Based on preclinical research, sevuparin is believed to counteract systemic inflammation by binding and neutralizing harmful substances secreted by activated white blood cells as well as modifying the action of these cells in experimental systemic inflammation (like sepsis and endotoxemia), providing robust vascular protection. In healthy volunteers (Phase 1b), sevuparin significantly counteracted the decreased levels of certain white blood cells, and dose-dependently inhibited the increased respiratory rate caused by LPS, which is similar to the respiratory effects often seen in sepsis patients. Conceivably, sevuparin could break the molecular chain of events that lead to loss of blood vessel integrity, plasma leakage, and ultimately failing organ function insystemic inflammatory conditions. 

Data presented in 2023 show that sevuparin could represent a major advance in research into new treatments for anemia of the type where high levels of hepcidin have been shown to cause and worsen anemic conditions that often complicate chronic kidney disease and chronic inflammatory conditions. Hepcidin is a hormone that is ultimately responsible for regulating iron levels in the body, which is important for the production of red blood cells and many other processes. High levels of hepcidin have also been shown to represent a resistance mechanism to standard treatments for anemia in patients unresponsive to such therapy. Mechanistic data generated in cells show that sevuparin can inhibit production of hepcidin stimulated both by BMP (bone morphogenic protein) and inflammatory signaling. Furthermore, it was seen in studies in mice that sevuparin can significantly reduce levels of hepcidin in the liver 6 hours after dosing. Finally, data from healthy volunteers (Phase 1) showed that plasma hepcidin was reduced to 30–50% of baseline in the presence of sevuparin at three different, clinically safe dose levels with peak effect between 6 – 24 hours.

Malaria-infected red blood cells can, under certain circumstances, stick together in groups on the inside of blood vessels, so-called sequestration, which is believed to be an important cause of the development of severe malaria. Because severe malaria develops rapidly, antimalarial drugs do not have time to start working within the window of time that could avert the worst course of severe complications and death. There is thus a lack of treatments that can be started and work fast enough in the acute course. During the 60s and 70s, it was discovered that ordinary heparin worked as a treatment for severe malaria, and researchers were able to show that it was not linked to heparin's blood-thinning properties. However, the form of treatment with heparin in severe malaria was discontinued after it was found that the occurrence of bleeding meant too great a risk. Sevuparin was created with the aim of retaining all the properties of heparin but without blood thinning. Beneficial effects of sevuparin have already been seen in mechanistic studies (so-called proof of mechanism) with sevuparin in patients with mild malaria without risk of bleeding and in preclinical studies have also shown that sevuparin affects the malaria parasite in the same way as heparin. Taken together, the data show that sevuparin has the potential both to prevent malaria-infected blood cells from sticking to the inside of the vessels (de-squestration) and to prevent free parasites in the bloodstream from infecting new blood cells which, taken together, suggest that sevuparin warrants further clinical exploration in severe malaria.

Further Reading

Non-anticoagulant effect of Heparin: An Overview. Handbook of Experimental Pharmacology. January 2020

Heparin and non-anticoagulant heparin attenuate histone-induced inflammatory responses in whole blood. Plos One. May 2020

Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients, EBio Medicine. August 2020

Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins. FASEB Journal. June 2019