There is hardly an indication which has accumulated more failed clinical trials than the sepsis area. Called first bacteremia, later sepsis, sepsis syndrome or septic shock, there have been numerous attempts to influence the cascade of events that eventually lead to MSOF and death. While it is convenient to think of a bacterial origin for this syndrome, there are non-bacterial causes for ‘toxemia’ as well which present in a similar fashion.
If bacteria and their toxins are the root problem, the condition should be manageable with antibiotics, antitoxins, and immunomodulators. However, while the role of antibiotics is undisputed, additional interventions have not improved outcomes.
After the early but unwarranted euphoria for the HA1A antibody to LPS, the endotoxin released by Gram-negative bacteria, it failed in a confirmatory trial [1]. So did the E5 anti-endotoxin [2]. TNF-alpha, an immune product revved up in sepsis, seemed an attractive target but treatment with an anti-TNF alpha mAb did not benefit patients [3]. For Lilly’s roller coaster drotrecogin alpha program, an activated protein C inhibitor, a separate blog would be in order but suffice it to say it failed in every single repeat study after gaining approval and was eventually mercifully taken off the market [4]. Then there was the large and ill-conceived tifacogin trial in CAP (Community-acquired pneumonia) and severe sepsis which showed that this TFPI did not reduce mortality [5]. Despite the industry’s disillusion with sepsis trials which consumed so much effort, time and money, Eisai embarked on a 5-yr Phase 3 trial with Eritoran, a lipid A mimetic and TLR4 inhibitor only to fail yet again [6].
Unfortunately, the Bone definition of sepsis and sepsis syndrome has not served us well in the clinical trials arena
Unfortunately, the definition of sepsis and sepsis syndrome introduced by R. Bone et al. has not served us well in the clinical trials arena. Because of these frustrating setbacks, treatment of sepsis has actually changed very little in the last 30 years. Antibiotics and supportive ICU care to manage organ failure are still the mainstay of therapy. There is a die-hard group of folks that believe in steroids despite overwhelming data that they don’t work, and also some stake holders that decry the demise of drotrecogin (Xigris). The fact remains that neither drug has stood the test of time or shown benefit in any consistent fashion.
Two innovative approaches were recently described to deal with bacteremia / toxemia:
Henry et al. [7] developed liposomes composed of sphingomyelin alone or in combination with cholesterol to trap microbial toxins. Unlike the use of liposomes as delivery vehicles, the underlying idea was to provide a toxin ‘sink‘ thus competitively preventing toxin binding to their mammalian cell target. In-vitro testing showed binding and inactivation of many toxins, including pneumolysin, alpha-hemolysin, streptolycin O, and phospholipase C, i.e., membrane lysing toxins and virulence factors in staphylococci, streptococci, pneumococci and clostridia. In animal experiments these liposomes were able to prevent mortality in staphylococcal and streptococcal mouse models.
A somewhat similar approach was taken by a group from Boston. Kang and colleagues[8] used a dialysis system to clear blood of pathogens and toxins with the help of magnetic nanospheres coated with mannose-binding lectin (MBL), a universal bacteria- and toxin-binding substance which is part of our innate immune system. The researchers were able to show in a rat sepsis model that circulating pathogen levels declined by 90% and that sepsis-related inflammatory response markers and LPS levels were much reduced.
Both approaches are innovative and could be put to test in clinical trials. Nonetheless I am skeptical that either interventions will prove successful at reducing 28-day mortality reproducibly. Animal models have misled us too often in the past; they are just not reflecting the breadth and complexity of what we call sepsis syndrome. Among friends, the next sepsis program will cost at least $100 million, a major high-risk investment even for Big Pharma.
But who knows: Glory goes to the brave who dares to execute the next severe sepsis mega-trial even if he fails. Just as we all like a good old Greek tragedy…
References:
[1] E. Ziegler. NEJM 324, 1991: 429
[2] D. Angus. JAMA. 2000 Apr 5;283(13):1723
[3] E. Abraham. Lancet. 1998;351(9107):929
[4] http://www.fda.gov/Drugs/DrugSafety/ucm277114.htm
[5] R. Wunderink. Am J Respir Critical Care Medicine, Vol. 183, (2011), pp. 1561
[6] S. Opal. JAMA. 2013;309:1154
[7] B. Henry. Nature Biotechnology: advance online publication published online 2 November 2014; doi:10.1038/nbt.3037
[8] J Kang. Nature Medicine 20; 2014: 1211
