New Agents in Development for Sepsis: Any Reason for Hope?

Abstract

Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.

Novel Diagnostics and Therapeutics in Sepsis

“…IVIG has been used in sepsis to both inhibit the inflammatory response and to opsonize the offending infectious agent. Data are inconclusive regarding its efficacy in sepsis and is currently not recommended for routine use [ 85 , 92 ]. However, a recent meta-analysis of IV IgM infusions showing reduced mortality in those with septic shock has renewed interest in this therapy [ 103 ].…”

“…Direct antibacterial antibodies targeting Pseudomonas aeruginosa and Staphylococcus aureus are undergoing clinical trials [ 85 ]. Two monoclonal antibodies against Staphylococcus aureus toxin, suvratoxumab and AR-301, exist.…”

“…AR-301, in a phase 2 trial, showed a trend towards faster resolution of pneumonia in those with severe Staphylococcus aureus hospital-acquired pneumonia, ventilator-associated pneumonia, or community-acquired pneumonia [ 105 ]. A phase 3 trial is currently underway [ 85 ].…”

“…Many bacteria secrete toxins that damage cellular structures. Artificial liposomes, which can bind and sequester these toxins [ 106 ], have demonstrated improved survival in mice with Streptococcus pneumonia septicemia [ 85 ]. When compared to controls, CAL02, one such agent, showed a reduction in organ dysfunction scores in 19 patients admitted to an intensive care unit for severe pneumococcal pneumonia [ 86 ].…”

“…Sepsis-mediated acute kidney injury causes renal cell apoptosis and increases the risk of mortality and progression to end-stage kidney disease [ 85 ]. Alkaline phosphatase protects against renal inflammation by deactivating bacterial LPS [ 85 ]. A phase 2 study in patients with sepsis-induced acute kidney injury demonstrated a measurable improvement in renal function in those with shock [ 107 ].…”