Treatment of Severe Infection With Antihyperlipidemia Drug

Summary

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors increase LDL receptors by decreasing its degradation. In sepsis the pathogenic substances, endotoxin, lipoteichoic acid, phospholipomannan are the main cause of the ongoing inflammation that causes the severe damage and outcome. these substances are removed from the blood by the LDL receptors. By administering PCSK9 inhibitors to patients with sepsis/septic shock this inflammatory response can be stopped and by doing so improve the patients outcome.

Timeline

Start

2019-01

Primary completion

2021-01

Completion

2021-02

Publications

• Background Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
• Background Sriskandan S, Cohen J. Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis. Infect Dis Clin North Am. 1999 Jun;13(2):397-412. doi: 10.1016/s0891-5520(05)70082-9.
• Background Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997 Jul 24;388(6640):394-7. doi: 10.1038/41131.
• Background Ramachandran G. Gram-positive and gram-negative bacterial toxins in sepsis: a brief review. Virulence. 2014 Jan 1;5(1):213-8. doi: 10.4161/viru.27024. Epub 2013 Nov 5.
• Background Branger J, Knapp S, Weijer S, Leemans JC, Pater JM, Speelman P, Florquin S, van der Poll T. Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice. Infect Immun. 2004 Feb;72(2):788-94. doi: 10.1128/IAI.72.2.788-794.2004.
• Background Liao W, Rudling M, Angelin B. Endotoxin suppresses rat hepatic low-density lipoprotein receptor expression. Biochem J. 1996 Feb 1;313 ( Pt 3)(Pt 3):873-8. doi: 10.1042/bj3130873.
• Background Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007 Feb;32(2):71-7. doi: 10.1016/j.tibs.2006.12.008. Epub 2007 Jan 9.
• Background Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014 Mar 14;114(6):1022-36. doi: 10.1161/CIRCRESAHA.114.301621.
• Background Gouni-Berthold I, Descamps OS, Fraass U, Hartfield E, Allcott K, Dent R, Marz W. Systematic review of published Phase 3 data on anti-PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J Clin Pharmacol. 2016 Dec;82(6):1412-1443. doi: 10.1111/bcp.13066. Epub 2016 Oct 4.
• Background Feingold KR, Moser AH, Shigenaga JK, Patzek SM, Grunfeld C. Inflammation stimulates the expression of PCSK9. Biochem Biophys Res Commun. 2008 Sep 19;374(2):341-4. doi: 10.1016/j.bbrc.2008.07.023. Epub 2008 Jul 16.
• Background Grefhorst A, McNutt MC, Lagace TA, Horton JD. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J Lipid Res. 2008 Jun;49(6):1303-11. doi: 10.1194/jlr.M800027-JLR200. Epub 2008 Mar 19.
• Background dos Santos C, Marshall JC. Bridging lipid metabolism and innate host defense. Sci Transl Med. 2014 Oct 15;6(258):258fs41. doi: 10.1126/scitranslmed.3010501.
• Background Norata GD, Tavori H, Pirillo A, Fazio S, Catapano AL. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res. 2016 Oct;112(1):429-42. doi: 10.1093/cvr/cvw194. Epub 2016 Aug 5.
• Background Walley KR, Francis GA, Opal SM, Stein EA, Russell JA, Boyd JH. The Central Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance. Am J Respir Crit Care Med. 2015 Dec 1;192(11):1275-86. doi: 10.1164/rccm.201505-0876CI.
• Background Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, Christie JD, Nakada TA, Fjell CD, Thair SA, Cirstea MS, Boyd JH. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014 Oct 15;6(258):258ra143. doi: 10.1126/scitranslmed.3008782.
• Background Berger JM, Loza Valdes A, Gromada J, Anderson N, Horton JD. Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice. J Lipid Res. 2017 Aug;58(8):1661-1669. doi: 10.1194/jlr.M076844. Epub 2017 Jun 9.
• Background Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99. doi: 10.1056/NEJMoa1501031. Epub 2015 Mar 15.
• Background Karatasakis A, Danek BA, Karacsonyi J, Rangan BV, Roesle MK, Knickelbine T, Miedema MD, Khalili H, Ahmad Z, Abdullah S, Banerjee S, Brilakis ES. Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta-Analysis of 35 Randomized Controlled Trials. J Am Heart Assoc. 2017 Dec 9;6(12):e006910. doi: 10.1161/JAHA.117.006910.
• Background Choi J, Khan AM, Jarmin M, Goldenberg N, Glueck CJ, Wang P. Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study. Lipids Health Dis. 2017 Jul 24;16(1):141. doi: 10.1186/s12944-017-0493-7.
• Background Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.

Drugs

Indications