Alex Nading explains how brincidofovir's path to the front lines of the Ebola crisis underscores the contingent, speculative, “chimeric” nature of contemporary global health

Nading, Alexander

Nading, Alex

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UCLAlimnTitleEbola, Chimeras, and Unexpected SpeculationPermalinkhttps://escholarship.org/uc/item/8ms2h5fgJournallimn, 1(5)AuthorNading, AlexPublication Date2014-12-18Copyright InformationThis work is made available under the terms of a Creative Commons Attribution-ShareAlike License, available at https://creativecommons.org/licenses/by-sa/3.0/eScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaLIMN EBOLA'S ECOLOGIES   43 Ebola, chimeras, and unexpected           speculationIF YOU WERE STUDYING EBOLA before 2014, chances are that you wouldn’t have heard of brincidofovir, an antiviral drug cre-ated by a North Carolina company called Chimerix. Within the span of a few weeks in October and November 2014, however, brincidofovir became one of the most promising Ebola countermeasures in clin-ical development. The story of the drug’s path to the front lines of the Ebola crisis underscores the contingent, specula-tive, “chimeric” nature of contemporary global health. BRINCIDOFOVIR WAS NEVER MEANT to be an Ebola drug. It was designed, in part, as a smallpox therapy. Commercial drug mak-ers have had vaccines and drugs for small-pox and Ebola in their pipelines for some time, but the market has tended to be too small to attract much private investment. Although humanitarian groups have pub-licly encouraged (and financially pushed) pharmaceutical companies to develop treatments for “neglected diseases,” until very recently, they gave Ebola minimal attention in these efforts (McGoey et al. 2001). In fact, U.S. biopreparedness pro-grams were paying more attention to Ebola, which joined smallpox on a list of “select agents.” In the wake of a series of international bioterror attacks in the 1990s, the U.S. Department of Defense (DOD) began investing in pharmaceuti-cal countermeasures to potential bioter-ror threats, including anthrax, smallpox, and Ebola. After the 2001 anthrax scare, the National Institute for Allergy and Infectious Diseases (NIAID)—a domestic agency of the Department of Health and Human Services (HHS)—saw an increase in its budget for biothreat research. Both DOD and NIAID used this money to entice private pharmaceutical companies to de-velop drugs and vaccines, but by the end of the George W. Bush administration, bil-lions in (largely uncoordinated) military and civilian investments failed to move most potential countermeasures out of the laboratory and into late-stage clini-cal trials. This became painfully clear in 2014 when supplies of ZMapp, a drug that showed potential against Ebola in early animal studies, quickly ran out. Even though HHS had founded the Biomedical Advanced Research and Development Authority (BARDA) in 2006 to move drugs like ZMapp from labs to clinical develop-ment more efficiently, the agency’s fund-ing had consistently fallen short of the to-tals necessary for full-scale tests (Greeley and Chen 2014).Amid this series of bureaucratic and appropriations missteps, the government did have a few successes. Brincidofovir was one of them. It was just the kind of drug that the government’s medical countermeasure programs were initiated to support, a therapy that would be ef-fective in patients already infected with a virus: the smallpox virus. Chimerix Alex Nading explains how brincidofovir’s path to the front lines of the Ebola crisis underscores the contingent, speculative, “chimeric” nature of contemporary global health.44   LIMN EBOLA'S ECOLOGIESreceived millions in funding, first from the NIAID and later from BARDA. The compa-ny fought vigorously for BARDA’s atten-tion, even filing a complaint with the U.S. Government Accountability Office (GAO) in 2011 when BARDA inserted an option into its contract with a competitor firm to purchase millions of extra doses of its pro-spective smallpox therapy. The GAO up-held Chimerix’s complaint. The company used the language of biopreparedness and market fairness to justify the complaint, saying that the GAO’s decision to nullify BARDA’s option to buy extra doses of the competing product “allows BARDA the opportunity to competitively procure a second smallpox antiviral, consistent with the U.S. government’s long-stated strategy of having two smallpox antiviral drugs for protecting the public against the intentional or unintentional release of the smallpox virus” (Chimerix 2011). BRINCIDOFOVIR IS A “PRODRUG,” a weak-ened form of the antiviral cidofovir. It becomes fully active only when human bodies begin to metabolize it. This makes it potentially more suitable in patients already infected with smallpox and other DNA viruses. Until recently, no one had considered brincidofovir’s efficacy in patients infected with RNA viruses like Ebola. In early 2014, however, Chimerix was asked to provide brincidofovir to the U.S. Centers for Disease Control (CDC) and the National Institutes of Health (NIH) to determine its efficacy against Ebola. Somewhat surprisingly, it showed high potency against the RNA virus in culture (Kroll 2014b). In October 2014, with the ZMapp failure making headlines and other therapies such as Tekmira’s TKM-Ebola causing worry about harsh side effects, Chimerix received U.S. Food and Drug Administration (FDA) approval to test brincidofovir in U.S. patients with Ebola (Racaniello 2014). One of the first recipients was Thomas Eric Duncan, the Liberian man who remains the only person to die of Ebola on U.S. soil (Kroll 2014a). At the time of these American tests, one financial analyst noted that Chimerix “shares [were] likely to be (awkwardly) tracking the fate of the Ebola outbreak” (Tirrell 2014). Indeed, by November, the company’s stock rose from a midyear low of $14 per share to $35 per share, and the company raised more than $121 million in a stock offering (Chimerix 2014a). Chimerix’s approach to Ebola trials for brincidofovir was initially domestic and defensive. As the company’s chief medi-cal officer explained when the trials were announced, “Our objective is really for us to determine what the safety and antiviral activity is of brincidofovir when used to treat Ebola virus, and really in the set-ting of the U.S., where we have patients that are basically being relocated from the West African theater, or in patients…who presented with Ebola virus disease in the U.S.” (Loftus 2014; emphasis added). The use of the military term “theater” here is telling. BARDA’s interest in smallpox (for which brincidofovir was to be a counter-measure) stemmed in part from a war-time mindset: in the early 2000s, small-pox attack scenarios were at the heart of a civilian-cum-military biopreparedness complex (Lakoff 2008). While a “natural” disease outbreak such as the 2014 Ebola event was one of the many scenarios for which planners had prepared, at no point did BARDA couch smallpox (or anthrax or Ebola) as a matter of humanitarian concern. Rather, it was framed as a threat to U.S. lives and property. Testing it in the context of a medical infrastructure that had been preparing for more than a decade to address a novel biothreat from a neglected pathogen seemed most ap-propriate. Chimerix claimed it needed that infrastructure to carry out its trial, and its public communications expressed uncertainty about “whether brincidofovir is effective in the West African theater” (Loftus 2014). Just one month later, however, on November 13, Chimerix announced that brincidofovir would be one of two drugs used in a clinical Ebola trial in West Africa, operated with the support of Oxford University and the Oxford-based International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) (Chimerix 2014b). ISARIC, an initiative to facilitate open-access proto-cols and data sharing in clinical research on acute respiratory diseases including SARS, bird flu, and swine flu, is partner-ing with Médecins Sans Frontieres (MSF; Doctors Without Borders), a humanitar-ian organization that has been confront-ing Ebola outbreaks for decades, to help design and plan the trial. ISARIC’s pivot from its focus on respiratory diseases like SARS to viral hemorrhagic fevers like Ebola was propelled by a WHO initiative and a 3.2-million-pound grant from the Wellcome Trust (Wellcome Trust 2014). Less than a week later, the Bill and Melinda Gates Foundation committed $5.7 million to a similar multidrug trial in Africa, also including brincidofovir (Bracken 2014). Brincidofovir’s prodrug design made it highly portable and suitable for oral ad-ministration. In addition, the drug’s his-tory of human clinical trial success (albeit in trials against DNA viruses) made it a good bet (Kroll 2014b). Chimerix, a pharmaceutical firm once seeded by BARDA to build countermea-sures against domestic biothreats, was now joining the world’s most prominent humanitarian medical institutions: MSF and the Gates Foundation. Thus, brin-cidofovir has drifted from one pharma-ceutical infrastructure to another: it has been partially disembedded from the biopreparedness complex in which it was incubated, and moved to the humanitar-ian complex where it provides hope. The company’s leaders now find themselves in novel ethical territory. Chimerix’s CEO told attendees at a biotech conference in December 2014 that “innovation [is] not just in the products, but in the trial de-sign.” Brincidofovir will not be tested in randomized control trials with placebo, but in adaptive trials that provide treat-ment to all infected patients (Oleniacz 2014). Meanwhile, MSF is pushing Ebola drugmakers, including Chimerix, to scale up production of their drugs in advance of trial completion (Moran 2014).Chimerix rings the bell at NASDAQ.At no point did BARDA couch smallpox (or anthrax or Ebola) as a matter of humanitarian concern.LIMN EBOLA'S ECOLOGIES   45 THIS UNEXPECTED INSTITUTIONAL recom-bination contains a few lessons for criti-cal scholars of global health. A clue lies in the proto-mythological company name, “Chimerix.” The root word “chimera” can connote something spectral or elusive. For many years, the spread of Ebola beyond isolated “hot zones” in Africa’s interior was thought to be unlikely without a sig-nificant genetic mutation (Preston 1994). In the United States, stories of Ebola epi-demics in such zones enabled speculation about whether a mutant strain might wreak havoc on political and economic stability, but most actual epidemics seemed manageable using response kits devised by MSF. As Peter Redfield notes in this issue of Limn, MSF’s kits helped con-tain outbreaks, but they could do little to stem the progression of Ebola in infected patients. BARDA was established to de-velop countermeasures in the event Ebola or another pathogen started to spread at a larger scale, whether through a terror attack or through a “natural” mu-tation. In addition, a variety of American funders—from USAID to DOD to Google—have begun to support “virus-hunting” projects to identify new pathogens before they emerge. In 2014, the Ebola-related deaths of thousands of West Africans (far outside the original central African “hot zone”) revealed that the “global” reach of this predictive biosecurity infrastructure was itself somewhat spectral and elusive. Ebola mutates frequently, but there is no clear evidence that a mutation caused the current crisis. It seems just as likely that transformations in the West African land-scape (including deforestation and road building) have combined with increased human mobility and a chronic deficiency in public health infrastructure to make human-to-human transmission possible (Nguyen 2014; Street 2014). The word “chimera” also refers to a multiheaded monster. Responses to global health crises tend to be governed by what Andrew Lakoff (2010) has called “two re-gimes,” that of humanitarianism and bi-osecurity. These operations are sometimes enabled (and sometimes hampered) by a third regime: pharmaceutical capitalism. The efforts of the DOD, NIAID, and BARDA to seed the work of companies such as Chimerix (efforts supplemented by the Wellcome Trust and Gates Foundation in the latest Ebola crisis) are one example. Larger corporations like GlaxoSmithKline and Johnson & Johnson, who have had Ebola vaccines in their pipelines for years, have also benefitted from a resurgence of philanthropic, investor, and government support (The Economist 2014). What the story of brincidofovir re-veals is that the institutional assem-blages of global health operate as much in contingency and chance as in plan-ning and preparedness. The story of the drug’s journey from prospective domes-tic smallpox countermeasure to the front lines of the African Ebola crisis is less one 46   LIMN EBOLA'S ECOLOGIESof concerted corporate “rollout” than of recursive scenes of threat and response, sudden promise and enthusiastic invest-ment. Chimeras—monstrous, hybrid, or simply fantastical—tend to be figures of liminality. Their importance is heightened in moments when someone or something sits betwixt and between social categories and states of being (Turner 1964). Drugs like brincidofovir appear promising, but BIBLIOGRAPHYBracken, David. 2014. “Gates Foundation to Fund Chimerix Drug Trial on Ebola Patients in Africa.” News Observer, November 19. Available at http://www.newsobserver.com/2014/11/19/4335255_gates-foundation-to-fund-chimerix.html?rh=1.Chimerix. 2011. “Chimerix and BARDA Reach Agreement Ending GAO Review of Smallpox Antiviral Contract.” Press release, June 27. Available at http://ir.chimerix.com/releasedetail.cfm?releaseid=752171.————. 2014a. “Chimerix Announces Completion of Public Offering of Common Stock and Exercise in Full of Option to Purchase Additional Shares of Common Stock.” Press release, November 5. Available at http://ir.chimerix.com/releasedetail.cfm?ReleaseID=880800.————. 2014b. “Chimerix’s Brincidofovir Selected for Use in Ebola Clinical Trial in West Africa by International Consortium.” Press release, November 13. Available at http://ir.chimerix.com/releasedetail.cfm?releaseid=882888.The Economist. 2014. “Giving It a Shot: Drugmakers Bet that Vaccines Will Help in the Fight Against Ebola.” November 1. Available at http://www.economist.com/news/business/21629399-drugmakers-bet-vaccines-will-help-fight-against-ebola-giving-it-shot. Greeley, Brendan, and Caroline Chen. 2014. “How the U.S. Screwed Up in the Fight Against Ebola.” BloombergBusinessweek, September 24. Available at http://www.businessweek.com/articles/2014-09-24/ebola-drug-zmapps-development-delayed-by-pentagon-agency.Kroll, David. 2014a. “Chimerix’s Brincidofovir Given To Dallas, Nebraska Ebola Patients.” Forbes, October 7. Available at http://www.forbes.com/sites/davidkroll/2014/10/07/chimerixs-brincidofovir-given-to-dallas-nebraska-ebola-patients/.————. 2014b. “The Rationale For Clinical Trials of Brincidofovir (BCV) In West African Ebola Patients.” Forbes, November 13. Available at http://www.forbes.com/sites/davidkroll/2014/11/13/the-rationale-for-using-brincidofovir-bcv-in-ebola-patients/.Lakoff, Andrew. 2008. “The Generic Biothreat, or, How We Became Unprepared.” Cultural Anthropology, 23(3):399-428.————. 2010. “Two Regimes of Global Health.” Humanity, 1(1):59-79.Loftus, Peter. 2014. “Chimerix to Conduct Ebola Drug Trial: Drug Company Gets FDA Approval to Start Trial Immediately in Infected Patients.” Wall Street Journal, October 16. Available at http://www.sanderling.com/Chimerix_%20to_Conduct_Ebola_Drug_Trial.pdf.McGoey, Lindsay, Julian Reiss, and Ayo Wahlberg. 2011. “The Global Health Complex.” BioSocieties, 6:1-9.Moran, Nuala. 2014. “Chimerix, Toyama Drugs, Whole Blood and Plasma in First Ebola Clinical Trials.” BioWorld. Available at http://www.bioworld.com/content/chimerix-toyama-drugs-whole-blood-and-plasma-first-ebola-clinical-trials-0.Nguyen, Vinh-Kim. 2014. “Ebola: How We Became Unprepared, and What Might Come Next.” Field Sites–Hot Spots, Cultural Anthropology Online, October 7. Available at http://www.culanth.org/fieldsights/605-ebola-how-we-became-unprepared-and-what-might-come-next.Oleniacz, Laura. 2014. “Chimerix CEO Talks about Ethical Challenges of West Africa Ebola Drug Tests.” The Herald Sun, December 12. Available at http://www.heraldsun.com/news/showcase/x761898222/Chimerix-CEO-talks-about-ethical-challenges-of-West-Africa-Ebola-drug-tests.Preston, Richard. 1994. The Hot Zone. New York: Random House.Racaniello, Vincent. 2014. “Treatment of Ebola virus infection with brincidofovir.” Virology Blog, October 9. Available at http://www.virology.ws/2014/10/09/treatment-of-ebola-virus-infection-with-brincidofovir/.Street, Alice. 2014. “Rethinking Infrastructures for Global Health: A View from West Africa and Papua New Guinea.” Somatosphere, December 11. Available at http://somatosphere.net/2014/12/rethinking-infrastructures.html.Tirrell, Meg. 2014. “A Tale of Two Ebola Stocks: Chimerix and Tekmira.” CNBC, October 9. Available at http://www.forbes.com/sites/davidkroll/2014/10/07/chimerixs-brincidofovir-given-to-dallas-nebraska-ebola-patients/.Turner, Victor. 1964. “Betwixt and Between: The Liminal Period in Rites of Passage.” Proceedings of the American Ethnological Society, 4-20.Wellcome Trust. 2014. “Ebola treatment trials to be fast-tracked in West Africa.” Press release, September 23. Available at http://www.wellcome.ac.uk/News/Media-office/Press-releases/2014/WTP057419.htm.are still short of assured. Likewise, Ebola’s shift from potential domestic biothreat to global humanitarian concern is far from complete. If the crisis abates, or if media and lawmakers become crisis-weary, we may see Ebola’s profile shift again, from humanitarian concern back to biothreat (and, as the financial pages remind us, Chimerix’s stock price may suffer as a result). This uncertainty illustrates the chimeric nature of global health, a net-work of sites and practices in which crisis is how we come to know life, and how life becomes capital. ALEX NADING is Lecturer in Social Anthropology at the University of Edinburgh and author of Mosquito Trails: Ecology, Health, and the Politics of Entanglement.

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Ebola, Chimeras, and Unexpected Speculation

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     Edinburgh Research Explorer                                      Ebola, Chimeras, and Unexpected SpeculationCitation for published version:Nading, A 2015, 'Ebola, Chimeras, and Unexpected Speculation' Limn, vol. 5.Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:LimnPublisher Rights Statement:© Limn is licensed under a Creative Commons Attribution-ShareAlike 3.0 Unported LicenseGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 05. Apr. 2019

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Ebola, Chimeras, and Unexpected Speculation

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