Since the discovery of the contribution of extracellular histones to endothelial dysfunction in response to inflammatory challenges as a result of sepsis by Esmon et.al. in 2009 several groups have suggested pharmacological solutions to neutralize histones. Histones have found to be highly toxic for endothelial cells especially H3 and H4 type of histones and are being released during the development of sepsis by damaged endothelial cells as a result of inflammatory mechanisms and activated innate immune components like neutrophil extracellular traps. The released histones affect healthy endothelial cells resulting in a vigorous chain reaction leading to organ failure at last.
In 2012 the Matisse patent was filed claiming the use of M6229 in the prevention of or treatment of sepsis and septic shock using the non-anticoagulant fraction of heparin (M6229). This non-anticoagulant fraction M6229 can be obtained by removing the pentasaccharide containing fraction in heparin. Heparin has a history of clinical safe use for more than a century. When comparing a M6229 treated group vs non treated a statistical significant improvement in overall survival was observed in the cecal ligation and puncture mouse model [Wildhagen (2013)]. A significant correlation has been observed between human histone H3 plasma levels and mortality in the ICU [Wildhagen (2015)]. Survivors showed significant lower H3 levels (0.57 µg/ml) compared to non-survivors (3.15 µg/ml). Despite advances made with the standard of care for the treatment of sepsis there still is a big unmet medical need reflected by a mortality rate up to 50% in case of septic shock and 30% in case of sepsis. With M6229 a universally effective therapeutic can be presented for the first time, capable of preventing or to alleviate high histone levels in the vascular compartment independent of the exact threat or cause for sepsis. Currently the sepsis treatment market mainly consists of antimicrobial agents that have a limited effect on disease course for 20 million sepsis patients at an annual base world wide. The 2010 sepsis treatment market was valued at €3.7 billion.