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Friday, 24 November 2017

(Almost) all quiet on the sepsis front

UC Riverside researchers
Meera Nair and Jessica Jang
Sepsis, a massive systemic immune response to infection leading to multiple organ damage and, more often than not, death, has proved resistant to drug development efforts over the last four decades. 

Spectacular late stage clinical study failures in the early 90s of drug candidates developed by some of the then brightest stars of the sector, including Centocor, Xoma, Synergen and Chiron led to sepsis treatment development being tagged as a "biotech graveyard".

Large  pharmaceutical companies have fared no better in sepsis therapy development and commercialisation. Eli Lilly's Xigris®, the first (and only) sepsis treatment to receive regulatory approval was pulled in 2011 after a decade in the market as growing clinical evidence indicated that it was of no significant benefit. In the following year, AstraZeneca abandoned development of the BTG Group's CytoFab®. More recently, Eritoran®, a synthetic lipid developed by Eisai failed to show sufficient efficacy in a pivotal clinical study.

Historically, sepsis treatment development attempts were aimed at blocking events which initiate the inflammatory cascade, such as the binding of bacterial lipid to "toll like" receptors which trigger our first line of defence, the innate immune system, or on neutralizing the cytokines (tumour-necrosis factor, interleukin-1) that ramp up the inflammatory response. Sepsis involves a variety of runaway biological processes, including vascular leakage and activation of the complement and coagulation systems, and, with hindsight, strategies that target any single contributing factor are not likely to element of the storm is likely to have only a minimal effect.

Sepsis remains a major problem, with a mortality rate somewhere in the 30% to 50% range and is the cause of around 37,000 deaths each year in the UK alone. It goes without saying that better interventions are required, but the combination of biological complexity, the challenges in designing and executing meaningful clinical studies and a history of high profile failures means that the pipeline is slender.

Work on new therapies is more or less confined to a handful of small-cap biopharmas, although several once promising although candidates with novel modes of action, such as Altor Biosciences’s anti-tissue factor antibody ALT-836 and InflaRx's anti-complement antibody, IFX-1, appear to have been quietly ditched. AM Pharma is currently evaluating a recombinant version of alkaline phosphatase in sepsis patient with acute kidney failure, although the reason for the apparent protective effect of the enzyme remains a mystery.

The lack of anything newsworthy in the sepsis field made two recent articles stand out. Critical Pressure Ltd, a UK start-up received funds to evaluate a small molecule selective inhibitor of nitric oxide (NO) synthesis. Nitric oxide is a potent vasodilator and contributes to vascular collapse. At the same time, NO also protects against the effects of infection, chiefly through macrophage and cardiomyocyte activation. Critical Pressure is banking on the selectivity of its candidate enzyme inhibitor to reduce the unwanted consequence of NO production.

A research paper from a group at the University of California (Riverside) suggests that resistin, a hormone associated with insulin resistance in diabetes and the accumulation of “bad” (low-density lipoprotein) cholesterol might actually have a protective effect in sepsis through binding to a toll-like receptor and preventing cytokine release. Resistin was shown to provide 100% protection from mortality in an animal model of sepsis. A synthetic analogue of resistin, “Retn N-Pep” is undergoing laboratory development as a possible sepsis treatment.

Photo credit:  Ross French, UC Riverside.