Familial Chylomicronemia is a rare genetic disorder and a severe form of hypertriglyceridemia often due to the absence of a key enzyme needed to remove triglycerides from the blood. Patients diagnosed with FC often have as much a 15X the normal amount of triglycerides resulting in recurrent episodes of acute pancreatitis, a sometimes life-threatening inflammation of the pancreas.
It effects both children and adults. It is typically caused by defects in the gene causing an apoC-II deficiency or the gene that produces an enzyme called lipoprotein lipase, or LPL, resulting in extremely low or absent LPL activity. LPL is an enzyme that facilitates the removal of triglycerides (TG) from the blood. Low levels, or lack of this enzyme, result in the accumulation of TGs in the blood. Familial chylomicronemia is also referred to as “Familial lipoprotein lipase deficiency” and "Type I hyperlipoproteinemia"
Patients with FC have extremely high levels of triglycerides in the blood, generally greater than 2,000 mg/dL, that typically result in recurrent episodes of acute pancreatitis, a significant and sometimes life-threatening inflammation of the pancreas. Acute pancreatitis results in significant abdominal pain and potential complications, such as organ failure, respiratory complications, significant enlargement of the liver and spleen and eruptive xanthomas, or poolings of triglycerides around the tendons in the body to such a degree that the swelling is easily visible.
Plasma TG levels are typically considered ideal if they are below 150 mg/dL. At levels of approximately 150-500 mg/dL, studies have demonstrated an increased risk for cardiovascular disease.
Current Treatments
There are several dietary and existing therapies to treat high triglyceride levels but in some patients these are either ineffective, patient baseline TG levels are too high, or patients are unable to comply with the dietary restrictions. There is a significant unmet medical need for patients with these severe forms of hypertriglyceridemia, and patients who are refractory to currently available treatments.
Aegerion’s product candidate lomitapide, a potent Microsomal Triglyceride Transfer Protein (MTP) inhibitor, is being studied to treat patients with FC by lowering plasma triglyceride levels beyond reductions seen with standard therapies.
FC can be seen in both adults and children. Ideally, triglycerides in the blood should be less than 150 mg/dL in adults. Levels of 150-500 mg/dL are thought to be associated with obesity, insulin resistance and the metabolic syndrome and pose additional risk for cardiovascular disease. If plasma TG levels surpass 500 mg/dL, the risk shifts to a more acute threat of pancreatitis and with levels of 1000-2000 mg/dL a more definite risk.
Plasma triglycerides can be derived from two sources: the VLDL lipoprotein derived from the liver and the larger chylomicron-derived source derived in the intestine from triglycerides obtained from food. Triglyceride levels of 1000 mg/dL or more are generally thought to be dominated by chylomicrons and it is these large particles that may interfere with blood flow through the fine blood vessels that supply the pancreas and lead to pancreatitis. Patients with untreated levels of triglycerides to the degree seen in familial chylomicronemia show symptoms as abdominal pain and can be seen as early as childhood. As the disease progresses later in life, it can result in multiple and recurrent cases of acute pancreatitis, associated abdominal pain, eruptive xathomas due to the collection/pooling of extracellular lipids and enlargement of the liver and spleen.
For patients with FC and severe hypertriglyceridemia, the goal of treatment is to reduce the plasma triglyceride levels. First-line therapy for these patients is a low-fat diet, oral drug therapies to further reduce triglyceride levels, and, in some cases, plasmapheresis to physically remove TG-carrying lipoproteins. However, this therapy is not available at all medical centers and provides only temporary triglyceride reductions.
The current and existing therapies for the treatment of familial chylomicronemia are the following:
- Low-fat diets – Diets where the percentage of calories derived from fat are reduced to levels of <15% or <20 g/day are the mainstay of treatment in these patients.
- Fibrates (PPAR-alpha agonists) – The use of fibrates as the primary treatment results in reductions of TG as high as 40%. However, the effectiveness is variable, dependent upon the baseline level and patient population. There are few studies that document the use of fibrates in patients with severe TG elevations.
- Omega 3 Fatty Acids – Use of high dose omega 3 fatty acids are indicated for patients with TGs >500 mg/dL and can reduce TG levels by up to approximately 40% in some patient populations. These studies have covered a broad segment of patients with elevated TGs and have not focused specifically on the most severe patients with FC.
- Statins (HMG CoA Reductase Inhibitors) – while primarily utilised as a method for reducing LDL-C, certain statins have demonstrated efficacy in reducing TGs in patients with milder forms of hypertriglyceridemia
In some patients, existing therapies such as low fat diets and omega 3 fatty acids can reduce plasma triglycerides to the point that acute symptoms like abdominal pain and pancreatitis can resolve, though triglycerides may remain at a level that keeps the patient at risk of pancreatitis. In other patients, existing therapies are either ineffective, baseline levels are too high, or patients are unable to comply with the dietary restrictions.