat, the U.S. Department of Defence has established a special program – the Defence Threat Reduction Agency (DTRA) – to seek out and finance research into biological countermeasures. Already, several projects are underway, including a multimillion-dollar contract with a Canadian company from Burnaby, British Columbia and an American company headquartered in Bothell, Washington. The key problem, obviously, is ­testing. It would be unethical to deliberately infect people with Ebola and other fatal viruses in order to test a new drug, therefore, how can researchers be certain that their medications will work?

The Swiss Option
Evolva, a small biotech company near Basel, Switzerland, may have come up with a unique answer: a drug that will be effective against both influenza and Ebola. It has received approval from the U.S. Food and Drug Administration to launch human influenza trials, along with a US$27 million, five-year grant from the Defence agency for animal trials for Ebola.

There’s obviously no ethical problem with testing people who have the flu. Evolva will be “using the influenza trials to gain information,” says president Alexandra Sorensen, “and we can use that to build the Ebola case.”

Evolva’s secret? Most flu medicines target a specific strain of the virus; Evolva’s drug focuses instead on mechanism the human immune system uses to fight viral attacks in general. Indeed, the drug could – in theory – be effective against other viruses besides flu and Ebola.

That fits in nicely with the DTRA’s mandate which looks for “broad-spectrum approaches to developing medical countermeasures,” according to Alan S. Rudolph, director of the agency’s chemical and biological technologies directorate. As he explains, it’s not cost-effective “to develop products for specific agents on specific lists. There are too many threats, and the threats are too dynamic.”

However, even under stringent legal restrictions, research into bioterror medicines is not totally impossible. Bioterror drugs – like all drugs that come before the FDA – can, and indeed must be tested for safety on healthy humans, and for effectiveness on animals that are deliberately infected with the disease. Normally, drugs are then tested for effectiveness on humans who have the disease. Because of the ethical risks of testing humans in cases like Ebola (a fatal disease with no cure), a special FDA rule allows approval solely on the basis of human-safety and animal-efficacy tests, without human-efficacy trials. This rule is for “a potentially lethal or permanently disabling toxic substance or organism” and is the standard that most researchers are following in the DTRA program. Still, the evidence would be a lot stronger if the drug could be tested for effectiveness on people.

Drugs are just one aspect of the seven-year-old biotech company’s operations. It has about US$27.5 million in 10 partnerships with chemical, pharmaceutical, and other companies, plus the Danish Council for Strategic Research and the U.S. Defence Department, to develop products ranging from food flavourings to crop protection to medicines. The vanilla flavouring molecule, for example, which Evolva has been working on with New York-based company International Flavours and Fragrances, could be available for sale by 2014. Yet, despite the variety, all this research is based on ordinary baker’s yeast. Evolva concocts artificial chromosomes that are injected into the yeast to create the various specialized molecules.

Electron micrographic photo of Ebola virus.

The potential bioterror antidote is a drug called EV-077. Essentially, it blocks the thromboxane (TP) receptor, a versatile mechanism that can perform a range of functions – mainly negative ones – in ­different human tissues.

One such function involves Type II diabetes, where the receptor spurs an increase of platelets in the bloodstream, which in turn raises the risk of heart attack and inflammation. Evolva is testing EV-077 for treating coronary side effects of that disease (not the disease itself). The company finished Phase I safety trials this summer, and is now seeking a large pharmaceutical manufacturer to help it conduct Phase II ­trials for efficacy, to be conducted on up to 64 people at one site. Both trials are taking place in Germany.

The TP receptor is also a factor in the human immune system. In order for the body to fight off a viral attack – including from the influenza or Ebola viruses – two types of immune cells must interact in a certain way. Scientists believe that viruses (and other disease-causing microorganisms) can interfere with this interaction through a complex process that ultimately stimulates the TP receptors.

The first step was to expose animals to the influenza virus and test the drug on them. In trial results published a year ago, animals that were given EV-077 experienced fewer symptoms, compared with control subjects that got the standard flu drug Tamiflu.

The next step is safety trials on about 20 healthy people. (Even though the drug’s safety has already been proved with diabetes, company officials explain that more trials are needed for the influenza indication, because diabetes is a chronic condition, while flu is acute.)

After that, the crucial question is human efficacy – whether EV-077 can have the same beneficial effect on humans who have the flu as it did on animals. And how about Ebola fever? Although the two diseases attack different physiological processes (flu lowers the level of the hormone cortisol, while Ebola interferes with blood coagulation), the body’s immune response to both is similar – and, according to Evolva scientists, that’s one reason for hope.

More hope comes from some unusual results in the animal testing. Normally, scientists might expect to rejigger the dosage when comparing two diseases like flu and Ebola. Assuming the influenza tests on people showed efficacy, says Neil Goldsmith, Evolva’s chief executive, “you will look at the dose response in humans for flu, and then you will look at the same points measured in animals for Ebola, and you will extrapolate from the human data to the animal data, in an effort to predict a human dose [for Ebola].” However, in this case such an adjustment may not be necessary. When animals (the company won’t disclose what type) were infected with Ebola, “the dose that is efficacious for flu models is quite similar to the dose that is efficacious for Ebola,” says company president Sorensen.

The possibility of multipronged testing and approvals carries several advantages. As with other bioterror drugs, if it passes the human safety trials and the animal efficacy trials, the FDA could approve EV-077 for Ebola under the “animal rule.” But in addition, the regulators could authorize it for influenza in the standard way, based on eventual human efficacy trials – and ditto for diabetes, for that matter.

As soon as it’s authorized for one disease, EV-077 could be legally prescribed “off-label” for any other condition – such as a bioterror attack – without awaiting further regulatory approval, according to American law. This happens with nearly half of the prescriptions written in the United States, especially those for cancer, certain mental illnesses, and rare diseases.

Another advantage to the multiple usage lies in the profit potential. Goldsmith estimates that EV-077 could bring in more than US$500 million a year as a flu treatment and as much as US$2 billion for diabetes. By contrast, the bioterror use – essentially, purchases by the Pentagon for stockpiling – would probably come to just “tens to low hundreds of millions of dollars,” Goldsmith says. He estimates that the stockpiles might have to be replaced every two years.

The Defence Department grant covered only the activity through preclinical testing, and expired in January. However, if the company can get next-stage funding, it may find a more active government partner. Critics assert that the grants and research have produced paltry results to date. “We had been perhaps more of a strictly funding source,” doing fairly cursory reviews, admits Dr. Rudolph of the Pentagon. The agency has now established a new translational medical division, and is “getting more engaged to help guide companies in managing the appropriate technology studies, preclinical design, and efficacy studies.”

Other firms are also winning Pentagon funding to work on Ebola countermeasures, and some of them have already progressed further than Evolva, For instance, the agency has given Tekmira Pharmaceuticals, a biotech company in British Columbia, US$34.7 million to investigate manipulating three crucial Ebola genes. The company, working with scientists from Boston University, has achieved preliminary success with two different dosages on seven rhesus monkeys that were infected with Ebola. The biggest grant (US$291 million) has gone to a company based in Washington State, AVI BioPharma, which is investigating both Ebola and another deadly viral disease – ­Marburg Fever. That company has started Phase I safety trials on people, however, all of these other products suffer from the typical testing problems, because they attack a specific virus, rather than a general virus.

The Challenges
Even with its advantages, EV-077 faces plenty of hurdles. Most likely, at least half a dozen years and dozens of trials lie ahead. And it may fail in ordinary ways.

For starters, as with any drug, trials may uncover unexpected and serious side effects. Or the medication may not effectively fight the disease – either flu in humans or Ebola in animals. Then, even if it passes those tests, the animal results may not be completely applicable to people. “You can only draw very limited inferences from animal models,” warns Jonathan Kimmelman, an associate professor of biomedical ethics at McGill University in Montreal. After all, he points out, all drugs begin by being tested on animals, yet only 11% of those that pass the animal testing ever make it to market.

But what’s the alternative? Two other standard methods of bypassing human trials – testing on cell cultures or utilizing computer modeling options – are even less applicable in the real world. “I can tell you many times where a compound does wonderful things in cell cultures and does nothing in humans,” Kimmelman remarks.

Another possibility is to wait for an outbreak to occur. However, and luckily, those are rare. Moreover, they usually ­happen in remote locales in Africa or Asia, which present logistical and cultural problems. For instance, when Pfizer in 1996 conducted field tests of the experimental meningitis medication Trovan on 200 children in Nigeria, 11 children died, dozens more were harmed, and the company was accused of violating international law by not fully informing the children’s families of the risks. Pfizer claimed that it acted out of philanthropic motives and that the victims died of the original meningitis, not Trovan; however, in 2009 the drug maker signed a US$75 million settlement with the local government. (This controversy is considered the inspiration for John le Carre’s 2005 novel, The Constant Gardener, which was later made into an award-winning movie.)

Beyond the political controversy, there are basic scientific problems with field tests, because the living conditions are far different from those in the American or European cities that are most likely to be bioterror targets. Western urban residents have different illnesses, diets, and cultural habits that could affect the way a drug works, compared with people in the areas where Ebola might occur naturally, Kimmelman of McGill notes. “Unless you’ve actually tested in the exact disease, you cannot draw any inferences.”

Thus, for all the obstacles, we can take comfort in the knowledge that medical scientists, in labs around the world, continue to search for a verifiable Ebola treatment. And any kind of testing would seem better than waiting for a bioterror attack.

Fran Hawthorne is an award-winning author and journalist, specializing in health care and business ethics at Beacon Press. Her most recent book, The Overloaded Liberal, has received excellent reviews.
© FrontLine Security 2011