No cure: Behind the lack of options to treat Ebola

The absence of a medical cure or vaccine for Ebola has clearly demonstrated that private investment, even when supplemented with government research grants, especially grants oriented towards national defence, cannot be relied upon to tackle infectious diseases that primarily impact the poor and occur where the drug industry's market incentives do not function. It is time to turn to alternative models and approaches, says Edward Hammond.

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AS the 2014 Ebola epidemic in West Africa took root, it became widely apparent that there is no ready drug to cure the disease, nor any vaccine available to stop its spread. Gut-wrenching scenes have been televised worldwide of overworked doctors and nurses isolating victims and treating their symptoms, but unable to cure infections. 

Why is medicine so often helpless in the face of this disease? Where are the potential treatments, who controls them, and why weren't they ready to be used?

Part of the answer is obvious and unsurprising: Before the current epidemic, Ebola only occasionally appeared, usually in remote areas of Africa where, after causing localised mayhem, the virus receded to its poorly understood forest reservoirs. Because rural Africans don't present much of a market to drug companies, particularly for a disease that only appears intermittently, no company ever invested heavily in an Ebola cure.

If that's the case, however, why have so many potential Ebola treatments appeared?  More than a dozen companies are offering possible vaccines or antiviral drugs. But all of these possible cures are in development, don't have regulatory approvals, and have limited or no availability for patients. Were these companies altruistically pursuing an Ebola cure before the epidemic? Did they sagely anticipate a dramatically more intense outbreak and the West Africa epidemic came too soon? 

Neither is the case. Few of the candidate treatments widely mentioned in the media today - both antiviral drugs and vaccines - were developed from the ground up as Ebola treatments. Instead, most candidate therapies for Ebola rely on research and technology whose aim is the treatment of other, more potentially profitable conditions ranging from hepatitis to cancer. Ebola has been an ancillary aim of drug and vaccine development efforts, undertaken not as the primary objective but rather when companies have been able to obtain grants for Ebola research that will, in parallel, advance other goals.

The overwhelming driver of Ebola research has thus not been private investment but the public sector. This includes both the work of public laboratories, such as Canada's National Microbiology Laboratory in Winnipeg, which created a leading candidate vaccine, and research by companies working under public grants and contracts.

For example, the candidate Ebola vaccine typically described as coming from industry giant GlaxoSmithKline is built on vaccine research whose main target is hepatitis C. A version of GSK's hepatitis C vaccine for Ebola was created under an agreement with the US National Institutes of Health, which contributed key expertise, materials and lab work by its governmental Vaccine Research Center.

But while in mid-2014 GSK had pushed the hepatitis version of the vaccine to Phase II human trials, the Ebola vaccine lingered behind. It was untested in humans until Phase I studies were recently initiated with more public funding, spurred by the Ebola epidemic. Even if it works, and despite an accelerated testing programme, it may not be available for the African public until 2016.

In other cases, discoveries were incidental. Brincidofovir, a broad-spectrum antiviral drug recently touted for Ebola and owned by US company Chimerix, emerged from 1990s publicly funded research at the University of California aimed at finding drugs to treat eye infections. BCX4430, an antiviral owned by Biocryst, another American company, appears to have been identified as having potential use against Ebola by the US Army, not Biocryst. Until recently, Biocryst gave BCX4430 little attention compared to its focus on drugs for influenza, gout and other conditions, pursuing BCX4430 to the extent that the government funded research.

Since Ebola was often only a side-interest in research focused on more profitable diseases, many half-developed drugs have resulted, only ready for Ebola to the extent to which they have received public funding, with none ready to treat the disease's victims.

Not only has Ebola typically been a sideline in research, treating Africans hasn't been the primary objective of much of the government investment that has taken place. That's because a substantial proportion of the funding for research into antivirals to treat haemorrhagic fevers like Ebola and its close cousin Marburg virus hasn't come from public health budgets but rather from military coffers. The immediate objectives of these military programmes are to protect troops and stockpile against the (often remote) possibility of a terrorist attack, rather than treating foreign civilians.

For example, JK-05, a possible Ebola drug controlled by China's Sihuan Pharmaceutical, emerged from research supported by the People's Liberation Army's biodefence programme, and appears to have been stockpiled by the PLA for defence purposes. (Some JK-05 has been shipped to Africa, but with the intent of only treating Chinese citizens there, since testing and regulatory approvals for regular civilian use were not obtained.)

JK-05 mirrors brincidofovir from Chimerix, a company that has been kept afloat for years by defence grants from the US government. Brincidofovir, and perhaps the chemically related JK-05, were supported by defence programmes intended to build military stockpiles of treatments against smallpox, a disease (at least until recently) considered by some militaries to be a greater security threat than Ebola.

Understanding these funding dynamics that have ruled Ebola research since at least the early 2000s explains why there's no treatment on the shelf, and why a confusing panoply of partially developed drugs and vaccines must be further tested and sorted out before treatments become available. 

Those dynamics also show why proven antiviral drugs and vaccines against Ebola, both of which may emerge in 2015, even if too late for tens of thousands of West Africans, are unlikely to be drug company miracles. Rather, they will substantially be the result of public sector scientists and publicly funded research, raising questions about patents, and who should profit, if anybody, from efforts to contain the horrifying epidemic.

Public confidence shaken

As the Ebola epidemic gained momentum and desperation mounted in Liberia, Guinea and Sierra Leone, public health officials in developed countries were initially overconfident about their own capacities to both help Africa and control spread of the disease to other regions. Blame for much of the epidemic, health officials declared, was attributable to poor infection control practices in West Africa and the particularly weak healthcare systems in the countries where the disease had taken root.

There is certainly some truth to that explanation for Ebola's spread in Africa - the number of doctors is appallingly low and appropriate equipment and hospitals scarce in Liberia, Sierra Leone and Guinea, a situation that presented preventable opportunities for the disease to spread.

Adding to the confidence, two American health workers who contracted Ebola in Africa were flown back to the US for treatment and recovered from the disease. Both were administered an unusual antibody therapy called ZMapp, an experimental drug grown in genetically engineered plants by an obscure California company. While health officials knew better - there were signs that at least one patient's recovery had little or nothing to do with the drug - they allowed the apparent success to buoy public hopes of a cure.

(ZMapp is a privately owned product of publicly funded biodefence research in Canada and the US. The US and German interests that own the majority of ZMapp are primarily focused on 'pharming' - growing drugs in plants - a controversial technique considered risky from a biosafety perspective. Pharming has a history of commercial failure, in no small part due to opposition from safety activists.)

In an interview published on 29 September, the US's top infectious disease official, Anthony Fauci, declared that the US could 'shut off' any domestic outbreak. He was quickly proven half-right. The next day, an American who travelled from Liberia to Texas was diagnosed with Ebola. He died eight days later, and two nurses became infected while treating him.  With widely reported difficulties, public health officials contained the nurses' cases. While Ebola had been 'shut off' in a manner of speaking, it had been transmitted in the United States and public confidence shaken.

In a European parallel, a Spanish nurse treating a victim that had travelled from West Africa also became infected. It became clear the world over that conditions in Africa weren't the only factor allowing the epidemic to grow. Even the most sophisticated and well-equipped healthcare systems could not reliably control or cure the disease.

While the small number of Northern cases unduly distracted from the far greater human suffering taking place in Africa, the possibility of Ebola taking root on other continents had been demonstrated, changing international perceptions of the severity of the threat.

From the beginning of the epidemic, experts knew that Ebola was incurable, and that there is little to be done for those infected but to treat symptoms and let the disease take its course, hoping for the best. Because previous outbreaks tended to occur sporadically in relatively sparsely populated rural areas - far away from the media spotlight - reducing opportunities for transmission, the brutal reality of an Ebola ward hadn't entered the public consciousness.

By late September, however, few remained naive. Seeking to allay concern, governments, the World Health Organisation (WHO) and Britain's Wellcome Trust were rushing ahead with clinical trials of a number of possible Ebola treatments, suspending normal testing procedures and timelines.

NewLink Genetics, a small US research company that bought rights to Health Canada's candidate Ebola vaccine, has received millions of dollars in new grants, even as Canadians have questioned why an unknown US company should control the fate of the country's publicly developed vaccine, and if commercial interests are being put in front of public health.

Yet NewLink may be as much a symptom of failure in the drug development system as the problem itself. In a stroke of potential financial luck, in 2010 NewLink, whose main focus is cancer research, licensed the candidate vaccine through its tiny biodefence subsidiary (which subsisted on small government grants). The vaccine had languished without active development since shortly after it was created in the mid-2000s and, until 2014, NewLink had also failed to move it far down the course towards approval.

Profectus, a US company with a vaccine very similar to the Canadian one, has received new grants, as has Tekmira, a company with a more speculative drug based on RNA interference technology that, like others, was primarily developed not to treat Ebola but other conditions.

For some companies the Ebola outbreak has been a godsend not only for grants but also in the stock market. Chimerix, the company that has never commercialised a product, was worth as little as $15 a share in May, but hit over $35 by mid-November, in large part on the basis of hopes that a drug it controls will be bought in large quantities to be used against Ebola.

Chimerix's gain in market capitalisation since the epidemic took off, over $650 million as of mid-November, is nearly as much as the entire Ebola aid pledge to date from the United Kingdom (œ475 million or $750 million), Europe's largest Ebola donor and a leader of efforts to aid Sierra Leone.

At least five vaccines are being moved into trials, in one case with two products from different companies used together in what is termed a 'prime boost' regime (two shots spread over time). A half-dozen antiviral drugs are also being tested in humans. 

It is cold comfort for West Africa, but that these tests are occurring in the midst of an Ebola epidemic makes some technical aspects of the trials easier - there is no shortage of people being exposed to the virus, yielding far better data than animal studies - but raises ethical dilemmas about use of placebos and control subjects. Pity the participant in a study who receives a placebo instead of a potentially effective vaccine and later contracts Ebola. Or what to do about vulnerable groups, such as children, the elderly and those with other diseases?

It can be hoped that the phase that is now being entered will end quickly. So many parallel trials, while necessary, divide effort and spending. Some work will not be successful, at least not in a useful time frame for the present epidemic. Adding to confusion and potential waste, some companies too will likely continue to push their drug, even if results aren't as promising as for other products.

Who will pay?

It is impossible to know if any of these candidate vaccines and drugs will be validated as safe and effective in the course of the present epidemic before it winds down as a result of non-pharmaceutical control efforts. Effective treatments may come too late, or they may be crucial. If treatments are approved, they will be regarded as crucial to control future outbreaks, which are a virtual certainty (although it can be hoped that none will reach the present scale again).

This raises the question of who will receive and who will pay for any successful vaccines and antiviral drugs, all of which are covered by patent claims.

For Ebola vaccines, as long as they remain in private hands, and as long as epidemics and the unknown natural reservoir(s) of the virus remain constricted to Africa, routine vaccination is unlikely to become the norm anywhere.

Outside Africa, Ebola vaccination would be unnecessary, except for those who travel to a location where an epidemic was underway or recently occurred. Inside Africa, assuming that the present epidemic is stopped, routine vaccination appears unlikely because economic conditions will not support a commercial market, and public healthcare systems in affected countries are unlikely to be able to buy large quantities of vaccine on their own.

With Ebola's ability to cause destruction so visibly demonstrated, a more reliable market will be created for biodefence stockpiling. Such vaccine reserves are typically costly and mostly maintained by developed countries. 

Bavarian Nordic, a Danish company that also has a candidate Ebola vaccine in the running, holds a contract with the US government to provide it with smallpox vaccine. (Smallpox has been eradicated from the wild since the 1970s.)  The deal is worth up to $1.78 billion, and since vaccines expire, the US and other governments can be counted on to eventually order more. The US and a number of countries in Europe and Asia will also likely stockpile an effective Ebola antiviral drug.

The other market is in aid for Africa. It is presently easy to see a need for tens of millions of doses of vaccine (the population of affected countries and some surrounding areas) and potentially hundreds of thousands of courses of antivirals predominantly delivered as aid. If the epidemic spreads and takes root in more populous African nations, such as Nigeria, vaccine numbers could easily leap much higher.

Before results begin to come back from clinical trials, there are too many unknowns to predict what treatments will be delivered and how. What seems certain is that there will be tension between companies, which will claim proprietary rights and expect profits, versus humanitarian imperatives and the limited resources of affected countries. 

Should companies profit from the Ebola outbreak? Most Ebola therapies have directly and significantly benefited from public grants, contracts and science. Few, maybe none, would exist without that public support.  Since the public has paid much of the development costs for Ebola drugs and vaccines, should companies have any expectation of royalties or other profit in excess of recovering production costs?

Might a better way not be to open production of Ebola products to any entity able to do it? Knocking down patent barriers has had public health benefits with AIDS and other diseases. Doing so seems to offer a much better potential return on the public's investment, and seems more likely to result in affordable products worldwide.

Although Ebola has been dreaded for decades as one of the world's most fearsome viruses, private pharmaceutical research and development failed to provide any viable treatments before the West African epidemic, despite the fact that technical barriers to an Ebola vaccine do not appear insurmountable. 

Since the 2000s, government spending spurred some development of candidate Ebola treatments, but government efforts failed on follow-through because their research and development model relied on market forces that did not work. 

Companies were happy to take public money for Ebola research in order to supplement and advance their work on other, more profitable goals, but no company put in the extra investment needed to bring a product to fruition before today.

US conservatives like Senator Richard Burr, a champion of militarising infectious disease research, have seized upon the situation to demand that more public money be given to companies that promise possible cures so that they can bridge the so-called 'valley of death' between drug discovery and licensure.

But this 'solution', in addition to heightening questions about who should own such subsidised products, relies on the false premise that the market would steer a licensed vaccine to those that need it (rather than limited and pricey production for defence stockpiles). Further public research subsidies might increase the rate of Ebola drug development, but will not correct for markets that won't function - like trying to sell expensive new patented vaccines and drugs in rural Africa.

There are many other cases in both Africa and other regions. For example, it is very hard to imagine bringing to market a vaccine against Bolivian Haemorrhagic Fever (Machupo virus). Lethal in up to a third of cases, the virus occasionally breaks out in the country's north, where per capita incomes are low and the burden of treatable diseases is higher.

Although it will come too late for many thousands in West Africa who have died and will continue to die of Ebola in the coming months, and for a few people elsewhere, it seems likely now that Ebola treatments will be finalised, approved and produced in the next two years, greatly reducing the chances of a future outbreak of such severity. 

While reassuring, that is cold comfort for West Africa, and a lesson for other regions. Ebola has proven especially wicked, but there are haemorrhagic fevers and other ill-understood transmissible viruses, like SARS and MERS, that have the potential to begin to move through human populations across the world. Traditional drug industry research and development, even supplemented by government grants, doesn't serve the need for treatments for these diseases very well either. 

And that is one important long-term lesson: Thousands shouldn't have died before companies were spurred to take half-developed treatments off the shelf and put them into testing. Private investment, supplemented with government research grants, especially grants oriented towards national defence, cannot be relied upon to produce treatments for infectious diseases that primarily impact the poor and occur where the drug industry's market incentives do not function. 

The Ebola outbreak is thus another clear example for the growing movement to change the incentive structure of drug research away from patents and proprietary approaches and towards more open and collaborative models with economic and non-economic incentives.                    

Edward Hammond directs Prickly Research (www.pricklyresearch.com), a research and writing consultancy based in Austin, Texas, USA. He has worked on biodiversity and infectious disease issues since 1994.

*Third World Resurgence No. 290/291, October/November 2014, pp 24-27