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BIOBUSINESS BRIEFS community-acquired pneumonia or peritonitis — or specific biomarkers to TRIAL WATCH identify patients who are likely to benefit from the intervention,” agrees Opal. “We have to come up with a strategy to use rapid nucleic acid-based diagnostics study failure highlights and other ‘omics’ approaches to pick out potentially responsive patients with an need for trial design rethink attributable risk of sepsis mortality, along with immune phenotyping of patients and The failure of Eisai’s eritoran to improve Steven Opal, Division of Biology and their likelihood of responding to specific survival in a Phase III trial in patients with Medicine, Brown University, Rhode therapies,” he adds. severe sepsis (JAMA 309, 1154–1162; 2013) Island, USA, and lead author of the paper, Such approaches could then be coupled adds to the long list of ineffective experimental attributes the failure of eritoran largely to with innovative trial designs incorporating treatments for such patients. It also suggests the underlying hypothesis being incorrect, parallel arms with different interventions that a complete rethink is needed in the and suggests some explanations. “It might and/or drug doses. “We need better surrogate strategies to evaluate novel agents for sepsis. be too late to use this kind of therapy once markers of survival that can be used in The trial tested the hypothesis that is underway. Alternatively, there small Phase II studies to screen lots of administering the synthetic Toll-like may be redundant inflammatory pathways potential therapeutic strategies for efficacy. receptor 4 (TLR4) antagonist eritoran to that lead to continued pathology other than Adaptive designs should be used for Phase II block the interaction of the TLR4 pathway, such as TLR2, TLR9 and and even Phase III registration trials,” (LPS) — a component of the cell wall of complement.” says Fink. Gram-negative bacteria and a potent inducer Mitchell P. Fink, David Geffen School In the meantime, the focus turns to of immune responses — with its receptor of Medicine, University of California, sepsis therapies remaining or embarking in MD2-TLR4 could improve survival in Los Angeles, USA, agrees. “The trial failure clinical trials, which include biologics such as patients with severe sepsis, in whom there suggests that LPS is not an important upstream granulocyte–macrophage colony-stimulating is a systemic uncontrolled inflammatory trigger for the deleterious manifestations factor (to enhance immune responsiveness in response to . However, among of sepsis, or that inflammatory pathways selected patients with sepsis and biochemical the 1,961 patients evaluated, who were activated by other pathogen-associated evidence of immunoparalysis) and soluble randomized and treated with either eritoran or molecular pattern molecules, instead of human recombinant thrombomodulin placebo within 12 hours of onset of first organ or in addition to LPS, are important.” (focused on patients with sepsis-induced dysfunction, there was no reduction in 28-day However, he adds: “It is also important coagulopathy). New vasopressors, new mortality in the group receiving eritoran. to note that patients were not enrolled in antibiotics and improved intravenous the Phase III trial for eritoran on the basis immunoglobulins are also under evaluation. of the presence of LPS in the circulation.” Non-pharmacological approaches are This indicates a key change that is needed also in progress: “A well-designed trial The old way of doing sepsis in future clinical trials in sepsis if the dismal of haemofiltration, using a cartridge success rate is to be increased — enrolling containing LPS-absorbing fibres, is in studies should be largely only patients who are likely to respond to the progress [ClinicalTrials.gov identifier: abandoned and we should drug on the basis of appropriate biochemical NCT01046669], in which only patients with focus on more homogeneous screening. “So, for example, if one is seeking biochemical evidence of endotoxaemia are to test an antibody to TNF [tumour necrosis being enrolled,” says Fink. “In addition, the populations … or specific factor], one should enrol only patients with ‘Cooling And Surviving Septic Shock Study’ biomarkers to identify pathological circulating levels of TNF,” [ClinicalTrials.gov identifier: NCT01455116] patients who are likely to suggests Fink. is studying the effect of moderate induced benefit from the intervention “The old way of doing sepsis studies hypothermia in reducing mortality. Data should be largely abandoned and we should from a single-centre Phase II trial of this focus on more homogeneous populations intervention showed encouraging results.” with either specific diseases — for example, Man Tsuey Tse

334 | MAY 2013 | VOLUME 12 www.nature.com/reviews/drugdisc

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