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Anti-PCSK9 Antibody — A New Approach for the Treatment
of Severe Infection and Sepsis
Sepsis is a serious medical condition caused by an uncontrolled immune response to infection. Immune chemicals released into the blood to combat the infection trigger widespread inflammation. This results in direct vital organ injury and impaired blood flow, which damages the body’s organs by depriving them of nutrients and oxygen. Septic shock is a complication of the infection characterized by low blood pressure which can lead to respiratory, heart, or organ failure and death.
Sepsis is among the leading causes of death globally. Annually, five million cases of sepsis are reported worldwide with more than one million people succumbing to this disease. In hospitals, sepsis is the major cause of death among patients admitted to intensive care units.
Treatment for sepsis often involves a prolonged stay in the intensive care unit, with administration of intravenous antibiotics and, if required, supportive resuscitation. Sepsis is the most expensive condition treated in U.S. hospitals responsible for 6.2% of hospital admissions in 2013 costing the U.S. healthcare system $24 billion. Currently, there is no diagnostic test or approved treatment for sepsis. This results in a very high risk of death for any person with this condition. Thus, sepsis represents one of the greatest unmet medical needs globally.
Cyon Therapeutics Inc., a spin-off clinical phase biotechnology company from the University of British Columbia, is evaluating an anti-PCSK9 antibody as a new therapeutic approach for the treatment of severe infection and sepsis. Cyon licensed the anti-PCSK9 from Norvatis AG, acquiring the worldwide rights to use the compound for the prevention and treatment of sepsis and Systemic Inflammatory Response Syndrome (SIRS).
Anti-PCSK9 antibodies were originally developed as a new class of cholesterol-lowering drugs. The PCSK9 protein interferes with the clearance of LDL (“bad”) cholesterol from the blood. LDL receptors on liver cells remove LDL cholesterol from the blood by binding LDL cholesterol and then moving it into the cell for elimination. The lipid-free LDL receptors then return to the surface of the liver cell. When PCSK9 binds to the LDL receptor, however, the LDL receptor is unable to re-emerge on the cell surface to remove more LDL cholesterol, which then remains in the blood. By inhibiting the PCSK9 protein, PCSK9 inhibitors essentially improve the liver’s ability to recycle LDL receptors, resulting in a greater number of receptors on the cell surface and enabling more LDL cholesterol to be removed from circulation.
A team of University of British Columbia researchers discovered that controlling levels of the human PCSK9 could potentially improve survival rates for patients with sepsis. The anti-PCSK9 antibody could allow the patient’s body to clear sepsis-induced bacterial toxins. These toxins are fat soluble and concentrate in LDL cholesterol, and trigger the complex severe immune reaction if not quickly removed. Anti-PCSK9 antibody quickly increases the number of LDL receptors in the liver that pull LDL cholesterol and LDL-associated bacterial toxins out of circulation thereby flushing sepsis-associated toxins from the bloodstream.
UBC Professors Drs. John Boyd, Keith Walley and Jim Russell found that treatment of mice with severe sepsis using the anti-PCSK9 antibody increased survival rates. Mice with a genetic variation that reduced the levels of PCSK9 also showed improved sepsis outcomes and survival rates.
Based on this research, Drs. Boyd, Walley and Russell, who also work as critical care physicians at Vancouver’s St. Paul’s Hospital ICU and as researchers at the Centre for Heart Lung Innovation, launched Cyon Therapeutics Inc. in 2014. The company is planning to initiate a Phase II randomized controlled clinical trial of the anti-PCSK9 antibody in the spring of 2017 to evaluate the compound’s safety and efficacy in removing sepsis-induced bacterial toxins from the bloodstream and improving clinical outcomes of patients with severe infection.
Cyon plans to enroll up to 300 sepsis patients admitted to hospital emergency departments at approximately 40 sites across Canada and the U.S. Clinical trial participants will be screened for specific genetic markers related to PCSK9 to identify individuals most or less likely to respond to treatment. Patients in the trial will receive intravenous doses of the anti-PCSK9 antibody five to ten times higher than the dose that patients receive to lower cholesterol. The clinical trial, which is one of the largest Phase II trials on severe infection, is expected to be completed within 18 months.
Cyon Therapeutics Inc. gratefully acknowledges the ongoing support of Genome B.C., the National Research Council, Mitacs, the Canadian Institutes of Health Research, the University of British Columbia and Providence Health Care Research Institute.
For additional information, please visit: www.cyontherapeutics.com