SOURCES for EIGHT LIVES ​ ​ Although Eight Lives is not a depiction of any real person, event or organisation, the story ​ ​ sometimes unfolds against a background of historical events, and the characters refer to real scientific concepts, medical conditions and drug development processes. In the novel, I’ve mostly simplified the discussion of these topics for clarity, although in some instances I’ve exaggerated them for dramatic effect. This document is for readers interested in learning about the research that underpinned Eight ​ Lives and understanding how the facts relate to the fiction. It has two sections. The first is a ​ referenced summary of the tragic 2006 London drug trial that prompted me to write the novel. Although Eight Lives is in no sense a fictionalised account of that trial, the ​ ​ pharmacological effects of the fictional drug, SMB1412, largely correspond to those of the drug tested in the trial: TGN1412, otherwise known as theralizumab. The second section comprises a chapter-by-chapter summary of the key written sources for the novel, with brief comments on how the source content relates to the novel’s text. The page numbers for the chapters refer to the 2019 edition published by Affirm Press. The internet links were correct at the time this document was prepared (March 2019). Note also that expert opinion may vary about some of the matters touched on in Eight Lives: ​ ​ for example, the number of people who perished fleeing Vietnam after the war, or the extent to which the serious adverse effect of TGN1412 was foreseeable. Inclusion in Eight Lives of ​ ​ a statistic or a character’s viewpoint relating to such topics does not infer my agreement with a side of any argument. Finally, this document comes with a ‘spoiler alert’. It should be read after the novel, not concurrently. 1 SOURCES for EIGHT LIVES The TeGenero Trial TGN1412 was a novel monoclonal antibody being developed by TeGenero Immuno Therapeutics AG. Before the trial, TGN1412 was expected to therapeutically balance the immune system in diseases as diverse as chronic lymphocytic leukaemia and rheumatoid arthritis. It was referred to as a superagonist. The trial took place in London on 13 March 2006 and was conducted by the contract research organisation Parexel. Six of the eight volunteers were randomly assigned to receive TGN1412; the other two received placebo doses. A single dose was administered to each participant ten minutes apart. Within 90 minutes, all six men who received TGN1412 suffered a severe systemic inflammatory response. TGN1412 had caused a rapid release of proinflammatory cytokines, an event known as a ‘cytokine storm’. The six men became critically ill with multi-organ failure and were placed on life support in hospital. The men survived the reaction. Five were discharged from hospital within two months; the sixth had more prolonged multi-organ failure, pneumonia and septicaemia. He lost toes and fingers due to gangrene. There have been suggestions that damage to the men’s immune systems will be lifelong. Within six months of the trial, one of the men was reported to have developed early signs of a lymphoid malignancy and another to have early signs of lymphatic cancer. TeGenero became insolvent in 2006, and the study participants attempted to sue Parexel. The United Kingdom Secretary of State for Health established an Expert Scientific Group to investigate the incident. Their recommendations included a longer interval of observation between sequential dosing of subjects and a broader approach to calculating safe starting doses for first-in-human drug trials, that incorporate the ‘minimum anticipated biological effect level’ (MABEL), rather than just the ‘no observable adverse effect level’ (NOAEL). 2 SOURCES for EIGHT LIVES Since the trial, some scientists have claimed that the harmful effects of TGN1412 were foreseeable. Researchers have discovered that TGN1412 stimulates massive cytokine release because of a specific characteristic of human memory T-cells. The corresponding T-cells of the animals on which TGN1412 was tested lack this characteristic. In vitro assays have been developed to screen new monoclonal antibodies for any propensity to cause similar adverse effects. One of these assay systems predicted that a lower dose of TGN1412 would not cause a cytokine storm. TGN1412 has been renamed TAB08 and is being developed by TheraMAB LLC. A trial of TAB08 was conducted in Yaroslovl, Russia, from 2011 to 2013. Cohorts of three healthy male volunteers received doses between 1000-fold and 14-fold less than the volunteers in the TGN1412 trial. None experienced a cytokine storm. In 2017, the BBC produced a documentary about the TeGenero trial: The Drug Trial: Emergency at the Hospital. Three of the men who volunteered for the trial, including actor Rob Oldfield, appeared in the documentary. References Beyersdorf N, Hanke T, Kerkau T, Hunig T. Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Annals of the Rheumatic Diseases 2005; 64(11): IV91(5). Available from: https://ard.bmj.com/content/64/suppl_4/iv91.long Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti- CD28 monoclonal antibody TGN1412. The New England Journal of Medicine 2006; 355(10): 1018-28. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa063842 Yaqoob T. ‘Elephant man’ drug trial victim has cancer. Daily Mail. 7 August 2006. Available from: http://www.dailymail.co.uk/news/article-399350/Elephant-man-drug-trial- victim-cancer.html Four drug-trial victims ready to sue for millions. Daily Mail. 9 March 2007. Available from: http://www.dailymail.co.uk/news/article-441318/Four-drug-trial-victims-ready-sue- millions.htm 3 SOURCES for EIGHT LIVES Ferguson PR. The TGN1412 drug disaster. The SciTech Lawyer Spring 2009; 5: p 12+. Available from: http://go.galegroup.com/ps/i.do?id=GALE%7CA206395206&v=2.1&u=unimelb&it=r&p=L T&sw=w&asid=8e8310d6e67ff14d694a44b727dffac7 Expert Group on Phase One Clinical Trials: Final report. The Stationery Office 7 December 2006. Available from: http://webarchive.nationalarchives.gov.uk/+/http://www.dh.gov.uk/en/Publicationsandstatisti cs/Publications/PublicationsPolicyAndGuidance/DH_063117 Horvath CJ, Milton MN. The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event? Toxicologic Pathology 2009; 37(3): 372-83. Available from: http://tpx.sagepub.com/content/37/3/372.full.pdf Horvath C, Andrews L, Baumann A, et al. Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial. Nature Reviews Immunology 2012; 12(10): 740. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+22941443 Eastwood D, Findlay L, Poole S, et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. British Journal of Pharmacology 2010; 161(3): 512-26. Available from: http://dx.doi.org/10.1111/j.1476- 5381.2010.00922.x Stebbings R, Eastwood D, Poole S, Thorpe R. After TGN1412: recent developments in cytokine release assays. Journal of Immunotoxicology 2013; 10(1): 75-82. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541671/pdf/IMT-10-1.pdf Tabares P, Berr S, Romer PS, et al. Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB08. European Journal of Immunology 2014; 44(4): 1225-36. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24374661 Hunig T. The rise and fall of the CD28 superagonist TGN1412 and its return as TAB08: a personal account. The FEBS Journal 2016; 283(18): 3325-34. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=hunig+the+rise+and+fall The Drug Trial: Emergency at the Hospital. BBC Documentary. https://www.bbc.co.uk/mediacentre/proginfo/2017/08/the-drug-trial 4 SOURCES for EIGHT LIVES Prologue (The Australian Times) Two books provided background about the exodus from Vietnam after the fall of Saigon in 1975: Nghia M Vo. The Vietnamese Boat People, 1954 and 1975-1992. Jefferson, NC: McFarland & Company, 2006. and Carina Hoang, Editor. Boat People: Personal Stories from the Vietnamese Exodus 1975- 1996. Cloverdale, WA: Carina Hoang Communications, 2010. Nghia Vo describes the history of the exodus, as well as individual case studies. Carina Hoang’s moving book is a compilation of stories told by boat people, including herself, with photographs and illustrations. In the introduction, she estimates that 1.5 million people attempted to escape Vietnam by sea after the end of the Vietnam War, mainly headed for Hong Kong, Malaysia, Thailand, Indonesia or the Philippines. Hong Kong was a more typical destination for escapees from Northern Vietnam than for those, like Mai and Dung, leaving regions near Saigon. Most refugees escaped on large and typically overcrowded boats, but both Vo and Hoang include stories of families leaving on rafts or small wooden fishing vessels. Pirates, who were often fishermen, were prevalent, robbing, raping and murdering the refugees. By mid 1979, there was a major humanitarian crisis in the region, with 200,000 Vietnamese refugees housed in camps, and aid workers suffering ‘compassion fatigue’. Vo reports that ‘Local governments refused to take any refugee picked up at sea by tankers and ships’ and ‘Shipping companies advised their skippers not to pick up any refugee at sea’. Countries were ‘pushing back’ boats that attempted to land and many people are believed to have perished as a result. Overall, Carina Hoang estimates that nearly half a million died attempting to escape Vietnam. 5 SOURCES for EIGHT LIVES The Malaysian government reportedly made, then retracted, the threat referred to in Eight Lives. See: Chapman W. Malaysia, in clarification, says it will not shoot refugees. The Washington Post, 19 June 1979.