Cholesterol drugs may aid in fighting sepsis
Medicine can flush out LDL that carries toxic substances in blood
Vancouver doctors are hoping to repurpose recently approved cholesterol-lowering drugs for the treatment of severe sepsis, a complication of bacterial infection that kills nearly 10,000 Canadians each year and millions of people worldwide.
“Of the sickest patients that arrive at St. Paul’s Hospital, about two-thirds to three-quarters are there due to severe infection,” said lead researcher John Boyd, founder of Cyon Therapeutics. “That’s around 500 patients a year and half of them will die. It’s even worse in the developing world, where six to eight million people die of sepsis every year.”
Boyd and his colleagues hope to exploit the effects of anti-PCSK9 biologics — a new class of drugs approved last year to lower LDL cholesterol — to “pull” the toxic byproducts of bacterial infection from the blood in an effort to reduce the number of people who end up on life support and potentially save lives.
Bacterial toxins naturally bind to LDL cholesterol, which can be flushed from the bloodstream by the liver and destroyed.
Cyon Therapeutics — a spinoff from the University of British Columbia — will treat 300 sepsis patients at up to five centres across Canada and up to 40 centres in the United States later this year.
“We expect to see the amount of bacterial toxins in the blood clear much more quickly in patients who get the drugs,” said Boyd. “These new drugs are an immensely more powerful way to remove LDL cholesterol than the old class of drugs.”
Serious infections can trigger sepsis, an inflammatory response throughout the body and vital organs in response to the presence of bacteria or even the byproducts of bacteria that have been killed by antibiotics.
“When your body responds aggressively to infection for example in the lungs, you will see high temperatures, racing heart and low blood pressure and when those get extremes you will see other organs failing,” said Boyd. “Even if you defeat the infection, your body has a memory that can trigger a response when it finds parts of the bug in your blood stream.
“Sepsis isn’t an active infection, it’s your body’s response to the toxic parts of the bug,” he said.
In the course of their research on sepsis patients at St. Paul’s, Boyd and Cyon co-founders Keith Walley and James Russell realized that up to half of their patients were genetically predisposed to PCSK9 protein inhibition, which allowed their bodies to naturally flush bad cholesterol from their blood.
“Those patients were 15 per cent less likely to die when they came in with a bad infection,” said Boyd. “It’s unusual to see such a power- ful effect.”
That’s where the cholesterollowering medication comes in.
“The parts of the bug that your body recognizes as toxic ride around almost exclusively on LDL cholesterol, what doctors call bad cholesterol,” said Boyd. “We came to that key realization just as a new class of drugs come to market that function very differently from old cholesterol-lowering drugs.”
The new drugs enable the body to suck the LDL cholesterol from the bloodstream and — hopefully — take the toxins along with them.
The patients in the Cyon trials will receive doses of PCSK9 inhibitors five to 10 times higher than patients receive to lower bad cholesterol. The researchers hope that will eliminate up to 95 per cent of the LDL cholesterol and the attached bacterial toxins from the bloodstream.
“A number of pharmaceutical companies have developed very effective medications, antibodies that create this effect, which you can give in high doses and they are safe,” he said. “If a patient arrives with an infection we can give this medication and have an immediate effect and that is something we have never been able to achieve before.”
The researchers will also collect DNA from participants to see if people with a certain genetic markers related to PCSK9 are more or less likely to respond to the treatment.
The clinical trials are being funded by Genome B.C., the National Research Council, Mitacs, the Canadian Institutes of Health Research and Providence Health Care Research Institute.
We expect to see the amount of bacterial toxins in the blood clear much more quickly in patients who get the drugs.