Familial chylomicronaemia syndrome (FCS) is an ultra-rare genetic disorder of lipid metabolism, affecting 3000 to 5000 individuals globally [1,2]. This disorder is characterised by severe elevations in triglyceride (TG) levels (>10 mmol/L; >885 mg/dL), carried predominantly in chylomicrons [3]. FCS is caused by a marked reduction in or absence of lipoprotein lipase (LPL) activity. LPL is an enzyme that mediates the lipolysis of TGs in chylomicrons and TG-rich lipoproteins [4]. The genetic defect in FCS is attributed to inactivating mutations in both LPL gene alleles in about 80% of cases or in other genes including APOC2, APOA5, GPIHBP1, and LMF1, among others, that encode proteins required for LPL activity in about 20% of cases [5]. Chylomicronaemia-associated reductions in blood flow in the microcirculation cause a range of symptoms including recurrent episodes of abdominal pain, diarrhoea, impaired cognition (“brain fog”), and fatigue [6,7]. It has been previously hypothesized that a serious manifestation of reduced blood flow in the microcirculation may lead to high risk of acute pancreatitis. Repeated episodes of acute pancreatitis may result in exocrine and endocrine pancreatic insufficiency, are associated with substantial morbidity, and can be fatal [2,5]. Management of FCS requires limiting total fat intake to <10%–15% of daily calories or 15–20 g per day, which is burdensome for patients. Treatment with statins, fibrates, nicotinic acid, and fish oils is largely ineffective [2,5,8].

Volanesorsen, a 2′-O-(2-methoxyethyl)–modified antisense oligonucleotide molecule, reduces plasma TG levels through the inhibition of apoC-III via LPL-dependent and -independent pathways [9,10]. Volanesorsen received conditional European Union marketing authorisation in May 2019 as an adjunct to diet in adults with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and TG-lowering therapy has been inadequate. The approved recommended dose is 285 mg subcutaneously once weekly for 3 months. After 3 months, dose frequency should be reduced to 285 mg every 2 weeks with further dose adjustment possible at subsequent 3-month intervals. In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency granted early access to volanesorsen for the treatment of adults with FCS through an Early Access to Medicines Scheme (EAMS) on 20 March 2018 (EAMS 47857/0001) at a dose of 285 mg once every 2 weeks (a lower dose than that which was subsequently approved). The current study (VOL4002) was designed to describe the efficacy and safety of volanesorsen in patients with FCS who received volanesorsen through the UK EAMS.