Title: Volanesorsen for treating familial chylomicronaemia syndrome [ID1326]
Funder: Department of Health and Social Care

Abstract: To evaluate the benefits and costs of volanesorsen within its marketing authorisation for treating familial chylomicronaemia syndrome in adults for national commissioning by NHS England.

Lay abstract: Familial chylomicronaemia syndrome (FCS) is an inherited metabolic disorder of lipid metabolism, characterised by extremely high levels of chylomicrons in the blood. Chylomicrons are triglyceride-rich lipoprotein particles that transport dietary fat absorbed from the intestine to the organs like skeletal muscle, adipose tissue and cardiac muscle for energy production and storage.(1) It is caused by the absence or low activity of enzymes that control lipids in the blood. It is most commonly due to mutations in the LPL gene causing deficiency in the enzyme lipoprotein lipase (LPL), responsible for the uptake of triglycerides from the circulating chylomicrons into the tissues.(2) Other causes of FCS include apolipoprotein C-II deficiency and mutations in APOA5, GP1HBP1 and LMF1 genes.(2) FCS may present in infancy or childhood, although diagnosis (including genetic testing and/or measurement of enzyme activity) is sometimes not confirmed until adolescence or adulthood. Symptoms include repetitive episodes of severe abdominal pain, repeated episodes of pancreatitis (inflammation of the pancreas), enlargement of the liver and spleen and fatigue. The severity of the symptoms depends on the levels of chylomicrons in the blood. Acute pancreatitis is a life-threatening condition which may require intensive care and repeated attacks of pancreatitis may lead to chronic pancreatitis. FCS is associated with diabetes, which can develop as a result of pancreatitis and often makes FCS more difficult to manage. FCS can be particularly difficult to manage during pregnancy, as triglyceride levels rise and the risks of pancreatitis and diabetes increase.(3) The prevalence of FCS is estimated to be 1 to 2 per million people (4),(5) which equates to approximately 55 to 110 people in England.(6) Currently, the management of FCS in England consists of severe restriction of dietary fat intake, usually to between 10 and 20 g/day, and no alcohol intake, in order to keep plasma triglyceride levels low.(1) Essential fatty acids (linoleic and alpha linolenic acids) and fat soluble vitamins (vitamins A, D, E and K) supplements are required for patients on a fat restricted diet. In addition, treatments for hypercholesterolaemia (such as fibrates, nicotinic acids and statins) may be prescribed but have limited value.(7) The strict dietary regimen is highly restrictive and often challenging for patients and their families, and even when the diet is closely followed people often still have high triglyceride levels. References 1. Dixon JB (2010) Mechanisms of chylomicron uptake into lacteals. Annals of the New York Academy of Sciences 1207(Suppl 1): E52– E57. [accessed April 2018] 2. Burnett JR, Hooper AJ, Hegele RA. (2017) Familial Lipoprotein Lipase Deficiency, GeneReviews [accessed April 2018]. 3. National Organisation for Rare Disorders (2016) Familial Lipoprotein Lipase Deficiency [accessed April 2018]. 4. Heart UK (2018) Lipoprotein Lipase Deficiency (LPLD) [accessed April 2018]. 5. European Medicines Agency (2013) Public summary of opinion on orphan designation: Adeno-associated viral vector expressing lipoprotein lipase for the treatment of lipoprotein lipase deficiency [accessed April 2018]. 6. Office for National Statistics (2017) Population Estimates for UK, England and Wales, Scotland and Northern Ireland: mid-2016 [accessed April 2018]. 7. Heart UK (2012) LPLD04 Fact Sheet – Treatment options [accessed April 2018].

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS