By Robert Hegele, MD, as told to Wendy Haaf
Robert Hegele, MD, is a distinguished professor of medicine at Western University's Schulich School of Medicine and a staff endocrinologist at the London Health Sciences Centre in London, Ontario, Canada.
Hegele was involved in clinical trials of the two new medications for familial hyperchylomicronemia syndrome (FCS). He has also chaired an expert committee that created a North American scoring system for diagnosing the disorder.
Familial hyperchylomicronemia syndrome (FCS) is a very rare inherited condition – so rare, in fact, that even though I specialize in blood fat disorders, just 11 of the approximately 6,000 people I have cared for over the past 35 years have been people with FCS.
The name chylomicronemia comes from chylomicrons, which are enormous fat particles that form in the blood when triglycerides climb above a certain level. People with FCS can't break these particles down normally, which is why their triglyceride levels can climb to levels 10 to 100 times normal.
People with mildly high triglycerides are at an increased risk of heart disease. But that's not what we worry about the most in FCS. Our biggest concern is a medical complication called acute pancreatitis, or inflammation of the pancreas. My patients who've been through it say it was the worst pain they've ever felt. Acute pancreatitis is very serious, and sometimes even life-threatening. When it's severe, people can go into shock, and they often need to spend a long time in the intensivecare unit (ICU). Some people get pancreatitis multiple times.
The constant threat of pancreatitis isn't the only aspect of FCS that can take a toll on an individual's quality of life. Anytime someone with FCS eats too much fat, they'll have nausea and vomiting, and feel sick for a week.
First Approved FCS Medications
Two new drugs for FCS were approved by the FDA within about a year of each other. They are used to treat extremely high levels of triglycerides (a type of blood fat). These new therapies don't work the same way as standard medications. When you take a pill, like a statin, it works by acting on a protein the body has already made. These new therapies prevent a protein from being made in the first place.
How Do These Newer Medications Work?
Both of the new medications for FCS target something called messenger RNA (mRNA). Messenger RNA is like the work order the factory puts out to make a certain protein. It's also like a recipe – it has all the instructions to make that protein. If you interfere with the mRNA, no protein gets made. That's what both of these drugs are doing. They cut off the same message, using slightly different methods.
In the case of these biological treatments for FCS, that protein is called Apo-CIII. Apo-CIII acts like a set of brakes on the machinery that breaks down triglycerides. This means the drugs are actually targeting the process that causes triglycerides to build up.
Research has shown that high levels of that protein are linked with high levels of triglycerides. It's very rare, but some people naturally make very little Apo-CIII, so they have very low levels of triglycerides. This happens because these people have inherited certain changes, or mutations, in a gene. The new FCS medications mimic the effects of this protective mutation.
Olezarsen
Olezarsen belongs to a class of drugs called antisense oligonucleotides. This type of therapy is a bit like a magnet that's specially made to attach to a specific spot on the mRNA. In the case of olezarsen, when the magnet sticks in place, the mRNA falls apart before Apo-CIII can be made. The medication is injected under the skin, and a dose lasts three months.
Plozasiran
The 'siran' part of the name plozasiran is a slightly mixed-up version of siRNA, which means short interfering RNA. The siRNA is something like a computer virus. It essentially erases the message to make Apo-CIII by triggering a process that causes the mRNA to break down. Like olezarsen, plozasiran is injected under the skin. But it has to be taken more often: every month instead of every three months.
How Successful Are These New Therapies?
Studies looking at each of these treatments in people with FCS were published in The New England Journal of Medicine in 2024.
A normal triglyceride level is less than 150 mg/dL. When triglycerides climb above 1,000 mg/dL, particles called chylomicrons start appearing in the blood. They are like gigantic tankers that hold huge amounts of triglycerides. It's the chylomicrons that are linked to the most dangerous and painful complication of FCS: pancreatitis, or inflammation of the pancreas. We think chylomicrons get stuck in the pancreas, and that triggers inflammation. Then it's a vicious cycle: more damage to the pancreas, more inflammation.
In the two studies that led to the approval of these drugs, patients had triglyceride levels of about 2,000 to 2,600 mg/dL on average. While their triglyceride levels didn't go down to normal on the medications, they went down low enough – below 1,000 mg/dL. The risk of pancreatitis was reduced dramatically – between 83% and 85%.
Usually, studies of new treatments need hundreds or thousands of people before you can detect an effect. In these studies, the effect was so dramatic, you could see it even though the numbers of participants were very small: 66 and 75. We also know from all kinds of data from thousands of people enrolled in HMOs that if you get triglycerides down below 1,000 mg/dL, you've largely protected the person from getting pancreatitis.
How Do These Therapies Compare With Older Standards of Treatment?
None of the other treatments we have for lowering cholesterol or triglycerides work in people with FCS. That shows how precisely these new therapies target the specific pathway that drives the condition.
Until these drugs became available, the best treatment was a very strict low-fat diet. Anything with even a little fat or sugar in it raises the triglyceride levels of someone with FCS. Their bodies just aren't equipped to handle it. That kind of very limited diet is difficult to follow. And it can be very isolating. For example, if you're a teen and you're invited to a friend's party and they ask, 'How come you can't have pizza?'
The trials of these drugs had two stages. In the first stage, participants didn't know whether they were getting a placebo or the drug, and neither did the researchers. But afterward, all participants went into what's called an open-label study. That means everyone gets the actual drug, and they're followed for more time.
What we have found from open-label studies is that these drugs definitely don't work as well when people eat a lot of fatty, sugary foods. That's not what this is about. But they can eat a more normal diet. So instead of this extreme diet with only 10% of calories from fat, it can be more like 20% or 25%.
New Tools for Diagnosing FCS
With DNA testing, we can prove someone has inherited mutations for FCS from both parents. There's a list of genes that can cause it. The process is very rigorous.
But if DNA testing isn't available, there are other tools that can be used. One was created for people in Europe. We developed a scoring system called the North American Familial Chylomicronemia Score. It's an online app that gives you a score in about three minutes. You fill in answers to eight questions, such as the person's age when they first experienced symptoms, and how high their triglyceride levels are. It also asks whether the individual has other conditions or factors that can cause high triglycerides. For example, diabetes, alcohol, and even certain medications will raise triglycerides.
These tools allow physicians who don't specialize in cholesterol disorders to quickly sort out whether someone with high triglycerides actually has FCS. Without them, doctors sometimes used to lump everyone with triglycerides over 1,000 mg/dL together. And because the doctors learned about FCS in medical school, they would think of that.
The scoring tools provide a more personalized approach. They can identify people who really need these new drugs, versus those with more common conditions that respond well to other medications. Now that we do have targeted drugs for FCS, we want to make sure we're using them appropriately. Because these tools are easy to access and simple to use, they may prevent delays in diagnosis and treatment. I think they also increase understanding and awareness of FCS.
When I started my first faculty job in 1990, the first patient I saw had FCS caused by a gene change called APO-III Toronto, because that's where it was discovered. So from the very beginning of my career, I've been aware of this condition, but I had nothing to offer people who had it, other than a strict diet. It's very meaningful to me that we finally have something to offer them that works and can improve their quality of life.