Tumor Necrosis Factor Inhibition in Severe Sepsis: A Promise Not Fulfilled* Tom van der Poll, MD Division of Infectious Diseases Center of Experimental and Molecular Medicine Academic Medical Center University cf Amsterdam Amsterdam, The Netherlands

The study by Bernard et al ( 1 ) in this issue of Critical Care Medicine is the most recent clinical trial in which an anti-TNF agent was examined in patients with severe sepsis. The compound tested, AZD9773, is based on a product named CytoFab, a preparation of polyclonal ovine Fab IgG fragments purified ftom blood of sheep immunized with recombinant human TNF-a. The first clinical results with CytoFab were obtained in a multicenter trial conducted in 1997 and 1998 in 81 patients ne of the most cited motivational quotes is Sir Winwith severe sepsis, in which CytoFab was reported to reduce ston Churchill's "Success is the ability to go from one failure to another with no loss of enthusiasm." After 28-day mortality from 37% in placebo recipients to 26% (p = 0.27) and to significantly increase ventilator-fiee and intensive the publication of the most recent sepsis trial in this issue of Critical Care Medicine by Bernard et al ( 1 ), one cannot stop to care-free days (8). AstraZeneca obtained the rights for CytoFab, and subsequently AZD9773, produced by a slightly modified wonder what the famous British politician would have thought manufacturing procedure to facilitate increased production, about therapeutic strategies seeking to inhibit tumor necrosis was shown to have an acceptable safety profile in a small phase factor (TNF)-a in severe sepsis. lia dose escalation study in 70 patients (47 of whom received TNF-a was once considered the therapeutic target to go AZD9773) without infiuencing mortality (27.7% across after in severe sepsis. TNF-a is a potent proinñammatory AZD9773 cohorts and 26.1% in placebo patients) (9). Now, Bercytokine produced by immune cells, in particular monocytes nard et al (1) report on the efficacy and safety of AZD9773 in a and macrophages, upon exposure to bacteria. The excitement phase lib trial that enrolled 300 patients with severe sepsis and/ about the contribution of TNF-a to sepsis pathogenesis was or septic shock, 200 of whom received AZD9773 by repeated IV launched by a landmark article published in 1985 by Beuinfusion (every 12hr) during 5 days in two different dose regitler et al (2) in which elimination of TNF-a activity after IV mens ("low" and "high" doses). Infusion of AZD9773 resulted injection of endotoxin was reported to prevent death in mice. in a decrease in circulating TNF-a levels without infiuencing Two years later, these results were extended by Tracey et al (3), the more "downstream" cytokines interleukin-6 and interleuwho showed that a monoclonal anti-TNF-a antibody prokin-8. This finding contrasts with several previous anti-TNF tected baboons against lethal sepsis produced by IV infusion of Escherichia coll These findings changed the way of thinking trials in patients with sepsis in which TNF-a inhibition was found to result in decreased interleukin-6 levels (7) and could about sepsis pathogenesis and gave rise to the concept that a point to only partial elimination of TNF-a activity by AZD9973 single mediator, produced by the host in response to a bac(i.e., TNF-a antigen rather than activity levels were measured). terial challenge, could be responsible for sepsis lethality. This Importantly, the study did not show benefit of AZD9773 for the hypothesis was further supported by studies in animals and primary endpoint of ventilator-free days. Although not powhumans revealing that administration of recombinant TNFered for mortality, the study by Bernard et al (1) showed intera could reproduce many features of systemic infiammation esting trends: 28-day mortality rates were 20.0% for patients associated with severe sepsis (4, 5). As a consequence, different who received placebo versus 15.0% for the low-dose AZD9773 pharmaceutical companies developed anti-TNF strategies for and 27.0% for high-dose AZD9973 groups. Remarkably, the the use in patients with severe sepsis. Twenty years ago, the first relative risk of death for high-dose AZD9773 was 1.64 (95% results of a trial with one of these agents, a monoclonal antiCIs, 1.19-2.26; p = 0.05). Although this difference might have TNF antibody, became available (6). Since then, 14 additional been caused by unequal distribution of other covariates and placebo-controlled trials evaluating anti-TNF agents in severe although other safety outcomes were similar across groups (1), sepsis have been published (7). None of these investigations this finding should not be totally ignored. Indeed, a previous showed statistically significant benefit of TNF-a inhibition in study that examined the effect of another TNF inhibitor (etanthe overall population of patients with severe sepsis (7). ercept, a soluble TNF receptor p75) in patients with severe sepsis reported a dose-dependent increase in mortality (10). Since the publication of the original articles exposing the detrimental role of TNF-a in severe systemic inñammation elicited by bolus 'See also p. 504. administration of high-dose bacteria or bacterial products (2, Key Words: clinical trial; editorial; sepsis; tumor necrosis factor 3), many preclinical studies have documented the important The author has disclosed that he does not have any potential conflicts of interest. protective role for this cytokine in host defense against localCopyright ® 2013 by the Society of Critical Care Medicine and Lippincott ized bacterial infections (11). On the reassuring side, a recent Williams & Wilkins meta-analysis showed good safety profiles of anti-TNF agents

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March 2014 • Volume 42 • Number 3

Editorials

in human sepsis and no evidence for increased susceptibility for secondary infections (7). Does the study by Bernard et al (1) put the lid on efforts to examine anti-TNF agents in severe sepsis? A recent meta-analysis encompassing the earlier 15 randomized placebo-controlled trials evaluating TNF inhibitors in patients with sepsis showed a modest but significant survival benefit provided by anti-TNF agents (relative risk 0.93,95% CIs, 0.88-0.98; p = 0.01) (7). Overall mortality in 4,913 patients treated with an anti-TNF agent was 35.2% versus 37.5% in 3,983 patients who received placebo. A power analysis demonstrated that at least 10,000 patients would be required to reveal a significant survival benefit in a sepsis population with a "control" mortality of 38% (7). Notably, however, sepsis mortality has decreased in recent years (12,13), implying that even higher enrolment numbers would be required and making the performance of such a trial very unlikely. It is safe to say that even Winston Churchill would be pessimistic about the future of anti-TNF agents in the treatment of severe sepsis. One of the great challenges in sepsis remains the translation of our advanced knowledge of sepsis pathogenesis into new therapies. The time is right for alternative sepsis trial designs, incorporating targeted selection of those patients that are most likely to benefit, tools that monitor the biological response to a specific therapy, and biologically plausible and clinically meaningful outcome measures other than the standard 28-day all-cause mortality.

REFERENCES 1. Bernard GR, Francois B, Mira J-P, et al: Evaluating the Efficacy and Safety of Two Doses of the Polyclonal Anti-Tumor Necrosis Factor-a Fragment Antibody AZD9773 in Adult Patients With Severe Sepsis and/or Septic Shock: Randomized, Double-Blind, Placebo-Controlled Phase lib Study Crit Care Med 2014; 42:504-511

Critical Care Medicine

2. Beutler B, Milsark IW, Cerami AC: Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 229:869-871 3. Tracey KJ, Fong Y, Hesse DG, et al: Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330:662-664 4. Tracey KJ, Beutler B, Lowry SF, et al: Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470-474 5. van der Poll T, Büller HR, ten Cate H, et al: Activation of coagulation after administration of tumor necrosis factor to normal subjects. N EngI J Med 1990; 322:1622-1627 6. Fisher CJ Jr, Opal SM, Dhainaut JF, et al: Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Crit Care Med 1993; 21:318-327 7 Oiu P, Cui X, Sun J, et al: Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: A meta-analysis. Crit Care Med 2013; 41:2419-2429 8. Rice TW, Wheeler AP, Morris PE, et al: Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine fab for injection (CytoFab) in severe sepsis. Crit Care Med 2006; 34:2271-2281 9. Morris PE, Zeno B, Bernard AC, et al: A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock. Crit Care 2012; 16:R31 10. Fisher CJ Jr, Agosti JM, Opal SM, et al: Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N EngI J Med 1996; 334:1697-1702 11. Lorente JA, Marshall JC: Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock 2005; 24(Suppl 1):107-119 12. Levy MM, Dellinger RP, Townsend SR, et al; Surviving Sepsis Campaign: The Surviving Sepsis Campaign: Results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 201 0; 38:367-374 13. Gaieski DF Edwards JM, Kalian MJ, et al: Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013; 41:1167-1174

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Tumor necrosis factor inhibition in severe sepsis: a promise not fulfilled*.

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