At just three weeks old, Darlene was sent to the emergency room after her mom had brought her to a pediatrician. The baby wouldn’t stop crying and wasn’t eating. Concerningly, her triglyceride levels were in the 20,000’s, far over the normal 150 level. Darlene was referred to a lipid specialist at John Hopkins University Hospital and, after being genetically tested, was diagnosed with familial chylomicronemia syndrome (FCS), a rare, highly debilitating, and life-threatening disease.

FCS is a genetic disorder that leads to extremely high levels of triglycerides in the blood and poses significant health risks, including recurrent episodes of acute pancreatitis. Standard triglyceride-lowering medications such as fibrates are generally ineffective in people with FCS. The FDA’s recent approval of TRYNGOLZA (olezarsen) is an important moment for those affected by this debilitating condition, as previously, the only recourse was following a very low-fat diet, which is not always effective.

Familial Chylomicronemia Syndrome: severe, life-long pain with limited treatments

Affecting up to around 3,000 people in the U.S. and 5,000 people globally, people with FCS lack functional lipoprotein lipase (LPL), the enzyme responsible for breaking down fats, which impairs the body’s ability to remove triglycerides from the bloodstream. Normally, triglyceride levels are below 150 mg/L, but for those with FCS, these levels are more than 880mg/dL. When caused by a variant in the lipoprotein lipase (LPL) gene or one of the genes related LPL function, it’s called familial chylomicronemia syndrome (FCS).

Due to the buildup of triglycerides, people with FCS have a high risk of acute pancreatitis, a painful and potentially fatal swelling of the pancreas. According to a new study from the University of Montreal, 67% of patients with FCS have experienced acute pancreatitis that required a hospital visit. Darlene’s second pancreatitis episode happened when she was eight, and she was hospitalized for a week. After that, she didn’t have an episode until she became pregnant with her first child at age 23.

“That pancreatitis attack was the worst attack I remember having. I was in the ICU for weeks and ended up losing my pregnancy at 22 weeks gestation,” she said in an interview with the National Pancreas Foundation.

Since then, Darlene has had two children, but her pancreatitis still hospitalizes her for about a week once every three years. She’s had her gall bladder, spleen, and parts of her pancreas and stomach all removed due to pancreatitis and FCS complications.

A diagnosis of FCS is based on clinical, laboratory, and/or genetic analysis, with clinical criteria including a history of pancreatitis or abdominal pain, high fasting triglyceride levels, and no known secondary causes to help identify patients with FCS (2). However, FCS has signs and symptoms commonly confused with more common conditions (such as multifactorial syndrome or MCS), causing the disease to often be misdiagnosed. Chronic fatigue and other symptoms, including forgetfulness, swelling of the liver and spleen, or fatty deposits in the skin, especially the arms, buttocks, and/or knees, are characteristics of FCS. People with FCS may also experience psychological and financial stress and have reported feelings of anxiety, isolation, and depression.

“As a rare and difficult to diagnose disease, FCS has a profound impact on the lives of patients and families. Many people living with FCS have experienced severe pain their whole lives – sometimes so intense they require lengthy hospitalization stays – and struggle through life with daily fatigue, nausea, brain fog and stomach pain,” explained Lindsey Sutton Bryan, co-founder and co-president of FCS Foundation.

For many FCS patients like Darlene, social situations involving food can be difficult and isolating. Darlene often eats before a social event, so she’s not frustrated or embarrassed that she can’t eat the food offered or has to explain her condition, which can become overwhelming.

“People don’t really understand what it’s like to have such a strict diet that you must follow, or you will be sick,” Darlene explained.

The only treatment for FCS is a highly fat-restricted diet and lifestyle modifications, like exercise and cutting out alcohol and simple carbohydrates, but TRYNGOLZA may provide a more effective option.

“Until now, our treatment options have been limited, relying on diet alone or trying to manage triglyceride levels and keep acute pancreatitis attacks at bay. For the first time, adults with FCS have seen their hope for a treatment become a reality,” said Sutton Bryan.

TRYNGOLZA approval: transformational for patients and their families

The end of 2024 saw the FDA approval of TRYNGOLZA, the first-ever treatment shown to significantly and substantially reduce triglyceride levels in adults with FCS and meaningfully reduce acute pancreatitis events when paired with an appropriate diet.

TRYNGOLZA (olezarsen) is an antisense oligonucleotide (ASO) that acts by targeting and binding to a specific protein called apolipoprotein C-III (APOC-III), which is normally responsible for slowing down the breakdown of fats. By reducing APOC-III levels, TRYNGOLZA helps the body break down and clear out triglycerides more effectively, lowering the fat concentration in the blood.

The FDA approval of TRYNGOLZA was based on a successful Phase 3 clinical trial in 66 adult patients with FCS and very high triglyceride levels. In the study, patients received either 80 or 50 mg of TRYNGOLZA or placebo subcutaneously every four weeks for 53 weeks. After six months, triglyceride levels dropped by 42.5% in those taking 80mg of TRYNGOLZA, and after 12 months, this number jumped to a 57% reduction compared to placebo. Significant reductions in TGs were seen as early as one month. The lower 50mg dose did not lead to a significant decrease in triglycerides at month 6. Importantly, patients on the drug were less likely to develop acute pancreatitis, with only 5% of patients on TRYNGOLZA experiencing an episode compared to 30% in the placebo group experiencing one or more episodes.

TRYNGOLZA has a favorable safety profile. The most common side effects were skin reactions from the injection, decreased platelet count, and joint pain. It is currently unknown if TRYNGOLZA is safe and effective in children.

Ionis CEO Brett Monia, Ph.D., said in a release that the FDA approval of TRYNGOLZA is “a transformational moment for patients and their families,” adding that it’s the first time adults with FCS can access a treatment that substantially reduces triglycerides and the risk of debilitating and potentially life-threatening acute pancreatitis.

The treatment is self-administered once a month via an auto-injector, and is indicated for adults with FCS regardless of a genetically or clinically confirmed diagnosis and is to be paired with a low-fat diet.

Ionis is also expecting TRYNGOLZA to be approved for severe hypertriglyceridemia (sHTG), which affects an estimated 3 million people in the United States and is another disorder caused by too many triglycerides in the blood (greater than or equal to 500 mg / dL). Currently, Ionis has three ongoing Phase 3 trials of TRYNGOLZA in sHTG, and the company expects a readout of these trials in the second half of 2025, with a possible approval in 2026.

Competition: Arrowhead Pharmaceuticals FCS drug designated as Breakthrough Therapy

Arrowhead Pharmaceuticals presented its Phase 3 clinical trial findings in November for Plozasiran, which has also been tested in adults with FCS. The small interfering-RNA (siRNA) therapy was designed to specifically target and reduce apolipoprotein C-III (APOC-III) production, thus reducing triglyceride levels and the associated health risks of FCS.

The Phase 3 clinical trial included 75 patients with FCS who had persistent chylomicronemia, who received quarterly doses of Plozasiran at 25 or 50mg or were given a placebo every three months for 12 months. The trial results showed that participants receiving 25 mg and 50mg of Plozasiran had lowered median triglycerides by 80% and 78% (placebo adjusted to 63% and 61%), respectively, from baseline at month 10, a significant improvement compared to the 17% reduction in the placebo group. Additionally, the trial demonstrated further drops in triglycerides and APOC-III levels as early as one month, which persisted throughout the 12 months. Plozasiran also decreased the rate of acute pancreatitis and showed a favorable safety profile.

In September, the FDA designated Plozasiran as a Breakthrough Therapy, a status intended to speed up the development and review of drugs designed to treat serious conditions where preliminary clinical evidence shows the drug may provide improvement.

Future of FCS treatment

Darlene said there are still times she’ll become sick regardless of following a strict diet.

“Understanding that pancreatitis is not my fault, and I can’t always control it has helped me feel better and less guilty with myself,” she said. “I try to find a balance between following this diet and living life to the fullest. Also, knowing that new treatment options and medicines are   helps me maintain a positive outlook.”

The recent FDA approval of TRYNGOLZA represents a significant advancement in treating familial chylomicronemia syndrome (FCS). For patients like Darlene, who have faced the debilitating consequences of this rare condition, the ability to effectively manage triglyceride levels and reduce the risk of acute pancreatitis could be life-changing. The promising results from both the clinical trials of TRYNGOLZA and Plozasiran have demonstrated they can not only lower triglyceride levels but also minimize pancreatitis episodes, potentially changing how individuals with FCS live with their condition.

Sources

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