Finding a Path Forward: The Continued Unmet Medical Need in FCS

“‘Cathy’ appeared to be a normal, healthy teenager until age 18, when she first developed severe abdominal pain and was admitted to the hospital. There, she found out she had a triglyceride (TG) level of 3500 and was diagnosed with acute pancreatitis. Other than her very high TG level, doctors did not find any other possible causes of her pancreatitis.

She was sent home without a clear diagnosis and a recommendation to follow a “diabetic diet” and avoid alcohol as her only treatment.

Over the next several years she had recurrent and sometimes long-term episodes of mild to severe abdominal pain, which seemed to be worse when she ate certain foods, especially those high in fat, or when she had even 1 drink of alcohol. Her TG levels would range from 800 to 2900 at the time of those episodes. Doctors told her to avoid sugar and prescribed different medications, which did not help control her recurring severe TG elevations.

Years later, she finally referred herself to me after experiencing significant challenges with her work and social life due to her recurring abdominal pain. On our first visit, I immediately diagnosed her with familial chylomicronemia syndrome (FCS) and recommended she adopt a strict low-fat, moderately low-sugar, and alcohol-free diet for the rest of her life, which has helped reduce her episodes of severe abdominal pain.

FCS is an ultra-rare disease (roughly 1 per million) caused by an inability to break down chylomicrons, which are the lipoprotein particles that carry fat from the intestines (absorbed from food) to the rest of the body. Chylomicrons are about 90% TG and are normally broken down very quickly in the circulation from the action of an enzyme called lipoprotein lipase (LPL).

In FCS patients, LPL activity is very low or absent, which inhibits chylomicrons from being efficiently removed from the blood stream. This means that TG levels increase after eating most foods, and they remain very high all the time, even 10-fold or 50-fold higher than normal.

FCS patients often have debilitating symptoms, including fatigue, severe abdominal pain, and unpredictable attacks of pancreatitis. Pancreatitis can occur as frequently as every few weeks or months, often requires hospitalization, can harm other organs, cause diabetes, and may even lead to death.

Most FCS patients have frequent abdominal pain, weekly or even daily, and they often become socially isolated due to their need to avoid most normal foods. Chronic fatigue, recurrent abdominal pain, and fear of a severe pancreatitis episode can cause significant emotional and psychosocial effects, including anxiety and depression. These usually also cause significant problems at work and may result in complete disability.

Unfortunately, none of the currently available TG-lowering medications work in FCS, and the only effective treatment for now remains a very low-fat diet. Even just a single tablespoon of vegetable oil has more fat than FCS patients should eat in an entire day. Most of the time they cannot eat in a restaurant or at a party or in the house of a family member or friend. As a lipidologist, I have seen first-hand the large adverse impact that FCS has on health and quality of life and I urgently feel the need for an effective medical therapy.

A few years ago, research efforts began to develop a new medication for moderately elevated TG levels called volanesorsen. It blocks production of apolipoprotein C-III, which inhibits LPL activity. Unexpectedly, volanesorsen dramatically lowered TG in 3 patients with FCS, and this was confirmed in larger trials.

For the first time, the TG levels of FCS patients could be reduced dramatically, by about 75%, and patients have also had reduced abdominal pain and pancreatitis with the treatment. Unfortunately though, volanesorsen use was also associated with large decreases in the blood platelet levels, the very small pieces of cells which help prevent excess bleeding from the circulation. However, platelet levels returned to normal after discontinuing volanesorsen, and no significant bleeding episodes were observed.

Akcea Pharmaceuticals submitted a new drug application (NDA) for volanesorsen (proposed brand name WAYLIVRA), which would have been the first-ever treatment for patients with FCS. Unfortunately, in August 2018, the US Food and Drug Administration (FDA) decided not to approve this medication.

It is surprising and very disappointing to me that its approval was denied, but the FDA is open to a re-submission of the application once additional information about this medication has been obtained and analyzed.”

About the Author:

Eliot A. Brinton, MD, FAHA, FNLA, earned his MD from the University of Utah, completed a residency in internal medicine at Duke University Hospital in Durham, NC, and completed a 3-year research fellowship in endocrinology at the University of Washington in Seattle. He has held faculty positions at several prestigious medical research institutions, including The Rockefeller University, Wake Forest University and the University of Utah.

Dr. Brinton is the founder and president of the Utah Lipid Center, a non-profit clinic and research laboratory in Salt Lake City, UT. Dr. Brinton is past president of the American Board of Clinical Lipidology and a diplomate of that organization.

He is also the past chair and a current fellow of the Clinical Lipidology Committee of the American Heart Association (AHA). Dr. Brinton is a founding and current member of the board of directors of the National Lipid Association (NLA), and he served as president of the Pacific Chapter of the NLA.

He is founding president of the Utah Atherosclerosis Society, an associate editor of the Journal of Clinical Lipidology and an assistant editor of the Journal of Obesity. Dr. Brinton is widely published in the scientific literature, has received numerous research awards, and is widely sought nationally and internationally as a speaker to educate scientists, physicians, and other healthcare providers on the field of lipidology.